Novel ligands of estrogen receptors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

 

The technical field to which the invention relates.

The invention relates to compounds that are ligands of estrogen receptors and preferably election in respect of the β-isoform of the estrogen receptors, to methods for producing such compounds and for methods of using such compounds in the treatment connected with estrogen receptors in diseases such as depressive disorders, anxiety disorders, Alzheimer's disease, disorders of cognitive abilities, osteoporosis, elevated triglycerides in the blood, atherosclerosis, endometriosis, urinary incontinence, autoimmune disease and cancer of the lung, colon, breast, uterus and prostate.

Background of invention

Estrogen receptor (ER) is a ligand-activated transcription factor mammals, involved in the activation and suppression of gene expression. Natural hormone to estrogen receptor is 17β-estradiol (E2) and closely related metabolites. The binding of estradiol to estrogen receptor causes receptor dimerization and dimer, in turn, binds to estrogen response elements (ERE) on DNA. Complex ER/DNA recruits other transcription factors responsible for the transcription of DNA, located on ERE in the course of transcription is AI, in mRNA, which, ultimately, translates into protein. Alternatively, the interaction of ER with DNA may be indirect and oposredovanie other transcription factors, in particular, fos and jun. Due to the fact that the expression of a large number of genes regulated by estrogen receptor and estrogen receptor is expressed in many cell types, modulation of the estrogen receptor through binding of the natural hormone or synthetic ER ligands can have a strong effect on the physiology and pathophysiology of the body.

Historically it was believed that there is only one estrogen receptor. However, it was discovered the second subtype of receptor (ER-β). Although "classic" ERα later outdoor ER-β is widely distributed in various tissues, however, their distribution in the types of cells and tissues is quite different. Therefore, synthetic ligands that are selective against ER-α or ER-β, can have a positive effect of estrogen, reducing at the same time, the risk of unwanted side effects.

Estrogens are crucial for sexual development in women. In addition, estrogens play an important role in maintaining bone density, regulation of lipid in the blood, and, apparently, have neuroprotective effects. Therefore, reduced production of estrogen in wives who in postmenopausal women is associated with a number of diseases, such as osteoporosis, atherosclerosis, depression, and disorders of cognitive abilities. Conversely, some types of proliferative diseases, such as breast cancer, uterine cancer and endometriosis, stimulated by estrogen, but because antiestrogens (i.e. antagonists estrogen) applicable to the prevention and treatment of these types of violations.

It was also demonstrated the effectiveness of the natural estrogen, 17β-estradiol for the treatment of various forms of depressive illness, and it has been suggested that the antidepressant activity of estrogen may oposredovanie regulation of the activity of tryptophan hydroxylase and subsequent synthesis of serotonin (see, for example, Lu N.Z., Shlaes T.A., Cundlah C., Dziennis S.E., Lyle R.E., Bethea C.L., "Ovarian steroid action on tryptophan hydroxylase protein and serotonin compared to localization of ovarian steroid receptors in the midbrain of guinea pigs." Endocrine 11:257-267, 1999). Pleiotropic nature of natural estrogen prevents its wider, more long-term use due to increased risk of proliferative action on the tissues of the breast, uterus and ovaries. Identification of the estrogen receptor, ERβ, has enabled the identification of more selective estrogen agents that have the desired antidepressant activity in the absence of proliferative actions, mediated by ERα. Thus, it was shown that therapeutic is the means, with selectivity against Erβ, potentially effective in the treatment of depression.

In the art there is a need for compounds that are able to induce the same positive effects as estrogen replacement therapy without the negative side effects. There is also a need in estrogen-like compounds that have effects selective in respect to the various tissues of the body.

In WO 2006/019831 revealed some indole derivatives useful for the prevention or treatment of infection by hepatitis C virus In WO 2005/018636 disclosed certain indole derivative having modulating activity against estrogen receptor, and all these indoles are oximes.

Compounds of the present invention are ligands of estrogen receptors, and therefore can be applicable for the treatment or prevention of a wide range of conditions related to estrogen, including bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, elevated cholesterol low-density lipoprotein, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, degenerative abnormalities in the brain, the rest is LCM, gynecomastia, the proliferation of smooth muscle cells of blood vessels, obesity, incontinence, anxiety, depression, depression during perimenopause, postpartum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, hyperactivity, attention deficit, sleep disorders, irritability, impulsivity, anger management, hearing impairment, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, autoimmune disease, inflammation, inflammatory bowel disease, irritable bowel syndrome, sexual dysfunction, hypertension, degeneration of the retina, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer and cholangiocarcinoma.

A brief description of the invention

The present invention relates to the compound of formula (I) or its pharmaceutically acceptable complex ether, amide, carbamate, MES or salt, including salt of such a complex ester, amide or carbamate and MES such a complex ester, amide, carbamate, or a salt

where R1selected from the group consisting of halogen atom, cyano, nitro, ORΛN(RB)2, -C(O)C1-4 of alkyl, -SO2C1-4of alkyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, Halogens2-6alkenyl, dihalogens2-6alkenyl, trihalogen2-6alkenyl, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORΛ, halogen atom, cyano, nitro, -C(O)C1-4of alkyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl;

R2selected from the group consisting of halogen atom, cyano, nitro, ORAN(RB)2N(OH)2, -C(O)C1-4the alkyl, optionally substituted by 1-3 halogen atoms, -SO2C1-4of alkyl, -C(O)NH-OH, -C(NH2)=N-OH, -C(CO2H)=N-OH, -C(NH2)=NH, -C(NHC1-4alkyl)=NH, -C(O-C1-4alkyl)=NH, -C(NH2)=N-NH2, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), -S-CN, -S,-C(NH2)=NH, -S-C(NH2)=N-OH, -CO2H, -CH2-CO2H, -CH(OH)CO2H, -C(O)CO2H, SO3H, CH2SO3H, C1-6is Lila, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORΛ, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl; provided that when one of R1and R2represents a halogen atom, the other must represent a group other than a halogen atom;

each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, ORA, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl;

each RAindependently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, C6-10aryl and C6-10ar what drug 1-6of alkyl, each of which is optionally substituted by 1 to 3 halogen atoms; and

each RBindependently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, C6-10aryl and C6-10arils1-6of alkyl, each of which is optionally substituted by 1 to 3 halogen atoms;

provided that the compound of formula (I) is not a

4-[3-(4,5-Dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indol-1-yl]phenol;

1-(4-Hydroxyphenyl)-2-(4-Mei-1-yl)-1H-indol-3-carbonitrile;

1-(4-Hydroxyphenyl)-2-(1H-pyrazole-3-yl)-1H-indol-3-carbonitrile;

1-(3-Chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;

Amide 1-(4-Hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid; or

1-(4-Hydroxyphenyl)-2-thiazol-2-yl-1H-indole-3-carboxylic acid.

Surprisingly it was found that the compounds of the present invention are ligands of the estrogen receptor. Accordingly, the compounds find use in the treatment and prevention of conditions associated with the activity of estrogen receptors.

Detailed description of the invention

Compounds of the present invention may contain chiral (asimmetricheskie) centers, or the molecule as a whole can be chiral. Separate stereo the Windows (enantiomers and diastereoisomers) and mixtures thereof fall under the scope of the present invention.

The present invention relates to compounds that are ligands of estrogen receptors. Used in this document, the term "ligand of the estrogen receptor" is intended to encompass any fragment that binds to the estrogen receptor. The ligand may act as an agonist, partial agonist, antagonist or partial antagonistical can be selective against ERβ or show a mixed activity against ERα and ERβ. For example, the ligand may act as an agonist or partial agonist of ERβ and the antagonist or partial antagonist of ERα.

If R1represents heterocyclyl group, this group may be saturated or unsaturated and may contain one or more atoms of O, N and/or S. It is preferably 5 - or 6-membered. Suitable heterocyclyl groups include furyl, thienyl, pyrrolyl, pyrrolidyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, pyridyl, morpholinyl and piperidyl, and isoxazolyl is especially preferred heterocyclyl group. Preferred substituents for heterocyclyl groups include 1-3, e.g. 1 or 2 substituent, and each Deputy is chosen from the group consisting of OR , halogen atom, cyano, -C(O)C1-4of alkyl, C1-4of alkyl, C2-4alkenyl, C2-4the quinil, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4the alkyl. Particularly preferred substituents selected from a halogen atom, cyano, C1-4the alkyl (especially methyl), -C(O)C1-4the alkyl and ORAwhere RApreferably represents a hydrogen atom or a C1-4alkyl group. More preferred substituents selected from a halogen atom, cyano, and C1-4the alkyl (especially methyl or ethyl).

Preferred substituents for the phenyl or benzyl group, R1include the substituents mentioned above for heterocyclyl group, R1.

If R2represents heterocyclyl group, this group may represent, for example, one of the preferred groups mentioned above for R1.

Preferred substituents for the phenyl or benzyl group, R2include the substituents mentioned above for heterocyclyl group, R1.

Unless otherwise expressly stated, each RApreferably independently selected from the group consisting of a hydrogen atom, a C1-4of alkyl, C2-4alkenyl, C2-4the quinil, C3-6cycloalkyl, phenyl and benzyl. Preferably, each RAindependently made the focus of an atom of hydrogen or C 1-4alkyl, in particular methyl.

Unless otherwise expressly stated, each RBpreferably independently selected from the group consisting of a hydrogen atom and C1-4the alkyl.

Preferably, R1selected from the group consisting of ORAN(RB)2, -C(O)C1-4of alkyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-4of alkyl, dihalogens1-4of alkyl, trihalogen1-4of alkyl, Halogens2-4alkenyl, dihalogens2-4alkenyl, trihalogen2-4alkenyl, phenyl and 5-6-membered heterocyclyl where the above-mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted as described above. More preferably, R1selected from the group consisting of ORAN(RB)2, -C(O)C1-4of alkyl, C1-4of alkyl, C2-4alkenyl, C2-4the quinil, phenyl and 5-6-membered heterocyclyl where the above-mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted as described above.

R2can be selected, for example, from one of the preferred groups mentioned above for R1. In one embodiment of the present invention R2selected from the group consisting of halogen atom, cyano, nitro, ORAN(RB)2N(OH)2, -C(O)C1-4the alkyl, optional samemanner is 1 to 3 halogen atoms, -SO2C1-4of alkyl, -C(O)NH-OH, -C(NH2)=N-OH, -C(CO2H)=N-OH, -C(O-C1-4alkyl)=NH, -C(NH2)=N-NH2, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), -S-CN, -S,-C(NH2)=NH, -S-C(NH2)=N-OH, -CO2H, -CH2-CO2H, -CH(OH)CO2H, -C(O)CO2H, SO3H, CH2SO3H, C1-6of alkyl, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORΛ, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6the alkyl.

In an alternative embodiment of the present invention R2selected from the group consisting of a halogen atom, nitro, ORAN(RB)2, -C(O)C1-4the alkyl, optionally substituted by 1-3 halogen atoms, -SO2C1-4of alkyl, -C(O)NH-OH, -C(NH2)=N-OH, -C(NH2)=NH, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), -S-C(NH2)=NH, -CO H, -CH2-CO2H, SO3H, CH2SO3H, C1-6of alkyl, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, tsianos1-6of alkyl, C1-4alkoxyl1-6the alkyl,C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORA, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6the alkyl.

In a preferred embodiment of the present invention R2selected from the group consisting of a halogen atom, nitro, ORAN(RB)2, -C(O)C1-4the alkyl, optionally substituted by 1-3 halogen atoms, -SO2C1-4of alkyl, -C(O)NH-OH, -C(NH2)=N-OH, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), -S-C(NH2)=NH, -CO2H, -CH2-CO2H, C1-6of alkyl, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, tsianos1-6of alkyl, C1-4alkoxyl1-6the alkyl,C2-6alkenyl, C2-6the quinil, C3-8the CEC is valkila, C3-8cycloalkyl1-6alkyland,phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORA, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6the alkyl. More preferably, R2selected from the group consisting of-C(O)C1-4the alkyl (especially-C(O)CH3), -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-4of alkyl, C2-4alkenyl, C2-4the quinil and 5-6-membered heterocyclyl where the above-mentioned heterocyclyl group can be either unsubstituted or substituted as described above. Most preferably, R2selected from the group consisting of-C(O)CH3), -C(NH2)=N-OH, -CO2H and-CH2-CO2H, and-C(NH2)=N-OH is particularly preferred R2group.

Preferably, each of R3, R4, R5and R6selected from the group consisting of a hydrogen atom, ORΛ, halogen atom, cyano, C1-4of alkyl, for example methyl, Halogens1-4of alkyl, for example, chlormethyl or formatie, dihalogens1-4of alkyl, for example, dichloromethyl or deformed the La, and trihalogen1-4of alkyl, for example, trichloromethyl or trifloromethyl. Preferably, each of R3, R4, R5and R6selected from the group consisting of a hydrogen atom, OH, halogen atom, cyano, methyl or trifloromethyl. Most preferably, at least one of R3and R4represents a hydrogen atom. Most preferably, each R5and R6independently represents a hydrogen atom and/or halogen, in particular fluorine atom.

Accordingly, in one preferred group of compounds of the present invention R1selected from the group consisting of ORAN(RB)2, -C(O)C1-4of alkyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-4of alkyl, dihalogens1-4of alkyl, Halogens2-4alkenyl, dihalogens2-4alkenyl, trihalogen2-4alkenyl, phenyl and 5-6-membered heterocyclyl where the above-mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted as described above; more preferably, R1selected from the group consisting of ORAN(RB)2, -C(O)C1-4of alkyl, C1-4of alkyl, C2-4alkenyl, C2-4the quinil, phenyl and 5-6-membered heterocyclyl where the above-mentioned phenyl or heterocyclyl group can be either unsubstituted or is replaced the military, as described above;

R2selected from the group consisting of-C(O)C1-4the alkyl (especially-C(O)CH3), -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-4of alkyl, C2-4alkenyl, C2-4the quinil and 5-6-membered heterocyclyl where the above-mentioned heterocyclyl group can be either unsubstituted or substituted as described above;

each of R3, R4, R5and R6selected from the group consisting of a hydrogen atom, ORA, halogen atom, cyano, C1-4of alkyl, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4of alkyl, in particular hydrogen, OH, halogen atom, cyano, methyl or trifloromethyl; in particular, each of R5and R6represents a hydrogen atom and/or halogen, in particular fluorine atom;

each RApreferably independently selected from the group consisting of a hydrogen atom, a C2-4alkenyl, C2-4the quinil, C3-6cycloalkyl, phenyl and benzyl, in particular from a hydrogen atom and C1-4of alkyl, in particular methyl; and

each RBindependently selected from the group consisting of a hydrogen atom and C1-4the alkyl.

In an additional embodiment, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable complex ether, amide, MES or with the and, including a salt of such a complex ester, amide and MES such a complex ester, amide or salt

where R1selected from the group consisting of halogen atom, cyano, nitro, ORAN(RB)2, -C(O)C1-4of alkyl, -SO2C1-4of alkyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, Halogens2-6alkenyl, dihalogens2-6alkenyl, trihalogen2-6alkenyl, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORA, halogen atom, cyano, nitro, -C(O)C1-4of alkyl, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl;

R2selected from the group consisting of halogen atom, cyano, nitro, ORAN(RB)2, -C(O)C1-4the alkyl, optionally substituted by 1-3 halogen atoms, -SO2C1-4of alkyl, -C(O)NH-OH, -C(NH2)=N-OH, -C(NH2)=NH, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH CH2-NH-), -S-C(NH2)=NH, -CO2H, -CH2-CO2H, SO3H, CH2SO3H, C1-6of alkyl, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, phenyl, benzyl and 5-10 membered heterocyclyl where the above-mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORA, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl; provided that when one of R1and R2represents a halogen atom, the other must represent a group other than a halogen atom;

each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, ORA, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl;

each RΛindependently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C2-6alkenyl, C-6 the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, C6-10aryl and C6-10arils1-6of alkyl, each of which is optionally substituted by 1 to 3 halogen atoms; and

each RBindependently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C2-6alkenyl, C2-6the quinil, C3-8cycloalkyl, C3-8cycloalkyl1-6of alkyl, C6-10aryl and C6-10arils1-6of alkyl, each of which is optionally substituted by 1 to 3 halogen atoms;

provided that the compound of formula (I) is not 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indol-1-yl]phenol.

The compounds of formula (I) include, without limitation compounds specifically named in this document examples. In the examples the names of the compounds were formed in accordance with IUPAC using software ACD Labs 8.0/program name, version 8.05 and/or using ISIS DRAW Autonom 2000 and/or ChemBioDraw Ultra, version 11.0.

Depending on the substituents present in the compounds of formula (I)compounds can form esters, amides, carbamates and/or salt. Salts and solvate of the compounds of formula (I)suitable for use in medicine are those in which the counterion or associated solvent is pharmaceutically acceptable. However, salt and SOLV is you, containing pharmaceutically unacceptable counterions or associated solvents, fall under the scope of the present invention, for example, for use as intermediates in obtaining the compounds of formula (I) and their pharmaceutically acceptable salts, solvate and physiologically active derivatives. The term "physiologically active derivative" understand chemical derivative compounds of formula (I)having the same physiological activity as the free compound of the formula (I), for example, into his body. Esters, amides and carbamates are examples of physiologically active derivatives.

Suitable salts of the present invention include salts formed with organic or inorganic acids or bases. Particularly suitable salts formed with acids of the present invention include salts formed with inorganic acids, strong organic carboxylic acids, such as alcancarao acid containing 1-4 carbon atoms, which are unsubstituted or substituted, for example, a halogen atom, such as unsaturated or saturated dicarboxylic acids, such as hydroxycarbonate acid, such as amino acids, or with organic sulfonic acids, such as (C1-C 4)-alkylsulfonyl or arylsulfonyl acids which are unsubstituted or substituted, for example, by a halogen atom. Pharmaceutically acceptable acid additive salts include salts formed with hydrochloric, Hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, pyruvic, triperoxonane, amber, perarnau, fumaric, maleic, glycolic, salicylic, salewoman, methansulfonate, econsultancy, para-toluensulfonate, formic, benzoic, malonic, naphthalene-2-sulfonic, benzosulfimide, italianboy, ascorbic, malic, phthalic, aspartic and glutamic acids, lysine and arginine. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be used as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid additive salts.

Pharmaceutically acceptable basic additive salts include ammonium salts, alkali metal salts, for example, salts of potassium and sodium, salts of alkaline earth metals, e.g. calcium salts and magnesium, and salts formed with organic bases, for example, dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, with mono-, di - the three-(lower alkyl)amine, for example, ethyl-, tert-butyl-, diethyl-, aminobutiramida-, triethyl-, tributyl or dimethylpropylene, or with mono-, di - or trihydroxy(lower alkyl)amine, for example, mono-, di - or triethanolamine. Optionally can form internal salts.

The compounds of formula (I) may contain a suitable group converted to an ester, amide or carbamate. So, a typical ester and amide groups, formed from the acid group in the compound of formula (I)include-COORB, -CONRB2, -SO2ORBor-SO2NRB2while typical ester, amide and urethane groups formed from-OH or-otherBgroup in the compound of formula (I)include-OCORB, -NRBCORB, -NRBCO2R8-OSO2RBand-NRBSO2RBwhere the value of RBis one of the above.

Experts in the field of organic chemistry should understand that many organic compounds can form complexes with solvents in which they interact, or in which they precipitate or crystallize. Such complexes are known as "solvate". For example, a complex of water known as "hydrate".

Compound that when administered to the recipient can be converted into the above-described compound of formula (I), is whether his active metabolite or residue, known as a "prodrug". The prodrug can be converted inside the body, for example, by hydrolysis in blood, in its active form that has medical effects. Pharmaceutically acceptable prodrugs described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series (1976); "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated in this document by reference.

The following definitions apply to terms used throughout this description, unless specified otherwise in special cases.

Used in this document, the term "alkyl" means a saturated hydrocarbon group and unbranched and branched chain.

Examples of alkyl groups include methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, tert-boutelou, isobutylene, second-boutelou, pentelow and hexoloy group. Among unbranched alkyl groups, preferred are methyl, ethyl, n-sawn, ISO-propyl and n-bucilina group. Among the branched alkyl groups may be mentioned tert-bucilina, isobutylene, 1-ethylpropyl and 1-ethylbutyl group.

Used in this document, the term "alkoxy" means the group O-alkyl, where the term "alkyl" described the above.

Examples of alkoxygroup include a methoxy group and ethoxypropan. Other examples include propoxy, butoxy.

Used in this document the term "alkenyl" means an unsaturated hydrocarbon group and unbranched and branched chain, containing at least one double carbon-carbon bond. Examples alkenyl groups include ethynyl, propenyl, butenyl, pentenyl and hexenyl. Preferred alkeneamine groups include ethynyl, 1-propenyl and 2-propenyl.

Used in this document the term "quinil" means an unsaturated hydrocarbon group and unbranched and branched chain, containing at least one triple carbon-carbon bond. Examples etkinlik groups include ethinyl, PROPYNYL, butynyl, pentenyl and hexenyl. Preferred alkeneamine group include ethinyl, 1-PROPYNYL and 2-PROPYNYL.

Used in this document the term "cycloalkyl" means a saturated group in the ring system. Cycloalkyl group can be monocyclic and bicyclic. Bicyclic group may be, for example, condensed or linked bridge connection. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and the CEC is octyl. Examples of bicyclic cycloalkyl groups include bicyclo[2.2.1]hept-2-yl. Preferably, cycloalkyl group is monocyclic.

Used in this document, the term "aryl" means a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. Naftalina group can be attached via the 1 - or 2-position. In bicyclic aromatic group, one of the rings may be, for example, partially saturated. Examples of such groups include indanyl and tetrahydronaphthyl. Specifically used in this document, the term "C5-10aryl" means a group containing from 5 to 10 carbon atoms in the monocyclic or bicyclic aromatic group. Particularly preferred C5-10aryl group is phenyl.

Used in this document, the term "halogen atom" means a fluorine atom, chlorine, bromine or iodine. Especially preferred are fluorine atom, chlorine and bromine.

Used in this document the term "halogenated" means an alkyl group containing halogen Deputy, and the meaning of the terms "alkyl" and "halogen atom" defined above. By analogy, the term "dehalogenated" means an alkyl group containing two halogen substituent, and the term "trihalomethyl" means alkyl group, with whom containing a series of three halogen substituent. Examples halogenating groups include formeterol, chlormethine, bromatology, forprofile and terbutaline group; examples dehalogenating groups include deformational and deperately group; examples trialogical groups include triptorelin and triptorelin group.

Used in this document the term "heterocyclyl" means consisting of carbon atoms, aromatic or nonaromatic cyclic group, in which from 1 to 3 carbon atoms substituted by one or more heteroatoms independently selected from nitrogen atoms, oxygen or sulfur. Heterocyclyl group can be, for example, monocyclic or bicyclic. In bicyclic heterocyclyl group one or more heteroatoms may be contained in each ring or in only one of the rings. Heteroatom preferably represents O or N. Heterocyclyl group containing a suitable nitrogen atom, include the corresponding N-oxides.

Examples of monocyclic non-aromatic heterocyclyl groups (also referred to as monocyclic heteroseksualnymi rings) include aziridinyl, azetidin, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidine, piperazinil, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholine and azepane.

Examples of monocyclic GE is erotikbilder groups, in which one of the rings is non-aromatic, include dihydrobenzofuranyl, indanyl, indolinyl, isoindolyl, tetrahydroisoquinoline, tetrahydroquinoline and benzodazepines.

Examples of the monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridil, isothiazolin, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidyl.

Examples of bicyclic aromatic heterocyclyl groups (also called bicyclic heteroaryl groups include honokalani, hintline, perioperative, benzoxazolyl, benzothiophene, benzimidazole, naphthyridine, chinoline, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridinyl, pyridopyrimidines, ethenolysis and benzodioxol.

Examples of preferred heterocyclyl groups include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrimidyl and indolyl. Preferred heterocyclyl groups also include thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, isoxazolyl and imidazolyl.

Used in this document the term "cycloalkenyl" means a group cycloalkyl-alkyl-, attached through an alkyl group, it is understood that the meaning of the Oia, the terms "cycloalkyl" and "alkyl" is defined above.

As mentioned above, the compounds of the present invention have activity as ligands of estrogen receptors. Compounds of the present invention have activity as modulators of estrogen receptors and may be agonists, partial agonists, antagonists or partial antagonists of the estrogen receptor. In particular, preferred compounds of the present invention have activity as an agonist or partial agonist of ERβ. Preferred compounds of this type are selective agonists of the estrogen receptor β (ERβ).

Thus, the compounds of the present invention may be applicable in the treatment of diseases or disorders associated with the activity of estrogen receptors. In particular, the compounds of the present invention, which are agonists or partial agonists of the estrogen receptor may be applicable in the treatment of diseases or disorders for which illustrates the use of selective agonists or partial agonists of the estrogen receptor. Compounds of the present invention, which are antagonists or partial antagonists of the estrogen receptor may be applicable in the treatment of diseases or disorders for which illustrates the application of selectivedecontamination or partial antagonists of the estrogen receptor.

Clinical conditions for which illustrates the application of the agonist or partial agonist include, without limitation, loss of bone mass, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, elevated cholesterol low-density lipoprotein, cardiovascular disease, impairment of cognitive function, degenerative abnormalities in the brain, restenosis, gynecomastia, proliferation of smooth muscle cells of blood vessels, obesity, incontinence, anxiety, depression, autoimmune disease, inflammation, inflammatory bowel disease, irritable bowel syndrome, sexual dysfunction, hypertension, retinal degeneration and cancer, lung cancer, colon cancer, breast cancer, uterine cancer and prostate cancer, and/or disorders associated with estrogen.

Compounds of the present invention find particular use for the treatment or prevention of the following: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, hot flashes, high cholesterol low-density lipoprotein, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, degenerative disorders in the brain, reste the oz, gynecomastia, proliferation of smooth muscle cells of blood vessels, obesity, incontinence, anxiety, depression, depression during perimenopause, postpartum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, hyperactivity disorder attention deficit, sleep disorders, irritability, impulsivity, anger management, hearing impairment, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, spinal cord injuries, stroke, autoimmune disease, inflammation, inflammatory bowel disease, irritable bowel syndrome, sexual dysfunction, hypertension, retinal degeneration, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer and bile duct cancer called cholangiocarcinoma.

In one embodiment of the present invention compounds of the present invention find particular use for the treatment or prevention of depression, depression during perimenopause, postpartum depression, premenstrual syndrome and manic depression.

Treatment or prevention of tidal (or tidal blood) men preferred for patients, passing on the gene-deprivation therapy for prostate cancer.

The expression "depression" includes without limitation, major depressive disorder, delimitable disorder, bipolar disorder, cyclothymic disorder, mood disorder due to General health, induced by substances mood disorder, seasonal affective disorder (SAD), postpartum depression and premenstrual dysphoric disorder.

The present invention also relates to a method of treatment or prevention mediated by estrogen receptor status in a mammal which comprises the administration to a mammal a therapeutically effective amount of the compounds of the present invention. Mediated by estrogen receptors clinical condition that can be treated by the method according to the present invention, preferably represent a condition described above.

The present invention also relates to the use of compounds of the present invention for the manufacture of a medicinal product for the treatment or prevention mediated by estrogen receptor status. Mediated by estrogen receptors clinical condition that can be treated by the method according to the present invention, preferably represent a condition described above.

To the number of the active ingredient, want to achieve a therapeutic effect, without doubt, will vary from exactly the connection you use, route of administration, subject to the treatment of the subject, including type, species, age, body weight, sex and health status of the patient, kidney and liver of the patient, and concrete exposed to the treatment of disorders or diseases, as well as its severity. The physician, veterinarian, or the Clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or suppress the progression of the disease.

Oral dosages of the present invention, in the case of application to achieve these effects will vary from about 0.01 mg per kg of body weight per day (mg/kg/day) for an adult to approximately 100 mg/kg/day, preferably from 0.01 mg per kg of body weight per day (mg/kg/day to 10 mg/kg/day, and most preferably from 0.1 to 5.0 mg/kg/day. For oral administration the compositions are preferably provided in the form of tablets or other forms, is presented in the form of discrete elements, containing 0,01, 0,05, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0, 100 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to treatment of the patient. The drug typically has approximately the t 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of the active ingredient. For intravenous administration, the most preferred doses will range from about 0.1 to about 10 mg/kg/min constant rate infusion. Preferably, the compounds of the present invention can be administered as a single daily dose, or the total daily dose may be given fractional doses 2, 3 or 4 times a day. In addition, preferred compounds of the present invention can be administered in intranasal form suitable for topical application, intranasal carriers, or percutaneously using forms transcutaneous patches well known to specialists in this field of technology. For administration in the form of transcutaneous delivery system, the dose, without a doubt, will be more permanent than intermittent throughout the dosage regimen of the drug.

Although it is possible to introduce only the active ingredient is preferred that it be included in a pharmaceutical preparation or composition. Accordingly, the present invention relates to pharmaceutical compositions containing the compound of the present invention and a pharmaceutically acceptable diluent, excipient or media (collectively referred to in this document as "carriers"). Headlight is asepticheskie compositions of the present invention may take the form of a pharmaceutical preparation, described below.

The pharmaceutical preparations of the present invention include preparations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion] and intraarticular), inhalation (including fine powders or aerosols, which can be generated by applying different types of dosing inhalers under pressure), with the use of nebulizers or insufflators, rectal, intraperitoneal and local (including dermal, buccal, sublingual and intraocular) administration although the most suitable path may depend, for example, from the condition of the patient and disturbance.

Drugs can be appropriately presented in the form of unit dosage forms and may be prepared by any of the methods well known in the field of pharmacy. All methods include the stage of mixing the active ingredient with the carrier that contains one or more additional ingredients. In General, the drugs produced by uniform and thorough mixing of the active ingredient with liquid carriers or finely dispersed solid carriers, or both, and then, if necessary, shaping the product in the form of the desired drug.

Drugs in this izobreteny is, suitable for oral administration may be presented as discrete units such as capsules, pills, pills or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous liquid or non-aqueous liquid, for example, in the form of elixirs, tinctures, suspensions or syrups; or in the form of a liquid emulsion of the type oil-in-water or a liquid emulsion of the type water-in-oil". The active ingredient may also be presented in the form of a bolus, electuary or paste.

