Cytoskeletally active rho-kinase inhibiting compounds, compositions and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula II , where Q is (CR4R5)n3; n1 equals 1 or 2; n2 equals 1 or 2; n3 equals 1; R2 is R2-1 or R2-2 , Ar is phenyl or a heteroaryl ring consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S; X denotes 1-2 substitutes located on Ar, each independently selected from a group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9 and CN; R3-R5 denote H; R8 is H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted with one or more halogens or heteroatom-containing substitutes selected from a group consisting of OR11, NR11R12, CO2R11, CONR11R12, NRnC(=O)Ri2; R9 is H or alkyl; R11-R12 independently denote H, alkyl, pyridinyl or morpholinyl.

EFFECT: compounds are inhibitors of rho-associated protein kinase which can be used in medicine to prevent or treat diseases or conditions associated with cytoskeleton readjustment, specifically treat high intraocular pressure such as primary open angle glaucoma.

10 cl, 3 tbl, 226 ex

 

The technical field to which the invention relates

This invention relates to synthetic cytoskeleton-active compounds, such as compounds that inhibit rho-svjazanno kinase (ROCK), and to methods of producing these compounds. The invention also relates to the use of these compounds for the prevention or treatment of diseases or disorders that are affected or which promotes change integrity or reorganization of the cytoskeleton, including, but not limited to, actomyosin interact closely related connective and focal adhesion complexes, such as the treatment of disorders in which increased intraocular pressure, such as primary open-angle glaucoma.

Background of invention

Glaucoma is an eye disease that leads to irreversible vision loss. It is the fourth most common cause of blindness and the second most common causes of vision loss in the United States of America, as well as the most common cause of irreversible vision loss among African-Americans. In General, the disease is characterized by progressive optic neuropathy caused, at least in part, the adverse effect of increased intraocular pressure. In individuals with normal the major intraocular pressure it ranges from 12 to 20 mm Hg, averaging about 16 mm Hg. However, individuals suffering from primary open-angle glaucoma, intraocular pressure usually rises to approximately 22-30 mm Hg. In angle-closure glaucoma or acute glaucoma intraocular pressure can reach up to 70 mm Hg. Interestingly, loss of vision can occur as a result of the statistically normal intraocular pressure in individuals with extremely sensitive to pressure the eyes, a condition known as normotensive glaucoma [see, for example, P. L. Kaufman and T. W. Mittag, "Medical Therapy Of Glaucoma", Ch. 9, Sec. II (pp. 9.7-9.30) in P. L. Kaufman and T. W. Mittag (eds.): Glaucoma (volume 7, edited by S. M. Podos and Yanoff M.(eds.): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994); A. C. Guyton, Textbook of Medical discrimination (W. B. Saunders Co., Sixth Ed.), pp. 386-89 (1981)].

Open-angle glaucoma accounts for approximately 90% of all cases of primary glaucoma, and it is characterized by abnormally high resistance to removal of the fluid (intraocular fluid from the eye. Normal resistance is necessary to maintain intraocular pressure sufficient to maintain the shape of the eye for optical integrity. This resistance is provided trabecular mesh structure is complex, megaplasticheskoi tissue composed of specialized cells with dense cytoskeletal network is, collagen rungs and the extracellular matrix. The resistance of the trabecular mesh structure is usually such that the intraocular pressure is ~16 mm Hg, the pressure at which the intraocular fluid leaves the eye at the same speed, which is formed (2,5 μl/minute). In the eye affected by glaucoma, the rate of formation of intraocular fluid remains constant, then appears as an increased resistance to withdrawal, which is responsible for increased intraocular pressure.

Conventional treatment for glaucoma includes many pharmaceutical approaches to reduce intraocular pressure (IOP), each of which has its own disadvantages. Beta-blockers and inhibitors of carbonic carbonic anhydrase reduces the production of intraocular fluid, which is necessary for the power of avascular lens and endothelial cells of the cornea, and prostaglandins affect Avelino-scleral outflow path, which is only 10% of the total possible outflow. Currently, no commercial tools that are approved for use, which act directly on the trabecular mesh structure, the place of removal of intraocular fluid, where increased resistance to withdrawal of the intraocular fluid is responsible for increased IOP. Followed the Sabbath.) maintained medical need for improved lowering IOP drugs that directionally focused on this mesh structure. Pharmacological agents aimed trabecular lattice structure, can provide relief to a significant number of patients showing inadequate response to current medicines, lowering IOP, and/or do not tolerate the side effects associated with such drugs. In addition, such molecules can be an advantage as adjuvant therapy in combination with other classes of drugs that lower IOP.

In U.S. patent No. 6586425, 6110912 and 5798380 described a method of treating glaucoma with the use of compounds that affect the integrity of the actin fibers of the eye to increase the outflow of aqueous humor. In these patents specifically described kinase inhibitors, as well as latrunculin, latrunculin, swinholide and jasplakinolide that cause the violation of the actin cytoskeleton and dense connective complexes in the trabecular mesh structure or modulation of its interaction with the underlying membrane. Violation of the cytoskeleton and associated adhesion reduces the resistance to flow of aqueous humor through the trabecular searchtoolbarcorp and thereby reduces intraocular pressure.

Wound healing is a different approach, in which these classes of molecules may contribute to the modulation of IOP. Trabeculoectomy represents the most common form of filtration surgery for glaucoma and remains the mainstay of treatment for surgical reduction pharmacologically uncontrolled intraocular pressure in primary open-angle glaucoma. When such a procedure is set limbus fistula through which the intraocular fluid flowing in podklyuchenie space, forming filter the water bubble for lowering intraocular pressure. The success of the procedure highly depends on pharmacological modulation/inhibition of wound healing.

The main success in the surgical correction of glaucoma is the use of antimetabolites to prevent scarring after filtration surgery for glaucoma. Postoperative scarring of the filtering water bladder is the most decisive factor in determining short-term and long-term outcome of modern filtering glaucoma surgery. The antimetabolite mitomycin C (MMC) and 5-fluorouracil (5-FU) is widely used to inhibit scarring and damage, thus filtering the water bladder. In a large retrospective study, it was shown that performed the usual trabeculoectomy has the degree of damage up to 30% within 3 months after surgery. To reduce such adverse complications were investigated various ways in order to avoid scarring of the filtering water bladder, mostly associated with the use of antimetabolite medicines during surgery or after surgery.

Despite the positive long-term impact on the duration of the filtration, the use of cytotoxic drugs to surgically open the eye increases the frequency of serious complications, such as pollution, increases complications that threaten vision. MMS gives a high incidence of serious complications after the use as 5-FU; although its side effects mainly affect the corneal epithelium, its clinical use is limited due to severe pain and discomfort to the patient. To date, there is no way that would ensure the achievement of satisfactory prolonged postoperative surgical outcomes with only minimal side effects or no side effects for the patient.

There is a need for effective and real cost cytoskeleton-active compounds for the treatment of glaucoma, for modulation of wound healing after trabeculectomy or to treat other diseases or disorders, which is affected by the integrity of the actin cytoskeleton. There is a need for new cytoskeleton-active compounds which can be obtained using a convenient synthetic methods.

Summary of the invention

The present invention relates to compounds of formula I and formula II, which are inhibitors of rho-kinase. The present invention also relates to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier.

The present invention also relates to a method for prevention or treatment of diseases or conditions associated with a decrease in tone of the cells and/or changes in adhesion cell-substrate. The invention relates to a method of reducing intraocular pressure including glaucoma treatment, such as primary open-angle glaucoma; to a method of treating reducing the field of view; to a method of inhibiting wound healing after trabeculectomy; to a method of treatment of late clouding of the capsule after extracapsular cataract extraction and implantation of an artificial lens; to a method of inhibiting angiogenesis; to a method of modulating transport of liquid on the surface of the eye; to a method for controlling vascular spasm; to a method of increasing tissue perfusion; to a method of neuroprotection and to the way vasoprotective (protection of vessels) in respect atherogen what x means.

The method includes the stage of identifying the subject in need of treatment, and the introduction of the subject of the compounds of formula I or formula II in an amount effective to modify the actin cytoskeleton, for example, by inhibiting the interactions of actomyosin.

Brief description of figures

Figure 1 shows the observed concentrations of the test compounds in aqueous humor after 0.5, 2 and 4 hours after instillation of the compounds in the animal's eyes.

Figure 2 (2-1 - 2-4) shows the intraocular pressure in animals after treatment, the test compound or the media.

Detailed description of the invention

The ROCK inhibitors strongly influence a variety of physiological functions associated with the restructuring of the cytoskeleton, leading to changes in cell morphology, sacramenti cells, cell motility and cytokinesis. They play a key role in the modulation of focal adhesion and inhibit the formation of fibers in the cells of the trabecular meshwork structures that Express a dense, dynamic cytoskeletal network. Thus, the change in sacramemto data cells leads to expansion of the drainage surface of the trabecular meshwork structure and channel Slamma. Additionally, the loss of adhesion interactions cell-substrate can affect the flow paracetomol of liquid through the channel Slamma or and the to change the path of fluid flow through ecolocalizer tissue of the trabecular mesh structure. Both, perhaps, is the basis of the effect of lowering intraocular pressure when using inhibitors of ROCK.

The authors of the present invention have identified compounds that are cytoskeleton-active agents, which modify the contractility of cells, the interaction between cell-cell and cell-substrate, for example, by inhibiting actomyosin interactions. These compounds contain structural distinctive features that make them suitable for use as therapeutic agents, especially for use in the exterior (local) drugs, for example, for use in the treatment of ophthalmic diseases. These patterns relate to new compounds with therapeutic utility.

Definition

In the case of presence, unless otherwise stated, the following terms in the General form as follows, but not limited to.

Halogen substituents are selected from fluorine, chlorine, bromine and iodine.

The term "alkyl" refers to groups of 1-12 carbon atoms, inclusive, or a linear or branched, more preferably from 1 to 8 carbon atoms, inclusive.

The term "alkenyl" refers to groups of 2-12 carbon atoms, inclusive, or a linear or branched, containing at least odnogolosy communication, but not necessarily containing more than one double bond.

The term "quinil" refers to groups of 2-12 carbon atoms, inclusive, or a linear or branched, containing at least one triple bond, but does not necessarily contain more than one triple bond and optionally optionally containing one or more fragments with double bonds.

The term "alkoxy" refers to the group alkyl-O-, where the alkyl group is as defined above including optionally substituted alkyl groups, as defined above.

The term "alconox" refers to a group of alkenyl-O-, where Alchemilla group is as defined above including optionally substituted alkeneamine group, as defined above.

The term "alkyloxy" refers to a group quinil-O-, where Alchemilla group is as defined above including optionally substituted alkyline group, as defined above.

The term "aryl" refers to an unsaturated aromatic carbocyclic group comprising 6-14 carbon atoms inclusive and having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl or until). Preferred arily include phenyl, naphthyl and the like.

The term "arylalkyl" refers to arylalkyl groups, preferably provided is of 1 to 6 carbon atoms inclusively in the alkyl portion and from 6 to 10 carbon atoms inclusive in the aryl fragment. Such arylalkyl group illustrated by benzyl, Venetian and the like.

The term "arylalkyl" refers to arylalkyl groups, preferably containing from 2 to 6 carbon atoms inclusive in Alchemilla fragment and from 6 to 10 carbon atoms inclusive in the aryl fragment.

The term "arylalkyl" refers to arylalkyl groups, preferably containing from 2 to 6 carbon atoms inclusive in alchenilla fragment and from 6 to 10 carbon atoms inclusive in the aryl fragment.

The term "cycloalkyl" refers to cyclic alkyl groups of 3-12 carbon atoms, inclusive, having a single cyclic ring or multiple condensed rings, which optionally can be substituted by 1-3 alkyl groups. Such cycloalkyl groups include, for example, the structure of a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentanol, 2-methylcyclohexyl and the like, or patterns from a variety of rings, such as substituted and the like.

The term "cycloalkenyl" refers to cyclic alkenyl groups consisting of 3-12 carbon atoms, inclusive, having a single cyclic ring or multiple condensed rings and at least one internal ninasimone the tee, which optionally can be substituted by 1-3 alkyl groups. Examples of suitable cycloalkenyl groups include, for example, cyclobuta-2-enyl, cyclopent-3-enyl, cycloocta-3-enyl and the like.

The term "cycloalkenyl" refers to cycloalkenyl groups, preferably having from 1 to 6 carbon atoms inclusively in the alkyl portion and from 6 to 10 carbon atoms inclusive in cycloalkenes fragment. Cyclopropylmethyl, cyclohexylethyl and the like illustrate such cycloalkenyl group.

The term "cycloalkenyl" refers to cycloalkenyl groups, preferably having from 2 to 6 carbon atoms inclusive in Alchemilla fragment and from 6 to 10 carbon atoms inclusive in cycloalkenes fragment. Cyclohexylidene and the like illustrate such cycloalkenyl group.

The term "cycloalkylcarbonyl" refers to cycloalkenyl groups, preferably having from 2 to 6 carbon atoms inclusive in alchenilla fragment and from 6 to 10 carbon atoms inclusive in cycloalkenes fragment. Cyclopropylethyl and the like illustrate such cycloalkenyl group.

The term "heteroaryl" refers to a monovalent aromatic heterocyclic group consisting of 1 to 10 carbon atoms inclusive and from 1 to 4 heteroa the Ohm inclusive, selected from oxygen, nitrogen and sulfur, in the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothiazyl).

The term "heteroaromatic" refers to heteroallyl groups, preferably containing from 1 to 6 carbon atoms inclusively in the alkyl portion and from 6 to 10 atoms, inclusive, in the heteroaryl portion. Such heteroallyl group illustrated by pyridylmethyl and the like.

The term "heteroaromatic" refers to heteroarylboronic groups, preferably containing from 2 to 6 carbon atoms inclusive in Alchemilla fragment and from 6 to 10 atoms including at heteroaryl fragment.

The term "heteroarylboronic" refers to heteroarylboronic groups, preferably containing from 2 to 6 carbon atoms inclusive in alchenilla fragment and from 6 to 10 atoms including at heteroaryl fragment.

The term "heterocycle" refers to a saturated or unsaturated group having a single ring or multiple condensed rings comprising 1 to 8 carbon atoms inclusive and from 1-4 heteroatoms inclusive, selected from nitrogen, sulfur or oxygen within the ring. Such heterocyclic groups can have a single ring (EmOC is emer, piperidinyl or tetrahydrofuryl) or multiple condensed rings (e.g., indolinyl, dihydrobenzofuran or hinokitiol). Preferred heterocycles include piperidinyl, pyrrolidinyl and tetrahydrofuryl.

The term "heterocycle-alkyl" refers to a heterocycle-alkyl group, preferably having from 1 to 6 carbon atoms inclusively in the alkyl portion and from 6 to 10 atoms inclusive in heterocyclic fragment. Such a heterocycle-alkyl group is illustrated by morpholino-ethyl, pyrrolidinyl and the like.

The term "heterocycle-alkenyl" refers to a heterocycle-alkenyl groups, preferably having from 2 to 6 carbon atoms inclusive in Alchemilla fragment and from 6 to 10 atoms inclusive in heterocyclic fragment.

The term "heterocycle-quinil" refers to a heterocycle-alkynylaryl groups, preferably having from 2 to 6 carbon atoms inclusive in alchenilla fragment and from 6 to 10 atoms inclusive in heterocyclic fragment.

Examples of heterocycles and heteroaryl include, but are not limited to specified, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, hemolysin, isoquinoline, quinoline, phthalazine, naftemporiki, cinoxacin, hinzelin, cannoli is, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazol, fenesin, isoxazol, phenoxazin, phenothiazines, imidazolidin, imidazoline, piperidine, piperazine, pyrrolidine, indoline and the like.

Unless otherwise stated, the position occupied by hydrogens in the above groups may be further substituted by substituents illustrated, but not limited to, hydroxy, oxo, nitro, methoxy, ethoxy, alkoxy, substituted alkoxy, triptoreline, halogenoalkane, fluorine, chlorine, bromine, iodine, halogen, stands, ethyl, propylene, bootrom, alkyl, alkenyl, quinil, substituted alkyl, trifluoromethyl, halogenation, hydroxyalkyl, alkoxyalkyl, thio, alkylthio, acyl, carboxy, alkoxycarbonyl, carboxamido, replaced carboxamido, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl sulfonamide, replaced sulfonamide, cyano, amino, substituted amino, alkylamino, dialkylamino, aminoalkyl, acylamino, amidino, amidoxime, gidroksamovoi, phenyl, aryl, substituted aryl, aryloxy, arylalkyl, arylalkyl, arylalkyl, pyridium, imidazolium, heteroaryl, replaced by heteroaryl, heteroaromatic, heteroallyl, heteroallyl, heteroallyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl, cycloalkenyl is m, cycloalkylation, replaced by cycloalkyl, cycloalkane, pyrrolidinium, piperidinium, morpholino, heterocycle, (heterocycle)oxy, and (heterocycle)alkyl; and preferred heteroatoms are oxygen, nitrogen and sulfur. It should be understood that when the unoccupied valences exist in these substituents, they may be additionally substituted alkyl, cycloalkyl, aryl, heteroaryl and/or heterocyclic groups, which, if unoccupied valence exist on the carbon can be further substituted with halogen, or oxygen-, nitrogen - or sulfur-linked substituents, and when there are many unoccupied valences, these groups can be combined to form a ring, either through direct education, communication, or by education relations with the new heteroatom, preferably oxygen, nitrogen or sulfur. In addition, it should be understood that the above substitution may be made, provided that the substitution of hydrogen by the Deputy does not lead to unacceptable instability of the molecules of the present invention and in the rest of the chemically justified.

The term "heteroatom-containing Deputy" refers to substituents containing at least one heteroatom, which is not a halogen. Examples of such substituents include, but are not limited icehouse specified, hydroxy, oxo, nitro, methoxy, ethoxy, alkoxy, substituted alkoxy, triptoreline, halogenoalkane, hydroxyalkyl, alkoxyalkyl, thio, alkylthio, acyl, carboxy, alkoxycarbonyl, carboxamido, replaced carboxamido, alkylsulfonyl, alkylsulfanyl, alkylsulfonyl, sulfonamide, replaced sulfonamide, cyano, amino, substituted amino, alkylamino, dialkylamino, aminoalkyl, acylamino, amidino, amidoxime, hydroxamic, aryloxy, pyridyl, imidazolyl, heteroaryl, substituted heteroaryl, heteroaromatic, heteroallyl, heteroaromatic, heteroallyl, cycloalkane, pyrrolidinyl, piperidinyl, morpholino, heterocycle, (a heterocycle)oxy, and (heterocycle)alkyl; and preferred heteroatoms are oxygen, nitrogen and sulfur. It should be understood that when the unoccupied valences exist in these substituents, they may be additionally substituted alkyl, cycloalkyl, aryl, heteroaryl and/or heterocyclic groups, which, if unoccupied valence exist on the carbon can be further substituted with halogen, or oxygen-, nitrogen - or sulfur-linked substituents, and when there are many unoccupied valences, these groups can be combined to form a ring, either through direct education, communication, or by education relations with the new a heteroatom, preferably oxygen, nitrogen or sulfur. In addition, it should be understood that the above substitution may be made, provided that the substitution of hydrogen by the Deputy does not lead to unacceptable instability of the molecules of the present invention and in the rest of the chemically justified.

"Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not have undesirable toxic effects. Form pharmaceutically acceptable salts include various polymorphs, and amorphous form of various salts, obtained by joining acids or bases. Acid additive salts can be formed of inorganic or organic acids. Illustrative, but not limiting examples of such acids include hydrochloric, Hydrobromic, sulfuric, phosphoric, citric, acetic, propionic, benzoic, naphthoic acid, oxalic acid, succinic, maleic, fumaric, malic, adipic, lactic, tartaric, salicylic, methanesulfonate, 2-hydroxyethanesulfonic, toluensulfonate, benzosulfimide, camphorsulfonate and econsultancy acid. Pharmaceutically acceptable basic additive salts can be formed using a metal or organic counterions and include, but are not exhaust uniqueuse specified, alkali metal salts, such as sodium or potassium, salts of alkaline earth metals such as magnesium or calcium, and ammonium salts or tetraalkylammonium, i.e. NX4+(where X represents a C1-4).

"Tautomers" are compounds that can exist in one or more forms, called tautomeric forms, which can be converted into each other by migration of one or more hydrogen atoms in the compound, accompanied by a rearrangement of the position of the adjacent double bond. Data tautomeric forms are in equilibrium with each other, and the position of the equilibrium will depend on the specific nature of the physical connection status. It should be understood that when the possible tautomeric forms, the present invention relates to all possible tautomeric forms.

"Solvate" represent additive complexes, in which the compound of formula I or formula II is combined with a pharmaceutically acceptable co-solvent in some fixed proportion. The co-solvents include, but are not limited to specified, water, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, Isobutanol, tert-butanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, benzene, toluene, xylene(s), ethylene glycol, dichloromethane, 1,2-dichloroethane, N-methylformamide, N,N-dimethylformamide, N-is ethylacetamide, pyridine, dioxane and diethyl ether. Hydrates are a solvate, in which the co-solvent is water. It should be understood that the definitions of the compounds of formula I and formula II encompass all possible hydrate and a solvate, in any proportion, which possess the indicated activity.

Connection - inhibitors of Rho kinase

Connection - inhibitors of rho kinase used in this invention include compounds of General formula I and formula II, and/or their tautomers and/or a pharmaceutically acceptable salt and/or solvate and/or hydrate.

The compound corresponding to formula I or formula II can exist in several diastereoisomeric forms. The General structure of formula I and formula II include all diastereomeric forms of such substances, unless otherwise stated. Formula I and formula II also include mixtures of the compounds of these formulas, including mixtures of enantiomers, diastereomers and/or other isomers in any proportion.

A. Formula I

The compounds of formula I are the following.

The formula I

where

R1represents optionally substituted aryl or heteroaryl;

Q represents C=O, SO2or (CR4R5n3;

n1represents 1, 2 or 3;

n2represents 1 or 2;

n3represents 1, 2 or 3;

where the ring presents

is optionally substituted by alkyl, halogen, oxo, OR6, NR6R7or SR6;

R2choose from the following optionally substituted heteroaryl systems

R3-R7independently represent H, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl or cycloalkylcarbonyl, optionally substituted.

In the formula I preferred R1represents a substituted aryl, more preferred R1is a substituted phenyl, the preferred Q is a (CR4R5)n3preferably Q represents CH2preferred n1represents 1 or 2, preferably n2equal to 1, the preferred n3represents 1 or 2, and the preferred R3-R7represent H.

[1] One variant of implementation of the present invention represented by formula I, in which R2represents an optionally substituted 5-indazoles or 6-indazole (R2-1).

[1a] In the embodiment 1 R2-1 is substituted by one or more alkyl or halogen substituents.

[1b] In the embodiment 1 R2-1 which is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[1c] In the embodiment 1 R2-1 is unsubstituted.

[2] In another embodiment, the invention is represented by formula I, in which R2represents an optionally substituted 5-ethenolysis or 6-ethenolysis (R2-2).

[2a] In the embodiment 2 R2-2 is substituted by one or more alkyl or halogen substituents.

[2b] In the embodiment 2 R2-2 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[2c] In the embodiment 2 R2-2 is unsubstituted.

[3] In another embodiment, the invention is represented by formula I, in which R2represents a 4-pyridyl or 3-pyridyl (R2-3), optionally substituted.

[3a] In the embodiment 3 R2-3 is substituted by one or more alkyl or halogen substituents.

[3b] In the embodiment 3 R2-3 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[3c] In the embodiment 3 R2-3 is unsubstituted.

[4] In another embodiment, the invention is represented by formula I, in which R2is soboy-isoindol-4-yl or 7-azaindole-5-yl (R 2-4), optionally substituted.

[4a] In the embodiment 4 R2-4 is substituted by one or more alkyl or halogen substituents.

[4b] In the embodiment 4 R2-4 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[4c] In the embodiment 4 R2-4 is unsubstituted.

[5] In another embodiment, the invention is represented by formula I, in which R2represents an optionally substituted 4-(3-amino-1,2,5-oxadiazol-4-yl)phenyl or 3-(3-amino-1,2,5-oxadiazol-4-yl)phenyl (R2-5).

[5a] In the embodiment 5 R2-5 is unsubstituted.

[6] In another embodiment, the invention is represented by formula I, in which R2represents one of the groups R2-1 - R2-5 substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[6a] In the embodiment 6 R2is substituted by one or more alkyl or halogen substituents.

[6b] In the embodiment 6 R2is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[7] In another embodiment, the invention presents the form of the Oh I, in which R2represents one of the groups R2-1 - R2-5 and is unsubstituted.

[8] In another embodiment, the invention is represented by formula I, in which R3represents H.

[9] In another embodiment, the invention is represented by formula I in which Q represents a (CR4R5)n3and n3represents 1 or 2.

[10] In another embodiment, the invention is represented by formula I in which Q represents (CH2)n3and n3is 1.

[11] In another embodiment, the invention is represented by formula I, in which R1represents aryl or heteroaryl substituted by one or more alkenylamine, alkenylamine, aryl, arylalkyl, arylalkylamine, arylalkylamine, heteroaryl, heteroallyl, heteroarylboronic, heteroallyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heterocyclic, (heterocycle)alkyl, (heterocycle)alkenylamine or (heterocycle)alkenylamine substituents, optionally additionally substituted.

Connection illustrating an implementation option 11, include compounds 1.009, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011, 2.019, 2.020, 2.022, 2.023 and 2.031, Azania below in table I.

[12] In another embodiment, the invention is represented by formula I, in which R1represents aryl or heteroaryl substituted by one or more heteroatom-containing substituents, provided that when the substituent R1is acyclic and is connected with R1through a carbon atom, the Deputy contains at least one atom of nitrogen or sulfur, in the second condition, that if the Deputy is acyclic and is connected with R1through an oxygen atom or nitrogen, the Deputy comprises at least one additional atom of oxygen, nitrogen or sulfur, and with the third proviso that if the Deputy is associated with R1by sulfonic outliners "-SO2-", R2is not nitrogen - or oxygen-substituted R2-2.

