Hydroxybenzamide derivatives and use thereof as hsp90 inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (VI): or its pharmaceutically acceptable salts; wherein n is equal to 0, 1, 2 or 3; R1 means -OH, H; R2a means OH, -CH3, provided at least one of R1 and R2a means -OH;R3 means Cl, Br, cyclopropyl, branched C3-5alkyl R4a means H; R8 means H; wherein the fragment: may be one of the groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B54, B56, B58, B59, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B84, B86, B87, B88, B89, B90, B91, B93, B94, B95, B96, B97, B98, B99, B100 and B101 wherein the values are disclosed in the patent claim 1.

EFFECT: compounds show Hsp90 inhibitory activity that enables using them for treating the diseases caused by abnormal cell growth in mammals.

26 cl, 8 dwg, 2 tbl, 82 ex

 

The invention relates to compounds that inhibit or modulate the activity of heat shock protein Hsp90, to the use of compounds for the treatment or prevention of disease conditions mediated by Hsp90, and to new compounds with activity, inhibitory, or modulating Hsp90. Also provided pharmaceutical compositions containing the compounds, and novel chemical intermediate compounds.

Background of invention

In response to cellular stresses, including heat, toxins, irradiation, infection, inflammation and oxidants, all cells produce a standard set of heat shock proteins (Hsp) (Macario and de Macario 2000). Most heat shock proteins act as molecular chaperones. Chaperones bind and stabilize proteins at intermediate stages of installation and enable proteins to fold to their functional States. Hsp90 is the most abundant cytosolic Hsp in normal conditions. There are two isoforms of Hsp90 person, the main form of Hsp90α and minor form Hsp90ß. Hsp90 binds to proteins in the final stages of collapse and differs from other Hsp, the fact that the majority of its protein substrates involved in signal transduction. Hsp90 has a special ATP-binding site, including feature packaging Bergerac (Bergerat) bacterial gyrase and topoisomerases histidinemia kinases. It was shown that ATP bound in the N-terminal pocket of Hsp90, hydrolyses. This ATP-phase activity leads to conformational changes in the Hsp90, which is required in order to make possible conformational changes in client protein.

Domain dimerization and the second ATP-binding site, which may regulate ATP-asnow activity detected near the c-Terminus of Hsp90. Dimerization of HSP90 appears to be critical for ATP hydrolysis. Activation of Hsp90 is also governed by interaction with other various chaperone proteins and can be separated in a complex with other chaperones, including Hsp70, Hip, Hop, p23, and p50cdc37. It has been demonstrated that a number of other cochaperone proteins bind HSP90. Appeared simplified model in which ATP-binding amino-terminal pocket changes the conformation of Hsp90 in order to make possible Association with multichaperone complex. The first client protein binds to the complex of Hsp70/Hsp40. This complex then associates with Hsp90 through the Hop. When ADP is replaced ATP conformation of Hsp90 changes, Hop and Hsp70 are released and updated by a different set of cochaperones, including p50cdc37 and p23. The ATP hydrolysis leads to the release of these cochaperones and client protein of the Mature complex. Ansamycins antibiotics herbimycin, geldanamycin (GA) and 17 allylamino-17-de is methoxysilanes (17-AAG) are inhibitors of ATP-binding site, which block binding of ATP and prevents the conversion in Mature complex (Grenert et. al., 1997, J. Biol. Chem., 272:23834-23850).

Although Hsp90 is expressed everywhere, GA has a higher affinity binding to Hsp90 derived from tumor cell lines compared with normal (Kamal et. al., Nature 2003; 425: 407-410). GA also shows more potent cytotoxic activity in tumor cells, and is found at higher concentrations in tumor models xenotransplantation mice (Brazidec J. Med. Chem. 2004, 47, 3865-3873). In addition, ATP-asna activity of Hsp90 is increased in cancer cells and is an indication of increased stress levels in these cells. It is also reported that Hsp90 gene amplification occurs in the last stages of cancer (Jolly and Morimoto JNCI Vol.92, No.19, 1564-1572, 2000).

Increased genetic instability associated with a cancerous phenotype, leading to increased production negativnyh or mutant proteins. Obyedinenie path also serves to protect cells from negativnyh or incorrectly Packed proteins by sending such proteins on proteasomal degradation. Mutant proteins are not in their nature, native and, therefore, are able to detect structural instability and increased demand in the chaperone system. (Giannini et al., Mol Cell. Biol. 2004; 24(13):5667-76).

Things is only a small amount of data that Hsp90 was found originally in the "activated" multichaperone complexes in tumor cells as opposed to a "latent" complexes in normal cells. One component multichaperone complex is cochaperone cdc37. Cdc37 binds to Hsp90 at the base of the ATP-binding site and may affect the rate of deactivation for inhibitors that bind to Hsp90 in the "activated" state (Roe et. al., Cell 116, (2004), pp.87-98). Client protein associated with Hsp90-Hsp70 form of the chaperone complex is assumed to be more susceptible to obyedinyonniy and direction to the proteasome for degradation. E3 ubicacin ligase were identified motifs, interacts with a chaperone, and one of them (CHIP), as has been shown, promotiom obyedinenie and degradation of Hsp90-client protein ('connell et al., 2001, Xu et al., 2002).

Hsp90-client protein

The number of published Hsp90-client protein to the present time exceeds 100. Because many of its client proteins involved in cell signaling proliferation and survival, Hsp90 remains the main subject of interest as a cancer target. Two groups of client proteins, cell signaling protein kinases and transcription factors, in particular, assume that the regulation of Hsp90 may have a potential advantage ol the anti-cancer therapy.

Client proteins of Hsp90 protein kinase involved in cell proliferation and survival include the following:

c-Src

Cellular Src (c-Src) is a receptor tyrosinekinase required to mitogenesis initiated multiple receptors growth factor, including receptors, such as receptor epidermalnogo growth factor (EGFR), a receptor for platelet-derived growth factor (DERIVED), the receptor for colony stimulating factor-1 (CSF-IR) and the receptor for basic fibroblast growth factor (bFGFR). C-Src is also sverkhekspressiya and activated in many human carcinomas, which sverkhekspressiya EGFR and ErbB2. Src is also required for maintenance of normal bone homeostasis through the regulation osteoclastic functions.

p185erbB2

ErbB2 (Her2/neu) is a receptor tyrosinekinase, sverkhekspressiya in a variety of tumors, including breast cancer, ovarian, prostate and stomach. ErbB2 was originally identified as an oncogene, and inhibition of Hsp90 leads to polyubiquitination and degradation of erbB2.

Polo-mitotic kinase

Polo-like kinase (Plk) are important regulators of promoting cell cycle in M phase. Plk involved in the Assembly of mitotic spun apparatus and in the activation of complexes of CDK/cyclin. Plk1 regulates dephosphorylation of CDK tyrosine cher the C phosphorylation and activation of Cdc25C. Activation of CDK1, in turn, leads to the formation of the spindle and entry into M-phase.

Akt (PKB)

Akt is involved in pathways that regulate cell growth by stimulating cell proliferation and suppression of apoptosis. Inhibition of Hsp90 by the action of ansamycins reduces the half-life of Akt through Obyedinyonnye and proteasomal decomposition. The binding of cdc37 with Hsp90 is also required for suppression of Akt. After processing ansamycins cancer cells are delayed in G2/M-phase of the cell cycle at 24 hours after treatment and transferred to apoptosis in 24-48 hours. Normal cells also delayed for 24 hours after treatment with ansamycins, but do not transfer to apoptosis.

c-Raf, B-RAF, Mek

RAS-RAF-MEK-ERK-MAP kinase path mediates cellular responses to growth signals. RAS mutated in oncogenic form approximately 15% of cancer man. Three RAF gene are serine/treningowy kinases that are regulated by RAS binding.

EGFR

The receptor for epidermal growth factor (EGFR) is involved in cell growth, differentiation, proliferation, survival, apoptosis, and migration. Overexpression of EGFR has been detected in many different types of cancer and activating mutations of its kinase domain appear to be pathogenic in a subset of lung adenocarcinoma./p>

Flt3

FMS-like tyrosinekinase 3 (FLT3) is a receptor tyrosinekinase involved in cell proliferation, differentiation and apoptosis. Flt3 activation also leads to activation of phosphatidylinositol-3-kinase (PI3k) and RAS cascades of signal transduction.

c-Met

c-Met is a receptor tyrosinekinase that binds a growth factor for hepatocytes (HGF) and regulates both cell motility and cell growth; c-Met sverkhekspressiya in tumors, including cancer of the thyroid gland, stomach, pancreas and colon. HGF also detected around tumors, including metastases to the liver. This suggests that c-Met and HGF plays an important role in invasion and metastasis.

Cdkl, Cdk2, Cdk4, Cdk6

Cdkl, Cdk2, Cdk4 and Cdk6 control the cell cycle. The activity of cdks is regulated by their binding to specific subunits, such as collini, factors inhibiting and Assembly. Substrate specificity and the timing of CDK activity is determined by their interaction with specific cyclename. Cdk4/cyclin D and Cdk6/cyclin D is active in G1-phase, Cdk2/cyclin E and Cdk2/cyclin A in S-phase, and Cdc2/cyclin A and Cdc2/cyclin B in G2/M-phase.

Cyclin-dependent kinase 4 (CDK4) plays a key role in the ability of the cell to move from G1 - to S-phase of the cell cycle and significantly activated in the many cancer malignancy person. Activator CDK4, cyclin Dl, sverkhekspressiya and CDK4 inhibitor, p16, is absent in a variety of human cancers.

Developed Cdkl/Cdk2 inhibitors that reversibly block the normal cells in the Gl/S phase or G2/M border. G2/M delay is generally less well tolerated by the cells and, consequently, they undergo apoptotic cell death. As it is also known that Hsp90 affects the way cell survival, this effect can be further enhanced by inhibitors of Hsp90.

Wee-1

Protein kinase Wee-1 performs the vast phosphorylation of CDC2 on tyrosine 15 (Tyrl5). This is required to activate the checkpoint G2-phase in response to DNA damage.

Hsp90 factors of transcription involved in cell proliferation and survival include the following:

Mutant p53

P53 is a tumor suppressor protein, which causes a delay of the cell cycle and induces apoptosis. P53 is mutated in approximately half of all cancers. Mutant p53 is associated with Hsp90 and acts as a step-down regulator in cancer lines treated with inhibitors of Hsp90, while the levels of p53 wild-type remain unaffected.

Progesterone receptor/estrogen receptor/receptor androgen hormone

In the absence of hormones, progesterone receptor and androgen hormone binding what are Hsp90 in an inactive form. After binding to their cognate hormones, receptors undergo a conformational change and dissociation of hsp90. Then associated ligand receptor capable of dimerization, phosphorylation and translocation into the nucleus. The activated receptors then contact elements hormonal response (HRE) within the regulatory sites of target genes involved in maintaining cell proliferation.

Hif-1a

Hypoxia-induced factor-1a (HIF-1a) is a transcription factor that controls the expression of genes that play a role in angiogenesis. HIF-1a is expressed in the majority of metastases and is known to be associated with Hsp90. Processing ansamycins cell lines of renal carcinoma leads to obyedinyonniy and proteasomal degradation of HIF-1a.

Inhibitory Hsp90 can affect a large number of targets that are important for signal transduction during cell proliferation of tumor cells. Inhibitors of signal transduction that regulate the activity of individual target may not be as effective due to the redundancy of signaling pathways and rapid development of resistance. By regulating multiple targets involved in cellular signaling process and cell proliferation, inhibitors of Hsp90 may provide benefit in the treatment of a wide spectrum of PR is operativnyh disorders.

hERG

In the late 1990s, the number of drugs approved by Management under the control over products and medicines (USA), were withdrawn from trade in the United States, when it was discovered that they lead to deaths caused by dysfunction of the heart. Subsequently it was discovered that a side effect of such drugs is the development of arrhythmias caused by blockage of hERG channels in heart cells. hERG channel is a channel from the family potassium ion channels, the first of which was identified in the late 1980s in mutant fruit fly Drosophila melanogaster (seeJan, L.Y. and Jan, Y.N. (1990). A Superfamily of Ion Channels. Nature, 345(6277):672). Biophysical properties of hERG potassium ion channel describedSanguinetti, M.C., Jiang C, Curran, M.E., and Keating, M.T. (1995). A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel. Cell, 81:299-307, and Trudeau, M.C., Warmke, J. W., Ganetzky, B., and Robertson, G.A. (1995). HERG, a Human adopts inward Rectifier in the Voltage-Gated Potassium Channel Family. Science, 269:92-95.

Elimination of hERG blocking activity, remains an important consideration in the development of any new drug.

Prior art

In EP 0474403 (Eli Lilly) describes a class of derivatives of 4-hydroxybenzamide for the treatment of inflammatory bowel disease.

In EP 0722723 (Eli Lilly) describes a class of derivatives of 4-hydroxybenzamide for the treatment of disseminated is lerosa.

In EP 0500336 (University of Colorado Foundation) describes a class of derivatives of 4-hydroxybenzamide for the treatment of type I diabetes.

In WO 00/59867 (Pharmacor) described hydroxyproline derivatives for use as inhibitors of HIV integrase.

In JP 09194450 (Fujirebio) described derivatives Orchidaceae as pharmaceutical intermediates.

In EP 0486386 described substituted derivatives benzoylpyridine.

In WO 2005/012297 (Janssen) described piperidine 4-hydroxy-3-fermenting acid as an intermediate compound in the formation of compounds having modulating activity against LTA4-hydrolases.

In WO 2005/000839 (Tanabe) described morpholine 4-hydroxy-3-bromobenzoyl acid as an intermediate connection when receiving arylaminobenzothienoand connections.

The use of derivatives hydroxybenzamide as a synthetic intermediate compounds described in U.S. patent 5310951, JP 49010506, WO 01/36351, WO 98/45255 and WO 97/35999.

In EP 0347168 (Ono Pharmaceutical Co.) described para-substituted phenyl esters pavlinovoi acids as inhibitors of elastase. One particular connection described in this patent is a 3-hydroxy-4-[(N-methyl-N-phenyl)carbamoylphenoxy ether pavlinovoi acid.

In EP 0353753 (Takeda) describes compounds of amides of substituted benzoic acid having inhibitory activity against the GLA is amataga receptor.

In U.S. patent 2005/0037922 (Bayer Cropscience) described various gidratirovannye dimethylamide and diethylamide benzoic acid as a means of preserving agricultural crops.

In WO 2005/009940 (Leo Pharma) described aminobenzophenone connection, which, as indicated, may be useful in the treatment of inflammatory diseases and cancer.

In WO 99/29705 (Glycomed et al.) describes a class of compounds-glycomimetics with a number of possible applications, including the treatment of cancer. One connection specifically described in WO 99/29705 represents a 2-(2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

The invention

The invention relates to compounds that have the Hsp90-inhibiting or modulating activity, and which are expected to be useful in the prevention or treatment of disease conditions mediated by Hsp90. For example, it is assumed that the compounds according to the invention can be useful for alleviating or reducing cases of cancer.

In the first aspect, the invention is a compound of formula (I):

or salts, tautomers, solvate and N-oxides;

where R1represents a hydroxy-group or hydrogen;

R2represents a hydroxy-group; a methoxy group or hydrogen; provided that at least of the Institute of R 1and R2is a hydroxy-group;

R3selected from a hydrogen atom; halogen; cyano; C1-5hydrocarbide and C1-5hydrocarbonate; where C1-5hydrocarbonyl and C1-5hydrocarbonate fragments, each optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having 5 to 12 atoms in the ring;

R4selected from a hydrogen atom; a group -(Q)n-R7where n is 0 or 1, and R7is an acyclic C1-5hydrocarbonous group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 atoms in the ring; halogen; cyano; hydroxy; amino; and mono - or di-C1-5gidrokarbanatno, where the acyclic C1-5gidrolabilna group and mono - and di-C1-5gidrokarbonatnye fragments in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having 5 to 12 atoms in the ring;

or R3and R4together form a monocyclic carbocyclic or heterocyclic ring of 5-7 atoms in the ring;

R5and R6together with the nitrogen atom to which they are attached, clicks the form a bicyclic heterocyclic group, having 8 to 12 atoms in the ring, of which up to 5 atoms in the ring are heteroatoms selected from oxygen, nitrogen and sulfur; where the bicyclic heterocyclic group is optionally substituted by one or more substituents R10;

R8chosen from hydrogen atoms and fluorine; and

R10choose from:

halogen;

hydroxy;

trifloromethyl;

cyano;

nitro;

carboxy;

amino;

mono - or di-C1-4 gidrocarburi;

carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring; and

group Ra-Rb,

where Rarepresents a bond, O, CO, X1C(X2), C(X2X1X1C(X2X1, S, SO, SO2, NRc, SO2NRcor NRcSO2; and

Rbselected from hydrogen; carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring; and (C1-12hydrocarbide (such as C1-10hydrocarbon), optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, non-aromatic mono - or di-C1-8gidrokarbanatno (for example, mono - or di-C1-4gidrokarbanatno), and carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring, and where one or more carbon atoms C1-12hydrocar the ilen group (or C 1-10hidrocarburos group can be optionally replaced by O, S, SO, SO2, NRcX1C(X2), C(X2X1X1C(X2X1;

Rcselected from Rbatom of hydrogen and C1-4 gidrocarburi; and

X1represents O, S or NRcand X2represents=O,=S or=NRc;

but excluding the compound 2-(2-hydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

The invention, inter alia, provides:

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use in the prevention or treatment of the disease condition mediated by Hsp90;

the use of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for the manufacture of a medicinal product for the prevention or treatment of the disease condition mediated by Hsp90;

the method of prevention or treatment of the disease condition mediated by Hsp90, which includes an introduction to the subject, the needy, the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any the x sub-groups or examples as defined in the present description, to apply for relief or reduction of cases of the disease condition mediated by Hsp90;

the use of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for the manufacture of a medicinal product for the relief or reduction of cases of the disease condition mediated by Hsp90;

the way of relief or reduction of cases of the disease condition mediated by Hsp90, which includes an introduction to the subject, in need thereof, the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use in the treatment of a disease or condition comprising or arising from abnormal cell growth in a mammal;

the use of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for the manufacture of a medicinal product for the treatment of a disease or condition comprising or arising from abnormal cell growth in a mammal;

the method of treatment of a disease or condition, Lucaya or arising from abnormal cell growth in a mammal, which includes an introduction to the mammal the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, in the amount effective for inhibiting abnormal cell growth;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, to apply for relief or reduction of cases of a disease or condition comprising or arising from abnormal cell growth in a mammal;

the use of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for the manufacture of a medicinal product for the relief or reduction of cases of a disease or condition comprising or arising from abnormal cell growth in a mammal;

method for alleviating or reducing the incidence or condition comprising or arising from abnormal cell growth in a mammal which comprises the administration to a mammal the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, in the amount effective for inhibiting abnormal cell growth;

a method of treating ill the treatment or condition, comprising or arising from abnormal cell growth in a mammal which comprises the administration to a mammal the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb)or any subgroups or examples, as defined in the present description, in the amount effective for inhibiting the activity of Hsp90;

the way of relief or reduction of cases of a disease or condition comprising or arising from abnormal cell growth in a mammal which comprises the administration to a mammal the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, in the amount effective for inhibiting the activity of Hsp90;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use as an inhibitor of Hsp90;

method of inhibiting Hsp90, which comprises contacting the Hsp90 with an Hsp90-inhibiting compound of the formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use in modulating a cellular process (for example cell division)by inhibiting the activity of Hsp90;

the method of modulating a cellular process (for example cell division) by inhibiting the activity of Hsp90 using the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use in the prevention or treatment of painful conditions, as described above;

the use of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for the manufacture of a medicinal product, where the drug is intended for any one or more of the uses defined above;

a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, and pharmaceutically acceptable carrier;

a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, and pharmaceutically acceptable carrier in a form suitable for oral administration;

the pharmaceutical composition containing the compound is of ormula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, and pharmaceutically acceptable carrier in a form suitable for parenteral administration, for example, by intravenous (i.v.) introduction;

a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, and pharmaceutically acceptable carrier in a form suitable for intravenous (i.v.) administration by injection or infusion;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use in medicine;

the connection, as described above, for any of the applications and methods presented above, as described in the present description in other places;

the compound of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for use in the treatment or prevention of the disease condition in a patient who was examined and diagnosed as suffering from or at risk of a disease or condition which would be susceptible to treatment with a compound having activity against Hsp90;

the use of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description, for the manufacture of a medicinal product for the treatment or prevention of a disease or condition in a patient who was examined and diagnosed as suffering from or at risk of a disease or condition which would be susceptible to treatment with a compound having activity against Hsp90;

a method for the diagnosis and treatment of the disease condition mediated by Hsp90, which comprises (i) screening a patient to determine whether a disease or condition in which the patient suffers, or may suffer a disease or condition which would be susceptible to treatment with a compound having activity against Hsp90; and (ii) where it is discovered that the disease or condition that affects the patient, thus, is susceptible, after administration to a patient compounds of formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) or any subgroups or examples, as defined in the present description.

Total preferred values and definitions

In this section, as in all other sections of this description, while in the context not stated otherwise, references to a compound of formula (I) includes all subgroups of formula (I)as defined in the present description, including formulas (I), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) and (VIIb), and the term 'subgroups' includes all preferred variants of the implementation examples and particular compounds defined in the present description.

In addition, the reference to the connection of the formula (I), (II), (III), (IV), (V), (VI), (VIa), (VII), (VIIa) or (VIIb) and their subgroups includes ionic forms, salts, solvate, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms, as discussed below, preferably the salts or tautomers or isomers or N-oxides, or their solvate, and more preferably, the salts or tautomers or N-oxides, or their solvate.

The following General preferred values and definitions should be applied to each of R1-R8, R10, Ra, Rb, RcX1and X2and their various subgroups, Pogorelaya, examples and options for implementation, while the context is not specified.

Any references to formula (I) in the present description also mean any subgroup of compounds within formula (I) and any preferred meanings and examples, while in the context not specified.

References to "carbocyclic" and "heterocyclic group" used in the present description, unless the context otherwise specified, include both aromatic and nonaromatic ring system. For example, the term "carbocyclic and Goethe is alcocebre group" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. Typically, such groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 atoms in the ring, more specifically 5 to 10 atoms in the ring. Examples of monocyclic groups include groups containing 3, 4, 5, 6, 7, and 8 atoms in the ring, more specifically from 3 to 7, for example from 5 to 7, and preferably 5 or 6 atoms in the ring. Examples of bicyclic groups are those which contain 8, 9, 10, 11 and 12 atoms in the ring, more specifically, 9 or 10 atoms in the ring.

Used in the present description, the term "bicyclic"refers to groups that have two rings connected together in such a way that at least one atom of the ring is involved in both rings. So, bicyclic group may be a condensed ring (two atoms in the ring are involved in both rings), spirocyclohexane (one atom of the ring is involved in both rings) or bridged ring (three or more atoms in the ring are involved in both rings).

Carbocyclic or heterocyclic group may be an aryl or heteroaryl group having from 5 to 12 atoms in the ring, more specifically, from 5 to 10 atoms in the ring. The term "aryl"used in the present about what Isani, refers to a carbocyclic group, having aromatic character, and the term "heteroaryl" is used in this description to denote a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl include polycyclic (e.g. bicyclic) ring systems, where one or more of the rings are non-aromatic, provided that at least one ring is aromatic. In such poliklinik systems group can be attached via an aromatic ring or through non-aromatic ring. Aryl or heteroaryl groups can be monocyclic or bicyclic groups, and may be unsubstituted or substituted by one or more substituents, for example one or more groups R10as specified above.

The term "non-aromatic group" includes unsaturated ring system, having aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "unsaturated" and "partially saturated" refers to the rings, where the ring structure(s) contains the atoms associated with more than one valence bond, that is, the ring contains at least one multiple bond, such as C=C, C=C or N=C bond. The terms "fully saturated" and "rich" relative to the tsya to the rings, where there are no multiple bonds between atoms of the ring. Saturated carbocyclic groups include cycloalkyl group, as defined below. Partially saturated carbocyclic groups include cycloalkenyl group, as defined below, for example, cyclopentenyl, cycloheptenyl and cyclooctanol. The following example cycloalkenyl group is cyclohexenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve atoms in the ring, and, more specifically, from five to ten atoms in the ring. Heteroaryl group may represent, for example, five-membered or six-membered monocyclic ring or bicyclic structure formed from condensed five - and six-membered rings or two condensed six-membered rings or, as the next example, two condensed five-membered rings. Each ring can hold approximately up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Usually heteroaryl ring contains up to 4 heteroatoms, more specifically up to 3 heteroatoms, more particularly to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one nitrogen atom of the ring. The nitrogen atoms in the heteroaryl rings can be primary, as in SL the tea imidazole or pyridine, or actually denied basic properties, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in the heteroaryl group, including any amine substituents of the ring will be less than five.

Examples of five-membered heteroaryl groups include, but without limitation, pyrrole, furan, thiophene, imidazole, furazane, oxazoline, oxadiazoline, oxadiazoline, isoxazole, thiazole, isothiazol, pyrazol, triazole and tetrazole group.

Examples of six-membered heteroaryl groups include, but are not limited to, pyridine, pyrazin, pyridazine, pyrimidine and triazine.

Bicyclic heteroaryl group can represent, for example, a group selected from:

a) a benzene ring, a condensed 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

b) a pyridine ring, a condensed 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

c) a pyrimidine ring, a condensed 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

d) a pyrrole ring, a condensed 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

e) pyrazol ring, a condensed 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

f) pirazinamida ring condensed with a 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

g), imidazole ring, a condensed 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

h) oxazoline ring condensed with a 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

i) isoxazoline ring condensed with a 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

j) thiazole ring, a condensed 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

k) isothiazol ring condensed with a 5 - or 6-membered ring containing 1 or 2 heteroatoms in the ring;

l) thiophene ring, a condensed 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

m) furanose ring condensed with a 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

n) tsiklogeksilnogo ring condensed with a 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring; and

o) cyclopentene ring condensed with a 5 - or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring.

One group of bicyclic heteroaryl groups consist of groups (a)-(e) and (g)to(o) above.

Particular examples of bicyclic heteroaryl groups containing five-membered ring, conden is new with the other five-membered ring, include, but without limitation, imidazothiazole (for example, imidazo[2,1-b]thiazole) and imidazolides (for example, imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to the five-membered ring include, but without limitation, benzofuranol, benzothiophene, benzimidazole, benzoxazole, itbasically, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g. adenine, guanine), indazol, pyrazolopyrimidinone (for example, pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g., [1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole and pyrazolopyrimidine (for example, pyrazolo[1,5-a]pyridine) groups.

Particular examples of bicyclic heteroaryl groups containing two condensed six-membered rings include, but without limitation, quinoline, isoquinoline, chromanone, mikrokonomie, chromenone, isochromosome, isochromosome, benzodioxane, hinolinovy, benzoxazinone, benzodiazines, perioperative, hinoksalinovym, hintline, cinnoline, phthalazine, naphthyridine and pteridine group.

One subgroup of heteroaryl groups include pyridinoline, pyrrolidine, pureline, thienyl imidazolidine, oxazolidine, oxadiazolidine, oxadiazolidine, isoxazolidine, thiazolidine, isothiazolinone, pyrazolidine, personilnya, pyridinoline, pyrimidinyl, triazinyl, triazolyl, tetrazolyl, hyalinella, izohinolinove, benzoperylene, benzothiazoline, chromaline, tiromancino, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole and benzisothiazole, isobenzofuran, indolenine, isoindoline, indolizinyl, indolinyl, isoindolyl, polyline (e.g., adenine, guanine), indazolinone, benzodioxolyl, chromeline, ethnomedicine, thrombilia, benzodioxole, chinoiserie, benzoxazinone, benzodiazepine, pyridopyrimidines, khinoksalinona, chinadaily, indolenine, phthalazinone, naphthyridinone and pteridinyl group.

Examples of the polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzofuranyl, dihydrobenzofuranyl, 2,3-dihydrobenzo[1.4]dioxin, benzo[1.3]dioxole, 4,5,6,7-tetrahydroxybenzophenone, indolinone and Indonesia group.

Examples of carbocyclic aryl groups include phenyl, raftiline, indenyl the e and tetrahydronaphthalene group.

Examples of non-aromatic heterocyclic groups include unsubstituted or substituted (by one or more groups R10) heterocyclic groups having from 3 to 12 atoms in the ring, specifically 4-12 atoms in the ring, and, more specifically, from 5 to 10 atoms in the ring. Such groups may be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatoms in the ring (more specifically 1, 2, 3 or 4 heteroatoms in the ring selected from nitrogen, oxygen and sulphur.

When sulfur is present, it may, where it allows the nature of the adjacent atoms and groups to exist as-S-, -S(O)- or-S(O)2-.

Heterocyclic groups can contain, for example, fragments of cyclic simple ether (e.g. as in tetrahydrofuran and dioxane), cyclic fragments tiefer (e.g. as in tetrahydrothiophene and dithiane), cyclic amine fragments (such as pyrrolidine), cyclic amide fragments (such as pyrrolidone), cyclic fragments thioamides, cyclic thioesters, cyclic ethers (such as butyrolactone), cyclic sulfones (such as sulfolane and sulfolane), cyclic sulfoxidov, cyclic sulfonamides and their combinations (for example, morpholine and thiomorpholine and its S-oxide and S,S-dioxide). Further, examples of the heterocyclic groups are such that with the, may contain cyclic fragment of urea (for example, as in imidazolidin-2-Ohe).

In one subset of the heterocyclic groups, heterocyclic groups contain fragments of cyclic simple ether (e.g. as in tetrahydrofuran and dioxane), cyclic fragments tiefer (e.g. as in tetrahydrothiophene and dithiane), cyclic amine fragments (such as pyrrolidine), cyclic sulfone (such as sulfolane and sulfolane), cyclic sulfoxidov, cyclic sulfonamides and their combinations (for example, thiomorpholine).

Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6 - and 7-membered monocyclic heterocyclic group. Specific examples include morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (for example, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, Piran (2H-Piran or 4H-Piran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazolo, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (for example, 4-tetrahydropyranyl), imidazolin, imidazolidine, oxazoline, thiazoline, 2-pyrazolin, pyrazolidine, piperazine and N-alkylpiperazine such as N-methylpiperazin. Further, the examples include thiomorpholine and its S-oxide and S,S-dioxide (especially thiomorpholine). The following examples include azetidin, piperidone, piperazine and N-alkylpiperidines, that is s how N-methylpiperidin.

One preferred sub-group of non-aromatic heterocyclic group consists of saturated groups such as azetidin, pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine-S,S-dioxide, piperazine, N-alkylpiperazine and N-alkylpiperidines.

Another sub-group is non-aromatic heterocyclic group consists of pyrrolidine, piperidine, research, thiomorpholine, thiomorpholine-S,S-dioxide, piperazine and N-alkylpiperazine, such as N-methylpiperazine.

One particular subgroup heterocyclic group consists of pyrrolidine, piperidine, research and N-alkylpiperazine (for example, N-methylpiperazine) and do not necessarily thiomorpholine.

Examples of non-aromatic carbocyclic groups include cycloalkane groups, such as tsiklogeksilnogo and cyclopentamine, cycloalkenyl groups, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol and cyclohexadienyl, cyclooctatetraene, tetrahydronaphthyl and declines.

Preferred non-aromatic carbocyclic groups are monocyclic rings, and most preferably saturated monocyclic ring.

Specific examples are three-, four-, five - and six-membered saturated carbocyclic ring, for example, optionally substituted cyclopentenone and tsiklogeksilnogo rings.

Od is and the subgroup of non-aromatic carbocyclic groups include unsubstituted or substituted (by one or more groups R 10) monocyclic group and especially saturated monocyclic group, such as cycloalkyl group. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more specifically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, especially cyclohexyl.

Further examples of non-aromatic cyclic groups include a bridging ring system, such as bicycloalkanes and azabicycloalkanes, although such bridged ring systems are generally less preferred. Under the "bridge ring system" refers to a ring system in which two rings are generalized to more than two atoms; see,for example,Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages131-133, 1992. Examples of bridged ring systems include bicyclo[2.2.1]heptane, azabicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, azabicyclo[2.2.2]octane, bicyclo[3.2.1]octane and azabicyclo[3.2.1]octane. A specific example of a bridging ring system is 1-azabicyclo[2.2.2]Octan-3-ilen group.

If this description refers to carbocyclic and heterocyclic groups, carbocyclic or heterocyclic ring may, while in the context specifies otherwise be unsubstituted or substituted by one or more groups of the substituents R10selected from halogen, is hydroxy, trifloromethyl, cyano, nitro, carboxy, amino, mono - or di-C1-4gidrokarbanatno, carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring; the group Ra-Rbwhere Rarepresents a bond, O, CO, X1C(X2), C(X2X1X1C(X2X1, S, SO, SO2, NRc, SO2NRcor NRcSO2; and Rbselected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring, and C1-12hidrocarburos group (such as C1-10gidrolabilna group), optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, non-aromatic mono - or di-C1-8gidrokarbanatno (for example, mono - or di-C1-4 gidrocarburi), carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring, and where one or more carbon atoms C1-12hidrocarburos group (or C1-10hidrocarburos group can be optionally replaced by O, S, SO, SO2, NRcX1C(X2), C(X2X1or X1C(X2X1;

Rcselected from Rbatom of hydrogen and C1-4 gidrocarburi; and

X1represents O, S or NRcand X2represents=O,=S or=NRc.

If the group for which estately R 10contains or includes carbocyclic or heterocyclic group specified carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted by one or more additional groups of the substituents R10. In one subset of compounds of formula (I) such additional groups of substituents R10may include carbocyclic or heterocyclic groups which, as a rule, are not additionally substituted. In another subgroup of compounds of formula (I), these additional substituents do not include carbocyclic or heterocyclic groups, but, on the other hand, selected from the groups listed above in the definition of R10.

The substituents R10can be chosen so that they contain not more than 20 non-hydrogen atoms, for example not more than 15 non-hydrogen atoms, for example, not more than 12 or 11 or 10 or 9 or 8 or 7 or 6 or 5 non-hydrogen atoms.

If carbocyclic and heterocyclic groups are a pair of substituents on the same or adjacent atoms in the ring, two Deputy may be connected so that they form a cyclic group. Thus, two adjacent groups R10together with the carbon atom or heteroatom to which they are attached, may form a 5-membered heteroaryl is also or 5 - or 6-membered nonaromatic carbocyclic or heterocyclic ring, where mentioned heteroaryl and heterocyclic groups contain up to 3 heteroatoms in the ring selected from N, O and S. for Example, adjacent pairs of substituents on adjacent carbon atoms of the ring may be linked via one or more heteroatoms and optionally substituted alkionovymi groups with the formation of condensed oxa-dioxa-, Aza-, diaza - or oxazoline group.

Examples of such related substituting groups include:

Examples of halogen substituents include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred.

In the definition of compounds of formula (I) above and in the application in the future, the term "hydrocarbon" is a General designation that encompasses aliphatic, alicyclic and aromatic groups having fully carbon skeleton consisting of carbon and hydrogen atoms, unless otherwise specified.

In some cases, as defined in the present description, one or more of the carbon atoms constituting the carbon skeleton may be replaced by certain atoms or groups of atoms.

Examples hydrocarbonrich groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkeline, alkyline, cycloalkylation, cyclooctylamine and carbocyclic kalkilya, and alkeneamine and aralkylamines group. Such groups may be unsubstituted or, where indicated, substituted by one or more substituents, as defined in the present description. Examples and preferred values described below are applied to each of hydrocarbonrich replacement groups or hydrocarbondegrading substitute group described in the various definitions of the substituents for compounds of formula (I), while in the context not specified.

The prefix "Cx-y-" (where x and y are integers)used in the present description, refers to the number of carbon atoms in the group. So, C1-4gidrolabilna group contains from 1 to 4 carbon atoms, and C3-6cycloalkyl group contains from 3 to 6 carbon atoms, and so on.

The term "acyclic hydrocarbon" (for example, as in the term "acyclic C1-5hydrocarbon")used in the present description, refers to an acyclic hydrocarbonyl groups and, in particular, alkyl, alkenyl and alkynylaryl groups, as defined above.

The term "mono - or di-C1-5 gidrocarburi"used in the present description, refers to a monosubstituted or disubstituted amino group, a carrier or one or two hydrocarbonrich replacement groups, so that each contains from 1 to 5 carbon atoms.

Preferred non-aromatic gidrolabilna groups represent the keys of a saturated group, such as alkyl and cycloalkyl group.

Typically, as an example, gidrolabilna group can have up to ten carbon atoms (and more specifically up to eight carbon atoms), while the context is not specified. Within the subset hydrocarbonrich groups having 1-10 carbon atoms, specific examples are C1-8gidrolabilna group or a C1-6gidrolabilna groups, such as C1-4gidrolabilna group (for example, C1-3gidrolabilna group or a C1-2gidrolabilna group or a C2-3gidrolabilna group or a C2-4gidrolabilna group), specific examples have any individual value or combination of values selected from C1C2C3C4C5C6C7C8C9and C10hydrocarbonrich groups.

The term "alkyl" refers to alkyl groups as straight and branched chain. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methylbutyl and n-hexyl, and isomers. Within the subset of alkyl groups having 1-8 carbon atoms, and specific examples include alkyl groups such as C1-4alkyl groups (for example, C1-3alkyl group, or a C1-2alkyl group, or a C2-3 alkyl group, or a C2-4alkyl group).

Examples cycloalkyl groups are those that are derived from cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and Cycloheptane. Within the subset cycloalkyl groups cycloalkyl group has from 3 to 10 carbon atoms, more specifically of 3-8 carbon atoms, particular examples are C3-6cycloalkyl group.

Examples alkenyl groups include, but without limitation, ethynyl (vinyl), 1-propenyl, 2-propenyl (allyl), Isopropenyl, butenyl, buta-1,4-dienyl, pentenyl and hexenyl. Within subgroups alkenyl groups Alchemilla group has from 2 to 10 carbon atoms, more specifically from 2 to 8 carbon atoms, particular examples are C2-6alkeneamine groups, such as C2-4alkeneamine group.

Examples cycloalkenyl groups include, but without limitation, cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the subset cycloalkenyl groups cycloalkenyl groups have from 3 to 10 carbon atoms, more specifically of 3-8 carbon atoms, and specific examples are C3-6cycloalkenyl group.

Examples etkinlik groups include, but are not limited to, ethinyl and 2-PROPYNYL (propargyl) group. Within the subset alkyline groups have from 2 to 10 atoms of carbon is a, more specifically from 2 to 8 carbon atoms, particular examples are C2-6alkyline groups, such as C2-4alkyline group.

Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl groups.

Examples cycloalkylation, cycloalkenyl, carbocyclic Uralkalij, kalkanli and aralkylamines groups include fenetylline, benzyl, sterilnye, phenylethylene, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentylmethyl group.

The terms of C1-12hydrocarbon, C1-10hydrocarbon and C1-8hydrocarbon used in the present description, include alkyl, alkeline, alkyline, cycloalkyl, cycloalkenyl, phenyl, benzyl and phenylethylene group, where preferred values and examples of each of the above groups defined above. Within this definition, individual gidrolabilna groups represent alkyl, cycloalkyl, phenyl, benzyl and phenylethylene (for example, 1-phenylethylene or 2-phenylethylene)groups, one group hydrocarbonrich group consisting of alkyl and cycloalkyl groups and, in particular, C1-4alkyl and cycloalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclo is ropel and cyclobutyl.

The term C1-4hydrocarbon used in this description, includes alkyl, alkeline, alkyline, cycloalkyl and cycloalkenyl group, where preferred values and examples of the above groups defined above. Within this definition, individual C1-4gidrolabilna groups are alkyl and cycloalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl.

When there is and where it is stated, gidrolabilna group may be optionally substituted by one or more substituents selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono - or di-C1-4 gidrocarburi, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 (specifically 3-10 and more specifically 5-10) atoms in the ring. Preferred substituents include halogen, such as fluorine. So, for example, substituted gidrolabilna group may be partially fluorinated or perfluorinated group, such as deformity or trifluoromethyl. In one embodiment, preferred substituents include monocyclic carbocyclic and heterocyclic groups having from 3 to 7 atoms in the ring, more specifically 3, 4, 5 or 6 atoms in the ring.

If specified, the Dean or more carbon atoms hidrocarburos group can be optionally replaced by O, S, SO, SO2, NRcX1C(X2), C(X2X1or X1C(X2X1(or subgroup), where X1and X2defined above, provided that at least one carbon atom hidrocarburos group remains. For example, 1, 2, 3 or 4 carbon atoms hidrocarburos group may be replaced by one of the following atoms or groups, and substituting atoms or groups may be the same or different. Typically, the number of substituted linear or skeletal carbon atoms corresponds to the number of linear or skeletal atoms in the group, replacing them. Examples of groups in which one or more carbon atoms hidrocarburos group substituted by substituting atom or group as defined above, include ethers, and simple thioethers (C replaced by O or S), amides, esters, thioamides and thioethers (C-C replaced by X1C(X2) or C(X2X1), sulfones and sulfoxidov (C replaced SO or SO2), amines (C replaced by NRc). The following examples include urea, carbonates and carbamates (C-C-C replaced by X1C(X2X1).

If the amino group has two hydrocarbonrich Deputy, they can, together with the nitrogen atom to which they are attached, and optionally another heteroatom, such as nitrogen, sulfur or oxygen, to be associated with the formation of a cyclic structure of 4 to 7 atoms in the ring, more is specifically 5-6 atoms in the ring.

The term "azacyclonol"used in the present description, refers to cycloalkyl group, in which one of the atoms in a ring carbon has been replaced by a nitrogen atom. So, examples azacycloheptane groups include piperidine and pyrrolidine. The term "oxocyclohexyl"used in the present description, refers to cycloalkyl group, in which one of the carbon atoms in the ring is replaced by an oxygen atom. So, examples exoticlooking groups include tetrahydrofuran and tetrahydropyran. Similarly, the terms "disallowance", "dioxocyclohexa and isoxazolyl" refer, respectively, to cycloalkyl groups in which two atoms in a ring carbon is substituted by two nitrogen atoms, or two oxygen atoms, or one nitrogen atom and one oxygen atom. So, oxa-C4-6cycloalkyl group, is present from 3 to 5 carbon atoms in the ring and the oxygen atom in the ring. For example, oxocyclohexyl group is tetrahydropyranyloxy group.

The definition of "Ra-Rb"used in this description or in relation to substituents present in the carbocyclic or heterocyclic fragment, or in regard to other substituents present at other positions of the compounds of formula (I), includes inter alia compounds wherein Rachoose the connection, O, CO, OC(O), SC(O)NRcC(O), OC(S), SC(S)NRcC(S), OC(NRc), SC(NRc), NRcC(NRc), C(O)O, C(O)S, C(O)NRcC(S)O, C(S)S, C(S)NRcC(NRc)O, C(NRc)S, C(NRc)NRc, OC(O)O, SC(O)O, NRcC(O)O, OC(S)O, SC(S)O, NRcC(S)O, OC(NRc)O, SC(NRc)O, NRcC(NRc)O, OC(O)S, SC(O)S, NRcC(O)S, OC(S)S, SC(S)S, NRcC(S)S, OC(NRc)S, SC(NRcS, NRcC(NRc)S, OC(O)NRcSC(O)NRc, NRcC(O)NRc, OC(S)NRcThe SC(S)NRc, NRcC(S)NRc, OC(NRc)NRcSC(NRc)NRc, NRcC(NRc)NRc, S, SO, SO2, NRc, SO2NRcand NRcSO2where Rcdefined above.

The fragment of Rbcan represent hydrogen, or it can represent a group selected from carbocyclic and heterocyclic groups having from 3 to 12 atoms in the ring (specifically 3 to 10 and more particularly from 5 to 10), and C1-8hidrocarburos group, optionally substituted, as defined above. Examples hydrocarbonrich, carbocyclic and heterocyclic groups described above.

When Rarepresents O and Rbrepresents a C1-10hydrocarbonous group, Raand Rbtogether form hydrocarbonate group. The preferred hydrocarbonate groups include saturated, hydrocarbonate, such as alkoxy (e.g., C1-6alkoxy, more specifically C1-43-6cycloalkane, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy), cycloalkylcarbonyl (for example, C3-6cycloalkyl-C1-2alkoxy, such as cyclopropylmethoxy).

Hydrocarbonsoluble can be substituted by various substituents, as defined in the present description. For example, alkoxygroup may be substituted with halogen (e.g., as in deformedarse, triptoreline), hydroxy (e.g., as in hydroxyethoxy), C1-2alkoxy (e.g., as in methoxyethoxy), hydroxy-C1-2alkyl (as in hydroxyethoxyacetic) or a cyclic group (for example, cycloalkyl group or non-aromatic heterocyclic group, as defined above). Examples of alkoxygroup bearing non-aromatic heterocyclic group as a substituent are those where the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4alkylpiperazine, C3-7cycloalkylcarbonyl, tetrahydropyran or tetrahydrofuran; and alkoxygroup represents a C1-4alkoxygroup, more specifically C1-3alkoxygroup, such as methoxy, ethoxy or n-propoxy.

Alkoxygroup can be substituted monocyclic groups is th, such as pyrrolidine, piperidine, morpholine and piperazine and their N-substituted derivatives, such as N-benzyl, N-C1-4acyl and N-C1-4alkoxycarbonyl. Some examples include pyrrolidinedione, piperidineacetic, piperazinone.

When Rais a bond and Rbrepresents a C1-10 ghydrocarbonous group, examples hydrocarbonrich groups Ra-Rbdefined above. Gidrolabilna groups can be saturated groups such as cycloalkyl and alkyl, and specific examples of such groups include methyl, ethyl and cyclopropyl. Gidrolabilna (e.g., alkyl) groups can be substituted by various groups and atoms, as defined in the present description. Examples of substituted alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (specific examples include bromacil, chloroethyl and trifluoromethyl) or hydroxy (e.g. hydroxymethyl and hydroxyethyl), C1-10acyloxy (for example, acetoxymethyl and benzyloxyethyl), amino and mono - and dialkylamino (for example, aminoethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl andtert-butylaminoethyl), alkoxy (for example, C1-2alkoxy, such as methoxy, as in methoxyethyl) and cyclic groups such as cycloalkyl group, aryl group, heteroaryl the major groups and non-aromatic heterocyclic group, as specified above.

Specific examples of alkyl groups, substituted cyclic group, are those, where the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4alkylpiperazine, C3-7cycloalkylcarbonyl, tetrahydropyran or tetrahydrofuran; and the alkyl group is a C1-4alkyl group, more specifically C1-3alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups, substituted cyclic group include pyrrolidinyl, pyrrolidinone, morpholinomethyl, morpholinoethyl, morpholinopropan, piperidinylmethyl, piperazinylmethyl and their N-substituted form, as defined above.

Specific examples of alkyl groups, substituted aryl groups and heteroaryl groups include benzyl and pyridylmethyl group.

When Rarepresents the SO2NRc, Rbcan represent, for example, hydrogen or optionally substituted C1-8 ghydrocarbonous group, or a carbocyclic or heterocyclic group. Examples Ra-Rbwhere Rarepresents the SO2NRcinclude aminosulfonyl, C1-4alkylaminocarbonyl and di-C1-4alkylaminocarbonyl group, and sulfonamides formed from a cyclic amino group, such as piperidine, morpholine, pyrrolidine or optionally N-substituted piperazine such as N-methylpiperazine.

Examples of groups Ra-Rbwhere Rarepresents the SO2include alkylsulfonyl, heteroarylboronic and arylsulfonyl groups, particularly monocyclic aryl and heteroaryl sulfonylurea group. Specific examples include methylsulphonyl, phenylsulphonyl and toluensulfonyl.

When Rarepresents NRc, Rbcan represent, for example, hydrogen or optionally substituted C1-10hydrocarbonous group, or a carbocyclic or heterocyclic group. Examples Ra-Rbwhere Rarepresents NRcinclude amino, C1-4alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C1-4alkylamino (for example, dimethylamino, diethylamino), cyclooctylamine (for example, cyclopropylamino, cyclopentylamine, cyclohexylamine).

Specific embodiments of and preferred values for R1-R10

R1and R2

R1represents a hydroxy-group or hydrogen; and R2represents a hydroxy-group, methoxy or hydrogen; provided that at least one of R1and R2 is a hydroxy-group.

Preferably, R1represents a hydroxy-group or hydrogen; and R2represents a hydroxy-group or hydrogen; provided that at least one of R1and R2is a hydroxy-group.

In one embodiment, R1represents a hydroxy-group, and R2represents a hydrogen atom or methoxy, preferably hydrogen atom.

In another embodiment, R1represents a hydrogen atom and R2is a hydroxy-group. In the following embodiment, R1represents a hydroxy-group, and R2represents a hydroxy-group or methoxy.

In a preferred embodiment, R1and R2both represent a hydroxy-group.

R8

R8selected from a hydrogen atom and fluorine. Preferably R8represents a hydrogen atom.

R3

R3selected from a hydrogen atom, halogen, cyano, C1-5hydrocarbide and C1-5hydrocarbonate; where C1-5hydrocarbon and C1-5hydrocarbonate fragments, each optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having 12 atoms in the ring.

In one subgroup of compounds R3selected from a hydrogen atom, halogen, cyano, C1-5hydrocarbide and C1-5hydrocarbonate; where C1-5gidrolabilna fragments in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy and amino.

In another subgroup of compounds R3selected from halogen (e.g. chlorine or bromine), C1-5the alkyl and C3-4cycloalkyl.

More specifically, R3selected from a hydrogen atom, chlorine, C1-5hydrocarbide and C1-5hydrocarbonate.

Separate groups of R3include a hydrogen atom, a C1-5alkyl, C2-5alkeneamine and C3-4cycloalkyl group, preferably a secondary alkyl and alkeneamine groups such as isopropyl,second-butyl, tert-butyl, 1,2-dimethylallyl and 1,2-dimethylpropyl; or cycloalkyl groups, such as cyclopropyl.

The following subgroup of the substituents R3consists of C1-5alkyl, C2-5alkenyl and C3-4cycloalkyl groups, preferably secondary alkyl and alkenyl groups such as isopropyl,second-butyl, 1,2-dimethylallyl and 1,2-dimethylpropyl; or cycloalkyl groups, such as cyclopropyl.

When only one of R1and R2represents a hydroxy-group, R3can be great about the hydrogen.

In one particular embodiment, R1and R2both represent hydroxy and R3represents a hydrogen atom.

The following specific embodiment, R3choose from isopropyl and tert-butyl.

In one General embodiment, R3different from halogen.

In another General embodiment, R3may be different from fluorine.

The following General embodiment, R3may be different from fluorine or methoxy.

R4

In one embodiment, R4selected from a hydrogen atom; a group -(O)n-R7where n is 0 or 1 and R7is an acyclic C1-5hydrocarbonous group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 atoms in the ring; halogen; cyano; hydroxy; amino and mono - or di-C1-5 gidrocarburi, where the acyclic C1-5gidrolabilna group and mono - and di-C1-5gidrokarbanatno fragments in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups have 5 to 12 atoms in the ring.

In one subset of compounds, R4selected from a hydrogen atom; a group -(O)n-R7where n is 0 is 1 if and R 7is an acyclic C1-6hydrocarbonous group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 atoms in the ring; halogen; cyano; hydroxy; amino; and mono - or di-C1-5gidrokarbanatno, where C1-5hydrocarbonyl fragment in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy and amino groups.

Within this subgroup, R4more specifically selected from hydrogen, methoxy, halogen (e.g. fluorine or chlorine), cyano; hydroxy, amino, and C3-6cycloalkyl.

More specifically, R4can be selected from a subgroup of R4awhere a subgroup of R4aconsists of a hydrogen atom, methoxy, fluorine and chlorine.

Preferably R4represents a hydrogen atom.

In another embodiment, R3and R4together form a carbocyclic or heterocyclic ring having 5-7 atoms in the ring. Carbocyclic and heterocyclic groups can be any of the groups listed above in the General section of the preferred meanings and definitions", and one particular group is a group in which R3and R4together with the phenyl ring form dihydrobenzofuranyl group.

Specific examples of the phenyl ring containing f is Agency R 1, R2, R3and R4presented in table 1. The place of attachment to the carbonyl group are indicated by asterisks.

Table 1

In one embodiment, the phenyl fragment selected from groups A1-A21.

In another embodiment, the phenyl fragment selected from groups A1-A18.

Preferred phenyl fragments include groups A5, A7, All, A13, A14, A15, A16, A17 and A18.

Particularly preferred phenyl fragments represent A5, A7, A13, A14 and A17.

Particularly preferred phenyl fragments represent A1 and A13.

One particularly preferred phenyl fragment is a group A13.

R5and R6

R5and R6together with the nitrogen atom to which they are attached, form a bicyclic heterocyclic group having up to 12 atoms in the ring, of which up to 5 atoms in the ring are heteroatoms selected from oxygen, nitrogen and sulfur. Bicyclic group may be any of the groups listed above in the General section of the preferred meanings and definitions" or below in the section "Special and preferred sub-groups, and such groups can be unsubstituted or substituted by one or more substituents R10to whom to defined above.

Bicyclic heterocyclic group is usually a condensed bicyclic cyclic group or spirocyclic group, and more specifically represents a condensed bicyclic cyclic group. Specific condensed ring system of interest in the context of the invention represent a 5.6 - 6.6-condensed ring system. In bicyclic heterocyclic groups, one of the rings may represent a heterocyclic ring, and the other may represent a carbocyclic ring or both rings may be heterocyclic.

In one subset of compounds of one of the rings of the bicyclic heterocyclic group is non-aromatic and the other is aromatic. Preferably, the nitrogen atom of the group NR5R6forms part of a nonaromatic ring. Specific examples of such groups are dihydroindole, dihydroisoquinoline, tetrahydroquinoline and tetrahydroisoquinoline group.

More specific examples of such groups are dihydroindole, dihydroisoquinoline, tetrahydroquinoline and tetrahydroisoquinoline group, but in which tetrahydroisoquinoline group shall not be a substitute groups in its non-aromatic ring.

Bicyclic heterocyclic ring neo is Astelin substituted by one or more groups of the substituents R 10as specified above.

In one embodiment, a bicyclic heterocyclic ring substituted by 1, 2 or 3 groups of the substituents R10as specified above.

In another embodiment, a bicyclic heterocyclic ring substituted by 1 or 2 groups of the substituents R10as specified above.

The group of substituents or groups of R10can be attached or to one or both of the two rings, forming a bicyclic heterocyclic group. In one embodiment, the ring containing the nitrogen atom of the group NR5R6not have any substituents R10. In another embodiment, the ring containing the nitrogen atom of the group NR5R6has a substituent R10but this Deputy is different from the group of carboxylic acid.

In one subgroup of compounds, the bicyclic heterocyclic group is unsubstituted or substituted one, two or three (preferably one or two) substituents selected from the group R10consisting of halogen , hydroxy, amino group and Ra-Rbwhere Rachoose from the links, O, CO, C(O)O, C(O)NRc, NRcC(O)NRcC(O)O, NRc.SO, SO2, SONRcand SO2NRc; and Rbselected from hydrogen; carbocyclic and heterocyclic groups having 5 or 6 atoms in the ring; and (C 1-10hydrocarbide (for example, C1-8hydrocarbide, such as C1-8alkyl or C3-7cycloalkyl), optionally substituted by one or more substituents selected from hydroxy, oxo, amino, non-aromatic mono - or di-C1-8gidrokarbanatno, (for example, mono - or di-C1-4gidrokarbanatno), carboxy, and carbocyclic and heterocyclic groups having from 3 to 7 atoms in the ring, and in which one or more carbon atoms in the C1-8hidrocarburos group can be optionally replaced by O, S, C(O)O, C(O)NRcor NRc.

Within this subgroup of compounds and its subgroups, the preferred values and examples where it is alleged that one or more of the carbon atoms in the C1-8hidrocarburos group can be optionally replaced by O, S, C(O)O, C(O)NRcor NRcthat ether , ester and amide groups can be oriented in both direction until you specify otherwise.

In the above subgroups, when Rbrepresents a carbocyclic or heterocyclic group, carbocyclic or heterocyclic group may be substituted by one or more substituents R10as defined above. For example, when Rbrepresents a carbocyclic or heterocyclic group, carbocyclic or heterocyclic group may the be substituted by one or more substituents, selected from CO2R14where R14represents a hydrogen atom or a C1-6alkyl;

C1-4the alkyl, optionally substituted by hydroxy or C1-2alkoxy;

C1-4alkoxy, optionally substituted by hydroxy or C1-2alkoxy; or

group [sol], CH2[sol], C(O)[sol], OCH2CH2[sol] or OCH2CH2CH2[sol]where [sol] is as defined below.

In a more specific subgroup of the bicyclic heterocyclic group is unsubstituted or substituted one, two or three (preferably one or two) substituents selected from the group R10bconsisting of halogen, OH, NH2CH2OH, CH2NH2O-C1-6of alkyl, NH-C1-6of alkyl, aryl, heteroaryl, C3-7cycloalkyl, heterocyclyl, O-heteroaryl, O-C3-7cycloalkyl, O-geterotsiklicheskie, C(=O)C1-6of alkyl, C(=O)OC1-6of alkyl, C(=O)NH2C(=O)NHC1-6of alkyl, C(=O)N(C1-6alkyl)2, NH(C1-6alkyl), N(C1-6alkyl)2, NC(=O)C1-6of alkyl, C6-aryl, OC6aryl, C(=O)C6aryl, C(=O)OC6aryl, C(=O)NH2C(=O)NHC6aryl, C(=O)N(C6aryl)2, NH(C6aryl), N(C6aryl)2, NC(=O)C6aryl, C5-6heterocyclyl, OC5-6heterocyclyl, C(=O)C5-6heterocyclyl, C(=O)OC5-6heterocyclyl, C(=O)NHC5-6heterocyclyl, C(=O)NC 5-6heterocyclyl)2, NH(C5-6heterocyclyl), N(C5-6heterocyclyl)2, NC(=O)C5-6heterocyclyl, C(=O)NHC1-6of alkyl, C5-6aryl, S(=O)C1-6of alkyl, S(=O)N-C1-6the alkyl and SO2N-C1-6of alkyl; and a group [sol], CH2[sol] or OCH2CH2[sol]where [sol] is selected from the following groups:

In another subgroup of compounds, the bicyclic ring is unsubstituted or substituted 1, 2 or 3 (for example, 1 or 2, for example, 1) the groups R10cwhere R10cis a group [sol], CH2[sol] or OCH2CH2[sol]where [sol] is selected from the following groups:

and where (i) R10coptional extras selected from the group OCH2CH2CH2[sol] and/or (ii) [sol] additionally choose from other11where R11is a COR12or R12and R12represents a C1-4alkyl, aryl or aryl-C1-4alkyl.

In another subgroup of compounds, the bicyclic ring is unsubstituted or substituted by one or two substituents R10sswhere R10ccchoose from:

halogen;

CO2R14where R14represents a hydrogen atom or a C1-6alkyl;

C1-4the alkyl, optionally substituted by hydroxy or C1-2alkoxy;

C1-4alkoxy, not necessarily Sames the frame hydroxy or C 1-2alkoxy; or

group [sol], CH2[sol], C(O)[sol], OCH2CH2[sol] or OCH2CH2CH2[sol]where [sol] is selected from the following groups:

where X4represents NH or O, m is 0 or 1, n is 1, 2 or 3, R11represents a hydrogen atom, COR12C(O)OR12or R12; R12represents a C1-6alkyl, C3-6cycloalkyl, aryl, aryl-C1-6alkyl or CH2R15; and R15selected from a hydrogen atom, a C1-6of alkyl, C3-6cycloalkyl, hydroxy-C1-6of alkyl, piperidine, N-C1-6alkylpiperazine, piperazine, research, COR13or C(O)OR13; and R13represents a C1-6alkyl.