A tablet may be made by extrusion or molding, optionally with one or more additional ingredients. Compressed tablets can be obtained by pressing in the appropriate mechanism of the active ingredient in a free flowing condition, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be obtained by molding in a suitable mechanism of a mixture of powdered compound moistened inert liquid diluent. On the pill may not necessarily be coated and risks, and tablets can be prepared in such a way as to provide slow or kontroliruemoe the release of the contained active ingredient. Compounds of the present invention, for example, can be entered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved through the use of suitable pharmaceutical compositions containing compounds of the present invention, or, especially in the case of extended release, by the use of devices such as subcutaneous implants or osmotic load. Compounds of the present invention can also be entered inside the liposomes.

Typical compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting flowability, alginic acid or sodium alginate as a suspending agent, methylcellulose as an amplifier viscosity, and sweeteners and flavorings, such as known in the art; and tablets of immediate release, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, tools increase, disintegrant, diluents and lubricants, such as known in the art. Suitable binders incl the Ute starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural or synthetic gums such as acacia, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Disintegrant include without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. The compounds of formula (I) can also be delivered into the oral cavity by sublingual and/or buccal administration. Typical forms, which can be used are molded tablets, compressed tablets or freeze-dried tablets. Typical compositions include preparations containing the compound(I) of the present invention, and soluble diluents, such as lures, lactose, sucrose and/or cyclodextrins. Such drugs may also be included high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). These preparations may also contain excipient to improve the adhesion to mucous membranes, such as hydroxypropylcellulose (HPC), hypromellose (HPMC), sodium carboxymethylcellulose (SCMC), a copolymer of maleic anhydride (e.g., Gantrez), and control release such as polyacrylic copolymer (e.g., Carbopol 934). For ease of manufacturing and using the Oia can also be added lubricants, glidant, flavorings, colorants and stabilizers. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. For oral administration in liquid form components of oral medications can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.

Compounds of the present invention can also be administered in the form of liposomal delivery systems, such as small manelmellado vesicles, large manelmellado vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (Catalina) or phosphatidylcholine (lecithin).

Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffering agents, bacteriostatic and soluble substances that confer drug property isotonicity with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspendresume agents and thickeners. Drugs can be presented in the form of containers with single or mnogokrat the diversified doses for example, sealed ampoules or vials and may be stored in dried by sublimation (lyophilized) condition requiring only the addition of sterile liquid carrier, for example, saline or water for injection, immediately prior to use. Spontaneously prepared for immediate introduction of injectable solutions or suspensions may be prepared from sterile powders, granules or tablets previously described species. Typical compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic acceptable for parenteral diluents or solvents, such as mannitol, 1,3-butanediol, water, ringer's solution, isotonic solution of sodium chloride, or other suitable dispersing, moisturizing or suspendresume agents, including synthetic mono - or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

Typical compositions for nasal aerosol or inhalation include solutions in saline solution, which may contain, for example, benzyl alcohol or other suitable preservatives, enhancers suction to improve the bioavailability and/or other solubilizing or dispersing agents such as known in the art.

The preparations for the local introduction of the oral cavity, e.g., buccal or sublingual, include lozenges, containing the active ingredient in a flavored basis such as sucrose, acacia or tragakant, and tablets containing the active ingredient in a base such as gelatin and glycerin, or sucrose and acacia. Typical compositions for local injection include local media, such as Plastibase (mineral oil, generowanie with polyethylene).

Preferred unit dosage drugs are drugs that contain defined earlier in this document effective dose of the active ingredient or its relevant part.

It should be understood that in addition to the ingredients, specifically mentioned above, the preparations according to the present invention can contain other conventional in the art agents, taking into account the type discussed drug, for example, preparations for oral administration may include flavoring agents.

Although the compound of the present invention may what to use as the sole active ingredient in a medicinal product, you can also use the connection in combination with one or more other additional active agents. Such additional active agents may be additional compounds of the present invention, or they may represent other therapeutic agents, for example, antidepressant, anxiolytic, antipsychotic agent, tool, applicable for the prevention or treatment of osteoporosis, tool, applicable to the prevention or treatment of cancer, or another pharmaceutically active substance. For example, the compounds of the present invention can be effectively administered in combination with effective amounts of other agents such as antidepressant, anxiolytic, antipsychotic agent, organic biphosphonate or inhibitor of cathepsin K. In one preferred embodiment, compounds of the present invention can be effectively administered in combination with an effective amount of an antidepressant. Non-limiting examples of antidepressants include serotonin reuptake inhibitors norepinephrine (NRI), selective inhibitors of reuptake of serotonin, monoamine oxidase inhibitors, tricyclic antidepressants (TCA), inhibitors of reuptake of dopamine (DRI), opioids, selective amplifiers serotonin reuptake, tetracyclic antidepressant, reversible monoamine oxidase inhibitors, agonists, melatonin, serotonin reuptake inhibitors of serotonin and norepinephrine (SNRI), antagonists of the corticotropin-releasing factor antagonists, α-adrenergic receptors, agonists and antagonists 5HT1(receptor, lithium and atypical antipsychotics. Examples of antidepressants SSRI class including fluoxetine and sertraline; examples of antidepressants SNRI class include venlafaxine, citalopram, paroxetine, ESCITALOPRAM, fluvoxamine; examples of antidepressants SNRI class include DULOXETINE; examples of antidepressants DRI and NRI classes include bupropion; examples of antidepressants TCA class include amitriptyline and dothiepin (dosulepin). Examples of atypical antipsychotics include clozapine, olanzapine, risperidone, quetiapine, ziprasidone and partial agonists of dopamine. Non-limiting examples of anxiety include benzodiazepines and dibenzodiazepine. Examples of benzodiazepines include lorazepam, alprazolam and diazepam. Examples of dibenzodiazepine include buspirone (Buspar®), barbiturates, and meprobamate or more of these additional antidepressants can be used in combination.

Examples of anti-cancer tools include tamoxifen or an aromatase inhibitor used in the treatment of breast cancer.

In the case when the tides cause the Xia specific treatment, the compound of the present invention can be used in combination therapy with an agent for the treatment of such diseases. Non-limiting examples of these types of combination therapy include: the connection of the present invention in combination with tamoxifen in the treatment of breast cancer, the compound of the present invention in combination with an aromatase inhibitor in the treatment of breast cancer or the compound of the present invention in combination with raloxifene in the treatment of osteoporosis.

Non-limiting examples of the aforementioned organic bifosfonatami include alendronate, clodronate, etidronate, ibandronate, encadrant, minodronate, meridional, risedronate, Piedmont, pamidronate, tiludronate, zoledronate, their pharmaceutically acceptable salts and esters, and mixtures thereof. Preferred organic bisphosphonates include alendronate and its pharmaceutically acceptable salts and mixtures. Most preferred is alendronate sodium trihydrate.

The precise dosage of biphosphonate will vary along with the mode of dosing, efficacy after oral administration of specifically chosen biphosphonate, age, size, sex and condition of the mammal or human, the nature and severity of the subject to treatment disorders, and other relevant medical and physical factors. So the m way accurate pharmaceutically effective amount cannot be specified in advance and can be easily determined by a person providing care for the patient, or clinical doctor. The appropriate amount can be determined by routine experimentation in animal models and in clinical trials on humans. As a rule, choose the number of biphosphonate suitable to achieve the inhibitory effect on bone resorption, i.e. enter the number of biphosphonate inhibiting bone resorption. For a person effective oral dose of biphosphonate typically ranged from approximately 1.5 to approximately 6000 mg/kg of body weight and is preferably from approximately 10 to approximately 2000 mg/kg body weight.

Intended for human oral compositions containing alendronate, its pharmaceutically acceptable salts or its pharmaceutically acceptable derivatives, the unit dosage form typically contains approximately of 8.75 mg to approximately 140 mg alendronate connection, in terms of active weight alendronova acid, i.e. in terms of the corresponding acid.

Compounds of the present invention can be used in combination with other agents, applicable to the treatment mediated by estrogen States. The individual components of such combinations can in order to live separately at different times during the course of treatment or simultaneously in separate or single combination forms. Therefore, the present invention is understood as encompassing all such schemes of simultaneous or alternating treatment and the term "introduction" should be interpreted accordingly. It should be understood that the scope of combinations of the compounds of the present invention with other agents, applicable to the treatment mediated by estrogen States, includes in principle any combination with another pharmaceutical composition suitable for treating disorders associated with the activity of estrogen.

When used in combination with the compounds of the present invention, the above other therapeutic agents can be used, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by the person skilled in the technical field.

If the compounds of the present invention are used in combination with one or more other therapeutic means, concurrently or sequentially, preferred are the following ratio and dose ranges:

in combination with antidepressant, anxiolytic, antipsychotic means, organic biphosphonates or inhibitor of cathepsin K, the compounds of formula (I) can be used in a mass ratio with additional means in the range of from about 10:1 to about 1:10.

The above connection is possible under the present invention also find application, not necessarily in labeled form, as diagnostic tools for the diagnosis of conditions associated with dysfunction of the estrogen receptor. For example, this connection can be radiolabelled.

The above-described compounds of the present invention, optionally in labeled form, also used as a reference compound in the ways of development of other agonists, partial agonists, antagonists or partial antagonists of the estrogen receptor. Thus, the present invention relates to a method of designing a ligand of the estrogen receptor, which includes the use of compounds of the present invention or compounds of the present invention in labeled form, as a reference compound. For example, such a method may include the test is a competitive binding in which the binding of the compounds of the present invention with the estrogen receptor is reduced due to the presence of other compounds with the ability to bind to the estrogen receptor, for example, a stronger binding parameters with estrogen receptor compared to the compound of the present invention.

Any specialist in this field of technology can be offered numerous ways of synthesis of compounds really to the invention, and the following possible ways of synthesis do not limit the present invention. Many methods for the synthesis of indoles presented in the literature, for example: Indoles Part One, W.J. Houlihan (ed.), 1972; Indoles, Sundberg, R.J., 1996; Heterocyclic Chemistry, Joule, J.A.; Mills, K. 2000; Chem. Rev., 2005, 105, 2873-2920; Org. Lett. 2006, 8, 5919-5922; and Bioorg. Med. Chem. Lett., 2007, 77, 902-906. A number of possible ways of synthesis is presented schematically below. If necessary, any initially the compound obtained according to the present invention can be converted into another compound of the present invention by known methods.

General method 1

General method 1 described above in reaction scheme used for the synthesis of compounds of the following examples:

examples 46-159 and 211 - all the details of the experiments for each of the individual stages of a General method applicable for the synthesis of the final compounds of examples 46-159 and 211, as described in examples 1-5, 16, 38-40;

examples 160-162 and 196-210 - all the details of the experiments for each of the individual stages of a General method applicable for the synthesis of the final compounds of examples 160-162 and 196-210 described in examples 1-4, 8, 16, 38-40;

examples 169 and 173-195 - all the details of the experiments for each of the individual stages of a General method applicable for the synthesis of the final compounds of examples 169 and 173-195 described in examples 1-4, 8, 10-13, 14-16, 20, 25, 38-40 and 45;

- when the minimum level 233-270 - all the details of the experiments for each of the individual stages of a General method applicable for the synthesis of the final compounds of examples 233-270 described in examples 1-4, 10-11, 14-16, 38 to 40 and 45.

General method 2

General method 2 described above in reaction scheme used for the synthesis of compounds of example 6.

General method 3

General method 3 above in reaction scheme used for the synthesis of compounds of examples 212-232 and 271. All the details of the experiments for each of the individual stages of a General method applicable for the synthesis of the final compounds of examples 212-232 and 271 described in examples 2-4, 8, 16, 24, 38-40.

General method 4

General method 4 described above in reaction scheme used for the synthesis of compounds of examples 163-168 and 170-172. All the details of the experiments for each of the individual stages of a General method applicable for the synthesis of the final compounds of examples 163-168 and 170-172 described in examples 2-4, 9, 20-21.

General method 5

General method 5 described above in reaction scheme, also potentially applicable for the synthesis of compounds of the present invention. Suitable 3-cyano-N-arylindole can be obtained from N-arylindole by formirovaniya, as the present is divided into stage (a), for example, in the reaction of Vilsmeier-khaak, with the subsequent implementation of the interaction of the aldehyde with hydroxylamine hydrochloride and subsequent elimination with acetic anhydride, as shown in stage (b).

The following examples illustrate the present invention.

Example 1

2-Bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E1)

Scheme 1

Stage (a): 1 EQ. 3-cyanoindole, 2 EQ. 4-yoganidra, 2.1 EQ. potassium phosphate, 4.5 EQ. N,N'-dimethylethylenediamine and 0.2 EQ. Iodide copper(I) mixed dried in the furnace vessel was added toluene. The mixture was stirred in nitrogen atmosphere at 110°C over night. The reaction mixture was cooled to room temperature, filtered and evaporated under vacuum. The crude product was purified on silica gel using n-heptane/EtOAc (4:1) as mobile phase.

Stage (b): 1-(4-Methoxyphenyl)-1H-indol-3-carbonitrile was dissolved in anhydrous THF and cooled to -78°C was added dropwise 1.1 EQ. t-buLi, and the mixture was stirred for 1 hour. Solution was added 1,3 EQ. 1,2-dibromotetrachloroethane in anhydrous THF, and the mixture was stirred for 4 hours, slowly warming it to room temperature, and then extinguished the addition of H2O. the Reaction mixture was diluted with DCM, the phases were separated, and the organic phase is evaporated under vacuum. Neojidanni the product was purified on silica gel using n-heptane/DCM (1:1) as mobile phase.

Stage (c): 2-Bromo-1-(4-methoxyphenyl)-1H-indol-3-carbonitrile was dissolved in anhydrous DCM and cooled to 0°C. was Added 5 EQ. BBr3(a 1.0 M solution in hexane) and stirred the mixture overnight. Staying at 0°C, the reaction mixture was suppressed by the addition of MeOH. The mixture was diluted with H2O, and separated phases. The organic phase was concentrated, and purified the crude product on silica gel using n-heptane:EtOAc (4:1) as mobile phase. ES/MS m/z: 313, 315 (M+H), 311, 313 (M-H);1H-NMR (acetone-d6, 500 MHz): of 7.69 (m, 1H), 7,38-7,30 (m, 4H) and 7,16-7,10 (m, 3H).

Example 2

1-(4-Hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile (E2)

Scheme 2

To 2-bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 1) was added 2 EQ. 3-tiefenbronn acid, 2.1 EQ. potassium carbonate and 10 mol.% tetrakis(triphenylphosphine)palladium. Added THF:EtOH:H2O (4:1:0.5), and the vessel was purged with nitrogen, tightly closed and stirred at 100°C for 48 hours. The reaction mixture was cooled to room temperature, diluted with H2O, was extracted with EtOAc and filtered through silica gel. The organic phase was evaporated to dryness, and subjected to the crude product of preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified according to the method1H-NMR and LC/MS. The purity was determined by analytical method HPLC. ES/MSm/z: 317,9 (M+H), 314,8 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,73 (m, 1H), 7.62mm (DD, 1H, J=1,3, 2,9 Hz), 7,54 (DD, 1H, J=2,9, 5.0 Hz), 7,37-7,30 (m, 2H), 7,26 (m, 2H), 7,18 (m, 1H), 7,15 (DD, 1H, J=1,3, 5.0 Hz) and 7,03 (m, 2H).

Example 3

2-(3-Cianfuran-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E3)

Scheme 3

2-Bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 1, 40 mg, 0.13 mmol, 1 EQ.), 2-tributylstannyl-3-carbonitrile (63.5 mg, 0,17 mmol, 1.3 EQ.) and dichlorobis(triphenylphosphine)palladium(II) (9 mg, 0.01 mmol, 0.1 EQ.) hung in a vessel for microwave processing. Added dioxane (1 ml), the vessel was purged with nitrogen and closed the lid. The reaction mixture was treated with microwaves at 130°C for 30 min, and then filtered the solution. Was added a saturated aqueous solution of ammonium chloride (5 ml)and the mixture was extracted with DCM several times. The combined DCM phases were passed through a membrane to separate the phases and evaporated. The crude product was purified by the method of flash chromatography on silica gel using a gradient of n-heptane:ethyl acetate (7:3) to remove residual tin-containing reagent. The appropriate fractions were collected and evaporated, dissolved in acetonitrile (1 ml) and purified by the method of preparative HPLC to obtain 33 mg (yield 79%) of product with a purity of 99%, determined according to the method of analytical HPLC. (Column: Reprosil-Pur 120 ODS-3 (C18), 30×100 mm, 5 μm. The mobile phase A: formic acid is one of 0.05%, The mobile phase B: ACN. The gradient of 20% A-100% b ES/MS m/z: to 326.1 (M+H), (324,1 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,89 (d, 1H, J=2.2 Hz), the 7.85 (m, 1H), of 7.48-the 7.43 (m, 2H), 7,34 (m, 1H), 7,32 (m, 2H) and 7.04-7,01 (m, 3H).

Example 4

1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile (E4)

Scheme 4

2-Bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 1), 1.4 EQ. of pyrrole, 2 EQ. of cesium carbonate and 20 mol.% iodide copper(I) mixed dried in the furnace vessel, was added DMF and blowing the mixture with nitrogen. The vessel was tightly closed and stirred at 120°C for 48 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through silica gel. The crude mixture was evaporated to dryness and subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified by the methods1H-NMR and LC/MS. The purity was determined by analytical method HPLC. ES/MS m/z: to 300.2 (M+H), 298,3 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,41-7,35 (m, 2H), 7,27 (m, 2H), 7.23 percent (m, 1H), 6,98 (m, 2H), 6,95 (t, 2H, J=2.2 Hz) and 6.23 (t, 2H, J=2.2 Hz).

Example 5

2-Dimethylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E5)

Scheme 5

2-Bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 1) was mixed with excess dimethylamine in DMF (1:3), and the mixture was stirred in a tightly closed vessel at 80°C during the night. The reaction mixture is cooled is about room temperature, diluted H2O and DCM, and then separate the phases. The organic phase was evaporated to dryness and subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified by the methods1H-NMR and LC/MS. The purity was determined by analytical method HPLC. ES/MS m/z: 278,1 (M+H), (276,1 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,42 (m, 1H), 7,33 (m, 2H), 7,17 (m, 1H), 7,09-7,05 (m, 3H), to 6.95 (m, 1H) and 2.93 (s, 6H).

Example 6

1-(4-Hydroxyphenyl)-2-isopropyl-1H-indol-3-carbonitrile (E6)

Scheme 6

Stage (a): Benzylcyanide (1500 mg, 12.8 mmol) was dissolved in 150 ml of anhydrous THF and cooled to 0°C. the Solution was stirred at this temperature, the process was slowly added NaH (60% in mineral oil, 663 mg). After complete addition, the mixture was stirred at 0°C for 30 min, then bath with ice was removed and continued stirring at room temperature for 120 minutes. One portion was added utilizabilitate (1785 mg of 15.4 mmol)and the reaction mixture was heated at 60°C for 2 h THF was removed under vacuum and poured the rest into the water with ice. Added 6M HCl with stirring until reaching neutral pH values. The mixture was extracted with EtOAc, dried over MgSO4and concentrated under vacuum. The compound was purified by the method of flash chromatography [silica gel; n-heptane:EtOAc (9:1)] to obtain 4-methyl-3-oxo-phenylpentane (460 mg, 19%).

Stage (b): 4-Methyl-3-oxo-2-phenylpentane (100 mg, of 0.53 mmol) and 4-methoxyaniline was dissolved in 100% AcOH (1 ml). The mixture was heated at 160°C for 30 min in a microwave reactor. The solvent together evaporated with toluene under vacuum. The residue was dissolved in CH2Cl2and filtered through a layer of silica gel. The solvent was removed, and used the resulting mixture directly in the next stage without additional purification.

Stage c: the Mixture obtained in stage (b) (65 mg), and PDPA (26 mg) was dissolved in CH2Cl2(anhydrous, 1.5 ml) and stirred at room temperature overnight. The mixture was extracted by adding NaHCO3/CH2Cl2using separate phases. The mixture was purified by the method of preparative HPLC to give the desired 2-isopropyl-1-(4-methoxyphenyl)-1H-indol-3-carbonitrile (3 mg).

Stage (d): 2-Isopropyl-1-(4-methoxyphenyl)-1H-indol-3-carbonitrile (3 mg, 0.01 mmol) was dissolved in anhydrous CH2Cl2(0.5 ml) and stirred at 0°C. was Added BBr3(1M in CH2Cl2, 50 μl) and left the mixture in the refrigerator while stirring overnight. Added a few drops of MeOH and stirred. The solvent was removed under vacuum, and distributed the mixture by adding in the H2O/DCM. The organic phase was separated using a separator phases. The solvent deletion is whether under vacuum and the mixture was subjected to chromatography using pre-filled with silica gel column (solvent: EtOAc/n-heptane 3:7) to give the desired 1-(4-hydroxyphenyl)-2-isopropyl-1H-indol-3-carbonitrile (1.1 mg, 39%).1H-NMR (acetone-d6, 500 MHz): to 7.64 (m, 1H), 7,32 (m, 2H), 7,28 (m, 1H), 7,22 (m, 1H), 7,11 (m, 2H), 6,98 (m, 1H), of 3.07 (m, 1H) and 1.43 (d, 6H, J=7,0 Hz).

Example 7

2-Acetyl-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E7)

Specified in the title compound was synthesized by hydrolysis of 2-(1-ethoxyphenyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile. ES/MS m/z: 277,1 (M+H), (275,1 (M-H);1H-NMR (acetone-d6, 500 MHz): to 7.84 (d, 1H, J=7.5 Hz), 7,49-7,42 (m, 2H), 7,32 (m, 2H), 7,18 (m, 1H, J=8.0 Hz), 7,06 (m, 1H) and 2.46 (s, 3H).

Example 8

2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid (E8)

Scheme 7

2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 51) was dissolved in a 1:2 mixture of THF and LiOH (aq., 2M) and processed in a microwave reactor at 160°C for 1 hour. The mixture was diluted with H2O and DCM, acidified to pH 1 by addition of HCl (1M) and separated phases. The organic phase was concentrated under vacuum and purified on Chromatotrone using 5% MeOH in DCM as the mobile phase. ES/MS m/z: 349,4 (M+H), 347,2 (M-H);1H-NMR (acetone-d6; 500 MHz): 8,31 (m, 1H), 7,32-of 7.23 (m, 3H), 7,20 (m, 1H), 7,12 (users, 1H), 6,97 (m, 2H), 2,16 (s, 3H) and was 2.05 (s, 3H).

Example 9

1-[1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]alanon (E9)

Stage (a) and (b): 1 EQ. 3-bromo-1-(4-methoxyphenyl)-2-phenyl-1H-indole (synthesized from 1-(4-methoxyphenyl)-1H-indole way similar to that used on the Tudeh (a), (b) and (c) of example 21, with subsequent stages (a) and (b) of example 22), 5 EQ. moulinrouge ether of ethylene glycol, 5 mol.% Pd(OAc)2, 10 mol.% dppp, 1.3 EQ. potassium acetate, 5 mol.% tetrabutylammonium bromide was mixed with toluene/water in a vessel for microwave treatment in a nitrogen atmosphere. The reaction was carried out in a microwave reactor at 150°C for 20 minutes was Added 2 ml of 3M HCl, and the mixture was stirred at room temperature for 30 minutes was Added water and DCM, and separated phases. After evaporation of the solvents the residue was purified by the method of flash chromatography with heptane/EtOAc 9:1.

Stage (c): the Original substance was dissolved in anhydrous DCM under nitrogen atmosphere and cooled to 0°C. was Added BBr3and allow the temperature to reach room temperature for 2 hours, the Reaction mixture was suppressed by the addition of water, are of the same phase. After evaporation of the solvents the residue was purified by the method of preparative HPLC. ES/MS m/z: 328,16 (M+H), 326,2 (M-H);1H-NMR (DMSO-d6, 500 MHz): 8,35 (m, 1H), 7,43 (m, 2H), 7,40-7,37 (m, 3H), 7,28 (m, 1H), 7,24 (m, 1H), 7,10 (m, 2H), 7,00 (m, 1H), 6.73 x (m, 2H) and of 1.88 (s, 3H).

Example 10

Amide 1-(4-hydroxyphenyl)-2-phenyl-1H-indole-3-carboxylic acid (E10)

Scheme 9

1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile (example 46, 10 mg, 0.03 mmol) was dissolved in 1 ml MeOH. Added H2O2(1 ml, 35% by mass in the H2O) and 2M KOH (0.5 ml)and heated the reaction mixture is under reflux overnight. The mixture was acidified by addition of 1M HCl was added EtOAc. The phases were separated and the organic solvents evaporated. The crude product was purified by the method of preparative HPLC with reversed phase with obtaining specified in the title amide. ES/MS m/z: 329,1 (M+H), 327,13 (M-H);1H-NMR (acetone-d6, 500 MHz): a 8.34 (m, 1H), 7,46 (m, 2H), 7,40-7,37 (m, 3H), 7.24 to to 7.18 (m, 2H), 7,12 (m, 2H), 7,07 (m, 1H) and 6,85 (m, 2H).

Example 11

(Z)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (E11)

Scheme 10

Under nitrogen atmosphere a solution of 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 51), 12 EQ. hydroxylamine hydrochloride and 12 EQ. of triethylamine in EtOH was heated at 100°C for 24 hours. The reaction mixture was cooled to room temperature, diluted with methanol, the precipitate was filtered and subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified according to the method1H-NMR and LC/MS. The purity was determined by analytical method HPLC. ES/MS m/z: 363,5 (M+H), 361,6 (M-H);1H-NMR (acetone-d6, 500 MHz): 8,14-8,13 (s, OH), 8,08-of 8.04 (m, 1H), 7.23 percent-7,14 (m, 3H), 7,15-7,06 (m, 2H), of 6.96-6,91 (m, 2H), 5,18 is 5.07 (m, 2H), 2,16 (s, 3H), from 2.00 (s, 3H).

Examples 12 and 13

[2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl]carbamino acid complex tert-butyl ether (E12)

4-(3-Amino-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)Hairdryer is l (E13)

Scheme 11

Stage (a): a Mixture of 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid (example 8), diphenylphosphinite (1.1 EQ.) triethylamine (1.1 EQ.) in tert-BuOH was heated in a microwave reactor at 90°C for 1 hour. After cooling, the mixture was subjected to preparative HPLC with reversed phase. The appropriate fractions were combined and evaporated to obtain [2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl]carbamino acid complex tert-butyl ether (E12). ES/MS m/z: 420,21 (M+H), 418,22 (M-H);1H-NMR (acetone-d6, 500 MHz): to 7.61 (m, 1H), 7,26-7,13 (m, 5H), 6,93 (m, 2H), 2,22 (s, 3H), 1,89 (s, 3H), and 1.44 (s, 9H).

Stage (b): Tert-butyl-2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-ylcarbamate was dissolved in DCM and treated with a catalytic amount of TFA to complete the reaction. The mixture was concentrated under vacuum and was co-evaporated with MeOH. 4-(3-Amino-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol (E13) identified according to the method LC/MS and the purity was determined by the method of analytical HPLC. ES/MS m/z: 320,2 (M+H) and 318,2 (M-H).

Example 14

(Z)-2-(3,5-Dimethylisoxazol-4-yl)-7-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (E14)

Scheme 12

Stage (a): Chilled (0°C) solution of 2-(3,5-dimethylisoxazol-4-yl)-7-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 230, 19 mg, 0.05 m is ol) in dioxane (1.5 ml) and MeOH (0.5 ml) was barbotirovany gaseous HCl for 10 minutes The tube is sealed closed, leaving the temperature to rise to room temperature, and stirred the mixture overnight. The solvents are evaporated under vacuum.

Stage (b): To a solution of hydroxylamine hydrochloride (19 mg, 0.27 mmol) in water under stirring at room temperature was added solid NaHCO3(23 mg, 0.27 mmol). Added the above Amidah dissolved in EtOH (1.5 ml), and stirred the solution at 90°C in a tightly closed vessel for 1 h the Mixture was purified by the method of preparative HPLC to obtain specified in the title compound, (Z)-2-(3,5-dimethylisoxazol-4-yl)-7-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamidine, with the release of 10%. ES/MS m/z: 381,1 (M+H), 279,2 (M-H);1H-NMR (methanol-d4, 500 MHz): to 7.68 (DD, 1H, J=8,1, 0.7 Hz), 7,13 (m, 1H), was 7.08 (m, 2H), 6,93 (m, 1H), 6,77 (m, 2H), 2,16 (s, 3H) and 2.00 (s, 3H).

Example 15

(Z)-2-(5-Chlorothiophene-2-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (E15)

Scheme 13

2-(5-Chlorothiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 86) was dissolved in DMSO (0.25 ml) was added hydroxylamine (0.25 ml, 100 equiv.) of 2M stock solution of hydroxylamine hydrochloride, neutralized with sodium hydroxide (pH 7,01, as measured by pH-meter). The mixture was stirred at 60°C for 18 hours. The cooled mixture was diluted salt solution was extracted with EtOAc and subjected to p is operativnoy HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified by the methods1H-NMR and LC/MS. The purity was determined by analytical method HPLC. ES/MS m/z: 386,3 (M+H), 384,2 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,89 (m, 1H), 7,21-7,13 (m, 4H),? 7.04 baby mortality (m, 1H), 7,00-6,97 (m, 3H) and 6,91 (d, 1H, J=4.0 Hz).

Example 16

1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carbonitrile (E16)

Scheme 14

To 2-bromo-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 103) was added 1.5 EQ. 3,5-dimethylisoxazol-4-Bronevoy acid, 4 EQ. potassium carbonate, 2 EQ. of sodium iodide and 10 mol.% tetrakis(triphenylphosphine)palladium. Added DME/H2O (1:1), the vessel was purged with nitrogen, tightly closed and stirred at 150°C for 10 min. the Reaction mixture was cooled to room temperature, diluted with H2O and was extracted with DCM. The organic phase was evaporated to dryness and purified on a column of silica gel using 1:1 n-heptane/EtOAc as the mobile phase. ES/MS m/z: 366,20 (M+H), 364,20 (M-H);1H-NMR (CDCl3, 500 MHz): to 7.84 (d, 1H), 7,39 (m, 2H), 7,19 (d, 1H), 6,93 (osirm, 2H), 2,42 (s, 1,5H), 2,24 (s, 1.5 H), 2,19 (s, 1,5H), for 2.01 (s, 1,5H).