[12a] In the embodiment, 12 heteroatom-containing Deputy associated with R1through an oxygen atom or nitrogen.

[12b] In the embodiment, 12 heteroatom-containing Deputy associated with R1through sulfide linker, "-S".

Connection illustrating an implementation option 12, include compounds 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, to 2,007, 1.003, 1.006, 1.007, 1.018, 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095 has, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118, 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.04, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044, 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029, shown below in table I.

[13] In another embodiment, the invention is represented by formula I, in which R1represents aryl or heteroaryl substituted by one or more alkyl, alkenylamine, alkenylamine, aryl, arylalkyl, arylalkylamine, arylalkylamine, heteroaryl, heteroallyl, heteroarylboronic, heteroallyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heterocyclic, (heterocycle)alkyl, (heterocycle)alkenylamine or (heterocycle)alkenylamine substituents, which optionally are substituted by one or more heteroatom-containing substituents, provided that when the substituent R1is acyclic and its heteroatom-containing Deputy falls on the carbon by which it is connected with R1then the heteroatom-containing Deputy contains at least one atom of nitrogen or sulfur.

Connection illustrating an implementation option 13, include compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106, 1.107, 1.108, 1.109, 1.112, 1.114, 1.119, and 1.122, shown below in table I.

[14] In another embodiment, implementation is tvline invention represented by formula I, in which R1represents aryl or heteroaryl substituted by one or more alkenylamine, alkenylamine, aryl, arylalkyl, arylalkylamine, arylalkylamine, heteroaryl, heteroallyl, heteroarylboronic, heteroallyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heterocyclic, (heterocycle)alkyl, (heterocycle)alkenylamine or (heterocycle)alkenylamine substituents, optionally additionally substituted, and R2represents a 5-indazole (R2-1) or 5-ethenolysis (R2-2), optionally substituted.

[14a] In embodiment 14 R2represents a 5-indazole (R2-1), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[14b] In embodiment 14 R2represents a 5-ethenolysis (R2-2), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[14c] In the embodiment 14 R2is unsubstituted.

Connection illustrating an implementation option 14 include compounds 1.009, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1083, 2.010, 2.011, 2.019, 2.020, 2.022, 2.023 and 2.031, shown below in table 1.

[15] In another embodiment, the invention is represented by formula I, in which R1represents aryl or heteroaryl substituted by one or more heteroatom-containing substituents, and R2represents a 5-indazole (R2-1) or 5-ethenolysis (R2-2), optionally substituted, provided that when the substituent R1is acyclic and is connected with R1through a carbon atom, the Deputy contains at least one atom of nitrogen or sulfur, in the second condition, that if the Deputy is acyclic and is connected with R1through an oxygen atom or nitrogen, the Deputy comprises at least one additional atom of oxygen, nitrogen or sulfur, and with the third proviso that if the Deputy is associated with R1by sulfonic outliners "-SO2-", R2is not nitrogen - or oxygen-substituted R2-2.

[15a] In embodiment 15 R2represents a 5-indazole (R2-1), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[15b] In embodiment 15 R2represents a 5-ethenolysis (R2-2), optionally substituted by one or several is likemy alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[15c] In embodiment 15 R2is unsubstituted.

[15d] In embodiment 15, the heteroatom-containing Deputy associated with R1through an oxygen atom or nitrogen.

[15e] In embodiment 15, the heteroatom-containing Deputy associated with R1through sulfide linker, "-S".

Connection illustrating an implementation option 15, include compounds 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, to 2,007, 1.003, 1.006, 1.007, 1.018, 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095 has, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118, 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044, 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029, shown below in table I.

[16] In another embodiment, the invention is represented by formula I, in which R1represents aryl or heteroaryl substituted by one or more alkyl, alkenylamine, alkenylamine, aryl, arylalkyl, arylalkylamine, arylalkylamine, heteroaryl, heteroallyl, heteroarylboronic, heteroallyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heterocyclic, (hetero is Tcl)alkyl, (heterocycle)alkenylamine or (heterocycle)alkenylamine substituents, at least one of which is optionally substituted by one or more heteroatom-containing substituents, and R2represents a 5-indazole (R2-1) or 5-ethenolysis (R2-2), optionally substituted, provided that when the substituent R1is acyclic and its heteroatom-containing Deputy falls on the carbon by which it is connected with R1then the heteroatom-containing Deputy contains at least one atom of nitrogen or sulfur.

[16a] In the embodiment, 16 R2represents a 5-indazole (R2-1), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[16b] In the embodiment, 16 R2represents a 5-ethenolysis (R2-2), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[16c] In the embodiment, 16 R2is unsubstituted.

Connection illustrating an implementation option 16 include compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106, 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122, shown below in table I.

B. Formula II

Site is citicoline compound of the formula I is, in which R1= Ar-X, shown below as formula II.

Formula II

where

Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, such as phenyl;

X represents from 1 to 3 substituents located on Ar, each of which independently exists in the form Y-Z, in which Z is attached to Ar;

Y represents one or more substituents located on Z, and each of them is selected independently from H, halogen or heteroatom-containing substituents, including but not limited to, specified, OR8, NR8R9, NO2, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, OCF3, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9, OC(=O)NR8R9or NR8C(=O)NR9R10;

in each case, Z is chosen independently from alkyl, alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, heteroaryl, heteroaromatic, heteroallyl, heteroallyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)quinil, or is missing;

R8represents H, alkyl, alkenyl, quinil, aryl, arylalkyl, arylalkyl, ar is alkinyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)quinil or heterocycle; optionally substituted by one or more halogen or heteroatom-containing substituents, including but not limited to, specified, OR11, NR11R12, NO2, SR11, SOR11, SO2R11, SO2NR11R12, NR11SO2R12, OCF3, CONR11R12, NR11C(=O)R12, NR11C(=O)OR12, OC(=O)NR11R12or NR11C(=O)NR12R13;

R9and R10independently represent H, alkyl, alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)quinil or heterocycle; optionally substituted by one or more halogen or heteroatom-containing substituents, including but not limited to, specified, OR14, NR14R15, NO2, SR14, SOR14, SO2R14, SO2NR14R15, NR14SO2R15, OCF3, CONR14R15, NR14C(=O)R , NR14C(=O)OR15, OC(=O)NR14R15or NR14C(=O)NR15R16;

any two of the groups R8, R9and R10optional are connected by a connection selected from the group consisting of bond-O-, -S-, -SO-, -SO2- , and-NR17-, with the formation of the ring;

R11-R17independently represent H, alkyl, alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)quinil or heterocycle.

In formula II, the preferred Y is H, halogen, OR8, NR8R9, NO2, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, OCF3, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9, OC(=O)NR8R9or NR8C(=O)NR9R10preferably Y represents H, halogen, OR8, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9or NR8C(=O)NR9R10preferred Z represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, cycloalkenyl or missing; more preferred Z represents Ala is l, alkenyl, quinil, cycloalkyl or missing, the preferred Q is a (CR4R5)n3preferably Q represents CH2preferred n1represents 1 or 2, preferably n2is a 1, the preferred n3represents 1 or 2, the preferred R3-R7represent H, preferred R8represents H, alkyl, arylalkyl, cycloalkyl, cycloalkenyl or heterocycle, preferred substituents R8are H, halogen, OR11, NR11R12, SR11, SOR11, SO2R11, SO2NR11R12, NR11SO2R12, CONR11R12, NR11C(=O)R12and the preferred R9-R17are H or alkyl.

[1] One variant of implementation of the present invention represented by formula II in which R2represents a 5-indazoles or 6-indazole (R2-1), optionally substituted.

[1a] In the embodiment 1 R2-1 is substituted by one or more alkyl or halogen substituents.

[1b] In the embodiment 1 R2-1 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[1c] In the embodiment 1 R2-1 is nezameshchenny is.

[2] In another embodiment, the invention is represented by formula II in which R2represents a 5-ethenolysis or 6-ethenolysis (R2-2), optionally substituted.

[2a] In the embodiment 2 R2-2 is substituted by one or more alkyl or halogen substituents.

[2b] In the embodiment 2 R2-2 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[2c] In the embodiment 2 R2-2 is unsubstituted.

[3] In another embodiment, the invention is represented by formula II in which R2represents a 4-pyridyl or 3-pyridyl (R2-3), optionally substituted.

[3a] In the embodiment 3 R2-3 is substituted by one or more alkyl or halogen substituents.

[3b] In the embodiment 3 R2-3 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[3c] In the embodiment 3 R2-3 is unsubstituted.

[4] In another embodiment, the invention is represented by formula II in which R2is a 7-isoindol-4-yl or 7-azaindole-5-yl (R2-4), optionally substituted.

[4a] In the embodiment 4 R2-4 is the replacement of the military by one or more alkyl or halogen substituents.

[4b] In the embodiment 4 R2-4 is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[4c] In the embodiment 4 R2-4 is unsubstituted.

[5] In another embodiment, the invention is represented by formula II in which R2represents a 4-(3-amino-1,2,5-oxadiazol-4-yl)phenyl or 3-(3-amino-1,2,5-oxadiazol-4-yl)phenyl (R2-5), optionally substituted.

[5a] In the embodiment 5 R2-5 is unsubstituted.

[6] In another embodiment, the invention is represented by formula II in which R2represents one of the groups R2-1 - R2-5 substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[6a] In the embodiment 6 R2is substituted by one or more alkyl or halogen substituents.

[6b] In the embodiment 6 R2is substituted by one or more amino, alkylamino, hydroxyl or CNS deputies.

[7] In another embodiment, the invention is represented by formula II in which R2represents one of the groups R2-1 - R2-5 and is unsubstituted.

[8] In another embodiment of the invention, not only the but the formula II, in which R3represents H.

[9] In another embodiment, the invention is represented by formula II in which Q represents a (CR4R5)n3and n3represents 1 or 2.

[10] In another embodiment, the invention is represented by formula II in which Q represents (CH2)n3and n3represents 1.

[11] In another embodiment, the invention is represented by formula II in which Z represents alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylcarbonyl, cycloalkenyl, cycloalkenyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl or (heterocycle)quinil.

Connection illustrating an implementation option 11, include compounds 1.009, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011, 2.019, 2.020, 2.022, 2.023 and 2.031, shown below in table I.

[12] In another embodiment, the invention is represented by formula II in which Z is absent, Y is a heteroatom-containing Deputy, including, but not limited to, specified, OR8, NR8R9, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NRsub> 8C(=O)OR9, OC(=O)NR8R9or NR8C(=O)NR9R10provided that if the Deputy Y is acyclic and is connected to Ar by a carbon atom, the Deputy contains at least one atom of nitrogen or sulfur, in the second condition, that if the Deputy Y is acyclic and is connected to Ar by an oxygen atom or nitrogen, the Deputy comprises at least one additional atom of oxygen, nitrogen or sulfur, and with the third proviso that if the Deputy Y is linked to Ar via sulfonic linker "-SO2-", R2is not nitrogen - or oxygen-substituted R2-2.

[12a] In the embodiment, 12 heteroatom-containing Deputy associated with R1through an oxygen atom or nitrogen.

[12b] In the embodiment, 12 heteroatom-containing Deputy associated with R1through sulfide linker, "-S".

Connection illustrating an implementation option 12, include compounds 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, to 2,007, 1.003, 1.006, 1.007, 1.018, 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095 has, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118, 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044, 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029, shown below in table I.

[13] In another embodiment, the wasp is estline the invention is represented by formula II, in which Z represents an alkyl, alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl or (heterocycle)quinil and Y is a heteroatom-containing Deputy, including, but not limited to, specified, OR8, NR8R9, NO2, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, OCF3, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9, OC(=O)NR8R9or NR8C(=O)NR9R10provided that if Z is acyclic and Y falls on the carbon by which Z is attached to Ar, then Y contains at least one atom of nitrogen or sulfur.

Connection illustrating an implementation option 13, include compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106, 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122, shown below in table I.

[14] In another embodiment, the invention is represented by formula II in which Z represents alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, cycloalkyl, cycloalkenyl, cycloalkyl is alkyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl or (heterocycle)quinil and R2represents a 5-indazole (R2-1) or 5-ethenolysis (R2-2), optionally substituted.

[14a] In embodiment 14 R2represents a 5-indazole (R2-1), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[14b] In embodiment 14 R2represents a 5-ethenolysis (R2-2), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[14c] In the embodiment 14 R2is unsubstituted.

Connection illustrating an implementation option 14 include compounds 1.009, 1.010, 1.011, 1.012, 1.020, 1.021, 1.030, 1.034, 1.037, 1.044, 1.047, 1.076, 1.077, 1.083, 2.010, 2.011, 2.019, 2.020, 2.022, 2.023 and 2.031, shown below in table I.

[15] In another embodiment, the invention is represented by formula II in which Z is absent, Y is a heteroatom-containing Deputy, including, but not limited to, specified, OR8, NR8R9, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR 9, OC(=O)NR8R9or NR8C(=O)NR9R10and R2represents a 5-indazole (R2-1) or 5-ethenolysis (R2-2), optionally substituted, provided that if the Deputy Y is acyclic and is connected to Ar by a carbon atom, the Deputy contains at least one atom of nitrogen or sulfur, in the second condition, that if the Deputy Y is acyclic and is connected to Ar by an oxygen atom or nitrogen, the Deputy comprises at least one additional atom of oxygen, nitrogen or sulfur, and with the third proviso that if the Deputy Y is linked to Ar via sulfonic linker "-SO2-", R2is not nitrogen - or oxygen-substituted R2-2.

[15a] In embodiment 15 R2represents a 5-indazole (R2-1), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[15b] In embodiment 15 R2represents a 5-ethenolysis (R2-2), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[15c] In embodiment 15 R2is unsubstituted.

[15d] In embodiment 15, the heteroatom-containing C is the election agent is associated with R 1through an oxygen atom or nitrogen.

[15e] In embodiment 15, the heteroatom-containing Deputy associated with R1through sulfide linker, "-S".

Connection illustrating an implementation option 15, include compounds 1.001, 1.002, 1.004, 1.005, 1.038, 1.048, 1.055, 1.056, 2.002, 2.003, 2.005, to 2,007, 1.003, 1.006, 1.007, 1.018, 1.039, 1.051, 1.058, 1.060, 1.084, 1.085, 1.086, 1.087, 1.088, 1.090, 1.091, 1.092, 1.093, 1.094, 1.095 has, 1.096, 1.097, 1.098, 1.102, 1.111, 1.113, 1.115, 1.116, 1.117, 1.118, 1.120, 1.121, 1.123, 1.124, 1.125, 1.126, 1.127, 1.128, 1.129, 1.130, 2.004, 2.008, 2.032, 2.033, 2.034, 2.035, 2.036, 2.037, 2.038, 2.039, 2.040, 2.041, 2.042, 2.043, 2.044, 1.008, 1.017, 1.026, 1.040, 1.074, 1.075, 2.009, 2.012, 2.021, 2.024, 2.026 and 2.029, shown below in table I.

[16] In another embodiment, the invention is represented by formula II in which Z represents an alkyl, alkenyl, quinil, aryl, arylalkyl, arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic, heteroallyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkenyl or (heterocycle)quinil and Y is a heteroatom-containing Deputy, including, but not limited to, specified, OR8, NR8R9, NO2, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, OCF3, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9, OC(=O)NR8R9or NR8C(=NR 9R10and R2represents a 5-indazole (R2-1) or 5-ethenolysis (R2-2), optionally substituted, provided that if Z is acyclic and Y falls on the carbon by which Z is attached to Ar, then Y contains at least one atom of nitrogen or sulfur.

[16a] In the embodiment, 16 R2represents a 5-indazole (R2-1), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[16b] In the embodiment, 16 R2represents a 5-ethenolysis (R2-2), optionally substituted by one or more alkyl, halogen, amino, alkylamino, hydroxyl or CNS deputies.

[16c] In the embodiment, 16 R2is unsubstituted.

Connection illustrating an implementation option 16 include compounds 1.019, 1.027, 1.028, 1.029, 1.035, 1.041, 1.042, 1.043, 1.057, 1.061, 1.099, 1.101, 1.103, 1.104, 1.105, 1.106, 1.107, 1.108, 1.109, 1.112, 1.114, 1.119 and 1.122, shown below in table I.

In embodiments implementing 11-16 formula II, the preferred Q is a (CR4R5)n3preferably Q represents CH2preferred n1represents 1 or 2, preferably n2equal to 1, the preferred n3represents or 2, and the preferred R3represents H.

These compounds can be used for ophthalmic applications, in particular for the reduction of intraocular pressure or glaucoma treatment. In order to be therapeutically effective for ophthalmic use, the compounds should have an adequate effectiveness and appropriate pharmacokinetic properties, such as good permeability through the eye surface. In General, compounds having polar functional groups, are preferred absorption properties and are particularly suitable for topical ocular use. In General, compounds having a small lipophilic functional group, possess good inhibitory activity against ROCK.

The authors of the present invention found that the substitution of R1in formula I and X in formula II, are important factors for pharmacokinetic properties and inhibitory efficiency actions against the ROCK. The authors of the present invention optimized and selected compounds that have improved permeability for the eyes and effectiveness as an inhibitor of ROCK. In particular, compounds containing a polar functional group, in particular those specified above options exercise 11, 12, 13, 14, 15 and 16 in which ormula I and II, are particularly suitable for topical ocular use in adequate inhibitory activity against ROCK. Compounds having a small lipophilic functional group, as defined above in embodiments implementing 11, 12, 13, 14, 15 and 16 in the formula I and II, show inhibition of ROCK with adequate permeability for the eyes.

Specific compounds illustrating the formula I and formula II, shown in the following table I. Compounds of the examples were numbered in such a way that the numbers in the form 1.nnn indicate compounds in which R2is an R2-1, accommodation in the form of 2.nnn indicate compounds in which R2is an R2-2, and so on in a similar manner for the remaining compounds and groups of R2. In the following structures hydrogens are omitted in the figures for simplicity. Shows the tautomers represent all possible tautomers. Patterns are depicted so that the preferred stereochemistry; where these compounds can be formed stereoisomers, patterns cover indicate any possible stereoisomer individually or as a mixture of stereoisomers in any ratio.

Table I
Examples of connections
ConnectionStructureOptions for implementation
1.001
N-(1-(4-(methylsulphonyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12, 15C
1.002
3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzonitrile
1C, 7, 8, 9, 10, 12, 15C

1.003
N-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)ndimethylacetamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.004
N-(1-(4-(methylsulphonyl)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12, 15C
1.005
3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)benzonitrile
1C, 7, 8, 9, 10, 12, 15C
1.006
N-(4-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)IU who yl)phenyl)ndimethylacetamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.007
N-(1-(4-(3-(dimethylamino)propoxy)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.008
N-(1-(4-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12b, 15C, 15e
1.009
N-(1-(biphenyl-4-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C

1.010
N-(1-(1H-imidazol-1-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.011
N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.012
N-(1-(4-morpholinomethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.013
N-(1-(4-isobutylphenyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.014
N-(1-(4-butylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.015
N-(1-(4-isopropoxyphenyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.016
N-(1-(2,3-dimethylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.017
N-(1-(4-(ethylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12b, 15C, 15e

1.018
2-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.019
N-(1-(4-((dimethylamino)methyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 13, 16C
1.020
N-(1-(4-cyclopropylmethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.021
N-(1-(3-cyclopropylmethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.022
N-(1-(4-(triptoreline)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.023
N-(1-(4-isopropylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.024
N-(1-(2,4-dimethylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.025
(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanol
1C, 7, 8, 9, 10
1.026
N-(1-(4-(cyclopropylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12b, 15C, 15e

1.027
tert-butyl 4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzylcarbamoyl
1C, 7, 8, 9, 10, 13, 16C
1.028
N-(1-(4-(methylthiomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 13, 16C
1.029
N-(1-(4-(methylsulfonylmethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 13, 16C
1.030
N-(1-(4-(thiophene-2-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.031
N-(1-benzylation-4-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.032
N-(1-(4-(dimethylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.033
N-(1-(4-active compounds)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.034
N-(1-(4-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C

1.035
N-(1-(4-(aminomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 13, 16C
1.036
1-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)alanon
1C, 7, 8, 9, 10
1.037
N-(1-(4-vinylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.038
4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzonitrile
1C, 7, 8, 9, 10, 12, 15C
1.039
2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.040
N-(1-(3-(methylthio)benzyl)piperidine-3-and the)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12b, 15C, 15e
1.041
N-(1-(3-(methylsulfonylmethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 13, 16C
1.042
3-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)prop-2-in-1-ol
1C, 7, 8, 9, 10, 13, 16C

1.043
4-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)but-3-in-1-ol
1C, 7, 8, 9, 10, 13, 16C
1.044
N-(1-(4-(cyclopropylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.045
N-(1-(3-bromobenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.046
3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenol
1C, 7, 8, 9, 10
1.047
N-(1-(3-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.048
N-(1-(3-(methylsulphonyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12, 15C
1.049
N-(1-benzylpiperidine-3-yl)-3-methyl-1H-indazol-5-amine
1A, 6A, 8, 9, 10
1.050
N5-(1-benzylpiperidine-3-yl)-1H-indazole-3,5-diamine
1b, 6b, 8, 9, 10

1.051
N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.052
N-(1-(benzofuran-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.053
N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.054
N-(1-(benzo[b]thiophene-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.055
3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzamide
1C, 7, 8, 9, 10, 12, 15c
1.056
3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzosulfimide
1C, 7, 8, 9, 10, 12, 15c
1.057
tert-butyl 3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzylcarbamoyl
1C, 7, 8, 9, 10, 13, 16c
1.058
2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-methylphenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d

1.059
5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-METHYLPHENOL
1C, 7, 8, 9, 10
1.060
ethyl-2-(3-((3-(1H-indazol-5-eliminability-1-yl)methyl)phenoxy)acetate
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.061
N-(1-(3-(aminomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 13, 16c
1.062
N-(1-(3,4-dichlorobenzyl)pyrrolidin-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
Blade 1.063
N-(1-(3-(trifluoromethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.064
N-(1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.065
N-(1-(3-ethoxybenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.066
N-(1-(3-methylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10

1.067
N-(1-(2-methoxybenzyl)Pipa is one-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.068
5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-itfinal
1C, 7, 8, 9, 10
1.069
N-(1-(3-(4-chlorophenoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.070
N-(1-(3-(3-(trifluoromethyl)phenoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.071
N-(1-(2,5-dibromobenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.072
(S)-N-(1-(3,4-diferensial)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.073
(R)-N-(1-(3,4-diferensial)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.074
(R)-N-(1-(4-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12b, 15C, 15e

1.075
(S)-N-(1-(4-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12b, 15C, 15e
1.076
(R)-N-(1-(4-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.077
(S)-N-(1-(4-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 11, 14C
1.078
(S)-N-(1-(4-methylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.079
(S)-N-(1-(4-methoxybenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.080
((S)-N-(1-(3,4-dichlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.081
(S)-N-(1-(4-Chlorobenzyl)piperidine-3-yl)-1H-ind is evil-5-amine
1C, 7, 8, 9, 10
1.082
N-(1-((1H-indol-6-yl)methyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.083
5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-ethynylphenyl
1C, 7, 8, 9, 10, 11, 14C

1.084
3-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-1-ol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.085
N-(1-(3-(2-aminoethoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.086
2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetic acid
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.087
N-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
.088
2-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.089
N-(1-(3-amino-4-Chlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.090
(S)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.091
(S)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d

1.092
(R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.093
(R)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.094br/> (S)-2-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol1C, 7, 8, 9, 10, 12A, 15C, 15d
1.095 has
(S)-N-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.096
(R)-2-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.097
(R)-N-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.098
2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ndimethylacetamide
1C, 7, 8, 9, 10, 12A, 15C, 15d

1.099
2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide
1C, 7, 8, 9, 10, 13, 16C
1.100
N-(1-((1H-indol-5-yl)methyl)Pieper is DIN-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.101
2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol
1C, 7, 8, 9, 10, 13, 16C
1.102
N-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-chlorophenyl)methanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.103
2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetic acid
1C, 7, 8, 9, 10, 13, 16C
1.104
2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)indolin-1-yl)ethanol
1C, 7, 8, 9, 10, 13, 16C
1.105
2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide
1C, 7, 8, 9, 10, 13, 16C

1.106
(R)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide
1C, 7, 8, 9, 10, 1, 16C
1.107
(S)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide
1C, 7, 8, 9, 10, 13, 16C
1.108
(R)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol
1C, 7, 8, 9, 10, 13, 16C
1.109
(S)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol
1C, 7, 8, 9, 10, 13, 16C
1.110
(R)-N-(1-benzylpiperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.111
N-(2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethyl)ndimethylacetamide
1C, 7, 8, 9, 10, 12A, 15C, 15d

1.112
tert-butyl 2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetate
1C, 7, 8, 9, 10, 13, 16C
1.113
(S)-3-(3-(((R)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.114
2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol
1C, 7, 8, 9, 10, 13, 16C
1.115
(R)-3-(3-(((R)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.116
(R)-1-(3-(((R)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-2-ol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.117
(R)-3-(3-(((S)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.118
(R)-1-(3-(((S)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-2-ol
1C, 7, 8, 9, 10, 12A, 15C, 15d

1.119
2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetic acid
1C, 7, 8, 9, 10, 13, 16C
1.120
N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.121
N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)-N-methylmethanesulfonamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.122
N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzyl)ndimethylacetamide
1C, 7, 8, 9, 10, 13, 16C
1.123
(R)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.124
(S)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.125
(R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)uksu the Naya acid
1C, 7, 8, 9, 10, 12A, 15C, 15d

1.126
(R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-N-(pyridin-3-yl)ndimethylacetamide
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.127
(R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-1-morpholinothio
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.128
(R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-1-(4-methylpiperazin-1-yl)alanon
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.129
(R)-diethyl-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)methylphosphonate
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.130
2-(3-((4-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
1C, 7, 8, 9, 10, 12A, 15C, 15d
1.131
(R)-N-(1-(benzofuran-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-a is in
1C, 7, 8, 9, 10
1.132
(R)-N-(1-(4-Chlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.133
(R)-N-(1-(4-methylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10