In the next sub-group of compounds, the bicyclic ring is unsubstituted or substituted by one or two substituents R10cccwhere R10cccchoose from:

group [sol] or CH2[sol]where [sol] is selected from the following groups:

where X4represents NH or O, m is 0 or 1, n is 1, 2 or 3, R11represents a hydrogen atom, COR12C(O)OR12or R12; R12represents a C1-6alkyl, C3-6cycloalkyl, aryl, aryl-C1-6alkyl or CH2R15; and R15selected from a hydrogen atom, a C1-6of alkyl, C3-6cycloalkyl, hydroxy-C1-6 of alkyl, piperidine, N-C1-6alkylpiperazine, piperazine, research, COR13or C(O)OR13; and R13represents a C1-6alkyl.

In another subgroup of compounds, where R10bor R10cor R10ccis a group [sol], CH2[sol], OCH2CH2[sol] or OCH2CH2CH2[sol] [sol] contains primary or secondary amino group and a primary or secondary amino group can be converted into a derivative with the formation of the acyl derivative such as an amide, carbamate or urea. For example, the amino group can be converted into derived for the formation of a carbamate, such as C1-4alkoxycarbonylmethyl, or benzyloxycarbonylamino.

In one subgroup of compounds R5and R6together with the nitrogen atom to which they are attached, form an optionally substituted dihydroisoquinolyl group, where the optional substituents are selected from the group R10, R10a, R10b, R10cand R10ccand their sub-groups and examples, as defined above.

Specific examples of the group NR5R6shown in table 2. The attachment point to the carbonyl group shown by an asterisk.

Table 2

One series of preferred groups NR5R6consists of or includes group B8 and B30.

Another preferred group NR5R6is a group B8.

The following series of preferred groups NR5R6consists of groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B53, B54, B55, B55, B57, B58, B59, B60, B61 and B62.

The following series of preferred groups NR5R6consists of groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B53, B54, B55, B56, B57, B58, B59, B60, B61 and B62.

Another series of preferred group consists of B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B53, B54, B55, B56, B57, B58, B59, B60, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B83, B85, B86, B87, B93, B94, B95, B97, B98, B99, B100 and B10l.

Following a number of subgroups NR5R6consists of B43, B46, B48, B76, B82, B89, B91 and B96. Within specified subgroups more preferred are groups B43, B46, B48, B76, B82, B89 and B91, where B76, B82 and B89 are particularly preferred.

Special and preferred subgroup

One group of new compounds according to the invention may be represented by the General formula (II):

or salts, tautomers, solvate and N-oxides;

where R3aselected from a hydrogen atom, halogen, cyano, C1-5hydrocarbide and C1-5hydrocarbonate; where C1-5hydrocarbon and C1-5hydrocarbonate fragments, each optionally substituted by one or not is how many deputies, selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having 5 to 12 atoms in the ring;

R4selected from a hydrogen atom; a group -(O)n-R7where n is 0 or 1 and R7is an acyclic C1-5 ghydrocarbonous group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 atoms in the ring; halogen; cyano; hydroxy; amino and mono - or di-C1-5 gidrocarburi, where the acyclic C1-5 ghydracarina group and mono - and di-C1-5 gidrocarburi fragments in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having 5 to 12 atoms in the ring;

or R3aand R4together form a monocyclic carbocyclic or heterocyclic ring having 5-7 atoms in the ring; R5and R6together with the nitrogen atom to which they are attached, form a bicyclic group having up to 12 atoms in the ring (for example, 8 to 12 atoms in the ring or 9-10 atoms in the ring), of which up to 5 atoms in the ring are heteroatoms selected from oxygen, nitrogen and sulfur; and R8chosen from hydrogen atoms and fluorine.

Another new subgroup with the joining according to the invention can be represented by formula (III):

or salts, tautomers, solvate and N-oxides;

where R3bselected from a hydrogen atom, halogen, cyano, C1-5hydrocarbonate C1-5hydrocarbonate; where C1-5hydrocarbonyl and C1-5hydrocarbonate fragments, each optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having 5 to 12 atoms in the ring;

R4selected from a hydrogen atom; a group -(O)n-R7where n is 0 or 1 and R7is an acyclic C1-5hydrocarbonous group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 atoms in the ring; halogen; cyano; hydroxy; amino and mono - or di - C1-5gidrokarbanatno, where the acyclic C1-5gidrolabilna group and mono - and di - C1-5gidrokarbanatno fragments in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having from 5 to 12 atoms in the ring;

or R3band R4together form a monocyclic carbocyclic or heterocyclic ring having 5-7 atoms in the ring; R5and R6 together with the nitrogen atom to which they are attached, form a bicyclic group having from 5 to 12 atoms in the ring (for example, 8 to 12 atoms in the ring or 9-10 atoms in the ring), of which up to 5 atoms in the ring are heteroatoms selected from oxygen, nitrogen and sulfur; and

R8selected from a hydrogen atom and fluorine.

The following subgroup of novel compounds according to the invention can be represented by formula (IV):

or salts, tautomers, solvate and N-oxides;

where R2aselected from hydroxy and methoxy (and preferably represents hydroxy);

R3cselected from a hydrogen atom, halogen, cyano, C1-5hydrocarbide and C1-5hydrocarbonate; where C1-5hydrocarbon and C1-5hydrocarbonate fragments, each optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, and aryl and heteroaryl groups having from 5 to 12 atoms in the ring;

R4selected from a hydrogen atom; a group -(O)n-R7where n is 0 or 1 and R7is an acyclic C1-5hydrocarbonous group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 atoms in the ring; halogen; cyano; hydroxy; amino and mono - or di-C gidrokarbanatno, where the acyclic C1-5gidrolabilna group and mono - and di-C1-5gidrokarbanatno fragments in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy, amino, mono - and di-C1-2alkylamino, aryl and heteroaryl groups having 5 to 12 atoms in the ring;

or R3cand R4together form a monocyclic carbocyclic or heterocyclic ring having 5-7 atoms in the ring;

R5and R6together with the nitrogen atom to which they are attached, form a bicyclic group having up to 12 atoms in the ring (for example, 8 to 12 atoms in the ring or 9-10 atoms in the ring), of which up to 5 atoms in the ring are heteroatoms selected from oxygen, nitrogen and sulfur; and

R8selected from a hydrogen atom and fluorine.

Within formula (II), (III) and (IV) private subgroup of compounds are those where NR5R6form a bicyclic ring, containing up to 10 atoms in the ring (for example, 9 or 10 atoms in the ring, preferably 9 atoms in the ring), of which up to 5 atoms in the ring are heteroatoms selected from O, N and S, monocyclic or bicyclic ring optionally substituted with up to three alternative groups of R10, R10a, R10b, R10cand R10ccas defined above,more specifically up to two substituents, for example, one Deputy.

More specific substituents for the bicyclic heterocyclic group NR5R6are substituents that form part of the subgroup R10d, which consists of members of the subgroup R10sand fluorine, chlorine, bromine, trifloromethyl, deformedarse, triptoreline, cyano, methyl, ethyl, cyclopropyl, hydroxy, methylsulphonyl, amino, methylamino, dimethylamino, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, ethoxycarbonyl, methoxycarbonyl, aminocarbonyl, oxo, methoxymethyl, carboxy, phenyl, C1-2alkoxycarbonyl, aminocarbonyl, acetyl, methylsulfonyl and pyridinyl. Within this subgroup one series of substituents include methyl, ethyl, chlorine, fluorine, hydroxy, methylsulphonyl, amino, methylamino, dimethylamino, cyano, methoxy, ethoxy, hydroxymethyl, cyclopropyl, hydroxyethyl, etoxycarbonyl, methoxycarbonyl, aminocarbonyl, oxo, methoxymethyl and acetyl.

For example, NR5R6can form 5,6 - or 6,6-condensed bicyclic ring of 9 or ten atoms in the ring, of which 1-3 are heteroatoms, and the bicyclic ring is optionally substituted by one or more substituents R10or R10aor R10bor R10cor R10ccor R10dand their subgroups and examples, as defined above.

In before the lah this subgroup examples of condensed bicyclic rings are such in which the non-aromatic ring, such as pyrolidine, piperidine, pieperazinove or morpholino ring condensed with a 6-membered aryl or heteroaryl ring, such as benzene or pyridine ring, and in which the nitrogen atom present in the non-aromatic ring, linked to the carbonyl group in formula (II), (III) or (IV).

Specific condensed bicyclic rings include dihydroindol, dihydroindol, tetrahydroquinolin and tetrahydroisoquinoline, and their Aza-analogues in which one or two carbon atom in the ring of the aromatic ring is replaced by nitrogen.

One group bicyclic heterocyclic groups formed NR5R6consists of dihydroindole, optionally substituted by one or more (e.g. 1, 2 or 3 optional substituents selected from the group R10, R10a, R10band R10cor R10ccand/or R10dand their sub-groups and examples, as defined above.

The preferred compounds are those in which R3aor R3bor R3cselected from a hydrogen atom, halogen and C1-5of alkyl; where C1-5the alkyl fragment in each case optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy and amino.

More preferably, the group is and R 3aor R3bor R3crepresents a hydrogen atom or a C3-5alkyl group, optionally substituted by one or more substituents selected from hydroxy, halogen, C1-2alkoxy and amino. In particular, the group R3aor R3bor R3cselected from a hydrogen atom and ISO-propyl, sec-Budilnik, tert-Budilnik and 1,2-dimethylpropylene groups.

Another subgroup of compounds according to the invention is represented by formula (V):

or salts, tautomers, solvate and N-oxides;

where R1represents a hydrogen atom or hydroxy; R2arepresents a hydroxy or methoxy group; provided that at least one of R1and R2arepresents a hydroxy-group; R3dselected from ethyl and secondary and tertiary alkyl groups having 3-6 carbon atoms; R4aselected from a hydrogen atom, fluorine, chlorine and methoxy; and R5, R6and R8defined above; provided that when R1and R2both represent hydroxy, R3dcan be optionally selected from a hydrogen atom.

In one embodiment, when R1and R2both represent hydroxy, R3dis a hydrogen atom.

In another embodiment, R3dis a FL is the function or secondary, or tertiary alkyl group. Especially preferred alkyl groups of R3drepresent ethyl, isopropyl and tert-butyl, and, in particular, isopropyl.

Within formulae (II)to(V) is preferred group NR5R6are dihydroisoquinoline group that may be unsubstituted or unsubstituted by one, two or three groups of R10, R10aor R10bor R10cor R10ccor R10dand their subgroups and examples, as defined above, but in one particular embodiment, are unsubstituted.

Another preferred subgroup of compounds may be represented by formula (VI):

or salts, tautomers, solvate and N-oxides;

where R1represents a hydroxy-group or hydrogen; R2arepresents a hydroxy-group or methoxy (preferably hydroxy), provided that at least one of R1and R2arepresents a hydroxy-group, ring B represents an aromatic ring containing up to two (preferably 0 or 1) of the nitrogen heteroatoms in the ring; T represents a group (CHR10)jand Q represents a group (CHR10)kwhere j and k are each 0, 1, 2 or 3, provided that the sum of j and k is 2 or 3; n is 0, 1, 2 or 3, and R3, R4a, R8 and R10are as defined above.

Another preferred subgroup of compounds may be represented by formula (VIa):

or salts, tautomers, solvate and N-oxides;

where R1represents a hydroxy-group or hydrogen; R2arepresents a hydroxy-group or methoxy (preferably hydroxy), provided that at least one of R1and R2arepresents a hydroxy-group, ring B is an aromatic ring containing up to two (preferably 0 or 1) of the nitrogen heteroatoms in the ring; T represents a group (CHR10b)jand Q represents a group (CH R10b)kwhere j and k are each 0, 1, 2 or 3, provided that the sum of j and k is 2 or 3; n is 0, 1, 2 or 3, and R3, R4a, R8and R10bare as defined above.

In one subgroup of compounds within formula (VI) or formula (VIa), R1represents a hydrogen atom.

In another subgroup of compounds within formula (VI) or formula (VIa), R1is a hydroxy-group.

In the formula (VI), examples of bicyclic groups:

include group, C1-C6 below

The preferred groups are groups C1, C5 and C6.

In groups, the C1-C6 fragment R10can the t to represent a group R 10as defined above, or can represent a group R10b, R10c, R10ccor RStas defined in the present description. In each case, n is preferably 1, 2 or 3, and more preferably is 1 or 2, for example, 1.

In this case, the preferred group is a group C1.

Within formula (VI) one particular group of compounds may be represented by formula (VII):

or salts, tautomers, solvate and N-oxides;

where R1, R2a, R3R4a, R8and R10bare as defined above, and n is 0, 1, 2 or 3 (more preferably 0, 1 or 2, for example, 0 or 1), and, provided that at least one of R1and R2ais a hydroxy-group.

Within formula (VI) and (VII) Deputy R3preferably represents a group R3das defined above, and/or the substituent R10bor missing (n=0), or selected from the group R10cand R10band their sub-groups and examples, as defined above. Preferably, R1and R2aboth are hydroxy-group.

One particular group of compounds according to the invention within formula (VII) is represented by formula (VIIa):

or salts, tautomers, solvate and N-oxides;

where R3choose from the volume of hydrogen, halogen, C1-5alkyl, C2-5alkenyl and C3-4cycloalkyl group; R4aselected from a hydrogen atom, fluorine, chlorine and methoxy; R8represents a hydrogen atom or fluorine; n is 0, 1, 2 or 3; and R10is the same as defined above.

Within formula (VIIa) R10can be selected from, for example, one, two or three groups of R10aor R10bor R10cor R10ccor R10dand their sub-groups and examples, as defined above.

One preferred group of compounds according to the invention within formula (VII) is represented by the formula (VIIb):

or salts, tautomers, solvate and N-oxides;

where R3selected from a hydrogen atom, halogen, C1-5alkyl, C2-5alkenyl and C3-4cycloalkyl group; R4aselected from a hydrogen atom, fluorine, chlorine and methoxy; R8represents a hydrogen atom or fluorine; n is 0, 1, 2 or 3; and R10ccchoose from:

halogen;

CO2R14where R14represents a hydrogen atom or a C1-6alkyl;

C1-4the alkyl, optionally substituted by hydroxy or C1-2alkoxy;

C1-4alkoxy, optionally substituted by hydroxy or C1-2alkoxy; or

group [sol], CH2[sol], C(O)[sol], OCH2CH2[sol] or OCH2CH2CH2 [sol]where [sol] is selected from the following groups:

where X4represents NH or O, m is 0 or 1, n is 1, 2 or 3, R11represents a hydrogen atom, COR12C(O)OR12or R12; R12represents a C1-6alkyl, C3-6cycloalkyl, aryl, aryl-C1-6alkyl or CH2R15; and R15selected from a hydrogen atom, a C1-6of alkyl, C3-6cycloalkyl, hydroxy-C1-6of alkyl, piperidine, N-C1-6alkylpiperazine, piperazine, research, COR13or C(O)OR13; and R13represents a C1-6alkyl.

In the following embodiment, the connection may be an Aza - or diaza-analogue compounds of the formula (VI), (VII) and (VIIa), as defined above, where one or two carbon atoms of the benzene ring attached to the five-membered ring, substituted by a nitrogen atom.

For example:

in the compound of formula (VIIa) can be replaced with:

In each of formulas (VI), (VIa), (VII), (VIIa) and (VIIb) and their subgroups, as defined above, preferably n is 1, 2 or 3, and more preferably is 1 or 2. In one embodiment, n is 1.

Specific compounds according to the invention include:

(5-chloro-2-hydroxyphenyl)-(1,3-dihydroindol-2-yl)methane is n;

(3-tert-butyl-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl)methanon;

(3-tert-butyl-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoline-1-yl)methanon;

(3,4-dihydro-1H-isoquinoline-2-yl)-(4-hydroxy-3-isopropylphenyl)methanon;

(1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(3-tert-butyl-4-hydroxyphenyl)-(l,4-dioxa-8 azaspiro[4.5]Dec-8-yl)methanon;

(3-tert-butyl-4-hydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(3-tert-butyl-4-hydroxyphenyl)pyrrolo[3,2-b]pyridine-1-ylmethanone;

8-(3-tert-butyl-4-hydroxybenzoyl)-2-methyl-2,8-diazaspiro[4.5]Decan-1-it;

(1,3-dihydroindol-2-yl)-(4-hydroxy-3-isopropylphenyl)methanon;

(3-tert-butyl-4-hydroxyphenyl)-(3,4-dihydro-1H-isoquinoline-2-yl)methanon;

(1,3-dihydroindol-2-yl)-(5-ethyl-2,4-dihydroxyphenyl)methanon;

(5-cyclopropyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(5-sec-butyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(1,3-dihydroindol-2-yl)-(2,4-dihydroxyphenyl)methanon;

(5-chloro-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;

[5-(3-aminopropoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(5-bromo-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-triptoreline)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-{4-[2-(2-methoxyethoxy)ethoxy]-1,3-dihydroindol-yl}meanon;

(2,4-dihydroxy-5-isopropylphenyl)-[4-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano;

(3-sec-butyl-4-hydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(5-tert-butyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(5-chloro-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;

(1,3-dihydroindol-2-yl)-(2-hydroxy-5-isopropyl-4-methoxyphenyl)methanon;

(4,7-debtor-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-(5-fluoro-1,3-dihydroindol-2-yl)methanon;

(1,3-dihydroindol-2-yl)-(3-fluoro-2,4-dihydroxy-5-isopropylphenyl)methanon;

(1,3-dihydroindol-2-yl)-(2-fluoro-4,6-dihydroxy-3-isopropylphenyl)methanon;

hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-(4-fluoro-1,3-dihydroindol-2-yl)methanone;

(5-chloro-6-methoxy-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-methoxyethoxy)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanon;

(3,4-dihydro-1H-isoquinoline-2-yl)-(2,-dihydroxy-5-isopropylphenyl)methanon;

(5-amino-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-(5-methoxy-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-(5-morpholine-4-yl-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;

methyl ester of 2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid;

2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid;

(2,4-dihydroxy-5-isopropylphenyl)-(5-morpholine-4-ylmethyl-1,3-dihydroindol-2-yl)methanon;

tert-butyl ether {3-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]propyl}carbamino acids;

(2,4-dihydroxy-5-isopropylphenyl)-(5-methyl-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-isopropylaminoethyl)-1,3-dihydroindol-2-yl]metano;

N-{2-[2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]ethyl}-2-morpholine-4-ylacetamide;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}meanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-piperazine-1-ylphenyl)-1,3-dihydroindol-2-yl]metano;

2,4-dihydroxy-5-isoprop fenil)-[5-(1-dimethylamino-2-hydroxyethyl)-1,3-dihydroindol-2-yl]metano;

dihydroxy-5-isopropylphenyl)-[5-(2-dimethylamino-1-hydroxyethyl)-1,3-dihydroindol-2-yl]metano;

hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-[5-(piperazine-1-carbonyl)-1,3-dihydroindol-2-yl]methanone;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano;

[5-(2-aminoethoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-(5-hydroxy-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(2-hydroxyethyl)piperazine-1-yl]-1,3-dihydroindol-2-yl}meanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-(morpholine-4-reparacin-1-yl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-isopropylpiperazine-1-yl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-(5-piperazine-1-yl-1,3-dihydroindol-2-yl)methanon;

tert-butyl ester 4-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-ylamino]piperidine-1-carboxylic acid;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(piperidine-4-ylamino)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[4-(4-methylpiperazin-1-yl)-1,3-Digi rozonda-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[4-(piperidine-4-ylamino)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-(5-dimethylaminomethyl-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-carbonyl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-{5-[2-(2,2-dimethylpropylene)ethoxy]-1,3-dihydroindol-2-yl}meanon;

[5-(2-cyclopentylamine)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-(5-piperidine-1-ylmethyl-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxypiperidine-4-yl)-1,3-dihydroindol-2-yl]metano;

(5-chloro-2,4-dihydroxyphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;

(5-chloro-6-hydroxy-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;

(5-chloro-2,4-dihydroxyphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-7-methyl-1,3-dihydroindol-2-yl]metano;

and their salts, solvate, N-oxides and tautomers.

Preferred individual compounds of formula (I) are:

(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-and the]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,3-dihydroindol-2-yl]metano;

(2,4-dihydroxy-5-isopropylphenyl)-(5-piperazine-1-yl-1,3-dihydroindol-2-yl)methanon;

(2,4-dihydroxy-5-isopropylphenyl)-(5-dimethylaminomethyl-1,3-dihydroindol-2-yl)methanon;

or their salts, solvate, N-oxides and tautomers.

Particularly preferred individual compounds consists of:

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone;

(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]methanone and

(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,3-dihydroindol-2-yl]methanone;

or their salts, solvate or tautomers.

To remove doubt, it should be understood that each General and specific value, an implementation option and example of the groups R1can be combined with each General and specific value, the embodiment and example of the groups R2and/or R3and/or R4and/or R and/or R5and/or R6and/or R10and/or Q and/or T and/or their subgroups, as defined above, and that all such combinations are encompassed by the present invention.

Various functional groups and substituents comprising the compounds of formula (I), typically chosen so that the molecular weight of the compounds of formula (I) does not exceed 1000. More specifically, the molecular weight of the compound is less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525, for example, 500 or less.

Salt, solvate, the tautomers, the isomers, N-oxides, esters, prodrugs and isotopes

The reference compound of formula (I) and its subgroups also includes ionic forms, salts, solvate, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms, for example, as discussed below; preferably their salts or tautomers or isomers or N-oxides. or a solvate; and more preferably, the salts or tautomers or N-oxides or solvate.

Many of the compounds of formula (I) can exist in the form of salts, for example salts of accession acid or, in certain cases, salts of organic and inorganic bases, such as phenolate, carboxylate, sulphonate and phosphate salts. All such and included in the scope of the present invention, and references to the compounds of formula (I) include the salt forms of the compounds.

Salt of the present invention can be synthesized from the parent compound which contains a basic or acidic fragment, traditional chemical methods, such as methods described inPharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be obtained by reaction of these compounds in the form of the free acid or base with the appropriate base or acid in water or in an organic solvent, or a mixture of two; commonly used non-aqueous environment, such as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

Salt accession acid can be formed with a wide range of acids, both inorganic and organic. Examples of salts of accession acid include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloracetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzosulfimide, benzoic, 4-acetamidobenzoyl, butane, (+)-camphor, camphorsulfonate, (+)-(lS)-camphor-10-sulphonic, capric, Caproic, Caprylic, cinnamon, lemon, reklamowa, modellserie, ethane-1,2-disulfonate, econsultancy, 2-hydroxyethanesulfonic is, formic, fumaric, galatarasay, hentaimovi, glucoheptonate, D-gluconic, glucuronic (for example, D-glucuronic), glutamic (for example, L-glutamic), alpha-oxoglutarate, glycolic acid, hippuric, Hydrobromic, hydrochloric, itestosterone, isetionate, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic acid, malonic acid, (±)-DL-almond, methansulfonate, naphthalene-2-sulphonic, naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthoic, nicotine, nitrogen, oleic, orotovoy, oxalic, palmitic, pambou, phosphoric, propionic, L-Pyroglutamate, salicylic, 4-aminosalicylic, sebacinales, stearic, succinic, sulfuric, tanimowo, (+)-L-tartaric, titanoboa, paratoluenesulfonyl, undecylenoyl and valerianic acids, acylated amino acids and cation exchange resins.

If the compound is anionic, or has a functional group which may be anionic (e.g.,- COOH may be-COO-), the salt can be obtained with acceptable cation. Examples of acceptable inorganic cations include, but without limiting them, alkali metal ions, such as Na+and K+the cations of the alkali earth metal such as Ca2+and Mg2+and other cations, such as Al3+. Examples of suitable organic cations VK is ucaut, but without their limitations, ammonium ion (i.e. NH4+) ions and substituted ammonium (e.g., NH3R+, NH2R2+, Other3+, NR4+). Examples of some suitable substituted ammonium ions are those that are derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylendiamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a conventional Quaternary ammonium ion is N(CH3)4+.

If the compounds of formula (I) contain an amine function, they may form a Quaternary ammonium salt, for example, by reaction with an alkylating reagent, according to methods well known to the person skilled in the art. Such Quaternary ammonium compounds are included in the scope of formula (I).

Salt forms of the compounds according to the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed inBerge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL, Vol.66, pp. 1-19. However, salts which are not pharmaceutically acceptable may also be obtained as an intermediate form, which can then be converted into pharmaceutically acceptable salts. Such fo what we pharmaceutically unacceptable salts, which can be useful, for example, when cleaning or separation of the compounds according to the invention, also form part of the present invention.

The compounds of formula (I)containing an amine function may also form N-oxides. In this case, the reference to the compound of formula (I), which contains an amine, also includes N-oxide.

If the compound contains several functions amine, one or more than one nitrogen atom can be oxidized with the formation of N-oxide. Specific examples of the N-oxides are the N-oxides of tertiary amine or a nitrogen atom nitrogen-containing heterocycle.

N-Oxides can be obtained by treating the corresponding amine oxidizing agent such as hydrogen peroxide or percolate (for example, peroxocarbonate acid), see, for example,Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. In particular, N-oxides can be obtained by the method L.W. Deadfly (Syn. Comm. 1977, 7, 509-514), in which the amine compound is introduced into the reaction metallocarboxypeptidase acid (MCPBA), for example in an inert solvent such as dichloromethane.

The compounds of formula (I) can exist in different geometrical isomeric and tautomeric forms and references to compounds of formula (I) include all such forms. To remove doubt, if the connection can exist in one of several geometries the x isomeric or tautomeric forms and only one is specifically described or shown, all others, however, are covered by formula (I).

Examples of tautomeric forms include, for example, keto-, enol and enolate forms, as, for example, the following tautomeric pairs: ketone/enol (illustrated below), Imin/enamine, amide/iminspect, amicin/amidin, nitroso/oxime, thioketone/ential and nitro/acentro.

If the compounds of formula (I) contain one or more chiral centers and may exist in the form of two or more optical isomers, references to compounds of formula (I) include them all optical isomeric forms (e.g., enantiomers, epimere and diastereoisomers), or in the form of the individual optical isomers, or mixtures (e.g. racemic mixtures) of two or more optical isomers, unless the context otherwise indicated.

The optical isomers can be characterized and identified by their optical activity (i.e. as + and - isomers, ordandlisomers) or they can be characterized in terms of their absolute stereochemistry using "R/S" nomenclature proposed by Kahn, ingoldo and Prelogon (Cahn, Ingold, Prelog), seeAdvanced Organic Chemistry, by Jerry March, 4thEdition, John Wiley & Sons, New York, 1992, pages 109-114,see alsoCahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl, 1966, 5, 385-415.

The optical isomers can be separated by a number of methods, including chiral chromatography chromatography on a chiral substrate), and such methods are well known to specialists in this field. Alternatively, chiral chromatography, optical isomers can be separated by formation of diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-Pyroglutamate acid, (-)-getaway-L-tartaric acid, (+)-mandelic acid, (-)-malic acid and (-)-camphorsulfonate, separation of the diastereomers by fractional crystallization and subsequent dissociation of salts, which gives an individual enantiomer free base.

If the compounds of formula (I) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may be advantages in comparison with the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent is only one of a pair of enantiomers, or only one of a multitude of diastereomers. Accordingly, the invention provides compositions containing a compound of the formula (I)having one or more chiral centres, where at least 55%, at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compounds of formula (I) is present in the form of the individual optical isomers (e.g., enantiomer or diastereoisomer). In one General embodiment, to implement the Oia 99% or more (for example, essentially all) of the total amount of compounds of formula (I) may be present in the form of the individual optical isomers (e.g., enantiomer or diastereoisomer).

Compounds according to the invention include compounds with one or more isotopic substitutions, and link to a separate element includes, within its scope, all the isotopes of an element. For example, the reference hydrogen includes, within its scope,1H,2H (D) and3H (T). Similarly, references to carbon and oxygen include, within their volume, respectively12C,13C and14C; and16O and18O.

Isotopes can be radioactive or non-radioactive. In one embodiment, compounds of the invention do not contain radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the connection may include one or more radioisotopes. Compounds containing these radioisotopes can be used for diagnostic purposes.

Esters, such as esters of carboxylic acids and complex allactivity compounds of formula (I)bearing a carboxylic acid group or hydroxyl group, are also covered by formula (I). Examples of esters are compounds containing the group-C(=O)OR, where R represents cloneprincipal, for example, C1-7alkyl group, a C3-20heterocyclyl group or a C5-20aryl group, preferably C1-7alkyl group. Specific examples of ester groups include, but without limitation, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3and-C(=O)OPh. Examples of acyloxy (reverse ester) represented by the formula-OC(=O)R, where R is a Deputy alloctype, for example, C1-7alkyl group, a C3-20heterocyclyl group or a C5-20aryl group, preferably C1-7alkyl group. Specific examples of acyloxy include, but without limitation, -OC(=O)CH3(acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph and-OCC=O)CH2Ph.

In one General embodiment, formula (I) and its podhorany, subgroups, preferred values and examples do not include esters, such as esters of carboxylic acids and allactivity.

In one particular embodiment, formula (I) and its podhorany, subgroups, preferred values and examples do not include esters of hydroxycodone, where R2is a hydroxy-group and an ester formed by a hydroxy-group, R2.

Also covered by formula (I) are any polymorphic forms of the compounds, solvate (e.g., hydrates), complexes of compounds (for example, complexes of on the or clathrates with compounds such as cyclodextrins, or complexes with metals) and prodrugs of the compounds. By "prodrug" refers to, for example, any compound which becomesin vivoin biologically active compound of the formula (I).