Example 17

2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbohydrazone (E17)

Scheme 15

2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbimide (example 184) was dissolved in EtOH and we use the and 10 EQ. hydrazine. The resulting mixture was stirred at 90°C for 10 hours. The reaction mixture was diluted with EtOAc and washed with saline. The organic phase was evaporated to dryness under vacuum, and then purified by the method of preparative HPLC with reversed phase. Fractions were combined, concentrated and identified the final product on methods1H-NMR and LC/MS. The purity was determined by analytical method HPLC. ES/MS m/z: 362,21 (M+H), 360,28 (M-H);1H-NMR (methanol-d3, 500 MHz): 7,81 (m, 1H), was 7.36-to 7.32 (m, 3H), was 7.08 (m, 2H), 6.90 to (m, 2H), 2,16 (s, 3H) and 1.96 (s, 3H).

Example 18

4-(2-(3,5-Dimethylisoxazol-4-yl)-3-(1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)phenol (E18)

Scheme 16

(Z)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (example 11) was dissolved in THF containing 4Å powdered molecular sieves. The mixture was stirred for 30 min in an atmosphere of N2. Added NaH (60% dispersion in mineral oil, 7,0 mg, 2.1 EQ.) and stirred the mixture at 60°C for 20 min After cooling to room temperature, was added dropwise ethyl formate (25.6 mg, 2.5 EQ.) in THF. The resulting mixture was heated under reflux for 1 h, and then cooled to room temperature. The mixture was filtered and concentrated. The residue was filtered through silica gel and then purified by the method of HPLC with reversed phase to obtain 4-(2-(3,dimethylisoxazol-4-yl)-3-(1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)phenol as a white powder: ES/MS m/z: 395,17 (M+H), 393,19 (M-H);1H-NMR (acetone-d6, 500 MHz): of 9.21 (s, 1H), 8,40 (m, 1H), 7,37-7,31 (m, 2H), 7,26-7,22 (m, 3H), 6,98 (m, 2H), 2,17 (s, 3H) and to 1.98 (s, 3H).

Example 19

Methyl-2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylate (E19)

Scheme 17

Stage (a): 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid (example 8, 6.0 mg, 0.02 mmol) was dissolved in 0.5 ml of thionyl chloride was added 2 drops of DMF. The mixture was heated at 70°C for 1 h, and then gently evaporated under vacuum.

Stage (b): 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonylchloride was dissolved in 0.5 ml anhydrous MeOH and cooled the mixture in a bath with ice. Prepare fresh hydroxylamine infusion solution (0.3 ml), hydroxylamine hydrochloride (12 mg, 0,17 mmol) in MeOH solution (0.3 ml), KOH (19 mg, 0.33 mmol) in MeOH. The mixture was filtered through syringe filter the cooled solution of the acid chloride. After 5 min the cooling bath was removed, leaving the reaction mixture to warm to room temperature and was stirred for 10 minutes was Added water, 1M HCl and EtOAc and separated phases. After evaporation of the solvents the residue was purified by the method of preparative HPLC to obtain methyl 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylate with the release of 16%. ES/MS m/z: 363,11 (M+H), 361,13 (M-H); 1H-NMR (methanol-d4, 500 MHz): 8,21 (m, 1H), 7,32-7,26 (m, 2H), 7,20 (m, 1H), 7,13 (users 1H), 7,01 (users, 1H), to 6.88 (m, 2H), 3,83 (s, 3H), 2,12 (s, 3H) and 2.03 (s, 3H).

Example 20

2-(3,5-Dimethylisoxazol-4-yl)-N-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (E20)

Scheme 18

Stage (a): Oxalidales (75 μl, 0.86 mmol) and a drop of DMF was added to a cooled (0°C) solution of 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid (example 8, 30 mg, 0.09 mmol) in anhydrous DCM. The temperature was left to rise to room temperature and was stirred for 2 h, the Solvents evaporated.

Stage (b): The crude product obtained in stage (a)was added to a mixture of hydroxylamine hydrochloride (30 mg, 0.43 mmol) and triethylamine (60 μl, 0.43 mmol) in 3 ml of NMP. The mixture was stirred at room temperature for 15 minutes was Added water and EtOAc, and the separated phases. After evaporation of the solvents the residue was purified by the method of preparative HPLC to obtain specified in the title compound, 2-(3,5-dimethylisoxazol-4-yl)-N-hydroxy-1-(4-hydroxyphenyl)-1H-indole-3-carboxamide, yield 32%. ES/MS m/z: 364,15 (M+H), 362,19 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,40 (m, 1H), 6,80-6,70 (m, 3H), 6,62 (m, 2H), 6,39 (m, 2H), 1,65 (s, 3H) and for 1.49 (s, 3H).

Example 21

4-[2-(3,5-Dimethylisoxazol-4-yl)-3-methanesulfonamido-1-yl]phenol (E21)

Scheme 19

Stage (a): 1-(4-Methoxyphenyl)-1H-indole (synthesized from indole by arilirovaniya, Ana is Oginga described in stage (a) of example 1 [process arilirovaniya also described in J. Org. Chem. 2008, 73(14), 5529-5535], 1.0 g, 4,48 mmol), 2-(methylthio)isoindoline-1,3-dione (0.95 g, is 4.93 mmol) and magnesium bromide (8 mg, 0.045 mmol) were mixed in degassed DMA and stirred in nitrogen atmosphere at 90°C for 90 min was Added 1M NaOH and EtOAc. The phases were separated, and evaporated organic solvents. The residue was purified by the method of flash chromatography with heptane/EtOAc 20:1 to obtain 1-(4-methoxyphenyl)-3-(methylthio)-1H-indole with yields of 80%. ES/MS m/z: 270,11 (M+H).

Stage (b): To a cooled (0°C) solution of 1-(4-methoxyphenyl)-3-(methylthio)-1H-indole (800 mg, of 2.97 mmol) in 10 ml DMF was added NBS (529 mg, of 2.97 mmol). The temperature was left to rise to room temperature, and the mixture was stirred at room temperature for 30 minutes was Added water and DCM, and separated phases. After evaporation of the solvents the residue was purified by the method of flash chromatography with heptane/EtAc 20:1 to obtain 2-bromo-1-(4-methoxyphenyl)-3-(methylthio)-1H-indole with an output of 66%. ES/MS m/z: 348,04, 350,01 (M+H).

Stage (c): 4-(1-(4-Methoxyphenyl)-3-(methylthio)-1H-indol-2-yl) - for 3,5-dimethylisoxazol synthesized from the product obtained in stage (b), using a technique similar to that described in example 16.

Stage (d): Oxon (152 mg, 0.25 mmol) was mixed with water (1 ml) and added to a cooled (0°C) mixture of 4-(1-(4-methoxyphenyl)-3-(methylthio)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (30 mg, 0.08 mmol) in 2 ml of MeOH. The temperature was left to rise to room so the temperature, and was stirred suspension at room temperature over night. Added 1M HCl and EtOAc and separated phases. The organic phase was concentrated.

Stage (e): 4-(1-(4-Methoxyphenyl)-3-(methylsulphonyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazol was dissolved in 2 ml anhydrous DCM and cooled to -78°C under nitrogen atmosphere. Added BBr3(31 μl, 0.33 mmol) and left the temperature to rise to room temperature during 2 h was Added water and EtOAc, and the separated phases. After evaporation of the solvents the residue was purified by the method of preparative HPLC to obtain 4-[2-(3,5-dimethylisoxazol-4-yl)-3-methanesulfonamido-1-yl]phenol with the release of 27%. ES/MS m/z: 383,11 (M+H), 381,13 (M-H);1H-NMR (acetone-d6, 500 MHz): to 8.12 (m, 1H), 7,39-7,34 (m, 2H), 7,25-7,19 (m, 3H), 6,98 (m, 2H), 3,06 (s, 3H), of 2.30 (s, 3H) and is 2.09 (s, 3H).

Example 22

1-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2,2,2-triptoreline (E22)

Scheme 20

Stage (a): To 5 ml of triperoxonane acid at room temperature was added 4-(1-(4-methoxyphenyl)-3-(methylthio)-1H-indol-2-yl) - for 3,5-dimethylisoxazol (intermediate product stage (c) of example 21, 140 mg, 0.38 mmol) and 2-mercaptobenzoic acid (118 mg, 0.77 mmol). The mixture was stirred as a suspension at room temperature under nitrogen atmosphere overnight. Added 2M NaOH and EtAc, and separated phases. The solvents are evaporated, and the residue was purified by the method of flash chromatography of the heptane/EtAc 4:1 as eluent to obtain 4-(1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole with the release of 86%. ES/MS m/z: 319,1 (M+H).

Stage (b): To a cooled (0°C) solution of 4-(1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (105 mg, 0.33 mmol) in 5 ml DMF was added NBS (59 mg, 0.33 mmol). The temperature was left to rise to room temperature and the mixture was stirred at room temperature for 30 minutes DMF evaporated. Added DCM and water, and separated phases. After evaporation of the solvents the residue was purified by the method of flash chromatography with heptane/EtOAc 9:1 to obtain 4-(3-bromo-1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole with the release of 98%. ES/MS m/z: 365,14 (M+H), 363,30 (M-H).

Stage (c): To a cooled (-78°C) solution of 4-(3-bromo-1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (10 mg, 0.03 mmol) under nitrogen atmosphere was added n-BuLi (10 μl, 0.03 mmol). After 5 min was added 2,2,2-triperoxonane anhydride (7 μl, 0.05 mmol). The temperature was left to rise to room temperature and stirred the mixture overnight. Added 1M NaHCO3and the DCM phase was separated and evaporated solvents.

Stage (d): 1-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indol-3-yl)-2,2,2-triptoreline was dissolved in anhydrous DCM and cooled the mixture in a bath with ice in a nitrogen atmosphere. Added BBr3(17 μl, 0.1 mmol), leaving the temperature to rise to room temperature and stirred the mixture overnight. Added water, DCM and a bit of dioxane, the phases were separated and evaporated dissolve the I. The residue was passed through a thin layer of silica gel with EtOAc as eluent. The residue was purified by the method of preparative HPLC to obtain specified in the title compound, 1-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2,2,2-triptoreline, with the release of 46%. ES/MS m/z: 401,1 (M+H), (399,1 (M-H);1H-NMR (methanol-d4, 500 MHz): compared to 8.26 (m, 1H), 7,41-7,34 (m, 2H), 7,18 (m, 1H), 7,11 (m, 2H), 6.89 in (m, 2H), 2,19 (s, 3H) and a 2.01 (s, 3H).

Example 23

4-[3-Bromo-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl]phenol (E23)

Scheme 21

At 0°C to 4-[3-bromo-1-(4-methoxyphenyl)-1H-indol-2-yl] - for 3,5-dimethylisoxazole (intermediate stage (b) of example 22), dissolved in DCM, was added 10 EQ. trichotillimania boron and stirred at ambient temperature overnight. The mixture was diluted with EtOAc and washed with salt solution, the organic phase was concentrated and subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified according to the method of ES/MS m/z: 385,1 (M+H), 383,09 (M-H) and1H-NMR (acetone-d6, 500 MHz): 7,60 (m, 1H), 7,31-of 7.23 (m, 3H), 7,17 (m, 2H), 6,95 (m, 2H), 2,28 (s, 3H) and 1.99 (s, 3H).

Example 24

2-Bromo-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E24)

Scheme 22

Stage (a): 4-Fluoro-1-(4-methoxyphenyl)-1H-indole (synthesized from 4-farindola by arilirovaniya, similar to that described in stage (a) an example1 [process arilirovaniya also described in J. Org. Chem. 2008, 73(14), 5529-5535]) was dissolved in 1,2-dichloroethane, was added 1.2 EQ. chlorosulfonylisocyanate, and the mixture was stirred at room temperature for 2 hours. To the mixture was added water, adjust pH to neutral values by adding NaOH (aq., 1M), and then the mixture was extracted with EtOAc. The organic phase is washed with saline and dried over Na2SO4. The crude product was purified on a column of silica gel using 50% EtOAc in n-heptane as the mobile phase.

Stage (b): To 4-fluoro-1-(4-methoxyphenyl)-1H-indol-3-carboxamide was added 50 EQ. phosphorus oxychloride and the reaction was performed at 60°C for 2 hours. The mixture was cooled to room temperature and was co-evaporated with toluene. The residue was diluted with EtOAc, first washed saturated. NaHCO3, then brine and the organic phase is dried over Na2SO4. The crude product was purified on a column of silica gel using 10% EtOAc in n-heptane as the mobile phase.

Stage (c): Intermediate product was synthesized from the product obtained in stage (b), using a technique similar to that described in stage (b) of example 1.

Stage (d): listed in the title compound, 2-bromo-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile, was synthesized from the product obtained in stage (c) using a technique similar to that described Primera 23. ES/MS m/z: 333,04 (M+H), 331,04 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,44 (DD, 1H, J=8,9, and 2.6 Hz), 7,39 (m, 2H), 7,18 (DD, 1H, J=8,5, 4,2 Hz) and 7,15-to 7.09 (m, 3H).

Example 25

(Z)-2-(4-Pertenece)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (E25)

Scheme 23

Stage (a): a Mixture of 2-bromo-1-(4-methoxyphenyl)-1H-indol-3-carbonitrile (intermediate stage (b) of example 1), 5 EQ. 4-terfenol and 5 EQ. potassium carbonate was heated at 200°C for 20 minutes in a microwave reactor in an inert atmosphere. The cooled mixture was diluted with water and was extracted with EtOAc, the combined organic phases were dried over Na2SO4and concentrated. The crude product was purified on a column of silica gel using 20% EtOAc in n-heptane as the mobile phase.

Stage (b): 2-Bromo-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril synthesized from the product obtained in stage (a) using a technique similar to that described in example 23.

Stage (c): is Specified in the title compound, (Z)-N'-hydroxy-1-(4-hydroxyphenyl)-2-phenoxy-1H-indol-3-carboxamide, was synthesized from the product obtained in stage (b) using techniques similar to those described in example 14. ES/MS m/z: 360,18 (M+H), 358,22 (M-H);1H-NMR (acetone-d6, 500 MHz): 8,24 (m, 1H), 7,25-7,14 (m, 6H), to 7.09 (m, 1H), 7,00 (m, 1H) and 6,90-6,85 (m, 4H).

Example 26

4-(2-(3,5-Dimethylisoxazol-yl)-3-nitro-1H-indol-1-yl)phenol (E26)

Scheme 24

Stage (a): To a solution of 4-(1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (intermediate stage (a) of example 22) in DCM was slowly added to a mixture of 2 EQ. nitric acid and 20 EQ. of acetic acid. After 1 hour stirring at room temperature the mixture was diluted with water and separated phases. The organic phase was concentrated and was purified on a column of silica gel using 30% EtOAc in n-heptane as the mobile phase.

Stage (b): listed in the title compound, 4-(2-(3,5-dimethylisoxazol-4-yl)-3-nitro-1H-indol-1-yl)phenol was synthesized from the product obtained in stage (a), using a technique similar to that described in example 23. ES/MS m/z: 350,18 (M+H), 348,22 (M-H);1H-NMR (acetone-d6, 500 MHz): a 8.34 (m, 1H), 7,50 (m, 1H), 7,44-7,40 (m, 2H), 7,29 (m, 1H), 7,20 (m, 1H), 7,01 (m, 2H), 2,22 (s, 3H) and are 2.11 (s, 3H).

Example 27

4-(3-(Dihydroxyaryl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol (E27)

Scheme 25

Stage (a): 4-(1-(4-Methoxyphenyl)-3-nitro-1H-indol-2-yl) - for 3,5-dimethylisoxazol (intermediate product of stage (a) of example 26) was dissolved in EtOH (99%), was added a catalytic amount of Pd/C (10%) and stirred the mixture under pressure of 4 pounds/inch2H2throughout the night. The mixture was filtered through a layer of celite, concentrated and purified on a column of silica gel using 45% EtOAc in n-GE is Tanya as mobile phase.

Stage (b): listed in the title compound, 4-(3-(dihydroxyaryl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol was synthesized from the product obtained in stage (a), using a technique similar to that described in example 23. ES/MS m/z: 351,13 (M+H), 350,18 (M-H);1H-NMR (acetone-d6, 500 MHz): 8,31 (d, 1H, J=8,2 Hz), 7,44 (t, 1H, J=7.4 Hz), was 7.36 (m, 1H), 7,30 (m, 2H), 7,22 (d, 1H, J=8,2 Hz), 7,05 (m, 2H), is 1.81 (s, 3H) and of 1.80 (s, 3H).

Example 28

N-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)ndimethylacetamide (E28)

Scheme 26

Stage (a): To a solution of 4-[1-(4-methoxyphenyl)-3-nitro-1H-indol-2-yl] - for 3,5-dimethylisoxazole (intermediate product of stage (a) of example 26) in DMF/water (10/1) at 0°C was added ammonium chloride (5 EQ.) and zinc (5 EQ.). The mixture was stirred for 2 hours at this temperature, then diluted with EtOAc, the precipitate was filtered, the organic phase is washed with saline and dried over Na2SO4. The mixture was concentrated and used in the next stage without additional purification.

Stage (b): 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1Η-indole-3-amine was dissolved in diethyl ether and cooled to 0°C, then added NaHCO3(2 EQ.) and the acid chloride (2 EQ.) in the form of a solution in diethyl ether, the mixture was maintained at 0°C and was stirred for 1 hour. The solvent was removed, the residue was dissolved in EtOAc and washed with water, the eat salt solution, then was dried over Na2SO4. The mixture was concentrated and used in the next stage without additional purification.

Stage (c): is Specified in the title compound, N-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)acetamide", she was synthesized from the product obtained in stage (b), using a technique similar to that described in example 23. ES/MS m/z: 361,21 (M+H), 360,17 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,58 (m, 1H), 7,21-7,11 (m, 5H), 6,93 (m, 2H), measuring 2.20 (s, 3H), 2,07 (s, 3H) and a 1.88 (s, 3H).

Example 29

N-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)methanesulfonamide (E29)

Scheme 27

Stage (a): 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indole-3-amine (intermediate product of stage (a) of example 28) was dissolved in diethyl ether and cooled to 0°C, then added NaHCO3(2 EQ.) and methansulfonate (2 EQ.) in the form of a solution in diethyl ether, the mixture was maintained at 0°C and was stirred for 1 hour and then at room temperature over a weekend. The solvent was removed, the residue was dissolved in EtOAc and washed with water, then brine, then dried over Na2SO4. The mixture was concentrated and used in the next stage without additional purification.

Stage (b): listed in the title compound, N-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)methanesulfonyl is d, synthesized from the product obtained in stage (a), using a technique similar to that described in example 23. ES/MS m/z: 398,17 (M+H), 396,15 (M-H);1H-NMR (acetone-d6, 500 MHz): of 7.82 (m, 1H), 7.24 to 7,20 (m, 3H), 7,17 (m, 2H), 6,95 (m, 2H), 2,89 (s, 3H), and 2.26 (s, 3H) and 1.96 (s, 3H).

Example 30

1-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)urea (E30)

Scheme 28

Stage (a): Degassed (N2) a mixture of 2-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indole-3-amine (intermediate product of stage (a) of example 28) and isocyanatomethyl (6 EQ.) in DMF was heated in a microwave reactor at 200°C for 2×20 minutes the Mixture was cooled, concentrated and used in the next stage without additional purification.

Stage (b): 1-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indol-3-yl)urea was heated in itestosterone acid (aq., 57%) at 100°C for 3 hours. The reaction mixture was cooled, concentrated and was co-evaporated with DCM and EtOAc. The residue was subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified according to the method1H-NMR. ES/MS m/z: 363,19 (M+H), 362,18 (M-H);1H-NMR (acetone-d6, 500 MHz): the 7.65 (m, 1H), 7,22-to 7.09 (m, 5H), 6,93 (m, 2H, in), 2.25 (s, 3H) and was 1.94 (s, 3H).

Examples 31 and 32

4-(2-(3,5-Dimethylisoxazol-4-yl)-3-thiocyanato-1H-indol-1-yl)phenol (E31)

2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-shall ndol-3-yl-N'-hydroxycarbonylmethyl (E32)

Scheme 29

Stage (a): 4-(1-(4-Methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazol (intermediate product of stage (a) of example 22) was dissolved in AcOH was added 1.2 EQ. ammonium thiocyanate. Then added 3 EQ. acetate magnesium(III) and stirred the reaction mixture at room temperature for 45 minutes, after which the monitoring method TLC showed complete consumption of the original substance. The reaction mixture was diluted with EtOAc and washed with saline. The phases were separated, and washed the organic phase NaHCO3(aq.). Then the organic phase was evaporated to dryness under vacuum, and used the crude product without further purification. ES/MS m/z: 376,14 (M+H).

Stage (b): the Product obtained in stage (a)were subjected to demethylation using BBr3in accordance with the method described in stage (c) of example 9, to obtain 4-(2-(3,5-dimethylisoxazol-4-yl)-3-thiocyanato-1H-indol-1-yl)phenol (E31). ES/MS m/z: 362,14 (M+H), 360,18 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,86 (m, 1H), 7,43-7,37 (m, 2H), 7,31 (m, 1H), 7,26 (m, 2H), 6,98 (m, 2H), 2,34 (s, 3H) and 2.03 (s, 3H).

Stage (c): 4-(2-(3,5-Dimethylisoxazol-4-yl)-3-thiocyanato-1H-indol-1-yl)phenol was dissolved in DMSO and added 10 EQ. 2M stock solution of hydroxylamine/NaHCO3(aq.). The reaction mixture was stirred at 65°C overnight, and then diluted with H2O. After stirring for 5 minutes about what was razvivalsya sediment. The mixture was diluted with EtOAc and diethyl ether, washed with NH4Cl (aq.) and separated phases. The organic phase was evaporated to dryness under vacuum and subjected to purification by the method of preparative HPLC with reversed phase with obtaining specified in the title compound, 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl-N'-hydroxycarbonylmethyl (E32). ES/MS m/z: 395,17 (M+H), 393,19 (M-H);1H-NMR (acetone-d6, 500 MHz): 8,88 (users, 1H), 8,73 (users, 1H), 7,80 for 7.78 (m, 1H), 7,29-7,24 (m, 3H), 7,18 (d, 2H), 6,95 (d, 2H), 5,11 (users, 2H), 2,28 (s, 3H), from 2.00 (s, 3H).

Example 33

4-(3-Benzyl-2-phenyl-1H-indol-1-yl)phenol (E33)

Scheme 30

Stage (a): To a mixture of 47 mg of 1-(4-methoxyphenyl)-2-phenyl-1H-indole (synthesized from 2-phenylindole by arilirovaniya described in J. Org. Chem. 2001, 66(23), 7729-7737) and 19 μl of benzaldehyde in 1 ml of anhydrous DCM at 0°C under nitrogen atmosphere is added dropwise within 5 min was added to a mixture of 19 μl TFA and 80 ál Et3SiH in 0.5 ml of anhydrous DCM. The mixture was left to warm to room temperature overnight, after which the mixture was cooled to 0°C and was added 160 μl of Et3SiH and 38 μl of TFA dissolved in 1 ml of CH2Cl2. The mixture was stirred for 40 min, then was podslushivaet the addition of 2M NaOH (~pH 13), then added salt solution was extracted with dichloromethane (×3) and was evaporated. To the crude product in 3 ml of dichloromethane was added 0.2 g TsNHNH2to firmly the substrate. The mixture was carefully stirred for 1 hour and 20 minutes the Polymer was filtered, and the filtered crude product through a layer of silica gel. The product was obtained pure, does not require additional purification.

Stage (b): the Product obtained in stage (a)were subjected to demethylation using BBr3in accordance with the method described in stage (c) of example 9, to obtain 4-(3-benzyl-2-phenyl-1H-indol-1-yl)phenol. ES/MS m/z: 376,4 (M+H), 374,2 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,86 (m, 1H), 7,43-7,37 (m, 2H), 7,31 (m, 1H), 7,26 (m, 2H), 6,98 (m, 2H), 2,34 (s, 3H) and 2.03 (s, 3H).

Examples 34 and 35

2-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetate (E34)

2-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-(hydroxyimino)ndimethylacetamide (E35)

Scheme 31

Stage (a): 4-(2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol was synthesized from 4-(1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (intermediate stage (a) of example 22) in the manner similar to that described in stage (c) of example 1.

Stage (b): 4-(2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol was dissolved in 1 ml anhydrous dichloromethane under nitrogen atmosphere and cooled to 0°C. was Added 4 ml of oxalicacid and the mixture was stirred at 0°C for 2 h 15 min and then at room temperature for 1 h 15 min the Mixture was concentrated under vacuum without heating, and EXT is ulali 1 ml NH 3/MeOH (us.). The mixture was stirred for 1 h, and then concentrated. The crude product was purified by the method of flash chromatography (EtOAc/heptane; 4:6 to 8:2) to give 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetate (E34). ES/MS m/z: 376,18 (M+H), 374,17 (M-H);1H-NMR (acetone-d6, 500 MHz): 8,33 (m, 1H), 7,37-to 7.15 (m, 5H), 6,98 (users, 2H), and 2.27 (s, 3H) and 2.00 (s, 3H).

Stage (c): 8,8 mg of 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetate and 32.6 mg of hydroxylamine hydrochloride in 1.5 ml EtOH in a vessel for microwave processing was added 50 μl of pyridine. The vessel was tightly closed and purged with nitrogen. The mixture was heated up to 150°C for a period of 7.5 min, and then to 150°C for 5 min in a microwave Biotage Initiator. The mixture was concentrated under vacuum and purified by the method of preparative HPLC (formic acid/buffer/acetonitrile). 2-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2(hydroxyimino)ndimethylacetamide (E35) was obtained as a mixture of syn and anti oxomnik isomers. ES/MS m/z: 391,4 (M+H), to 389.5 (M-H);1H-NMR (DMSO-d6, 500 MHz): 7,37 (m, 1H), 7,20-7,03 (m, 5H), at 6.84 (m, 2H), of 2.15 (s, 3H) and is 1.77 (s, 3H).

Examples 36 and 37

2-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-hydroxyacetate (E36)

2-(2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)ndimethylacetamide (E37)

Scheme 32

Stage (a): 9 mg of 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-GI is roxiprin)-1H-indol-3-yl)-2-oxoacetate (example 34) was mixed with 1 ml EtOH, added 1.8 mg NaBH4and the mixture was stirred for 1.5 hours the Mixture was evaporated, added water and then was extracted with EtOAc. The crude product was purified by the method of flash chromatography with reversed phase (acetonitrile/water) to give 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-hydroxyacetamido (E36). ES/MS m/z: 376.3 on (M-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,13-6,93 (m, 5H), 6,79 (m, 2H), 2,23, 2,21 (2 s, 3H) and 1,93, 1,90 (2 s, 3H).

Stage (b): To 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-hydroxyacetamido at 0°C was added 1 ml of TFA and 19 ál Et3SiH and stirred the mixture for 60 minutes, the Solvent was evaporated without heating, have a little cleanup on silica gel (EtOAc/heptane; from 1:9 to 8:2) to give 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)ndimethylacetamide (E37). ES/MS m/z: 362,3 (M+H);1H-NMR (methanol-d3, 500 MHz): 8,98 (m, 1H), 8,46-8,35 (m, 5H), 8,16 (m, 2H), 4,78 (d, 2H, J=1.9 Hz), of 3.54 (s, 3H) and 3.19 (s, 3H).

Example 38

2-((Z)-Buta-1-enyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E38)

Scheme 33

Stage (a): To a cooled solution of 2-bromo-1-(4-methoxyphenyl)-1H-indol-3-carbonitrile (intermediate stage (b) of example 1) in anhydrous THF at -78°C was slowly added n-BuLi (of 1.6 M in hexane, 1.2 EQ.), and stirred the mixture for 30 minutes. Added anti-chloride (1.5 EQ.), maintained the mixture at -78°C for 1 h, and C is the was stirred at room temperature overnight. The mixture was suppressed by adding us. NH4Cl, and then concentrated. The residue was absorbed EtOAc, washed with brine, dried over Na2SO4and was purified on a column of silica gel using 20% EtOAc in n-heptane as the mobile phase.

Stage (b): a Mixture of 1-(4-methoxyphenyl)-2-(tributylstannyl)-1H-indol-3-carbonitrile, (Z)-1-brombach-1-ene (1.2 equiv.) Pd2(dba)3(3%) and three(ortho-tolyl)phosphine (17%) in DMF was degirolami with N2and heated at 80°C during the night. The mixture was diluted with us. NH4Cl and EtOAc and separated phases. The organic phase is washed with saline, dried over Na2SO4and subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified according to the method1H-NMR.

Stage (c): is Specified in the title compound, 2-((Z)-buta-1-enyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile, was synthesized from the product obtained in stage (b), using a technique similar to that described in example 23. ES/MS m/z: 289,11 (M+H), 287,15 (M-H).

Example 39

2-(Isobut-1-enyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (E61)

Scheme 34

Stage (a): 1 EQ. 2-bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 1) was dissolved in 1,4-dioxane and stirred at room temperature. Added 1.9 EQ. hexabutylditin and 0.04 EQ. palladium di(triphenylphosphine)DIH orida, was degirolami nitrogen and heated the mixture to 80°C for 4 hours. The mixture was filtered to remove the catalyst was evaporated to remove most of the solvent, and the residue was purified on a column of silica gel using 75:25 n-heptane:ethyl acetate as the mobile phase (yield 65%).

Stage (b): 1 EQ. Stanila obtained at stage (a), was dissolved in a mixed solvent (1-methyl-2-pyrrolidinone and 1,4-dioxane, 2:1), stirred at room temperature, was added 2 EQ. 1-brometalia-1-ene and 0.2 wt.% tetrakis(triphenylphosphine)palladium were degirolami nitrogen, the mixture was heated up to 80°C during the night. The mixture was filtered to remove the catalyst was evaporated to remove most of the solvent, and the residue was purified by the method of preparative HPLC. ES/MS m/z: 289,11 (M+H), 287,15 (M-H);1H-NMR (chloroform-d, 500 MHz): 7,76 (m, 1H), 7,28 (m, 1H), 7.23 percent (m, 1H), 7,17 (m, 2H), 7,13 (m, 1H), 6,98 (m, 2H), 5,86 (m, 1H), up to 1.98 (d, 3H, J=1.3 Hz) and 1,89 (d, 3H, J=1.2 Hz).