1.134
(R)-N-(1-(4-bromobenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.136
(R)-N-(1-(4-active compounds)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.137
(R)-N-(1-(2,4-dimethylbenzyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
1.138
(R)-N-(1-(benzo[b]thiophene-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine
1C, 7, 8, 9, 10
2.001
N-(1-(4-methoxybenzyl)piperidine-3-yl)skinoren-Amin
2C, 7, 8, 9, 10
2.002
N-(1-(4-(methylsulphonyl)benzyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12, 15C
2.003
3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)benzonitrile
2C, 7, 8, 9, 10, 12, 15C
2.004
N-(4-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)ndimethylacetamide
2C, 7, 8, 9, 10, 12a, 15C, 15d

2.005
N-(1-(4-(methylsulphonyl)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12, 15C
2.006
N-(1-benzylpyrrolidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
To 2,007
3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)benzonitrile
2C, 7, 8, 9, 10, 12, 15C
2.008
N-(4-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)ndimethylacetamide
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.009
N-(1-(4-(methylthio)benzyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12b, 15C, 15e
2.010
N-(1-(4-cyclopropylmethyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.011
N-(1-(3-cyclopropylmethyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.012
N-(1-(4-(cyclopropylamino)benzyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12b, 15C, 15e

2.013
N-(1-benzylation-4-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.014
N-(1-(3,4-dichlorobenzyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2015
N-(1-(3-(trifluoromethyl)benzyl)piperidine-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.016
N-(1-(3,4-dichlorobenzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.017
N-(1-(4-methoxybenzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.018
N-(1-(3-(trifluoromethyl)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.019
(S)-N-(1-(4-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.020
(R)-N-(1-(3-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.021
(R)-N-(1-(4-(cyclopropylamino)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12b, 15C, 15e

2.022
(R)-N-(1-(4-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.023
(S)-N-(1-(3-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.024
(S)-N-(1-(4-(cyclopropylamino)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12b, 15C, 15e
2.025
(R)-N-(1-(4-methylbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.026
(R)-N-(1-(4-(methylthio)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12b, 15C, 15e
2.027
(R)-N-(1-(4-chlorbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.028
(S)-N-(1-(4-methylbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C,7, 8, 9, 10
2.029
(S)-N-(1-(4-(methylthio)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 12b, 15C, 15e

2.030
(S)-N-(1-(4-chlorbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10
2.031
(R)-N-(1-(4-ethynylphenyl)pyrrolidin-3-yl)isoquinoline-5-amine
2C, 7, 8, 9, 10, 11, 14c
2.032
(S)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.033
(R)-N-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.034
(R)-2-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.035
(S)-N-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.036
(S)-2-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.037
(S)-N-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide
2C, 7, 8, 9, 10, 12a, 15C, 15d

2.038
(R)-N-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.039
(R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.040
(R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ndimethylacetamide
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.041
(R)-N-(3-((3-(from inulin-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)econsultant
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.042
2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.043
(R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)-1-morpholinoethyl
2C, 7, 8, 9, 10, 12a, 15C, 15d
2.044
(R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)acetic acid
2C, 7, 8, 9, 10, 12a, 15C, 15d
3.001
N-(1-benzylpiperidine-3-yl)pyridine-4-amine
3C, 7, 8, 9, 10

3.002
N-(1-benzylpyrrolidine-3-yl)pyridine-4-amine
3C, 7, 8, 9, 10
4.001
N-(1-benzylpiperidine-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine
4C, 7, 8, 9, 10
4.002
N-(1-benzylpyrrolidine-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine
4C, 7, 8, 9, 10
5.001
4-(4-(1-(4-benzylpiperidine-3-ylamino)phenyl)-1,2,5-oxadiazol-3-amine
5A, 7, 8, 9, 10
5.002
4-(4-(1-(4-benzylpyrrolidine-3-ylamino)phenyl)-1,2,5-oxadiazol-3-amine
5A, 7, 8, 9, 10

Obtaining compounds of formula I and formula II

The present invention additionally relates to methods of preparing compounds of formula I and formula II. General approaches to obtaining the compounds of these formulas described in scheme 1 and scheme 2. Specialists in this field will be clear that to obtain the compounds covered by the present invention, it is possible to replace the original substances and to use an additional stage. In some cases it may be necessary to protect certain reactive functional groups for some of the above transformations. In General, the need for such protective groups, as well as the conditions required for attachment and removal of such groups, it will be obvious to experts in the field of organic synthesis.

Specialists in this area will be known according to CNAE methods of synthesis, which can be used to obtain non-toxic pharmaceutically acceptable prodrugs, for example acylated prodrugs, compounds according to this invention.

Scheme 1

Obtaining substances described by the formula shown in scheme 1. This diagram is protected heterocyclic ketone 1.1, easily accessible using the methods of obtaining, are well known in the literature, is subjected to the interaction with the amine 1.2 under conditions of reductive amination, usually using borhydride reductant, such as triacetoxyborohydride sodium. In the resulting protected diamine 1.3 remove the protective group using conditions appropriate for the selected protective group, for example, acidic conditions in the case of the BOC-protective group, or restorative conditions for the CBZ group. Product 1.4 with remote protective group is then subjected to condensation with a partner for condensing 1.5 containing functional group Q-Z that is appropriate for the introduction of the substituent R1-Q. Typical illustrative reactions of condensation of from 1.5 include reductive amination with aldehyde, alkylation using alkylhalogenide and acylation using acylhomoserine or sulphonylchloride. Such reactions condensation lead to connect the tion 1.6, which is an example of the substances described by formulas.

Scheme 2

Additional obtaining substances described by formula I and formula II, shown in scheme 2. In this diagram, protected diamine 2.1, easily accessible using the methods of obtaining, are well known in the literature, provide an opportunity to interact with a suitable activated form of a substituent R2, 2.2, optionally in the presence of a catalyst. Examples of activating groups Y include halides and triflate, and usually use a palladium catalyst. This condensation reaction leads to a protected product of diamine 2.3, which is similar to a protected diamine 1.3 in figure 1 and which transform in the same sequence of transformations to obtain 2.6, which is an example of the substances described by formulas. Because protected diamines 2.1 easily available in optically active form using methods well known in the literature, the methods of scheme 2 provide a convenient method of obtaining compounds of the above formula in optically active form. It will be seen that modifications to the above two synthetic schemes using well-known methods will be to give the possibility of obtaining other members included in the volume described by the formula.

Adequate protection IU is non functional groups can be important to obtain a satisfactory reaction 2.1 and 2.2 to obtain 2.3. In particular, when R2represents indazoles, protection of any unsubstituted nitrogen indazole is crucial to the success of the reaction. Preferred protective groups in this case are p-methoxybenzyl (RMV) and 2-tetrahydropyranyl (TNR), where TPR is the most preferred. The use of protective TPR group provides high outputs at the stages of introduction of the protective group, the condensation and removal of the protective group and enables the removal of the protective group in the absence of the necessary reagents-absorbers, which are otherwise necessary for clean conduct the removal of the protective group.

Pharmaceutical composition and use

The present invention also relates to pharmaceutical compositions. Pharmaceutical compositions are pharmaceutically acceptable preparations, including pharmaceutically acceptable carrier and one or more compounds of the formula I and/or formula II, pharmaceutically acceptable salt, solvate and/or hydrate. Pharmaceutically acceptable carrier can be selected by the specialists in this field in accordance with the usual criteria. Pharmaceutically acceptable carriers include, but are not limited to specified, solutions, suspensions, emulsions, microemulsions, micellar solutions, gels and ointments on the water and the net is th basis. Pharmaceutically active media can also contain ingredients that include, but are not limited to specified, saline and aqueous solutions of electrolytes; ionic and non-ionic osmotic agents such as sodium chloride, potassium chloride, glycerin and dextrose; pH regulators and buffers, such as hydroxide, hydromyelia, phosphate, citrate, acetate, borate and tromethamine salts; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfate, ascorbic acid, acetylcysteine, cysteine, glutathione, bottled hydroxyanisole, bottled hydroxytoluene, Tocopherols and ascorbyl palmitate; surfactants, such as lecithin, phospholipids, including, but not limited to, phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol; poloxamer and poloxamine, Polysorbate, such as Polysorbate 80, Polysorbate 60 and Polysorbate 20, polyethers such as polyethylene glycols and polypropyleneglycol; polyvinyl, such as polyvinyl alcohol and povidone; cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethyl cellulose and hypromellose and their salts; derivatives of oil, such as mineral oil and white petrolatum; fats such as lanolin, Rahimova little palm oil, soybean oil; mono-, di - and triglycerides; polymers of acrylic acid, such as carboxypolymethylene gel, and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers can be protected from bacterial contamination using well-known preservatives, which include, but are not limited to the specified chloride benzalconia, ethylenediaminetetraacetic acid and its salts, chloride benzene, chlorhexidine, chlorobutanol, methylparaben, thimerosal and phenethyl alcohol, or may be included in the formulations as drug without preservatives either for single or multiple applications.

In one embodiment of the invention the compositions have in the form of ophthalmic topical preparations with a pH of about 3-9, preferably from 4 to 8. Compounds according to the invention typically contain these drugs in the amount of at least about 0.001% by weight, for example from 0.001% to 5% by weight, preferably approximately from 0.003% to about 2% by weight, most preferred is an amount from about 0.02% to about 1% by weight. For the local introduction of one or two drops of these drugs is applied to the surface of the eye one to four times per day in accordance with the usual prescription kvalificerad the frame of the doctor.

In one embodiment of the invention the compositions have in the form of an aqueous pharmaceutical preparations comprising at least one compound of the formula I and/or formula II in an amount of 0.001-2 wt%./about. and isotonic agent to maintain isotonicity between 200-400 mOsm/kg, where the pH of the solution is 3-9.

In another the next embodiment of the invention the pharmaceutical preparation comprises at least one compound of the formula I and/or formula II in an amount of 0.001-2 wt%./about., one or more complexing and/or solubilizing agent, 0.01 to 0.5% preservative, 0.01 to 1% chelating agent and an isotonic agent to maintain isotonicity between 200-400 mOsm/kg, where the pH of the solution is 4-8. The preferred amount of the compound is in the range of 0.01-1% wt./about.

Delivery of such ophthalmic preparations can be carried out using a bubble with only a single dose, which can be eliminated by adding preservative. Alternatively, the ophthalmic drug can be contained in the ophthalmic container with a pipette designed for multiple applications. In this case, the container for reuse may contain a preservative or may not contain, especially in the case of compositions samasewaya composition. Also what about the, container with a pipette is designed to deliver a certain fixed amount of the product of preparation in every drop. Typical volume drops for such ophthalmic drug will vary from 20 to 60 microliters, preferably 25-55 microliters, more preferably 30-50 microliters where 35-50 microlitres is the most preferred.

Glaucoma is an eye disease that leads to irreversible vision loss. Primary open-angle glaucoma is characterized by an abnormally high resistance to removal of the fluid (intraocular fluid from the eye. The contractility of cells and changes in adhesion cell-cell and cell-trabecula in the trabecular mesh structure are major determinants of resistance to flow. Compounds of the present invention cause a temporary pharmacological violation as sacramenti cells, and cell adhesion, mainly due to destruction associated with actomyosin cytoskeletal structures and/or modulate their interaction with membranes. Changing sacramenti cells of the trabecular meshwork structure leads to expansion of the surface removal of fluid. Loss of adhesion cell-cell and cell-trabecula can influence the flow paracetomol of liquid through the channel SLE the mA or change the path of fluid flow through kalokalo tissue of the trabecular mesh structure. Both mechanisms probably reduce the resistance of the trabecular mesh structure to the fluid flow and thereby reduce the intraocular pressure therapeutically useful.

Compounds of the present invention can be used for modulation of wound healing after trabeculectomy. Compounds are generally less toxic to the corneal epithelium and endothelial cells than the antimetabolites, such as 5-fluorouracil or mitomycin C. the Compounds inhibit driven actomyosin the contractility, resulting in damage to the actin microfiber system and the violation of its membrane rigid attachment, which weakens the cell-extracellular matrix adhesion interactions. Such properties inhibit wound healing and thereby reduce the destruction of a water bladder after surgery.

Frequent complication after extracapsular cataract extraction and implantation of an artificial lens (KIC) is the subsequent clouding of the capsule (CPD); the type of secondary cataract caused by residual epithelial cells after removal of the crystalline lens. Violation of the actin cytoskeleton and vokalnyh adhesive interactions by inhibition of rho kinase may facilitate surgical removal of all cells from the capsular bag and the sama is to reduce ACC.

Angiogenesis is characterized by the development of a new vascular system from pre-existing vessels and plays a Central role in physiological processes such as embryogenesis, wound healing and reproductive function in women, as well as in pathophysiological processes such as cancer, rheumatoid arthritis and diabetic retinopathy. Growth and metastasis of tumors is critically dependent on angiogenesis. Angiogenesis is a multi-stage process, including the involvement of the cytoskeleton of endothelial cell (EC) migration, proliferation and stabilization of the barrier. Angiogenesis is also involved in a number of eye diseases such as age related macular degeneration, diabetic retinopathy, retinopathy of premature birth, corneal angiogenesis, choroidal neovascularization, neovascularization, glaucoma, ocular appoligizes. The authors of the present invention believe that the interaction between the cytoskeleton and apoptosis are involved in the intercellular route, which leads to the formation of angiogenic vessel. Compounds of the present invention can be used for the inhibition of angiogenesis and treatment of tumors and related angiogenesis ophthalmologic diseases.

Regulation of the actin cytoskeleton is important for the modulation of the transport fluid. Anti-Christ. eroticheskie drugs significantly affect the antidiuretic response, clearly suggesting that the integrity of the cytoskeleton is essential for this function. This role of the cytoskeleton in the control of epithelial transport is a necessary stage in the translocation of water channel containing units parts, and their delivery to the apical membrane. Osmotically-induced reorganization of the cytoskeleton and the expression of specific proteins shock are important components in the regulatory system involved in the adaptation of medullary cells to osmotic shock. Compounds of the present invention can be used to control epithelial function and modulation of the transport fluid, in particular modulation of the transport of liquid on the surface of the eye.

Inhibitors of rho-associated protein kinases, through the regulation of the contraction of smooth muscles, can be used for the treatment of vascular spasm, in particular retinal (relating to the retina of the eye) vascular spasm. Relaxation of the vascular system of the retina increases the degree of perfusion, thereby providing a neuroprotective mechanism (reduction of apoptosis and necrosis) in diseases of the retina and retinopathy, such as glaucoma, increased eye pressure, age related macular degeneration or pigmentary degeneration of the retina. In addition, these inhibitors Ki is the basics regulate the permeability of endothelial vessels and as such can play vasoprotective role in relation to the various atherogenic agents.

The present invention relates to a method of reducing intraocular pressure including glaucoma treatment, such as primary open-angle glaucoma; treatment of narrowing of the field of view; the way of inhibition of wound healing after trabeculectomy; the method of treatment further clouding of the capsule after extracapsular cataract extraction and implantation of an artificial lens; method of inhibiting angiogenesis; method of modulating transport of liquid on the surface of the eye; the method of controlling spasm of the vessels; the way to increase the perfusion of tissues; the manner of treatment and method of vasoprotective against atherogenic agents. The method includes the stage of identifying needs in the treatment of the subject and the introduction of the subject of the compounds of formula I or formula II in an amount effective to modify the actin cytoskeleton, as for example, by inhibiting actomyosin interactions.

In one embodiment, the pharmaceutical composition of the present invention introduce a local image in the eye (for example, externally, nutricline, inside the vitreous, subretinal (under the retina), podklyucheno, retrobulbarno or via an implant) in the form of ophthalmic drugs. Compounds of the present invention can be combined with ophthalmologist acceptable to the servante, surface-active substances that increase the viscosity agents, amplifiers permeability, bioadhesive, antioxidants, buffers, sodium chloride and water to obtain an aqueous or non-aqueous, sterile ophthalmic suspension, emulsion, microemulsion, gel, or solution to obtain compositions according to the invention.

Described here, the active compounds can be entered into the patient's eye in any suitable way, but preferably they are administered by injecting a liquid or gel-like suspensions of the active compounds in the form of drops, spray or gel. Alternatively, the active compounds can be applied to the eye using liposomes. In addition, the active compounds can be administered by infusion in a tear film using the supply system pump catheter. Another variant of implementation of the present invention includes an active compound contained in the device a continuous or selective release, for example, membranes such as, but not limited to, developed in the Ocusert system™ (Alza Corp., Palo Alto, CA). As an additional variant implementation, the active compounds can be contained within contact lenses, or transferred, or to join contact lenses, which are placed in the eye. Another variant of implementation of the present invention comprises the active compounds contained in the swab or sponge, you can apply on the surface of the eye. Another variant of implementation of the present invention includes the active substance contained in a liquid spray that can be applied to the eye surface. Another variant of implementation of the present invention includes the injection of active compounds directly into the tissue of the lacrimal glands or on the surface of the eye.

In addition to the outdoor use of compounds on the surface of the eye, compounds of the present invention can be applied systematically by using any of the methods known to the expert, if they are used for the purposes described above.

The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention is described in specific methods.

EXAMPLES

Example 1

2,2-Dimethyl-1-(5-nitro-1H-indazol-1-yl)propane-1-he

A 3-necked round bottom flask with a capacity of 4 l, equipped with input for nitrogen and a mechanical stirrer, was loaded a solution of 5-nitroindazole (80,0 g, 0.49 mol) in tetrahydrofuran (1 l). The mixture was cooled to 0°C was added triethylamine (85,4 ml, 0.61 mol). To the mixture was added dropwise pivaloate (63,4 ml, 0.52 mol) over 15 minutes. The reaction mixture was allowed to warm to 20°C within 2 hours. The reaction mixture was filtered and to the have centriole to produce a dark red oil. To the oil was added methylene chloride (60 ml). The resulting suspension was intensively mixed, obtaining a white precipitate, which was isolated by filtration. The solid was dried in a vacuum oven at 40°C during the night, getting mentioned in the title compound (95 g, 79%).

Example 2

Maleate of 1-(5-amino-1H-indazol-1-yl)-2,2-DIMETHYLPROPANE-1-it

In a steel reaction vessel with a capacity of 0.5 l) was added 2,2-dimethyl-1-(5-nitro-1H-indazol-1-yl)propane-1-he (25,0 g, 0.10 mol), ethanol (300 ml) and 10% palladium-on-coal (2.0 g, 1.9 mmol). The vessel was tightly corked, was pumped under vacuum and re-filled with nitrogen three times, was pumped under vacuum and re-filled with hydrogen to a pressure of 75 ft/psi. As the consumption of hydrogen in the vessel was re-filled to maintain a pressure of 75 ft/psi. The vessel was degirolami and deleted the reaction mixture was filtered through celite and concentrated, obtaining the target product as a yellow oil (~22 g, 100% yield). The crude product was dissolved in ethanol (220 ml). Was added in a single portion to a solution of maleic acid (11.8 g, 0.10 mol) in ethanol (60 ml). The mixture was intensively stirred. After began to precipitate formed, the mixture was cooled to 0°C and was stirred for thirty minutes. The precipitate was isolated by filtration and dried in a vacuum oven at 30°C during the night, getting listed in the title compound as a solid (30 g, 90%).

1H NMR (DMSO-d6, 300 MHz): δ 1,45 (s, N), to 6.22 (s, 2H), 7,00 (m, 2H), 8,07 (m, 1H), 8,23 (s, 1H).

Example 3

tert-Butyl 3-(1-pivaloyl-1H-indazol-5-ylamino)piperidine-1-carboxylate

A 3-necked round bottom flask with a capacity of 1 l, equipped with input for nitrogen and a mechanical stirrer, was added tert-butyl 3-oxopiperidine-1-carboxylate (14.2 g, 0.07 mol), 1,2-dichloroethane (300 ml) and maleato salt of 1-(5-amino-1H-indazol-1-yl)-2,2-DIMETHYLPROPANE-1-it (23,0 g, 0.07 mol). The flask was purged with nitrogen and stirred at 20°C for one hour. Added triacetoxyborohydride sodium (19,0 g, 0.09 mol) and the reaction course was monitored to completion by analytical TLC. The reaction mixture was diluted with 100 ml saturated sodium bicarbonate solution. The organic phase was isolated, dried over MgSO4, was filtered and was evaporated to dryness, obtaining mentioned in the title compound as a yellow solid (25,0 g, 91%).

Example 4

2,2-Dimethyl-1-(5-(piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he

A 3-necked round bottom flask equipped with an additional drip funnel and a magnet for stirring on a magnetic stirrer, was added tert-butyl 3-(1-pivaloyl-1H-indazol-5-ylamino)piperidine-1-carboxylate (25,0 g, 0.06 mol)and dichloromethane (150 ml). The mixture was cooled to 0°C and added dropwise triperoxonane acid (150 ml). The reaction was monitored by HPLC to verify the disappearance of the original substance. After completion of the reaction, the reaction mixture was concentrated, receiving trifenatate salt of the desired product. Residual triperoxonane acid was removed in vacuum. Salt was converted to free base by distributing the mixture of 75 ml of saturated sodium bicarbonate solution and ethyl acetate (300 ml). The organic phase was separated, dried over MgSO4was filtered and concentrated, obtaining mentioned in the title compound as an amorphous solid (15.5 g, 83%).

Example 5

2,2-Dimethyl-1-(5-(pyrrolidin-3-ylamino)-1H-indazol-1-yl)propane-1-he

The interaction of tert-butyl 3-oxopyrrolidin-1-carboxylate and maleate salt of 1-(5-amino-1H-indazol-1-yl)-2,2-DIMETHYLPROPANE-1-it using the method of example 3 with the subsequent removal of the protective group using the method of example 4 resulted specified in the header of the connection.

Example 6

N-(piperidine-3-yl)isoquinoline-5-amine

The interaction of tert-butyl 3-oxopiperidine-1-carboxylate and isoquinoline-5-amine using the method of example 3 with the subsequent removal of the protective group by using method p is the emer 4 led to headline the connection.

Example 7

N-(Pyrrolidin-3-yl)isoquinoline-5-amine

The interaction of tert-butyl 3-oxopyrrolidin-1-carboxylate and isoquinoline-5-amine using the method of example 3 with the subsequent removal of the protective group using the method of example 4 resulted specified in the header of the connection.

Example 8

2,2-Dimethyl-1-(5-(1-(4-(methylthio)benzyl)piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he

In a round bottom flask with a capacity of 25 ml was combined 2,2-dimethyl-1-(5-(piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he (0,250 g, 0.8 mmol), 1,2-dichloroethane (5 ml), 4-(methylthio)benzaldehyde (to 0.127 g, 0.8 mmol), glacial acetic acid (50 μl, 0.8 mmol) and triacetoxyborohydride sodium (0,229 g, 1.1 mmol). The reaction mixture was pumped under vacuum and filled with nitrogen. The reaction course was monitored by HPLC and believed that the reaction ended with the disappearance of the original amine. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 ml) and dichloromethane (5 ml). After stirring the organic phase was isolated, dried over MgSO4was filtered and concentrated, obtaining the crude product. Chromatography of the residue on silica gel gave specified in the title compound in the form of not-quite-white solid (250 mg, 69%).

Example 9

N-(1-(4-(Methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.008

In a round bottom flask with a capacity of 25 ml) was added 2,2-dimethyl-1-(5-(1-(4-(methylthio)benzyl)piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he (250 mg, 0.6 mmol), methanol (5 ml) and sodium methoxide (93 mg, 1.7 mmol). The reaction mixture was stirred at room temperature until, until he trashdolls original substances when testing using HPLC. The mixture was diluted with ethyl acetate (10 ml), washed with water (2×10 ml) and the organic phase was separated, dried over MgSO4, was filtered and was evaporated to dryness, obtaining mentioned in the title compound (180 mg, 89%).

1H NMR (CDCl3, 300 MHz): δ 9,8 (users, 1H), 7,86 (s, 1H), 7.3 to to 7.18 (m, 5H), PC 6.82 (m, 2H), 3,6-3,4 (m, 3H), 2,74 (m, 1H), 2,47 (s, 3H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 10

2,2-Dimethyl-1-(5-(1-(3-(methylthio)benzoyl)piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he

To a solution of 3-(methylthio)benzoic acid (200 mg, 1.2 mmol) in DMF (4.5 ml) was added sequentially hydroiodide N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (345 mg, about 1.75 mmol), hydrate of 1-hydroxybenzotriazole (186 mg, 1.2 mmol) and diisopropylethylamine (0,630 ml, 3.6 mmol). After stirring at room temperature for 10 minutes was added in one portion 2,2-dimethyl-1-(5-(piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he (300 mg, 1.0 mmol). The solution paramashiva and in nitrogen atmosphere overnight. The solution was poured in 1.0 M HCl (20 ml), was extracted with EtOAc twice and the organic phase was washed with 10% NaOH, dried over Na2SO4and was evaporated. Chromatography of the residue on silica gel with elution with mixture of EtOAc/heptane gave specified in the title compound as a pale yellow foam substances (240 mg, 53%).

Example 11

N-(1-(3-(Methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.040

In a round bottom flask was added 2,2-dimethyl-1-(5-(1-(3-(methylthio)benzoyl)piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-he (240 mg, 0,655 mmol) and THF (3 ml). The solution was heated to 60°C and was added to the complex of borane-dimethyl sulfide in THF (3.0 ml of a 2.0 M solution in THF, 6.0 mmol), allowing dimethyl sulfide to Athanasia. After the initial substance was trashdolls, the reaction mixture was evaporated, added 5N. NaOH (10 ml) and the mixture was extracted with EtOAc. The organic phase was dried, evaporated and the residue was chromatographically on silica gel, elwira mixture 3/1 - EtOAc/heptane, getting mentioned in the title compound (95 mg, 41%).