For example, some prodrugs are esters of active compounds (for example, physiologically acceptable and metabolically labile ester). During metabolism ether group (-C(=O)OR), is cleaved to form the active drug. Such esters can be obtained by etherification, for example, any of carboxilate groups (-C(=O)OH) in the original connection, preliminary, where necessary, the protection of any other reactive groups present in the initial compound, followed, if necessary, removing the protection.

Examples of such metabolically labile esters include esters of the formula-C(=O)OR where R represents:

C1-7alkyl

(for example, -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C1-7aminoalkyl

(for example, aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and

acyloxy-C1-7alkyl

(for example, acyloxymethyl;

acyloxyacyl;

pivaloyloxymethyl;

acetoxymethyl;

1-acetoxyethyl;

1-(1-methoxy-1-methyl)ethylcarboxylate;

1-(benzoyloxy)ethyl; isopropoxycarbonyloxymethyl;

1-from propoxycarbonyl;

cyclohexylcarbodiimide;

1-cyclohexylcarbodiimide;

cyclohexyloxycarbonyloxy;

1-cyclohexyloxycarbonyloxy;

(4 tetrahydropyranyloxy)carbonylmethyl;

1-(4-tetrahydropyranyloxy)carbonylmethyl;

(4-tetrahydropyranyl)carbonylmethyl and

1-(4-tetrahydropyranyl)carbonyloxy).

In addition, some prodrugs are activated by enzymes to form the active compound or compounds, which in the following chemical reaction to form an active connection (such as ADEPT, GDEPT, LIDEPT etc). For example, the prodrug may be a derivative of sugar or other glycoside conjugate or may be a derived complex ester of the amino acids.

Biological activity

The compounds of formula (I) and its subgroups are inhibitors of Hsp90 and therefore expected to be useful in the treatment of a wide spectrum of proliferative disorders. Examples of such proliferative disorders include, but are not limited to, a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g. colorectal carcinoma, such as adenocarcinoma of colon cancer and adenoma of the colon, kidney, epidermis, liver, lung, for example adenocarcinoma, small cell lung cancer and Nemacolin is know carcinoma of the lung, esophagus, gall bladder, ovary, pancreas e.g. exocrine pancreatic carcinoma, stomach, cervix, thyroid, prostate, gastrointestinal system, e.g. gastrointestinal stromal tumours, or skin, for example squamous cell carcinoma; a hematopoietic tumor of lymphoid origin, such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (such as diffuse large b-cell lymphoma), T-cell lymphoma, Hodgkin's lymphoma, nahodkinskuju lymphoma, hairy cell lymphoma or lymphoma Burket (Burkett); hematopoietic tumor of myeloid origin, for example acute and chronic myelogenous leukemia, imatinib-sensitive and-resistant chronic myelogenous leukemia, myelodysplasias syndrome, bortezomib sensitive and refractory multiple myeloma, myeloproliferative disease or promyelocytic leukemia; follicular thyroid cancer; a tumour of mesenchymal origin, for example fibrosarcoma or rabdomyosarcoma; tumors of the Central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or neurinomas; melanoma; seminomy; teratocarcinoma; osteosarcoma; pigmentary xeroderma; keratoakantoma or Kaposi's sarcoma.

Rakovi the disease may represent a cancer, which are sensitive to inhibition of Hsp90 and such cancers can be determined in the manner specified in the section entitled "Methods of diagnosis".

One group of cancer includes cancers of the breast person (e.g., primary tumors of the breast, neoslavery breast cancer, invasive adenocarcinoma of the ducts of the breast, endometrioid breast cancer) and lymphoma epithelial cells. In addition, other cancers are colorectal and endometrial cancers.

Another sub-group of cancers includes hematopoietic tumors of lymphoid origin, such as leukemia, chronic lymphocytic leukemia, lymphoma cells of the mantle tissue and B-cell lymphoma (such as diffuse large b-cell lymphoma) and optional further includes chronic myelogenous leukemia and multiple myeloma.

A preferred subgroup of cancer consists of ErbB2-positive breast cancer, prostate, lung and stomach; chronic myeloid leukemia; cancer of the prostate is dependent on receptor androgen hormone; Flt3-dependent acute myeloid leukemia; melanoma associated with mutation of skin disease; multiple myeloma; Velcade-resistant multiple myeloma; and gastrointestinal stromal tumors (GIST).

One of them features the preferred cancer is multiple myeloma and walked-resistant types of tumors, as specified above.

Inhibitory Hsp90 can also be used to treat other conditions such as viral infections, parasitic disease, autoimmune diseases, neurodegenerative disorders, inflammation, diabetes type I and II and heart disease.

Hsp90 inhibitors may have clinical benefit in transplantation and immunosuppression. Hsp90 inhibitors may have clinical benefit in the previously described diseases, when used in combination with existing or new therapeutic agents.

Based on the activities of Hsp90-client protein and experimental evidence, the following disorders may be particularly sensitive to treatment with Hsp90 inhibitors.

ErbB2-positive breast cancer, prostate, lung and stomach

Overexpression of ErbB2 (HER-2) occurs in approximately 30% of cancers of the breast, and down-regulation of ErbB2-receptor under the action of cells, Herceptin is activated to Taxol. Overexpression of ErbB2 is associated with poor prognosis and drug resistance (Tsugawa et. al., 1993, Oncology 1993; 50: 418).

Mutant EGFR for lung cancer

Somatic mutations in the kinase domain of the receptor for epidermal growth factor (EGFR), including deletions L858R and exon 19, underlie responsiveness to gefitinib and erlotinib if not elcalito.com lung cancer (NSCLC). Acquired resistance to these tyrosinekinase inhibitors in some cases mediated by the second mutation, TM. Ansamycins antibiotics, such as validamycin, strongly inhibit heat shock protein 90 (Hsp90), promotora ubicacin-mediated degradation of oncogenic kinases that require a chaperone for proper conformation and packing. Effects on EGFR-mutant cell lines validamycin induces a marked decrease in the concentration of phospho-Akt and cyclina Dl, and apoptosis. These data assume that mutational activation of EGFR is associated with dependence on Hsp90 for stability and that the inhibition of Hsp90 may represent a new strategy for the treatment of EGFR-mutant NSCLC.

Chronic myeloid leukemia

Aberrantly BCR-AbI protein is created through chromosomal translocation leads to constitutionmaking AbI kinase domain. This translocation event, as has been shown, is the cause of CML. P210BcrAbl is known client protein for Hsp90. Treatment of BCR-AbI cell line K562 inhibitor of hsp90 induces apoptosis. Bcr-Abl inhibitor Gleevec®also induces apoptosis in K562 cells; however Gleevec®-resistant K562 cells still retain sensitivity to Hsp90 inhibitors (Gorre et al. 2002, Blood 100: 3041-3044).

Prostate cancer is mediated by the androgen receptor th the Mona

Androgen-receptor kinase is an Hsp90-client protein. Usually hormonogenesis therapy is used if surgery does not eliminate the cancer. Ultimately, through a mutation in the receptor, cancer becomes resistant to the hormone analogue. Hsp90-regulation of the receptor must remain still works after mutation.

The same should be referred to estrogenzawisimy cancers of the breast.

Flt3-dependent acute myeloid leukemia (AML)

Internal doubling tyrosinekinase Flt3 receptor leads to its essential constitutive activation and oncogenesis. These internal doubling is observed in 20% of all cases of AML and are a symptom of poor prognosis. How many like activation of ABL kinase in CML, this is another example of individual genetic damage, leading to increased malignancy. Inhibitory Hsp90, as predicted, create a clinical benefit for these patients, as Flt3 is a Hsp90-client protein (Bali et al., 2004 Cancer Res. 64(10):3645-52).

Melanoma is associated with mutation of a skin disease

Skin disease encodes a serine/trionychinae that metirovan 70% of all melanomas. 80% of them are single V599E point mutation that provides increased kinase activity for skin disease. This mutation also what transforms NIH3T3 cells ( Bignell et al., 2002 Nature. 417(6892):949-54).

Multiple myeloma

The Hsp90 inhibitor 17-AAG strongly inhibits the proliferation of bortezomib-resistant cell lines of multiple myeloma. The levels on the cell surface IGF-IR and IL-6R is also reduced in the treated 17-AAG cells MM-I (Mitsiades et al., Blood 107:1092-1100, 2006). Autocrine stimulation of multiple myeloma cells, as well as paracrine stimulation of stromal bone marrow cells by the action of IL-6, also attenuated through the lower regulation of Hsp90-client IKK.

Walked-resistant multiple myeloma

Compounds of the present invention may be useful for treatment of Velcade-resistant tumor types, including treatment of patients with lymphoma mantle cell of the second line, indolent non-Hodgkin lymphoma, bronchoalveolar carcinoma IIIB and stage IV, advanced non-small cell lung cancer, cancers of the breast, prostate and ovarian cancers and non-Hodgkin lymphoma.

Gastrointestinal stromal tumor (GIST)

Disease GIST is, in particular, disease-dependent activation or overexpression of growth factor (e.g., c-kit).

Other conditions or disorders for which an inhibitor of Hsp90 may provide clinical benefit include, but without limitation:

Neurodegenerative disorders

Disease hunting is she (Huntington) (HD) is a progressive neurodegenerative disorder, which has no effective treatment. Inhibition of Hsp90 by validamycin (GA) and the resulting increase regulation of Hsp are effective in preventing protein aggregation with trochaic of Hattington in neuronal cells. (Sittler et al., 2001, Human Molecular Genetics, Vol.10, No. 12, 1307-1315). Increasing regulation of HSP may also provide clinical benefit in other diseases with incorrect folding of the protein, such as illness of Creutzfeld-Jakob(CJD) and Alzheimer's disease.

Inflammatory disease, including rheumatoid arthritis, asthma, chronic obstructive pulmonary disease and inflammatory bowel disease

As shown, validamycin (GA) releases HSF-1 of Hsp90, leading to the activation and nuclear translocation of HSF-1. HSF-1 subsequently acts as a transcription factor inducyruya HSP90 and Hsp70. Induction of Hsp70 is involved in the reduction of inflammation in induced models of edema in mice (Ianaro et al., 2004 Human Molecular Genetics, 2001, Vol.10, No. 12 1307-1315). In addition, processing validamycin inhibits the activation of the IkappaB kinase (IKK) under the action of TNF-α or PMA. IkBa is a regulator of Nf-kB and Ap-1. (Broemer et al., 2004). Ap-I and Nf-kB are the main transcription factor, leading to production of proinflammatory cytokines (Yeo et al., 2004 Biochem Biophys Res Commun. 30; 320(3):816-24). The stability of the transcripts of Pro-inflammatory cytokine is also regulated through in euromania p38Map-kinase (Wax et al., 2003. Rheumatism Vol.48. No. 2, pp. 541-550).

A disease associated with angiogenesis, including, but not limited to tumor angiogenesis, psoriasis, rheumatoid arthritis and diabetic retinopathy

Induction of angiogenesis is regulated by Hsp90-client protein eNOS and Akt in endothelial cells (Sun and Liao, 2004 Arterioscler Thromb Vase Biol. 24(12):2238-44). Suppression of hypoxia-induced factor (HIF)-1a can also damage the growth, angiogenesis and maturation of vessels of gastric tumors in mice. (Stoeltzing et. al., 2004 J Natl Cancer Inst; 96:946-956).

Diabetes type I and type II

Inhibition of Hsp90 has a strong effect on the Akt signaling, as well as e-nos. They represent two key regulator induced by high glucose concentration apoptosis of endothelial cells in type I diabetes (Lin et al., 2005 J Cell Biochem. 1; 94(1): 194-201and the development of hypertension in diabetes of II type (Kobayashi et. al., 2004 Hypertension, 44(6):956-62).

Immunosuppression and transplantation

Inhibition of Hsp90, as shown, has a downward regulation of Lck, T-cell specific tyrosinekinase required for T-cell activation (Yorgin et al., 2000 J. Immunol. 15; 164(6):2915-23).

Heart disease

Myocardial ischemia is the most common cause of death in the Western world. Hsp, and in particular Hsp70 (inducible by treatment with radicicola), is displayed on the t cardiotoxin activity in rat cardiomyocytes (Griffin et al., 2004). Inhibition of Hsp90 leads to the release of HSF-1 from the chaperone complex and its subsequent activation of Hsp genes. Inhibition of Hsp90 also leads to down-regulation of HIF-1, which is involved in the pathogenesis of coronary heart disease and stroke.

Infectious disease

Virus NS2/3 protease of hepatitis C is an Hsp90-client protein and viral processing and replication requires the activity of Hsp90 (Whitney et al., 2001, Proc. Natl.Acad. Sci USA, 20;98(24):13931-5).

Disease caused by a parasite

Validamycin (GA) showed antimalarial activity to gene-Hsp90 ortholog of Plasmodium falciparum. The growth of Plasmodium inhibited by validamycin with IC50like observed for chloroquine. GA was also effective against chloroquine-resistant strains of Plasmodium falciparum (Kamar et al., 2003, Malar. J. 15; 2(l):30).

The biological activity of the compounds according to the invention, for example as inhibitors of Hsp90, can be measured using the assays set forth in the examples below, for example, in experiments on calorimetry isothermal titration (ITC), described in example 80 and analyses antiproliferative activity described in example 81. The level of activity shown by this connection in ITC-analysis may be defined in terms of the values of Kd, and the preferred compounds of the present invention are compounds which Oia, having a value of Kdless than 1 micromoles, more preferably less than 0.1 micromoles. In the analysis of antiproliferative activity the level of activity shown by this connection in the analysis, can be defined in terms of the value of the IC50and the preferred compounds of the present invention are compounds having the value of the IC50less than 1 micromoles, more preferably less than 0.1 micromoles.

It was also discovered that many of the compounds of formula (I) have low hERG activity and a significant difference between Hsp90-suppressive activity and hERG activity.

Preferred compounds of formula (I) have values IC50against hERG that are greater than 30 times, or more than 40 times, or more than 50 times the value IC50compounds in assays of cell proliferation. Preferred compounds of formula (I) are the values of IC50against hERG, which is more than 5 μm, especially not more than 10 μm, and more preferably more than 15 μm. Some compounds according to the invention have values of IC50against hERG, which is more than 50 μm.

Compounds according to the invention have favourable properties distribution in the body (ADME) and, in particular, a better distribution in the tumor.

Methods for obtaining compounds of formula (I)

In mannarasala, as in all other sections of the present description, unless the context indicated otherwise, references to formula (I) also include all its subgroups and examples, as defined above. If you link to the group R1, R2, R3, R4, R5, R6, R10or any other group "R", the definition of the group is as described above and as described in the following sections of the present description, unless the context otherwise indicated.

The compounds of formula (I) can be obtained according to synthetic methods known to the person skilled in the art. For example, the compounds of formula (I) can be obtained by the coupling of compounds of formula (X):

or activated and/or protected form, with an amine of the formula HNR5R6in conditions suitable for the formation of amide linkages, and further, if necessary, removing any protective groups and optionally converting one compound of formula (I) into another compound of formula (I).

Amines of the formula HNR5R6are either commercially available or can be obtained using methods well known to the person skilled in the art; see, for example,Advanced Organic Chemistry, by Jerry March, 4thEdition, 119, Wiley Interscience, New York;Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volume 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).

Carboxylic acid (X) can be converted into an amide of formula (I) first, through the formation of the acid chloride by treating the carboxylic acid with thionyl chloride or interaction with oxalylamino in the presence of catalytic amounts of dimethylformamide, or interaction of the potassium salt of the acid with oxalylamino. The acid chloride can then be introduced into the reaction with the amine HNR5R6in the presence of an inert base, such as triethylamine. The reaction can be conducted at room temperature in a polar solvent such as dioxane.

As an alternative to the above chloranhydride way carboxylic acid (X) can be converted to amide (I) by reacting with an amine HNR5R6in the presence of reagents of type aminooctane commonly used in the formation of peptide bonds. Examples of such compounds include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al., J. Amer. Chem Soc. 1955, 77, 1067), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (referred to in the present description or as EDC or EDAC, but also known in this area as EDCI and WSCDI) (Sheehan et al., J. Org. Chem., 1961, 26, 2525), the reagent combination Orangevale type, such as hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU) and reagent combinations postoyalogo type, that is their as hexaphosphate 1-benzothiazolylthio(pyrrolidino)phosphonium (PyBOP) (Castro et al., Tetrahedron Letters, 1990, 31, 205). Reagents combinations, based on carbodiimide, have been used successfully in combination with 1-hydroxy-7-isobenzofuranone (HOAt) (L. A. Carpino, J. Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt) (Konig et al., Chem. Ber., 103, 708, 2024-2034). Preferred reagents combinations include EDC (EDAC) and DCC in combination with HOAt or HOBt.

The reaction mix is usually carried out in non-aqueous, aprotic solvent such as acetonitrile, dioxane, dimethyl sulfoxide, methylene chloride, dimethylformamide or N-methylpyrrolidine or in an aqueous solvent, optionally together with one or more miscible with alcohol. The reaction can be conducted at room temperature or, if the source reagents are less reactive (for example, in the case of electron anilines bearing electron-withdrawing groups, such as sulfenamidovy), with correspondingly high temperatures. The reaction can be carried out in the presence of an inert base such as a tertiary amine, such as triethylamine or N,N-diisopropylethylamine.

Illustrative route to compounds of formula (I) described in more detail below.

The compounds of formula (I), in which bentely fragment is derived from 2-hydroxy-5-substituted benzoic acid, can be obtained via the sequence of reactions shown in scheme 1.

The outcome of the second substance to the synthetic path, shown in figure 1, represents 5-chloro-2-hydroxybenzoic acid, which may be commercially available. Conversion to the acid chloride is carried out by heating with thionyl chloride. The acid chloride may be used, orin situand brought into reaction with various amines, or may be allocated in the form of a stable white solid. Other simple 2-hydroxy-5-substituted benzoic acids may be used in this method for the synthesis of other amides of 2-hydroxy-5-substituted benzoic acids.

Scheme 1: Amides of 5-chloro-2-hydroxybenzoic acid

The compounds of formula (I) can also be obtained according to the method shown in scheme 2. Starting material for the synthetic route shown in scheme 2, is a 4-Atienza, which may be commercially available. Conversion to carboxylic acid can be carried out by litvinovna at low temperature, followed by quenching of the resulting anion with solid carbon dioxide. The carboxylic acid may be subjected to reaction combination with various amines using standard reagents of type aminooctane commonly used in the formation of peptide bonds, as described above.

Unprotect simple methyl ester can be carried out with use what Itanium tribromide boron (for example, the method described inSynthesis, 1991, 469,)that gives compound of formula (I). The method, illustrated in scheme 2, can be applied to other simple 2-hydroxy-5-substituted benzoic acids, which can then be subjected to reaction combination with the corresponding amine, which gives the compounds of formula (I). The method of combining the intermediate acids with amines, aniline or aminoheterocycles compounds, with the subsequent removal of any protective groups, is immediately directed to the goal and are suitable for the synthesis of large combinatorial libraries of molecules that may be useful for the present invention. Examples of combinatorial libraries is described in theSolid-Phase Synthesis and Combinatorial Technologies by Pierfausto Seneci. Wiley-Interscience, New York, 2000, xii+637 pp. ISBN 0471331953).

Scheme 2

The compounds of formula (I) can also be obtained according to the methods described in scheme 3. Starting material, 3-tert-butyl-4-hydroxybenzoic acid (X=tert-butyl), is commercially available and can be subjected to reaction in combination with the use of reagents of aminooctane (as outlined above) with a wide range of amines of the formula HNR5R6that leads to the compounds according to the invention. The other starting material, is shown in figure 3, 3-isopropyl-4-hydroxybenzoic acid X=isopropyl), can be obtained by modification of the literature method using carbon tetrachloride and copper powder in the reaction-type Friedel-in which representatives of intermediate compounds undergo hydrolysis to the carboxylic acid (J. Chem. Soc., Chem. Commun. 1985, 1134). The way Friedel-can be applied to other simple 2-hydroxy-3-substituted benzoic acids.

Scheme 3: Amides of 3-alkyl-4-hydroxybenzoic acid

The compounds of formula (I) can also be obtained according to the method presented in scheme 4. Amide of 2,4-dihydroxy-5-isopropylbenzoic acid can be obtained by aminooctane using reagent combinations (as described above) from the protected simple dibenzylamino intermediate compounds shown in the diagram, with subsequent catalytic hydrogenation using hydrogen gas and palladium on carbon. The intermediate compound of benzoic acid, as such, is obtained by acylation according to the Friedel-Crafts methyl ester 2,4-dihydroxybenzoic acid (from commercial sources) with the use described in the literature methods (J. Ind. Chem. Soc., 1953, 30, 269,). Typically, the acylation of phenol under Friedel-Crafts conduct processing of phenol allermuir agent (such as chloramine is or acid anhydride) in the presence of Lewis acid as a catalyst (such as boron TRIFLUORIDE or aluminum chloride) or at room temperature, or at higher temperatures (60-120ºC). Benzyl protection of the phenolic groups, the Wittig reaction of the ketone with the olefin and the hydrolysis of ester (saponification) can be conducted under standard conditions, well known to experts in the field of organic synthesis (see, for example,Advanced Organic Chemistry, by Jerry March, 4thEdition, 119, Wiley Interscience, New York;Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8). For example, the Wittig reaction can be carried out in an inert polar solvent (such as tetrahydrofuran) and may include the processing of aldehyde or ketone phosphorus ylides, which can be obtained by the reaction of postnasal salt with a base (such as utility or tert-piperonyl potassium). Hydrolysis of ester to carboxylic acid is usually carried out by treatment of aqueous alkali metal hydroxide such as sodium hydroxide. The saponification reaction can be carried out with the use of organic co-solvent, such as alcohol (e.g. methanol) and the reaction mixture is usually heated to a critical temperature, for example approximately 50-60ºC.

It should be understood that other 2,4-dihydroxy-5-substituted benzoic acid can be obtained by applying this methodology to the synthesis of various examples of compounds of formula 1, not bring what the R in the present description as an example specifically.

In figure 4, as an alternative to the application of the Wittig reagent MePPH3Br for the formation of olefin (XXVI), ketone (XXV) may be subjected to interaction with methylmagnesium in the standard conditions of the Grignard reaction, which gives an intermediate gidroksosoedinenii, which then dehydration to olefin by reaction with a suitable reagent, such as sodium acetate and acetic acid.

The intermediate compound, 2,4-bis-benzyloxy-5-isopropylbenzoic acid (XXVII) and its predecessors, the compound (XXV) and (XXVI), shown in figure 4, as expected, are new and, therefore, each of the connections is another aspect of the invention.

Amide of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (XXVIII), as expected, also are novel and constitute another aspect of the invention.

Scheme 4: Amides of 2,4-dihydroxy-5-isopropylbenzoic acid

The intermediate compound, 2,4-bis-benzyloxy-5-isopropylbenzoic acid (XXVII), in figure 4, can be obtained using various methods well known to the person skilled in the art. For example, the compound (XXVII) can be obtained synthetically presented in figure 4A.

Scheme 4A

As shown in scheme 4A, 5-bromo-2,4-dihydroxybenzoic the acid will versaut basiliani using benzylbromide in the presence of a base, such as potassium carbonate, which gives the benzyl ether of bis-benzyloxypropionic acid (XXX). Ether (XXX) is then subjected to interaction with isoprenylation potassium in the presence of compounds of palladium (0) or palladium (II) and a base that gives isopropylbenzylamine ester (XXXI). The connection of palladium can be a compound of palladium(O), such as Pd(PPh3)4or a compound of palladium(II), such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The base can be an organic base, such as n-butylamine, or inorganic base such as a metal carbonate such as cesium carbonate. Reaction with isoprenylation potassium is usually carried out at the boiling point under reflux for an extended period of time, for example 15 hours or more. The resulting isopropylbenzylamine (XXXI) is then subjected to hydrolysis, which gives a carboxylic acid (XXVII), using, for example, alkali metal hydroxide such as lithium hydroxide, typically by heating to a temperature which is not critically high.

The compounds of formula (I) can also be obtained by, illustrated in scheme 5. Amides of 4-hydroxy-3-(l',2'-dimethylpropyl)benzoic acid can be obtained by aminooctane using standard reagents combinations (as in asana above) alkyl substituted acid. Itself olefinic acid can be obtained by rearrangement of Clausena preceding simple ester, as shown in the diagram by thermal rearrangement of the anisole, followed by saponification, which in this case can give more than one olefin isomer; main isomer shown in the diagram. Such reactions Clausena well known in the literature, see, for example,J. Chem. Soc, Perkin Trans. 1 1981. 897. By itself, a simple ester can be obtained by simple alkylation of commercially available ethyl ester of 4-hydroxybenzoic acid. The reaction of alkylation and saponification are simple modifications that can be performed under various conditions (see, for example,Advanced Organic Chemistry, by Jerry March, 4thEdition, 119, Wiley Interscience, New York;Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8)). It should be understood that other 4-hydroxy-3-substituted benzoic acid can be obtained by applying this methodology to the synthesis of various examples of compounds of formula 1, not shown in the present description as an example specifically.

Figure 5: Amides of 4-hydroxy-3-(l',2'-dimethylpropyl)benzoic acid

The compounds of formula (I) can also be obtained according to the method presented in scheme 6. 2,4-Dihydroxy-5-bro is benzoic acid, used as the starting material, is commercially available. Simple stage protect and unprotect lead to the predecessor benzoic acid (see, for example,Advanced Organic Chemistry, by Jerry March, 4thEdition, 119, Wiley Interscience, New York;Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8), which can be used in reactions aminooctane with a variety of amines (as described above). These intermediate amides can be subjected to reactions cross-combination Suzuki to get alkyl substituted compounds. A wide range of conditions combination Suzuki described in the literature, and the conditions used in this case, taken fromJ. Am. Chem. Soc. 2003, 11148. The reaction mix by Suzuki is also widely used in the synthesis alcylaryl and aryl-aryl compounds. The Suzuki reaction is usually carried out in the presence of a palladium catalyst such as bis(tri-tert-butylphosphine)palladium, and a base (e.g. carbonate, such as potassium carbonate). The reaction can be carried out in water solvent, e.g. aqueous ethanol, and the reaction mixture is usually subjected to heat, for example, to temperatures above 100ºC. Many boronates suitable for use in obtaining the compounds according to the invention are KOMMERCHESKIY available for example, Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc., of San Diego, USA. If boronate are not commercially available, they can be obtained by methods known in this field, for example, as described in the review ofN. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. So, boronate can be obtained by interaction of the corresponding bromoethane with alkyllithium, such as utility, and subsequent reaction with bronovil ether. Derived complex broowaha ether, if necessary, can be hydrolyzed, giving appropriate Bronevoy acid. The final products of the sequence of reactions illustrated in scheme 6, produced by the catalytic hydrogenation (as above) to remove the benzyl protective groups and for recovery of the olefin formed in the Suzuki reaction, to the alkyl substituent. It should be understood that other 2,4-dihydroxy-5-substituted benzoic acid can be obtained by applying this methodology to the synthesis of various examples of compounds of formula I that are not mentioned in the present description as an example specifically.

Scheme 6: Amides of 2,4-dihydroxy-5-(alkyl)benzoic acid

The compounds of formula (I)where the group NR5R6optionally substituted isoindoline group, such as compounds of formulas (VII) and (VIIa)can the be obtained by means illustrated in figure 7, or similar methods.

Scheme 7

As shown in scheme 7, optionally substituted 1,2-xylene (XI) is heated with N-bromosuccinimide in the presence of dibenzoylperoxide that gives dibromoethane (XII). The reaction is usually carried out in carbon tetrachloride by heating at boiling under reflux. Dibromoethane (XII) is then subjected to interaction with the connection PG-NH2where PG is a protective group, such as tosyl or parametersjpanel, in the presence of a base such as a metal hydride (e.g. sodium hydride), when PG represents tonilou group; or a carbonate of an alkali metal (e.g. sodium carbonate), if PG is parametersjpanel. The protective group PG can then be removed, which gives the amine (XIV). For example, Casilina group can be removed by heating with a mixture of phenol, Hydrobromic acid and propanoic acid, whereas parametersbodily group can be removed in the standard manner using triperoxonane acid and anisole. The amine (XIV) is then subjected to reaction in combination with a carboxylic acid of formula (X)as described above.

By varying the sequence of reactions of scheme 7, one or more functional groups, R10bpresent in protected isoindoline (XIII) or isoindoline connection with the removed protection (XIV), can be converted to other groups of R10b. For example, if the group R10bin the compound (XIV) is a nitro-group, it can be restored, which gives the corresponding amino group, for example, by catalytic hydrogenation in the presence of a catalyst, palladium on carbon. In the following example, when R10bin the compound (XIII) is a complex ester group (for example, CO2Me), it can be hydrolyzed, resulting in carboxylic acid, which can then be subjected to interaction with an amine, such as morpholine, which gives the corresponding amide. Later can be carried out with mutual transformations of functional groups (for example, the restoration of the amide to the corresponding aminomethyl compound with lithium aluminum hydride) before removing the protective group PG.

Alternative synthesis isoindoline compound (XIV) is shown in scheme 8.

Scheme 8

Starting material for scheme 8 is altogether (XV), which is subjected to hydrolysis to the corresponding dicarboxylic acid (XVI) using a hydroxide of alkali metal such as potassium hydroxide, before cyclization to phthalic anhydride (XVII) interaction with acetic anhydride. Phthalic anhydride (XVII) can be change is in the appropriate phthalimide (XVIII) interaction with formamide at elevated temperature (for example, approximately 210ºC). Phthalimide (XVIII) can then be restored to isoindoline (XIV) with an appropriate reducing reagent such as borane in tetrahydrofuran (THF).

The compounds of formula (VIIb), as defined above, can be obtained by the coupling of compounds of formula (XIX) or its protected derivative with a compound of formula (XX):

where n, R3, R4a, R8and R10ccare as defined above, in the amide formation conditions as described above and in the examples.

Many of the compounds of formula (XX) are novel and as such form another aspect of the invention. So, in this aspect, the invention provides a compound of formula (XX), but excluding any and all connections, known as such in the prior art.