Example 40

1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-methylallyl)-1H-indol-3-carbonitrile (E40)

Scheme 35

A mixture of 2-bromo-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile (example 103), metallici-n-butyanova (2 equiv.) Pd2(dba)3(0,05%) and three(ortho-tolyl)phosphine (20%) was dissolved in DMF, was degirolami N2and heated at 80°C during the night. The reaction mixture was suppressed by adding us. NH4Cl, diluted with EtOAc,washed with brine and then dried over Na 2SO4. The residue was subjected to preparative HPLC with reversed phase. The appropriate fractions were combined, evaporated and identified according to the method1H-NMR. ES/MS m/z: 289,11 (M+H), 287,15 (M-H);1H-NMR (chloroform-d, 500 MHz): 7,76 (m, 1H), 7,28 (m, 1H), 7.23 percent (m, 1H), 7,17 (m, 2H), 7,13 (m, 1H), 6,98 (m, 2H), 5,86 (m, 1H), up to 1.98 (d, 3H, J=1.3 Hz) and 1,89 (d, 3H, J=1.2 Hz).

Example 41

(Z)-2-(5-Ethyl-3-methylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide (E41)

Scheme 36

Stage (a): 2-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indol-3-carbonitrile (synthesized in the reaction of a combination of an intermediate product obtained in stage (b) of example 1, 3,5-dimethylisoxazol-4-Bronevoy acid using the method described in example 16) in 1 ml of anhydrous THF in an argon atmosphere at -78°C was added dropwise 38 μl of n-utility (1,6M in hexano). The mixture was stirred at -78°C for 45 minutes was Added 34 μl of methyliodide, and leave the mixture to warm to room temperature. After 4 h the mixture was concentrated under vacuum and purified on silica gel (EtOAc/heptane; 1:1).

Stage (b): Intermediate product was obtained from 4-(1-(4-methoxyphenyl)-3-phenyl-1H-indol-2-yl) - for 3,5-dimethylisoxazole manner similar to that described in stage (c) of example 1.

Stage (c): is Specified in the title compound was obtained from 2-(5-ethyl-3-methylisoxazol-4-yl)-1-(4-hydrox is phenyl)-1H-indol-3-carbonitrile way similar to that described in example 11. ES/MS m/z: 377,3 (M+H), 375,4 (M-H);1H-NMR (acetone-d6, 500 MHz): of 8.06 (m, 1H), 7,22-7,10 (m, 5H), 6,94 (m, 2H), has 2.56 (m, 2H), 2,02 (s, 3H) and 1.03 (t, 3H, J=7,3 Hz).

Example 42

4-(2-(3,5-Dimethylisoxazol-4-yl)-3-phenyl-1H-indol-1-yl)phenol (E42)

Scheme 37

Stage (a): a Mixture of DME/dioxane (1:1) three degirolami by freezing and thawing, and then placed in an atmosphere of argon. 4-(3-Bromo-1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazol (10 mg), intermediate stage (b) of example 22)and 6.1 mg of phenylboronic acid, 2,9 mg Pd(PPh3)4, 21 mg of potassium carbonate and 7.6 mg Nal was placed in a vessel for microwave processing, which is hermetically closed and purged with argon. In the vessel for microwave processing through the cannula was added 0.7 ml of a solution of DME/water.

The mixture was twice degirolami by freezing and thawing, and then purged with argon. The mixture was heated up to 150°C/15 min in the microwave Biotage Initiator. The crude product was filtered, then evaporated and filtered through a thin layer of silica gel (EtOAc). By cleaning method flash chromatography (EtOAc/heptane; from 1:9 to 2:8) received 22,2 mg mixture dibromononane educt and product with a small amount of substance (in accordance with LC/MS). The compounds were well separated on the HPLC method, but formed only a single spot by TLC method. Neocis the TES substance was used directly in the next stage demethylation.

Stage (b): listed in the title compound was obtained from 4-(1-(4-methoxyphenyl)-3-phenyl-1H-indol-2-yl) - for 3,5-dimethylisoxazole manner similar to that described in stage (c) of example 1. ES/MS m/z: 381,2 (M+H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,43-7,37 (m, 4H), 7,30-7,19 (m, 4H), 7,17 (m, 2H), of 6.96 (m, 2H), 1,99 (s, 3H) and is 1.77 (s, 3H).

Example 43

4-(3-Chloro-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol (E43)

Scheme 38

Stage (a): To a solution of 4-(1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (intermediate product of stage (a) of example 22, 7.5 mg, 0,024 mmol) in DCM was added 1.5 EQ. SO2Cl2and the mixture was stirred at room temperature for 1.5 hours the Solution was concentrated to obtain the crude product which was used directly in the next stage.

Stage (b): listed in the title compound was obtained from 4-(1-(4-methoxyphenyl)-3-phenyl-1H-indol-2-yl) - for 3,5-dimethylisoxazole manner similar to that described in example 23. ES/MS m/z: 339,1/341,1 (M+H), 337,2/339,2 (M-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,43-7,37 (m, 4H), 7,30-7,19 (m, 4H), 7,17 (m, 2H), of 6.96 (m, 2H), 1,99 (s, 3H) and is 1.77 (s, 3H).

Example 44

2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-sulfonamide (E44)

Scheme 39

Stage (a): To a solution of 4-(1-(4-methoxyphenyl)-1H-indol-2-yl) - for 3,5-dimethylisoxazole (intermediate product of stage (a) of example 22, 7.5 mg, 0,024 mmol) in DCM n and 0°C was added 1.0 EQ. HSO3Cl, and the mixture was stirred at room temperature for 1 h the Solution was concentrated to obtain the crude product, which was used in the next stage.

Stage (b): To a solution of the crude product obtained in stage (a), in DCM was added 0.5 ml of SOCl2and stirred the mixture at 70°C for 15 minutes the Solution was concentrated, added 2 ml of saturated NH3in MeOH, and the mixture was stirred over night. The solution was concentrated to obtain the crude product which was used directly in the next stage.

Stage (c): is Specified in the title compound was obtained from the crude product obtained in stage (b), using the method described in example 23. ES/MS m/z: 384,2 (M+H), 382,2 (M-H);1H-NMR (acetone-d6, 500 MHz): 8,13 (m, 1H), 7,32-7,28 (m, 2H), 7,19-to 7.15 (m, 3H), 6,93 (m, 2H), 2,24 (s, 3H) and was 2.05 (s, 3H).

Example 45

2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide (E45)

Scheme 40

0.5 mmol of (Z)-2-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamidine (Example 235) was dissolved in 5 ml of acetic acid. Was slowly added acetic anhydride (4 EQ.), and stirred the mixture overnight. Was added Pd-C catalyst (10% coal), and the mixture was placed overnight in an apparatus for the hydrogenation under a pressure of 50 pounds/inch2H2 . The mixture was filtered through celite and concentrated. The crude product was purified by HPLC method: (column: Sunfire, 20 min acid gradient: 5-50% MeCN. ES/MS m/z: 365,15 (M+H), 363,18 (M-H);1H-NMR (MeOD, 500 MHz): 7,86 (m, 1H), 7,41-7,31 (m, 2,5H), 7,25-7,13 (m, 1,5H), 6,76 (m, 1H), 6,67 (m, 1H), 2,21, 2,15 (2 s, 3H) and 2,08, to 2.06 (2 s, 3H).

Example 46-95

The following compounds were obtained in accordance with the above-described General method 1. All the details of the experiments for each of the individual stages of the General method described above in examples 1-5, 16 and 38-40.

E46 1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl

ES/MS m/z: 311,1 (polojim+H), 309,11 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,74 (m, 1H), 7,31-to 7.15 (m, 8H), 7,00 (m, 2H), and 6.80 (m, 2H).

E47 1-(4-Hydroxyphenyl)-2-methyl-1H-indol-3-carbonitril

R1=methyl

ES/MS m/z: 249,1 (polojim+H), 247,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,63 (m, 1H), 7,33 (m, 2H), 7,27 (m, 1H), 7.23 percent (m, 1H), 7,10 (m, 2H), was 7.08 (m, 1H) and 2.43 (s, 3H).

E48 2-(3-Cyanothiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3-cyanothiophene-2-yl

ES/MS m/z: 342,1 (polojim+H), (340,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.95 (d, 1H, J=5.4 Hz), to 7.84 (m, 1H), 7,52 (d, 1H, J=5.4 Hz), 7,46-7,42 (m, 2H), 7,32-7,28 (m, 3H) and to 7.00 (m, 2H).

E49 1-(4-Hydroxyphenyl)-2-((E)-propenyl)-1H-indol-3-carbonitril

R1=(E)-propenyl

ES/MS m/z: 275,3 (polojim+H)273,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): the 7.65 (m, 1H), 7,32-of 7.23 (m, 4H), 7,10 (m, 2H), 7,06 (m, 1H), 6,85 (m, 1H), of 6.26 (m, 1H) and at 1.91 (DD, 3H, J=1,8, 6,9 Hz).

E50 1-(4-Hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile

R1=thiophene-2-yl

ES/MS m/z: 317,0 (polojim+H), (315,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,73 (m, 1H), 7,65 (DD, 1H, J=1,1, 5.0 Hz), 7,54 (DD, 1H, J=1,1, 3.8 Hz), 7,37-7,29 (m, 4H), to 7.15 (DD, 1H, J=3,8, 5.0 Hz), 7,11 (m, 1H) and 7,06 (m, 2H).

E51 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl

ES/MS m/z: 330,2 (polojim+H), 328,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,42-to 7.32 (m, 3H), 7,28 (m, 2H), 7,00 (m, 2H), a 2.36 (s, 3H) and 2.02 (s, 3H).

E52 1-(4-Hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile

R1=pyridine-4-yl

ES/MS m/z: 312,2 (polojim+H), 310,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,35 (m, 2H), 7,38 (m, 1H), 7,20 (m, 2H), 6,98 (m, 2H), PC 6.82 (m, 1H), 6,79 (m, 2H) and 6,44 (m, 2H).

E53 1-(4-Hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrrol-2-yl

ES/MS m/z: 314,3 (polojim+H), (312,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.75 (m, 1H), 7,38-to 7.32 (m, 2H), 7,29 (m, 1H), 7,20 (m, 2H), 6,95 (m, 2H), 6,83 (DD, 1H, J=1,9, 2,5 Hz), 6,24 (DD, 1H, J=1,9, 3.8 Hz), 6,09 (DD, 1H, J=2.5 and 3.8 Hz) and 3,51 (s, 3H).

E54 1-(4-Hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=3-methylthiophene-2-yl

ES/MS m/z: 331,4 (polojim+H), 329,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,56 (d, 1H, J=5,1 Hz), 7,40-7,34 (m, 2H), 7,27 (m, 1H), 7,21 (m, 2H), 6,97 (d, 1H, J=5,1 Hz), to 6.95 (m, 2H) and of 2.21 (s, 3H).

E55 1-(4-Hydroxyphenyl)-2-isopropylamino-1H-indol-3-carbonitril

R1=isopropylamino

ES/MS m/z: 292,1 (polojim+H), 290,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,34 (m, 1H), 7,25 (m, 2H), to 7.09 (m, 1H), 7,06 (m, 2H), 6,95 (m, 1H), 6,70 (m, 1H), 4,33 (m, 1H) and 1.28 (d, 6H, J=6.5 Hz).

E56 2 Ethylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=ethylamino

ES/MS m/z: 278,3 (polojim+H), (276,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,33 (m, 1H), 7,26 (m, 2H), to 7.09 (m, 1H), 7,06 (m, 2H), 6,95 (m, 1H), 6,70 (m, 1H), the 3.65 (q, 2H, J=7.4 Hz) and of 1.27 (t, 3H, J=7.4 Hz).

E57 2 Butylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=butylamino

ES/MS m/z: 306,2 (polojim+H), 304,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,33 (m, 1H), 7,26 (m, 2H), 7,10-7,05 (m, 3H), 6,94 (m, 1H), 6,69 (m, 1H), 3,61 (m, 2H), by 1.68 (m, 2H), 1,41 (m, 2H) and 0.92 (t, 3H, J=7.4 Hz).

E58 1-(4-Hydroxyphenyl)-2-piperidine-1-yl-1H-indole-3-carbonitrile

R1=piperidine-1-yl

ES/MS m/z: 317,9 (polojim+H), 316,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): was 7.45 (m, 1H), was 7.36 (m, 2H), 7,18 (m, 1H), 7,12-7,07 (m, 3H), 7,01 (m, 1H), 3.27 to (m, 4H), and 1.54 (m, 2H) and for 1.49 (m, 4H).

E59 1-(4-Hydroxyphenyl)-2-pyrrolidin-1-yl-1H-indole-3-carbonitrile

R1=pyrrolidin-1-yl

ES/MS m/z: 304,4 (polojim+H), 302,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,33-7,29 (m, 3H), 7,11 (m, 1H),? 7.04 baby mortality (m, 2H), of 6.96 (m, 1H), 6.73 x (m, 1H), 3,40 (m, 4H) and to 1.87 (m, 4H).

E60 1-(4-Hydroxyphenyl)-2-morpholine-4-yl-1H-indole-3-carbonitrile

R1=morpholine-4-yl

ES/MS m/z: 320,3 (polojim+H), 317,8 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,49 (m, 1H), 7,40 (m, 2H), 7,21 (m, 1H), 7,14 (m, 1H), 7,10 (m, 2H), 7,05 (m, 1H)and 3.59 (m, 4H) and of 3.28 (m, 4H)./p>

E61 2 Diethylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=diethylamino

ES/MS m/z: 306,2 (polojim+H), 304,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,47 (m, 1H), 7,31 (m, 2H), 7,19 (m, 1H), 7,10 (m, 1H), was 7.08 (m, 2H), of 6.96 (m, 1H), 3,28 (q, 4H, J=6,9 Hz) and 1.05 (t, 6H, J=6.9 Hz).

E62 2-Ethinyl-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=ethinyl

ES/MS m/z: 259,1 (polojim+H), 257,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,44-7,37 (m, 4H), 7,26 (m, 1H), 7,10 (m, 2H) and 4.45 (s, 1H).

E63 1-(4-Hydroxyphenyl)-2-vinyl-1H-indole-3-carbonitrile

R1=vinyl

ES/MS m/z: 261,1 (polojim+H), 259,0 (africatm-H);1Η-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,34-7,27 (m, 4H), 7,13-to 7.09 (m, 3H), 6,56 (DD, 1H, J=17,6, and 11.6 Hz), 6,24 (DD, 1H, J=17,6, 0.6 Hz) and 5.69 (DD, 1H, J=11,6, 0.6 Hz).

E64 1-(4-Hydroxyphenyl)-1H-indole-2,3-dicarbonitrile

R1=cyano

ES/MS m/z: 258,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,88 (m, 1H), to 7.59 (m, 1H), 7,56 (m, 2H), 7,52 (m, 1H), 7,42 (m, 1H) and to 7.15 (m, 2H).

E65 1-(4-Hydroxyphenyl)-2-prop-1-inyl-1H-indol-3-carbonitril

R1=prop-1-inyl

ES/MS m/z: 273,1 (polojim+H), (271,1 (africatm-H)1H-NMR (acetone-d6, 500 MHz): to 7.68 (m, 1H), 7,38 (m, 2H), was 7.36-7,33 (m, 2H), 7,22 (m, 1H), was 7.08 (m, 2H) and of 2.09 (s, 3H).

E66 1-(4-Hydroxyphenyl)-2-pyridin-2-yl-1H-indole-3-carbonitrile

R1=pyridine-2-yl

ES/MS m/z: 312,1 (polojim+H), 310,2 (africatm-H)1H-NMR (acetone-d6, 500 MHz): 8,63 (m, 1H), 7,84 for 7.78 (m, 2H), 7,49 (m, 1H), 7,41 and 7.36 (m, 3H), 7,26 (m, 1H), 7,22 (m, 2H) and of 6.96 (m, 2H).

E67 1-(4-Hydroxyphenyl)-2-(2-methylallyl)-1H-indol-3-carbonitril the

R1=2-methylallyl

ES/MS m/z: 289,1 (polojim+H), 287,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.67 (m, 1H), 7,31-7,24 (m, 4H), 7,10-7,05 (m, 3H), amounts to 4.76 (s, 1H), to 4.41 (s, 1H), 3,55 (s, 2H) and of 1.66 (s, 3H).

E68 1-(4-Hydroxyphenyl)-2-((Z)-propenyl)-1H-indol-3-carbonitril

R1=(Z)-propenyl

ES/MS m/z: 275,1 (polojim+H)273,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,71 (m, 1H), 7,33-7,27 (m, 4H), 7,17 (m, 1H), 7,06 (m, 2H), 6,20-6,12 (m, 2H) and was 1.94 (d, 3H, J=5.3 Hz)

E69 2-(Butylmethylamine)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=butylmethylamine

ES/MS m/z: 320,3 (polojim+H), (318,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): the 7.43 (m, 1H), 7,31 (m, 2H), 7,17 (m, 1H), 7,09-7,06 (m, 3H), 6,93 (m, 1H), 3.15 in (m, 2H), 3.00 and (s, 3H), of 1.45 (m, 2H), 1,20 (m, 2H) and of 0.83 (t, 3H, J=7.4 Hz).

E70 1-(4-Hydroxyphenyl)-2-((Z)-1-methylpropenyl)-1H-indol-3-carbonitril

R1=(Z)-1-methylpropenyl

ES/MS m/z: 289,2 (polojim+H), 287,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,33-7,27 (m, 4H), 7,22 (m, 1H), 7,05 (m, 2H), 5,90 (m, 1H), 1,78 (m, 3H) and of 1.66 (m, 3H).

E71 1-(4-Hydroxyphenyl)-2-imidazol-1-yl-1H-indole-3-carbonitrile

R1=imidazol-1-yl

ES/MS m/z: 301,1 (polojim+H), 299,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): a 7.85 (t, 1H, J=0.9 Hz), 7,79 (m, 1H), 7,47-7,40 (m, 2H), 7,34-7,31 (m, 3H), 7,26 (m, 1H), 7,06 (DD, 1H, J=0,9, 1,6 Hz) and of 6.99 (m, 2H).

E72 1-(4-Hydroxyphenyl)-2-[1,2,4]triazole-1-yl-1H-indole-3-carbonitrile

R1=[1,2,4]triazole-1-yl

ES/MS m/z: 302,3 (polojim+H), 300,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,73 (s, 1H), 8,15 (s, 1H), to 7.84 (m, 1H), 7,49-7,46 (m, 2H), 7,33-7,28 (m, 3H) and of 6.99 (m, H).

E73 2-(3,5-Dimethylpyrazol-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-dimethylpyrazol-1-yl

ES/MS m/z: 329,3 (polojim+H), 327,4 (africatm-H);1Η-NMR (acetone-d6, 500 MHz): 7,81 (m, 1H), 7,46-7,42 (m, 2H), 7,35 (m, 1H), 7,21 (m, 2H), 6,93 (m, 2H), 5,98 (s, 1H), 2,15 (s, 3H) and 2.12 (s, 3H).

E74 1-(4-Hydroxyphenyl)-2-pyrazole-1-yl-1H-indole-3-carbonitrile

R1=pyrazole-1-yl

ES/MS m/z: 301,4 (polojim+H), 299,5 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,89 (d, 1H, J=2.6 Hz), 7,79 (m, 1H), 7,72 (d, 1H, J=1.8 Hz), 7,45-7,39 (m, 2H), 7,29-of 7.23 (m, 3H), 6,97 (m, 2H) and 6,47 (DD, 1H, J=1,8, 2,6 Hz).

E75 1-(4-Hydroxyphenyl)-2-(5-Mei-1-yl)-1H-indol-3-carbonitril

R1=5-Mei-1-yl

ES/MS m/z: 315,2 (polojim+H), 313,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.82 (m, 1H), 7,76 (d, 1H, J=0.9 Hz), 7,47-the 7.43 (m, 2H), 7,33-7,27 (m, 3H), 6,97 (m, 2H), 6,76 (m, 1H) and 2.13 (d, 3H, J=1.1 Hz).

E76 1-(4-Hydroxyphenyl)-2-(5-methylpyrazole-1-yl)-1H-indol-3-carbonitril

R1=5-methylpyrazole-1-yl

ES/MS m/z: 315,2 (polojim+H), 313,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,83 (m, 1H), 7,55 (d, 1H, J=1.3 Hz), 7,47-7,44 (m, 2H), 7,37 (m, 1H), 7,20 (m, 2H), 6,93 (m, 2H), to 6.19 (m, 1H) and 2,22 (s, 3H).

E77 1-(4-Hydroxyphenyl)-2-(3-methylpyrazole-1-yl)-1H-indol-3-carbonitril

R1=3-methylpyrazole-1-yl

ES/MS m/z: 315,2 (polojim+H), 313,3 (polojim+H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), 7,69 (d, 1H, J=2.5 Hz), 7,42 and 7.36 (m, 2H), 7,27-of 7.23 (m, 3H), 6,98 (m, 2H), and 6.25 (d, 1H, J=2.5 Hz) and of 2.21 (s, 3H).

E78 1-(4-Hydroxyphenyl)-2-thiazol-2-yl-1H-indole-3-carbonitrile

R1=thiazol-2-yl

ES/MS /z: 318,1 (polojim+H), 316,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.99 (d, 1H, J=3.2 Hz), 7,81 (m, 1H), 7,76 (d, 1H, J=3.2 Hz), 7,42-7,37 (m, 4H) and 7,15-7,11 (m, 3H).

E79 1-(4-Hydroxyphenyl)-2-(2-methoxythiazole-4-yl)-1H-indol-3-carbonitril

R1=2-methoxythiazole-4-yl

ES/MS m/z: 348,1 (polojim+H), (346,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.75 (m, 1H), 7,37-7,31 (m, 4H), 7,11 (m, 1H), 7,07 (m, 2H), of 6.68 (s, 1H) and 4.04 (s, 3H).

E80 1-(4-Hydroxyphenyl)-2-thiazol-4-yl-1H-indole-3-carbonitrile

R1=thiazol-4-yl

ES/MS m/z: 318,1 (polojim+H), (316,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): remaining 9.08 (d, 1H, J=1.9 Hz), 7,78 (m, 1H), 7,41 (d, 1H, J=1.9 Hz), 7,39-7,33 (m, 2H), 7,29 (m, 2H), 7,17 (m, 1H) and 7.04 (m, 2H).

E81 1-(4-Hydroxyphenyl)-2-(3-methylbut-2-enyl)-1H-indol-3-carbonitril

R1=3-methylbut-2-enyl

ES/MS m/z: 303,1 (polojim+H), 301,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.64 (m, 1H), 7,30 (m, 2H), 7,29-7,21 (m, 2H), to 7.09 (m, 2H), 7,03 (m, 1H), 5,11 (m, 1H), 3,54 (m, 2H), 1,62 (m, 3H) 1.48 (s, 3H).

E82 2-((E)-But-1-enyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=(E)-But-1-enyl

ES/MS m/z: 289,1 (polojim+H), 287,2 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,73 (m, 1H), 7,28 (m, 1H), 7,22-7,19 (m, 3H),? 7.04 baby mortality (m, 2H), 7,02 (m, 2H), 6,92 (m, 1H), 6,11 (m, 1H), 2,23 (m, 2H) and 1.04 (t, 3H, J=7,1 Hz).

E83 1-(4-Hydroxyphenyl)-2-(5-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=5-methylthiophene-2-yl

ES/MS m/z: 331,1 (polojim+H), 329,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,35-7,28 (m, 5H), 7,09-7,05 (m, 3H), PC 6.82 (m, 1H) and 2.45 (s, 3H).

E84 2-(5-Acetylthiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indole-3-Carbo is itril

R1=5-acetylthiophene-2-yl

ES/MS m/z: 359,3 (polojim+H), (357,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): a 7.85 (d, 1H, J=4,1 Hz), to 7.77 (m, 1H), EUR 7.57 (d, 1H, J=4,1 Hz), 7,41-7,34 (m, 4H), to 7.15 (m, 1H), was 7.08 (m, 2H) and 2.54 (s, 3H).

E85 1-(4-Hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrazole-4-yl

ES/MS m/z: 315,2 (polojim+H), 313,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,73 (s, 1H), to 7.67 (m, 1H), 7,35 (s, 1H), 7,32-7,28 (m, 3H), 7,26 (m, 1H), to 7.09 (m, 2H), 7,07 (m, 1H) and are 3.90 (s, 3H).

E86 2-(5-Chlorothiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=5-chlorothiophene-2-yl

ES/MS m/z: 351,2 (polojim+H), 349,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,45 (d, 1H, J=4,1 Hz), 7,39-to 7.32 (m, 4H) and 7,13-was 7.08 (m, 4H).

E87 1-(4-Hydroxyphenyl)-2-(4-methylthiophene-3-yl)-1H-indol-3-carbonitril

R1=4-methylthiophene-3-yl

ES/MS m/z: 331,4 (polojim+H), 329,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), to 7.59 (d, 1H, J=3.2 Hz), 7,39-7,33 (m, 2H), 7,29 (m, 1H), 7,21 (m, 2H), 7,18 (m, 1H), 6,93 (m, 2H) and of 2.08 (d, 3H, J=0.9 Hz).

E88 1-(4-Hydroxyphenyl)-2-(4-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=4-methylthiophene-2-yl

ES/MS m/z: 331,4 (polojim+H), 329,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,71 (m, 1H), 7,39 (d, 1H, J=1.3 Hz), of 7.36-7,29 (m, 2H), 7,27 (m, 2H), 7,22 (m, 1H), was 7.08 (m, 1H),? 7.04 baby mortality (m, 2H) and of 2.23 (d, 3H, J=0.9 Hz).

E89 2-(4-Cyanothiophene-3-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=4-cyanothiophene-3-yl

ES/MS m/z: 342,2 (polojim+H), 340,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,49 (d, 1H, J=3.1 Hz), 7,98 (d, 1H,J=3.1 Hz), 7,81 (m, 1H), 7,44-7,39 (m, 2H), 7,31 (m, 1H), 7,26 (m, 2H) and 6,97 (m, 2H).

E90 1-(4-Hydroxyphenyl)-2-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-carbonitril

R1=2-methyl-2H-pyrazole-3-yl

ES/MS m/z: 315,2 (polojim+H), 313,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,80 (m, 1H), 7,45 (d, 1H, J=2.0 Hz), 7,43-7,39 (m, 2H), 7,32 (m, 1H), 7,27 (m, 2H), 6,97 (m, 2H), 6.42 per (d, 1H, J=2.0 Hz) and of 3.77 (s, 3H).

E91 1-(4-Hydroxyphenyl)-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitril

R1=1,3,5-trimethyl-1H-pyrazole-4-yl

ES/MS m/z: 343,1 (polojim+H), 341,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,73 (m, 1H), was 7.36-7,30 (m, 3H), 7,17 (m, 2H), 6,94 (m, 2H), 3,69 (s, 3H), 2,11 (s, 3H) and 1.96 (s, 3H).

E92 2-(2-Acetylpyrrole-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-acetylpyrrole-1-yl

ES/MS m/z: 342,2 (polojim+H), 340,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), 7,44 (DD, 1H, J=1,6, 2,8 Hz), 7,42-7,37 (m, 2H), 7.23 percent (m, 1H), 7,13 (DD, 1H, J=1,6, 3,9 Hz), to 7.09 (m, 2H), to 6.88 (m, 2H), 6,41 (DD, 1H, J=2,8, 3,9 Hz) and of 2.23 (s, 3H).

E93 2-(2-Acylpyrrole-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-acylpyrrole-1-yl

ES/MS m/z: 328,4 (polojim+H), 326,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,44-7,39 (m, 2H), 7,30 (m, 1H), 7,22 (m, 2H), 6,93 (m, 2H), to 6.88 (DD, 1H, J=2,9, and 1.6 Hz), 6,11 (t, 1H, J=3.2 Hz), 5,95 (m, 1H), 2.49 USD (m, 1H), 2,37 (m, 1H) and 1.09 (t, 3H, J=7.5 Hz).

E94 2-(2-Cyanoprop-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-cyanoprop-1-yl

ES/MS m/z: 325,4 (polojim+H), 323,5 (africatm-H);1H-NMR (acetone-d6, 500 MHz): a 7.85 (m, 1H), 7,49-7,46 (m, 3H), 7,32 (m, 1H), 7,28 (m, 2H), 7,11 (DD, H, J=4,1, 1,6 Hz), of 6.99 (m, 2H) and of 6.45 (DD, 1H, J=4,1, 2,9 Hz).

E95 1-(4-Hydroxyphenyl)-2-(2-methylpyrrole-1-yl)-1H-indol-3-carbonitril

R1=2-methylpyrrole-1-yl

ES/MS m/z: 314,3 (polojim+H), 312,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,44,7,39 (m, 2H), 7,31 (m, 1H), 7,22 (m, 2H), 6,94 (m, 2H), 6,85 (DD, 1H, J=3,0, 1,6 Hz), 6,07 (t, 1H, J=3.3 Hz), of 5.92 (m, 1H) and 2.12 (d, 3H, J=0.7 Hz).

Examples 96-159

The following compounds were obtained in accordance with the above-described General method 1. All the details of the experiments for each of the individual stages of the General method described above in examples 1-5, 16 and 38-40.

E96 1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R=3-chloro-5-fluoro-4-hydroxyphenyl

ES/MS m/z: 363,1 (polojim+H), (361,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,56-7,53 (m, 2H), 7,50 was 7.45 (m, 3H), 7,41-7,34 (m, 4H) and to 7.32 (DD, 1H, J=10,8, 2,5 Hz).

E97 1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-2-(3-cyanothiophene-2-yl)-1H-indol-3-carbonitril

R1=3-cyanothiophene-2-yl; R=3-chloro-5-fluoro-4-hydroxyphenyl

ES/MS m/z: 392,0, 394,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,00 (d, 1H, J=5.4 Hz), to 7.84 (m, 1H), 7,56 (d, 1H, J=5.4 Hz) and 7,49-7,41 (m, 5H).

E98 1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-2-(3-cianfuran-2-yl)-1H-indol-3-carbonitril

R1=3-cianfuran-2-yl; R=3-chloro-5-fluoro-4-hydroxyphenyl

ES/MS m/z: 376,0, 378,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.97 (d, 1H, J=2.0 Hz), 7,86 (m, 1H), 7,52-7,44 (m, 5H) and 7,07 (d, 1H, J=2.0 Hz).

E99 2-Bromo-1-(3-the ENT-5-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=3-chloro-5-fluoro-4-hydroxyphenyl

ES/MS m/z: 362,0, 364,0, 366,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,54 (t, 1H, J=2.5 Hz), to 7.50 (DD, 1H, J=2,5 and 10.7 Hz), 7,39-7,34 (m, 2H) and 7,27 (m, 1H).