1H NMR (CDCl3, 300 MHz): δ 7,87 (s, 1H), 7,26-to 7.15 (m, 4H), 7,11 (t, J=7.2 Hz, 1H), 6,83 (m, 2H), 3,61 (m, 1H), 3,50 (m, 2H), 2,80 (m, 1H), 2.49 USD (s, 3H), 2,43 (users, 2H), 2,29 (users, 1H), about 1.75 (m, 2H), 1,59 (m, 3H).

Example 12

5-Bromo-1-(4-methoxybenzyl)-1H-indazol

To a suspension of KOtBu (8,13 g, to 72.4 mmol) in THF (60 ml) to relax is whether 5-bromo-1H-indazole (12,98 g, 65,9 mmol) in THF (60 ml). After 30 minutes, was added 4-methoxybenzylamine (9,38 ml of 69.2 mmol) (undiluted) and the resulting pale yellow solution was stirred for 48 hours. The reaction was suppressed by adding a saturated solution of NH4Cl and the mixture was extracted with EtOAc. Evaporation of the organic phase and subsequent column chromatography of the residue on silica gel with elution with a mixture 1/9 - EtOAc/heptane gave specified in the title compound, which was recrystallized from a mixture of toluene/heptane (1/5), getting mentioned in the title compound as colourless cubes (of 7.65 g, 37%). As a result chromatography was isolated 5-bromo-2-(4-methoxybenzyl)-2H-indazol (8.0 g, 38%).

Example 13

(S)-tert-Butyl-3-(1-(4-methoxybenzyl)-1H-indazol-5-ylamino)piperidine-1-carboxylate

To a solution of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (870 mg, of 2.75 mmol) in toluene (10 ml) was added sequentially (S)-tert-butyl-3-aminopiperidin-1-carboxylate (660 mg, 3.3 mmol), tert-piperonyl sodium (475 mg, 5 mmol) and rat-(±)-BINAP (180 mg, 0.29 mmol). The flask was pumped under vacuum and filled with nitrogen three times, then was added Pd2dba3(83 mg, and 1.5 mol.%). The flask was again purged with nitrogen three times and then heated at 80°C during the night. The solution was cooled to room temperature and then filtered through a layer of celite, washing out dopolnitelnaya. Toluene solution is then directly loaded on a column of silica gel, which was filled with heptane. The column was washed with heptane 2 column volumes, and then suirable a mixture of 40/60 - EtOAc/heptane, getting mentioned in the title compound (1,00 g, 82%).

Example 14

(S)-N-(piperidine-3-yl)-1H-indazol-5-amine

A solution of (S)-tert-butyl 3-(1-(4-methoxybenzyl)-1H-indazol-5-ylamino)piperidine-1-carboxylate (240 mg, 0.55 mmol) in TFOC (2 ml) was stirred at room temperature for 15 minutes, after which the solvent was evaporated. Chromatography of the residue on silica gel with elution initially with dichloromethane and then a mixture of dichloromethane:MeOΗ:NH4OH in the ratio of 90:9:1 gave the substance, which was the removal of the BOC-protective group.

Thus obtained residue was then dissolved again in TFOC (2 ml) together with 1,3-dimethoxybenzene (151 mg, 1.1 mmol) and was heated at the boil under reflux overnight. TFUK was removed by evaporation and the residue was again chromatographically, as described above, receiving specified in the title compound (90 mg, 75% for 2 stages).

Example 15

(R)-N-(piperidine-3-yl)-1H-indazol-5-amine

The interaction of 5-bromo-1-(4-methoxybenzyl)-1H-indazole and (R)-tert-butyl-3-aminopiperidin-1-carboxylate using the method of PR is a measure of 13 followed by removal of the protective group using the method of example 14 was led to headline the connection.

Example 16

(R)-tert-Butyl 3-(isoquinoline-5-ylamino)pyrrolidin-1-carboxylate

In a round bottom flask with a capacity of 50 ml was added 5-bromoisoquinoline (1.12 g, 5.4 mmol), toluene (10 ml), (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1,00 g, 5.4 mmol), palladium acetate (0.18 g, 0.8 mmol), RAC-(±)-BINAP (0,500 g, 0.8 mmol) and cesium carbonate (2,80 g, 8.6 mmol). The flask was pumped under vacuum, filled with nitrogen and stirred at 80°C for 12 hours. The mixture was diluted with ethyl acetate (20 ml), washed with water (10 ml) and the organic phase was dried over MgSO4, was filtered and was evaporated, getting mentioned in the title compound (1,00 g, 59%). This substance was of sufficient quality for use without additional purification.

Example 17

1

(R)-N-(Pyrrolidin-3-yl)isoquinoline-5-amine

The removal of the protective group in the (R)-tert-butyl-3-(isoquinoline-5-ylamino)pyrrolidin-1-carboxylate according to the method of example 4 gave specified in the header of the connection.

Example 18

(S)-N-(Pyrrolidin-3-yl)isoquinoline-5-amine

The interaction of (S)-tert-butyl-3-aminopyrrolidine-1-carboxylate and 5-bromoisoquinoline using the method of example 16, followed by removal of protective groups in accordance with the method of example 4 resulted specified in the header of the connection.

Example 19

(S)-N-(1-(4-(Methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.075

The interaction of (S)-N-(piperidine-3-yl)-1H-indazol-5-amine and 4-(methylthio)benzaldehyde using the method of example 8 and THF as solvent for the reaction led to headline the connection.

Example 20

(R)-N-(1-(4-(Methylthio)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.026

The interaction of (R)-N-(pyrrolidin-3-yl)isoquinoline-5-amine and 4-(methylthio)benzaldehyde using the method of example 8 was led to headline the connection.

Example 21

N-(1-Benzylation-4-yl)-1H-indazol-5-amine, compound 1.031

Specified in the title compound was obtained by interaction of 2,2-dimethyl-1-(5-(piperidine-3-ylamino)-1H-indazol-1-yl)propan-1-one with tert-butyl-4-oxazepan-1-carboxylate using the method of example 3, the removal of the protective groups using the method of example 4, the interaction with benzaldehyde in accordance with the method of example 8, and the final removal of the protective groups using the method of example 9.

1H NMR (CDCl3, 300 MHz): δ 7,88 (s, 1H), was 7.36-7,26 (m, 6H), to 6.80 (m, 2H, in), 3.75 (m, 1H), to 3.67 (s, 2H), 2,80-to 2.57 (m, 4H), 2.05 is-of 1.27 (m, 8H).

Examples 22-81

The interaction of 2,2-dimethyl-1-(5-(piperidine-3-Ilam is but)-1H-indazol-1-yl)propane-1-it with the appropriate aldehydes using the method of example 8 with the subsequent removal of the protective group using the method of example 9 were obtained compounds of examples 22-81.

Example 22

N-(1-(4-(Methylsulphonyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.001

1H NMR (DMSO-d6300 MHz): δ 12,53 (users, 1H), 7,86 (s, 1H), 7,34 (m, 4H), 7,22 (d, J=9.0 Hz, 1H), 6,78 (DD, J=1,8, 9.0 Hz, 1H), 6,60 (s, 1H), of 5.05 (s, J=8,4 Hz, 1H), 3,47 (users, 2H), 3,30 (m, 4H), 2,90 (d, J=9,3 Hz, 1H), 2,60 m, 1H), 2,03 (m, 1H), of 1.85 (m, 2H), 1,65 (m, 1H), 1.55V (m, 1H), 1,22 (m, 1H).

Example 23

3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)benzonitrile, the connection 1.002

1H NMR (CDCl3, 300 MHz): δ 7,88 (s, 1H), 7,65 (s, 1H), 7,53 (m, 2H), 7,39 (t, J=7.5 Hz, 1H), 7,31 (m, 1H), PC 6.82 (m, 2H), 3,61 (users, 1H), 3,51 (m, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), 1.77 in (m, 2H), 1.57 in (m, 2H).

Example 24

N-(4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)ndimethylacetamide, the connection 1.003

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), a 7.85 (s, 1H), 7,42 (m, 2H), 7,30-7,26 (m, 3H), was 7.08 (s, 1H), PC 6.82 (m, 2H), 3,60 (users, 1H), of 3.45 (m, 2H), 2,74 (m, 1H), 2,45 to 2.35 (m, 3H), of 2.18 (s, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 25

N-(1-(Biphenyl-4-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.009

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), to 7.59 (m, 4H), 7,43-7,29 (m, 6H), at 6.84 (m, 2H), 3,62 (users, 1H), of 3.56 (DD, J=10,2, or 21.0 Hz, 2H), 2,80 (m, 1H), 2,45-of 2.30 (m, 3H), of 1.75 (m, 2H), 1.55V (m, 3H).

Example 26

N-(1-(1H-Imidazol-1-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.010

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,83 (s, 1H), 7,42 (m, 2H), 7,29 (m, 5H), PC 6.82 (m, 2H), 3,63 (users, 1H), of 3.56 (DD, J=13,5, 27,3 Hz, 2H), 2,78 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 2H).

Example 27

N-(1-(4-(Pyrrol the DIN-1-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, connection 1.011

1H NMR (CDCl3, 300 MHz): δ 10,15 (users, 1), 7,86 (s, 1H), 7,27 (m, 1H), 7,16 (d, J=8,4 Hz, 2H), PC 6.82 (m, 2H), of 6.52 (d, J=8,4 Hz, 2H), 3,64 (users, 1H), 3,53 (users, 2H), 3,23 (m, 5H), 2,83 (users, 1H), 2,42-of 2.30 (m, 3H), 2,00 (m, 4H), a 1.75 (m, 2H), 1,58 (m, 2H).

Example 28

N-(1-(4-Morpholinomethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.012

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,27 (m, 3H), at 6.84 (m, 4H), a 3.87 (m, 4H), 3,60 (users, 1H), 3,47 (m, 2H), 3,13 (m, 4H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 2H).

Example 29

N-(1-(4-Isobutylphenyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.013

1H NMR (CDCl3, 300 MHz): δ 9,95 (users, 1H), 7,86 (s, 1H), 7,27 (m, 3H), was 7.08 (d, J=7.8 Hz, 2H), PC 6.82 (m, 2H), 3,95 (users, 1H), 3,60 (users, 1H), 3,50 (m, 2H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 5H), to 1.86 (m, 1H), about 1.75 (m, 2H), 1,58 (m, 3H), 0,89 (d, J=6.6 Hz, 6H).

Example 30

N-(1-(4-Butylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.014

1H NMR (CDCl3, 300 MHz): δ 9,85 (users, 1H), 7,86 (s, 1H), 7,27 (m, 1H), 7,22 (d, J=8.1 Hz, 2H), 7,12 (d, J=8.1 Hz, 2H), PC 6.82 (m, 2H), 3,60 (users, 1H), 3,49 (m, 2H), was 2.76 (d, J=9.6 Hz, 1H), has 2.56 (t, J=7.8 Hz, 2H), 2,42-2,30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 4H), of 1.30 (sextet, J=7.8 Hz, 2H), to 0.92 (t, J=7.8 Hz, 3H).

Example 31

N-(1-(4-Isopropoxyphenyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.015

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,86 (s, 1H), 7,25 (m, 3H), 6,83 (m, 4H), to 4.52 (p, J=6 Hz, 2H), 3,60 (users, 1H), 3.45 points (users, 2H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 3H), at 1.73 (m, 2H), 1.57 in (m, 2H), 1,32 (d, J= 6 Hz, 6H).

Example 32

N-(1-(2,3-Dimethylbenzyl)piperidin the-3-yl)-1H-indazol-5-amine, connection 1.016

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,28 (m, 1H), 7,05 (m, 3H), PC 6.82 (m, 2H), 3,60 (users, 1H), of 3.45 (m, 2H), 2,70 (m, 1H), 2,42 (m, 2H), 2,30 (s, 6H), of 1.75 (m, 2H), 1,58 (m, 3H).

Example 33

N-(1-(4-(Ethylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.017

1H NMR (CDCl3, 300 MHz): δ 10,15 (users, 1H), 7,87 (s, 1H), 7,25 (m, 5H), PC 6.82 (m, 2H), 3,95 (users, 2H), 3,60 (users, 1H), 3,49 (DD, J=13,5, 20.7 Hz, 2H), 2.91 in (kV, J=7.2 Hz, 2H), was 2.76 (d, J=9.6 Hz, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H,), was 1.58 (m, 2H), of 1.30 (t, J=7.2 Hz, 3H).

Example 34

2-(4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 1.018

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,21 (m, 3H), 6,79 (m, 4H), of 4.05 (m, 2H), 3,95 (m, 2H), 3,59 (users, 1H), 3,50 (DD, J=11,7, 24.3 Hz, 2H), 2,74 (d, J=8.7 Hz, 1H), 2,42-of 2.30 (m, 3H), 1.77 in (m, 2H), 1,58 (m, 2H).

Example 35

N-(1-(4-((Dimethylamino)methyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.019

1H NMR (CDCl3, 300 MHz): δ 10.30 a.m. (users, 1H), a 7.85 (s, 1H), 7,30-7,20 (m, 5H), to 6.80 (m, 2H), 3,95 (users, 1H), 3,59 (users, 1H), 3,49 (DD, J=13,2, 18.6 Hz, 2H), 3,42 (s, 2H), 2,74 (d, J=8.7 Hz, 1H), 2,42-of 2.30 (m, 3H), 2,24 (s, 6H), 1,76 (m, 2H), 1,58 (m, 2H).

Example 36

N-(1-(4-Cyclopropylmethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.020

1H NMR (CDCl3, 300 MHz): δ 9,85 (users, 1H), 7,87 (s, 1H), 7,30-7,20 (m, 3H), 7,03 (m, 2H), 6,83 (m, 2H), 4.0 (with users, 1H), 3,60 (users, 1H), 3,53 (DD, J=13,2, to 18.9 Hz, 2H), 2,74 (d, J=8.7 Hz, 1H), 2,42-of 2.30 (m, 3H), of 1.87 (m, 1H), 1,76 (m, 2H), 1,58 (m, 2H), and 0.98 (m, 2H), 0,72 (m, 1H).

Example 37

N-(1-(3-Cyclopropylmethyl)piperidine--yl)-1H-indazol-5-amine, connection 1.021

1H NMR (CDCl3, 300 MHz): δ 9,85 (users, 1H), 7,87 (s, 1H), 7,32 (m, 1H), 7,21 (m, 1H), 7,18 (m, 1H), 7,10 (m, 1H), 6,97 (m, 1H), 6,83 (m, 2H), 4.0 (with users, 1H), 3,62 (users, 1H), 3,49 (m, 2H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 3H), 1,89 (m, 1H), 1,76 (m, 2H), 1,58 (m, 2H), and 0.98 (m, 2H), 0,72 (m, 1H).

Example 38

N-(1-(4-(Triptoreline)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.022

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), 7,86 (s, 1H), 7,35 (d, J=8,4 Hz, 2H), 7,27 (m, 1H), 7,15 (d, J=8.1 Hz, 2H), 6,83 (m, 2H), 3,62 (users, 1H), 3,51 (m, 2H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H,).

Example 39

N-(1-(4-Isopropylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.023

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,27 (m, 5H), PC 6.82 (m, 2H), 3,60 (users, 1H), 3,50 (m, 2H), 2,90 (m, 1H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 3H)and 1.15 (m, 6H).

Example 40

N-(1-(2,4-Dimethylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.024

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,27 (d, J=9.0 Hz, 1H), 7,13 (d, J=7.8 Hz, 1H), 6,94 (m, 2H), to 6.80 (m, 2H), 3,60 (users, 1H), 3.43 points (m, 2H), 2,70 (m, 1H), 2,48-of 2.30 (m, 3H), is 2.37 (s, 3H), to 2.29 (s, 3H), by 1.68 (m, 2H,), and 1.56 (m, 2H).

Example 41

(4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanol, the connection 1.025

1H NMR (CDCl3, 300 MHz): δ 10,2 (users, 1H), 7,86 (s, 1H), 7,37 (DD, J=1.5 and 7.5 Hz, 1H), 7,25 (m, 2H), 6,93 (t, J=7.5 Hz, 1H), 6,83 (m, 3H), of 3.80 (s, 3H), 3,60 (users, 3H), 2,85 (m, 1H), 2,48-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 2H).

Example 42

N-(1-(4-(Cyclopropylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.026

1H NMR (CDCl3, 300 MHz): δ 7,89 (s, 1H), and 7.3-of 7.23 (m, 5H), 6,83 (m, 2H), 3,62 (m, 1H), 3,51 (DD, J=13,5, to 21.6 Hz, 2H), 2,77 (d, J=8,1 Hz, 1H), 2,45-of 2.30 (m, 3H), 2,12 (m, 1H), about 1.75 (m, 2H), and 1.56 (m, 3H), of 1.05 (m, 2H), 0.70 to (m, 2H).

Example 43

tert-Butyl 4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzylcarbamoyl, the connection 1.027

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), and 7.3-7,20 (m, 5H), to 6.80 (m, 2H), 4,85 (users, 1H), 4,28 (d, J=4.5 Hz, 2H), 3.75 to of 3.53 (m, 4H), 2,80 (m, 1H), 2,45-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H), of 1.46 (s, 9H).

Example 44

N-(1-(4-(Methylthiomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.028

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), and 7.3-of 7.23 (m, 5H), PC 6.82 (m, 2H), the 3.65 (s, 2H), 3,62 (m, 1H), 3,53 (m, 2H), 2,80 (m, 1H), 2,45-of 2.30 (m, 3H), of 1.97 (s, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 45

N-(1-(4-(Methylsulfonylmethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.029

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,39-7,26 (m, 5H), PC 6.82 (m, 2H), is 4.21 (s, 2H), 3,61 (users, 1H), 3,54 (DD, J=10,2, of 19.5 Hz, 2H), 2,74 (m, 1H), 2,69 (s, 3H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 46

N-(1-(4-(Thiophene-2-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.030

Example 47

N-(1-(4-(Dimethylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.032

1H NMR (CDCl3, 300 MHz): δ 7,88 (s, 1H), 7.23 percent (m, 3H), PC 6.82 (m, 2H), 6,69 (d, J=8,4 Hz, 2H), 3,60 (users, 1H), 3,47 (m, 2H), with 2.93 (s, 6H), 2,80 (m, 1H), 2,45-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 48

N-(1-(4-active compounds)piperidine-3-yl)-1H-indazol-5-amine, compound 1.033

1 H NMR (CDCl3, 300 MHz): δ 10.30 a.m. (users, 1H), 7,87 (s, 1H), 7,25 (m, 3H), 7,16 (m, 2H), PC 6.82 (m, 2H), 4.00 points (users, 1H), 3,60 (users, 1H), 3,51 (m, 2H), 2,75 (m, 1H), 2.63 in (kV, J=7.5 Hz, 2H), 2,50 to 2.35 (m, 3H), of 1.75 (m, 2H), 1.55V (m, 2H), 1,23 (t, J=7.5 Hz, 3H).

Example 49

N-(1-(4-Ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.034

Obtained by removing the protective group from the compound 1.027 using the method of example 4.

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,43 (d, J=8,4 Hz, 2H), 7,26 (m, 3H), at 6.84 (m, 2H), 3,60 (users, 1H), 3,49 (DD, J=5,4, and 9.1 Hz, 2H), 3,05 (s, 1H), 2,74 (m, 1H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 50

N-(1-(4-(Aminomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.035

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,39-7,26 (m, 7H), PC 6.82 (m, 2H)and 4.65 (s, 2H), is 4.21 (s, 2H), 3,61-3,4 (m, 5H), is 2.74 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 51

1-(4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)Etalon, the connection 1.036

1H NMR (CDCl3, 300 MHz): δ 7,89 (m, 3H), 7,42 (d, J=7.8 Hz, 2H), 7,33 (m, 1H), 6,84 (m, 2H), 3,60 (users, 1H), only 3.57 (DD, J=13,5, 24,9 Hz, 2H), 2,74 (m, 1H), 2,59 (s, 3H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 52

N-(1-(4-Vinylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.037

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,32 (d, J=9.0 Hz, 2H), 7,29 (m, 3H), at 6.84 (m, 2H), 6,70 (DD, J=10,8, and 17.7 Hz, 1H), 5,73 (d, J=17.7 and Hz, 1H), 5,22 (d, J=10,8 Hz, 1H), 3,60 (users, 1H), 3,54 (m, 2H), 2,74 (m, 1H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 53

4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)Ben is ontril, connection 1.038

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,68 (d, J=8,4 Hz, 2H), 7,38 (d, J=8.1 Hz, 2H), 7,29 (d, J=8.7 Hz, 1H), 6,84 (m, 2H), 3,92 (s, 2H), 3,60 (users, 1H), 3,54 (DD, J=13,2, to 21.6 Hz, 2H), 2,74 (m, 1H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 54

2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 1.039

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,31 to 7.2 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4.09 to (m, 2H), 3.96 points (m, 2H), 3,61 (m, 1H), 3,50 (m, 2H), 2,80 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 3H).

Example 55

N-(1-(3-(Methylsulfonylmethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.041

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,41 (s, 1H), was 7.36-7,26 (m, 4H), 6,83 (DD, J=2.1 a, 9,3 Hz, 1H), 6,79 (d, J=1.5 Hz, 1H), 4,20 (s, 2H), 3,63 (m, 1H), 3,55 (DD, J=13,5, 34,2 Hz, 2H), 2,70 (m, 1H), to 2.67 (s, 3H), 2,41 (users, 2H), 2,29 (users, 1H), about 1.75 (m, 2H), 1,59 (m, 3H).

Example 56

3-(4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)prop-2-in-1-ol, compound 1.042

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,32 (d, J=8,4 Hz, 2H), 7.23 percent (m, 3H), to 6.80 (m, 2H), 4,49 (s, 2H), 3,57 (users, 1H), 3,48 (DD, J=13,2, and 19.8 Hz, 2H), 2,69 (d, J=9.0 Hz, 1H), 2,42 (users, 2H), and 2.27 (users, 1H), about 1.75 (m, 2H), of 1.56 (m, 3H).

Example 57

4-(4-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)but-3-in-1-ol, compound 1.043

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,32 (d, J=8.1 Hz, 2H), 7.23 percent (m, 3H), to 6.80 (m, 2H), 3,82 (t, J=6.0 Hz, 2H), 3,55 (users, 1H), 3,47 (DD, J=13,2, of 19.5 Hz, 2H), to 2.67 (t, J=6.0 Hz, 1H), 2,66 (m, 1H), 2,41 (users, 2H), 2.26 and (users, 1H), about 1.75 (m, 2H), and 1.56 (m, 3H).

Example 58

N-(1(4-(Cyclopropylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine, connection 1.044

1H NMR (CDCl3, 300 MHz): δ 7,87 (s, 1H), 7,33-to 7.15 (m, 5H), 6,83 (m, 2H), to 3.58 (users, 1H), 3,48 (DD, J=13,5, of 19.5 Hz, 2H), 2,75 (d, J=9,3 Hz, 1H), 2,35 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 3H), of 1.44 (m, 1H), 0,93-0,76 (m, 4H).

Example 59

N-(1-(3-Bromobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.045

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,87 (s, 1H), 7,52 (s, 1H), 7,38-7,14 (m, 4H), 6,83 (m, 2H), 3,90 (users, 1H)and 3.59 (m, 1H), 3,47 (DD, J=13,5, 15.3 Hz, 2H), was 2.76 (d, J=9.9 Hz, 1H), 2,41 (users, 2H), 2,29 (users, 1H), 1,75 m, 2H), 1,59 (m, 3H).

Example 60

3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenol, compound 1.046

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,26 (d, J=9,3 Hz, 1H), 7,15 (t, J=7.8 Hz, 1H), 6,83 (m, 4H), of 6.71 (DD, J=1.5 and 7.5 Hz, 1H)and 3.59 (m, 1H), 3,47 (DD, J=12,9, 20,1 Hz, 2H), was 2.76 (d, J=9,3 Hz, 1H), 2,42 (users, 2H), 2,36 (users, 1H), about 1.75 (m, 2H), 1,59 (m, 3H).

Example 61

N-(1-(3-Ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.047

1H NMR (CDCl3, 300 MHz): δ 7,87 (s, 1H), of 7.48 (s, 1H), 7,37 (d, J=7.2 Hz, 1H), 7,33-7,24 (m, 3H), PC 6.82 (m, 2H), 3,60 (m, 1H), 3,48 (m, 2H), is 3.08 (s, 1H), was 2.76 (d, J=10.5 Hz, 1H), 2.40 a (users, 2H), 2,30 (users, 1H), about 1.75 (m, 2H,), to 1.59 (m, 3H).

Example 62

N-(1-(3-(Methylsulphonyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.048

1H NMR (CDCl3, 300 MHz): δ of 7.95 (s, 1H), 7,87 (s, 1H), 7,80 (d, J=7.5 Hz, 1H), 7.62mm (d, J=7.5 Hz, 1H), 7,50 (t, J=7.8 Hz, 1H), 7,28 (d, J=9.0 Hz, 1H), 6,83 (m, 2H), 3,60 (m, 1H), of 3.56 (DD, J=13,2, to 21.6 Hz, 2H), to 3.02 (s, 3H), was 2.76 (d, J=10,2 Hz, 1H), 2,45 (users, 2H), 2,32 (users, 1H), 1.77 in (m, 2H), 1.61 of (m, 3H).

Example 63

N-(3-((3-(indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide, connection 1.051

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,32-7,25 (m, 2H), to 7.09 (m, 2H), 6.87 in (DD, J=2,1, 9.0 Hz, 1H), 6,79 (s, 1H), 3,61 (m, 1H), 3,53 (DD, J=10,8, 35,1 Hz, 2H), 2.91 in (s, 3H), 2,61 (m, 1H), 2,45 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 3H).

Example 64

N-(1-(Benzofuran-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.052

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), to 7.84 (s, 1H), 7,56 (d, J=21,0 Hz, 1H), 7,44 (d, J=8,4 Hz, 1H), 7,29 (m, 4H), for 6.81 (m, 3H), of 3.60 (m, 3H), 2,80 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 3H).