Within formula (XX), a separate intermediate compounds according to the invention can be represented by the formula (XXI):

where n is 0 or 1; M is N or CHOH and R25represents a hydrogen atom or methyl; provided that when n is 0 and R25represents methyl, M represents CHOH.

Separate intermediate compounds within formula (XXI) are the compounds (XXII), (XXIII) and (XXIV) below.

Sub is full of compounds of formula (XXI) can be obtained by means well-known specialist in this field or similar ways. For example, the intermediate compound XXII can be obtained by exchange of the halogen on the lithium in the corresponding N-protected 5-promisingly, damping 1-methyl-4-piperidone and subsequent removal of the protection. Intermediate compound XXII can be obtained with palladium combination by Buchwald (Buchwald) 4-BOC-piperazine and the corresponding N-protected 5-promisingly, with subsequent removal of the protection. One way to obtain the intermediate compound XXIV involves the formation of amide Weinrebe (Weinreb) from an appropriately N-protected isoindole-5-carboxylic acid, the recovery of the aldehyde followed by reductive amination and subsequent removal of the protection.

After receipt, if the group of substituents, one compound of the formula (I) or a protected form can be converted into another compound of formula (I).

For example, when R1and R2both are protected hydroxy-group (for example, benzyloxy), and R3represents bromine, the bromine atom can be substituted by trifluoromethyl, by interaction with triptoreline salt (for example, trifurcation sodium) and copper iodide (I) in a polar solvent such as dimethylformamide (DMF). According to another method the compounds of formula (I), where R8 represents fluorine, can be obtained from compounds of formula (I), where R8represents a hydrogen atom, electrophilic fluorination. Electrophilic fluorination can be carried out using a fluorinating reagent, such as bis(tetrafluoroborate) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane or similar N-fordisney connections.

According to the following procedure the compounds of formula (I), where R1and R2both represent a hydroxy-group, can be subjected to monomethylamine that gives compound, where one of R1and R2represents a methoxy group, interaction with one equivalent meteorologi reagent, such as dimethylsulfate. The methylation reaction is usually carried out in a polar solvent such as acetonitrile, in the presence of a base, for example, carbonate of alkaline metal such as potassium carbonate. Similar methylation reaction can also be conducted at the intermediate compounds containing two phenolic hydroxy-group.

Many of the techniques described below and used in this synthesis are well known to specialists in this field, as well as examples of alkylation, acylation, mutual transformations of functional groups; reagents and conditions for such transformations can be found, for example, inAdvanced Organc Chemistry, by Jerry March, 4thEdition, 119, Wiley Interscience, New York;Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).

It should be understood that modifications of the described ways, as well as specific examples and methods of obtaining below give the possibility of the synthesis of numerous additional examples of compounds claimed in the formula 1. For example, can be obtained from an alternate source substances for benzoic acid with different or additional replacement parts.

In numerous reactions described above, it may be necessary to protect one or more groups to prevent passage of the reaction in an undesirable position of the molecule. Examples of protective groups, ways to protect and unprotect for functional groups, can be found inProtective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

The hydroxy-group may be protected, for example, in the form of simple ether (-OR) or of ester (-OC(=O)R), such as a simple tert-butyl ether; a simple benzyl, benzhydryl (diphenylmethylene) or tritherapy (triphenylmethyl) ether; simple trimethylsilyloxy or tert-butyldimethylsilyloxy ether; or acetyloxy ester (-OC(=O)CH3, -OAc). When the hydroxy-group represents a phenolic hydroxy-group, e.g. the in compounds of formula (I), where R1and/or R2represent hydroxy, preferred protecting group is a benzyl group.

Aldehyde or ketone group may be protected, for example, in the form of acetal (R-CH(OR)2or Catala (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to W (>C(OR)2), by reaction with, for example, a primary alcohol. Aldehyde or ketone group is easily regenerated by hydrolysis using a large excess of water in the presence of acid. The amino group may be protected, for example, in the form of an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: methylamide (-NHCO-CH3); benzylacetone (-NHCO-OCH2C6H5.-NH-Cbz); as tert-butoxide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxylated (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), 9-fluorenylacetamide (-NH-Fmoc), as a 6-nitroferricyanide (-NH-Nvoc), as a 2-trimethylsilylmethylamine (-NH-Teoc), as a 2,2,2-trichloroacetamide (-NH-Troc), as Alliaceae (-NH-Alloc) or as 2-(phenylsulfonyl)ethylacetamide (-NH-Psec). Other protective groups for amines, such as cyclic amines and heterocyclic N-H groups include toluensulfonyl (tselnye) and methanesulfonamide (mesil/methylsulfonyl) groups and benzyl groups, such as parametersbodily (PMB) group. Carboxilate group which may be protected in the form of ester, for example, as: complex C1-7alkilany ester (e.g. methyl ester; tert-butyl ether); complex C1-7 gallogeneically ether (for example, C1-7 tregularizability ether); complex three-C1-7alkylsilane-C1-7alkilany ether; or complex C5-2Oaryl-C1-7alkilany ether (for example, benzyl ether; nitrobenzyloxy ether); or in the form of an amide, for example methylamide. Tolna group may be protected, for example, in the form of tiefer (-SR), for example, as a simple benzyl thioether; simple acetamidomethyl thioether (-S-CH2NHC(=O)CH3).

How to clean

The compounds may be isolated and purified in a number of ways, well known to experts in this field, and examples of such methods include chromatographic techniques such as column chromatography (for example, flash chromatography) and HPLC. Preparative LC-MS is a standard and effective method for the purification of small organic molecules, such as described in the present description of the connection. Methods of liquid chromatography (LC) and mass spectrometry (MS) can be changed to provide better separation of the crude substances and improved detection method of mass spectroscopy. Optimization method preparative gradient liquid chromatography involves a change of speakers, volatile ale is new, modifiers and gradients. In this area is well known methods of optimization of preparative methods for LC-MS and their subsequent use for cleansing compounds. Such methods are describedRosentreter U, Huber U.; Optimal fraction collecting in preparative LC/MS; J. Comb. Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C, Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J. Comb. Chem.; 2003; 5(3); 322-9.

Alternatively, methods based on preparative liquid chromatography normal phase can be used instead obetovannim methods. Most preparative systems LC-MS using liquid chromatography reverse phase and volatile acid modifiers, as this approach is very effective for the purification of small molecules and used eluent compatible with mass spectrometry by elektrorazpredelenie with positive ions. Other chromatographic solutions, such as liquid chromatography, normal phase, alternative buffered mobile phase, the main modifiers, etc. as specified in the analytical methods described above can be used for alternative cleaning compounds.

The pharmaceutical composition

While active compound may be administered one, and preferably it is present in the pharmaceutical compo is icii (for example, the drug containing at least one active compound according to the invention together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other substances known to experts in this field, and optionally other therapeutic or prophylactic agents; for example, agents that reduce or alleviate some of the side effects associated with chemotherapy. Specific examples of such agents include antiemetic agents and agents that prevent or reduce the duration of neutropenia associated with chemotherapy, and prevent complications that arise due to low levels of red blood cells or white blood cells; for example, erythropoietin (EPO), granulocyte/macrophage-colony stimulating factor (GM-CSF) and granulocyte-colony stimulating factor (G-CSF).

Thus, the present invention further is a pharmaceutical composition, as defined above, and methods for producing pharmaceutical compositions, comprising mixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, is adjuvantly, stabilizers or other substances, as described above.

The term "pharmaceutically acceptable", as used in the present description, refers to compounds, substances, compositions and/or dosage forms which are, within announced medical diagnosis suitable for use in contact with tissues of the patient (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, which corresponds to an acceptable value benefit/risk. Each carrier, excipient, etc. must also be "acceptable" in the sense of compatibility with other components of the composition. According to this, in the following aspect, the invention provides compounds of formula (I) and its subgroups, as defined above, in the form of pharmaceutical compositions.

The pharmaceutical compositions can be in any form suitable for oral, parenteral, local, intranasal, ocular, aural, rectal, intravaginal, or percutaneous administration. If the compositions are intended for parenteral administration, they can be formulated in a composition for intravenous, intramuscular, intraperitoneal, subcutaneous injection, or for direct delivery to the target organ or tissue by injection, infusion or other means of delivery. Delivery may be PU is eat bolus injection, short-term infusion or continuous infusion and may be carried out by passive delivery or through the use of acceptable infusion pump.

Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile solutions for injection, which may contain antioxidatic, buffers, bacteriostatic, co-solvents, organic solvent mixture, cyclodextrine complex agents, emulsifying agents (for the formation and stabilization of emulsion preparations), liposomal components for the formation of liposomes, gelling polymers for the formation of polymer gels, protective equipment for lyophilization and combinations of agents for, among other things, stabilize the active component in soluble form and bring the drug to isotonicity with the blood of the intended recipient. Pharmaceutical preparations for parenteral administration may be in the form of aqueous and non-aqueous sterile suspensions that can include suspendresume agents and thickening agents (R.G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol. 21(2) 2004, p. 201-230).

The molecule drugs, which is insuetus, can be dissolved to the desired concentration by adjusting the pH, if pKamedicines DOS is enough deviates from the pH value of the drug. The acceptable pH range is 2-12 for intravenous and intramuscular injection, but subcutaneous pH range is 2.7 and 9.0. the pH of the solution is adjusted, or by salt forms of drugs, strong acids/bases, such as hydrochloric acid or sodium hydroxide, or solutions of buffers, which include, but without limitation, buferiruemoi solutions derived from glycine, citrate, acetate, maleate, succinate, histidine, phosphate, Tris(hydroxymethyl)aminomethane (TRIS) or carbonate.

The combination of aqueous and water-soluble organic solvent/surfactant (i.e. co-solvent) is often used in injectable preparations. Water-soluble organic solvents and surfactants used in injectable formulations include, but without limitation, propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP; Pharmasolve), dimethylsulfoxide (DMSO), Solutol HS 15,

Cremophor EL, Cremophor RH 60, and Polysorbate 80. Such drugs usually can be, but not always diluted before injection.

Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, and Polysorbate 80 are organic completely miscible with water, solvents and surface-active substances is STV, used in commercially available injectable drugs and can be used in combination, each, with each other. The obtained organic drugs are usually bred at least twice before i.v bolus. infusion or i.v infusion.

Alternatively, the increased solubility can be achieved through the formation of a molecular complex with the cyclodextrins.

Liposomes are closed spherical vesicles formed from the outer lipid bilayer membranes and internal aquatic centre with a total diameter of <100 μm. Depending on the level of hydrophobicity of moderately hydrophobic drugs can be converted into soluble form via liposomes, if the drug is encapsulated or intercalaries in the liposome. Hydrophobic drugs can also be solubilisation via liposomes, if the molecule drugs is a component of lipid bilayer membranes, and in this case, the hydrophobic drug is dissolved in the lipid portion of the lipid bilayer. Specific liposomal drug contains water with phosopholipid at a concentration of 5-20 mg/ml, giving isotonicity agent, a buffer with a pH of 5-8 and optional cholesterol.

Drugs can be supplied in containers with a single dose or mnojestvom, for example sealed ampoules and vials, and can be stored in dried by freezing (liofilizirovannom) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use.

The pharmaceutical preparation may be obtained by lyophilization of the compounds of formula (I) or its acid additive salts. Lyophilization relates to a method of drying a composition by freezing. Drying by freezing and lyophilization, therefore, used in the present description as synonyms. Specific method to solubilize compounds is that the resulting composition is clean, sterile filtered, transferred into sterile containers, suitable for lyophilization (e.g., bubbles). In the case of bubbles partially close the freeze plugs. The product can be cooled to freezing and subjected to freeze-drying under standard conditions, and then hermetically sealed with stable, freeze dry product. The composition typically has a low residual water content, for example less than 5%, for example less than 1% by weight, based on the weight of the lyophilisate.

The composition for lyophilization may contain other excipients, such as thickening agents, dispersing agents, buffers, antioxidants, preservatives and regulators toychest. To ncrete buffers include phosphate, acetate, citrate, and glycine. Examples of antioxidants include ascorbic acid, sodium bisulfite, sodium metabisulfite, monothioglycerol, thiourea, bottled hydroxytoluene, bottled hydroxyanisol and salts of ethylenediaminetetraacetic acid. Preservatives may include benzoic acid and its salts, sorbic acid and its salts, alkalemia esters by parahydroxybenzoic acid, phenol, chlorobutanol, benzyl alcohol, thimerosal, benzylaniline and cetylpyridinium. The buffers listed above, as well as dextrose and sodium chloride, can be used to adjust toychest, if necessary.

Agents for giving of volume commonly used in the technology of freeze-drying to facilitate and/or provide volume, and/or mechanical integrity of the lyophilisate. Agent for imparting means unlimited amount of water-soluble, granular solid diluent, which, when together liabilitiesa with the compound or its salt that provides physical stability of freeze-dried, more optimal process of freeze-drying and quick and full recovery of the moisture content. Agent to add volume can also be used to make the solution isotonic.

A water-soluble agent to add volume may be any of farmatsevticheskii inert solids, usually used for lyophilization. Such agents to add volume to include, for example, sugars such as glucose, maltose, sucrose and lactose; a polyalcohol such as sorbitol or mannitol; amino acids such as glycine; polymers, such as polyvinylpyrrolidine; polysaccharides, such as dextran.

The ratio of the mass of the agent to add volume to the weight of active compound is typically within the range of from about 1 to about 5, for example from about 1 to about 3, for example in the range of about 1-2.

Alternatively, they can be provided in the form of a solution, which can be concentrated and sealed in an appropriate ampoule. Sterilization dosage forms can be carried out by filtration or by heating in an autoclave vials and their contents at appropriate stages of the process of obtaining the drug. Supplied the drug may require, prior to delivery, the further cultivation or preparation of, for example, breeding in suitable sterile infusion bags.

Prepared injectable solutions or suspensions for immediate introduction can be obtained from sterile powders, granules and tablets. In one preferred embodiment of the invention the pharmaceutical composition is in a form suitable for intravenous (i.v) injection, for example by injection or infusion.

In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) introduction.

Pharmaceutical dosage forms acceptable for oral administration include tablets, capsules, caplet, pills, cakes, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, plates or cheek patches and the patches.

Pharmaceutical compositions containing the compounds of formula (I), can be formulated according to known methods, see, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Thus, the preformed composition may contain a single dose of the active compound together with an inert diluent or carrier, such as sugar or sugar alcohol, for example lactose, saccharose, sorbitol or mannitol; and/or is not derived from sugar diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as methylcellulose, ethylcellulose, hypromellose, and starches such as corn starch. Tablets may also contain such standard components as a binder and granulating agents, such as polyvinylpyrrolidone, dezintegriruetsja agents (e.g., capable of swelling the Popper is but-crosslinked polymers, such as cross-linked carboxymethyl cellulose), lubricants (for example, stearates), preservatives (e.g. parabens), antioxidants (such as BHT), buferiruemoi agents (e.g., phosphate or citrate buffers) and foaming agents, such as citrate/bicarbonate mixture. Such excipients are well known and there is no need to discuss them in detail.

Encapsulated drugs can be in the form of hard gelatin or soft gelatin capsules can contain the active ingredient in solid, semisolid, or liquid form. Gelatin capsules can be made from animal gelatin or synthetic or cash equivalents of vegetable origin.

Solid dosage forms (e.g. tablets, capsules etc) can be covered or uncovered, but, as a rule, have a coating, e.g. a coating of a protective film (for example, wax or varnish or coating that controls the release. Floor (for example, type polymer Eudragit™) can be designed to release the active component in the desired location within the gastrointestinal tract. Thus, the coating can be chosen in such a way as to decompose under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the connection in the stomach, or in the ileum, or Dvenadtsat the duodenal ulcer.

Instead of or in addition to coating, the drug may be provided in a solid matrix comprising the agent that controls the release, such as an agent, delaying the release, which can be adapted for selective release of the connection in the variable conditions of acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or coating that slows the release may take the form of easily erodible polymer (for example, a polymer of maleic anhydride), which essentially continuously decomposes as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound may be formulated in a delivery system, which provides the osmotic control of release of connection. Drugs osmotic release and another delayed or slow release can be prepared according to methods well known to specialists in this field.

Pharmaceutical drugs can be given to the patient in the packages of the patient containing the full course of treatment in one package, usually a blister pack. Packages the patient have an advantage compared to traditional methods, where the pharmacist selects the patient portion pharmaceutical pre the Arata from bulk kit that the patient always has access to the advertising liner contained in the package of the patient, usually missing in prescriptions for the patient. The inclusion of advertising liner, as shown, improves patient compliance with the instructions of the treating physician.

Compositions for local administration include ointments, creams, sprays, patches, gels, liquid drops and tabs (for example, intraocular tab). Such compositions can be formulated according to known methods.

Compositions for parenteral administration are typically provided as a sterile aqueous or oily solution or fine suspension, or can be provided in a highly dispersed form of sterile powder for unplanned cooking injection with sterile water.

Examples of drugs for rectal or intravaginal injection include pessaries and suppositories, which can be, for example, made from a shaped molded or waxy material containing an active connection.

Compositions for administration by inhalation may be in the form of inhalation powder compositions or fluids or powder sprays, and can be put into standard form using devices powder inhalations or aerosol devices dosing. Such devices are well known. For administration by which galazii, powder preparations generally contain the active compound together with an inert solid powder diluent, such as lactose.

The compounds of formula (I) will usually be provided in unit dosage form and, as such, will contain the connection is sufficient to provide a desired level of biological activity. For example, the preparation may contain from 1 nanogram to 2 grams of active ingredient, for example from 1 nanogram to 2 milligrams of the active ingredient. Within the specified range of the particular sub-bands for compounds comprise from 0.1 milligrams to 2 grams of active ingredient (more specifically from 10 milligrams to 1 gram, for example from 50 milligrams to 500 milligrams), or 1 micrograms to 20 milligrams (for example from 1 microgram to 10 milligrams, for example, from 0.1 milligrams to 2 milligrams of the active component).

For oral compositions, unit dosage form can contain from 1 milligram to 2 grams, more specifically from 10 milligrams to 1 gram, for example from 50 milligrams to 1 gram, for example from 100 milligrams to 1 gram of active connections.

The active compound will be administered to a patient in need this (for example, a person or an animal), in a quantity sufficient to achieve the desired therapeutic EF is known.

Treatment

It is expected that the compounds of formula (I) and sub-groups, as defined above, can be useful in the prevention or treatment of a number of disease conditions mediated by Hsp90-client protein. Examples of such diseases and conditions above.

Usually the compounds administered to a subject in need of such introduction, for example, a person or an animal, preferably a human.

The compounds are usually administered in amounts that are therapeutically or prophylactically useful and which, as a rule, are non-toxic. However, in certain situations (for example, in the case of life-threatening diseases), the benefits of introducing the compounds of formula (I) can outweigh the harm from any toxic effects or side effects, in this case, it may be considered desirable to introduce compounds in quantities that are associated with toxicity level.

The compounds may be introduced in the long term to maintain a favorable therapeutic effect or may be imposed only for a short time. Alternatively, they can be entered in a pulsed or continuous manner.

A daily dose of the compounds of formula (I) may be in the range from 100 picograms to 100 milligrams per kilogram body weight, more specifically from nanograms to 25 milligrams per kilogram of body weight, and most specifically from 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more specifically from 1 microgram per kilogram to 20 milligrams per kilogram, for example, from 1 microgram to 10 milligrams per kilogram) per kilogram of body weight, although, if necessary, may be entered higher or lower dose. The connection may be administered daily or repetitive manner, such as every 2 or 3 or 4 or 5, or 6, or 7, or 10, or 14, or 21, or 28 days.

In one particular graph dosing the patient will receive an infusion of connections for periods of one hour daily for up to ten days, in particular up to five days in one week, and the treatment is repeated after the desired time interval, such as two to four weeks, in particular every three weeks.

More specifically, the patient may receive an infusion of connections for periods of one hour daily for 5 days and the treatment will be repeated every three weeks.

In another special schedule of dosing, the patient receives an infusion within 30 minutes to 1 hour, then stored infusion of variable length, for example from 1 to 5 hours, for example 3 hours.

The following special schedule of dosing the patient receives continuous infusion over a period from 12 hours to 5 days, cha is in the surrounding area continuous infusion for 24 hours to 72 hours.

Ultimately, however, the number of established connections and the type of songs will be correlated with the nature of the disease or physiological condition that is being treated and will be at the discretion of the treating physician.

Compounds as defined above, can be entered as a separate therapeutic agent or they can be introduced in combination therapy with one of more other compounds for treatment of specific painful conditions such as neoplastic diseases, such as cancer, as defined above.

Examples of other therapeutic agents or treatments that can be implemented jointly (simultaneously or at different time intervals) with the compounds of formula (I)include, but without limitation:

Inhibitors of topoisomerase I;

Antimetabolites;

Tubulin-targeting agents;

DNA-binding and topoisomerase II inhibitors;

Alkylating agents;

Monoclonal antibodies;

Antihormone drugs;

Inhibitors of signal transduction;

Proteosome inhibitors;

DNA methyltransferase;

Cytokines and retinoids

The chromatin-targeted therapy, for example, modulators of HDAC or HAT;

The radiotherapy.

For the case of Hsp90 inhibitors combined with other therapies, two or more methods of treatment, the Oia can be assigned individually changing the schedule of dosing and in different ways.

If the compound is administered in combination therapy with one, two, three, four or more other therapeutic agents (preferably one or two, more preferably one), the compounds can be administered simultaneously or sequentially. The sequential introduction they can be entered in closely spaced time intervals (for example, during the period of 5-10 minutes) or longer intervals (e.g., after 1, 2, 3, 4 or more hours, or after even longer periods if required), the exact dosage will be consistent with the properties of therapeutic agent(s).

Compounds according to the invention can also be administered in combination with negitiations therapies, such as radiotherapy, photodynamic therapy, gene therapy; surgical intervention and controlled diets.

For use in combination therapy with other chemotherapeutic agent connection and one, two, three, four or more other therapeutic agents can be, for example, formulated together in a unit dosage form containing two, three, four or more therapeutic agents. Alternatively, individual therapeutic agents can be formulated separately and supplied in the form of a kit, optionally with instructions for their skin is of.

The specialist in this area generally known, according to his or her General knowledge, dosing regimens and combination therapy for use.

The diagnostic methods

Before the introduction of the connection, the patient may be examined to determine whether a disease or condition that the patient is suffering or likely to suffer, which is susceptible to treatment with a compound having activity against Hsp90.

For example, a biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, which the patient suffers, or may suffer, therefore, characterized by a genetic abnormality or abnormal protein expression which leads to mutation or overactivate Hsp90-client protein. Examples of such anomalistic that lead to activation of the Hsp90-client protein include Bcr-ABL translocation, Flt-3 internal duplication and mutation of a skin disease or overexpression of ErbB2.

Thus, the patient may be subjected to a diagnostic test to detect a marker characteristic of increasing regulation. The term "diagnosis" includes the examination. The term "marker" includes genetic markers including, for example, the measurement of the composition of DNA to identify a skin disease mutations, BCR-abl and Flt3 or other damaged Bel client is offering. The term "marker" includes proteins such as ErbB2, including the level or concentration of the protein or fragments or product degradation and, for enzymes, the enzymatic activity. Protein (e.g., phosphorylated or not) and mRNA levels of the aforementioned proteins can be evaluated for the characteristics of the activity change. For example, the level of phosphorylated AKT may be an indicator of sensitivity to HSP90 inhibitors.

Diagnostic tests are usually conducted on a biological sample selected from, for example, samples of tumor biopsies, blood samples (isolation and enrichment of tumor cells dropout), biopsies, stool, sputum, chromosomal analysis, pleural fluid, peritoneal fluid, buccal scrapings or biopsy, or from the urine.

The screening process usually involves direct sequencing, oligonucleotide analysis or analysis of protein microchip, proteomic analysis of mass spectrometry or determination using specific antibodies.

Methods of identification and analysis of mutations and activation of proteins is well known to specialists in this field. Methods of screening may include, but without limitation, standard methods, such as obratitsyasya-polymerase chain reaction (RT-PCR), hybridizationin situor Western blot turns.

In the screening method of RT-PCR the mRNA level in the tumor appreciate by creating copies of the cDNA to mRNA, followed by amplification of cDNA by PCR. Methods PCR amplification, primers and amplification conditions known to specialists in this field. Manipulation of nucleic acid and PCR carried out by standard methods, as described, for example,Ausubel, F.M. et al., eds. in Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et al., eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001, 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, it may be used commercially available kit for RT-PCR (e.g., Roche Molecular Biochemicals) or methodology, which is described in U.S. patent 4666828; 4683202; 4801531; 5192659, 5272057, 5882864 and 6218529 and incorporated herein by reference.

An example of a method of hybridizationin situto assess the mRNA expression is fluorescent hybridizationin situ(FISH) (seeAngerer, 1987 Meth. Enzymol., 152: 649).

Typically, hybridization ofin situincludes the following basic stages: (1) immobilization of the analyzed tissue; (2) pre-hybridization treatment of the sample to enhance the accessibility of the target nucleic acid and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids with the nucleic acid in biological structures is or tissue; (4) postliberalization washing to remove nucleic acid fragments not bound in the hybridization and (5) identification of hybridized nucleic acid fragments. Samples used in such applications are usually labeled, for example, radioisotopes or fluorescent reporters. Preferred samples are quite long, for example, from about 50, 100, or 200 nucleotides approximately 1000 or more nucleotides, to allow specific hybridization with the target nucleic acid(s) in harsh environments. There are also commercially available FISH probes for cytogenetic chromosome rearrangements that can be applied for detection of Flt3 and Bcr-Abl translocations in populations of leukemic cells. Standard methods for FISH describedAusubel, F.M. et al., eds. in Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

The described methods for the analysis of gene expression (DePrimo et al., BMC Cancer 2003. 3:3). Briefly, the Protocol is as follows: double-strand cDNA synthesized from total RNA using (dT)24 oligomer to premirovany synthesis of the first cDNA strands, followed by synthesis of the second cDNA strands with randomized open trial) the data review of the primers. Double-strand cDNA is used as a model for in vitro transcription joint Norwegian-Russian fishe with the use of biotinylated ribonucleotides. joint Norwegian-Russian fishe chemically fragmenting according to described protocols (Affymetrix, Santa Clara, CA, USA) and then hybridized during the night using the Human Genome Arrays.

Alternatively, the protein products expressed from mRNA, can be studied by immunohistochemistry of tumor samples, solid-phase immunoassay with microtiter tablets, Western blotting, two-dimensional electrophoresis on SDS-polyacrylamide gel, ELISA, flow cytometry and other methods known in this field to identify specific proteins. Methods definition should include the use of site-specific antibodies. The person skilled in the art it will be clear that all such well-known methods for determining "the Philadelphia chromosome" testify to the BCR-ABL translocation.

Therefore, all of these techniques can also be applied for the identification of tumors, especially suitable for treatment with the compounds according to the invention.

EXAMPLES

The invention will be further illustrated, but not limited to, reference to specific embodiments of described in the following examples.

In the examples can be used the following abbreviations:

AcOH acetic acid,

BOC tert-butyloxycarbonyl,

Bn benzyl,

CDI 1,1-carbonyldiimidazole,

DMAW90 Mixture of solvents: DCM:MeOH:AcOH:H2O(90: 18:3:2),

DMAW120 Mixture of solvents: DCM:MeOH:AcOH:H2O(120:18:3:2),

DMAW240 Mixture of solvents: DCM:MeOH:AcOH:H2O(240:20:3:2),

DCM, methylene chloride,

DMF dimethylformamide,

DMSO dimethyl sulfoxide,

EDC 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide,

Et3N triethylamine,

EtOAc ethyl acetate;

Et2O diethyl ether,

h hour(s)

HOAt 1-gidroksibenzotriazola,

HOBt 1-hydroxybenzotriazole,

MeCN acetonitrile,

MeOH methanol,

min minutes

P.E. petroleum ether,

K.T. room temperature,

SiO2silicon oxide,

TBTU tetrafluoroborate N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)Urania,

THF tetrahydrofuran.

Proton nuclear magnetic resonance spectrum (1H-NMR) were measured on the instrument Bruker AV400 operating at 400,13 MHz in DMSO-d6or MeOH-d4(where specified) at 27ºC, unless other terms, and in the following format: chemical shift δ/ppm (number of protons, multipletness denoted as s=singlet, d=doublet, t=triplet, square=Quartet, m=multiplet, usher.=broadened). As internal standard used residual proton solvent.

In the examples, the compounds obtained were characterized using liquid chromatography and mass is spektroskopii using systems and working conditions, mentioned below. If there were atoms of different isotopes and the individual mass, mass, provides for the connection is a monoisotopic mass (that is,35Cl;79Br and so on). Used various systems, as described below, and they were supplied with equipment and were prepared to conduct in such close conditions. Used conditions are also described below.

Description of systems:

System 1 (analytical system):

The HPLC system: Waters 2795;

The detector of the mass spectrograph: Micromass Platforma LC;

The PDA detector: Waters 2996 PDA;

System 2 (preparative and analytical system):

System HPLC system Waters Fractionlynx;

The detector of the mass spectrometer: Waters ZQ;

PDA Detector: Waters 2996 PDA;

System 3 (preparative and analytical system):

System HPLC system Agilent 1100;

The detector of the mass spectrometer: LC/MSD;

UV Detector: Agilent MWD;

Conditions:

Acidic analytical conditions:

Eluent A: H2O with 0.1% formic acid);

Eluent B: CH3CN (0,1% formic acid);

Gradient: 5-95% eluent B over 3.5 minutes (within 15 minutes w/column 2);

Flow: 0.8 ml/min;

Column 1: Phenomenex Synergi 4µ MAX-RP 8OA, 2,0×50 mm;

Column 2: Phenomenex Synergi 4µ MAX-RP 8OA, 2,0×150 mm;

Alkaline analytical conditions:

Eluent A: H 2O (10 mm NH4HCO3buffer, brought to pH=9,2 NH4OH);

Eluent B: CH3CN;

Gradient: 5-95% eluent B over 3.5 minutes;

Flow: 0.8 ml/min;

Column: Phenomenex Gemini 5µ of 2.0×50 mm;

Mass spectroscopic conditions (Waters Systems):

The voltage on the capillary: 3.6 kV (3,40 kV on ES negative);

The cone voltage: 25V;

The evaporator temperature: 120ºC;

Scanning range: 125-800 amu;

The ionization mode: Elektrorazpredelenie positive ions, negative ions or positive and negative ions;

Mass spectroscopic conditions (Agilent Systemss):

The voltage on the capillary: 4000 (W on ES negative);

Fragmentation/transfer rate: 150/1;

Drying gas (temperature/flow rate): 350ºC/13,0 l/min;

The pressure in the sprayer: 50 psi (pounds per square inch);

Scanning range: 125-800 amu;

The ionization mode: elektrorazpredelenie positive ions or negative ions.