E100 2-Bromo-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=2-fluoro-4-hydroxyphenyl

ES/MS m/z: 331,1, 333,2 (polojim+H), 328,9, 331,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,71 (m, 1H), of 7.48 (m, 1H), 7,38-7,33 (m, 2H), 7,14 (m, 1H) and 6,98-6,93 (m, 2H).

E101 1-(2-Fluoro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R=2-fluoro-4-hydroxyphenyl

ES/MS m/z: 329,3 (polojim+H), (327,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,52-7,49 (m, 2H), 7,47-7,44 (m, 3H), 7,42 and 7.36 (m, 3H), 7,19 (m, 1H), 6,84 (m, 1H) and 6,77 (DD, 1H, J=2.7, and an 11.7 Hz).

E102 2-Bromo-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 331,1, 333,2 (polojim+H), 329,2, 331,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,46 (DD, 1H, J=2,5, and 11.4 Hz), 7,38-to 7.32 (m, 2H), 7,31-7,25 (m, 2H) and 7,21 (m, 1H).

E103 2-Bromo-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 349,1, 351,2 (polojim+H), 346,9, 349,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,72 (m, 1H), 7,40-7,34 (m, 3H), 7,22 (m, 1H) and 7,14 (m, 1H).

E104 2-Bromo-1-(2,5-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=2,5-debtor-4-hydroxyphenyl

ES/MS m/z: 349,1, 351,2 (polojim+H), 346,9, 349,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,73 (m, 1H), to 7.61 (DD, 1H, J=7,2, 10.6 G is), 7,41-7,35 (m, 2H), 7.23 percent (m, 1H) and 7,16 (DD, 1H, J=7,6, to 10.7 Hz).

E105 2-Bromo-1-(3-chloro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 347,0, 349,1, (polojim+H), 344,8, 347,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,65 (d, 1H, J=2.5 Hz), 7,39 (DD, 1H, J=2.5 and 8.5 Hz), 7,38-to 7.32 (m, 2H), 7,30 (d, 1H, J=8.5 Hz) and 7,20 (m, 1H).

E106 2-Bromo-1-(3,5-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 349,1, 351,2 (polojim+H), 347,2, 349,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), 7,40-7,34 (m, 4H) and 7,27 (m, 1H).

E107 1-(3-Fluoro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 329,3 (polojim+H), (327,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,51 (m, 2H), 7,46-the 7.43 (m, 3H), 7,40-7,35 (m, 2H), 7,31-7,26 (m, 2H) and 7,14-7,07 (m, 2H).

E108 1-(3,5-Debtor-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 347,2 (polojim+H), 344,8 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,53 (m, 2H), 7,49-7,46 (m, 3H), 7,42-7,35 (m, 3H) and 7,19 (m, 2H).

E109 1-(3-Chloro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 344,9, 347,3 (polojim+H), 343,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,52 (m, 2H), of 7.48 (d, 1H, J=2.5 Hz), 7,47-7,44 (m, 3H), 7,41-7,35 (m, 2H), 7,29 (m, 1H), 7,22 (DD, 1H, J=2.5 a, 8,8 Hz) and 7,13 (d, 1H, J=8,8 Hz).

E110 1-(2,3-Debtor-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1 =phenyl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 347,2 (polojim+H), 344,8 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,80 (m, 1H), 7,52 (m, 2H), 7,49-7,46 (m, 3H), 7,43-7,38 (m, 2H), 7,29-7,25 (m, 2H) and to 7.00 (m, 1H).

E111 1-(2,5-Debtor-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R=2,5-debtor-4-hydroxyphenyl

ES/MS m/z: 347,3 (polojim+H), 344,8 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,79 (m, 1H), 7,54-7,51 (m, 3H), 7,50-7,46 (m, 3H), 7,43-7,37 (m, 2H), 7,27 (m, 1H) and of 6.96 (DD, 1H, J=1,6 and 10.7 Hz).

E112 1-(3,5-Debtor-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile

R1=thiophene-3-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 353,0 (polojim+H), 351,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,71 (DD, 1H, J=1,3, 2,9 Hz), to 7.59 (DD, 1H, J=2,9, 5,1 Hz), 7,40-7,34 (m, 2H), 7,30 (m, 1H) and 7,24-7,20 (m, 3H).

E113 1-(3,5-Debtor-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile

R1=thiophene-2-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 353,0 (polojim+H), 351,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,71 (DD, 1H, J=1,2, 5.0 Hz), 7,54 (DD, 1H, J=1,2, 3.8 Hz), 7,40-7,34 (m, 2H), 7,30 (m, 2H), 7,25 (m, 1H) and 7,19 (DD, 1H, J=3,8, 5.0 Hz).

E114 1-(3,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 366,2 (polojim+H), 364,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,45 (m, 1H), 7,44-7,40 (m, 2H), 7,22 (m, 2H), 2,41 (s, 3H) and is 2.09 (s, 3H).

E115 1-(3,5-Debtor-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitril

R1 =1-methyl-1H-pyrrol-2-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 350,3 (polojim+H), (348,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), 7,41 and 7.36 (m, 3H), 7,15 (m, 2H), 6.90 to (DD, 1H, J=1,8, and 2.6 Hz), 6,27 (DD, 1H, J=1,8, 3.8 Hz), 6,12 (DD, 1H, J=2,6, 3.8 Hz) and 3,61 (s, 3H).

E116 1-(3,5-Debtor-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=3-methylthiophene-2-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 367,1 (polojim+H), 365,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), to 7.61 (d, 1H, J=5,1 Hz), 7,42 and 7.36 (m, 3H), 7,16 (m, 2H), 7,02 (d, 1H, J=5,1 Hz) and 2.26 (s, 3H).

E117 1-(3,5-Debtor-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrazole-4-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 351,5 (polojim+H), 349,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,79 (s, 1H), 7,68 (m, 1H), 7,50 (s, 1H), 7,35-7,28 (m, 2H), 7,25 (m, 2H), 7,18 (m, 1H) and 3,91 (s, 3H).

E118 1-(3,5-Debtor-4-hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile

R1=pyridine-4-yl; R=3,5-debtor-4-hydroxyphenyl

ES/MS m/z: 348,2 (polojim+H);1H-NMR (acetone-d6, 500 MHz): 8,70 (m, 2H), 7,81 (m, 1H), 7,49 (m, 2H), 7,45-7,39 (m, 3H) and from 7.24 (m, 2H).

E119 1-(3-Chloro-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile

R1=thiophene-3-yl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 351,2 (polojim+H), 349,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), to 7.67 (DD, 1H, J=1,3, 2,8 Hz), EUR 7.57 (DD, 1H, J=2,8, 5,1 Hz), 7,52 (d, 1H, J=2.5 Hz), 7,39-to 7.32 (m, 2H), 7,27 (DD, 1H, J=2.5 and 8.6 Hz), 7.23 percent (m, 1H), 7,20 (d, 1H, J=8.6 Hz) and to 7.18 (DD, 1H, J=1,3, 5,1 Hz).

E120 1-(3-Chloro-4-hydroxyben the l)-2-thiophene-2-yl-1H-indole-3-carbonitrile

R1=thiophene-2-yl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 351,2 (polojim+H), 349,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,68 (DD, 1H, J=1,3, 5.0 Hz), 7,58 (d, 1H, J=2.5 Hz), 7,56 (DD, 1H, J=1,3, and 3.8 Hz), 7,39-7,31 (m, 3H), 7,24 (d, 1H, J=8.5 Hz) and 7,18-to 7.15 (m, 2H).

E121 1-(3-Chloro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 364,4 (polojim+H), 362,5 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,53 (users, 1H), 7,43 and 7.36 (m, 3H), 7,27 (userd, 1H, J=7,7 Hz), 7,19 (d, 1H, J=8,9 Hz), 2,39 (s, 3H) and to 2.06 (s, 3H).

E122 1-(3-Chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrrol-2-yl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 348,2 (polojim+H), 346,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.75 (m, 1H), 7,43 (d, 1H, J=2.5 Hz), 7,40-7,35 (m, 2H), 7,32 (m, 1H), 7,22 (DD, 1H, J=2.5 and 8.7 Hz), 7,14 (d, 1H, J=8.7 Hz), 6.87 in (DD, 1H, J=1,9, 2,8 Hz), and 6.25 (DD, 1H, J=1,9, 3.8 Hz), 6,10 (DD, 1H, J=2,8, 3.8 Hz) and to 3.58 (s, 3H).

E123 1-(3-Chloro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=3-methylthiophene-2-yl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 365,0 (polojim+H), 363,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), to 7.59 (d, 1H, J=5,1 Hz), 7,46 (d, 1H, J=2.6 Hz), 7,41 and 7.36 (m, 2H), 7,30 (m, 1H), 7,22 (DD, 1H, J=2,6, 8.5 Hz), 7,14 (d, 1H, J=8.5 Hz), 7,00 (d, 1H, J=5,1 Hz) 2.24 (, 3H).

E124 1-(3-Chloro-4-hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile

R1=pyridine-4-yl; R=3-chloro-4-hydroxyphenyl

ES/MS m/z: 346,1 (polojim+H), 343,9 (africatm-); 1H-NMR (acetone-d6, 500 MHz): 8,68 (m, 2H), 7,81 (m, 1H), 7,55 (d, 1H, J=2.5 Hz), 7,47 (m, 2H), 7,44-7,41 (m, 2H), 7,34 (m, 1H), 7,27 (DD, 1H, J=2.5 and 8.6 Hz) and 7,16 (d, 1H, J=8.6 Hz).

E125 1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile

R1=thiophene-3-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 335,6 (polojim+H), (333,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), to 7.67 (DD, 1H, J=1,3, 2,8 Hz), 7,56 (DD, 1H, J=2,8, 5.0 Hz), 7,38-7,30 (m, 3H), 7,24 (m, 1H), 7,21-7,17 (m, 2H) and 7,13 (m, 1H).

E126 1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile

R1=thiophene-2-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 335,6 (polojim+H), (333,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,73 (m, 1H), 7,68 (DD, 1H, J=1,3, 5.0 Hz), 7,54 (DD, 1H, J=1,3, and 3.8 Hz), 7,39-to 7.32 (m, 3H) and 7,25-7,16 (m, 4H).

E127 2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 348,2 (polojim+H), 346,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,79 (m, 1H), 7,43-7,39 (m, 3H), 7,32 (m, 1H), 7,20-7,13 (m, 2H), 2,39 (s, 3H) and was 2.05 (s, 3H).

E128 1-(3-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrrol-2-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 332,3 (polojim+H), (330,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.75 (m, 1H), 7,40-to 7.32 (m, 3H), 7,21 (DD, 1H, J=2,1, 11.3 Hz), 7,15-was 7.08 (m, 2H), 6.87 in (DD, 1H, J=1,8, 2,5 Hz), and 6.25 (DD, 1H, J=1,8, 3.8 Hz), 6,10 (DD, 1H, J=2.5 and 3.8 Hz) and of 3.56 (s, 3H).

E129 1-(3-Fluoro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=3-methyl shall iophen-2-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 349,4 (polojim+H), 347,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), to 7.59 (d, 1H, J=5,1 Hz), 7,41 and 7.36 (m, 2H), 7,32 (m, 1H), 7,25 (DD, 1H, J=2,4, and 11.4 Hz), 7,15-was 7.08 (m, 2H), 7,00 (d, 1H, J=5,1 Hz), 2.24 (s, 3H).

E130 1-(3-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrazole-4-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 333,2 (polojim+H), 331,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (users, 1H), 7,68 (m, 1H), 7,41 (d, 1H, J=0.6 Hz), of 7.36-7.23 percent (m, 4H), 7,16 (m, 1H), 7,12 (m, 1H) and 3,91 (s, 3H).

E131 1-(3-Fluoro-4-hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile

R1=pyridine-4-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 330,2 (polojim+H), 328,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,68 (m, 2H), 7,81 (m, 1H), 7,47 (m, 2H), 7,44-7,40 (m, 2H), 7,37-7,33 (m, 2H) and 7,17 for 7.12 (m, 2H).

E132 2-Dimethylamino-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=dimethylamino; R=2-fluoro-4-hydroxyphenyl

ES/MS m/z: 296,3 (polojim+H), (294,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,45-7,41 (m, 2H), 7,19 (m, 1H), 7,10 (m, 1H), 6,69-6,85 (m, 3H) and 2,96 (s, 6H).

E133 2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl; R=2-fluoro-4-hydroxyphenyl

ES/MS m/z: 348,2 (polojim+H), 346,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,80 (m, 1H), 7,47 (m, 1H), 7,42 (m, 1H), 7,27 (m, 1H), to 6.88 (m, 1H), 6,83 (m, 1H), 2,34, 2,33 (2 s, 3H) and 2.10, 2,09 (2 s, 3H).

E134 1-(3-Fluoro-4-hydroxyphenyl)-2-((E)-propenyl)-1H-indol-3-carbonitril

R1=(E)-ol which was panel; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 293,1 (polojim+H), 291,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,66 (m, 1H), 7,35-7,25 (m, 4H), 7,16 (m, 1H), 7,11 (m, 1H), 6,86 (m, 1H), 6,29 (m, 1H) and 1.92 (DD, 3H, J=1,9, 6,9 Hz).

E135 1-(3-Fluoro-4-hydroxyphenyl)-2-((Z)-propenyl)-1H-indol-3-carbonitril

R1=(Z)-propenyl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 293,1(polojim+H), 291,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,71 (m, 1H), 7,35-7,29 (m, 3H), 7,25-7,21 (m, 2H), 7,16 (m, 1H), 6,23-6,16 (m, 2H) and was 1.94 (m, 3H).

E136 1-(2,3-Debtor-4-hydroxyphenyl)-2-((Z)-propenyl)-1H-indol-3-carbonitril

R1=(Z)-propenyl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 311,0 (polojim+H), (309,1 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,79 (m, 1H), 7,35-7,28 (m, 2H), was 7.08 (m, 1H), 7,05-of 6.96 (m, 2H), 6,17 (m, 1H), 6,10 (m, 1H) and to 1.98 (DD, 3H, J=1,5, 6,9 Hz).

E137 1-(2,3-Debtor-4-hydroxyphenyl)-2-vinyl-1H-indole-3-carbonitrile

R1=vinyl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 297,0 (polojim+H), 295,1 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,78 (m, 1H), 7,34-7,27 (m, 2H), 7,08-of 6.99 (m, 3H), 6,46 (DD, 1H, J=11,7, to 17.8 Hz), of 6.31 (d, 1H, J=17,8 Hz) and 5,67 (d, 1H, J=11.7 Hz).

E138 1-(2,3-Debtor-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile

R1=thiophene-3-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 353,3 (polojim+H), 351,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), of 7.70 (DD, 1H, J=1,3, 2,8 Hz), to 7.61 (DD, 1H, J=2,8, 5.0 Hz), 7,41-7,35 (m, 2H), 7,31 (m, 1H), 7,25 (DD, 1H, J=1,3, 5.0 Hz), 7.23 percent (m, 1H) and 7,06 (m, 1H).

E139 1-(2,3-Debtor-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile

R1=type the-2-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 353,3 (polojim+H), 351,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), 7,71 (m, 1H), 7,60 (m, 1H), 7,42-to 7.32 (m, 3H), 7,21-7,19 (m, 2H) and 7.10 (m, 1H).

E140 1-(2,3-Debtor-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitril

R1=3-methylthiophene-2-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 367,1 (polojim+H), 365,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,80 (m, 1H), 7,60 (d, 1H, J=5,1 Hz), 7,44-7,39 (m, 2H9, 7,27 (m, 1H), 7,22 (m, 1H), 7,02 (d, 1H, J=5,1 Hz), 6,99 (m, 1H) and of 2.28 (s, 3H).

E141 1-(2,3-Debtor-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitril

R1=1-methyl-1H-pyrrol-2-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 350,3 (polojim+H), (348,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,78 (m, 1H), 7,42-7,37 (m, 2H), 7,26-7,22 (m, 2H), 6,99 (m, 1H), 6,93 (DD, 1H, J=1,5, 2,9 Hz),6,14 (DD, 1H, J=1,5, and 3.8 Hz), between 6.08 (DD, 1H, J=2,9, and 3.8 Hz) and 3.70 (s, 3H).

E142 2-(2-Acetylpyrrole-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-acetylpyrrole-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 360,2 (polojim+H), 358,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,31 (m, 1H), 7,41 (d, 1H, J=5,2 Hz), 7,32-7,26 (m, 2H), 7,18 (m, 1H), 7,16-of 6.96 (m, 3H), 6,85 (d, 1H, J=5,2 Hz) and is 2.09 (s, 3H).

E143 1-(3-Fluoro-4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile

R1=pyrrol-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 317,9 (polojim+H), 316,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,74 (m, 1H), 7,43-7,37 (m, 2H), 7,31-7,29 (m, 2H), 7,16-7,14 (m, 2H), 6,97 (t, 2H, J=2.2 Hz) and 6.26 (t, 2H, J=2.2 Hz).

E144 1-(2,3-Debtor-4-hydrox is phenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile

R1=pyrrol-1-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 336,5 (polojim+H), 334,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,46-7,40 (m, 2H), 7,31 (m, 1H), 7,27 (m, 1H), 7,02 (m, 1H), 6,99 (t, 2H, J=2.2 Hz) and 6,28 (t, 2H, J=2.2 Hz).

E145 1-(2,3-Debtor-4-hydroxyphenyl)-2-prop-1-inyl-1H-indol-3-carbonitril

R1=prop-1-inyl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 309,1 (polojim+H), 307,2 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,74 (m, 1H), 7,34-7,30 (m, 2H), 7,12 (m, 1H), 7,05 (m, 1H), 6,98 (m, 1H) and of 2.08 (s, 3H).

E146 1-(3-Fluoro-4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitril

R1=2-methylprop-1-enyl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: to 307.1 (polojim+H), 305,2 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,76 (m, 1H), 7,40 and 7.36 (m, 2H), 7.18 in-7,13 (m, 2H), 7,07 (m, 1H), 7,02 (m, 1H), 5,86 (m, 1H), up to 1.98 (d, 3H, J=1.3 Hz) and at 1.91 (d, 3H, J=1.4 Hz).

E147 1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitril

R1=2-methylprop-1-enyl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 325,1 (polojim+H), 323,2 (africatm-H);1H-NMR (CDCl3, 500 MHz): to 7.77 (m, 1H), 7,33-7,25 (m, 2H), 7,05-7,01 (m, 2H), of 6.96 (m, 1H), to 5.85 (m, 1H), 1,96 (d, 3H, J=1.2 Hz) and at 1.91 (d, 3H, J=1.3 Hz).

E148 2-(2-Acetylpyrrole-1-yl)-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-acetylpyrrole-1-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 378,2 (polojim+H), 376.3 on (africatm-H);1H-NMR (acetone-d6, 500 MHz): two conformations of the 2:1 ratio of 7.82-to 7.77 (m, 3H), 7,52 (DD, 1H, J=2,9, and 1.6 Hz), 7,47-7,42 (m, 6H), 7,35-7,34 (m, 2H), 7,31 (m, 1H), 7,27-7,25 (m, 2H), 7,2 (DD, 2H, J=4,1, 1,6 Hz), 7,16 (DD, 1H, J=4.0 a, and 1.6 Hz), 7.03 is-6,99 (m, 2H), of 6.96-to 6.88 (m, 3H), for 6.81 (m, 1H), 6,47 (DD, 1H, J=4.0 a, 2,8 Hz), 6,44 (DD, 2H, J=3,8, 2,8 Hz), to 2.29 (s, 6H) and of 2.21 (s, 3H).

E149 1-(3-Fluoro-4-hydroxyphenyl)-2-pyrazole-1-yl-1H-indole-3-carbonitrile

R1=pyrazole-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 319,1 (polojim+H), 317,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,98 (DD, 1H, 3=2,6, 0.6 Hz), 7,79 (m, 1H), 7,73 (d, 1H, J=1.8 Hz), 7,46-7,41 (m, 2H), 7,33 (m, 1H), 7,28 (m, 1H), 7,15-to 7.09 (m, 2H) and 6,51 (DD, 1H, J=2.5 and 1.7 Hz).

E150 1-(2,3-Debtor-4-hydroxyphenyl)-2-pyrazole-1-yl-1H-indole-3-carbonitrile

R1=pyrazole-1-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 337,4 (polojim+H), 335,5 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,14 (d, 1H, J=2.6 Hz), 7,82 (m, 1H), 7,72 (d, 1H, J=1.6 Hz), of 7.48-the 7.43 (m, 2H), 7,31 (m, 1H), 7,20 (m, 1H), of 6.96 (m, 1H) and 6,56 (DD, 1H, J=2.6, the 1,6 Hz).

E151 2-(2,5-Dimethylpyrrole-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2.5-dimethylpyrrole-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 346,1 (polojim+H), 344,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.82 (m, 1H), 7,46-the 7.43 (m, 3H), 7,15-7,10 (m, 2H),? 7.04 baby mortality (m, 1H), of 5.83 (s, 2H) and to 2.06 (s, 6H).

E152 2-(2-Acylpyrrole-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-acylpyrrole-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 346,1 (polojim+H), 344,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,79 (m, 1H), 7,45-7,41 (m, 2H), 7,37 (m, 1H), 7,22 (m, 1H), 7,13-to 7.09 (m, 2H), 6,92 (DD, 1H, J=2,9, and 1.6 Hz), 6,14 (t, 1H, J=3.3 Hz), 5,98 (m, 1H), 2,50 (m, 1H), 2.40 a (m, 1H) and 1,10 (t, 3H, J=7,6 Hz).

E153 2-(2-Cyanoprop-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-ind the l-3-carbonitril

R1=2-cyanoprop-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 343,1 (polojim+H), 341,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,86 (m, 1H), 7,52-of 7.48 (m, 3H), 7,39 (m, 1H), 7,32 (m, 1H), 7,19 for 7.12 (m, 3H) and 6.48 in (DD, 1H, J=3,9, 2,8 Hz).

E154 1-(3-Fluoro-4-hydroxyphenyl)-2-(2-methylpyrrole-1-yl)-1H-indol-3-carbonitril

R1=2-methylpyrrole-1-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 332,3 (polojim+H), (330,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,79 (m, 1H), 7,45-7,41 (m, 2H), 7,37 (m, 1H), 7.23 percent (m, 1H), 7,14-to 7.09 (m, 2H), to 6.88 (DD, 1H, J=3.1 and 1.7 Hz), 6,09 (t, 1H, J=3.1 Hz), 5,95 (m, 1H) and 2.14 (d, 1H, J=0.9 Hz).

E155 1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-acylpyrrole-1-yl)-1H-indol-3-carbonitril

R1=2-acylpyrrole-1-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 364,4 (polojim+H), 362,5 (africatm-H);1H-NMR (acetone-d6, 500 MHz): two conformations in the ratio of 1.5:1, 7,83-7,80 (m, 2,5H), of 7.48-the 7.43 (m, 5H), 7,33-7,28 (m, 4H), 7,10 (m, 1H), 6,99-of 6.90 (m, 4H), 6.73 x (m, 1H), 6,14-6,11 (m, 2,5H), 6,00 of 5.99 (m, 2,5H), 2,59 is 2.46 (m, 3,5H), a 2.36 (m, 1,5H) and 1,17-of 1.13 (m, 7,5H).

E156 2-(2-Cyanoprop-1-yl)-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=2-cyanoprop-1-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 361,4 (polojim+H), 359,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,88 (m, 1H), 7,55 is 7.50 (m, 2H), 7,46-7,33(m, 3H), 7,17 (DD, 1H, J=4,0, 1.5 Hz), 7,01 (m, 1H) and of 6.49 (DD, 1H, J=3,8, 2,9 Hz).

E157 1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-methylpyrrole-1-yl)-1H-indol-3-carbonitril

R1=2-methylpyrrole-1-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 350,3 (polojim+H), (348,1 (africatm-H);1H-NMR (ACE the he-d6, 500 MHz): of 7.82 (m, 1H), of 7.48-7,44 (m, 2H), 7,37 (m, 1H), 7,30 (m, 1H), 7,09-6,85 (m, 2H), between 6.08 (m, 1H), 5,97 (m, 1H) and 1.20 (s, 3H).

E158 1-(2-Fluoro-4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile

R1=pyrrol-1-yl; R=2-fluoro-4-hydroxyphenyl

ES/MS m/z: 317,9 (polojim+H), 316,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), 7,47 (t, 1H, J=8,8 Hz), 7,44-7,38 (m, 2H), 7,19 (m, 1H), of 6.96 (m, 2H), 6,86 (m, 1H), for 6.81 (DD, 1H, J=11,5, 2.5 Hz) and 6,27 (m, 2H).

E159 1-(2,3-debtor-4-hydroxyphenyl)-2-(3-methylbut-2-enyl)-1H-indol-3-carbonitril

R1=3-methylbut-2-enyl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 317,9 (polojim+H), 316,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,76 (m, 1H), 7,47 (t, 1H, J=8,8 Hz), 7,44-7,38 (m, 2H), 7,19 (m, 1H), of 6.96 (m, 2H), 6,86 (m, 1H), for 6.81 (DD, 1H, J=11,5, 2.5 Hz) and 6,27 (m, 2H).

Examples 160-195

The following compounds of examples 160-162 received in accordance with the above-described General method 1. All the details of the experiments for each of the individual stages of the General method applicable for the synthesis of compounds of examples 160-162 described above in examples 1-4, 8, 16, and 38-40.

The following compounds of examples 163-168 and 170-172 received in accordance with the above-described General method 4. All the details of the experiments for each of the individual stages of the General method described above in examples 2-4, 9, 20-21.

The following compounds of examples 173-195 received in accordance with the above-described General method 1. All the details of experiment is for each of the individual stages of the General method, applicable for the synthesis of compounds of examples 173-195 described above in examples 1-4, 10-11, 14-16, 38 to 40 and 45.

E160 [1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]acetonitrile

R1=phenyl; R2=cyanomethyl

ES/MS m/z: 325,1 (polojim+H), 323,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,81 (m, 1H), 7,41-to 7.32 (m, 5H), 7,25-7,22 (m, 2H), 7,19 (m, 1H), 7,11 (m, 2H), to 6.88 (m, 2H) and 3.97 (s, 2H).

E161 [1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]acetic acid

R1=phenyl; R2=carboxymethyl

ES/MS m/z: 344,1 (polojim+H), 342,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,71 (m, 1H), 7,39-7,27 (m, 5H), 7,17,7,12 (m, 3H), 7,07 (m, 2H), 6,86 (m, 2H) and 3.74 (s, 2H).

E162 2-[1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]ndimethylacetamide

R1=phenyl; R=carbarnoyl

ES/MS m/z: 313,1 (polojim+H), 311,2 (africatm-H);1H-NMR (CDCl3, 500 MHz): to 7.68 (m, 1H), 7,32-7-23 (m, 6H), 7,20-to 7.18 (m, 2H), 7,06 (m, 2H), for 6.81 (m, 2H) and of 3.77 (s, 2H).

E163 4-(3-Isopropenyl-2-phenylindol-1-yl)phenol

R1=phenyl; R=Isopropenyl

ES/MS m/z: 326,2 (polojim+H), 324,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,72 (m, 1H), 7,31-7,25 (m, 5H), 7,16-7,11 (m, 3H), 7,07 (m, 2H), 6,86 (m, 2H), 5,27 (m, 1H), 5,15 (m, 1H) and 1.83 (m, 3H).

E164 4-[3-(2-Methyl-2H-pyrazole-3-yl)-2-phenylindol-1-yl]phenol

R1=phenyl; R2=2-methyl-2H-pyrazole-3-yl

ES/MS m/z: 366,2 (polojim+H), 364,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,47 was 7.45 (m, 2H), 7,24-7,13 (m, 10H), 6,92 (m, 2H), 6,32 (d, 1H, J=1.9 Hz) and 3.33 (s, 3H).

E165 4-(2-Phenyl-3-thiazole-4-Jindal-1-yl)phenol

R1=phenyl; R2 =thiazol-4-yl

ES/MS m/z: 369,1 (polojim+H), (367,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 9,06 (d, 1H, J=2.0 Hz), 8.30 to (m, 1H), 7,35-7,31 (m, 5H), 7,22-to 7.18 (m, 2H), 7,16 for 7.12 (m, 3H), 6.87 in (m, 2H) and for 6.81 (d, 1H, J=2.2 Hz).

E166 4-(2-Phenyl-3-prop-1-yilinda-1-yl)phenol

R1=phenyl; R2=prop-1-inyl

ES/MS m/z: 324,2 (polojim+H), 322,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.70 (m, 1H), of 7.48-7,46 (m, 2H), 7,34-7,26 (m, 3H), 7,21-to 7.18 (m, 2H), 7,16 (m, 1H), 7,11 (m, 2H), 6,91 (m, 2H) and 2.07 (s, 3H).

E167 1-(4-Hydroxyphenyl)-2-((E)-propenyl)-1H-indole-3-carboxylic acid amide

R1=(E)-propenyl; R2=carbarnoyl

ES/MS m/z: 293,1 (polojim+H), 291,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.99 (m, 1H), 7,19 (m, 2H), 7,16-7,10 (m, 2H), 7,05 (m, 2H), 6,94 (m, 1H), 6.73 x (m, 1H), 5,91 (m, 1H) and at 1.73 (DD, 3H, J=1,3, and 6.6 Hz).

E168 1-(4-Hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indole-3-carboxylic acid amide

R1=2-methylprop-1-enyl; R2=carbarnoyl

ES/MS m/z: 307,2 (polojim+H), 305,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): at 8.36 (m, 1H), 7,20 (m, 2H), 7,17 for 7.12 (m, 2H), 7,05 (m, 1H), 7,01 (m, 2H), 6,17 (m, 1H)and 1.83 (d, 3H, J=1.4 Hz) and of 1.65 (d, 3H, J=1.2 Hz).

E169 1-(4-Hydroxyphenyl)-2-((Z)-1-methylpropenyl)-1H-indole-3-carboxylic acid amide

R1=(Z)-1-methylpropenyl; R2=carbarnoyl

ES/MS m/z: to 307.1 (polojim+H), 305,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 8.41 (m, 1H), 7.23 percent (users, 2H), 7,19-7,13 (m, 2H), 7.03 is-7,00 (m, 3H), 5,91 (m, 1H), 1,89 (m, 3H) and 1.59 (m, 3H).