Example 65

N-(1-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.053

1H NMR (CDCl3, 300 MHz): δ 9,75 (users, 1H), 7,86 (s, 1H), 7,29 (m, 1H), for 6.81 (m, 5H), 4,25 (s, 4H), 3,60 (users, 1H), 3,40 (m, 2H), 2,74 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 3H).

Example 66

N-(1-(Benzo[b]thiophene-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.054

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,80 (m, 1H), 7,44-7,26 (m, 5H), PC 6.82 (m, 2H), 3,60 (m, 3H), was 2.76 (m, 1H), 2,42-of 2.30 (m, 3H), of 1.75 (m, 2H), 1,58 (m, 3H).

Example 67

3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)benzamide, the connection 1.055

1H NMR (CDCl3, 300 MHz): δ a 7.85 (d, J=6.0 Hz, 2H), 7,65 (d, J=7.8 Hz, 1H), 7,49 (d, J=7.8 Hz, 1H), 7,38 (t, J=7.5 Hz, 1H), 7,27 (m, 1H), 6,83 (m, 2H), 6,15 (users, 1H), 5,80 (users, 1H), 3,60 (m, 1H), of 3.56 (DD, J=13,5, 23,1 Hz, 2H), a 2.75 (m, 1H), 2,45 was 2.25 (m, 3H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 68

3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)benzosulfimide, the connection 1.056

1H NMR (CDCl3, 300 MHz): δ to 7.84(m, 2H), the 7.65 (d, J=7.8 Hz, 1H), 7,49 (d, J=7.8 Hz, 1H), 7,38 (t, J=7.5 Hz, 1H), 7,27 (m, 1H), 6,83 (m, 2H), 6,10 (users, 1H), 5,7 (users, 1H), 3,60 (m, 1H), of 3.56 (DD, J=13,5, 23,1 Hz, 2H), 2,75 (m, 1H), 2,45 was 2.25 (m, 3H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 69

tert-Butyl 3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzylcarbamoyl, the connection 1.057

1H NMR (CDCl3, 300 MHz): δ 9,85 (users, 1H), 7,86 (s, 1H), 7,39-7,26 (m, 7H), PC 6.82 (m, 2H), 4,80 (users, 1H), 4,30 (d, J=5.4 Hz, 2H), 3,95 (users, 1H), 3,68-3,4 (m, 3H), 2,74 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H), of 1.46 (s, 9H).

Example 70

2-(5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-2-methylphenoxy)ethanol, compound 1.058

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,28 (d, J=8.7 Hz, 1H), 7,07 (d, J=7.5 Hz, 1H), 6,83 (m, 4H), of 4.13 (m, 2H), 4.00 points (m, 3H), of 3.60 (m, 1H), 3,47 (DD, J=14,1, 27,3 Hz, 2H), 2,70 (m, 1H), 2,45 was 2.25 (m, 3H), 2,22 (s, 3H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 71

5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-2-METHYLPHENOL, the connection 1.059

1H NMR (CD3OD, 300 MHz): δ for 7.78 (s, 1H), 7,31 (d, J=9.0 Hz, 1H), 6,97 (d, J=7.5 Hz, 1H), 6.90 to (DD, J=2,1, 9.0 Hz, 1H), 6,85 (s, 1H), 6,74 (d, J=1.2 Hz, 1H), 6,66 (DD, J=1,2, 7.5 Hz, 1H), 3,48 (m, 1H), 3,44 (m, 2H), 3.00 and (m, 1H), 2,70 (m, 1H), and 2.14 (s, 3H), 2.13 in (m, 1H), of 1.97 (m, 2H), 1,80-to 1.60 (m, 2H), 1,3 (m, 1H).

Example 72

Ethyl-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetate, a compound 1.060

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), a 7.85 (s, 1H), 7,35-7,26 (m, 2H), 6,95-PC 6.82 (m, 5H), 4,60 (s, 2H), 4,25 (m, 2H), 3,60 (users, 1H), of 3.45 (m, 2H), 2,74 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H), 1,25 (m, 3H).

Example 73

N-(1-(3-(S is said; " the)benzyl)piperidine-3-yl)-1H-indazol-5-amine, connection 1.061

Obtained by removing the protective groups from the compound 1.057 using the method of example 4.

1H NMR (CD3OD, 300 MHz): δ 7,79 (s, 1H), 7,68 (d, J=8.7 Hz, 1H), was 7.36 (d, J=9.0 Hz, 1H), to 7.09 (m, 2H), 6,95 (m, 2H), of 4.05 (m, 3H), 3,95 (m, 2H), 3,80 (m, 1H), 3,70 (m, 3H), 3,50 (m, 1H), 3,05 (m, 1H), 2,43 and 2.13 (m, 3H), 1,80-1,3 (m, 3H).

Example 74

N-(1-(3-(Trifluoromethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound blade 1.063

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,86 (s, 1H), a 7.85 (m, 2H), 7,53 (d, J=8,4 Hz, 2H), 7,30 (d, J=8,4 Hz, 1H), 6,84 (m, 2H), 3,60 (m, 3H), was 2.76 (d, J=10,8 Hz, 1H), 2,43 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 3H).

Example 75

N-(1-(3-Ethoxybenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.065

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), 7,86 (s, 1H), 7,30-to 7.18 (m, 2H), 6.90 to-6,76 (m, 5H), is 4.03 (q, J=6.9 Hz, 2H), 3,60 (m, 1H), 3,44 (DD, J=13,2, and 17.1 Hz, 2H), was 2.76 (d, J=10,8 Hz, 1H), 2,43 (m, 3H), of 2.35 (s, 3H), of 1.75 (m, 2H), 1,59 (m, 3H), of 1.42 (t, J=6.9 Hz, 3H).

Example 76

N-(1-(3-Methylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.066

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,30-7,05 (m, 5H), 6,83 (m, 2H), 3,62 (m, 1H), 3.43 points (m, 2H), 2,80 (m, 1H), 2,43 (m, 2H), 2,35 (s, 3H), of 1.75 (m, 2H), 1,59 (m, 3H).

Example 77

N-(1-(2-Methoxybenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.067

1H NMR (CDCl3, 300 MHz): δ of 10.25 (users, 1H), 7,86 (s, 1H), 7,37 (DD, J=1.5 and 7.5 Hz, 1H), 7,24 (m, 2H), 6,93 (t, J=7.5 Hz, 1H), to 6.80 (m, 3H), of 3.80 (s, 3H), 3,60 (users, 3H), 2,85 (m, 2H), 2,50 to 2.35 (m, 3H), of 1.75 (m, 2H), 1.55V (m, 2H).

Example 78

5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)shall ethyl)-2-itfinal, connection 1.068

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,63 (d, J=8,4 Hz, 1H), 7,26 (m, 2H), 6,93-to 6.80 (m, 3H), 6,50 (m, 1H), 3,62 (m, 1H), 3.43 points (m, 2H), 2,60 (m, 3H), 2,4 (m, 1H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 79

N-(1-(3-(4-Chlorophenoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.069

1H NMR (CDCl3, 300 MHz): δ 9,8 (users, 1H), 7,86 (s, 1H), and 7.3-of 7.24 (m, 5H), was 7.08 (d, J=7.5 Hz, 1H), 7,01 (s, 1H), 6,93 (DD, J=2,1, 6,6 Hz, 1H), 6.87 in (DD, J=2,1, 6,6 Hz, 1H), PC 6.82 (m, 2H), 3,6 (m, 1H), 3,48 (DD, J=13,5, to 18.9 Hz, 2H), 2,70 (m, 1H), 2,41-of 2.30 (m, 3H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 80

N-(1-(3-(3-(Trifluoromethyl)phenoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.070

1H NMR (CDCl3, 300 MHz): δ 9,8 (users, 1H), 7,86 (s, 1H), and 7.4 to 7.2 (m, 5H), was 7.08 (m, 2H), 7,01 (s, 1H), 6,93 (m, 1H), PC 6.82 (m, 2H), 3,6 (m, 1H), 3,48 (m, 2H), 2,75 (m, 1H), 2,41-of 2.30 (m, 3H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 81

N-(1-(2,5-Dibromobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.071

1H NMR (CDCl3, 300 MHz): δ 9,8 (users, 1H), 7,86 (s, 1H), 7.62mm (m, 1H), and 7.4 (m, 1H), 7,2-7,05 (m, 2H), PC 6.82 (m, 2H), 3,65 (m, 1H), 3,48 (m, 2H), 2,80 (m, 1H), 2,5-of 2.30 (m, 3H), 1,71 (m, 2H), and 1.56 (m, 3H).

Example 82

N-(1-Benzylpiperidine-3-yl)-3-methyl-1H-indazol-5-amine, compound 1.049

Specified in the title compound was obtained by interaction of 1-(5-amino-3-methyl-1H-indazol-1-yl)-2,2-DIMETHYLPROPANE-1-one with tert-butyl-3-oxopiperidine-1-carboxylate using the method of example 3, the removal of the protective group of the carboxylate using im is and example 4, interaction with benzaldehyde in accordance with the method of example 8, and the final removal of the protective group using the method of example 9.

1H NMR (CDCl3, 300 MHz): δ 7,4-to 7.18 (m, 6H), to 6.80 (m, 2H), 6,70 (s, 1H), 3,6 (m, 1H), 3.45 points (s, 2H), 2,74 (m, 1H), 2,50 (s, 3H), 2.40 a (m, 2H), 2,30 (m, 1H), about 1.75 (m, 2H), and 1.56 (m, 2H).

Example 83

N5-(1-Benzylpiperidine-3-yl)-1H-indazole-3,5-diamine, compound 1.050

Interaction tert-butyl-3,5-diamino-1H-indazol-1-carboxylate with 1-benzylpiperidine-3-one using the method of example 8 with the modification consists in the fact that cyanoborohydride sodium was used as reductant and methanol was used as solvent, followed by removal of the protective group using the method of example 4 has been specified in the header of the connection.

1H NMR (CDCl3, 300 MHz): δ of 9.55 (users, 1H), and 7.3 (m, 5H), 7,10 (m, 1H), 6,80 (m, 1H), 6,60 (s, 1H), 3,90 (s, 2H), 3,6-3,4 (m, 3H), 2,80 (m, 1H), 2,47 (m, 3H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Examples 84-89

The interaction of 2,2-dimethyl-1-(5-(pyrrolidin-3-ylamino)-1H-indazol-1-yl)propane-1-it with the appropriate aldehydes using the method of example 8 with the subsequent removal of the protective group using the method of example 9 was obtained compounds specified in the examples 84-89.

Example 84

N-(1-(4-(Methylsulphonyl)benzyl)pyrrolidin-3-yl)-1H-indazol-5-am is h, connection 1.004

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,88 (m, 3H), 7,55 (d, J=8.1 Hz, 2H), 7,31 (d, J=8.7 Hz, 1H), PC 6.82 (DD, J=2.1 a, 8,7 Hz, 1H), 6.75 in (d, J=2.1 Hz, 1H), of 4.05 (m, 1H), and 3.72 (m, 2H), 3,05 (s, 3H), 2,78 (m, 2H), 2,60 (DD, J=3.3V, 9.6 Hz, 1H), 2,45 to 2.35 (m, 2H), of 1.75 (m, 1H).

Example 85

3-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-yl)methyl)benzonitrile, the connection 1.005

1H NMR (CDCl3, 300 MHz): δ 10,7 (users, 1H), and 7.9 (s, 1H), 7,65 (s, 1H), 7,55 (m, 2H), 7,40 (m, 2H), 7,28 (m, 1H), 6,84 (m, 2H), 4,05 (users, 1), the 3.65 (s, 2H), 2,8 (m, 2H), 2,65 (m, 1H), 2,45 was 2.25 (m, 2H), of 1.75 (m, 2H).

Example 86

N-(4-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)ndimethylacetamide, the connection 1.006

1H NMR (CDCl3, 300 MHz): δ 7,88 (s, 1H), 7,43 (d, J=8,4 Hz, 2H), 7,24 (m, 3H), 7,18 (users, 1H), 6,77 (m, 2H), 4,01 (m, 1H), 3,60 (m, 2H), 2,78 (m, 2H), 2,60 (DD, J=3.3V, 9.6 Hz, 1H), 2,45 to 2.35 (m, 2H), 2,16 (s, 6H), of 1.75 (m, 1H).

Example 87

N-(1-(4-(3-(Dimethylamino)propoxy)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine, compound 1.007

1H NMR (CDCl3, 300 MHz): δ 10,45 (users, 1H), 7,88 (s, 1H), 7.23 percent (m, 3H), 6,85-of 6.73 (m, 4H), to 3.99 (t, J=6.3 Hz, 3H), of 3.57 (m, 2H), 2,78 (m, 2H), 2,60 (m, 1H), 2,45 (t, J=7.5 Hz, 4H), and 2.26 (s, 6H), of 1.95 (m, 2H), of 1.75 (m, 1H).

Example 88

N-(1-(3,4-Dichlorobenzyl)pyrrolidin-3-yl)-1H-indazol-5-amine, compound 1.062

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,86 (s, 1H), 7,40-7,20 (m, 3H), at 6.84 (m, 3H), 4,05 (users, 1), of 3.60 (s, 2H), 2,8 (m, 2H), 2,60 (m, 1H), 2,45 was 2.25 (m, 2H), of 1.75 (m, 2H).

Example 89

N-(1-(3-(Trifluoromethyl)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine, compound 1.064

Primary-92

The interaction of (R)-N-(piperidine-3-yl)-1H-indazol-5-amine with the appropriate aldehydes using the method of example 8 and using THF as the reaction solvent was obtained compounds described in the examples 90-92.

Example 90

(R)-N-(1-(3,4-Diferensial)piperidine-3-yl)-1H-indazol-5-amine, compound 1.073

1H NMR (CDCl3, 300 MHz): δ 7,87 (s, 1H), 7,29 (d, J=9,3 Hz, 1H), 7.23 percent? 7.04 baby mortality (m, 3H), 6,83 (m, 2H), 3,63 (m, 1H), 3,49 (m, 2H), 2,75 (m, 1H), 2,45 was 2.25 (m, 3H), 1,80 of 1.50 (m, 5H).

Example 91

(R)-N-(1-(4-(Methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.074

1H NMR (CDCl3, 300 MHz): δ 9,8 (users, 1H), 7,86 (s, 1H), 7.3 to to 7.18 (m, 5H), PC 6.82 (m, 2H), 3,6-3,4 (m, 3H), 2,74 (m, 1H), 2,47 (s, 3H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 92

(R)-N-(1-(4-Ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.076

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,43 (d, J=8,4 Hz, 2H), 7,26 (m, 3H), at 6.84 (m, 2H), 3,60 (users, 1H), 3,49 (DD, J=5,4, and 9.1 Hz, 2H), 3,05 (s, 1H), 2,74 (m, 1H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Examples 93-98

The interaction of (S)-N-(piperidine-3-yl)-1H-indazol-5-amine with the appropriate aldehydes using the method of example 8 and using THF as the reaction solvent was obtained compounds described in the examples 93-98.

Example 93

(S)-N-(1-(3,4-Diferensial)piperidine-3-yl)-1H-indazol-5-amine, compound 1.072

1H NMR (CDCl3, 300 MHz): δ 7,87 (s, 1H), 7,29 (d, J=9,3 Hz, 1H), 7.23 percent? 7.04 baby mortality (m, 3H), 6,83 (m, 2H), 3,63 (m, 1H), 3,49 (m, 2H), 2,75 (m, 1H), 2,45 was 2.25 (m, 3H), 1,80 of 1.50 (m, 5H).

Example 94

(S)-N-(1-(4-Ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.077

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,43 (d, J=8,4 Hz, 2H), 7,26 (m, 3H), at 6.84 (m, 2H), 3,60 (users, 1H), 3,49 (DD, J=5,4, and 9.1 Hz, 2H), 3,05 (s, 1H), 2,74 (m, 1H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 95

(S)-N-(1-(4-Methylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.078

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,28 (d, J=8.7 Hz, 1H), 7,21 (d, J=8.1 Hz, 2H), 7,11 (d, J=8.1 Hz, 2H), 6,84 (m, 2H), 4,40 (users, 1H), 3,60 (users, 1H), 3,49 (DD, J=13,2, or 21.0 Hz, 2H), 2,74 (m, 1H), 2,41 (m, 3H), 2,39 (s, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 96

(S)-N-(1-(4-Methoxybenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.079

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,30-7,20 (m, 5H), 6,91-to 6.80 (m, 4H), of 3.80 (s, 3H), 3,60 is 3.40 (m, 3H), 2,80 (s, 1H), 2,50-of 2.30 (m, 3H), 1,80-of 1.40 (m, 5H).

Example 97

((S)-N-(1-(3,4-Dichlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.080

1H NMR (CDCl3, 300 MHz): δ 10,0 (users, 1H), 7,87 (s, 1H), 7,45 (s, 1H), was 7.36 (d, J=8,1 Hz, 1H), 7,29 (d, J=8.7 Hz, 1H), 7,15 (DD, J=2,1, 8,1 Hz, 1H), PC 6.82 (m, 2H), 3,60 (m, 1H), of 3.45 (DD, J=13,8, 18 Hz, 2H), 2,75 (d, J=10,2 Hz, 1H), 2,45 was 2.25 (m, 3H), 1,80 of 1.50 (m, 5H).

Example 98

(S)-N-(1-(4-Chlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.081

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7.3 to to 7.18 (m, 5H), PC 6.82 (m, 2H), 3,6-3,4 (m, 3H), 2,74 (m, 1H), 2.40 a (m, 3H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 99

N-(1-Benzylation-4-yl)isoquinoline-5-amine, compound 2.013

Specified in the title compound was obtained by interaction of isoquinoline-5-amine with tert-butyl 4-oxazepan-1-carboxylate using the method of example 3 with the subsequent removal of the protective group using the method of example 4, and interaction with benzaldehyde in accordance with the method of example 8.

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,45 (d, J=6 Hz, 1H), EUR 7.57 (d, J=6 Hz, 1H), 7,46-7,25 (m, 7H), 6,72 (d, J=7.5 Hz, 1H), 4,0 (m, 1H), 3,71 (m, 2H), 2,92 (m, 1H), 2,80 (m, 1H), 2,7-2,6 (m, 2H), 2.05 is-to 1.87 (m,, 7H).

Examples 100-109

The interaction of N-(piperidine-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 were obtained compounds of examples 100-109.

Example 100

N-(1-(4-Methoxybenzyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.001

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,49 (d, J=6.0 Hz, 1H), 7,55 (m, 1H), 7,41 (t, J=7.8 Hz, 1H), 7,30 (m, 3H), to 6.88 (m, 2H), 6.73 x (d, J=6,6 Hz, 1H), of 5.05 (users, 1H), 3,81 (users, 4H), 3,63 (m, 2H), to 3.09 (s, 3H), 2,65 (m, 3H), 2,35 (m, 1H), 1.85 to to 1.60 (m, 4H).

Example 101

N-(1-(4-(Methylsulphonyl)benzyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.002

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,49 (d, J=6.0 Hz, 1H), 7,89 (d, J=8.1 Hz, 2H), 7,55 (m, 3H), 7,41 (t, J=7.8 Hz, 1H), 7,27 (d, J=6,9 Hz, 1H), 6.73 x (d, J=6,6 Hz, 1H), 4,88 (users, 1H), 3,81 (users, 1H), 3,63 (DD, J=10,8, to 22.5 Hz, 2H), to 3.09 (s, 3H), 2,74 (d, J=10,2 Hz, 1H), 2,45 (m, 3H), 1.85 to to 1.60 (m, 4H).

Example 102

3-((3-(Izogi the Olin-5-ylamino)piperidine-1-yl)methyl)benzonitrile, connection 2.003

1H NMR (CDCl3, 300 MHz): δ 9,10 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,69 (s, 1H), 7,55 (m, 3H), 7,45 (m, 2H), 7,24 (m, 1H), 6.73 x (d, J=7.5 Hz, 1H), 4,88 (users, 1H), 4,78 (s, 2H), 3,78 (users, 1H), 3,55 (DD, J=13,5, to 22.5 Hz, 2H), to 2.74 (d, J=10,2 Hz, 1H), 2,45 (m, 3H), 1.85 to to 1.60 (m, 4H).

Example 103

N-(4-((3-(Isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)ndimethylacetamide, the connection 2.004

1H NMR (CDCl3, 300 MHz): δ 9,13 (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7,55 (d, J=6 Hz, 1H), of 7.48-7,38 (m, 3H), 7,31 (d, J=8,4 Hz, 2H), 7,24 (d, J=8,4 Hz, 1H), 6,72 (d, J=7.5 Hz, 1H), of 5.05 (users, 1), 3,78 (users, 1H), 3,51 (m, 2H), 2,70-of 2.30 (m, 4H), of 2.16 (s, 3H), 1.85 to to 1.60 (m, 4H).

Example 104

N-(1-(4-(Methylthio)benzyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.009

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,49 (d, J=6 Hz, 1H), 7,55 (d, J=6 Hz, 1H), 7,41 (t, J=7.5 Hz, 1H), 7,27 (m, 5H), 6,72 (d, J=7.5 Hz, 1H), 5,00 (users, 1H), 3,78 (users, 1H), 3,51, (DD, J=12, 30 Hz, 2H), 2,70-2,55 (m, 3H), 2,47 (s, 3H), 2,35 (m, 1H), 1,80 of 1.50 (m, 4H).

Example 105

N-(1-(4-Cyclopropylmethyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.010

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), and 8.50 (d, J=6 Hz, 1H), 7,56 (d, J=4,8 Hz, 1H), 7,45 (t, J=7.5 Hz, 1H), 7,27 (m, 4H), 7,05 (d, J=7.5 Hz, 1H), 6.73 x (d, J=6 Hz, 1H), 5,06 (users, 1H), 3,78 (users, 1H), 3,54 (m, 2H), 2,61 (m, 3H), 2,35 (m, 1H), 1,94 of 1.50 (m, 6H), 1.27mm (m, 3H), 1.00 and is 0.80 (m, 3H), of 0.90 (m, 1H), 0.69 (m, 2H).

Example 106

N-(1-(3-Cyclopropylmethyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.011

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), and 8.50 (d, J=6 Hz, 1H), to 7.59 (users, 1H), 7,43 (t, J=7.5 Hz, 1H), 7,27-7,10 (m, 5H), of 6.99 (m, 1H), 6.73 x (d, J=7,5 Hz, 1H), 5,06 (users, 1H), 3,81 (users, 1H), 3,54 (m, 2H), 2,64 (m, 3H), 2.40 a (m, 1H), 1,94 of 1.50 (m, 6H), 1.27mm (m, 3H), 1.00 m (m, 2H), 0,90 (m, 1H), 0,72 (m, 2H).

Example 107

N-(1-(4-(Cyclopropylamino)benzyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.012

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), and 8.50 (d, J=6 Hz, 1H), to 7.59 (users, 1H), 7,46-7,25 (m, 7H), was 6.73 (d, J=7.5 Hz, 1H), 5,06 (users, 1H), 3,71 (m, 1H), 3,55 (DD, J=12, 30 Hz, 2H), 2,7-2,5 (m, 3H), 2.40 a (m, 1H), 2,20 (m, 1H), 1,80 of 1.50 (m, 5H), of 1.07 (d, J=6 Hz, 2H), 0,70 (s, 2H).

Example 108

N-(1-(3,4-Dichlorobenzyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.014

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,49 (d, J=6.0 Hz, 1H), 7,55 (d, J=6 Hz, 1H), 7,51 (d, J=1.8 Hz, 1H), 7,45 was 7.36 (m, 2H), 7,24 (m, 1H), 7,17 (DD, J=1,8, 8,1 Hz, 1H), 6,72 (d, J=7.5 Hz, 1H), 4.95 points (users, 1), 3,78 (users, 1H), 3,49 (DD, J=13,5, 32,4 Hz, 2H), 2,70-of 2.30 (m, 4H), 1.85 to to 1.60 (m, 4H).

Example 109

N-(1-(3-(Trifluoromethyl)benzyl)piperidine-3-yl)isoquinoline-5-amine, compound 2.015

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7,71 (s, 1H), 7,47-7,31 (m, 5H), from 7.24 (DD, J=6.0 Hz, 1H), of 6.71 (d, J=7.8 Hz, 1H), 5,0 (users, 1), 3,80 (users, 1H), 3,60 (DD, J=13,5, and 29.7 Hz, 2H), 2,70-of 2.30 (m, 4H), 1.85 to to 1.60 (m, 4H).

Examples 110-116

The interaction of N-(pyrrolidin-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 were obtained compounds of examples 110-116.

Example 110

N-(1-(4-(Methylsulphonyl)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.005

1H NMR (CDCl3, 300 MHz): δ 9,16 (s, 1H), 8,49 (d, J=6.3 Hz, 1H), of 7.90 (d, J=8,4 Hz,2H), 7,56 (d, J=8,4 Hz, 3H), 7,42 (t, J=7.8 Hz, 1H), 7,33 (d, J=8,1 Hz, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,58 (m, 1H), 4,19 (m, 1H), 3,76 (s, 2H), 3,05 (s, 3H), 2,88 (m, 2H), 2,70 (DD, J=3.3V, 9.6 Hz, 1H), 2,60-2,40 (m, 2H), of 1.85 (m, 1H).