Source materials for each of the examples were commercially available unless otherwise indicated.

A. General synthetic methods

In the following General ways these amounts can vary according to the scale of the response that will be obvious to a specialist in this field.

Method A1

Aminooctane (chloranhydride method)

A mixture of carboxylic acid (1 equivalent) and tion is chloride (1.5 equivalent) in benzene (or toluene) was stirred and kept at the boiling point under reflux for 2 hours. Was added dropwise an excess of amine to the hot solution and the mixture was stirred at room temperature for 15 minutes. Alternatively, the acid chloride of the acid can be isolated by evaporation and then re-dissolved in a mixture of methylene chloride:triethylamine 9:1; then added amine and the mixture was stirred in nitrogen atmosphere at room temperature for 1-18 hours. In another case, the mixture was diluted with ethyl acetate and extracted successively with water, saturated aqueous sodium bicarbonate and 2M hydrochloric acid. The organic layer was evaporated to dryness in vacuum and clean products received or rubbing in ethyl acetate, or column chromatography on silica gel (elution with mixtures of ethyl acetate in petroleum ether), or in some cases preparative HPLC/MS.

Method A2

Aminooctane (way with EDC, HOBt)

Mix a solution of acid (1 equivalent) in methylene chloride (10 ml) was treated sequentially hydrochloride N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents), 1-hydroxybenzotriazole (1.2 equivalents) and amine (1.5 equivalents) and the mixture was stirred at room temperature overnight. The mixture was washed successively 2M hydrochloric acid and 2M sodium hydroxide, the organic layer was separated and the solvent was removed in vacuo, giving the product of the s. Products received or pure or purified column chromatography on silica gel (elution with mixtures of ethyl acetate in petroleum ether or methanol in ethyl acetate, respectively).

Method A3

Dialkylamino simple antolovo or benzyl ester (method with BBr3)

Stir the solution is simple antolovo or benzyl ester (1 equivalent) in methylene chloride at 0 was treated dropwise 1M solution tribromide boron in methylene chloride (1.5 equivalents the group that you want) and the mixture was stirred for 2 hours. The reaction was suppressed by the addition of water and saturated aqueous sodium bicarbonate, the organic layer was separated and the solvent was removed in vacuum. Pure products were obtained, or by trituration in diethyl ether or ethyl acetate or column chromatography on silica gel (elution with mixtures of ethyl acetate in petroleum ether).

Method A4

Aminooctane (way with EDC, HOAt)

Mix a solution of acid (1 equivalent) in dimethylformamide (5 ml) was treated sequentially hydrochloride N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents), 1-hydroxy-7-isobenzofuranone (1.2 equivalent) and the amine (1.5 equivalents) and the mixture was stirred at room temperature overnight. DMF was evaporated, the crude residue was dissolved in EtOAc and washed the sequentially with saturated sodium bicarbonate, the organic layer was separated and the solvent was removed in vacuum. Products received or pure or purified column chromatography on silica gel (elution with mixtures of ethyl acetate in petroleum ether or methanol in ethyl acetate, respectively).

The way A5

Hydrogenation

Stir a solution of the protected derivative (1 equivalent) and a catalytic amount of 10% palladium on carbon (specifically 30-50 mg) in ethanol (5-10 ml), methanol (5-10 ml) or methanol/DCM (3 ml/3 ml) was stirred at room temperature in a hydrogen atmosphere for 2-16 hours. The catalyst was removed by filtration, washed with methanol (5 ml) and the solvent was removed in vacuo, the resulting products. Sometimes needed to clean flash chromatography, the elution is usually performed by a simple ether.

Method A6

The combination of Suzuki

Arilbred (1 equivalent, specifically, 0.5 mmol), baronova acid or vinylphosphonate of thriftimart potassium (1.2 equivalent) and cesium carbonate (3 equivalents) was dissolved in THF (10 ml) under nitrogen atmosphere. Added dichloride, 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.1 equivalent), then water (1 ml). The mixture began to darken until it became black. Then the mixture was heated at boiling under reflux in a nitrogen atmosphere until completion of the reaction (8-45 hours). The mixture was cooled, once alali DCM was added magnesium sulfate. The mixture was filtered and the solvent was evaporated. The obtained residue was purified with flash chromatography in the mixtures of petroleum ether/simple ether, and that usually resulted in a product with a good yield (~60-80%).

The way A7

Mono-O-methylation of resorcinol

Dimethylsulfate (1 equivalent) was added to a stirred solution of resorcinol (1 equivalent) and potassium carbonate (2.2 equivalents) in acetonitrile (10 ml per mmol of substrate) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo, the residue was distributed between methylene chloride and water, the organic layer was separated and the solvent was removed in vacuum. Pure products were obtained or after column chromatography on silica gel (elution with mixtures of petroleum ether and ethyl acetate) or preparative HPLC/MS.

Method A8

Electrophilic aromatic fluorination

Bis-tetrafluoroborate 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane (1 equivalent) was added to the substrate solution (1 equivalent) in acetonitrile (15 ml per mmol substrate) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo, and the residue was distributed between ethyl acetate and water. The organic layer was separated and evaporated to dryness in vacuum. Pure products were obtained or after column chromatography on silicagel is e (elution with mixtures of petroleum ether and ethyl acetate) or preparative HPLC/MS.

B. Synthesis of intermediate compounds carboxylic acids

Obtaining B1

4-hydroxy-3-isopropylbenzoic acid

Carbon tetrachloride (28 ml, 0.26 mol), and copper powder (1.0 g) was added to a stirred solution of 2-isopropylphenol to 27.2 g, 0.2 mol) in 50% aqueous sodium hydroxide (120 ml), and the mixture was stirred at the boiling point under reflux for 16 hours. After cooling, the mixture was acidified to pH 2 or below by the addition of concentrated hydrochloric acid and was extracted with ethyl acetate. The organic layer was extracted with saturated aqueous sodium bicarbonate, and the aqueous layer was acidified to pH 2 or below very careful addition of concentrated hydrochloric acid. The solution was extracted with ethyl acetate, the organic layer was washed with water, separated and the solvent was removed in vacuo gave 4-hydroxy-3-isopropylbenzoic acid (12.5 g, 35%) as a bright red solid, which was used without further purification.1H-NMR (DMSO-d6) 12,36 (1H, users), 10,13 (1H, users), 7,73 (1H, d), 7,63 (1H, DD), 6,85 (1H, d), up 3.22 (1H, m)to 1.19 (6H, d). MS: [M-H]+179.

Alternatively, if necessary, the crude product can be purified using a three-stage methodology, including dibenzylamine [according to conditions description the authorized below in obtaining B5 for the synthesis of methyl 5-acetyl-2,4-bis-benzyloxybenzoate (BnBr, K2CO3, MeCN, boiling under reflux)], column chromatography on silica gel to remove deeply colored impurities (elution 3-5% ethyl acetate in petroleum ether) and catalytic hydrogenation [according to the method A5 described above (10% Pd/C, EtOH, H2)], which leads to 4-hydroxy-3-isopropylbenzoic acid as colorless solid.

Obtaining B2

5-Ethyl-2-methoxybenzoic acid

n-Utility (2.5m in hexane, to 38.5 ml, 100.0 mmol) was added dropwise under nitrogen atmosphere to a stirred solution of 4-Atalanta (11,7 g, 86,0 mmol) and N,N,N',N'-tetramethylethylenediamine (10 ml, 88,0 mmol) in anhydrous diethyl ether (100 ml), the mixture was stirred, maintaining at 30ºC for 16 hours. The mixture was cooled and slowly poured into a mixture of solid carbon dioxide in anhydrous diethyl ether. After heating to room temperature the mixture was podslushivaet the addition of 2M sodium hydroxide, the aqueous layer was separated and acidified to pH 2 or below by the addition of concentrated hydrochloric acid. The mixture was extracted with diethyl ether, the organic layer was separated and the solvent was removed in vacuo, which gave 5-ethyl-2-methoxybenzoic acid (5.7 g, 37%) as a pale yellow oil.1H-NMR (DMSO-d6) 12,50 (1H, users), of 7.48 (1H, d), 7,33 (1H, DD), 7,03(1H, d)of 2.56 (2H, square), of 1.17 (3H, square). MS: [M+H]+181.

Obtaining B3

2,4-Bis-benzyloxy-5-chlorbenzene acid

l-(2,4-Bis-benzyloxy-5-chloro-phenyl)Etalon [obtained as described in WO 2004/0500087] (1.10 g, 3.0 mmol) was added to a mixed solution of sodium hydroxide (1.20 g, 30.0 mmol) in water (10 ml) and dioxane (10 ml). Was added dropwise bromine (1.44 g, 9.0 mmol) and the mixture was stirred at room temperature for 3 hours. The dioxane was removed by evaporation in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was separated, the solvent was removed in vacuo, which gave 2,4-bis-benzyloxy-5-chlorobenzoyl acid (900 mg, 81%) as a pale yellow solid.1H-NMR (DMSO-d6) to 12.58 (1H, users), to 7.77 (1H, s), 7,55-7,30 (10H, m), 7,11 (1H, s), 5,31 (2H, s), at 5.27 (2H, s). MS: [M+H]+369.

Obtaining B4

3-(1,2-Dimethylallyl)-4-hydroxybenzoic acid

Ethyl 4-hydroxybenzoate (1.66 g, 10.0 mmol) and anhydrous potassium carbonate (2,07 g, 15.0 mmol) in acetonitrile (30 ml) was treated with 3-methyl-2-butylchloride (1.35 ml to 12.0 mmol), the mixture was stirred and kept at the boiling point under reflux for 3 hours. After cooling, the solvent was removed in vacuum and the mixture was distributed between the stands is chloride and water. The organic fraction was separated, and the solvent was removed in vacuo, which gave ethyl 4-(3-methylbut-2-enyloxy)benzoate (2,23 g, 95%) as a pale yellow liquid which was used without further purification.1H-NMR (DMSO-d6) 7,89 (2H, d),? 7.04 baby mortality (2H, d), 5,44 (1H, t), to 4.62 (2H, d), 4,28 (2H, square), or 1.77 (3H, s)of 1.73 (3H, s)is 1.31 (3H, t). MS: [M+H]+235.

Ethyl 4-(3-methylbut-2-enyloxy)benzoate (2,23 g, at 9.53 mmol) was dissolved in anisole (8 ml), the mixture was stirred and kept at the boiling point under reflux for 4 days. The solvent was removed in vacuum and the residue was subjected to column chromatography on silica gel. Elution with a mixture of 20% ethyl acetate in petroleum ether was led to ethyl 3-(l,2-dimethylallyl)-4-hydroxybenzoate (600 mg, 27%) as a colourless solid.1H-NMR (DMSO-d6) 10,32 (1H, users), to 7.67 (1H, DD), a 7.62 (1H, s), make 6.90 (1H, d), the 4.90 (1H, s), is 4.85 (1H, s), 4,25 (2H, sq. in), 3.75 (1H, square), to 1.61 (3H, s)of 1.30 (3H, t), of 1.26 (3H, d). MS: [M+H]+235.

Ethyl 3-(l,2-dimethylallyl)-4-hydroxybenzoate (600 mg, 2.56 mmol) was dissolved in methanol (20 ml), was added a solution of potassium hydroxide (560 mg, 10.0 mmol) in water (10 ml), the mixture was stirred and kept at the boiling point under reflux for 16 hours. After cooling, the methanol was removed in vacuum and the solution was acidified to pH 2 or below by the addition of 2M hydrochloric acid. The solution was extracted with methylene chloride, the organic is the second layer was separated and the solvent was removed in vacuum, which gave 3-(l,2-dimethylallyl)-4-hydroxybenzoic acid (270 mg, 51%) as a colourless resin.1H-NMR (DMSO-d6) 12,38 (1H, users), 10,22 (1H, users), 7,63 (2H, m), to 6.88 (1H, d), the 4.90 (1H, s), to 4.87 (1H, in), 3.75 (1H, square), to 1.60 (3H, s)of 1.28 (3H, d). MS: [M-H]+205.

Obtaining B5

2,4-Bis-benzyloxy-5-isopropenylbenzene acid

Acetic anhydride (a 3.06 g, 30.0 mmol) was added to methyl 2,4-dihydroxybenzoate (5,04 g, 30.0 mmol) in detragiache of boron TRIFLUORIDE (7,6 ml), the mixture was stirred and kept at the boiling point under reflux for 3 hours and then allowed to cool to room temperature. Was added water (80 ml)and the mixture was stirred at room temperature for 30 minutes. The obtained yellow solid was separated by filtration and sucked out on the filter under vacuum for opportunities to dryness. The solid was dissolved in methylene chloride and washed with water, the organic layer was separated and the solvent was removed in vacuo, which gave methyl 5-acetyl-2,4-dihydroxybenzoate in the form of a bright yellow solid (2,62 g, 42%)which was used without further purification.1H-NMR (DMSO-d6) to 12.58 (1H, s), 11,22 (1H, s), with 8.33 (1H, s), of 6.45 (1H, s), 3,90 (3H, s), 2,62 (3H, s). MS: [M+H]+211.

Methyl 5-acetyl-2,4-dihydroxybenzoate (2,62 g, 12,48 mmol) was dissolved in acetonitrile (40 ml), was added anhydrous potassium carbonate (4,93 g,35,7 mmol), stir the mixture was treated with benzylbromide (5,09 g, 29,75 mmol) and kept at the boiling point under reflux for 3 hours. After cooling, the solvent was removed in vacuum and the mixture was distributed between water and methylene chloride. The organic layer was separated and the solvent was removed in vacuo, which gave methyl 5-acetyl-2,4-bis-benzyloxybenzoate (3,48 g, 71%) as a colourless solid, which was dried at 50ºC in a vacuum oven and used without further purification.1H-NMR (DMSO-d6) 8,21 (1H, s), 7,55 (4H, m), the 7.43 (4H, m), 7,37 (2H, m),? 7.04 baby mortality (1H, s)5,38 (4H, s), with 3.79 (3H, s), 2,48 (3H, s). MS: [M+H]+391.

Stir the suspension methyltriphenylphosphonium (1,96 g, 5.5 mmol) in anhydrous tetrahydrofuran (20 ml) at 0ºC in an atmosphere of nitrogen was treated dropwise with n-butyllithium (1.6 m in hexane, 3.5 ml, 5.5 mmol) and the resulting bright yellow solution was stirred at 0ºC for 30 minutes. Was added dropwise a solution of methyl 5-acetyl-2,4-bis-benzyloxybenzoate (1,95 g, 5.00 mmol) in anhydrous tetrahydrofuran (20 ml), the mixture was allowed to warm to room temperature and was stirred for 16 hours. Was added methanol (10 ml) and the solvent was removed in vacuum. The residue was distributed between methylene chloride and water, the organic layer was separated and the solvent was removed in vacuo gave a brown resin, which was purified column is a chromatography on silica gel. Elution 7% ethyl acetate in petroleum ether resulted in methyl 2,4-bis-benzyloxy-5-isopropylbenzoic in the form of a colorless solid (700 mg, 36%).1H-NMR (DMSO-d6) to 7.59 (1H, s), 7,52 (2H, d), of 7.64-to 7.32 (8H, m), 6,97 (1H, s), 5,28 (2H, s), with 5.22 (2H, s), 5,09 (1H, s), 5,04 (1H, s), 3,76 (3H, s)2,02 (3H, s). MS: [M+H]+389.

Methyl 2,4-bis-benzyloxy-5-isopropylbenzoic (700 mg, of 1.80 mmol) was dissolved in methanol (20 ml), was added a solution of potassium hydroxide (286 mg, 5.1 mmol) in water (4 ml), the mixture was stirred and kept at the boiling point under reflux for 3 hours. After cooling, the solvent was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with methylene chloride, the organic layer was separated and the solvent was removed in vacuo, which gave 2,4-bis-benzyloxy-5-isopropylbenzoic acid (600 mg, 89%) as a colourless solid.1H-NMR (DMSO-d6) 7,52 (2H, d), 7,47-7,29 (9H, m), PC 6.82 (1H, s), 5,20 (2H, s)to 5.17 (2H, s), is 5.06 (1H, s), 5,04 (1H, s)2,03 (3H, s). MS: [M+H]+375.

Obtaining B6

2,4-Bis-benzyloxy-5-brabantia acid

2,4-dihydroxy-5-bromobenzoyl acid (5,16 g, 22,15 mmol) was dissolved in DMF (40 ml) and sequentially added potassium carbonate (12.2 g) and benzylbromide (8 ml). The mixture was stirred at room temperature for 18 hours in the atmosphere is ore of nitrogen. Then added an aqueous solution of potassium hydroxide (2 g) in water (25 ml)was then added methanol (50 ml) and the mixture was heated at boiling under reflux with vigorous stirring for 24 hours. Then the mixture was allowed to cool, poured into in HCl (250 ml), then was extracted with ether and then DCM. The combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuum. The obtained solid was washed with petroleum ether, then Et2O (3×50 ml) to give the pure product (5.2 g, 56%).1H-NMR (MeOH-d4) of 8.06 (1H, s), 7,51-7,30 (10H, m), 6,85 (1H, s), with 5.22 (2H, s), 5,20 (2H, s). MS: [M+H]+413.

Getting B7

Synthesis of (Z)-4-benzyloxy-3-(1-methylpropenyl)benzoic acid

Methyl 3-bromo-4-hydroxybenzoate [obtained as described inTetrahedron, 2003, 59, 9173] (3,47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), was added anhydrous potassium carbonate (3.11 g, to 22.5 mmol), stir the mixture was treated with benzylbromide (is 3.08 g, 18.0 mmol) and kept at the boiling point under reflux for 5 hours. After cooling, the solvent was removed in vacuum and the mixture was distributed between water and methylene chloride. The organic layer was separated, the solvent was removed in vacuum and the residue was subjected to column chromatography on silica gel. Elution with 10% ethyl acetate in petrol is nom ether led to methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid.1H-NMR (DMSO-d6) to 8.12 (1H, d), of 7.96 (1H, DD), 7,51 (2H, m), the 7.43 (2H, t), 7,35 (2H, m), 5,32 (2H, s), of 3.84 (3H, s).

Methyl 4-benzyloxy-3-bromobenzoate (of 1.61 g, 5.0 mmol), cesium carbonate (4,89 g, 15.0 mmol), (E)-2-butene-2-Voronovo acid (600 mg, 6.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocenyl]palladium(II)chloride (204 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml)was added water (10 ml), the mixture was stirred and kept at the boiling temperature under nitrogen atmosphere for 16 hours. After cooling, the solvent was removed in vacuum and the mixture was distributed between methylene chloride and water. The organic layer was separated, the solvent was removed in vacuum and the residue was subjected to column chromatography on silica gel. Elution with 5% ethyl acetate in petroleum ether resulted in methyl (Z)-4-benzyloxy-3-(1-methylpropenyl)benzoate (600 mg, 41%) as a colourless solid.1H-NMR (DMSO-d6) 7,88 (1H, DD), to 7.59 (1H, d), 7,40 (4H, m), 7,34 (1H, m), 7.23 percent (1H, d), to 5.57 (1H, square), to 5.21 (2H, s), 3,82 (3H, s), of 1.94 (3H, s)to 1.38 (3H, d).

Methyl (Z)-4-benzyloxy-3-(1-methylpropenyl)benzoate (592 mg, 2.0 mmol) was dissolved in methanol (20 ml), was added a solution of potassium hydroxide (336 mg, 6.0 mmol) in water (7 ml), the mixture was stirred and kept at the boiling point under reflux for 3 hours. After cooling, the solvent was removed in vacuo and the mixture acidified d is pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with methylene chloride, the organic layer was separated and the solvent was removed under vacuum, giving (Z)-4-benzyloxy-3-(1-methylpropenyl)benzoic acid (460 mg, 82%) as a colourless solid.1H-NMR (DMSO-d6) a 7.85 (1H, DD), EUR 7.57 (1H, d), 7,40 (4H, m), 7,34 (1H, m), 7,18 (1H, d), to 5.57 (1H, square), to 5.21 (2H, s)a 1.96 (3H, s)of 1.40 (3H, d). MS: [M+H]+283.

Obtaining B8

Synthesis of 2,4-bis-benzyloxy-5-tert-butylbenzoic acid

1-(2,4-Bis-benzyloxy-5-tert-butylphenyl)Etalon [obtained as described in WO 2004/072051] (2,02 g, 5.2 mmol) was dissolved in 1,4-dioxane (30 ml), was added a solution of sodium hydroxide (2,08 g, with 52.0 mmol) in water (30 ml), the mixture was stirred and added dropwise bromine (0.8 ml, 15.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. 1,4-Dioxane was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was separated, the solvent was removed in vacuum and the residue was subjected to column chromatography on silica gel. The elution system 30% ethyl acetate in petroleum ether resulted in 2,4-bis-benzyloxy-5-tert-butylbenzoic acid (1.6 g, 79%) as a pale yellow oil.1H-NMR (DMSO-d6) 12,18 (1H, users), of 7.69 (1H, s), 7,52 (4H, t), 7,45-7,33 (6H, m), 6,93 (1H, s), of 5.24 (2H, s), 5,23 (2H, s)of 1.32 (9H, s). MS: [M+H]+391.

Getting B9

Synthesis of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (alternative synthesis)

Stage 1: Synthesis of benzyl ester of 2,4-bis-benzyloxy-5-bromobenzoyl acid.

In a vessel of 10 l jacketed equipped with a closed flange containing a stirrer, thermometer and addition funnel, was placed acetone (2.5 l), then was placed 5-bromo-2,4-dihydroxybenzoic acid (100 g, 0.43 mol) and potassium carbonate (356 g, 2.58 mol). To stir the mixture at ambient temperature was added benzylbromide (185 ml, 1.55 mol) at a speed of ~20 ml/min. and the Mixture was heated at 60ºC for 18 hours and then brought up to 45ºC. Was added water (1.5 l) and the mixture was stirred for 30 minutes the Mixture was extracted with EtOAc (2×1 l) and the combined organic fractions were evaporated in vacuum. To the residue was added Et2O (200 ml) and petroleum ether (1 l), and the mixture was stirred for 30 min, the resulting solid substance was separated by filtration and dried in vacuum, giving specified in the header connection (197,2 g), in the form of a white solid.

Stage 2: Synthesis of isopropylcarbonate potassium.

To a solution of 2-bromopropene (20 ml, 225 mmol) in anhydrous THF (250 ml), with stirring in an atmosphere of N2at-78ºC was added over 30 min n-Bui (2.5m in hexane) (100 ml, 250 mmol) and the mixture was stirred for 30 minutes To the mixture at-78ºC was slowly added triethylborane (58 ml, 340 mmol) at a rate that supports the temperature of the reaction mixture not exceeding-65ºC. The resulting solution was then stirred at-78ºC for 30 min, gave to slowly warm to ambient temperature and was stirred for another 90 minutes To the mixture was added hydrofloric potassium (105 g, 1.35 mol), then water (250 ml). The mixture was stirred at ambient temperature for 14 hours and then was evaporated to dryness.

The method was repeated as described above, and after evaporation to dryness the two residue was combined for further processing.

To the combined residues were added acetone (800 ml), the mixture was stirred for 1 hour and then filtered. The collected solid was washed with acetone (200 ml)and the combined filtrates were evaporated in vacuo gave a solid. The obtained solid is triturated with Et2O (250 ml) and then dried in vacuum, giving specified in the header of the connection (of 28.2 g), in the form of a white solid.

Stage 3: Synthesis of benzyl ester of 2,4-bis-benzyloxy-5-isopropylbenzoic acid

To a mixture of benzyl ester of 2,4-bis-benzyloxy-5-bromobenzoyl acid (42.9 g of 85.7 mmol), isopropylcarbonate potassium (14.0 g, is 95.2 mmol) and cesium carbonate 83,8 g, 257,1 mmol) in THF (800 ml) was added Pd(PPh3)4(2.0 g), then water (150 ml). The mixture was heated at the boil under reflux for 72 hours, then allowed to cool to ambient temperature. The mixture was evaporated in vacuo to remove THF and then distributed between water (500 ml) and EtOAc (300 ml). The organic fraction was washed with a saturated solution of salt, dried (MgSO4), was filtered and was evaporated in vacuo, which gave specified in the header of the connection (of 40.9 g) as a brown oil.

Stage 3A

Alternative synthesis of benzyl ester of 2,4-bis-benzyloxy-5-isopropylbenzoic acid

A mixture of benzyl ester of 2,4-bis-benzyloxy-5-bromobenzoyl acid (10.0 g, 20 mmol), isopropylcarbonate potassium (4.0 g, to 27.2 mmol) and n-butylamine (6,0 ml, 60 mmol) in a mixture of 2-propanol/water (2:1, 200 ml) was purged with N2within 5 minutes. To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (816 mg, of 1.09 mmol) and the mixture was heated at the boil under reflux for 20 hours. The mixture was allowed to cool to ambient temperature, then was diluted with water (400 ml) and was extracted with EtOAc (2×300 ml). The combined organic extracts washed with 1M aqueous HCl, saturated solution of salt, dried (MgSO4), filtered through a layer of celite and the filtrate was evaporated in is the Aquum, that led to headline the compound (11.1 g) as a brown resin.

Stage 4: Synthesis of 2,4-bis-benzyloxy-5-isopropylbenzoic acid

To a solution of benzyl ester of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (40,8 g, 87.9 mmol) in a mixture of THF-MeOH-water (3:1:1, 300 ml) was added lithium hydroxide (8,42 g, 352 mmol). The mixture was heated at 50ºC for 16 hours, allowed to cool to ambient temperature and then was diluted with water (300 ml). The mixture was brought to pH 1 using concentrated HCl (~30 ml) and then was extracted with EtOAc (2×200 ml). The combined organic extracts were washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated in vacuum. The solid residue suspended in a mixture of petroleum ether-MeOH (9:1, a total of 300 ml), the suspension was stirred for 1 hour at ambient temperature and the solid was isolated by filtration. The solid was dried in vacuum, giving specified in the header connection (26,8 g), in the form of not-quite-white solid.1H-NMR (400 MHz, DMSO-d6) 12,30 (s, 1H), to 7.61 (s, 1H), 7,53 (d, J=7,0 Hz, 2H), 7,47-7,31 (m, 8H), 6,94 (s, 1H), 5,23 (d, J=14,0 Hz, 4H), to 5.08 (d, J=9.0 Hz, 2H), 2,04 (s, 3H).

Getting B10

2,4-Bis-benzyloxy-5-isopropylbenzoic acid

Stage 1

Obtain 1-(2,4-Bis-benzylphenol)ethanone

Loading substances:

No.ConnectionNumberEquivalents
1.1,3-Dihydroxyacetophenone50 g1
2.Benzylbromide97 ml3
3.Acetonitrile750 ml15 volumes
4.Potassium carbonate115 g3

1,3-Dihydroxyacetophenone (50 g) were placed in 2 l odnogolosy RB-flask, equipped with a reflux condenser and a safety tube. Added acetonitrile (750 ml), potassium carbonate (115 g) and benzylbromide (97 ml), and the mixture was heated at the boil under reflux (90ºC) for 16 hours. Upon completion, the acetonitrile was removed under reduced pressure. To the reaction mixture were added water (200 ml), which was then extracted with ethyl acetate (500 ml). The organic layer was separated and dried over sodium sulfate. The solvent was removed when igenom pressure, which led to the residue, which was washed with n-hexane (600 ml), which gave the product.

The number of received product:105,1 g
Output:96,24%
Physical state:Solid
Color:Brown

Stage 2

Obtain 2,4-Bis-benzyloxy-1-isopropenylbenzene

Loading substances:

No.ConnectionNumberEquivalents
1.Connection stage 120 g1
2.n-BuLi (1.6 m)92,6 ml2,3
3.Methyltriphenylphosphonium53,4 g2,2
4.THF 200 ml10 volumes

Methyltriphenylphosphonium with 53.4 g) and THF (100 ml) were placed in 1-liter three-neck RB-flask, equipped with a dropping funnel and an inlet for nitrogen, and the mixture was cooled to 0ºC. n-BuLi (92,6 ml) was added dropwise to the reaction mixture for 15 min at 0ºC. The reaction mixture was stirred for 10 min at 0ºC and then stirred at room temperature for 30 minutes To the reaction mixture was added dropwise 1-(2,4-Bis-benzyloxyphenyl)alanon (20 g) in THF (100 ml) for 10 min at 0ºC, and the reaction mixture was stirred over night at room temperature. The completion of the reaction was controlled by TLC (10% EtOAc/n-hexane, Rfproduct of 0.9). Upon completion to the reaction mixture were added methanol (~100 ml) and the solvent was removed under reduced pressure, the resulting residue. To the residue was added n-hexane (1 l)was heated under reflux (75ºC) for 30 min before filtering the mixture was passed through a layer of celite and washed layer n-hexane (500 ml). The solvent was removed under reduced pressure gave a residue which was then purified column chromatography (SiO2, 2% EtOAc/n-hexane).