E170 4-(2-Phenyl-3-pyrazole-1-Jindal-1-yl)phenol

R1=phenyl; R2=pyrazole-1-yl

ES/MS m/z: 352,1 (pologamy), 350,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.68 (d, 1H, J=1.3 Hz), EUR 7.57 (m, 1H), 7,51 (DD, 1H, J=0,6, 2,5 Hz), 7,27-7,17 (m, 10H), 6,92 (m, 2H) and 6,34 (t, 1H, J=2.1 Hz).

E171 4-(3-Imidazol-1-yl-2-phenylindol-1-yl)phenol

R1=phenyl; R2=imidazol-1-yl

ES/MS m/z: 352,2 (polojim+H), 350,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,75 (users, 1H), 7,53 (m, 1H), 7,38-7,29 (m, 7H), 7,25-7,19 (m, 5H) and 6,91 (m, 2H).

E172 4-[3-(5-Methylpyrazole-1-yl)-2-phenylindol-1-yl]phenol

R1=phenyl; R2=5-methylpyrazole-1-yl

ES/MS m/z: 366,1 (polojim+H), 364,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.61 (m, 1H), 7,34 (d, 1H, J=2.1 Hz), 7,25-to 7.15 (m, 10H)6,91 (m, 2H), 6,11 (d, 1H, J=2.1 Hz) and to 2.29 (s, 3H).

E173 2-Bromo-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid amide

R1=bromo; R2=carbarnoyl

ES/MS m/z: 331,0, 333,0 (polojim+H), 329,0, 331,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): by 8.22 (m, 1H), 7,28 (m, 2H), 7,22-7,17 (m, 2H), was 7.08 (m, 2H) and to 7.00 (m, 1H).

E174 1-(4-Hydroxyphenyl)-2-((Z)-3,3,3-tryptophanyl)-1H-indol-3-carbonitril

R1=(Z)-3,3,3-triptocaine; R2=CN

ES/MS m/z: 329,1 (polojim+H), 327,13 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.75 (m, 1H), 7,39-7,34 (m, 2H), 7,31 (m, 2H), 7.23 percent (m, 1H), was 7.08 (m, 2H), 7,03 (d, 1H, J=12,2 Hz) and to 6.43 (m, 1H).

E175 (Z)-2-bromo-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=bromo; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 346,1, 347,9 (polojim+H), 343,9, 346,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,91-8,84 (s, OH), 7,98-to 7.95 (m, 1H), 7,27-of 7.23 (m, 2H), 7,17-7,10 (m, 2H), 7,09-7,05 (m, 2H), 7,00-6,97 (m, 1H),5,49 is 5.38 (m, 2H).

E176 (Z)-N'-hydroxy-1-(4-hydroxyphenyl)-2-(1H-pyrrol-1-yl)-1H-indol-3-carboximidic

R1=pyrrol-1-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 333,2 (polojim+H), 331,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,25 is 8.22 (m, 1H), 8,14-to 8.12 (s, OH), 7,25-7,16 (m, 4H), 7,10-7,06 (m, 1H), 6,92-6,90 (t, 2H), 6.90 to-6,86 (m, 2H), 6,16-6,14 (t, 2H), 4,71-a 4.53 (m, 2H).

E177 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid amide

R1=3,5-dimethylisoxazol-4-yl; R2=carbarnoyl

ES/MS m/z: 348,2 (polojim+H);1H-NMR (acetone-d6, 500 MHz): compared to 8.26 (m, 1H), 7,27-of 7.23 (m, 2H), 7,21-was 7.08 (m, 3H), to 6.95 (m, 2H), measuring 2.20 (s, 3H) and to 2.06 (s, 3H).

E178 (Z)-N'-hydroxy-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carboximidic

R1=2-methylprop-1-enyl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 322,4 (polojim+H), 320,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,14 (s, 1H), 7,99 (m, 1H), 7,29 (m, 2H), 7,13-7,05 (m, 5H) and 1.35 (s, 6H).

E179 1-(4-Hydroxyphenyl)-2-phenyl-1H-indole-3-carboxylic acid hydroxyamide

R1=phenyl; R2=hydroxycarbamoyl

ES/MS m/z: 345,13 (polojim+H), 343,13 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,04 (m, 1H), 7,38 (m, 2H), 7,34-7,31 (m, 3H), 7.23 percent-7,20 (m, 2H), 7,13-was 7.08 (m, 3H) and 6.87 in (m, 2H).

E180 (Z)-N'-hydroxy-1-(4-hydroxyphenyl)-2-phenyl-1H-indol-3-carboximidic

R1=phenyl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 344 (polojim+H), 342,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,03 (m, 1H), 7,39 (m, 2H), 7,31-7,28 (m, 3H), 7.18 in-7,13 (m, 2H), 7,09-7,06 (m, 3H) and 6,85 (m, H).

E181 1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carboxylic acid amide

R1=pyrrol-1-yl; R2=carbarnoyl

ES/MS m/z: 318,15 (polojim+H), 316,19 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,44 (m, 1H), 7,29-of 7.23 (m, 4H), 7,10 (m, 1H), 7,00 (t, 2H, J=2.1 Hz), 6.90 to (m, 2H) and 6,24 (t, 2H, J=2.1 Hz).

E182 [1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indol-3-yl]carbamino acid complex tert-butyl methyl ether

R1=pyrrol-1-yl; R2=tert-butoxycarbonylamino

ES/MS m/z: 390,16 (polojim+H), 388,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.59 (m, 1H), 7,22-to 7.15 (m, 3H), 7,11 (m, 2H), 6.89 in (m, 2H), 6,77 (m, 2H), 6,09 (m, 2H) and a 1.45 (s, 9H).

E183 2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-N-methyl-1H-indol-3-carboxamide

R1=3,5-dimethylisoxazol-4-yl; R2=N-methylcarbamoylmethyl

ES/MS m/z: 361,2 (polojim+H), 359,2 (africatm-H);1H-NMR (methanol-d4, 500 MHz): 7,81 (m, 1H), 7,38-7,34 (m, 3H), 7,07 (users, 2H), 6,91 (m, 2H), 3,11 (s, 3H), and 2.14 (s, 3H) and 1.96 (s, 3H).

E184 Methyl-2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbimide

R1=3,5-dimethylisoxazol-4-yl; R2=imino(methoxy)methyl

ES/MS m/z: 362,3 (polojim+H), 360,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz):compared to 8.26 (m, 1H), 7,27? 7.04 baby mortality (m, 5H), of 6.96 (m, 2H), 3.04 from (s, 3H), of 2.21 (s, 3H) and 2.07 (s, 3H).

E185 N-((2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)(imino)methyl)ndimethylacetamide

R1=3,5-dimethylisoxazol-4-yl; R2=(imino)methylacetamide

ES/MS m/z:1H-NMR (acetone-d6, 500 MHz): scored 8.38 (m, 1H), 7,34-7,29 (m, 2H), 7,25-720 (m, 3H), 6,97 (m, 2H), 2,59 (s, 3H), 2,17 (s, 3H) and of 1.97 (s, 3H).

E186 2-(5-Ethyl-3-methylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide

R1=5-ethyl-3-methylisoxazol-4-yl; R2=carbarnoyl

ES/MS m/z: 362,3 (polojim+H), 360,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.27 (m, 1H), 7,27-7,07 (m, 5H), of 6.96 (m, 2H), 2,58 (m, 2H), 2,09 (s, 3H) and 1.04 (t, 3H, J=7,6 Hz).

E187 (Z)-2-(2-Ethyl-1H-pyrrol-1-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=2-ethyl-1H-pyrrol-1-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 361,23 (polojim+H), 359,35 (africatm-H);1H-NMR (acetone-d6, 500 MHz): a 8.34 (d, 1H, J=7.9 Hz), 7.24 to (m, 1H), 7,20-7,17 (m, 3H), 7,11 (m, 1H), 6,91-6,87 (m, 3H), 6,13 (t, 1H, J=3.2 Hz), 5,91 (m, 1H), 2,35 (m, 1H, in), 2.25 (m, 1H) and 1.06 (t, 3H, J=7,6 Hz).

E188 (Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(2-methyl-1H-pyrrol-1-yl)-1H-indol-3-carboximidic

R1=2-methyl-1H-pyrrol-1-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 347,18 (polojim+H), 345,25 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,33 (d, 1H, J=7.8 Hz), 7.24 to (m, 1H), 7,20-7,17 (m, 3H), 7,12 (m, 1H), 6,91-6,87 (m, 3H), between 6.08 (t, 1H, J=3.0 Hz), 5,88 (m, 1H) and 1.99 (s, 3H).

E189 1-(4-Hydroxyphenyl)-2-(2-methyl-1H-pyrrol-1-yl)-1H-indol-3-carboxamide

R1=2-methyl-1H-pyrrol-1-yl; R2=carbarnoyl

ES/MS m/z: 332,16 (polojim+H), 330,21 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,50 (m, 1H), 7,31-7,27 (m, 2H), 7,25 (m, 2H), 7,14 (m, 1H), 6,98 (m, 1H), 6,93 (m, 2H), 6,16 (t, 1H, J=3,4 Hz), 5,96 (m, 1H) and 2.00 (s, 3H).

E190 4-(3-Chloro-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol

R1=3,5-dimethylisoxazol the l-4-yl; R2=Cl

ES/MS m/z: 339,1/341,1 (polojim+H), 337,2/339,2 (africatm-H);1H-NMR (CDCl3, 500 MHz): 7,72 (m, 1H), 7,32-7,27 (m, 3H), 7,02 (m, 2H9, 6,86 (m, 2H), 2,24 (s, 3H) and 1.99 (s, 3H).

E191 (Z)-2-((Z)-But-2-EN-2-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=(Z)-but-2-EN-2-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 322,19 (polojim+H), 320,27 (africatm-H);1H-NMR (methanol-d3, 500 MHz): of 7.69 (m, 1H), 7,30-7,24 (m, 2H), 7,19-7,10 (m, 3H), 6,94 (m, 2H), to 5.85 (m, 1H), 1,79 (t, 3H, J=1.3 Hz) and 1.57 (m, 3H).

E192 (Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(5-methyl-1H-pyrazole-1-yl)-1H-indol-3-carboximidic

R1=5-methyl-1H-pyrazole-1-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 348,22 (polojim+H), 346,23 (africatm-H);1H-NMR (methanol-d3, 500 MHz): 8,10 (d, 1H, J=8.1 Hz), to 7.59 (d, 1H, J=1.9 Hz), 7,32-7,21 (m, 3H), was 7.08 (m, 2H), 6,78 (m, 2H), 6,14 (m, 1H) and 2.02 (s, 3H).

E193 (Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(4-methylthiophene-3-yl)-1H-indol-3-carboximidic

R1=4-methylthiophene-3-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 364,17 (polojim+H), 362,2 (africatm-H);1H-NMR (methanol-d3, 500 MHz): 7,88 (m, 1H), 7,33 (d, 1H, J=3.2 Hz), 7.23 percent-7,20 (m, 2H), 7,17 (m, 1H), 7,02-of 6.99 (m, 3H), 6,78 (m, 2H) and 1.99 (s, 3H).

E194 (Z)-2-(2,5-Dimethyl-1H-pyrrol-1-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=2,5-dimethyl-1H-pyrrol-1-yl; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 361,4 (polojim+H), 359,5 (africatm-H);1H-NMR (acetone-d6, 500 MHz): scored 8.38 (m, 1H), 7,25 (m, 1H), 7,21-to 7.18 (m, 2H), 7,12 (m, 2H), 6,91 (m, 2H), 5,80 (s, 2H) and 2.00 (s, 6H).

E95 (Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-phenoxy-1H-indol-3-carboximidic

R1=phenoxy; R2=N-hydroxycarbonylmethyl

ES/MS m/z: 360,18 (polojim+H), 358,22 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,24 (m, 1H), 7,25-7,14 (m, 6H), to 7.09 (m, 1H), 7,00 (m, 1H) and 6,90-6,85 (m, 4H).

Examples 196-210

The following compounds of examples 196-210 received in accordance with the above-described General method 1. All the details of the experiments for each of the individual stages of the General method applicable for the synthesis of compounds of examples 196-210 described above in examples 1-4, 8, 16, and 38-40.

E196 1-(4-Hydroxyphenyl)-2-phenyl-1H-indole-3-carboxylic acid

R1=phenyl; R=carboxy

ES/MS m/z: 330,1 (polojim+H), (328,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,31 (m, 1H), 7,38 and 7.36 (m, 2H), 7,29-7,24 (m, 4H), 7,22 (m, 1H), 7,11-was 7.08 (m, 3H) and to 6.88 (m, 2H).

E197 2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indole-3-carboxylic acid

R1=3,5-dimethylisoxazol-4-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 367,1 (polojim+H), 365,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,31 (m, 1H), 7,33-7,28 (m, 2H), 7.23 percent (m, 1H), 7,21-to 6.95 (m, 3H), 2,19 (s, 3H) and 2.07 (s, 3H).

E198 2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indole-3-carboxylic acid

R1=3,5-dimethylisoxazol-4-yl; R=2-fluoro-4-hydroxyphenyl

ES/MS m/z: 367,1 (polojim+H), 365,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,32 (d, 1H, J=7,3 Hz), 7,46 (t, 1H, J=8,8 Hz), 7,34-7,25 (m, 2H), 7,13 (m, 1H), 6.89 in-6,77 (m, 2H), 2,16, 2,15 (2 s, 3H) and 2.07, 2.06 to (2 s, 3H).

E199 1-(2,3-Di is Thor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indole-3-carboxylic acid

R1=3,5-dimethylisoxazol-4-yl; R=2,3-debtor-4-hydroxyphenyl

ES/MS m/z: 385,1 (polojim+H), 383,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,32 (d, 1H, J=7,6 Hz), of 7.36-7,28 (m, 3H), 7,17 (m, 1H), 7,03 (m, 1H), 2,20, 2,17 (2 s, 3H) and 2,08, 2,05 (2 s, 3H).

E200 1-(4-Hydroxyphenyl)-2-((Z)-propenyl)-1H-indole-3-carboxylic acid

R1=(Z)-propenyl; R=4-hydroxyphenyl

ES/MS m/z: 294,1 (polojim+H), (292,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,24 (m, 1H), 7,25 (m, 2H), 7.23 percent (m, 1H), 7,19 (m, 1H), 7,14 (m, 1H), 7,03 (m, 2H), 6.42 per (m, 1H), 5,86 (m, 1H) and of 1.46 (DD, 3H, J=1,9, 7,1 Hz).

E201 1-(4-Hydroxyphenyl)-2-((E)-propenyl)-1H-indole-3-carboxylic acid

R1=(E)-propenyl; R=4-hydroxyphenyl

ES/MS m/z: 294,1 (polojim+H), (292,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 8.20 (m, 1H), 7,24 (m, 2H), 7,22-to 7.18 (m, 2H), 7,15 (m, 1H), was 7.08 (m, 2H), 6,94 (m, 1H), 5,72 (m, 1H) and 1,72 (DD, 3H, J=1,8, 6,7 Hz).

E202 1-(4-Hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indole-3-carboxylic acid

R1=2-methylprop-1-enyl; R=4-hydroxyphenyl

ES/MS m/z: 308,1 (polojim+H), 306,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,23 (m, 1H), 7.24 to 7,20 (m, 3H), 7,17 (m, 1H), 7,12 (m, 1H), 7,02 (m, 2H), 6,17 (m, 1H), about 1.75 (d, 3H, J=1.3 Hz) 1.48 (d, 3H, J=1.2 Hz).

E203 1-(4-Hydroxyphenyl)-2-(2-methylallyl)-1H-indole-3-carboxylic acid

R1=2-methylallyl; R=4-hydroxyphenyl

ES/MS m/z: 308,1 (polojim+H), 306,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,21 (m, 1H), 7,24 (m, 2H), 7,21 (m, 1H), 7,15 (m, 1H), 7,05 (m, 2H), 6,97 (m, 1H)and 4.65 (m, 1H), 4,24 (m, 1H), 3,83 (s, 2H) and of 1.62 (s, 3H).

E204 1-(4-Hydroxyphenyl)-2-((Z)-1-methylpropenyl)-1H-in the ol-3-carboxylic acid

R1=(Z)-1-methylpropenyl; R=4-hydroxyphenyl

ES/MS m/z: 308,1 (polojim+H), 306,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,24 (m, 1H), 7,26-7,21 (m, 3H), 7,17 (m, 1H), 7,05 (m, 1H), 7,02 (m, 2H), 5,59 (m, 1H), 1,92 (m, 3H) and of 1.39 (m, 3H).

E205 1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carboxylic acid

R1=thiophene-3-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 354,2 (polojim+H), 352,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,29 (m, 1H), of 7.48 (DD, 1H, J=1,3, 2,9 Hz), was 7.36 (DD, 1H, J=3.2, and 5.1 Hz), 7,28 (m, 1H), 7,24 (m, 1H), 7,17 for 7.12 (m, 3H), was 7.08 (DD, 1H, J=8,4, and 9.3 Hz) and to 7.00 (m, 1H).

E206 1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carboxylic acid

R1=thiophene-2-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 354,2 (polojim+H), 352,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,29 (m, 1H), 7,54 (DD, 1H, J=1,3, 5.0 Hz), 7,31-7,25 (m, 2H), 7,22-7,19 (m, 2H), 7,13 (m, 1H), to 7.09 (m, 1H),? 7.04 baby mortality (m, 1H) and of 7.00 (DD, 1H, J=3,5, 5.0 Hz).

E207 1-(3-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indole-3-carboxylic acid

R1=1-methyl-1H-pyrrol-2-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 351,5 (polojim+H), 349,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,30 (m, 1H), 7,31-7,25 (m, 2H), 7,17 (m, 1H), 7,16-6,93 (m, 3H), 6.75 in (m, 1H) and 5,96-to 5.93 (m, 2H).

E208 1-(3-Fluoro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indole-3-carboxylic acid

R1=3-methylthiophene-2-yl; R=3-fluoro-4-hydroxyphenyl

ES/MS m/z: 368,0 (polojim+H), (366,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,31 (m, 1H), 7,41 (d, 1H, J=5,1 Hz), 7,32-7,26 (m, 2H), 7,18 (m, 1H), 7,16-6,97 (m, 3H), 6,85 (d, 1H, J=5,1 Hz) and is 2.09 (s, 3H).

E209-Bromo-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid

R1=bromo; R=4-hydroxyphenyl

ES/MS m/z: 332,0, 334,0 (polojim+H), 330,0, 332,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): by 8.22 (m, 1H), 7,32-7,20 (m, 4H) and 7,12-7,01 (m, 3H).

E210 1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carboxylic acid

R1=pyrrol-1-yl; R2=carboxy

ES/MS m/z: 319,15 (polojim+H), 317,16 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,03 (m, 1H), 7,39 (m, 2H), 7,31-7,28 (m, 3H), 7.18 in-7,13 (m, 2H), 7,09-7,06 (m, 3H) and 6,85 (m, 2H).

Example 211

The following compound of example 211 was obtained in accordance with the above-described General method 1. All the details of the experiments for each of the individual stages of the General method applicable for the synthesis of the compound of example 211, as described above in examples 1-5, 16 and 38-40.

E211 2,7-Dibromo-1-(2,5-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=bromo; R2=cyano; R=2,5-debtor-4-hydroxyphenyl; R4=bromine

ES/MS m/z: 426,8 428,9 that amount to 431,3 (polojim+H), 425,0 427,1 429,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.77 (m, 1H), 7,44-7,37 (m, 2H) and 7,25-7,21 (m, 2H).

Examples 212-228

The following compounds of examples 212-228 received in accordance with the above-described General method 2. All the details of the experiments for each of the individual stages of the General method applicable for the synthesis of compounds of examples 212-228 described above in examples 2-4, 8, 16, 24, 38-40.

E212 2-Bromo-4-fluoro-1-(4-shall hydroxyphenyl)-1H-indol-3-carbonitril

R1=Br; R2=CN; R3=F; R4=H

ES/MS m/z: 332,97 (polojim+H), 331,01 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,40 (m, 2H), 7,30 (m, 1H), 7,12 (m, 2H), 7,07 (DD, 1H, J=10,4, 8,2 Hz) and 6,98 (d, 1H, J=8,2 Hz).

E213 4-Fluoro-1-(4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile

R1=pyrrol-1-yl; R2=CN; R3=F; R4=H

ES/MS m/z: 318,1 (polojim+H), 316,14 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,34 (m, 1H), 7,29 (m, 2H), 7,11 (DD, 1H, J=10,4, 8.0 Hz), 7,06 (d, 1H, J=8,3 Hz), of 6.99 (m, 2H), of 6.96 (t, 2H, J=2.2 Hz) and 6,24 (t, 2H, J=2.2 Hz).

E214 4-Fluoro-1-(4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R2=CN; R3=F; R4=H

ES/MS m/z: 329,11 (polojim+H), 327,15 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,51 (m, 2H), 7,45-7,42 (m, 3H), 7,31 (m, 1H), 7,25 (m, 2H), 7,09-7,06 (m, 2H) and to 6.95 (m, 2H).

E215 2-(3,5-Dimethylisoxazol-4-yl)-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-Dimethylisoxazol-4-yl; R2=CN; R3=F; R4=H

ES/MS m/z: 348,11 (polojim+H), 346,15 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 7.36 (m, 1H), 7,30 (users, 2H), 7,17 (d, 1H, J=8,3 Hz), 7,11 (DD, 1H, J=10,4, 7,8 Hz), 7,01 (m, 2H), of 2.38 (s, 3H) and was 2.05 (s, 3H).

E216 4-Fluoro-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitril

R1=2-methylprop-1-enyl; R2=CN; R3=F; R4=H

ES/MS m/z: 307,14 (polojim+H), 305,15 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,28 (m, 2H), 7,24 (m, 1H), 7,06 (m, 2H), 7,00 (DD, 1H, J=10,5, 8,2), 6,97 (d, 1H, J=8,2 Hz), 5,96 (m, 1H), was 1.94 (d, 3H, J=1.2 Hz) and 1,90 (d, 3H, J=1.4 Hz).

E217 5-fluoro-1-(4-guide is oxyphenyl)-2-phenyl-1H-indol-3-carbonitril

R1=phenyl; R2=CN; R3=H; R4=F

ES/MS m/z: 329,3 (polojim+H), 327,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,50-7,42 (m, 6H), 7,27-7,22 (m, 3H), 7,14 (m, 1H) and to 6.95 (m, 2H).

E218 2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-Dimethylisoxazol-4-yl; R2=CN; R3=H; R4=F

ES/MS m/z: 348,2 (polojim+H), 346,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,50 (DD, 1H, J=8,8, 2.2 Hz), 7,37 (DD, 1H, J=9,1, 4,4 Hz), 7,29 (m, 2H), 7,19 (m, 1H), 7,00 (m, 2H), a 2.36 (s, 3H) and 2.02 (s, 3H).

E219 5-fluoro-1-(4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile

R1=2-pyrrol-1-yl; R2=CN; R3=H; R4=F

ES/MS m/z: 317,9 (polojim+H), 316,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,46 (DD, 1H, J=8,8, 2,5 Hz), 7,29-7,24 (m, 3H), 7,16 (m, 1H), 6,99 (m, 2H), 6,94 (t, 2H, J=2.2 Hz) and 6,24 (t, 2H, J=2.2 Hz).

E220 5-fluoro-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitril

R1=2-methylprop-1-enyl; R2=CN; R3=H; R4=F

ES/MS m/z: 307,4 (polojim+H), to 305.5 (africatm-N);1H-NMR (acetone-d6, 500 MHz): 7,38 (DD, 1H, J=9,0, 2,5 Hz), 7,27 (m, 2H), 7,15 (DD, 1H, J=9,0, a 4.3 Hz), 7,09? 7.04 baby mortality (m, 3H), 5,97 (m, 1H), 1.93 and (d, 3H, J=1.2 Hz) and 1,90 (d, 3H, J=1,6 Hz).

E221 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H; R4=F

ES/MS m/z: 381,2 (polojim+H), 379,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,79 (DD, 1H; J=10,0, 2,5 Hz), 7,17-7,10 (m, 3H), 701 (m, 1H), 6,94 (m, 2H), 2,17 (s, 3H) and a 2.01 (s, 3H).

E222 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-4-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=F; R4=H

ES/MS m/z: 381,5 (polojim+H), 379,3 (africatm-H).

E223 (Z)-5-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carboximidic

R1=2-methylprop-1-enyl; R2=N-hydroxycarbamoyl; R3=H; R4=F

ES/MS m/z: 340,4 (polojim+H), 338,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.84 (DD, 1H, J=10,4, 2.7 Hz), 7,17 (m, 2H), 7,02-of 6.99 (m, 3H), 6.89 in (m, 1H), between 6.08 (m, 1H), 1,80 (d, 3H, J=1.4 Hz) and of 1.65 (d, 3H, J=1.1 Hz).

E224 4-Chloro-2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl; R2=CN; R3=Cl; R4=H

ES/MS m/z: 362,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,35-7,26 (m, 3H), 7,15 (users, 2H), 6.90 to (m, 2H), 2,32 (s, 3H) and 2.00 (s, 3H).

E225 2-(3,5-Dimethylisoxazol-4-yl)-4,5-debtor-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-dimethylisoxazol-4-yl; R2=CN; R3=F; R4=F

ES/MS m/z: 366,2 (polojim+H), 364,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,41-7,28 (m, 3H), 7,17 (m, 1H), 7,01 (m, 2H), of 2.38 (s, 3H) and 2,04 (s, 3H).

E226 2-(4-Cyano-1-methyl-1H-pyrazole-5-yl)-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=4-cyano-1-methyl-1H-pyrazole-5-yl; R2=CN; R3=F; R4=H

ES/MS m/z: 366,2 (polojim+H), 364,3 (africatm-H);1H-NMR (atzet the n-d6, 500 MHz): 7,41-7,28 (m, 3H), 7,17 (m, 1H), 7,01 (m, 2H), of 2.38 (s, 3H) and 2,04 (s, 3H).

E227 2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=3,5-dimethylisoxazol-4-yl; R2=carbamimidoyl; R3=H; R4=F

ES/MS m/z: 365,15 (polojim+H), 363,19 (africatm-H);1H-NMR (methanol-d3, 500 MHz): rate of 7.54 (DD, 1H, J=9,1, 2.2 Hz), 7,34 (DD, 1H, J=93, and 4.5 Hz), to 7.15 (m, 1H), 7,05 (users, 2H), 6,91 (m, 2H), of 2.15 (s, 3H) and 2.00 (s, 3H).

E228 2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide

R1=3,5-dimethylisoxazol-4-yl; R2=carbarnoyl; R3=H; R4=F

ES/MS m/z: 366,2 (polojim+H), 364,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.99 (DD, 1H, J=10,1, 2.6 Hz), 7,26-7,03 (m, 4H), of 6.96 (m, 2H9, of 2.21 (s, 3H) and 2.07 (s, 3H).

Examples 229-232

The following compounds of examples 229-232 received in accordance with the above-described General method 2. All the details of the experiments for each of the individual stages of the General method applicable for the synthesis of compounds of examples 229-232 described above in examples 2-4, 8, 16, 24, 38-40.

E229 2-Bromo-7-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=Br; R2=CN; R3=H; R4=F

ES/MS m/z: 331,0; 333,0 (polojim+H), 331,0; 329,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): was 7.45 (m, 1H), 7,28-7,22 (m, 3H), 7,00 (m, 1H) and 6,92 (m, 2H).

E230 2-(3,5-Dimethylisoxazol-4-yl)-7-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-Dimetyl oxazol-4-yl: R 2=CN; R3=H; R4=F

ES/MS m/z: 348,1 (polojim+H), (346,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): at 7.55 (DD, 1H, J=8,2, 0.9 Hz), 7,31 (m, 1H), 7,19 (m, 1H), 7,11 (m, 1H), was 7.08 (m, 1H), 6,84-6,79 (m, 2H), to 2.29 (s, 3H) and 2.00 (s, 3H).

E231 2-(3,5-Dimethylisoxazol-4-yl)-4,7-debtor-1-(4-hydroxyphenyl)-1H-indol-3-carbonitril

R1=3,5-Dimethylisoxazol-4-yl; R2=CN; R3=F; R4=F

ES/MS m/z: 366,2 (polojim+H), 364,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,39-to 7.32 (m, 2H), 7,13? 7.04 baby mortality (m, 2H) of 6.96-6.90 to (m, 2H), is 2.37 (s, 3H) and 2.07 (s, 3H).

E232 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-4,7-debtor-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=F; R4=F

ES/MS m/z: 399,2 (polojim+H), 397,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,06 (m, 2H), 6.87 in (m, 1H), 6,83 to 6.75 (m, 3H), of 2.21 (s, 3H) and a 2.01 (s, 3H).

Examples 233-270

The following compounds of examples 233-270 received in accordance with the above-described General method 1. All the details of the experiments for each of the individual stages of the General method applicable for the synthesis of compounds of examples 233-270 described above in examples 1-4, 10-11, 14-16, 38 to 40 and 45.

E233 1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carbonitril

R=2.5-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=CN; R3=H

ES/MS m/z: 366,2 (polojim+H), 364,6 (africatm-H);1H-NMR(acetone-d6, 500 MHz): 7,80 (m, 1H), 7,55 (m, 1H), 7,45-7,41 (m, 2H), 7,34 (m, 1H), 7,03 (m, 1H), 2,38, 2,34 (2 s, 3H) and 2.14, 2,10 (2 s, 3H).

E234 1-(3-Bromo-4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carboxamide

R=3-bromo-4-hydroxyphenyl; R1=2-methylprop-1-enyl; R2=carbarnoyl; R3=H

ES/MS m/z: 385,06/ 387,02 (polojim+H);1H-NMR (acetone-d6, 500 MHz): 8,35 (m, 1H), 7,55 (d, 1H, J=2.4 Hz), 7,25 (m, 1H), 7,21-7,14 (m, 3H), was 7.08 (m, 1H), 6,20 (m, 1H), of 1.85 (d, 3H, J=1.4 Hz) and of 1.66 (d, 3H, J=1.0 Hz).

E235 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=3,5-Dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 380,3 (polojim+H), 378,4 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.06 (m, 1H), 7,34 (t, 0,5H, J=8.7 Hz), 7,25-to 7.18 (m, 2,5H), 7,07 (m, 1H), 6,84-6,74 (m, 2H), 2,17, 2,15 (2 s, 3H) and 2.05 is, 2,02 (2 s, 3H).