Example 111

N-(1-Benzylpyrrolidine-3-yl)isoquinoline-5-amine, compound 2.006

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.3 Hz, 1H), 7,56 (d, J=6.3 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,30 (m, 7H), 6,69 (d, J=7.5 Hz, 1H)and 4.65 (m, 1H), 4,18 (m, 1H), 3,68 (m, 2H), 2,87 (m, 2H), 2,70 (DD, J=3.3V, 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Example 112

3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)benzonitrile, the connection to 2,007

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7,66 (s, 1H), 7,55 (m, 3H), 7,43 (DD, J=7,5, and 10.8 Hz, 2H), 7,32 (d, J=8,1 Hz, 1H), 6,70 (d, J=7.5 Hz, 1H), 4,57 (d, J=6,6 Hz, 1H), 4,18 (m, 1H), 3,68 (m, 2H), 2,87 (m, 2H), 2,70 (DD, J=3.3V, 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Example 113

N-(4-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)ndimethylacetamide, the connection 2.008

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,45 (d, J=6.0 Hz, 1H), EUR 7.57 (m, 2H), 7,47-7,27 (m, 5H), of 6.68 (d, J=7.5 Hz, 1H), of 4.66 (m, 1H), 4,14 (users, 1H), 3,63 (s, 2H), 3,47 (users, 1H), and 2.83 (m, 2H), 2,70 (m, 1H), 2,60-2,40 m, 2H), of 2.15 (s, 3H), of 1.85 (m, 1H).

Example 114

N-(1-(3,4-Dichlorobenzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.016

1H NMR (CDCl3, 300 MHz): δ 9,16 (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7,56 (d, J=6.0 Hz, 1H), 7,47-7,31 (m, 3H), 7,18 (DD, J=3,6, 8,1 Hz, 1H), of 6.68 (d, J=7.5 Hz, 1H), 4,60 (users, 1H), 4,18 (m, 1H), 3,62 (s, 2H), 2,87 (m, 2H), 2,70 (m, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Example 115

N-(1-(4-Methoxybenzyl)pyrrolidin-3 is)isoquinoline-5-amine, connection 2.017

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), of 8.47 (d, J=6.0 Hz, 1H), 7,56 (d, J=6.0 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), from 7.24 (m, 3H), 6.87 in (d, J=8.7 Hz, 2H), of 6.68 (d, J=8,4 Hz, 1H), 4,63 (users, 1), 4,20 (m, 1H), 3,81 (s, 3H), to 3.64 (s, 2H), 2,87 (m, 2H), 2,70 (m, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Example 116

N-(1-(3-(Trifluoromethyl)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.018

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), of 8.47 (d, J=6.0 Hz, 1H), 7.62mm (s, 1H), 7,56 (m, 3H), 7,45 (m, 2H), 7,31 (d, J=8,4 Hz, 1H), 6,70 (d, J=7.8 Hz, 1H), to 4.62 (d, J=6,9 Hz, 1H), 4,16 (m, 1H), 3,71 (s, 2H), 2,88 (m, 2H), 2,70 (DD, J=3.3V, 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Examples 117-122

The interaction of (R)-N-(pyrrolidin-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 were obtained compounds of examples 117-122.

Example 117

(R)-N-(1-(3-Cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.020

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,56 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31-of 7.23 (m, 5H), 6,69 (d, J=7.8 Hz, 1H), 4,69 (d, J=6.3 Hz, 1H), 4,18 (m, 1H), the 3.65 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 2,18 (m, 1H), of 1.85 (m, 2H), 1.04 million (m, 2H), 0.69 (m, 2H).

Example 118

(R)-N-(1-(4-(Cyclopropylamino)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.021

1H NMR (CDCl3, 300 MHz): δ 9,16 (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,44 (t, J=8,1 Hz, 1H), 7,32 (d, J=8,1 Hz, 1H), 7.23 percent (m, 2H), 7,10 (m, 2H), 6,69 (d, J=7.5 Hz, 1H), and 4.75 (d, J=6,6 Hz, 1H), 4,18 (m, 1H), 3,68 (m, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 2H), 095 (m, 2H), 0,70 (m, 2H).

Example 119

(R)-N-(1-(4-Cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.022

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7.62mm (d, J=6 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7.23 percent (m, 2H), 7,05 (m, 2H), to 6.67 (d, J=7.5 Hz, 1H), 4,88 (users, 1H), 4,21 (m, 1H), to 3.73 (m, 2H), 3,05 is 2.80 (m, 3H), 2,65-to 2.40 (m, 2H), of 1.88 (m, 2H), 0,97 (m, 2H), 0.69 (m, 2H).

Example 120

(R)-N-(1-(4-Methylbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.025

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), to 7.59 (d, J=6 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7.23 percent (d, J=8.1 Hz, 2H), 7,14 (d, J=8.1 Hz, 2H), of 6.68 (d, J=7.5 Hz, 1H), 4.75 in (m, 1H), 4,18 (m, 1H), 3,68 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 2,33 (s, 3H), 2.05 is (users, 1H), of 1.85 (m, 1H).

Example 121

(R)-N-(1-(4-Chlorbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.027

1H NMR (CDCl3, 300 MHz): δ 9,13 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (m, 5H), of 6.68 (d, J=7.5 Hz, 1H), 4,80 (users, 1H), 4,20 (m, 1H), 3,69 (s, 2H), 2,88 (m, 2H), 2,80 (m, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Example 122

(R)-N-(1-(4-Ethynylphenyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.031

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), of 8.47 (d, J=6.0 Hz, 1H), 7,58 (d, J=6 Hz, 1H), 7,45 (m, 3H), 7,31 (m, 3H), of 6.68 (d, J=7.8 Hz, 1H), 4,70 (users, 1H), 4,17 (m, 1H), to 3.67 (s, 2H), 3,06 (s, 1H), 2,88 (m, 2H), 2,70 (DD, J=3.3V, 9.9 Hz, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Examples 123-128

The interaction of (S)-N-(pyrrolidin-3-yl)isoquinoline-5-amine with the appropriate aldehydes using EQ is whether the method of example 8 were obtained compounds of examples 123-128.

Example 123

(S)-N-(1-(4-Cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.019

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7.62mm (d, J=6 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7.23 percent (m, 2H), 7,05 (m, 2H), to 6.67 (d, J=7.5 Hz, 1H), 4,88 (users, 1H), 4,21 (m, 1H), to 3.73 (m, 2H), 3,05 is 2.80 (m, 3H), 2,65-to 2.40 (m, 2H), of 1.88 (m, 2H), 0,97 (m, 2H), 0.69 (m, 2H).

Example 124

(S)-N-(1-(3-Cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.023

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,56 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31-of 7.23 (m, 5H), 6,69 (d, J=7.8 Hz, 1H), 4,69 (d, J=6.3 Hz, 1H), 4,18 (m, 1H), the 3.65 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 2,18 (m, 1H), of 1.85 (m, 2H), 1.04 million (m, 2H), 0.69 (m, 2H).

Example 125

(S)-N-(1-(4-(Cyclopropylamino)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.024

1H NMR (CDCl3, 300 MHz): δ 9,16 (s, 1H), 8,48 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,44 (t, J=8,1 Hz, 1H), 7,32 (d, J=8,1 Hz, 1H), 7.23 percent (m, 2H), 7,10 (m, 2H), 6,69 (d, J=7.5 Hz, 1H), and 4.75 (d, J=6,6 Hz, 1H), 4,18 (m, 1H), 3,68 (m, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 2H), 0,95 (m, 2H), 0,70 (m, 2H).

Example 126

(S)-N-(1-(4-Methylbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.028

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), to 7.59 (d, J=6 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7.23 percent (d, J=8.1 Hz, 2H), 7,14 (d, J=8.1 Hz, 2H), of 6.68 (d, J=7.5 Hz, 1H), 4.75 in (m, 1H), 4,18 (m, 1H), 3,68 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 2,33 (s, 3H), 2.05 is (users, 1H), of 1.85 (m, 1H).

Example 127

(S)-N-(1-(4-(METI the thio)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine, connection 2.029

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,56 (d, J=6 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,31 (m, 5H), of 6.68 (d, J=7.5 Hz, 1H), 4,66 (d, J=7.2 Hz, 1H), 4,18 (m, 1H), to 3.64 (s, 2H), 2,88 (m, 2H), a 2.71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 2,47 (s, 3H), 2.05 is (users, 1H), of 1.85 (m, 1H).

Example 128

(S)-N-(1-(4-Chlorbenzyl)pyrrolidin-3-yl)isoquinoline-5-amine, compound 2.030

1H NMR (CDCl3, 300 MHz): δ 9,13 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (m, 5H), of 6.68 (d, J=7.5 Hz, 1H), 4,80 (users, 1H), 4,20 (m, 1H), 3,69 (s, 2H), 2,88 (m, 2H), 2,80 (m, 1H), 2,60-to 2.40 (m, 2H), of 1.85 (m, 1H).

Example 129 (estimated example)

N-(piperidine-3-yl)pyridine-4-amine

The interaction of tert-butyl 3-oxopiperidine-1-carboxylate and 4-aminopyridine using the method of example 3 with the subsequent removal of the protective group using the method of example 4 receive specified in the header of the connection.

Example 130 (estimated example)

N-(1-Benzylpiperidine-3-yl)pyridine-4-amine, compound 3.001

The interaction of N-(piperidine-3-yl)pyridine-4-amine with benzaldehyde using the method of example 8 receive specified in the header of the connection.

Example 131 (Projected sample)

N-(1-Benzylpyrrolidine-3-yl)pyridine-4-amine, compound 3.002

The interaction of tert-butyl 3-oxopyrrolidin-1-carboxylate and 4-aminopyridine using the method of example 3 with the subsequent removal of the protective group using the method of example 4 get smart pyrrolidin, which is subjected to interaction with benzaldehyde in accordance with the method of example 8, receiving specified in the header of the connection.

Example 132 (Projected sample)

4-Bromo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine

The interaction of 4-bromo-1H-pyrrolo[2,3-b]pyridine with 4-methoxybenzylamine in accordance with the method of example 12 causes specified in the header of the connection.

Example 133 (Projected sample)

tert-Butyl 3-(1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-4-ylamino)piperidine-1-carboxylate

The interaction of 4-bromo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine with tert-butyl-3-aminopiperidin-1-carboxylate according to the method of example 13 causes specified in the header of the connection.

Example 134 (Projected sample)

N-(piperidine-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine

Removing the protective groups of the tert-butyl-3-(1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-4-ylamino)piperidine-1-carboxylate using the method of example 14 causes specified in the header of the connection.

Example 135 (Projected sample)

N-(1-Benzylpiperidine-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine, compound 4.001

The interaction of N-(piperidine-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-AMI is and with benzaldehyde using the method of example 8 causes specified in the header of the connection.

Example 136 (Projected sample)

N-(1-Benzylpyrrolidine-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-amine, compound 4.002

Application of the reaction sequence described in examples 133-135 with the modification consists in the fact that tert-butyl-3-aminopyrrolidine-1-carboxylate to replace tert-butyl 3-aminopiperidine-1-carboxylate, causes specified in the header of the connection.

Example 137

4-(4-Nitrophenyl)-1,2,5-oxadiazol-3-amine

In a round bottom flask was added 2-(4-nitrophenyl)acetonitrile (5,00 g, 30,8 mmol) and ethanol (25 ml). The suspension was cooled to 0°C was added dropwise ethoxide sodium in ethanol (12.0 ml, is 3.08 M, of 27.0 mmol). The reaction mixture was immediately purchased a bright pink color. After 10 minutes, was added dropwise amyl nitrate (5,42 g, 46.2 mmol). The reaction mixture became dark green. After 20 minutes the reaction mixture was hardened and solid substance was destroyed and was additionally added 25 ml of ethanol. Within one hour of data NMR spectroscopy showed that the reaction was completed. The reaction mixture was diluted with ethyl acetate and washed with 1 M HCl, saturated sodium bicarbonate solution and saturated salt solution. The organic phase was separated and dried over MgSO4, filtered and concentrated. Chromatography of the residue on silica gel with elution mixture is Yu 20% EtOAc/heptane gave specified in the title compound as a yellow solid (5,40 g, 92%).

The above product (of 4.00 g of 20.9 mmol) were combined in a round bottom flask with potassium carbonate in water (40 ml, 3,00 M, 120 mmol) and hydroxylamine in water (to 13.8 ml, 15,1 M, 208 mmol). The mixture was stirred at 95°C overnight, after which the water layer was poured and the remaining oil was dissolved in ethyl acetate, washed with water, dried over MgSO4and filtered. The crude product was concentrated and purified by chromatography on silica gel, elwira a mixture of 30% EtOAc/hexane, getting mentioned in the title compound as a yellow solid (2.00 g, 46%).

Example 138

4-(4-AMINOPHENYL)-1,2,5-oxadiazol-3-amine

4-(4-Nitrophenyl)-1,2,5-oxadiazol-3-amine (0,500 g, 2,42 mmol), tin dichloride (1,61 g, 8,49 mmol) and water (0,306 ml of 17.0 mmol) were combined in ethyl acetate (20 ml) in a round bottom flask and the mixture was stirred at room temperature overnight. The solvent was removed and added methylene chloride and the mixture was washed three times with an aqueous solution of NaOH. The organic phase was dried over MgSO4was filtered and concentrated, obtaining mentioned in the title compound as a yellow solid (400 mg, 94%).

Example 139

tert-Butyl 3-(4-(4-amino-1,2,5-oxadiazol-3-yl)phenylamino)piperidine-1-carboxylate

The interaction of tert-butyl 3-oxopiperidine-1-carboxylate and 4-(4-AMINOPHENYL)1,2,5-oxadiazol-3-amine using the method of example 3 resulted specified in the header of the connection.

Example 140

4-(4-(piperidine-3-ylamino)phenyl)-1,2,5-oxadiazol-3-amine

Removing the protective groups of the tert-butyl-3-(4-(4-amino-1,2,5-oxadiazol-3-yl)phenylamino)piperidine-1-carboxylate using the method of example 4 resulted specified in the header of the connection.

Example 141

4-(4-(1-(4-Benzylpiperidine-3-ylamino)phenyl)-1,2,5-oxadiazol-3-amine, compound 5.001

The interaction of 4-(4-(piperidine-3-ylamino)phenyl)-1,2,5-oxadiazol-3-amine with benzaldehyde using the method of example 8 was led to headline the connection.

1H NMR (CDCl3, 300 MHz): δ 7.50 for (m, 2H), 7,35-7,26 (m, 5H), of 6.66 (d, J=8.7 Hz, 2H), 4,5 (users, 1H), 4,23 (s, 2H), 3,63 (users, 1H), 3,52 (DD, J=13,5, and 17.7 Hz, 2H), to 2.67 (d, J=10.5 Hz, 1H), 2,50-2,31 (m, 2H), 1.70 to (m, 2H), and 1.56 (m, 2H).

Example 142

4-(4-(1-(4-Benzylpyrrolidine-3-ylamino)phenyl)-1,2,5-oxadiazol-3-amine, compound 5.002

The application of a sequence of reactions described in the examples 139-141, with the modification that tert-butyl-3-oxopyrrolidin-1-carboxylate to replace tert-butyl 3-oxopiperidine-1-carboxylate, led to headline the connection.

1H NMR (CDCl3, 300 MHz): δ 7.50 for (m, 2H), 7,35-7,26 (m, 5H), 6,63 (d, J=8.7 Hz, 2H), or 4.31 (d, J=7.5 Hz, 1H), 4,23 (s, 2H), of 4.05 (m, 1H), to 3.64 (m, 2H), 2,86-to 2.74 (m, 2H), 2,60 (DD, J=3,6, 9.9 Hz, 1H), 2,50-2,31 (m, 2H), 1,95 (users, 1H), 1,70 (m, 1H).

the example 143

5-Bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol

In a round bottom flask with a capacity of 250 ml was loaded 5-bromo-1Η-indazol (25,00 g to 0.127 mol, 1.0 EQ.) and dichloromethane (100 ml). To the suspension was added dihydropyran (32,0 g, 0,381 mol, 3.0 EQ.) and a catalytic amount of para-toluensulfonate pyridinium (3,19 g, 0,0127 mol, 0.10 equiv.). The mixture was stirred overnight and in the morning the solution was transparent. Methylene chloride was washed sequentially with saturated sodium bicarbonate solution, 10% citric acid and saturated salt solution and then evaporated. Chromatography of the residue on silica gel with elution with mixture of EtOAc/heptane gave specified in the title compound as a colourless liquid (28,00 g, 79%).

1H NMR (CDCl3, 300 MHz): δ 8,11 (s, 1H), 7,82 (d, J=1.8 Hz, 1H), 7,60 (d, J=9.0 Hz, 1H), 7,33 (DD, J=1,8, 9.0 Hz, 1H), to 5.66 (DD, J=3,6, and 8.4 Hz, 1H), 4,11 (m, 1H), 3,78 (m, 1H), measuring 2.20 (m, 2H), 2.05 is (m, 1H), 1,75 (m, 3H).

Example 144

(3S)-tert-Butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)piperidine-1-carboxylate

In a round bottom flask with a capacity of 500 ml, equipped with a magnet for stirring on a magnetic stirrer, was loaded with 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazol (28,0 g, 0,0996 mol, 1.00 equiv.) (S)-3-amino-Boc-piperidine (of 21.75 g, 0,109 mol, of 1.09 equiv.) Tris(dibenzylideneacetone)dipalladium and 4.75 g, 5.18 mmol, 0,052 equiv.) racemic BINAP (7,44 g, 12,0 mmol, 0.2 EQ.) and tert-piperonyl sodium (28,7 g, 0,299 mol, 3.00 equiv.). The flask containing solids, was then pumped under vacuum and again filled with nitrogen three times for degassing. Then was added pyridine (200 ml) and the flask is again three times was purged with vacuum and nitrogen. Dark green mixture was then stirred at 55°C overnight under nitrogen atmosphere. The next morning the reaction mixture was cooled to room temperature, diluted with 250 ml EtOAc, washed three times with portions of 250 ml of 10% NaHSO4and the organic phase was evaporated. The residue was dissolved in toluene and loaded on a column of silica gel, which was Packed using heptane. The column was washed with 5 column volumes heptane, after which the target product was suirable a mixture of EtOAc/heptane, getting mentioned in the title compound as a pale yellow foam substances (2.4 g, 81%).

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,54 (d, J=9.0 Hz, 1H), 6,72 (DD, J=2,1, 9.0 Hz, 1H), of 6.31 (s, 1H), 5,59 (DD, J=3,0, 9.0 Hz, 1H), 4,10 (m, 2H, in), 3.75 (m, 2H), 3,52 (m, 1H), 3,38 (m, 1H), of 3.07 (m, 1H), 2,88 (m, 1H), of 2.20 (m, 2H), 2.05 is (m, 2H), 1,75-of 1.65 (m, 8H), of 1.46 (s, 9H).

Example 145

(3R)-tert-Butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)piperidine-1-carboxylate

The condensation of 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole with (R)-3-amino-Boc-piperidine using method of example 144 led to headline the connection.

Example 146

(3S)-tert-Butyl 3-(1-(tetrahydro-2H-Piran-2-the l)-1H-indazol-5-ylamino)pyrrolidin-1-carboxylate

The condensation of 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole with (S)-3-amino-Boc-pyrrolidine using the method of example 144 led to headline the connection.

Example 147

(3R)-tert-Butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)pyrrolidin-1-carboxylate

The condensation of 5-bromo-1-(tetrahydro-2H-Piran-2-yl)-1H-indazole with (R)-3-amino-Boc-pyrrolidine using the method of example 144 led to headline the connection.

Example 148

The dihydrochloride (S)-N-(piperidine-3-yl)-1H-indazol-5-amine

In a round bottom flask with a capacity of 1 l was downloaded (3S)-tert-butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)piperidine-1-carboxylate (32,4 g, 0,0809 mol, 1.00 equiv.) and EtOH (500 ml). To a solution in ethanol was added 4N HCl in dioxane (40,0 ml, 0,160 mol, 2.0 EQ.) and the solution was stirred at room temperature for 2 hours, resulting in the formation of non-homogeneous dark brown solution. The solution is then heated to 75°C with a mechanical stirrer and maintained at this temperature for 2 hours, when the mixture was cooled to room temperature. Observed the formation of a large number of fine white solid and was collected by filtration, the filter cake was washed with isopropylacetate (500 ml). The solid was dried in vacuum pécs is at 45°C for 3 days, getting listed in the title compound in the form of not quite white powder (18,1 g, 77%).

1H NMR (CD3OD, 300 MHz): δ of 8.28 (s, 1H), of 7.70 (m, 2H), 7,46 (DD, J=2,1, 9.0 Hz, 1H), 3.96 points (m, 1H), 3,60 (m, 2H), 3,36 (m, 1H), 3.15 in (m, 1H), 3.04 from (m, 1H), measuring 2.20 (m, 2H), of 1.85 (m, 2H).

Example 149

The dihydrochloride of (R)-N-(piperidine-3-yl)-1H-indazol-5-amine

The removal of the protective group in (3R)-tert-butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)piperidine-1-carboxylate using the method of example 148 was led to headline the connection.

Example 150

The dihydrochloride (S)-N-(pyrrolidin-3-yl)-1H-indazol-5-amine

The removal of the protective group (3S)-tert-butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)pyrrolidin-1-carboxylate using the method of example 148 was led to headline the connection.

Example 151

The dihydrochloride of (R)-N-(pyrrolidin-3-yl)-1H-indazol-5-amine

The removal of the protective group in (3R)-tert-butyl-3-(1-(tetrahydro-2H-Piran-2-yl)-1H-indazol-5-ylamino)pyrrolidin-1-carboxylate using the method of example 148 was led to headline the connection.

Examples 152-175

The interaction of 2,2-dimethyl-1-(5-(piperidine-3-ylamino)-1H-indazol-1-yl)propane-1-it with the appropriate aldehydes using the method of example 8 with the subsequent removal of the protective group using the method of example 9 was brought to the compounds of sunnym in the examples 152-175.

Example 152

N-(1-((1H-Indol-6-yl)methyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.082

1H NMR (CDCl3, 300 MHz): δ 8,08 (users, 1H), 7,86 (s, 1H), 7,55 (m, 1H), 7,30 (m, 1H), 7,20 (m, 1H), 7,10 (m, 1H), PC 6.82 (m, 2H), 6,50 (m, 1H), 3,68-to 3.50 (m, 3H), 2,80 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 153

5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-2-ethynylphenyl, the connection 1.083

Example 154

3-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-1-ol, compound 1.084

1H NMR (CDCl3, 300 MHz): δ 9,85 (users, 1H), 7,86 (s, 1H), 7,31 to 7.2 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4.09 to (m, 2H), a 3.87 (m, 2H), 3,61 (users, 1H), 3,48 (m, 2H), was 2.76 (m, 1H), 2,45 (m, 3H), 2,04 (m, 2H), of 1.75 (m, 2H), 1,59 (m, 3H).

Example 155

N-(1-(3-(2-Aminoethoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.085

Obtained by condensation of BOC-protected aminoaldehyde with the subsequent removal of the protective group using the method of example 9.

Example 156

2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetic acid, compound 1.086

1H NMR (CD3OD, 300 MHz): δ 7,86 (s, 1H), 7,40 (m, 3H), 7,00 (m, 4H), around 4.85 (s, 2H)and 4.65 (users, 2H), 4,32 (DD, J=12,9, 30.0 Hz, 2H), 3,80 (users, 1H), 3,40 (users, 1H), 3,30 (s, 2H), 3.00 and (users, 1H), 2,13 (users, 2H), 1,90 (m, 1H), 1,60 (users, 1H).

Example 157

N-(1-(3-Amino-4-Chlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.089

1H NMR (CD3OD, 300 MHz): δ for 7.78 (s, 1H), 7,32 (d, J=9.0 Hz, 1H), 7,14 (d, J=8,1 Hz, 1H), 6,91 (DD, J=2,1, 9,0 is C, 1H), 6,83 (m, 2H), is 6.61 (DD, J=1,8, 8,1 Hz, 1H), 3,52 (m, 4H), of 3.07 (m, 1H), 2,80 (m, 1H), 2,35 (m, 1H), 2,15 (m, 1H), 2,00 (m, 1H), of 1.85 (m, 1H), 1,75 (m, 1H), 1,40 (m, 1H).

Example 158

2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ndimethylacetamide, the connection 1.098

1H NMR (CDCl3, 300 MHz): δ 9,95 (users, 1H), 7,86 (s, 1H), 7,27-to 7.18 (m, 2H), 6,97 (m, 2H), 6,83 (m, 3H), 6,58 (users, 1H), 5,65 (users, 1H), 4,50 (s, 2H), 3,61 (users, 1H), 3,50 (DD, J=13,5, with 23.7 Hz, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), to 1.76 (m, 2H), 1,60 (m, 2H).

Example 159

2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide, the connection 1.099

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), 7,82 (s, 1H), 7,60 (d, J=7.8 Hz, 1H), 7,27-to 7.18 (m, 2H), 7,18 (d, J=7.5 Hz, 1H), 7,07 (s, 1H), 6,83 (d, J=8.7 Hz, 1H), 6,77 (s, 1H), 6,59 (s, 1H), and 5.30 (users, 1H), 5,24 (users, 1H), 4,78 (users, 2H), 3,70 is 3.57 (m, 3H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 160

N-(1-((1H-Indol-5-yl)methyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.100

1H NMR (CD3OD, 300 MHz): δ of 7.75 (s, 1H), 7,50 (s, 1H), 7,32 (m, 2H), 7,20 (m, 1H), was 7.08 (m, 1H), 6.90 to (m, 1H), 6,83 (s, 1H), 6,40 (m, 1H), 4,6 (users, 2H), 3,65 (m, 2H), 3,50 (m, 1H), 3,30 (m, 1H), 3.15 in (m, 1H), 2,80 (m, 1H), measuring 2.20 (m, 1H), 2,00 (m, 2H), of 1.75 (m, 1H), 1,65 (m, 1H), 1,35 (m, 1H).

Example 161

2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol, compound 1.101

1H NMR (CD3OD, 300 MHz): δ 7,72 (s, 1H), 7,53 (d, J=8,1 Hz, 1H), 7,45 (s, 1H), 7,31 (d, J=9.0 Hz, 1H), 7,27 (d, J=3.0 Hz, 1H), 7,05 (DD, J=1,2, 8,1 Hz, 1H), 6,91 (DD, J=2.1 a, 8,7 Hz, 1H), PC 6.82 (s, 1H), 6,44 (s, 1H), 4,23 (t, J=5.4 Hz, 2H), 3,95 (DD, J=12,9, 28,2 Hz, 2H), 3,84 (t, J=54 Hz, 2H), 3,60 (m, 1H), 3,00 (m, 1H), 2,50 (m, 1H), a 2.36 (m, 1H), 2.05 is (m, 1H), 1,95 (m, 1H), 1,76 (m, 1H), 1,40 (m, 1H).