63,13%
The number of received product:12.5 g
Output:
Physical state:Liquid
Color:Colorless

Stage 3

4-Isopropylbenzene-1,3-diol

Loading substances:

No.ConnectionNumberEquivalents
1.2,4-Bis-benzyloxy-1-isopropenylbenzene12.5 g1
2.Ethanol125 ml10 volumes
3.20% palladium hydroxide2 g

To a mixture of 2,4-bis-benzyloxy-1-isopropenylbenzene (12.5 g) in ethanol (125 ml) in a 500 ml hydrogenation flask was added 20% palladium hydroxide (2 g). The reaction mixture was first made at 80 psig within 36 hours. The completion of the reaction was controlled by TLC (10% EtOAc/n-hexane, Rfproduct of 0.1). Upon completion, the reaction mixture was filtered through a layer of celite and the layer was washed with ethanol (30 ml). The solvent was removed under reduced pressure gave the crude product which was used without purification in the next stage.

The number of received product:5.8 g (crude)
Physical state:Solid
Color:Colorless

Stage 4

1-(2,4-Dihydroxy-5-isopropylphenyl)alanon

Loading substances:

No.ConnectionNumberEquivalents
1.4-Isopropylbenzene-1,3-diol5.8 g1
2.Athirat of boron TRIFLUORIDE28,7 ml6
3.Acetic acid4,55 ml2

4-Isopropylbenzene-1,3-diol (5.8 g) and athirat of boron TRIFLUORIDE (28,7 ml) were placed in a 250 ml od is overlow RB-flask, equipped with a reflux condenser and a supply of nitrogen, was stirred at room temperature for 10 minutes To the reaction mixture was added acetic acid (4,55 ml) and stirred at 90ºC for 16 hours. Upon completion to the reaction mixture was added 10% sodium acetate (300 ml)was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate (300 ml), washed with saturated sodium bicarbonate (100 ml) and the organic layer was dried over sodium sulfate. The reaction was controlled by TLC (10% EtOAc/n-hexane, Rfproduct of 0.5). The solvent was removed under reduced pressure gave a residue which was then purified column chromatography (SiO2, 10% EtOAc/n-hexane).

The number of received product:3.2 g
Output:43,24%
Physical state:Solid
Color:Colorless

Stage 5

l-(2,4-Bis-benzyloxy-5-isopropylphenyl)alanon

Loading substances:

No.Soy is inania NumberEquivalents
1.1-(2,4-Dihydroxy-5-isopropylphenyl)alanon3.2 g1
2.Benzylbromideof 5.89 ml3
3.Potassium carbonate6,82 g3
4.Acetonitrile60 ml20 volumes

To a mixture of 1-(2,4-dihydroxy-5-isopropylphenyl)ethanone (3.2 g), acetonitrile (60 ml) and potassium carbonate (10.6 g) in 250 ml odnogolosy RB-flask, equipped with a reflux condenser and a safety tube, was added benzylbromide (9.1 ml). The reaction mixture is boiled (90ºC) for 16 hours. The completion of the reaction was controlled by TLC (10% EtOAc/n-hexane, Rfproduct of 0.5). Upon completion of the acetonitrile was removed under reduced pressure. To the obtained residue was added water (100 ml)and the resulting mixture was extracted with ethyl acetate (200 ml). The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure gave a residue, to which was added the n-hexane (150 ml), that led to the product.

The amount of product5,1 g
Output83,6%
The aggregate stateSolid
ColorColorless

Stage 6

2,4-Bis-benzyloxy-5-isopropylbenzoic acid

Loading substances:

No.ConnectionNumber
1.1-(2,4-Bis-benzyloxy-5-isopropylphenyl)alanon7 g
2.Hypobromide sodium13 g in 100 ml water
3.Dioxane100 ml

Technique:

Mixture a mixture of 1-(2,4-Bis-benzyloxy-5-isopropylphenyl)ethanone (7 g) in dioxane (100 ml) in a 500 ml odnogolosy RB-flask, equipped with a safety tube was cooled to 10ºC and added hypobromide sodium [13 g in water (100 ml)]. The reaction mixture is stirred over night at room temperature. The completion of the reaction was controlled by TLC (30% EtOAc/n-hexane, Rfproduct of 0.5). Upon completion to the reaction mixture, which was cooled to 0ºC was added sodium bisulfite (7 g). The reaction mixture was then acidified with HCl (~10 ml) to pH 2, extracted with ethyl acetate (100 ml) and washed with water (25 ml). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure gave a residue which was then purified column chromatography (SiO2, 10% EtOAc/n-hexane).

The amount of product3.4 g
Output48,3%
The aggregate stateSolid
ColorColorless

C. Synthesis isoindoline intermediate compounds

Obtain C1

Synthesis of 4,7-depersonalise

A mixture of l,4-debtor-2,3-xylene (4.26 deaths / g, 30.0 mmol), N-bromosuccinimide (for 10.68 g, 60,0 mmol) and dibenzoylperoxide (75 wt.% in water, 120 mg) in carbon tetrachloride (50 ml) was stirred and kept at the boiling point under reflux for 16 hours. After cooling to room temperature the mixture is filtered, the solids were washed with carbon tetrachloride (10 ml), the organic extracts were combined and the solvent was removed in vacuo, which gave 2,3-bis-methyl bromide-1,4-differental (9.0 g, 100%) as a pale yellow liquid, which was aterials when standing.1H-NMR (DMSO-d6) of 7.36 (2H, DD), 4,78 (4H, s).

A solution of 4-toluensulfonate (2,44 g of 14.28 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to the intensively stirred suspension of sodium hydride (1.2 g, 60 wt.% in mineral oil, 30.0 mmol) in anhydrous N,N-dimethylformamide (60 ml). The mixture was stirred at room temperature for 1 hour, at 110ºC for 1 hour, then was cooled to 60ºC and was added dropwise a solution of 2,3-bis-methyl bromide-1,4-diferente (4,28 g of 14.28 mmol) in N,N-dimethylformamide (30 ml). The mixture was stirred at 60ºC for 1 hour and then at room temperature for 16 hours. The solvent was removed in vacuum and the residue was distributed between methylene chloride and 1M hydrochloric acid. The organic layer was separated, washed with 5% aqueous potassium carbonate solution, the organic layers was separated and the solvent was removed in vacuum. The residue was washed with diethyl ether, filtered and the solid was sucked out on the filter to dryness under reduced pressure, which gave 4,7-debtor-2-(toluene-4-sulfonyl)isoindoline (2,46 g, 56%) as pale yellow-brown solid substances is A. 1H-NMR (DMSO-d6) of 7.82 (2H, d), the 7.43 (2H, d), to 7.15 (2H, DD), of 4.66 (4H, s), a 2.36 (3H, s). MS: [M+H]+310.

A mixture of 4,7-debtor-2-(toluene-4-sulfonyl)isoindoline (2,36 g of 7.64 mmol), phenol (2,36 g, 25,11 mmol), 48% HBR in water (20 ml) and propionic acid (4 ml) was stirred and kept at the boiling point under reflux for 6 hours. After cooling to room temperature was added water (50 ml) and the mixture was extracted with diethyl ether (2×100 ml). The aqueous layer was podslushivaet the addition of 2M sodium hydroxide and was extracted with diethyl ether (3×100 ml). The combined extracts were evaporated to dryness in vacuo, which gave 4,7-diverisonary (586 mg, 50%) as a brown oil, which was aterials when standing.1H-NMR (DMSO-d6) 7,06 (2H, DD), of 4.12 (4H, s). MS: [M+H]+156.

Obtaining C2

Synthesis hydrobromide 5-hydroxyisoquinoline

A solution of dimethyl 4-methoxyflurane (36.75 per g, 0.16 mol) in methanol (100 ml) was treated with potassium hydroxide solution (28,0 g, 0.5 mol) in water (50 ml), the mixture was stirred and kept at the boiling point under reflux for 4 hours. After cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid was filtered, washed with water and otsenyv is whether the filter to dryness under reduced pressure overnight, what gave 4-methoxyflavone acid (31.8 g, 99%) as not quite white solid.1H-NMR (DMSO-d6) 12,90 (2H, users), 7,74 (1H, d), 7,12-7,05 (2H, m), of 3.84 (3H, s). MS: [M+H]+197.

Acetic anhydride (40 ml) was added to a mixture of 4-methoxyflavone acid (30,8 g, 0.16 mol) in anhydrous tetrahydrofuran (150 ml), the mixture was stirred and kept at the boiling point under reflux for 4 hours. After cooling to room temperature the solvent was removed in vacuo gave 4-methoxypoly anhydride (27.8 g, 99%) as not quite white solid.1H-NMR (DMSO-d6) 8,02 (1H, d), to 7.59 (1H, d), 7,49 (1H, DD), of 3.97 (3H, s). MS: [M+H]+179.

A mixture of 4-methoxyflavone anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and kept at 210ºC for 5 hours, then allowed to cool to room temperature overnight. The solid was filtered, washed successively with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked out on the filter to dryness under reduced pressure, which gave 4-methoxyflavone (21,3 g, 77%) as a pale yellow solid.1H-NMR (DMSO-d6) of 11.15 (1H, users), 7,74 (1H, d), 7,33-7,28 (2H, m)to 3.92 (3H, s).

Stir a solution of 4-metoclopramide (21,3 g, 0.12 mol) in anhydrous tetrahydrofuran (425 ml) at 0ºC was treated dropwise with a solution of borane in tetrahed is furane (1M, 340 ml, 0.34 mol), the mixture was stirred and kept at the boiling point under reflux for 16 hours. The mixture was cooled to 0ºC was added dropwise methanol (150 ml), then was added 5M hydrochloric acid (150 ml), the mixture was stirred and kept at the boiling point under reflux for 3 hours. After cooling to room temperature, the organic solvent was removed in vacuo, the mixture was diluted with water (750 ml) and was extracted with methylene chloride (3×750 ml). The aqueous layer was podslushivaet to pH 12 or higher by the addition of 5M sodium hydroxide, extracted with methylene chloride (3×750 ml) and the combined extracts were evaporated to dryness in vacuo, which gave 5-methoxyindole (a 8.34 g, 47%) as a brown oil.1H-NMR (DMSO-d6) 7,13 (1H, d), at 6.84 (1H, d), 6,74 (1H, DD), of 4.05 (2H, s)to 4.01 (2H, s), of 3.73 (3H, s). MS: [M+H]+150.

5-Methoxyindole (a 8.34 g, 55,97 mmol) in 48% aqueous Hydrobromic acid (100 ml) was stirred and kept at the boiling point under reflux for 16 hours. After cooling to room temperature the solvent was removed in vacuo, giving the hydrobromide 5-hydroxyisoquinoline (11,32 g, 93%) as a yellow-brown solid.1H-NMR (DMSO-d6) 9,63 (1H, users), to 9.32 (2H, users), 7,18 (1H, d), 6,79 (1H, d), 6,76 (1H, DD), 4,42 (2H, t), of 4.38 (2H, t). MS: [M+H]+136.

Received the e C3

Synthesis of 5-chloro-2,3-dihydro-1H-isoindole

A mixture of 3,4-dimethylcarbinol (10 g, 71,1 mmol), N-bromosuccinimide (25 g,142,2 mmol) and benzoyl peroxide (0,147 g, 0.6 mmol) was boiled under reflux in 80 ml of carbon tetrachloride for 18 hours. After cooling, the insoluble substance was filtered and washed with a small amount of carbon tetrachloride. The filtrate and washing were combined and concentrated under reduced pressure to obtain 20 g of the product l,2-bis-methyl bromide-4-chlorobenzene in the form of a pale yellow oil as the main component.

To a suspension of 60% sodium hydride (3.0 g, 0.125 mmol) in mineral oil in 80 ml of anhydrous DMF (100 ml) was added dropwise a solution of paratoluenesulfonyl (5.6 g, 32.60 high. mmol) in 30 ml of DMF for 1 hour under vigorous stirring at room temperature. After the addition the mixture was stirred for 1 hour at room temperature and 1 hour was heated at 90ºC. To the mixture was added dropwise a solution of l,2-bis-methyl bromide-4-chlorobenzene (4 g, 14,18 mmol) in 20 ml of anhydrous DMF at 60ºC, then stirred overnight at room temperature. The final mixture was poured over ice and the resulting precipitate was isolated by filtration. The precipitate was washed with hydrochloric acid, 5% sodium carbonate and a saturated salt solution, then sushi and (MgSO4), was filtered and evaporated, giving 2.8 g of 5-Chloro-2-(toluene-4-sulfonyl)-2,3-dihydro-1H-isoindole as a pale yellow solid. MS: [M+H]+308.

1.0 g of 2-(paratoluenesulfonyl)-5-chlorisondamine and 1.0 g of phenol was added to a mixture of 8 ml of 48% Hydrobromic acid and 1.4 ml of propionic acid, then the mixture was heated at boiling under reflux for 6 hours. The final reaction mixture was diluted with 10 ml water and was extracted with twice 50 ml of ethyl acetate. The aqueous layer was podslushivaet aqueous solution of sodium hydroxide and was extracted with ethyl acetate three times. The extract was concentrated and the crude product was diluted with a mixture of 4 N. HCl/dioxane and stirred for 15 minutes before evaporation of HCl and then three times re-evaporated with toluene, which gave 0.3 g of the hydrochloride of 5-chloro-2,3-dihydro-1H-isoindole as a black solid. MS: [M+H]+153-15

Getting C4

Synthesis of 5-chloro-6-methoxy-2,3-dihydro-1H-isoindole

A mixture of 1-chloro-2-methoxy-4,5-xylene (3 g, 17.6 mmol), N-bromosuccinimide (6.3 g, 35,3 mmol) and benzoyl peroxide (0,100 g, 0.41 mmol) in carbon tetrachloride (40 ml) was heated at the boil under reflux for 18 hours. After cooling, the insoluble substance was removed by filtration, washed with a small amount of tetrachloride of plastics technology : turning & the Yes and the filtrate was evaporated, that would give l,2-bis-methyl bromide-4-chloro-5-methoxybenzo in the form of an oily product as the main component. MS: [M+H]+329.

A solution of 4-methoxybenzylamine (2.4 g, 17.6 mmol) in acetone (110 ml) was added dropwise to a mixture of l,2-bis-methyl bromide-4-chloro-5-methoxybenzene (presumably theoretical amount, 17.6 mmol) and Na2CO3(12 g, 114 mmol) in a mixture of acetone/water (10 ml:12.5 ml), then stirred at room temperature for 2 hours and concentrated in vacuum. The crude substance was dissolved in ethyl acetate and was extracted with 2 N. HCl. The aqueous layer was neutralized with sodium carbonate, extracted with ethyl acetate (2 times), dried (MgSO4) and was evaporated in vacuo, which gave 5-chloro-6-methoxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindole (0.8 g, 2.6 mmol) as a brown resin. MS: [M+H]+304

A solution of 5-chloro-6-methoxy-2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindole (600 mg) and anisole (0.3 ml) in triperoxonane acid (6 ml) was heated at 180ºC (50 W) for 40 minutes in a microwave synthesizer for CEM test experiments. The reaction mixture was evaporated and re-evaporated with toluene. The crude substance was distributed between DCM and water, the aqueous layer washed with DCM (3 times), then evaporated and re-evaporated with toluene, which gave 5-chloro-6-methoxy-2,3-dihydro-1H-isoindole (256 mg) in the form of green crystals. MS: [M+H]+184

Obtaining C5/b>

Synthesis of triptoreline 2,3-dihydro-1H-isoindole-5-ylamine

A solution of 4-nitro-o-xylene (15,1 g; 0.1 mol) in carbon tetrachloride (150 ml) was treated with N-bromosuccinimide (36 g; 0.2 mol), followed by benzoyl peroxide (1 g), then heated at the boil under reflux overnight. The reaction was allowed to cool to ambient temperature, filtered and the filtrate was evaporated, which gave 32 g of crude l,2-bis-methyl bromide-4-nitrobenzene in the form of rolling oil. The crude product was dissolved in benzene (200 ml), then treated dropwise within 30 minutes with a solution of 2,4-dimethoxyaniline (15 ml) and triethylamine (27,85 ml) in benzene (100 ml), then was heated at 80ºC for 3 hours. The reaction mixture was cooled, washed with water, then saturated sodium bicarbonate. The organic fraction was extracted with 2M HCl (2×150 ml), then the combined aqueous extracts were podslushivaet 2M NaOH and was extracted with EtOAc (2 times). The combined EtOAc layer was dried (MgSO4), was evaporated, then purified column flash chromatography with elution systems EtOAc/petroleum ether (1:3-1:2-1:1). The fractions containing the product were combined and evaporated, giving 10,15 g 2-(2,4-dimethoxybenzyl)-5-nitro-2,3-dihydro-1H-isoindole as a brown solid.1H-NMR (DMSO-d6) to 8.12 (2H, m)to 7.50 (1H, d), 7,25 (1H, d), 6,55 (1H, d), of 6.52 (1H, DD, 3,93 (4H, s), of 3.80 (3H, s), of 3.78 (2H, in), 3.75 (3H, s).

2-(2,4-dimethoxybenzyl)-5-nitro-2,3-dihydro-1H-isoindole (13 g) in TFA (18 ml) was treated with anisole (6 ml), then was heated in a microwave synthesizer CEM at 120ºC (30 W) for 20 minutes (conducted in periodic mode, 6 times). The reaction mixture was evaporated in vacuo, and the residue was distributed between DCM and water. The aqueous layer was separated, washed with DCM (×3), then evaporated and re-evaporated with a mixture of toluene/MeOH (×3), which gave a value of 9.8 g of salt triperoxonane acid, 5-nitro-2,3-dihydro-1H-isoindole in the form of a beige solid.1H-NMR (DMSO-d6) 9,85 (2H, users), 8,32 (1H, d), of 8.25 (1H, DD), of 7.70 (1H, d), and 4.68 (2H, s)and 4.65 (2H, s).

The mixture of salt triperoxonane acid 5-nitro-2,3-dihydro-1H-isoindole (9,8 g) and 10% palladium on carbon (1 g) in methanol (75 ml) was first made at room temperature and pressure for 16 hours. The reaction was filtered through celite™, and the filtrate was evaporated and re-evaporated with toluene, which gave 8,76 g montefortino salt of 2,3-dihydro-1H-isoindole-5-ylamine in the form of a dark brown solid.1H-NMR (DMSO-d6) to 9.45 (2H, users), 7,05 (1H, d), 6,60 (2H, m), to 5.35 (2H, users), and 4.40 (2H, s), 4,30 (2H, s).

Obtaining C6

Synthesis of DATEFORMAT 5-morpholine-4-ylmethyl-2,3-dihydro-1H-isoindole

Stage 1 and 2 were carried out by a method similar to that described in obtaining C5 using the-W methyl 3,4-dimethylbenzoic as the original substance.

A mixture of methyl ester of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (4,65 g; of 14.2 mmol) and the monohydrate of lithium hydroxide (660 mg; 1.1 equiv.) in a mixture of 4:1:1 THF-MeOH-H2O (60 ml) was stirred at room temperature overnight. Then was added 170 mg of the base and the stirring was continued for 7 hours. The reaction mixture was evaporated and then re-evaporated with a mixture of MeOH/toluene (2 times). A mixture of the crude lithium salt of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (1.5 g, 4.7 mmol), research (820 μl; 2 equiv.), EDAC (1.1 g; 1.2 equiv.) and HOBt (760 mg; 1.2 equiv.) in DMF (25 ml) was stirred at room temperature overnight, then evaporated in vacuum. The residue was distributed between EtOAc and saturated NaHCO3separated EtOAc layer was washed with a saturated solution of salt, dried (MgSO4) and was evaporated. Purification column flash chromatography (2%, then 5% MeOH/DCM as eluent) gave 1.1 g of [2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-yl]morpholine-4-ylmethanone in the form of a red-brown resin.1H-NMR (DMSO-d6) 7,30-to 7.18 (4H, m), 6,56 (1H, d), of 6.52 (1H, DD), 3,85 (4H, s), of 3.78 (5H, m), of 3.73 (3H, s).

A solution of [2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-yl]-morpholine-4-ylmethanone (1,05 g; a 2.75 mmol) in dry THF (20 ml) under nitrogen atmosphere was treated with 1M solution of lithium aluminum hydride, and then stirred at room temperature for N. the Chi. The reaction was suppressed by careful addition of a saturated solution of sodium sulfate, then was diluted with EtOAc (40 ml), filtered through celite™ and evaporated. Purification column flash chromatography (2%, then 5% MeOH/DCM as eluent) gave 340 mg of 2-(2,4-dimethoxybenzyl)-5-morpholine-4-ylmethyl-2,3-dihydro-1H-isoindole as a pale brown resin.

A mixture of 2-(2,4-dimethoxybenzyl)-5-morpholine-4-ylmethyl-2,3-dihydro-1H-isoindole (340 mg) and anisole (350 μl) in triperoxonane acid (1.5 ml) was heated at 130ºC in a microwave synthesizer CEM for 1 hour, then evaporated and re-evaporated with toluene. The residue was distributed between DCM and water. The aqueous layer was separated, washed with DCM (×3), then evaporated and re-evaporated with a mixture of toluene/MeOH (×3), which gave 422 mg DATEFORMAT 5-morpholine-4-ylmethyl-2,3-dihydro-1H-isoindole as a brown resin.1H-NMR (DMSO-d6) 10,30 (1H, users), 9,60 (2H, users), 7,55 was 7.45 (3H, m), of 4.45 (4H, s), 4,45-4,30 (2H, m), 4,20-3,88 (2H, m), 3,70-3,55 (2H, m), 3,30-of 3.00 (4H, m).

Obtaining C7

Synthesis of triptoreline ethyl 2,3-dihydro-1H-isoindole-5-carboxylate

A solution of methyl ester of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (215 mg) and anisole (200 μl) in 1 ml of TFA was heated at 140ºC for 30 minutes in a microwave synthesizer for CEM test experiments. The reaction mixture was distributed between in the Oh and DCM, the aqueous layer was separated, washed with DCM, then evaporated and re-evaporated with a mixture of toluene/MeOH (×2), which gave 105 mg specified in the connection header.1H-NMR (DMSO-d6) to 9.70 (2H, users), 8,02 (1H, s), 8,98 (1H, d), EUR 7.57 (1H, d), 4,60 (2H, s), 4,56 (2H, s)to 3.89 (3H, s).

Getting C8

4-hydroxy-2-(4-methoxybenzyl)isoindole-1,3-dione

A mixture of 3-hydroxyphthalic anhydride (543 mg, of 3.31 mmol), 4-methoxybenzylamine (0,43 ml of 3.31 mmol) and acetic acid (3 ml) was heated at 100ºC for 4 hours. The mixture was allowed to cool and was diluted with water (20 ml). White solid was isolated by filtration, thoroughly washed with water and dried, giving specified in the title compound (760 mg, 81%).1H-NMR (DMSO-d6) 11,03 (1H, s), to 7.61 (1H, DD), 7,28 (1H, d), 7.23 percent-7,19 (3H, m), 6.89 in-6,86 (2H, m), 4,63 (2H, s), 3,71 (3H, s). MS: [M-H+] 282.

Obtaining C9

4-hydroxy-2-(2,4-dimethoxybenzyl)isoindole-1,3-dione

A mixture of 3-hydroxyphthalic anhydride (1.24 g, 7.6 mmol), 2,4-dimethoxyaniline (1,14 ml, 7.6 mmol) and acetic acid (5 ml) was heated at 80ºC for 24 hours. The mixture was allowed to cool and was diluted with water (20 ml). White solid was isolated by filtration, washed thoroughly with water and dried, giving specified in the title compound (1.73 g, 73%).1H-NMR (DMSO-d6) 11,00 (1H, s), a 7.62 (1H, DD), 7,29 (1H, d), 7,21 (1H, d), 6.90 to (1, d), 6,56 (1H, d), to 6.43 (1H, DD), 4,59 (2H, s), with 3.79 (3H, s), and 3.72 (3H, s). MS: [M-H+] 282.

Getting C10

2-(4-Methoxybenzyl)-4-[2-(2-methoxyethoxy)ethoxy]isoindole-1,3-dione

1-(2-Bromoethoxy)-2-methoxyethane (107 mg, of 0.58 mmol) was added to a suspension of 4-hydroxy-2-(4-methoxybenzyl)isoindole-1,3-dione (150 mg, of 0.53 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (2 ml). After 3.5 hours, was added a catalytic amount of potassium iodide. After 17 hours the mixture was heated to 60ºC. After 3 hours was added an additional amount of 1-(2-bromoethoxy)-2-methoxyethane (20 mg, 0.11 mmol) and the mixture was stirred at 60ºC for another 20 hours. The mixture was concentrated in vacuo, then the residue was dissolved in ethyl acetate and washed with a solution of potassium carbonate and a saturated solution of salt. The organic phase was dried (MgSO4) and concentrated, giving specified in the title compound as a yellow oil (149 mg, 73%).1H-NMR (methanol-d4) 7,71 (1H, t), 7,43-7,40 (2H, m), 7,31-7,27 (2H, m), 6.87 in-6,83 (2H, m), 4,71 (2H, s), 4,37-4,34 (2H, m), 3,92-to 3.89 (2H, m), of 3.77-3,74 (5H, m), 3,55-of 3.53 (2H, m)to 3.33 (3H, s). MS: [M+H]+386.

Getting C11

2-(2,4-Dimethoxybenzyl)-4-(2-dimethylaminoethoxy)isoindole-1,3-dione

A mixture of 2-(2,4-dimethoxybenzyl)-4-hidroxizina-1,3-dione (317 mg, 1.01 mmol), hydrochloride of 2-diethylaminoethylamine (160 mg, 1.11 mmol) and potassium carbonate (350 mg,2.5 mmol) in DMF (4 ml) was heated at 60ºC for 18 hours. The mixture was concentrated in vacuo, dissolved in ethyl acetate and was extracted twice 1 N. hydrochloric acid. Water extracts were podslushivaet solid potassium carbonate and extracted with ethyl acetate (2 times). The combined organic extracts were washed with a saturated solution of salt, dried (MgSO4) and concentrated, giving specified in the title compound (236 mg, 61%) as not quite white solid.1H-NMR (methanol-d4) 7,73 (1H, t), 7,44-7,40 (2H, m), 7,02 (1H, d), 6,51 (1H, d), 6.42 per (1H, DD), 4.72 in (2H, s)to 4.33 (2H, t), of 3.80 (3H, s), 3,76 (3H, s), 2,87 (2H, t), is 2.40 (6H, s). MS: [M+H]+385.

Getting C12

2-(2,4-Dimethoxybenzyl-4-(3-morpholine-4-ylpropionic)isoindole-1,3-dione

A mixture of 2-(2,4-dimethoxybenzyl)-4-hidroxizina-1,3-dione (313 mg, 1.00 mmol), 4-(3-chlorpropyl)of the research (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (5 ml) was heated at 60ºC for 18 hours. The mixture was diluted with ethyl acetate and was extracted twice 1 N. hydrochloric acid. Water extracts were podslushivaet solid potassium carbonate and extracted with ethyl acetate. The organic extract was washed with a saturated solution of salt, dried (MgSO4) and concentrated, resulting yellow solid substance, which was recrystallized from methanol/petroleum ether, then ethyl acetate/chloroform/petroleum EF the R, what gave you specified in the title compound (298 mg, 68%) as not quite white solid.1H-NMR (methanol-d4) 7,72 (1H, t), 7,41 (1H, d), 7,39 (1H, d), 7,02 (1H, d), 6,51 (1H, d), to 6.43 (1H, DD), 4.72 in (2H, s), 4,27 (2H, t), 3,81 (3H, s), 3,76 (3H, s), 3,68 (4H, t), 2,61 (2H, t), of 2.50 (4H, m), is 2.05 (2H, Queen.). MS: [M+H]+441.

Getting C13

2-(4-Methoxybenzyl)-4-[2-(2-methoxyethoxy)ethoxy]-2,3-dihydro-1H-isoindole

2-(4-Methoxybenzyl)-4-[2-(2-methoxyethoxy)ethoxy]isoindole-1,3-dione (149 mg, 0.38 mmol) was treated with 1M solution of lithium aluminum hydride in THF (5 ml, 5 mmol). The mixture was stirred at room temperature for 4 hours at 60ºC for 1 hour, then at room temperature for a further 18 hours. Then the mixture was cooled on ice and extinguished by adding dropwise water (0.2 ml), a solution of 2 n sodium hydroxide (0.4 ml) and water (0.4 ml). Added magnesium sulfate, and then ethyl acetate and then the mixture was stirred at room temperature for 15 minutes. Solids were removed by filtration, thoroughly rinsing with ethyl acetate. Concentration of the filtrate gave a residue, which was adsorbing on SCX cartridge and washed with a mixture of 5% methanol/methylene chloride, then was suirable 10% 1M ammonia in methanol/methylene chloride, which gave specified in the title compound (134 mg, 97%).1H-NMR (methanol-d4) 7,43-7,39 (2H, m), 7,27 (1H, t), 6,99-of 6.96 (2H, m), 6.90 to (1H, d), to 6.88 (1H, d), to 4.33 (2H, s), to 4.28 (2H, s)to 4.23 (2H, s), 4,18-to 4.15 (2H, m), 3,85-3,79 (5H, m), 3,67-of 3.64 (2H, m), 3,54-3,51 (2H, m)to 3.33 (3H, s). MS: [M+H]+358.

Getting C14

2-(2,4-Dimethoxybenzyl)-4-(2-dimethylaminoethoxy)-2,3-dihydro-1H-isoindole

2-(2,4-Dimethoxybenzyl)-4-(2-dimethylaminoethoxy)isoindole-1,3-dione (201 mg, 0.52 mmol) was treated with 1M solution of lithium aluminum hydride in THF (5 ml, 5 mmol). After 7.5 hours at room temperature was added an additional portion of a solution of lithium aluminum hydride (5 ml, 5 mmol) and the mixture was stirred for a further 18 hours. Then the mixture was cooled on ice and extinguished by adding dropwise water (0.4 ml), 2 n sodium hydroxide solution (0.8 ml) and water (0.8 ml). Added magnesium sulfate, and then ethyl acetate and then the mixture was stirred at room temperature for 1 hour. Solids were removed by filtration, thoroughly rinsing with ethyl acetate. Concentration of the filtrate gave specified in the title compound (192 mg, 103%) as a brown oil, which is then used without further purification.1H-NMR (methanol-d4) of 7.24 (1H, d), 7,16 (1H, t), 6,82-of 6.78 (2H, m), 6,55 (1H, d), 6,51 (1H, DD), of 4.12 (2H, t)to 3.92 (4H, s), 3,86 (2H, s), 3,82 (3H, s), of 3.80 (3H, s), was 2.76 (2H, t), of 2.33 (6H, s). MS: [M+H]+357.