E236 (Z)-1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboximidic

R=2.5-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 399,2 (polojim+H), 397 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,07 (m, 1H), 7,40 (DD, 0,5H, J=10,0, and 6.6 Hz), 7,28-7,19 (m, 2,5H), 7,12 (m, 1H), of 6.96 (m, 1H), 2,23, 2,17 (2 s, 3H) and 2,09, 2,02 (2 s, 3H).

E237 (Z)-1-(3,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboximidic

R=3,5-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z:399,2 (polojim+H), 397 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.06 (m, 1H), 7,28-7,19 (m, 3H), 7,06-7,00 (m, 2H), of 2.23 (s, 3H) and was 2.05 (s, 3H).

E238 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboximidic

R=3-fluoro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 381,5 (polojim+H), to 379.2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.06 (m, 1H), 7,25-7,17 (m, 3H9, 7,14-to 7.09 (m, 2H), 6,98 (m, 1H), measuring 2.20 (s, 3H) and 2.02 (s, 3H).

E239 (Z)-1-(3-Chloro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboximidic

R=3-chloro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 397,4/399,2 (polojim+H), 394,9/397,0 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7,50-7,14 (m, 6H), are 2.19 (s, 3H) and was 2.05 (s, 3H).

E240 2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide

R=2-fluoro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=carbarnoyl; R3=H

ES/MS m/z: 366,2 (polojim+H), 364,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7,38 (t, 0,6H, J=9.0 Hz), 7,29-7,25 (m, 2H), 7,21 (t, 0,4H, J=9.0 Hz), 7,10 (m, 1H), 6,84-6,72 (m, 2H), 2,21, 2,19 (2 s, 3H) and is 2.09, 2.06 to (2 s, 3H).

E241 (Z)-1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboximidic

R=2,3-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 399,2 (polojim+H), 397,2 (negative is .M-H); 1H-NMR (acetone-d6, 500 MHz): 8,07 (m, 1H), 7,27-7,19 (m, 3H), 7,13 (m, 1H), 6,99 (m, 1H), 2,19, 2,18 (2 s, 3H) and 2.05 is, 2,04 (2 s, 3H).

E242 1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carboxamide

R=2,3-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=carbarnoyl; R3=H

ES/MS m/z: 384,2 (polojim+H), 382,2 (africatm-H); 1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7,31-7,26 (m, 2,5H), 7,16 (m, 1H), 7,11 (m, 0,5H), 7,01 (m, 1H), 2,23, 2,22 (2 s, 3H) and 2,09, 2,08 (2 s, 3H).

E243 1-(2-Fluoro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitril

R=2-fluoro-4-hydroxyphenyl; R1=3-methylthiophene-2-yl; R2=CN; R3=H

ES/MS m/z: 349,1 (polojim+H), 347,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,83 (m, 1H), 7,38-7,31 (m, 3H), 7,13-7,11 (m, 2H), 6.89 in (d, 1H, J=5.8 Hz), of 6.71 is 6.67 (m, 2H) and 2.18 (s, 3H).

E244 2-(3,5-Dimethyl-1H-pyrazole-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitril

R=2-fluoro-4-hydroxyphenyl; R1=3,5-dimethyl-1H-pyrazole-4-yl; R2=CN; R3=H

ES/MS m/z: 347 (polojim+H), (345,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): to 7.75 (m, 1H), 7,39-7,31 (m, 3H), 7,21 (m, 1H), 6,83-6,76 (m, 2H), 2.13 and (s, 3H) and of 2.08 (s, 3H).

E245 1-(2-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carbonitril

R=2-fluoro-4-hydroxyphenyl; R1=1-methyl-1H-pyrazole-5-yl; R2=CN; R3=H

ES/MS m/z: 333,2 (polojim+H), 331,3 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,87 (m, 1H), of 7.48 (d, 1H, J=2.2 Hz), 7,42-7,37 (m, 2H), 7,20 (m, 1H), 7,15 (t, 1H, J=8.6 Hz), 6,69 (m, 1H), 6,60 (DD, 1H, J=2,5, and 11.0 Hz), to 6.22 (d, 1H, J=2.2 Hz) and a 3.87 (s, 3H).

E246 1-(-Fluoro-4-hydroxyphenyl)-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitril

R=2-fluoro-4-hydroxyphenyl; R1=1,3,5-trimethyl-1H-pyrazole-4-yl; R2=CN; R3=H

ES/MS m/z: 361,4 (polojim+H), 359,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,81 (m, 1H), 7,38-7,31 (m, 2H), 7,22 (m, 1H), 7,12 (t, 0,5H, J=8.7 Hz), 7,02 (t, 0,5H, J=8.7 Hz), 6,59 (m, 1H), 6,45 (m, 1H), to 3.73, 3,70 (2 s, 3H), 2,17, 2,09 (2 s, 3H) and 2.05 is, 1,96 (2 s, 3H). Two conformations.

E247 1-(2-Fluoro-4-hydroxyphenyl)-2-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indol-3-carbonitril

R=2-fluoro-4-hydroxyphenyl; R1=3-(trifluoromethyl)-1H-pyrazole-4-yl; R2=CN; R3=H

ES/MS m/z: 385,3 (polojim+H);1H-NMR (acetone-d6, 500 MHz): 7,73 (m, 1H), 7,35-7,22 (m, 4H), 7,05 (m, 1H) and 6,87-6,83 (m, 2H).

E248 (Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(3-methylthiophene-2-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl R1=3-methylthiophene-2-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 382,2 (polojim+H), (380,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7,41 (d, 1H, J=5.0 Hz), 7,33-7,27 (m, 3H), 7,06 (m, 1H), 6.87 in (d, 1H, J=5.0 Hz), 6,74 (users, 2H) and 2,09 (users, 3H).

E249 (Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=1-methyl-1H-pyrazole-5-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 366,2 (polojim+H), (364,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.27 (m, 1H), 7,50 (users, 1H), 7,37-7,31 (m, 3H), 7,12 (users, 1H), 6,84 (users, 1H), 6,70 (users, 1H), 6,14 (s, 1H) and 3,71 (s, 3H).

E250 (Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1,3,5-trimethyl-1H-piraso the-4-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=1,3,5-trimethyl-1H-pyrazole-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 394,3 (polojim+H), (392,1 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,23 (d, 1H, J=7.9 Hz), 7,30-7,20 (m, 3H), 7,07 (m, 1H), 6,80-6,70 (m, 2H), 3,64, 3,63 (2 s, 3H), 2.05 is, 1,92 (2 s, 3H) and 1.99, 1,88 (2 s, 3H). Two conformations.

E251 (Z)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=1-methyl-1H-pyrazole-5-yl; R2=N-hydroxycarbamoyl; R3=F

ES/MS m/z: 384,16 (polojim+H), 382,16 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,30-7,21 (m, 3H), 6,95-6,89 (m, 2H), 6,78-of 6.71 (m, 2H), 6,12 (d, 1H, J=1.9 Hz) and and 3.72 (s, 3H).

E252 (Z)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=1,3,5-trimethyl-1H-pyrazole-4-yl; R2=N-hydroxycarbamoyl; R3=F

ES/MS m/z: 412,18 (polojim+H), 410,21 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,17-7,11 (m, 2H), 6,88-6,83 (m, 2H), 6.75 in is 6.67 (m, 2H), 3,59, to 3.58 (2 s, 3H), 2,08, 2,02 (2 s, 3H) and 1.96, 1,91 (2 s, 3H). Two conformations.

E253 (Z)-2-(3,5-Dimethyl-1H-pyrazole-4-yl)-4-fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=3,5-dimethyl-1H-pyrazole-4-yl; R2=N-hydroxycarbamoyl; R3=F

ES/MS m/z: 399,16 (polojim+H), 397,18 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,30 (kV, 1H, J=9.1 Hz), 7,21 (m, 1H), 6,94-of 6.90 (m, 2H), 6,82 to 6.75 (m, 2H), 2,20, 2,19 (2 s, 3H) who 2,03, 2,01 (2 s, 3H). Two conformations.

E254 (Z)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(3-methylthiophene-2-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=3-methylthiophene-2-yl; R2=N-hydroxycarbamoyl; R3=F

ES/MS m/z: 400,14 (polojim+H), 398,12 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,30 (kV, 1H, J=9.1 Hz), 7,21 (m, 1H), 6,94-of 6.90 (m, 2H), 6,82 to 6.75 (m, 2H), 2,20, 2,19 (2 s, 3H) and 2.03, 2,01 (2 s, 3H). Two conformations.

E255 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-4-fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=F

ES/MS m/z: 399,16 (polojim+H), 397,18 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 7,30 (kV, 1H, J=9.1 Hz), 7,21 (m, 1H), 6,94-of 6.90 (m, 2H), 6,82 to 6.75 (m, 2H), 2,20, 2,19 (2 s, 3H) and 2.03, 2,01 (2 s, 3H). Two conformations.

E256 (Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(3-methylthiophene-2-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=3-methylthiophene-2-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 382,16 (polojim+H), 380,07 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.27 (m, 1H), 7,50 (users, 0,5H), 7,37-7,31 (m, 3H), 7,15-to 7.09 (m, 1,5H), 6,84 (users, 1H), 6,69 (users, 1H), 6,14 (s, 1H) and 1.41 (s,3H).

E257 (Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=1-methyl-1H-pyrazole-5-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 366,2 (polojim+H), 364,17 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7,41 (d, 1H, J=5.0 Hz), 7,33-7,27 (m, 2,5H), 7,13 (users, 0,5H), 7,06 (d, 1H, J=7.8 Hz), 6.87 in (d, 1H, J=5.0 Hz), 6.75 in (users, 2H) and 3.75 (s, 3H).

E258 (Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=1,3,5-trimethyl-1H-pyrazole-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 394,26 (polojim+H), 392,17 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,23 (m, 1H), 7,30-7,20 (m, 3H), 7,07 (m, 1H), 6,80-6,70 (m, 2H), 3,64, 3,63 (2 s, 3H), 2.05 is, 1,99 (2 s, 3H) and 1.92, 1,88 (2 s,3H).

E259 (Z)-2-(3,5-Dimethyl-1H-pyrazole-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboximidic

R=2-fluoro-4-hydroxyphenyl; R1=3,5-dimethyl-1H-pyrazole-4-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 380,16 (polojim+H), 378,18 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7.18 in for 7.12 (m, 3H), of 6.99 (m, 1H), 6,77-of 6.71 (m, 2H), 2,08 (s, 3H) and a 2.01 (s, 3H).

E260 Methyl-2-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbimide

R=2-fluoro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=imino(methoxy)methyl; R3=H

ES/MS m/z: 380,3 (polojim+H), 378,7 (africatm-H)

E261 2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide

R=3-fluoro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=carbarnoyl; R3=H

ES/MS m/z: 366,2 (polojim+H), 364,3 (africatm-H).

E262 1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-demetrise Sasol-4-yl)-1H-indol-3-carboximidic

R=2.5-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=carbamimidoyl; R3=H

ES/MS m/z: 383,3 (polojim+H);1H-NMR (acetone-d6, 500 MHz): to 7.95 (m, 1H), 7,56 (m, 1H), 7,42-7,30 (m, 3H), 7,01 (m, 1H), 2,27, 2,23 (2 s, 3H) and 2.13, 2,08 (2 s, 3H).

E263 2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carboximidic

R=3-fluoro-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=carbamimidoyl; R3=H

ES/MS m/z: 365,17 (polojim+H), 363,21 (africatm-H);1H-NMR (MeOD, 500 MHz): 7,86 (m, 1H), 7,40-7,37 (m, 3H), 7,08-7,01 (m, 3H), 6.90 to (users, 1H), 2,18 (s, 3H) and 2.02 (s, 3H).

E264 (Z)-1-(3-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1H-pyrrol-1-yl)-1H-indol-3-carboximidic

R=3-fluoro-4-hydroxyphenyl; R1=1H-pyrrol-1-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 351,16 (polojim+H), 349,14 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,24 (d, 1H, J=7.9 Hz), 7,27 for 7.12 (m, 4H), 7,08? 7.04 baby mortality (m, 2H), 6,94 (t, 2H, J=2.2 Hz) and 6,18 (t, 2H, J=2.2 Hz).

E265 1-(3-Fluoro-4-hydroxyphenyl)-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide

R=3-fluoro-4-hydroxyphenyl; R1=1H-pyrrol-1-yl; R2=carbarnoyl; R3=H

ES/MS m/z: 336,13 (polojim+H), 334,22 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,44 (m, 1H), 7,32-of 7.23 (m, 3H), 7,15 (m, 1H), 7,12-7,06 (m, 2H),? 7.04 baby mortality (t, 2H, J=2.2 Hz) and 6.26 (t, 2H, J=2.2 Hz).

E266 (Z)-1-(2,3-Debtor-4-hydroxyphenyl)-N'-hydroxy-2-(1H-pyrrol-1-yl)-1H-indol-3-carboximidic

R=2,3-debtor-4-hydroxyphenyl; R1=1H-pyrrol-1-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MSm/z: 369,14 (polojim+H), 367,19 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,24 (d, 1H, J=7.9 Hz), 7,27 (m, 1H), 7,22 (m, 1H), 7,14 (m, 1H), 7,06 (d, 1H, J=7.8 Hz), 6,92-to 6.88 (m, 3H) and of 6.17 (t, 2H,J=2.1 Hz).

E267 1-(2,3-Debtor-4-hydroxyphenyl)-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide

R=2,3-debtor-4-hydroxyphenyl; R1=1H-pyrrol-1-yl; R2=carbarnoyl; R3=H

ES/MS m/z: 354,12 (polojim+H), 352,19 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,44 (m, 1H), 7,34-7,29 (m, 2H), 7,20 (users, 1H), 7,11 (m, 1H), 6,99 (t, 2H, J=2.1 Hz), 6,91 (m, 1H) and 6.26 (t, 2H, J=2.1 Hz).

E268 (Z)-2-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboximidic

R=3-fluoro-4-hydroxyphenyl; R1=2,5-dimethyl-1H-pyrrol-1-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 379,21 (polojim+H), 377,29 (africatm-H);1H-NMR (acetone-d6, 500 MHz): of 8.37 (d, 1H, J=8.1 Hz), 7,34-7,20 (m, 4H), 7,11-6,98 (m, 4H), 2,52 (s, 3H) and a 2.01 (s, 3H).

E269 (Z)-1-(3-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(2-methyl-1H-pyrrol-1-yl)-1H-indol-3-carboximidic

R=3-fluoro-4-hydroxyphenyl; R1=2-methyl-1H-pyrrol-1-yl; R2=N-hydroxycarbamoyl; R3=H

ES/MS m/z: 365,18 (polojim+H), 363,2 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,33 (d, 1H, J=8.1 Hz), 7,29-7,14 (m, 4H), 7,09? 7.04 baby mortality (m, 2H), 6,92 (DD, 1H, J=2,8, 1.8 Hz), 6,10 (t, 1H, J=3.2 Hz), 5,90 (m, 1H) and a 2.01 (s, 3H).

E270 1-(3,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carboxamide

R=3,5-debtor-4-hydroxyphenyl; R1=3,5-dimethylisoxazol-4-yl; R2=carbarnoyl; R3=H

ES/MS m/z: 384,2 (polojim+H), 382,3 (OTP is catm-H) 1H-NMR (acetone-d6, 500 MHz): of 8.25 (m, 1H), 7,30-7,25 (m, 3H), 7,10 (users, 2H), and 2.27 (s, 3H) and are 2.11 (s, 3H).

Example 271

The following compound of example 271 was received in accordance with the above-described General method 3. All the details of the experiments for each of the individual stages of the General method described above in examples 2-4, 8, 16, 24, 38-40.

E271 (Z)-2-(3,5-Dimethylisoxazol-4-yl)-6-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboximidic

R=4-hydroxyphenyl; R1=3,5-methylisoxazol-4-yl; R2=N-hydroxycarbamoyl; R3=F

ES/MS m/z: 381,18 (polojim+H), 379,22 (africatm-H);1H-NMR (acetone-d6, 500 MHz): 8,08 (DD, 1H, J=8,9 and 5.7 Hz), 7,13 (users, 2H), 6,99 (m, 1H), 6,95 (m, 2H), 6.87 in (DD, 1H, J=9,8, and 2.3 Hz), 2,17 (s, 3H) and 2.00 (s, 3H).

Test link 1:

Test for binding to estrogen receptors

Test for ligand binding with estrogen receptors were carried out in the form of scintillation analysis of approximation (SPA) using labeled with tritium estradiol (3H-E2) and recombinate expressed biotinylated binding domain of the estrogen receptor. binding domains of proteins human ERα (ERα-LBD, pET-N-AT #1, amino acids 301-595) and ERβ person (ERβ-LBD, pET-N-AT #1, amino acids 255-530) was produced in E.coli ((BL21, (DE3), pBirA)) at 22°C in 2×LB medium with the addition of 50 μm Biotin. After 3 h after induction with isopropyl-β-D-1-thiogalactopyranoside is ω (IPTG, 0.55 mm), the cells were collected by centrifugation at 7300×g for 15 min and kept debris frozen at -20°C. Extraction of ERα and ERβ was performed using 5 g of cells, suspended in 50 ml of extracting buffer (50 mm Tris, pH 8.0, 100 mm KCl, 4 mm EDTA, 4 mm DDT, and 0.1 mm PMSF). The cell suspension twice chased through a Microfluidizer M-110L (Microfluidics) and centrifuged at 15000×g for 60 min, the Supernatant was divided into aliquots and stored at -70°C.

Extracts of ERα-LBD or ERβ-LBD was diluted in analytical buffer (18 mm K2HPO4, 2 mm KH2PO4, 20 mm Na2MoO4, 1 mm EDTA, 1 mm TCEP) in the ratio 1:676 1:517 for ERα-LBD and ERβ-LBD, respectively. The concentration of receptors should be 900 fmol/L. Extracts pre-incubated with streptavidin coated beads for SPA from polyvinyltoluene (RPNQ0007, GE Healthcare) at a concentration of 0.43 mg/ml for 1 hour at room temperature.

Test compounds were evaluated in the concentration range from 157 μm to 37.5 gr. The test was used to 5-fold (relative to the desired final concentration) uterine solutions of test compounds in 100% DMSO. The amount of DMSO in the wells of 384-hole microplate should be 20%. In analytical microplate was added to 18 ál aliquot of the test compounds, then 35 μl of pre-incubated mixture of receptor/beads for the SPA, and the head of the solution was added 35 μl of 3 nm 3H-E2. The microplate was covered with sealing plastic lid, centrifuged for 1 min at 1000 rpm and balanced over night on a shaker at room temperature. The next morning, the microplate was centrifuged for 5 min at 2000 rpm and measured on a tablet scintillation counter, for example, PerkinElmer Microbeta 1450 Trilux.

For compounds able to oust receptor3H-E2, using a non-linear four-parameter logistic model was defined by the value of the IC50(the concentration required to inhibit 50% of binding3H-E2)

b=((bmax-bmin)/(1+(I/IC50)S))+bmin

where I represents the added concentration of inhibitor binding, IC50represents the concentration of inhibitor at premaxilla binding, and S is the slope coefficient. The apparatus Microbeta generates average values of pulse/min (counts per minute) per minute and corrects single errors between the detectors, thereby giving the corrected values imp/min

Test link 2:

Test for binding to the filters with the estrogen receptors

The ligand-binding domain of the estrogen receptor β person (hERβ-LBD) used in the test for competitive binding to the separation of the filter bound and free ligand. the specified test used tritium-labeled estradiol ( 3H-E2) as emitting a β-particle isotopic marker and recombinate expressed binding domain of the estrogen receptor β person. Binding domain ERβ (hERβ-LBD, pET-N-AT #1, amino acids 255-530) was produced in Escherichia coli ((BL21, (DE3), pBirA)) at 22°C in 2×LB medium with the addition of 50 μm Biotin. After 3 h after induction with isopropyl-β-D-1-thiogalactopyranoside (0.55 mm), the cells were collected by centrifugation at 7300×g for 15 min and kept debris frozen at -20°C. extraction of the hERβ-LBD was performed using 5 g of cells, suspended in 50 ml of extracting buffer (50 mm Tris, pH 8.0, 100 mm KCl, 4 mm ethylenediaminetetraacetic acid (EDTA), 4 mm dithiothreitol and 0.1 mm phenylmethanesulfonyl (TCEP)). The cell suspension twice chased through a Microfluidizer M-110L (Microfluidics) and centrifuged at 15000×g for 60 min, the Supernatant was divided into aliquots and stored at -70°C. the Extract of the estrogen receptor was diluted 1:400 analytical buffer (18 mm K2HPO4, 2 mm KH2PO4, 20 mm Na2MoO4, 1 mm EDTA, 1 mm TCEP, pH 8.0). Test compounds were evaluated in the concentration range from 2 μm to 10 PM. For analysis was used to 51-fold (relative to the desired final concentration) uterine solutions of test compounds in 100% dimethyl sulfoxide (DMSO). The final content of DMSO in the wells of 96-hole microplate to which should be 2%. In analytical microplate was added 100 μl of3H-E2, then 4 ál aliquot of the test compounds and 100 µl of the diluted extract of the receptor. Analytical microplates were incubated overnight at +4°C. Associated with the receptor and free isotopic marker were separated on a glass fiber filter (FILTERMAT B, PerkinElmer) in a header cells (TOMTECMACH3, Tomtec) with wash buffer (18 mm K2HPO4, 2 mm KH2PO4, 0.5 mm EDTA). The filters were dried at 60°C for 1 hour, and then specaly with molten scintillator (MELTILEX, PerkinElmer) prior to measurement on a tablet β-counter (Wallac Microbeta Trilux 1450-028, PerkinElmer). The apparatus Trilux generates average counts per minute (pulse/min) per minute and corrects single errors between the detectors, thereby giving the corrected values imp/min (ccpm). The values of the IC50defined as the midpoint between the values of maximum binding, and minimal binding Sigmatel binding curve, was calculated using the software XLfit (version 2.0 or later) (IDBS) using a four-parameter logistic model

b=((bmax-bmin)/(1+(I/IC50)S))+bmin

where I represents the added concentration of inhibitor binding, IC50represents the concentration of inhibitor at premaxilla binding, and S p is ecstasy an angular factor.

Test for transactivation 1:

Test for transactivation in embryonic human kidney cells (HEK 293)stably transfected with pERE-ALP and estrogen receptor α man

Expressing the vector pMThERα contains the insertion of the estrogen receptor α human wild-type with remote leader sequence. Reporter design pERE-ALP gene contains Sekretareva form of placental alkaline phosphatase (ALP) and vitellogenin estrogen response element (ERE). Embryonic stem cells human kidney (HEK 293) were transfusional in two stages. At the first stage, we developed a mixture of stable clones transfected with the reporter construct pERE-ALP and the plasmid pSV2-Neo for breeding. In the second stage, the mixture is stable clones were transfusional pMThERα and determinant of resistance pKSV-Hyg for breeding. All procedures tranfection was performed using Lipofectamine (Invitrogen) in accordance with the recommendations of the supplier. In the test for the transactivation used selected clone containing and pERE-ALP, and pMThERα.

Cells were sown in 384-well microplates in the amount of 12,500 cells per well in modified according to Kuhn environment F12 ham (without phenol red) supplemented with 10% fetal bovine serum (FBS), processed, loaded with dextran coal dust (DCC), 2 mm L-glutamine and 50 μg/ml gentamicin. After incubation for 24 h(37°C, 5% CO2) used for seeding the medium was removed and replaced with 20 μl modified by Kuhn environment F12 ham (without phenol red) with the addition of 1.5% DCC-FCS, 2 mm L-glutamine, 100 units/ml penicillin and 100 μg/ml streptomycin. Selected compounds were added to the wells in 12 concentrations in the range from 3.3 PM to 33 μm. Compounds were dissolved in 100% dimethyl sulfoxide (DMSO)and the final concentration of DMSO in the assay was 0.1%. After incubation for 72 h (37°C, 5% CO2) conducted analysis of the environment on the activity of ALP in a method chemiluminescence: 10 µl aliquots of cell culture medium was mixed with 100 ál analytical buffer (0.1 M of diethanolamine, 1 mm MgCl2) and 0.5 mm disodium 3-(4-metoclopra-1,2-dioxetane-3,2'-(5'-chloro)-tricyclo[3.3.1.13,7]decane-4-yl)phenylphosphate (CSPD) (Tropix, Applied Biosystems) and incubated for 20 min at 37°C and 15 min at room temperature before measurement of the light signal chemiluminescence (1 per well) in a Wallac Microbeta Trilux 1450-028 (PerkinElmer). Premaxillae effective concentration (EC50) was calculated from the curves of concentration dependencies using a four-parameter logistic model using a software XLfit (version 2.0 or later) (IDBS).

Test for transactivation 2:

Test for transactivation in embryonic human kidney cells (HEK 293), stable transfected pERE2-ALP and ect is Oganova receptor β person

Generation of stable cell lines HEK293 (CRL-1573; American type culture collection)expressing the reporter vector pERE2-ALP and estrogen receptor β person (hERβ 530)were described previously (Mol. Pharmacol. 1998, 54, 105-112; Endocrinology 2002, 143, 1558-1561).

Cells were sown in 384-well microplates in the amount of 12,500 cells per well in modified according to Kuhn environment F12 ham (without phenol red) supplemented with 10% fetal bovine serum (FBS), processed, loaded with dextran coal dust (DCC), 2 mm L-glutamine and 50 μg/ml gentamicin. After incubation for 24 h (37°C, 5% CO2) used for seeding the medium was removed and replaced with 20 μl modified by Kuhn environment F12 ham (without phenol red) with the addition of 1.5% DCC-FCS, 2 mm L-glutamine, 100 u/ml penicillin and 100 μg/ml streptomycin. Selected compounds were added to the wells in 12 concentrations in the range from 3.3 PM to 33 μm. Compounds were dissolved in 100% dimethyl sulfoxide (DMSO)and the final concentration of DMSO in the assay was 0.1%. After incubation for 72 h (37°C, 5% CO2) conducted analysis of the environment on the activity of ALP in a method chemiluminescence: 10 µl aliquots of cell culture medium was mixed with 100 ál analytical buffer (0.1 M of diethanolamine, 1 mm MgCl2) and 0.5 mm disodium 3-(4-metoclopra-1,2-dioxetane-3,2'-(5'-chloro)-tricyclo[3.3.1.13,7]decane-4-yl)phenylphosphate (CSPD) (Tropix, Applied Bosystems) and incubated for 20 min at 37°C and 15 min at room temperature before measurement of the light signal chemiluminescence (1 per well) on a Wallac Microbeta Trilux 1450-028 (PerkinElmer). The ALP activity expressed as light pulses per second (lcps), is directly proportional to the content of ALP expressing cells. Premaxillae effective concentration (EC50) was calculated from the curves of concentration dependencies using a four-parameter logistic model using a software XLfit (version 2.0 or later) (IDBS).

Connection examples 1-271 have one or more of the following qualities:

(i) the affinity of binding to the estrogen receptor α-subtype in the range of values IC50from 1 to 10,000 nm in the test for binding 1;

(ii) the affinity of binding to the estrogen receptor β-subtype in the range of values IC50from 1 to 10,000 nm in the test for binding 1;

(iii) the affinity of binding to the estrogen receptor α-subtype in the range of values IC50from 1 to 10,000 nm in the test for binding 2;

(iv) the affinity of binding to the estrogen receptor β-subtype in the range of values IC50from 1 to 10,000 nm in the test for binding 2;

(v) effectiveness against the estrogen receptor α-subtype in the range of values EC50from 1 to 10,000 nm in the test for the transactivation 1;

(vi) effectiveness against the estrogen receptor β-subtype in the range of values EC50from 1 to 10,000 nm in the test for the transactivation 2.

Preferred compounds of note is the moat of the present invention are those compounds which have affinity binding to the estrogen receptor β-subtype in lower concentrations within the above range of values IC50. For example, in test 1 binding compounds of examples 1, 2, 4-6, 11, 23, 39, 42, 43, 46, 49-51, 53, 54, 63, 64, 68, 70, 83, 86, 87, 95, 100, 101, 107, 110, 125, 126, 128, 129, 132-141, 143, 144, 146, 147, 158, 163, 188, 191, 194, 212-217, 219-221, 223, 224, 235, 243 possess affinity binding estrogen receptor β-subtype in the range of values IC50from 1 to 200 nm.

Preferred compounds of examples according to the present invention are those compounds which in the test for the binding of 1 have a selectivity in relation to the estrogen receptor β-subtype in comparison with estrogen receptor α-subtype. For example, in the test for binding of the compounds of examples 2, 4, 5, 11, 23, 43, 51, 53, 68, 70, 39, 95, 133, 134, 143, 146, 188, 191, 213, 215, 221, 224, 235 have a selectivity in relation to the estrogen receptor β-subtype of 50 or greater.

Preferred compounds of examples according to the present invention are those compounds that are effective against estrogen receptor β-subtype in lower concentrations within the above range of values EC50. For example, in the test on the transactivation 2 connection examples 11, 14, 39, 41, 42, 47, 68, 163, 176, 187, 188, 191, 194, 220, 221, 223, 235-238, 255, 266, 268, 269, 271 have effectiveness against the AI of the estrogen receptor β-subtype in the range of values EC 50from 1 to 50 nm.

Preferred compounds of examples according to the present invention are those compounds which in tests on the transactivation 1 and 2 have a selectivity in relation to the estrogen receptor β-subtype in comparison with estrogen receptor α-subtype. For example, in tests on the transactivation connection examples 11, 14, 41, 42, 44, 221, 235-238, 241, 255, 260, 268, 271 have a selectivity in relation to the estrogen receptor β-subtype of 50 or greater.

Particularly preferred compounds of the examples according to the present invention are those compounds which have affinity binding to the estrogen receptor β-subtype in lower concentrations within the above range of values IC50and efficiency in relation to the estrogen receptor β-subtype in lower concentrations within the above range of values EC50. For example, connection 11, 39, 42, 68, 163, 188, 191, 194, 220, 221, 223, 235 have affinity binding to the estrogen receptor β-subtype values IC50in the range of 1 to 200 nm in the test for the binding of 1, and efficiency within the range of values EC50from 1 to 50 nm in relation to the estrogen receptor β-subtype in the test for the transactivation 2.