Example 162

N-(5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-2-chlorophenyl)methanesulfonamide, the connection 1.102

1H NMR (CD3OD, 300 MHz): δ for 7.78 (s, 1H), 7,58 (d, J=1.8 Hz, 1H), 7,41 (d, J=9.6 Hz, 1H), 7,31 (d, J=9.0 Hz, 1H), 7,18 (DD, J=1,8, and 8.4 Hz, 1H), 6,93 (DD, J=2,1, 9.0 Hz, 1H), 6,85 (s, 1H), 3,50 (m, 3H), 2.95 and (m, 1H), 2.91 in (s, 3H), and 2.26 (m, 1H), 2.05 is (m, 1H), 1,95 (m, 1H), 1,76 (m, 1H), 1,65 (m, 1H), 1,40 (m, 1H).

Example 163

2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetic acid, compound 1.103

Was obtained by condensation of the corresponding tert-butyl ether complex with the subsequent removal of the protective group using the method of example 4.

1H NMR (CD3OD, 300 MHz): δ 8,55 (s, 1H), of 7.75 (s, 1H), of 7.48 (m, 1H), 7,32 (m, 2H), 7,15 (m, 1H), 7,02 (d, J=7.5 Hz, 1H), 6,93 (m, 2H), 6,39 (m, 1H)and 4.65 (m, 2H), 3,70 is 3.57 (m, 3H), 2,78 (m, 1H), and 2.26 (m, 1H), 2,05 (m, 1H), 1,95 (m, 1H), 1,76 (m, 1H), 1,65 (m, 1H), 1,40 (m, 1H).

Example 164

2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)indolin-1-yl)ethanol, compound 1.104

1H NMR (CDCl3, 300 MHz): δ 7,87 (s, 1H), 7,27-to 7.18 (m, 2H), 7,02 (d, J=6,9 Hz, 1H), 6,83 (m, 2H), 6,63 (m, 2H), 3,80 (m, 2H), 3,70 is 3.57 (m, 3H), 3,40 (m, 2H), 3,25 (m, 2H), 2.95 and (m, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), to 1.76 (m, 2H), 1,60 (m, 2H).

Example 165

2-(5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide, the connection 1.105

1H NMR (CDCl3, 300 MHz): δ 7,79 (s, 1H), 7,55 (s, 1H), 7,27-to 7.18 (m, 3H), 7,05 (d, J=3.0 Hz, 1H), 6,79 (DD, J=2,1, 87 Hz, 1H), 6,76 (s, 1H), 6,55 (d, J=3.0 Hz, 1H), 5,96 (users, 1H), and 5.30 (users, 1H), and 4.75 (s, 2H), 3,70 is 3.57 (m, 3H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 166

N-(2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethyl)ndimethylacetamide, the connection 1.111

1H NMR (CD3OD, 300 MHz): δ to 7.77 (s, 1H), 7,31 (d, J=8.7 Hz, 1H), 7,21 (t, J=7.8 Hz, 1H), 6,94 (m, 3H), 6,83 (m, 2H), 4,14 (m, 2H), 3,53 (m, 4H), of 3.07 (m, 2H), 2,75, of 2.20 (m, 2H), 1,97 (m, 5H), of 1.78 (m, 1H), 1,68 (m, 1H), 1,40 (m, 1H).

Example 167

tert-Butyl 2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetate, the connection 1.112

1H NMR (CDCl3, 300 MHz): δ to 7.84 (s, 1H), 7,54 (s, 1H), 7,28 (m, 2H), 7,19 (s, 1H), 7,07 (d, J=3.0 Hz, 1H), PC 6.82 (m, 2H), 6,51 (d, J=3.0 Hz, 1H), 4.72 in (s, 2H), 3,63 (m, 3H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H,), to 1.60 (m, 2H), 1,45 (s, 9H).

Example 168

2-(5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol, compound 1.114

1H NMR (CDCl3, 300 MHz): δ 7,74 (s, 1H), EUR 7.57 (s, 1H), 7,27-to 7.18 (m, 4H), for 6.81 (d, J=8.7 Hz, 1H), 6,77 (s, 1H), of 6.49 (d, J=3.0 Hz, 1H), 4,27 (m, 2H), 3,92 (m, 2H), 3,61 (m, 2H), 3,57 (users, 1H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 169

2-(5-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetic acid, compound 1.119

Was obtained by removing the protective group in the compound 1.112 using the method of example 4.

Example 170

N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant, the connection 1.120

1H NMR (CD3OD, 300 MHz): δ to 7.77 (s, 1H), 7,35-of 7.23 (m, 3H), 7,10 (t,J=7.2 Hz, 2H), 6,91 (DD, J=1,8, 9.0 Hz, 1H), 6,83 (s, 1H), 3,50 (m, 2H), 3,48 (m, 1H), 2,96 (kV, J=7.2 Hz, 2H), 2,72 (m, 1H), 2,32 (m, 1H), of 1.97 (m, 2H), 1,78 (m, 1H), 1,68 (m, 1H), 1,40 (m, 1H), 1,19 (t, J=7.2 Hz, 3H).

Example 171

N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)-N-methylmethanesulfonamide, the connection 1.121

1H NMR (CD3OD, 300 MHz): δ for 7.78 (s, 1H), 7,42 (s, 1H), 7,35-of 7.23 (m, 4H), 6,91 (DD, J=2,1, 9.0 Hz, 1H), 6,84 (s, 1H), 3,50 (s, 2H), 3,48 (m, 1H), 3,25 (s, 3H), 2,97 (d, J=10.5 Hz, 1H), 2,80 (s, 3H), of 2.72 (m, 1H), 2,32 (m, 1H), of 1.97 (m, 2H), 1,78 (m, 1H), 1,68 (m, 1H), 1,40 (m, 1H).

Example 172

N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)benzyl)ndimethylacetamide, the connection 1.122

1H NMR (CDCl3, 300 MHz): δ a 7.85 (s, 1H), 7,32-of 7.23 (m, 4H), to 7.15 (d, J=6,9 Hz, 1H), PC 6.82 (m, 2H), 5,70 (users, 1H), and 4.40 (d, J=5.7 Hz, 1H), 3,60 (users, 1H), 3,52 (DD, J=13,5, 27,0 Hz, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), 2.00 (evens with, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 173

2-(3-((4-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 1.130

1H NMR (CDCl3, 300 MHz): δ 7,88 (s, 1H), 7,30-7,22 (m, 2H), 6,93 (m, 2H), PC 6.82 (m, 3H), of 4.13 (m, 2H), 3,95 (m, 2H), 3,53 (s, 2H), 3,30 (m, 1H), 2,88 (d, J=11,4 Hz, 1H), 2,3-2,00 (m, 4H), 1,76 of 1.50 (m, 2H).

Example 174

N-(3-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide, the connection 1.087

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), 7,88 (s, 1H), 7,32 (m, 2H), 7,16 (s, 1H), 7,11 (m, 2H), PC 6.82 (DD, J=2,1, to 8.7 Hz, 2H), 6,74 (d, J=1.5 Hz, 1H), 6.48 in (users, 1H), 4,11 (m, 1H), 3,63 (DD, J=13,5, 34,5 Hz, 2H), 2,93 (s, 3H), 2,89 (m, 1H), 2,71 (m, 2H), 2,45 (m, 1H), 2,35 (m, 1H), 1,73 (m, 1H).

Example 175

2-(3-((3-(1H-Indazol--ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol, connection 1.088

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), of 7.90 (s, 1H), 7,32 (m, 2H), 6,95 (m, 2H), PC 6.82 (m, 3H), 4,11 (m, 3H), 3,95 (m, 2H), 3,63 (m, 2H), 2,89 (m, 2H), 2,71 (m, 1H), 2,45 (m, 1H), 2,35 (m, 1H), 2,00 (m, 1H), 1,73 (m, 1H).

Examples 176-197

Interaction dihydrochloride (R)-N-(piperidine-3-yl)-1H-indazol-5-amine with the appropriate aldehydes using the method of example 8, with the change that cyanoborohydride sodium was used as reductant and methanol was used as the reaction solvent, led to compounds described in the examples 176-197.

Example 176

(R)-2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 1.092

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,31 to 7.2 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4.09 to (m, 2H), 3.96 points (m, 2H), 3,61 (m, 1H), 3,50 (m, 2H), 2,80 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 3H).

Example 177

(R)-N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide, the connection 1.093

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,32-7,25 (m, 2H), to 7.09 (m, 2H), 6.87 in (DD, J=2,1, 9.0 Hz, 1H), 6,79 (s, 1H), 6,32 (users, 1H), 3,61 (m, 1H), 3,53 (DD, J=10,8, 35,1 Hz, 2H), 2.91 in (s, 3H), 2,61 (m, 1H), 2,45 (m, 3H), 1,76 (m, 2H), 1,60 (m, 3H).

Example 178

(R)-2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide, the connection 1.106

1H NMR (CDCl3, 300 MHz): δ of 7.82 (s, 1H), 7,60 (d, J=8,1 Hz, 1H), 7,27-to 7.18 (m, 2H), 7,17 (d, J=7.5 Hz, 1H), 7,06 (d, J=3.0 Hz, 1H), 6,83 (d, J=7.8 Hz, 1H), 6,77 (s, 1H), 6,59 (d, J=3.0 Hz, 1H), 5,23 (OSiR.the, 2H), 4,78 (s, 2H), 3,70 is 3.57 (m, 3H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 179

(R)-2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol, compound 1.108

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,82 (s, 1H), to 7.59 (m, 1H), 7,37 (s, 1H), 7,24 (s, 1H), 7,15 (m, 2H), 6,83 (m, 2H), 6,50 (m, 1H), 4,28 (m, 2H), 3.96 points (m, 2H, in), 3.75 (m, 1H), 3,60 (m, 2H), 2,80 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 2H).

Example 180

(R)-N-(1-Benzylpiperidine-3-yl)-1H-indazol-5-amine, compound 1.110

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,37-7,24 (m, 6H), 6,83 (m, 2H), 3,62 (users, 1H), to 3.58 (m, 2H), 2,80 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 2H).

Example 181

(R)-3-(3-(((R)-3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol, compound 1.115

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,27-to 7.18 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4,10 (m, 3H), 3,85 (m, 1H), of 3.77 (m, 1H), 3,60 (users, 1H), 3,51 (m, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 182

(R)-1-(3-(((R)-3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-2-ol, compound 1.116

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,27-to 7.18 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4,20 (m, 1H), 3,95 (m, 1H), 3,81 (m, 1H), 3,60 (users, 1H), 3,51 (m, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H), of 1.29 (d, J=6.6 Hz, 3H).

Example 183

(R)-3-(3-(((S)-3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol, compound 1.117

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,27-to 7.18 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4,10 (m, 3H), 3,85 (m, 1H), of 3.77 (m, 1H), 3,60 (users, 1H), 3,51 (m, 2H), 2,78(m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 184

(R)-1-(3-(((S)-3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-2-ol, compound 1.118

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,27-to 7.18 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4,20 (m, 1H), 3,95 (m, 1H), 3,81 (m, 1H), 3,60 (users, 1H), 3,51 (m, 2H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H), of 1.29 (d, J=6.6 Hz, 3H).

Example 185

(R)-N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant, the connection 1.123

1H NMR (CDCl3, 300 MHz): δ 9,95 (users, 1H), 7,86 (s, 1H), 7,32-of 7.23 (m, 3H), was 7.08 (m, 2H), to 6.88 (DD, J=1,8, and 8.7 Hz, 1H), 6,79 (s, 1H), 6,50 (m, 1H), 3,60 (users, 1H), 3,43 (DD, J=13,5, 38,1 Hz, 2H), 3,06 (m, 2H), 2,68 (m, 2H), 2,45 to 2.35 (m, 2H), 1,76 (m, 2H), 1,60 (m, 2H), 1,28 (t, J=7.5 Hz, 3H).

Example 186

(R)-2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetic acid, compound 1.125

Was obtained by condensation of the corresponding tert-butyl ether complex with the subsequent removal of the protective group using the method of example 4.

1H NMR (CD3OD, 300 MHz): δ 7,86 (s, 1H), 7,40 (m, 3H), 7,00 (m, 4H), around 4.85 (s, 2H)and 4.65 (users, 2H), 4,32 (DD, J=12,9, 30.0 Hz, 2H), 3,80 (users, 1H), 3,40 (users, 1H), 3,30 (s, 2H), 3.00 and (users, 1H), 2,13 (users, 2H), 1,90 (m, 1H), 1,60 (users, 1H).

Example 187

(R)-2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-N-(pyridin-3-yl)ndimethylacetamide, the connection 1.126

1H NMR (CDCl3, 300 MHz): δ 9,95 (users, 1H), 8,65 (d, J=2.4 Hz, 1H), 8,40 (DD, J=1,2, 4,8 Hz, 1H), 8.34 per (s, 1H), they were 8.22 (d, J=6.3 Hz, 1H), 7,86 (s, 1H), 7,31 to 7.2 (m, 2H),7,03 (m, 2H), 6,83 (m, 3H), 5.40 to (users, 1H), with 4.64 (s, 2H), 3,65 (users, 1H), 3,52 (DD, J=13,5, or 21.0 Hz, 2H), was 2.76 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 2H).

Example 188

(R)-2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-1-morpholinoethyl, the connection 1.127

1H NMR (CDCl3, 300 MHz): δ 9,95 (users, 1H), 7,86 (s, 1H), 7,31 to 7.2 (m, 2H), 7,03 (m, 2H), 6,83 (m, 3H), 5.40 to (users, 1H), 4,69 (s, 2H), 3,62 (users, 9H), 3,49 (m, 2H), was 2.76 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 2H).

Example 189

(R)-2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-1-(4-methylpiperazin-1-yl)Etalon, the connection 1.128

Example 190

(R)-Diethyl-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)methylphosphonate, the connection 1.129

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,31 to 7.2 (m, 2H), 7,03 (m, 2H), 6,83 (m, 3H), 4,30 (s, 2H), 4,25 (m, 4H), 3,59 (users, 1H), 3,49 (m, 2H), was 2.76 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 2H), 1,36 (t, J=7.2 Hz, 6H).

Example 191

(R)-N-(1-(Benzofuran-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.131

Example 192

(R)-N-(1-(4-Chlorobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.132

Example 193

(R)-N-(1-(4-Methylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.133

Example 194

(R)-N-(1-(4-Bromobenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.134

Example 195

(R)-N-(1-(4-active compounds)piperidine-3-yl)-1H-indazol-5-amine, compound 1.136

Example 196

(R)-N-(1-(2,4-Dimethylbenzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.137

197

(R)-N-(1-(Benzo[b]thiophene-5-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.138

Examples 198-204

Interaction dihydrochloride (S)-N-(piperidine-3-yl)-1H-indazol-5-amine with the appropriate aldehydes using the method of example 8, with the change that cyanoborohydride sodium was used as reductant and methanol was used as the reaction solvent, led to compounds described in the examples 198-204.

Example 198

(S)-N-(1-(4-(Methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine, compound 1.075

1H NMR (CDCl3, 300 MHz): δ 9,8 (users, 1H), 7,86 (s, 1H), 7.3 to to 7.18 (m, 5H), PC 6.82 (m, 2H), 3,6-3,4 (m, 3H), 2,74 (m, 1H), 2,47 (s, 3H), 2,41-of 2.30 (m, 3H), of 1.75 (m, 2H), and 1.56 (m, 3H).

Example 199

(S)-2-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 1.090

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,31 to 7.2 (m, 2H), 6,94 (m, 2H), 6,83 (m, 3H), 4.09 to (m, 2H), 3.96 points (m, 2H), 3,61 (m, 1H), 3,50 (m, 2H), 2,80 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 3H).

Example 200

(S)-N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide, compound 1.091

1H NMR (CDCl3, 300 MHz): δ 7,86 (s, 1H), 7,32-7,25 (m, 2H), to 7.09 (m, 2H), 6.87 in (DD, J=2,1, 9.0 Hz, 1H), 6,79 (s, 1H), 6,32 (users, 1H), 3,61 (m, 1H), 3,53 (DD, J=10,8, 35,1 Hz, 2H), 2.91 in (s, 3H), 2,61 (m, 1H), 2,45 (m, 3H), 1,76 (m, 2H), 1,60 (m, 3H).

Example 201

(S)-2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide, the connection 1.107

1H NMR CDCl 3, 300 MHz): δ of 7.82 (s, 1H), 7,60 (d, J=8,1 Hz, 1H), 7,27-to 7.18 (m, 2H), 7,17 (d, J=7.5 Hz, 1H), 7,06 (d, J=3.0 Hz, 1H), 6,83 (d, J=7.8 Hz, 1H), 6,77 (s, 1H), 6,59 (d, J=3.0 Hz, 1H), 5,23 (users, 2H), 4,78 (s, 2H), 3,70 is 3.57 (m, 3H), 2,78 (m, 1H), 2,45 to 2.35 (m, 3H), of 1.76 (m, 2H), 1,60 (m, 2H).

Example 202

(S)-2-(6-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol, compound 1.109

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), 7,82 (s, 1H), to 7.59 (m, 1H), 7,37 (s, 1H), 7,24 (s, 1H), 7,15 (m, 2H), 6,83 (m, 2H), 6,50 (m, 1H), 4,28 (m, 2H), 3.96 points (m, 2H, in), 3.75 (m, 1H), 3,60 (m, 2H), 2,80 (m, 1H), 2,45 (m, 3H), of 1.75 (m, 2H), 1,59 (m, 2H).

Example 203

(S)-3-(3-(((R)-3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol, compound 1.113

Example 204

(S)-N-(3-((3-(1H-Indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant, the connection 1.124

1H NMR (CDCl3, 300 MHz): δ 9,95 (users, 1H), 7,86 (s, 1H), 7,32-of 7.23 (m, 3H), was 7.08 (m, 2H), to 6.88 (DD, J=1,8, and 8.7 Hz, 1H), 6,79 (s, 1H), 6,50 (m, 1H), 3,60 (users, 1H), 3,43 (DD, J=13,5, 38,1 Hz, 2H), 3,06 (m, 2H), 2,68 (m, 2H), 2,45 to 2.35 (m, 2H), 1,76 (m, 2H), 1,60 (m, 2H), 1,28 (t, J=7.5 Hz, 3H).

Examples 205-206

Interaction dihydrochloride (R)-N-(pyrrolidin-3-yl)-1H-indazol-5-amine with the appropriate aldehydes using the method of example 8, with the change that cyanoborohydride sodium was used as reductant and methanol was used as the reaction solvent, led to compounds described in the examples 205-206.

Example 205

(R)-2-(3-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-the l)methyl)phenoxy)ethanol, connection 1.096

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), of 7.90 (s, 1H), 7,32 (m, 2H), 6,95 (m, 2H), PC 6.82 (m, 3H), 4,11 (m, 3H), 3,95 (m, 2H), 3,63 (m, 2H), 2,89 (m, 2H), 2,71 (m, 1H), 2,45 (m, 1H), 2,35 (m, 1H), 2,00 (m, 1H), 1,73 (m, 1H).

Example 206

(R)-N-(3-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide, the connection 1.097

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), 7,88 (s, 1H), 7,32 (m, 2H), 7,16 (s, 1H), 7,11 (m, 2H), PC 6.82 (DD, J=2,1, to 8.7 Hz, 2H), 6,74 (d, J=1.5 Hz, 1H), 6.48 in (users, 1H), 4,11 (m, 1H), 3,63 (DD, J=13,5, 34,5 Hz, 2H), 2,93 (s, 3H), 2,89 (m, 1H), 2,71 (m, 2H), 2,45 (m, 1H), 2,35 (m, 1H), 1,73 (m, 1H).

Examples 207-208

Interaction dihydrochloride (S)-N-(pyrrolidin-3-yl)-1H-indazol-5-amine with the appropriate aldehydes using the method of example 8, with the change that cyanoborohydride sodium was used as reductant and methanol was used as the reaction solvent, led to compounds described in the examples 207-208.

Example 207

(S)-2-(3-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol, compound 1.094

1H NMR (CDCl3, 300 MHz): δ 9,80 (users, 1H), of 7.90 (s, 1H), 7,32 (m, 2H), 6,95 (m, 2H), PC 6.82 (m, 3H), 4,11 (m, 3H), 3,95 (m, 2H), 3,63 (m, 2H), 2,89 (m, 2H), 2,71 (m, 1H), 2,45 (m, 1H), 2,35 (m, 1H), 2,00 (m, 1H), 1,73 (m, 1H).

Example 208

(S)-N-(3-((3-(1H-Indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide, the connection 1.095 has

1H NMR (CDCl3, 300 MHz): δ 9,90 (users, 1H), 7,88 (s, 1H), 7,32 (m, 2H), 7,16 (s, 1H), 7,11 (m, 2H), PC 6.82 (DD,J=2,1, to 8.7 Hz, 2H), 6,74 (d, J=1.5 Hz, 1H), 6.48 in (users, 1H), 4,11 (m, 1H), 3,63 (DD, J=13,5, 34,5 Hz, 2H), 2,93 (s, 3H), 2,89 (m, 1H), 2,71 (m, 2H), 2,45 (m, 1H), 2,35 (m, 1H), 1,73 (m, 1H).

Example 209

2-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol, compound 2.042

The interaction of N-(pyrrolidin-3-yl)isoquinoline-5-amine 3-(2-hydroxyethoxy)benzaldehyde using the method of example 8 was led to headline the connection.

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), EUR 7.57 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7,22 (d, J=8,1 Hz, 1H), 6,94 (m, 2H), 6,83 (m, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,67 (d, J=7.5 Hz, 1H), 4,16 (m, 1H), 4,06 (m, 2H), 3,94 (m, 2H), the 3.65 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 1,80 (m, 1H).

Examples 210-211

The interaction of (R)-N-(piperidine-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 was led to the compounds described in the examples 210-211.

Example 210

(R)-N-(3-((3-(Isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide, the connection 2.033

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), charged 8.52 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,41 (t, J=7.8 Hz, 1H), 7,30-to 7.18 (m, 4H), 7,03 (m, 1H), 6,72 (d, J=7.8 Hz, 1H), of 5.05 (users, 1H), 3,81 (users, 1H), 3,55 (DD, J=13,5, 35,1 Hz, 2H), 2,99 (s, 3H), 2,65 (m, 3H), 2,35 (m, 1H), 1.85 to to 1.60 (m, 4H).

Example 211

(R)-2-(3-((3-(Isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 2.034

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,48 (d, J=6.0 Hz, 1H), EUR 7.57 d, J=6 Hz, 1H), 7,42 (t, J=7.8 Hz, 1H), 7,30-7,22 (m, 2H), 6,98 (m, 2H), for 6.81 (DD, J=1,8, 8,1 Hz, 1H), 6.73 x (d, J=7.8 Hz, 1H), of 5.05 (users, 1H), 4.09 to (m, 2H), 3.96 points (m, 2H), 3,80 (users, 1H), 3,54 (DD, J=13,2, 38,1 Hz, 2H), 2,99 (s, 3H), 2.63 in (m, 2H), 2,35 (m, 1H), 2,12 (users, 1H), 1.85 to to 1.60 (m, 4H).

Examples 212-213

The interaction of (S)-N-(piperidine-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 was led to the compounds described in the examples 212-213.

Example 212

(S)-2-(3-((3-(Isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol, compound 2.036

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), 8,48 (d, J=6.0 Hz, 1H), EUR 7.57 (d, J=6 Hz, 1H), 7,42 (t, J=7.8 Hz, 1H), 7,30-7,22 (m, 2H), 6,98 (m, 2H), for 6.81 (DD, J=1,8, 8,1 Hz, 1H), 6.73 x (d, J=7.8 Hz, 1H), of 5.05 (users, 1H), 4.09 to (m, 2H), 3.96 points (m, 2H), 3,80 (users, 1H), 3,54 (DD, J=13,2, 38,1 Hz, 2H), 2,99 (s, 3H), 2.63 in (m, 2H), 2,35 (m, 1H), 2,12 (users, 1H), 1.85 to to 1.60 (m, 4H).

Example 213

(S)-N-(3-((3-(Isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide, the connection 2.037

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), charged 8.52 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,41 (t, J=7.8 Hz, 1H), 7,30-to 7.18 (m, 4H), 7,03 (m, 1H), 6,72 (d, J=7.8 Hz, 1H), of 5.05 (users, 1H), 3,81 (users, 1H), 3,55 (DD, J=13,5, 35,1 Hz, 2H), 2,99 (s, 3H), 2,65 (m, 3H), 2,35 (m, 1H), 1.85 to to 1.60 (m, 4H).

Examples 214-220

The interaction of (R)-N-(pyrrolidin-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 was led to the compounds described in the examples 214-220.

Example 214

(R)-N-(1-(4-(Methylthio)benzyl)pyrrolidin-3-the l)isoquinoline-5-amine, connection 2.026

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), 7,56 (d, J=6 Hz, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,31 (m, 5H), of 6.68 (d, J=7.5 Hz, 1H), 4,66 (d, J=7.2 Hz, 1H), 4,18 (m, 1H), to 3.64 (s, 2H), 2,88 (m, 2H), a 2.71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 2,47 (s, 3H), 2.05 is (users, 1H), of 1.85 (m, 1H).

Example 215

(R)-N-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide, compound 2.038

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), of 8.47 (d, J=6.0 Hz, 1H), 7,58 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (m, 3H), 7,14 (m, 2H), 6,69 (d, J=7.5 Hz, 1H), 4,66 (d, J=7.2 Hz, 1H), 4,16 (m, 1H), 3,65 (DD, J=13,2, of 19.5 Hz, 2H), 2.95 and (s, 3H), 2,89-of 2.72 (m, 3H), 2,60-to 2.40 (m, 2H), 1,80 (m, 1H).

Example 216

(R)-2-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol, compound 2.039

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), EUR 7.57 (d, J=6 Hz, 1H), 7,43 (t, J=8,1, 1H), 7,31 (d, J=8,1 Hz, 1H), 7,22 (d, J=8,1 Hz, 1H), 6,94 (m, 2H), 6,83 (m, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,67 (d, J=7.5 Hz, 1H), 4,16 (m, 1H), 4,06 (m, 2H), 3,94 (m, 2H), the 3.65 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 1,80 (m, 1H).

Example 217

(R)-2-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ndimethylacetamide, the connection 2.040

1H NMR (CD3OD, 300 MHz): δ 9,05 (s, 1H), 8,32 (d, J=6.0 Hz, 1H), 7,98 (d, J=6 Hz, 1H), of 7.48 (t, J=8,1 Hz, 1H), 7,33 (d, J=8,1 Hz, 1H), 7,28 (t, J=8,1 Hz, 1H), 7,01 (m, 2H), 6,91 (m, 1H), 6,78 (d, J=7.5 Hz, 1H), of 4.49 (s, 2H), 4,21 (m, 1H), 3,70 (s, 2H), 3,01 (m, 1H), 2,85 (m, 1H), 2,74-2,60 (m, 2H), 2,45 (m, 1H), of 1.88 (m, 1H).

Example 218

(R)-N-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)econsultant, connected to the e 2.041

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,45 (d, J=6.0 Hz, 1H), 7,60 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (m, 3H), 7,12 (d, J=7.5 Hz, 2H), 6,69 (d, J=7.5 Hz, 1H), 4,67 (m, 1H), 4,16 (m, 1H), 3,65 (DD, J=13,2, to 21.6 Hz, 2H), of 3.07 (q, J=7.2 Hz, 2H), 2,89 (m, 1H), 2,75 (m, 2H), 2,60-to 2.40 (m, 2H), 1,80 (m, 1H), 1,30 (t, J=7.2 Hz, 3H).

Example 219

(R)-2-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)-1-morpholinoethyl, the connection 2.043

Example 220

(R)-2-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)acetic acid, compound 2.044

Was obtained by condensation of the corresponding complex ester with subsequent removal of the protective group using the method of example 4.

Examples 221-222

The interaction of (S)-N-(pyrrolidin-3-yl)isoquinoline-5-amine with the appropriate aldehydes using the method of example 8 was led to the compounds described in the examples 221-222.

Example 221

(S)-2-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol, compound 2.032

1H NMR (CDCl3, 300 MHz): δ 9,14 (s, 1H), 8,46 (d, J=6.0 Hz, 1H), EUR 7.57 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (d, J=8,1 Hz, 1H), 7,22 (d, J=8,1 Hz, 1H), 6,94 (m, 2H), 6,83 (m, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,67 (d, J=7.5 Hz, 1H), 4,16 (m, 1H), 4,06 (m, 2H), 3,94 (m, 2H), the 3.65 (s, 2H), 2,88 (m, 2H), 2,71 (DD, J=3,6, and 9.6 Hz, 1H), 2,60-to 2.40 (m, 2H), 1,80 (m, 1H).

Example 222

(S)-N-(3-((3-(Isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide, the connection 2.035

1H NMR (CDCl3, 300 MHz): δ 9.15, with (s, 1H), of 8.47 (d, J=6.0 Hz, 1H), and 7.8 (d, J=6 Hz, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (m, 3H), 7,14 (m, 2H), 6,69 (d, J=7.5 Hz, 1H), 4,66 (d, J=7.2 Hz, 1H), 4,16 (m, 1H), 3,65 (DD, J=13,2, of 19.5 Hz, 2H), 2.95 and (s, 3H), 2,89-of 2.72 (m, 3H), 2,60-2,40 m, 2H), 1,80 (m, 1H).

Example 223

Analysis of inhibition of Rho kinase

Inhibition of ROCK2 activity was determined using a kit for the rapid screening IMAP™ (Molecular Devices, product number #8073). Kinase ROCK2 (UpstateChemicon #14-451) and labeled with fluorescein substrate-peptide F1-AKRRRLSSLRA (Molecular Devices, product number R7184) pre-incubated with test compound for 5 minutes in buffer containing 10 mm Tris-HCl pH to 7.2, 10 mm MgCl2, and 0.1% BSA. After pre-incubation was added 10 μm ATP to initiate the reaction. After 60 minutes at room temperature to bind phosphorylated substrate was added binder Molecular Devices IMAP™. After incubation for 30 minutes in the presence of beads IMAP™ read fluorescence polarization and reflect as mP. The results for the IC50was calculated using the software Prism from Graphpad.

This analysis demonstrates the ability of compounds to inhibit ROCK2 in vitro using selected enzyme. Most of the investigated compounds inhibited ROCK2, when values of the IC50below 10 microns, many of them inhibited at concentrations below 1 μm. The most effective compounds in this analysis which showed values IC 50below 250 nm. It was shown that compounds having values IC50in respect of ROCK2 about 2 μm or below, are effective in numerous studies using in vivo models of course of painful conditions described in this application, in particular on models of elevated IOP and glaucoma. Cm. Tian et al., Arch. Ophthalmol. 116: 633-643, 1998; Tian et al., Invest. Ophthalmol. Vis. Sci. 40: 239-242, 1999; Tian et al., Exp. Eye Res. 68: 649-655; 1999; Sabanay, et al., Arch. Ophthalmol. 118: 955-962, 2000; Volberg, et al., Cell Motil. Cytoskel. 29: 321-338, 1994; Tian et al., Exp. Eye Res. 71: 551-566, 2000; Tokushige et al., Invest. Ophthalmol. Vis. Sci. 48: 3216-3222, 2007; Honjo, et al., Invest. Ophthalmol. Vis. Sci. 42: 137-144, 2001.

Example 224

Analysis of the morphology of the cells NIH/3T3

Cells NIH/3T3 were grown in DMEM-H containing glutamine and 10% calf serum Colorado. Cells were regularly massirovala before Confluencia. For 18-24 hours before the experiment the cells were placed in 24-hole is covered with a poly-1-lysine tablets with a glass bottom. On the day of the experiment cells were removed culture medium and replaced it on the same medium containing from 10 nm to 25 μm test compound, and the cells were incubated for 60 minutes at 37°C. Then the culture medium was removed and cells were washed with warm PBS and fixed for 10 minutes using a heat is about 4% paraformaldehyde. The cells were broken by the permeability of the membrane with the use of 0.5% Triton-X, dyed them TRITC-conjugated-phalloidin and visualized using a Nikon Eclipse E600 EPI-fluorescence microscope to determine the degree of destruction of actin. The results were expressed in digital points, indicating that the observed degree of destruction of the actin cytoskeleton at the tested concentrations, ranging from 0 (no effect) to 4 (complete destruction), and were averaged according to at least 2 definitions.

All tested compounds show the measured activity in the analysis of the morphology of the cells, while the majority of the compounds represented significant effect on the actin cytoskeleton at the tested concentrations (score equal to 2, with 1 µm). The analysis demonstrates that the activity of ROCK inhibition in vitro of compounds can be manifested in morphological changes, such as breaking device of actin fibers and changing the focal adhesion in intact cells, leading to inhibition managed actomyosin cell contraction. It is expected that these morphological changes will provide the basis for a favorable pharmacological effects, which are achieved by the flow of painful conditions described in this application, in particular the reduction of elevated intraocular pressure in hypertensive the eyes due to the increased outflow through the trabecular mesh structure.

Example 225

Analysis of the ocular pharmacokinetics

Intraocular fluid (intraocular fluid) collected in new Zealand rabbits for the determination of pharmacokinetics in the cornea and anterior chamber of the eye for preparations containing compounds 1.008, 1.039 and 1.051. Each bilateral animal was administered a dose of 2×10 μl of a 25 mm solution of each test compound (in 10 mm acetate buffered saline, 0.01% chloride benzalconia, of 0.05% EDTA, pH 4.5) or the media. During the instillation of the upper and lower eyelids fixed motionless and compounds were introduced to the highest point of the eyeball, allowing them to flow freely over the surface of the eye. After putting on 30 seconds to prevent closing of eyes. Intraocular fluid collected in the period from 30 minutes to 8 hours after local instillation using needle 30 rooms, introduced proximally in scleral border of the cornea. Subsequently, 30 μl of aqueous humor was aspirated using a syringe 300 ál. Samples of aqueous humor were analyzed to determine the concentration of test compounds using the system for the analysis of LC/MS/MS. All experiments were performed in accordance with Bulletin ARVO on the use of animals in ophthalmic research and investigations of view and according to the accordance with the instructions of the National Institute of health USA (National Institutes of Health). The results of the observed concentrations of the test compounds in aqueous humor after 0.5, 2 and 4 hours after instillation in the eyes of the animals shown in figure 1.

This pharmacokinetic analysis shows that the compounds according to the invention, when the outer introduction able to enter the eye and reach concentrations in intraocular fluid, adequate to provide a significant inhibition of ROCK at the site of action, i.e. the concentrations of the components or greater than the value of the IC50in relation to the ROCK for the considered compounds. In addition, he shows that these compounds may exhibit different pharmacokinetic profiles when the outer introduction dosage in the eye, where some compounds show a more continuous presence, while others quickly penetrate the eye and quickly removed from the intraocular fluid.

Example 226

Pharmacodynamic analysis of intraocular pressure

The study used adult macaque monkeys-Griboedov both sexes. All experiments were performed in accordance with Bulletin ARVO on the use of animals in ophthalmic research and investigations of view and in accordance with the guidelines of the National Institute of health, USA (National Institutes of Health).

Before inclusion in the study by a qualified ophthalmologist wire is l examination using a slit lamp to determine the integrity of the epithelium and endothelium of the cornea, the presence of extensions or cells in the AU and transparency of the crystalline lens. All animals in the study had no ophthalmologic anomalies.

After measuring the baseline IOP cooked preparations containing medium (buffered with 10 mm acetate saline containing 0.01% chloride benzalconia and 0.05% EDTA, pH 4.5) and one of the connections 1.008 (2.8 mm), 1.039 (7.1 mm), 1.051 (1.4 mm), 1.074 (2.8 mm), 1.123 (2.8 mm), 2.038 (2.8 mm) or 2.039 (2.8 mm), or only the media that was introduced externally to the Central part of the cornea lying on the back of the animals at a rate of two drops of 20 µl with 30-second intervals, thus preventing blinking in between drops. Handling of animals was performed twice daily for 3.5 days at 8 am and 4 PM. After the introduction of every hour was measured IOP in 6 hours using a reduced flattened tonometer Goldmann. A study using a slit lamp was performed after 3 and 6 hours. Intraocular pressure in animals after treatment of the test compounds or the media on day 1 and day 4 from 0 hours to 6 hours are shown in figure 2.

This pharmacodynamic analysis shows that the compounds according to the invention is able to achieve a significant reduction in intraocular pressure when the outer dosing in primates with normal blood pressure. It further shows that Yes the connections are well tolerated by the ocular surface when the dosage of therapeutically characteristic way. Reduction of intraocular pressure in this way is the primary goal of treatment of glaucoma at the present time. Described in this application is the analysis represents the most widely accepted method preclinical evaluation for agents that reduce intraocular pressure.

The invention method and the method of its implementation and enforcement currently described in such full, clear, concise and exact terms to give the opportunity to any specialist in the area to which it pertains to make and use the same. It should be understood that all of the above describes the preferred embodiments of the present invention and that can be done and modification without departing from the scope of the present invention, as set out in the claims. For specific guidance and a clear statement of claim on the subject of the discussion relating to the invention, the following claim completes the description of the invention.

1. The compound of formula II
Formula II

where Q is a (CR4R5)n3;
n1represents 1 or 2;
n2represents 1 or 2;
n3represents 1;
R2is an R2-1 or R2-2

Ar represents a phenyl or Goethe is Marilee ring, consisting of 8-10 carbon atoms and 1-2 heteroatoms selected from O or S;
X represents from 1 to 2 substituents located on Ar, each independently selected from the group consisting of OR8, NR8R9, SR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(=O)R9, NR8C(=O)OR9and CN;
R3-R5represent H;
R8represents H, alkyl, cyclopropyl, phenyl or pyridinyl; optionally substituted by one or more Halogens or heteroaromatics substituents selected from the group consisting of OR11, NR11R12, CO2R11, CONR11R12, NR11C(=O)R12;
R9represents H or alkyl;
R11-R12independently represent H, alkyl, pyridinyl or morpholinyl;
provided that if X is acyclic and is connected to Ar by an oxygen atom, then X contains at least one additional atom of oxygen or nitrogen;
and provided that the compound of the following formula
excluded.

2. The compound according to claim 1, where n2represents 1.

3. The compound according to claim 1, where R8represents H or alkyl.

4. A compound selected from the group consisting of:
compounds 1.001, which is th is a N-(1-(4-(methylsulphonyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.002, which is 3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzonitrile; connection 1.004, which is N-(1-(4-(methylsulphonyl)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine;
connection 1.005, which is 3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)benzonitrile; connection 1.038, which is 4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzonitrile; connection 1.048, which is N-(1-(3-(methylsulphonyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.055, which is 3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzamide; connection 1.056, which is 3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzosulfimide; connection 2.002, which is N-(1-(4-(methylsulphonyl)benzyl)piperidine-3-yl)isoquinoline-5-amine;
connection 2.003, which is 3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)benzonitrile; connection 2.005, which is N-(1-(4-(methylsulphonyl)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine;
connection to 2,007, which is 3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)benzonitrile; connection 1.003, which is N-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)ndimethylacetamide; connection 1.006, which is N-(4-((3-(1H-indazol-5-ylamino)PI is Raiden-1-yl)methyl)phenyl)ndimethylacetamide;
connection 1.007, which is N-(1-(4-(3-(dimethylamino)propoxy)benzyl)pyrrolidin-3-yl)-1H-indazol-5-amine;
connection 1.018, which is 2-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol; compound 1.039, which is 2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol; compound 1.051, which is N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide; connection 1.058, which is 2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-methylphenoxy)ethanol; compound 1.060, which is ethyl 2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetate;
connection 1.084, which is 3-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-1-ol;
connection 1.085, which is N-(1-(3-(2-aminoethoxy)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.086, which is 2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetic acid;
connection 1.087, which is N-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide;
connection 1.088, which is 2-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol;
connection 1.090, which is (S)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)Fe is hydroxy)ethanol;
compound 1.091, which is (S)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide;
connection 1.092, which is (R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol;
connection 1.093, which is (R)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide;
connection 1.094, which is (S)-2-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol;
connection 1.095 has, which is (S)-N-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide;
connection 1.096, which is (R)-2-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol;
connection 1.097, which is (R)-N-(3-((3-(1H-indazol-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide;
connection 1.098, which is 2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ndimethylacetamide;
connection 1.102, which is N-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-chlorophenyl)methanesulfonamide;
connection 1.111, which is N-(2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl) methyl)phenoxy)ethyl)ndimethylacetamide; connection 1.113, which is (S)-3-(3-(((R)-3-(1H-indazol-5-ylamino) piperidine-1-yl)methyl)phenoxy)propane-1,2-diol; compound 1.115, which is(R)-3-(3-(((R)-3-(1H-indazol-5-ylamino) piperidine-1-yl)methyl)phenoxy)propane-1,2-diol;
connection 1.116, which is (R)-1-(3-(((R)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-2-ol;
connection 1.117, which is (R)-3-(3-(((S)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propane-1,2-diol; compound 1.118, which is (R)-1-(3-(((S)-3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)propan-2-ol;
connection 1.120, which is N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant; connection 1.121, which is N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)-N-methylmethanesulfonamide;
connection 1.123, which is (R)-N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)econsultant;
connection 1.124. which is (S)-N-(3-((3-(1H-indazol-5-ylamino) piperidine-1-yl)methyl)phenyl)econsultant;
connection 1.125. which is (R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)acetic acid;
connection 1.126. which is (R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-N-(pyridin-3-yl)ndimethylacetamide;
connection 1.127, which is (R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-1-morpholinoethyl; connection 1.128, which is (R)-2-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)-1-(4-methylpiperazin-1-yl)Etalon; with the unity 1.129. which is (R)-diethyl (3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)methylphosphonate; connection 1.130. which is 2-(3-((4-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol; compound 2.004, which is N-(4-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)ndimethylacetamide;
connection 2.008, which is N-(4-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)ndimethylacetamide; connection 2.032, which is (S)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol; compound 2.033, which is (R)-N-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide; connection 2.034, which is (R)-2-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol; compound 2.035, which is (S)-N-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide; connection 2.036, which is (S)-2-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenoxy)ethanol; compound 2.037, which is (S)-N-(3-((3-(isoquinoline-5-ylamino)piperidine-1-yl)methyl)phenyl)methanesulfonamide; compound 2.038, which is (R)-N-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)methanesulfonamide; connection 2.039, which is (R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)Fe is hydroxy)ethanol; connection 2.040, which is (R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ndimethylacetamide; connection 2.041, which is (R)-N-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenyl)econsultant; connection 2.042, which is 2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol; compound 2.043, which is (R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)-1-morpholinoethyl;
connection 2.044, which is (R)-2-(3-((3-(isoquinoline-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)acetic acid; compounds 1.008, which is N-(1-(4-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.017, which is N-(1-(4-(ethylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.026, which is N-(1-(4-(cyclopropylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.040, which is N-(1-(3-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.074, which is (R)-N-(1-(4-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.075, which is (S)-N-(1-(4-(methylthio)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 2.009, which is a R-(1-(4-(methylthio)benzyl)piperidine-3-yl)isoquinoline-5-amine; compound 2.012, which is N-(1-(4-(is ecoproperty)benzyl)piperidine-3-yl)isoquinoline-5-amine;
connection 2.021, which is (R)-N-(1-(4-(cyclopropylamino)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine;
connection 2.024, which is (S)-N-(1-(4-(cyclopropylamino)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine;
connection 2.026, which is (R)-N-(1-(4-(methylthio)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine; and connections 2.029, which is (S)-N-(1-(4-(methylthio)benzyl)pyrrolidin-3-yl)isoquinoline-5-amine.

5. The compound of formula II
Formula II

where Q is a (CR4R5)n3;
n1represents 1 or 2;
n2represents 1 or 2;
n3represents 1;
R2is an R2-1 or R2-2

Ar represents phenyl;
X represents from 1 to 2 substituents located on Ar, each of which independently exists in the form Y-Z, in which Z is attached to Ar;
Y represents one or more substituents located on Z, and each of them represents H;
Z represents alkenyl, quinil, cycloalkyl, cycloalkenyl, phenyl, imidazolyl, pyrrolidinyl, morpholinyl and thiophenyl;
R3-R5independently represent N.

6. A compound selected from the group consisting of compounds 1.009, which is N-(1-(bi is enyl-4-ylmethyl)piperidine-3-yl)-1H-indazol-5-amine; connection 1.010, which is N-(1-(1H-imidazol-1-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.011, which is N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.012, which is N-(1-(4-morpholinomethyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.020, which is N-(1-(4-cyclopropylmethyl)piperidine-3-yl)-1H-indazol-5-amine; connection 1.021, which is N-(1-(3-cyclopropylmethyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.030, which is N-(1-(4-(thiophene-2-yl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.034, which is N-(1-(4-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.037, which is N-(1-(4-vinylbenzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.044, which is N-(1-(4-(cyclopropylamino)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.047, which is N-(1-(3-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.076, which is (R)-N-(1-(4-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.077, which is (S)-N-(1-(4-ethynylphenyl)piperidine-3-yl)-1H-indazol-5-amine; connection 1.083, which represents 5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-2-ethynylphenyl; connection 2.010, which made the focus of an N-(1-(4-cyclopropylmethyl)piperidine-3-yl) isoquinoline-5-amine; connection 2.011, which is N-(1-(3-cyclopropylmethyl)piperidine-3-yl)isoquinoline-5-amine; compound 2.019, which is (S)-N-(1-(4-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine; compound 2.020, which is (R)-N-(1-(3-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine; compound 2.022, which is a (R)-N-(1-(4-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine; compound 2.023, which is (S)-N-(1-(3-cyclopropylmethyl)pyrrolidin-3-yl)isoquinoline-5-amine; and connections 2.031, which is (R)-N-(1-(4-ethynylphenyl)pyrrolidin-3-yl)isoquinoline-5-amine.

7. The compound of formula II
Formula II

where Q is a (CR4R5)n3;
n1represents 1 or 2;
n2represents 1 or 2;
n3represents 1;
R2is an R2-1 or R2-2

Ar represents a phenyl or indolyl;
X represents from 1 to 2 substituents located on Ar, each of which independently exists in the form Y-Z, in which Z is attached to Ar;
Y represents one Deputy, located on the Z, which represents halogen, OR8, NR8R9, SR8, SO2R8, CO2R8, CONR8R9and NR8(=O)R 9;
Z represents alkyl, alkenyl, quinil;
R3-R5independently represent H;
R8represents H or alkyl;
R9represents H or alkyl;
provided that when Z is chosen from the group consisting of alkyl, alkenyl and quinil, and Y falls on the carbon by which Z is linked to Ar, then Y contains at least one atom of nitrogen or sulfur.

8. A compound selected from the group consisting of compounds 1.019, which is N-(1-(4-((dimethylamino)methyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.027, which represents tert-butyl 4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzylcarbamoyl; connection 1.028, which is N-(1-(4-(methylthiomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.029, which is N-(1-(4-(methylsulfonylmethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.035, which is N-(1-(4-(aminomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.041, which is N-(1-(3-(methylsulfonylmethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine;
connection 1.042, which is 3-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)prop-2-in-1-ol;
connection 1.043, which represents a 4-(4-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)phenyl)but-3-in-1-ol; connection 1.057, which represents a tert-butyl 3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzylcarbamoyl;
connection 1.061, which is N-(1-(3-(aminomethyl)benzyl)piperidine-3-yl)-1H-indazol-5-amine; compound 1.099, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide; connection 1.101, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol; compound 1.103, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetic acid;
connection 1.104, which is 2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)indolin-1-yl)ethanol;
connection 1.105, which is 2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide;
connection 1.106, which is (R)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide;
connection 1.107, which is (S)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ndimethylacetamide;
connection 1.108, which is (R)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol;
connection 1.109, which is (S)-2-(6-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol;
connection 1.112, which represents tert-butyl 2-(5-((3-(1H-indazol-5-the laminitis)piperidine-1-yl)methyl)-1H-indol-1-yl)acetate;
connection 1.114, which is 2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)ethanol; compound 1.119, which is 2-(5-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)-1H-indol-1-yl)acetic acid and compounds 1.122, which is N-(3-((3-(1H-indazol-5-ylamino)piperidine-1-yl)methyl)benzyl)ndimethylacetamide.

9. A method of reducing intraocular pressure in in need thereof of a subject, comprising the stage
identify needs in this subject and
the introduction of the subject compounds according to claims 1, 5 or 7 in the amount effective for inhibiting actomyosin interactions.

10. The method according to claim 9, where the specified method to treat glaucoma.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is oxazolidinone of general formula , where values of radicals are given in invention formula, and pharmaceutical antibiotic composition, which includes as active ingredient novel oxazolidinone derivative, its hydrate, solvate, isomer or pharmaceutically acceptable salt.

EFFECT: compounds are characterised by wide antibacterial spectrum and high antibacterial activity against gram-positive and gram-negative resistant bacteria, low toxicity and can be applied as antibiotic.

7 cl, 3 tbl, 106 ex

FIELD: medicine.

SUBSTANCE: described are novel heterocyclic compounds of general formulae and (values of radicals are given in invention formula), pharmaceutical compositions containing them and application of said heterocyclic compounds for treatment disorders mediated with MAP kinase cascade.

EFFECT: increase of compound efficiency.

67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula I: , where values of R1-R4, R7, R8 are given in claim 1. Compounds of formula I exhibit antagonistic activity on MR steroid receptors, which enables their use to produce a pharmaceutical composition and drugs with MR steroid receptor antagonist properties.

EFFECT: improved method.

95 cl, 26 dwg, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of formula I or their pharmaceutically acceptable salts showing activity with respect to HIV reverse transcriptase, as well as to a based pharmaceutical composition (I). In formula I R1 means phenyl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, phenyl or heteroaryl optionally substituted by one-three substitutes independently specified in groups (a)-(r), R2 means -CN, -CH=CHCN or halogen; R3 means hydrogen, halogen, amino group, halogen(C1-C6)alkyl, -CN or methyl; R4 means hydrogen, Br or amino group; R5a and R5b independently mean hydrogen, C1-C6alkyl, C1-C6alkoxy group or halogen; R6a and R6b either independently mean hydrogen, or together mean ethylene; X means NH or O. The groups (a)-(r) are such as presented in the patent claim.

EFFECT: preparing pharmaceutically acceptable salts possessing activity with respect to HIV reverse transcriptase.

17 cl, 42 ex, 6 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a deuterium-enriched α-ketoamide compound of formula wherein: D means a deuterium atom; the values R1-R5 are presented in cl.1 of the patent claim, and to a based pharmaceutical composition.

EFFECT: method improvement.

32 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a MMP12 inhibitor, a method for preparing them, an intermediate compound of formula (III), a pharmaceutical composition, a method for preparing it, using the compounds of formula (I) and versions of methods of treating with the use of the compounds of formula (I). The compounds may be used for treating the MMP12-mediated diseases, such as chronic obstructive pulmonary disease. In formula (I) and (III) R1 represents H, CH3, CH3CH2, CF3 or cyclopropyl; and R2 represents H or CH3.

EFFECT: higher clinical effectiveness.

15 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1,3-disubstituted 4-methyl-1H-pyrrol-2-carboxamides of formula I: wherein the values R1, R2, R3, R4 are presented in cl.1 of the patent claim.

EFFECT: preparing the compounds found to be serotonin-5-HT reuptake inhibitors that enables using them in medicine.

14 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

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