1. The compound of formula (I) or its pharmaceutically acceptable ester, amide, carbamate, MES and and salt, including a salt of such a complex ester, amide or carbamate and MES such a complex ester, amide, carbamate, or a salt

where R1selected from the group consisting of halogen atom, cyano, nitro, ORAN(RB)2-C(O)1-4of alkyl, -SO2C1-4of alkyl, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, Halogens2-6akeila, dihalogens2-6akeila, trihalogen2-6akeila, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C3-8cycloalkyl,3-8cycloalkyl1-6of alkyl, phenyl, benzyl and a 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORA, halogen atom, cyano, nitro, -C(Oh)1-4of alkyl, C1-6of alkyl, C1-6alkenyl,2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl;
R2selected from the group consisting of halogen atom, cyano, nitro, ORAN(RB)2, NOH) 2-C(O)1-4the alkyl, optionally substituted by 1-3 halogen atoms, -SO2C1-4of alkyl, -C(O)NH-OH, C(NH2)=N-OH, -C(CO2H)=N-OH, -C(NH2)=NH,- (NHC1-4alkyl)=NH, -C(O-C1-4alkyl)=NH, -C(NH2)=N-NH2, -NH-C(NH2)=NH, -NH-C(O)NH2, -N=C(-NH-CH2CH2-NH-), -S-CN, -S,-C(NH2)=NH, -S-C(NH2)=N-OH, -CO2H, -CH2-CO2H, -CH(OH)CO2H, -C(O)CO2H, SO3H, CH2SO3H1-6of alkyl, Halogens1-6of alkyl, dihalogens1-6of alkyl, trihalogen1-6of alkyl, tsianos1-6of alkyl, C1-4alkoxyl1-6of alkyl, C2-6akeila,2-6Akinola,3-8cycloalkyl,3-8cycloalkyl1-6of alkyl, phenyl, benzyl and a 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl, benzyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents, each Deputy is chosen from the group consisting of ORA, halogen atom, cyano, nitro, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl; provided that when one of R1and R2represents a halogen atom, the other should predstavljaetsja group, other than a halogen atom;
each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, ORAof halogen atom, cyano, nitro, C1-6of alkyl, C2-6akeila,2-6the quinil, Halogens1-6of alkyl, dihalogens1-6the alkyl and trihalogen1-6of alkyl;
each RAindependently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C2-6akeila,2-6Akinola,3-8cycloalkyl,3-8cycloalkyl1-6of alkyl, phenyl and panels1-6of alkyl, each of which is optionally substituted by 1 to 3 halogen atoms; and
each RBindependently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C2-6alkenyl,2-6the quinil,3-8cycloalkyl,3-8cycloalkyl1-6of alkyl, phenyl and panels1-6of alkyl, each of which is optionally substituted by 1 to 3 halogen atoms;
provided that the compound of formula (I) is not a
4-[3-(4,5-Dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indol-1-yl]phenol;
1-(4-Hydroxyphenyl)-2-(4-Mei-1-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(1H-pyrazole-3-yl)-1H-indol-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide or
1-(4-Hydroxyben the l)-2-thiazol-2-yl-1H-indole-3-carboxylic acid.

2. The compound according to claim 1, where each RAindependently selected from the group consisting of a hydrogen atom, a C1-4of alkyl, C2-4alkenyl,2-4the quinil,3-6cycloalkyl, phenyl and benzyl.

3. The compound according to claim 2, where each RAindependently represents a hydrogen atom or a C1-4alkyl.

4. The compound according to claim 1, where each RBindependently selected from the group consisting of a hydrogen atom and C1-4the alkyl.

5. The compound according to claim 1, where R1selected from the group consisting of ORAN(RB)2-C(O)1-4of alkyl, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Halogens1-4of alkyl, dihalogens1-4of alkyl, trihalogen1-4of alkyl, Halogens2-4alkenyl, dihalogens2-4alkenyl, trihalogen2-4alkenyl, phenyl and 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from the group consisting of ORA, halogen atom, cyano, -C(Oh)1-4of alkyl, C1-4of alkyl, C2-4alkenyl,2-4the quinil, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4the alkyl.

6. Connection P5, where R1selected from the group consisting of ORAN(RB)2-C(O)1-4of alkyl, C1-4of alkyl, C2-4alkenyl,2-4the quinil, phenyl and 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from halogen atom, cyano, C1-4of alkyl, -C(Oh)1-4the alkyl and ORAwhere RArepresents a hydrogen atom or a C1-4alkyl.

7. The compound according to claim 1, where R2selected from the group consisting of a halogen atom, ORAN(RB)2-C(O)1-4the alkyl, optionally substituted by 1-3 halogen atoms, -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Halogens1-4of alkyl, dihalogens1-4of alkyl, trihalogen1-4of alkyl, phenyl and 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from the group consisting of ORAof halogen atom,cyano, With1-4of alkyl, C2-4alkenyl,2-4the quinil, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4the alkyl.

8. The connection according to claim 7, where R2selected from the group consisting of-C(O)C1-4of alkyl, -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-4of alkyl, C2-4alkenyl,2-4the quinil and a 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from halogen atom, cyano, C1-4the alkyl and ORA.

9. The compound according to claim 1, where each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, ORA, halogen atom, cyano, C1-4of alkyl, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4the alkyl.

10. The connection according to claim 9, where each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, the halogen atom, cyano, methyl and trifloromethyl.

11. The compound according to claim 1, where R1selected from the group consisting of ORAN(RB)2-C(O)1-4of alkyl, C1-6of alkyl, C2-6alkenyl,2-6the quinil, Halogens1-4is Lila, dihalogens1-4of alkyl, trihalogen1-4of alkyl, Halogens2-4alkenyl, dihalogens2-4alkenyl, trihalogen2-4alkenyl, phenyl and 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from the group consisting of ORA, halogen atom, cyano, -C(Oh)1-4of alkyl, C1-4of alkyl, C2-4alkenyl,2-4the quinil, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-of alkyl;
R2selected from the group consisting of a halogen atom, ORAN(RB)2-C(O)1-4the alkyl, optionally substituted by 1-3 halogen atoms, -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-6of alkyl, C2-6alkenyl,2-6Akinola, Halogens1-4of alkyl, dihalogens1-4of alkyl, trihalogen1-4of alkyl, phenyl and 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from the GRU is dust, consisting of ORA, halogen atom, cyano, C1-4of alkyl, C2-4alkenyl,2-4the quinil, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4of alkyl;
each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, ORA, halogen atom, cyano, C1-4of alkyl, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4of alkyl;
each RAindependently selected from the group consisting of a hydrogen atom, a C1-4of alkyl, C2-4alkenyl,2-4the quinil,3-6cycloalkyl, phenyl and benzyl; and
each RBindependently selected from the group consisting of a hydrogen atom and C1-4the alkyl.

12. Connection to item 11, where R1selected from the group consisting of ORAN(RB)2-C(O)1-4of alkyl, C1-4of alkyl, C2-4alkenyl,2-4the quinil, phenyl and 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned phenyl or heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from halogen atom, cyano, C1-4of alkyl, -C(Oh)1-4the alkyl and ORA;
each RAindependently represents an atom of water is kind and 1-4alkyl; and each RBindependently selected from the group consisting of a hydrogen atom and C1-4the alkyl.

13. The compound according to claim 1, where R2selected from the group consisting of-C(Oh)1-4the alkyl, optionally substituted by 1-3 halogen atoms, -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-4of alkyl, C2-4alkenyl,2-4the quinil and a 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen atom, cyano, C1-4of alkyl, C2-4alkenyl,2-4the quinil, Halogens1-4of alkyl, dihalogens1-4the alkyl and trihalogen1-4the alkyl and ORAwhere RArepresents a hydrogen atom and C1-4alkyl.

14. The compound according to claim 1, where R2selected from the group consisting of-C(O)CH3, -C(NH2)=N-OH, -CO2H, -CH2-CO2H, C1-4of alkyl, C2-4alkenyl,2-4the quinil and a 5-6 membered aromatic or nonaromatic monocyclic heterocyclyl having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned heterocyclyl group can be either asamese is Noah, or substituted by 1-3 substituents selected from halogen atom, cyano, C1-4the alkyl, ORAwhere RArepresents a hydrogen atom and C1-4alkyl.

15. The compound according to claim 1, where each of R3, R4, R5and R6independently selected from the group consisting of a hydrogen atom, the halogen atom, cyano, methyl and trifloromethyl.

16. The compound according to claim 1, where R1is a 5-6-membered aromatic or nonaromatic monocyclic heterocyclyl group having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned heterocyclyl group can be either unsubstituted or substituted by 1-3 substituents selected from halogen atom, cyano and C1-4of alkyl; R2selected from the group consisting of-C(O)CH3, -C(NH2)=N-OH, -CO2H and - CH2-CO2N; and each of R3, R4, R5and R6independently selected from the group consisting of hydrogen atom and halogen atom.

17. Connection P16, where R1represents a 5-membered aromatic or nonaromatic monocyclic heterocyclyl group having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, where the mentioned heterocyclyl group substituted by two substituents, independently selected from methyl and ethyl; R2pre is is-C(NH 2)=N-OH and each of R3, R4, R5and R6independently selected from the group consisting of hydrogen atom and halogen atom.

18. The compound according to claim 1, which represents any of the following connections:
2-Bromo-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile;
2-(3-Cianfuran-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile;
2-Dimethylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-isopropyl-1H-indol-3-carbonitrile;
2-Acetyl-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid;
1-[1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]Etalon;
1-(4-Hydroxyphenyl)-2-phenyl-1H-indole-3-carboxylic acid amide;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
[2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl]carbamino acid complex tert-butyl ether;
4-[3-Amino-2-(3,5-Dimethylisoxazol-4-yl)indol-1-yl]phenol;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-7-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-2-(5-chlorothiophene-2-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-3-carbonitrile;
2-(3,5-dimethylisoxazol the-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbohydrazone;
4-(2-(3,5-dimethylisoxazol-4-yl)-3-(1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)phenol;
2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid methyl ester;
2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid hydroxyamide;
4-[2-(3,5-dimethylisoxazol-4-yl)-3-methanesulfonamido-1-yl]phenol;
1-[2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl]-2,2,2-triptoreline;
4-(3-Bromo-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol;
2-Bromo-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
(Z)-2-(4-Pertenece)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
4-(2-(3,5-dimethylisoxazol-4-yl)-3-nitro-1H-indol-1-yl)phenol;
4-(3-(Dihydroxyaryl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol;
N-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)ndimethylacetamide;
N-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)methanesulfonamide;
1-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)urea;
4-(2-(3,5-dimethylisoxazol-4-yl)-3-thiocyanato-1H-indol-1-yl)phenol;
(E)-2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl-N'-hydroxycarbonylmethyl;
4-(3-Benzyl-2-phenyl-1H-indol-1-yl)phenol;
2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetate;
(Z)-2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-(hydroxyimino)ndimethylacetamide;
2-(2-(3,5-dimethylisoxazol-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-hydroxyacetamido;
2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)ndimethylacetamide;
2-((Z)-Buta-1-enyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-methylallyl)-1H-indol-3-carbonitrile;
(Z)-2-(5-ethyl-3-methylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
4-(2-(3,5-dimethylisoxazol-4-yl)-3-phenyl-1H-indol-1-yl)phenol;
4-(3-Chloro-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol;
2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-sulfonamide;
2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide;
1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-methyl-1H-indol-3-carbonitrile;
2-(3-Cyanothiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-((E)-propenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-Hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-isopropylamino-1H-indol-3-carbonitrile;
2 Ethylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2 Butylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydrox is phenyl)-2-piperidine-1-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-pyrrolidin-1-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-morpholine-4-yl-1H-indole-3-carbonitrile;
2 Diethylamino-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-Ethinyl-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-vinyl-3-H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-1H-indole-2,3-dicarbonitrile;
1-(4-Hydroxyphenyl)-2-prop-1-inyl-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-pyridin-2-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(2-methylallyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-((Z)-propenyl)-1H-indol-3-carbonitrile;
2-(Butylmethylamine)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-((Z)-1-methylpropenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-imidazol-1-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-[1,2,4]triazole-1-yl-1H-indole-3-carbonitrile;
2-(3,5-Dimethylpyrazol-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-pyrazole-1-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(5-Mei-1-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(5-methylpyrazole-1-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(3-methylpyrazole-1-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-thiazol-2-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(2-methoxythiazole-4-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-thiazol-4-yl-1H-indole-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(3-methylbut-2-enyl)1H-indole-3-carbonitrile;
2-((E)-But-1-enyl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(5-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
2-(5-Acetylthiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
2-(5-Chlorothiophene-2-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(4-methylthiophene-3-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(4-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
2-(4-Cyanothiophene-3-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(2-methyl-2H-pyrazole-3-yl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
2-(2-Acetylpyrrole-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(2-Acylpyrrole-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(2-Cyanoprop-1-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(4-Hydroxyphenyl)-2-(2-methylpyrrole-1-yl)-1H-indol-3-carbonitrile;
1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-2-(3-cyanothiophene-2-yl)-1H-indol-3-carbonitrile;
1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-2-(3-cianfuran-2-yl)-1H-indol-3-carbonitrile;
2-Bromo-1-(3-Chloro-5-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-Bromo-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(2-fluoro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
2-Bromo-1-(3-fluoro-4-hydroxyphenyl)-1H-indole-3-Carbo is ITIL;
2-Bromo-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-Bromo-1-(2,5-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-Bromo-1-(3-chloro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-Bromo-1-(3,5-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(3-fluoro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(2,5-Debtor-4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
1-(3,5-Debtor-4-hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-(3-methylt is open-2-yl)-1H-indol-3-carbonitrile;
1-(3-Chloro-4-hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-pyridin-4-yl-1H-indole-3-carbonitrile;
2-Dimethylamino-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-((E)-propenyl)-1H-indol-3-carbonitrile;
1-(3-Fluoro-4-hydroxyphenyl)-2-((Z)-propenyl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-((Z)-propenyl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-vinyl-1H-indole-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indol-3-carbonitrile;
2-(2-Acetylpyrrole-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(3-fluoro-4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-to bontril;
1-(2,3-Debtor-4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-prop-1-inyl-1H-indol-3-carbonitrile;
1-(3-fluoro-4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitrile;
2-(2-Acetylpyrrole-1-yl)-1-(2,3-Debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(3-fluoro-4-hydroxyphenyl)-2-pyrazole-1-yl-1H-indole-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-pyrazole-1-yl-1H-indole-3-carbonitrile;
2-(2,5-Dimethylpyrrole-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(2-Acylpyrrole-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(2-Cyanoprop-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(3-fluoro-4-hydroxyphenyl)-2-(2-methylpyrrole-1-yl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-Acylpyrrole-1-yl)-1H-indol-3-carbonitrile;
2-(2-Cyanoprop-1-yl)-1-(2,3-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(2-methylpyrrole-1-yl)-1H-indol-3-carbonitrile;
1-(2-Fluoro-4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(3-methylbut-2-enyl)-1H-indol-3-carbonitrile;
[1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]acetonitrile;
[1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]acetic acid
2-[1-(4-Hydroxyphenyl)-2-phenyl-1H-indol-3-yl]ndimethylacetamide;
4-(3-Isopropenyl-2-phenylindol-1-yl)phenol;
4-[3-(2-Methyl-2H-Piras the l-3-yl)-2-phenylindol-1-yl]phenol;
4-(2-Phenyl-3-thiazole-4-Jindal-1-yl)phenol;
4-(2-Phenyl-3-prop-1-yilinda-1-yl)phenol;
1-(4-Hydroxyphenyl)-2-((E)-propenyl)-1H-indole-3-carboxylic acid amide;
1-(4-Hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indole-3-carboxylic acid amide;
1-(4-Hydroxyphenyl)-2-((Z)-1-methylpropenyl)-1H-indole-3-carboxylic acid amide;
4-(2-Phenyl-3-pyrazole-1-Jindal-1-yl)phenol;
4-(3-Imidazol-1-yl-2-phenylindol-1-yl)phenol;
4-[3-(5-Methylpyrazole-1-yl)-2-phenylindol-1-yl]phenol;
2-Bromo-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid amide;
1-(4-Hydroxyphenyl)-2-((Z)-3,3,3-tryptophanyl)-1H-indol-3-carbonitrile;
(Z)-2-Bromo-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid amide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carboxamide;
1-(4-Hydroxyphenyl)-2-phenyl-1H-indole-3-carboxylic acid hydroxyamide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-phenyl-1H-indol-3-carboxamide;
1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carboxylic acid amide;
[1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indol-3-yl]-carbamino acid complex tert-butyl ether;
2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-N-methyl-1H-indol-3-carboxamidine;
Methyl-2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbamic is t;
N-((2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)(imino)methyl)ndimethylacetamide;
2-(5-Ethyl-3-methylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-2-(2-Ethyl-1H-pyrrol-1-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(2-methyl-1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
1-(4-Hydroxyphenyl)-2-(2-methyl-1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
4-(3-Chloro-2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-1-yl)phenol;
(Z)-2-((Z)-But-2-EN-2-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(5-methyl-1H-pyrazole-1-yl)-1H-indol-3-carboxamide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-(4-methylthiophene-3-yl)-1H-indol-3-carboxamide;
(Z)-2-(2,5-Dimethyl-1H-pyrrol-1-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-N'-Hydroxy-1-(4-hydroxyphenyl)-2-phenoxy-1H-indol-3-carboxamide;
1-(4-Hydroxyphenyl)-2-phenyl-1H-indole-3-carboxylic acid;
2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indole-3-carboxylic acid;
2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indole-3-carboxylic acid;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-1H-indole-3-carboxylic acid;
1-(4-Hydroxyphenyl)-2-((Z)-propenyl)-1H-indole-3-carboxylic acid;
1-(4-Hydroxyphenyl)-2-((E)-propenyl)-1H-indole-3-carboxylic acid;
1-(4-Hydroxyphenyl)-2-(2-methylprop-1-enyl)1H-indole-3-carboxylic acid;
1-(4-Hydroxyphenyl)-2-(2-methylallyl)-1H-indole-3-carboxylic acid;
1-(4-Hydroxyphenyl)-2-((Z)-1-methylpropenyl)-1H-indole-3-carboxylic acid;
1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-3-yl-1H-indole-3-carboxylic acid;
1-(3-Fluoro-4-hydroxyphenyl)-2-thiophene-2-yl-1H-indole-3-carboxylic acid;
1-(3-Fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrrol-2-yl)-1H-indole-3-carboxylic acid;
1-(3-Fluoro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indole-3-carboxylic acid;
2-Bromo-1-(4-hydroxyphenyl)-1H-indole-3-carboxylic acid;
1-(4-Hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carboxylic acid;
2,7-Dibromo-1-(2,5-debtor-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-Bromo-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
4-Fluoro-1-(4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile;
4-Fluoro-1-(4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
4-Fluoro-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitrile;
5-fluoro-1-(4-hydroxyphenyl)-2-phenyl-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
5-fluoro-1-(4-hydroxyphenyl)-2-pyrrol-1-yl-1H-indole-3-carbonitrile;
5-fluoro-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carbonitrile;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-4-fluoro-N-g is droxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-5-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carboxamide;
4-Chloro-2-(3,5-Dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-4,5-debtor-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(4-Cyano-1-methyl-1H-pyrazole-5-yl)-4-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
2-(3,5-Dimethylisoxazol-4-yl)-5-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
2-Bromo-7-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-7-fluoro-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethylisoxazol-4-yl)-4,7-debtor-1-(4-hydroxyphenyl)-1H-indol-3-carbonitrile;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-4,7-debtor-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-3-carbonitrile;
1-(3-Bromo-4-hydroxyphenyl)-2-(2-methylprop-1-enyl)-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-1-(3,5-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-1-(-Chloro-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboxamide;
2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboxamide;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-3-carboxamide;
1-(2-fluoro-4-hydroxyphenyl)-2-(3-methylthiophene-2-yl)-1H-indol-3-carbonitrile;
2-(3,5-Dimethyl-1H-pyrazole-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbonitrile;
1-(2-fluoro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carbonitrile;
1-(2-fluoro-4-hydroxyphenyl)-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
1-(2-fluoro-4-hydroxyphenyl)-2-(3-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indol-3-carbonitrile;
(Z)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(3-methylthiophene-2-yl)-1H-indol-3-carboxamide;
(Z)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carboxamide;
(Z)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carboxamide;
(Z)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carboxamide;
(Z)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethyl-1H-pyrazole-4-yl)-4-fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(3-methylthiophene-2-yl)-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethylisoxazol the-4-yl)-4-Fluoro-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(3-methylthiophene-2-yl)-1H-indol-3-carboxamide;
(Z)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1-methyl-1H-pyrazole-5-yl)-1H-indol-3-carboxamide;
(Z)-1-(2-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1,3,5-trimethyl-1H-pyrazole-4-yl)-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethyl-1H-pyrazole-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
Methyl-2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-1H-indol-3-carbimide;
2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide;
1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-1H-indol-3-carboxamide;
2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-1-(3-fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
1-(3-fluoro-4-hydroxyphenyl)-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
(Z)-1-(2,3-Debtor-4-hydroxyphenyl)-N'-hydroxy-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
1-(2,3-Debtor-4-hydroxyphenyl)-2-(1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
(Z)-2-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-(3-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-1-(3-Fluoro-4-hydroxyphenyl)-N'-hydroxy-2-(2-methyl-1H-pyrrol-1-yl)-1H-indol-3-carboxamide;
1-(3,5-Debtor-4-hydroxyphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-carboxamide; and
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-6-fluoro-N'-hydroxy-1-(4-hydroxyphenyl)-1H-shall ndol-3-carboxamide;
or its pharmaceutically acceptable ester, amide, carbamate, MES or salt, including salt of such a complex ester, amide or carbamate and MES such a complex ester, amide, carbamate or salt.

19. The compound according to claim 1, which represents any of the following connections:
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-1-(2,5-Debtor-4-hydroxyphenyl)-2-(3,5-Dimethylisoxazol-4-yl)-N'-hydroxy-1H-indol-3-carboxamide;
(Z)-2-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluoro-4-hydroxyphenyl)-N'-hydroxy-1H-indol-3-carboxamide;
or its pharmaceutically acceptable ester, amide, carbamate, MES or salt, including salt of such a complex ester, amide or carbamate, and MES such a complex ester, amide, carbamate or salt.

20. The compound according to claim 1, which is (Z)-2-(3,5-dimethylisoxazol-4-yl)-N'-hydroxy-1-(4-hydroxyphenyl)-1H-indol-3-carboxamidine or its pharmaceutically acceptable ester, amide, carbamate, MES or salt, including salt of such a complex ester, amide or carbamate, and MES such a complex ester, amide, carbamate or salt.

21. Pharmaceutical composition having affinity binding of oestrogens receptor β-subtype, which sod is RIT compound according to any one of claims 1 to 20, together with a pharmaceutically acceptable carrier.

22. The compound according to any one of claims 1 to 20 for use as a drug that has affinity binding of oestrogens receptor β-subtype.

23. Connection on p.22 for use in the treatment or prevention of a condition associated with a disease or disorder associated with the activity of estrogen receptor β-subtype.

24. Connection item 23, where the condition associated with a disease or disorder associated with the activity of estrogen receptors, which are selected from bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, degenerative disorders in the brain, urinary incontinence, anxiety, depression, depression during perimenopause, postpartum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, hyperactivity disorder attention deficit, sleep disturbances, irritability, impulsivity, anger management, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, autoimmune diseases, inflammation, inflammatory bowel disease,irritable bowel syndrome, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer and cholangiocarcinoma.

25. The use of compounds according to any one of claims 1 to 20, for the manufacture of a medicinal product for the treatment or prevention of a condition associated with a disease or disorder associated with the activity of estrogen receptor β-subtype.

26. The method of treatment or prevention in a mammal of a disease or condition associated with the activity of estrogen receptor β-subtype, which includes an introduction to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 20 or composition according to item 21.

27. The method according to p, where the condition associated with a disease or disorder associated with the activity of estrogen receptors, which are selected from bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroids, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, degenerative disorders in the brain, urinary incontinence, anxiety, depression, depression during perimenopause, postpartum depression, premenstrual syndrome, manic depression, dementia, obsessive compulsive behavior, attention deficit disorder, hyperactivity disorder Def is citom attention sleep disorders, irritability, impulsivity, anger management, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, autoimmune diseases, inflammation, inflammatory bowel disease, irritable bowel syndrome, lung cancer, colon cancer, breast cancer, uterine cancer, prostate cancer and cholangiocarcinoma.



 

Same patents:

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention provides to a high degree a safe pharmaceutical drug which is effective for diseases caused by MMP-2 and/or MMP-9. The pharmaceutical drug contains, as an active ingredient, at least one member selected from a group which consists of thiazole derivatives of formula (1): where R1 is a phenyl group which can have 1-3 lower alkoxy groups as substitutes in the phenyl ring, and R2 is a pyridyl group which can have 1-3 carboxyl groups as substitutes in the pyridine ring, or salts thereof.

EFFECT: high activity and use when treating diseases such as fibrosis and pulmonary emphysema.

4 cl, 4 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention relates to methods of synthesis and to intermediate products of compounds of formula (XVII) and salts thereof.

EFFECT: preparing the hepatitis C virus protease inhibitor.

32 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indole compounds of formula:

wherein A means 5-member heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms specified in N, O and S, R1 means R5 -X-B-X'-, R2 means -(CR8 R9 )p-Y-R7, R3 means hydrogen, C1-C6-alkyl or -(CH2)q-C3-C6-cycloalkyl, R4 means C3-C6-cycloalkyl (the other radical values are presented in cl.1 of the patent claim), their pharmaceutically acceptable salts or isomers which may be used for preventing or treating cell necrosis and necrosis-related diseases.

EFFECT: preparing the compounds to be used for preventing or treating cell necrosis and necrosis-related diseases.

34 cl, 2 tbl, 263 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 7-substituted indoles of formula I:

or their pharmaceutically acceptable salts wherein the values A1, B1, C1, D1, E1, F1, G1, L are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit activity of anti-apoptotic protein Mc1-1 that enables using them in pharmaceutical compositions.

5 cl, 7 dwg, 2 tbl, 609 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) in free form or in form of a pharmaceutically acceptable salt or solvate, which are useful in treating inflammatory or obstructive airways, pulmonary hypertension, pulmonary fibrosis, liver fibrosis, muscle diseases and systemic skeletal disorders and other diseases which are mediated by activity of the ALK-5 receptor or ALK-4 receptor. The invention also relates to a method of producing compounds of formula (I) and pharmaceutical compositions. In formula , T is a pyridin-2-yl which is optionally substituted in one position with R1; T1 is a pyridinyl which is optionally substituted in one or two positions with R1, R2, R5, C1-C4-alkoxy group, C1-C4-alkoxycarbonyl or cyano group; and Ra and Rb are independently hydrogen; C1-C8-alkyl, optionally substituted in one, two or three positions with R4; C3-C10-cycloalkyl, which is optionally substituted in one or two positions with a hydroxy group, amino group, C1-C8-alkyl, C1-C8-alkoxy group, halogen, cyano group, oxo group, carboxy group or nitro group; or C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, amino group, cyano group, oxo group, carboxy group, nitro group or R5; R1 is C1-C8-alkyl; R2 is C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, R1, R5, C1-C8-alkylthio group, amino group, C1-C8-alkylamino group, etc. The rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of using said compounds.

20 cl, 2 tbl

Cytokine inhibitors // 2485113

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole compounds of formula wherein the radical values A, X, R1, R2, R3 are presented in clause 1 of the patent claim.

EFFECT: there are disclosed pharmaceutical compositions of sail compounds for cytokine (eg TNFα or IL-1β) reduction.

16 cl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted oxazolidinones of formula (I), wherein R1 means methyl, ethyl, n-propyl, methoxy, methoxymethyl or ethoxymethyl, R2 means hydrogen or methyl, and R3 means a group of formulas or , wherein * means an attachment point to an oxopyridine ring, n means number 1, 2, 3 or 4, m means number 1 or 2, R4 means hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, 2-hydroxyet-1-yl, 3-hydroxyprop-1-yl or 4-hydroxycyclohex-1-yl, R5 means hydrogen, methyl or ethyl, or R4 and R5 together with a nitrogen atom whereto attached, form a ring of morpholin-4-yl, a ring of 4-methyl-piperazin-1-yl or 4-hydroxy-piperidine-1-yl, R6 means hydrogen, cyclopropyl, cyclobutyl, 2-hydroxyet-1-yl, 3-hydroxyprop-1-yl, 2-methoxyet-1-yl, 3-methoyprop-1-yl, 4-hydroxycyclohex-1-yl, tetrahydrofuran-2-ylmethyl or 1,4-dioxan-2-ylmethyl, R7 means hydrogen, methyl or ethyl, or R6 and R7 together with a nitrogen atom whereto attached, form a ring of pyrrolidin-1-yl, a ring of 2-methoxymethyl-pyrrolidin-1-yl, a ring of 1,1-dioxo-morpholin-4-yl, a ring of 1,4-oxazepan-4-yl, a ring of 4-methyl-piperazin-1-yl or 4-hydroxy-piperidine-1-yl, or to physiologically acceptable salts thereof. The invention also concerns a method for preparing said compounds.

EFFECT: there are prepared new compounds which can find application in medicine for treating and/or preventing the diseases caused by thrombembolia.

8 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (1), wherein n means 0, 1, 2 or 3, R1 means chlorine, methyl, ethyl, n-propyl, methoxy, methoxymethyl or ethoxymethyl, R2 means hydrogen. The invention also refers to pharmaceutically acceptable salts of the compounds of formula (I) and to a method for preparing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) for treating and/or preventing thromboembolic diseases.

6 cl, 68 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1), in which Ar is a group of formula (Ar-1) or (Ar-2), in which R1 is a halogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, alkyl or alkenyl, X is a nitrogen atom or CH, R5 and R6 are each hydrogen and h equals 1; 1 equals 1 or 2; m equals 1 or 2; n equals 0, 1 or 2; o equals an integer from 0 to 3, under the condition that n and o are equal to 0 at the same time. Values of group A are as given in claim 1 of the invention. Described also is a pharmaceutical composition having agonistic activity with respect to 7 serotonin (5-HT4-receptors), which contains a compound of formula (1) and an agent which stimulates enterokinesis or improves functioning of the alimentary canal, which contains a compound of formula (1) as an active ingredient.

EFFECT: novel compounds are obtained and described, which have strong affinity towards 4 serotonin receptors, which are useful as an agent which stimulates enterokinesis or an agent which improves functioning of the alimentary canal.

28 cl, 233 ex, 29 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

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