Getting C15

2-(2,4-Dimethoxybenzyl)-4-(3-morpholine-4-ylpropionic)-2,3-dihydro-1H-isoindole

2-(2,4-Dimethoxybenzyl)-4-(3-morpholine-4-Elpro is hydroxy)isoindole-1,3-dione (298 mg, of 0.68 mmol) was treated with 1M solution of lithium aluminum hydride in THF (5 ml, 5 mmol) and kept at room temperature for 21 hours. The mixture was heated to 75ºC for 1 hour, then cooled on ice and extinguished by adding dropwise water (0.2 ml), 2 n sodium hydroxide solution (0.4 ml) and water (0.4 ml). Added magnesium sulfate, and then ethyl acetate and then the mixture was stirred at room temperature for 1 hour. Solids were removed by filtration, thoroughly rinsing with ethyl acetate. Kontsentrirovanie of the filtrate gave the crude product, which was purified flash chromatography on silica gel, with elution with 5% methanol in DCM. This led to headline the compound (233 mg, 83%) as a red oil.1H-NMR (methanol-d4) of 7.24 (1H, d), to 7.15 (1H, t), to 6.80 (1H, d), is 6.78 (1H, d), 6,56 (1H, d), of 6.52 (1H, DD), of 4.05 (2H, t), of 3.94 (2H, s), 3,88 (2H, s), a 3.87 (2H, s), 3,83 (3H, s), of 3.80 (3H, s), 3,70-3,68 (4H, m), 2,54-of 2.50 (2H, m), 2,49-2,47 (4H, m), 2.00 in of 1.93 (2H, m). MS: [M+H]+413.

Getting C16

4-[2-(2-Methoxyethoxy)ethoxy]-2,3-dihydro-1H-isoindole

A solution of 2-(4-methoxybenzyl)-4-[2-(2-methoxyethoxy)ethoxy]-2,3-dihydro-1H-isoindole (45 mg, 0.13 mmol) in 1,2-dichloroethane (2 ml) was treated with α-chloritisation (0.1 ml, of 0.93 mmol). After 17 hours was added methanol (5 ml) and the mixture was stirred for 3 hours. The solvents were removed in vacuo, which gave specified in the header is the connection in the form of a greenish-black solid, which was used without further purification.1H-NMR (methanol-d4) of 7.36 (1H, t), 6,98 (2H, d), 4,60 (2H, s), of 4.57 (2H, s), 4,23-is 4.21 (2H, m), 3,85-a 3.83 (2H, m), 3,69-to 3.67 (2H, m), 3,57-of 3.54 (2H, m)to 3.36 (3H, s). MS: [M+H]+238.

Getting C17

[2-(2,3-Dihydro-1H-isoindole-4-yloxy)ethyl]dimethylamine

A solution of 2-(2,4-dimethoxybenzyl)-4-(2-dimethylaminoethoxy)-2,3-dihydro-1H-isoindole (170 mg, 0.48 mmol) in triperoxonane acid (0.5 ml) and anisole (0.5 ml) was heated to about 150ºc microwave irradiation for 10 minutes. The mixture was diluted with ethyl acetate and was extracted twice with water. The combined aqueous extracts were concentrated, giving specified in the title compound as a purple oil (240 mg, including residual TFA and/or water).1H-NMR (methanol-d4) 7,42 (1H, t), 7,07 (1H, d),? 7.04 baby mortality (1H, d), with 4.64 (4H, users), 4,47-of 4.44 (2H, m), 3,65-3,63 (2H, m), 3,01 (6H, s). MS: [M+H]+207.

Getting C18

4-(3-Morpholine-4-ylpropionic)-2,3-dihydro-1H-isoindole

A solution of 2-(2,4-dimethoxybenzyl)-4-(3-morpholine-4-ylpropionic)-2,3-dihydro-1H-isoindole (233 mg, 0,56 mmol) in triperoxonane acid (1.0 ml) and anisole (0.5 ml) was heated to about 150ºc under microwave irradiation for 10 minutes. The mixture was diluted with diethyl ether and was extracted twice with water. The combined aqueous extracts were concentrated, the resulting oil was dissolved in meta is Ola and concentrated in vacuum, what gave you specified in the title compound as a brown oil (348 mg, including residual TFA and/or water).1H-NMR (methanol-d4) 7,40 (1H, t), 7,03 (1H, d), of 6.99 (1H, d), 4,63 (2H, s), 4,59 (2H, s), is 4.21 (2H, t), 4,14-Android 4.04 (2H, m), 3,85-to 3.73 (2H, m), 3,61-to 3.52 (2H, m), 3,41-to 3.36 (2H, m), 3.25 to of 3.13 (2H, m), 2,32 was 2.25 (2H, m). MS: [M+H]+263.

Getting C19

Synthesis of triptoreline 4-bromo-2,3-dihydro-1H-isoindole

Obtained according to a similar method for 5-nitro-2,3-dihydro-1H-isoindole (described in obtaining C5).1H-NMR (DMSO-d6) 9,73 (2H, users), 7,60 (1H, d), was 7.45 (1H, d), 7,35 (1H, t)and 4.65 (2H, s)4,55 (2H, s).

Getting C20

Synthesis of 5-bromo-2,3-dihydro-1H-isoindole

A mixture of 4-Brattleboro anhydride (25 g) in formamide (75 ml) was heated at 200ºc is manageable for 16 hours, then was allowed to cool to room temperature. The reaction mixture was diluted with water (200 ml), filtered, the filter residue was washed with water then diethyl ether and sucked out on the filter to dryness, which gave of 20.85 g light mustard solids.

280 ml of 1M complex, borane-THF was added dropwise to a stirred solution of 4-bromophthalimide (of 20.85 g; 92,2 mmol) in anhydrous THF (200 ml) at 0ºC, then was heated at the boil under reflux overnight. The reaction was cooled to 0ºC, then carefully treated with methanol (100 ml), then 2M HCl (100 ml), then reali at boiling under reflux for 3 hours. The reaction mixture was cooled and boiling substances evaporated. The aqueous layer was diluted with water (100 ml), was extracted with DCM (×3). The aqueous layer was podslushivaet 2M NaOH and then was extracted with DCM (×3). The combined DCM extracts were dried (MgSO4), filtered and evaporated, giving of 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown viscous solid.1H-NMR (DMSO-d6) was 7.45 (1H, s), of 7.36 (1H, d), 7,20 (1H, d), of 4.05 (4H, s).

Getting C21

Synthesis of triptoreline methyl ester of 2,3-dihydro-1H-isoindole-5-carboxylic acid

In the methyl ether of 2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (receiving C6, product stage 2) remove the protective function according to a similar method for 5-nitro-2,3-dihydro-1H-isoindole (described in obtaining C5), which gave specified in the header of the connection.1H-NMR (DMSO-d6) to 9.70 (2H, users), of 8.00 (1H, s), 7,95 (1H, d), EUR 7.57 (1H, d), 4,60 (4H, s), is 2.88 (3H, s).

D. Synthesis basiliani resorcinol intermediate compounds

Obtaining D1

Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(2-methoxyethoxy)-1,3-dihydroindol-2-yl]methanone

(2,4-Bis-benzyloxy-5-isopropylphenyl)-(5-hydroxy-1,3-dihydroindol-2-yl)methanon (A2) of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (getting B10) and 5-hydroxyisoquinoline) (100 is g, 0.2 mmol), 1-chloro-2-methoxyethane (23,6 mg, 0.25 mmol) and K2CO3(to 34.5 mg, 0.25 mmol) were combined in DMF (4 ml) and was stirred for 2 hours at room temperature. Additionally added 0.25 mmol of 1-chloro-2-methoxyethane and K2CO3, then was heated at 90ºC for 16 hours. The reaction was cooled to room temperature and was diluted with EtOAc, then filtered. The filtrate was evaporated in vacuo, then purified column flash chromatography, the elution from 100% petroleum ether to 100% ethyl acetate, which gave 115 mg specified in the title compound, as a colorless gel. MS: [M+H]+552

Obtain D2

Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone

A mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-hydroxy-1,3-dihydroindol-2-yl)methanone (100 mg, 0.2 mmol), 4-(3-chlorpropyl)of the research (82 mg, 0.5 mmol) and K2CO3(104 mg, 0.75 mmol) in DMF (5 ml) was heated at 90ºC for 16 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was evaporated in vacuo, and purified flash column-chromatography, the elution mixtures 0-100% petroleum ether/EtOAc, then 0-10% MeOH/EtOAc, giving specified in the title compound as colorless gel (90,1 mg). MS: [M+H]+621.

Getting D3

Synthesis of (2,4-bis-benzyloxy-5-isopropyl the Nile)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]methanone

A mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-hydroxy-1,3-dihydroindol-2-yl)methanone (100 mg, 0.2 mmol), hydrochloride of 2-diethylaminoethylamine (72 mg, 0.5 mmol) and K2CO3(173 mg, 1.25 mmol) in DMF (5 ml) was heated at 90ºC for 16 hours. The reaction mixture was diluted with EtOAc and filtered. The reaction mixture was diluted with EtOAc and filtered. The filtrate was evaporated in vacuo, and purified flash column-chromatography, the elution 100% DCM, then 90% of DMAW 90, which gave specified in the title compound in the form of not quite white gel (79 mg). MS: [M+H]+565.

Obtaining D4

Synthesis of 2,4-bis-benzyloxy-5-isopropylbenzaldehyde

2,4-Bis-benzyloxy-5-isopropylbenzoic acid (getting B10) (0.2 g, of 0.53 mmol) was dissolved in DCM (10 ml) and treated with oxalylamino (1.5 g, 12 mmol) and catalytic amount of DMF. The reaction mixture was stirred at room temperature for 14 hours and then the solvent was removed in vacuum. The crude substance was dissolved in toluene and evaporated. The crude 2,4-bis-benzyloxy-5-isopropylbenzoic received in the form of an oil (200 mg).

Obtaining D5

Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-morpholine-4-yl-1,3-dihydroindol-2-yl)methanon

A solution of 2,4-bis-benzyloxy-5-isopr what eventing acid (505 mg; 1.3 mmol) (obtaining B5), triptorelin 5-nitroisoquinoline (360 mg; 1 equiv.), EDAC (300 mg; 1.2 equiv.), HOBt (210 mg; 1.2 equiv.) and NEt3(270 μl; 1.5 equiv.) in DMF (10 ml) was stirred at room temperature overnight, then evaporated in vacuum. The residue was distributed between EtOAc and 2M HCl, the separated EtOAc layer was washed with saturated NaHCO3, dried (MgSO4) and was evaporated. Purification column flash chromatography (1:4, then 1:2, then 1:1 EtOAc/petroleum ether as eluent) gave 460 mg (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-nitro-1,3-dihydroindol-2-yl)methanone. MS: [M+H]+523.

A solution of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-nitro-1,3-dihydroindol-2-yl)methanon (460 mg; 0.88 mmol) in ethanol (25 ml) was treated with chloride dihydrate tin(II) (1 g; 5 equiv.), then, they were heated at the boil under reflux overnight, then evaporated in vacuum. The residue was distributed between EtOAc and saturated NaHCO3separated EtOAc layer was dried (MgSO4) and was evaporated, which gave 380 mg (5-amino-1,3-dihydroindol-2-yl)-(2,4-bis-benzyloxy-5-isopropylphenyl)methanone.

A mixture of (5-amino-1,3-dihydroindol-2-yl)-(2,4-bis-benzyloxy-5-isopropylphenyl)methanone (100 mg; 0.2 mmol), bis(2-hloretilova)ether (30 μl; 1.1 equiv.), the base of Hongsa (Hunigs) (125 μl; 3.5 equiv.) and tetrabutylammonium (10 mg) in NMP (1 ml) was heated in a microwave synthesizer CEM at about 150ºc for 30 minutes was Additionally added to 30 μl of the base of Hongsa (Hunigs) and 125 μl of bis(2-hloretilova)ether and heating was repeated during the same time. The reaction mixture was distributed between EtOAc and a saturated solution of NH4Cl, separated EtOAc layer was washed over a saturated solution of NH4Cl, then a saturated solution of salt, dried (MgSO4) and was evaporated. Purification column flash chromatography (1:2, then 1:1 then 2:1 EtOAc/petroleum ether as eluent) gave 60 mg (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-morpholine-4-yl-1,3-dihydroindol-2-yl)methanone. MS: [M+H]+563.

Obtaining D6

Synthesis of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid

A solution of methyl ester of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (390 mg) in methanol (10 ml) and 2M NaOH (10 ml) was heated at 50ºC for 48 hours, then evaporated. The residue was acidified using 2M HCl, the solid was separated by filtration, washed with water and sucked out on the filter to dryness, which gave 255 mg of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid as a white solid. [M+H]+520.

EXAMPLES

The compounds presented in the table below were obtained according to the methods described above.

Methodtd align="justify"> Method A4. 3-ethoxy-4-hydroxybenzoic acid and isoindoline
The other roomConnectionChemical nameThese NMRMass spectrum
1(5-Chloro-2-hydroxyphenyl)-(1,3-dihydroindol-2-yl)methanonA1. From 5-chloro-2-hydroxybenzoic acid and isoindoline1H NMR (MeOH-d4) 7,20-7,42 (6H, m), 6,92 (1H, d), 4,94 (2H, s), 4,74 (2H, s)MS: [M+H]+274
2(3-tert-Butyl-4-hydroxyphenyl)-(2,3-dihydroindol-1-yl)methanonA2. From 3-tert-butyl-4-hydroxybenzoic acid and indoline1H NMR (DMSO-d6) 7,56 (2H, osirm), 7,40 (1H, s), 7,33 (1H, d), 7,26 (1H, d), 7,13 (1H, t), 6,98 (1H, t), 6,85 (1H, d), 4,07 (2H, t), is 3.08 (2H, t)to 1.38 (9H, s)MS: [M+H]+296
3(3-tert-Butyl-4-hydroxyphenyl)-(3,4-dihydro-2H-quinoline-1-yl)methanonA2. From 3-tert-butyl-4-hydroxybenzoic acid and 1,2,3,4-tetrahydroquinoline1H NMR (DMSO-d6) 11,05 (1H, users), 8,17 (1H, d), of 8.04 (2H, m), 7,88 (1H, d), to 7.67 (1H, t), 7,54 (1H, t), to 7.09 (1H, d), 3,39 (1H, is), of 3.28 (1H, m)of 1.40 (9H, s)of 1.07 (3H, m), 0,84 (1H, m)MS: [M+H]+310
4(3,4-Dihydro-1H-isoquinoline-2-yl)-(4-hydroxy-3-isopropylphenyl)metanoA2. 3-isopropyl-4-hydroxybenzoic acid and 1,2,3,4-tetrahydroisoquinoline1H NMR (DMSO-d6) 9,77 (1H, users), from 7.24 (1H, d), 7,17 (4H, s), 7,18 (1H, DD), at 6.84 (1H, d), and 4.68 (2H, s), 3,70 (2H, users), 3,23 (1H, m), 2,87 (2H, m)of 1.18 (6H, d)MS: [M+H]+296
5(1,3-Dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)metanoA2 and A5. From 2,4-Bis-benzyloxy-5-isopropylbenzoic acid (B9) and isoindoline1H NMR (DMSO-d6) there is a 10.03 (1H, s), 9,63 (1H, s), 7,29 (4H, osirm), 7,03 (1H, s)6,40 (1H, s), of 4.77 (4H, users), to 3.09 (1H, m)to 1.14 (6H, d)MS: [M+H]+298
63-tert-Butyl-4-hydroxyphenyl)-(l,4-dioxa-8 azaspiro[4.5]Dec-8-yl)methanonA4. From 3-tert-butyl-4-hydroxybenzoic acid and atelectasia 4-piperidone 1H NMR (DMSO-d6) 9,82 (1H, s), 7,22 (1H, s), 7,13 (1H, DD), PC 6.82 (1H, d), 3,91 (4H, s), 3,52 (4H, osirm), and 1.63 (4H, osirm), to 1.37 (9H, s)MS: [M+H]+320
7(3-tert-Butyl-4-hydroxyphenyl)-(1,3-dihydroindol-2-yl)methanonA4. From 3-tert-butyl-4-hydroxybenzoic acid and isoindoline1H NMR (DMSO-d6) 9,82 (1H, s), 7,41 (1H, s), 7,38 (2H, DD), 7,29 (3H, osirm), PC 6.82 (1H, d), 4,82 (4H, osirm), to 1.37 (9H, s)MS: [M+H]+296
8(3-tert-Butyl-4-hydroxyphenyl)pyrrolo[3,2-b]pyridine-1-ylmethanoneA4. From 3-tert-butyl-4-hydroxybenzoic acid and 1H-pyrrolo[3,2-b]pyridine1H NMR (DMSO-d6) to 8.57 (1H, DD), 8,43 (1H, d), 7,89 (1H, DD), 7,63 (1H, s), 7,56 (1H, DD), 7,35 (1H, m), to 7.09 (1H, d), at 6.84 (1H, DD), to 1.37 (9H, s)MS: [M+H]+295
98-(3-tert-Butyl-4-hydroxybenzoyl)-2-methyl-2,8-diazaspiro[4.5]Decan-1-heA4. From 3-tert-butyl-4-hydroxybenzoic acid the hydrochloride of 4-Spiro[3-(N-methyl-2-pyrrolidinone]piperidine 1H NMR (DMSO-d6) 9,82 (1H, s), 7,22 (1H, s), 7,13 (1H, DD), PC 6.82 (1H, d), 3,98 (2H, osirm), to 3.34 (2H, s), of 3.13 (2H, m), 2,71 (3H, s)of 1.92 (2H, t)to 1.60 (2H, m), USD 1.43 (2H, m)to 1.37 (9H, s)MS: [M+H]+345
10(1,3-Dihydroindol-2-yl)-(4-hydroxy-3-isopropylphenyl)metanoA4. 3-isopropyl-4-hydroxybenzoic acid and isoindoline1H NMR (DMSO-d6) 9,82 (1H, s), and 7.4 (2H, s), 7,38 (1H, DD), 7,30 (3H, m), PC 6.82 (1H, d), 4,82 (4H, DD), 3,23 (1H, m)of 1.23 (6H, s)MS: [M+H]+282
11(3-tert-Butyl-4-hydroxyphenyl)-(3,4-dihydro-1H-isoquinoline-2-yl)methanonA4. From 3-tert-butyl-4-hydroxybenzoic acid and 1,2,3,4-tetrahydroisoquinoline1H NMR (DMSO-d6) 7,22 (1H, s), 7,13 (5H, m), PC 6.82 (1H, d), 4,70 (2H, in), 3.75 (2H, users), 2,85 (2H, t), of 1.37 (9H, s)[M+H]+310
12(1,3-Dihydroindol-2-yl)-(5-ethyl-2,4-dihydroxyphenyl)metanoA2, A6 and A5. From 2,4-Bis-benzyloxy-5-bromans Inoi acid, isoindoline and vinyltrifluoroborate potassium1H NMR (MeOH-d4) 7,30 (4H, s), to 7.15 (1H, s)6,38 (1H, s), 4,91 (4H, s), 2,58 (2H, square), of 1.18 (3H, t)MS: [M+H]+284
13(5-Cyclopropyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanonA2, A6 and A5. From 2,4-Bis-benzyloxy-5-bromobenzoyl acid, isoindoline and cyclopropylboronic acid1H NMR (DMSO-d6) 7,40-of 7.23 (4H, m), of 6.73 (1H, s)6,40 (1H, s), and 4.75 (4H, users), with 1.92 (1H, m)to 0.78 (2H, m)of 0.53 (2H, m)MS: [M+H]+296
14(5-sec-Butyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanonA2, A6 and A5. Of the 2.4-Bis-benzyloxy-5-bromobenzoyl acid, isoindoline and 2-butene-2-Voronovo acid1H NMR (MeOH-d4) 7,30 (4H, s), to 7.15 (1H, s), to 6.39 (1H, s)to 4.92 (4H, s)of 3.00 (1H, square), and 1.63 (2H, m)of 1.18 (3H, t)to 0.88 (3H, t)MS: [M+H]+312
15(1,3-Dihydroindol-2-yl)-(3-ethoxy-4-hydroxyphenyl)metano1H NMR (DMSO-d6) was 7.45 (1H, users), 7,30 (3H, d), 7,18 (1H, d), was 7.08 (1H, DD), 6,85 (1H, d), is 4.85 (4H, s), 4,10 (2H, square), to 1.38 (3H, t)MS: [M+H]+284
16(1,3-Dihydroindol-2-yl)-(2,4-dihydroxyphenyl)metanoA2 and A5. From 2,4-Bis-benzyloxy-5-bromobenzoyl acid and isoindoline1H NMR (MeOH-d4) 7,30 (5H, m), to 7.15 (1H, s), 6.42 per (1H, s)6,38 (1H, s)to 4.92 (4H, s)MS: [M+H]+256

EXAMPLE 17

Synthesis of (5-chloro-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanone

A solution of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (getting B10) (0,451 g, 1.2 mmol), EDC (0,276 mg, 1.44 mmol), HOAt (0,196 mg, 1.44 mmol), triethylamine (0.5 ml, 3.6 mmol) and 5-chloro-2,3-dihydro-1H-isoindole (0.187 g, 1.2 mmol) (obtaining C3) in DMF (5 ml) was stirred at room temperature for 16 hours, then evaporated in vacuum. The crude substance was dissolved in ethyl acetate and was extracted twice with saturated NaHCO3organic fractions were washed with water three times, then was evaporated in vacuo, which gave 0.5 g of 2,4-bis-benzyloxy-5-isopropylphenyl the)-(5-chloro-1,3-dihydroindol-2-yl)methanone. MS: [M+H]+512

Trichloride boron (1M in DCM) was added dropwise to a solution of 2,4-bis-benzyloxy-5-isopropylphenyl)-(5-chloro-1,3-dihydroindol-2-yl)methanone (0.5 g, 0.97 mmol) in dry DCM (10 ml) at 0ºC under nitrogen atmosphere, and then was stirred for at 0ºC for 1 hour, heated to room temperature and was stirred for another 3 hours. The reaction was suppressed by the ice, were distributed between DCM and water. DCM layer was dried (MgSO4), was evaporated in vacuo, then purified column flash chromatography on silica gel with elution with 80% petroleum ether in EtOAc, which gave 0.1 g (5-chloro-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanone in the form of a white solid. MS: [M+H]+332.1H-NMR (DMSO-d6) 10,0 (1H, s) 9,60 (1H, s), 7,45 (1H, users), 7,33 (2H, users), 7,0 (1H, s)of 6.4 (1H, s), 4,80 (4H, users), 3,10 (1H, m)and 1.15 (6H, d).

EXAMPLE 18

Synthesis of hydrochloride [5-(3-aminopropoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanone.

A solution of tert-butyl methyl ether {3-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]propyl}carbamino acid (example 46) (1 g) in EtOAc (10 ml) was treated with a saturated solution of HCl in EtOAC (20 ml), then stirred at room temperature for 2 hours. The reaction mixture was evaporated and re-evaporated with ethanol (3 times). Specified in the header soedineniya in the form of a cream foam (840 mg). 1H-NMR (DMSO-d6) of 10.05 (1H, users), a 9.60 (1H, s), 7,88 (3H, users), 7,30-to 7.18 (1H, m), 7,05(1H, s), 7,00-6,85 (2H, m), 6.42 per (1H, s), and 4.75 (2H, users) 4,70 (2H, users), of 4.05 (2H, t), 3,10 (1H, m), 3.00 and-2,95 (2H, m), from 2.00 (2H, TT)and 1.15 (6H d). MS: [M+H]+371.

EXAMPLE 19

(5-Bromo-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon

A solution of 5-bromo-2,4-dihydroxybenzoic acid (520 mg, of 2.33 mmol) in DMF (5 ml) was treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (471 mg, 2.45 mmol), then HOBt (362 mg, 2.68 mmol). After 25 min was added 2,3-dihydro-1H-isoindole (0.5 ml, 2,63 mmol), then the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, then the residue was dissolved in ethyl acetate and washed with 1 N. hydrochloric acid, saturated sodium bicarbonate solution and saturated salt solution, then dried (MgSO4) and concentrated. The residue is triturated in methanol, which gave specified in the title compound as a gray solid (328 mg, 44%).1H-NMR (DMSO-d6) 10,45 (1H, s), 10,32 (1H, s), of 7.36 (1H, users), 7,35 (1H, s), 7,28 (3H, users), 6,59 (1H, s), of 4.77 (2H, users), 4,71 (2H, users). MS: [M+H]+332/334.

EXAMPLE 20

(1,3-Dihydroindol-2-yl)-(2,4-dihydroxy-5-triptoreline)metano

20A. (2,4-Bis-benzyloxy-5-bromophenyl)-(1,3-dihydroindol-2-yl)methanon

According to the General method A2, 2,4-bis-benzyloxy-5-brabantia acid (1,02 g, 2,47 mmol) gave a residue that was purified flash chromatography on silica gel (gradient 0-20% ethyl acetate/petroleum ether)gave specified in the title compound as a white crystalline solid (501 mg, 39%).1H-NMR (methanol-d4) 7,52 (1H, s), 7,49-7,46 (2H, m), 7,42-7,37 (2H, m), 7,34 (t, 2H), 7,30-7,24 (4H, m), 7.23 percent-7,20 (3H, m), 7,16 (1H, d), 6,94 (1H, s), of 5.24 (2H, s), 5,16 (2H, s), a 4.86 (2H, s), 4,60 (2H, s). MS: [M+H]+514/516.

20B. (2,4-Bis-benzyloxy-5-triptoreline)-(1,3-dihydroindol-2-yl)methanon

A mixture of (2,4-bis-benzyloxy-5-bromophenyl)-(1,3-dihydroindol-2-yl)methanone (491 mg, 0.95 mmol), triptoreline sodium (649 mg, 4.8 mmol) and copper iodide(I) (364 mg, at 1.91 mmol) was dried in vacuum (0,04 mbar) for 6 hours. The flask was filled with nitrogen, was added DMF (5 ml) and the mixture was heated at about 150ºc for 17 hours. After cooling to room temperature the mixture was diluted with DCM (100 ml) and filtered through celite, washing DCM. The filtrate was concentrated to dryness, and the residue was partially purified flash chromatography on silica gel (gradient 0-20% ethyl acetate/petroleum ether). The most pure fraction was recrystallized from methanol, giving specified in the title compound as a white solid (140 mg, 29%).1H-NMR (methanol-d4) 7,60 (1H, s)of 7.48-7,44 (2H, m), 7,40 (2H, t), 7,37-7,21 (m, 9H), 7,17 (1H, d), 7,02 (1H, s), 29 (2H, C)of 5.24 (2H, s), 4,88 (2H, s), to 4.62 (2H, s). MS: [M+H]+504.

20C. (1,3-Dihydroindol-2-yl)-(2,4-dihydroxy-5-triptoreline)metano

A solution of (2,4-bis-benzyloxy-5-triptoreline)-(1,3-dihydroindol-2-yl)methanone (140 mg, 0.28 mmol) in methanol (5 ml) was first made at atmospheric pressure over 10% palladium on carbon (34 mg) for 4 hours. Additionally add a portion of the catalyst (31 mg) and the hydrogenation was continued for another 1.5 hours. The mixture was filtered through celite while elution with methanol, then the filtrate was concentrated in vacuo, which gave specified in the title compound as a white solid (91 mg, quantitative).1H-NMR (DMSO-d6) 10,79 (1H, s), 10,70 (1H, s), 7,40-to 7.35 (2H, m), 7,31-to 7.35 (3H, m), is 6.61 (1H, s), 4,79 (2H, users), and 4.68 (2H, users). MS: [M+H]+324.

EXAMPLE 21

(2,4-Dihydroxy-5-isopropylphenyl-{4-[2-(2-methoxyethoxy)ethoxy]-1,3-dihydroindol-2-yl}metano

A solution of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (96 mg, 0.26 mmol) and DMF (1 drop, catalytic) in DCM (3 ml) was cooled on ice, then treated with oxalylamino (112 μl, 1.28 mmol). After 2 hours the mixture was concentrated in vacuo, then azeotrope was distilled with toluene. The obtained acid chloride was dissolved in DCM (4 ml) was added to a solution of 4-[2-(2-methoxyethoxy)ethoxy]-2,3-dihydro-1H-isoindol is a (0.26 mmol, presumably the quantitative output of the preceding stage (dibenzylamine in obtaining C16)) and triethylamine (of 0.20 ml, 1.4 mmol) in DCM (1 ml). After 2 hours the mixture was diluted with ethyl acetate and washed with 1 N. hydrochloric acid, saturated salt solution, sodium bicarbonate solution and saturated salt solution. The organic phase was dried (MgSO4) and concentrated, giving a black residue. It was partially purified flash chromatography on silica gel (gradient 20-33% ethyl acetate/petroleum ether)gave the contaminated sample of intermediate compounds (2,4-bis-benzyloxy-5-isopropylphenyl)-{4-[2-(2-methoxyethoxy)ethoxy]-1,3-dihydroindol-2-yl}methanone.

A solution of (2,4-bis-benzyloxy-5-isopropylphenyl)-{4-[2-(2-methoxyethoxy)ethoxy]-1,3-dihydroindol-2-yl}methanone in methanol (5 ml) was first made at atmospheric pressure over 10% palladium on carbon (12 mg) for 3 hours. Additionally add a portion of the catalyst (12 mg) and the hydrogenation was continued for another 7 hours. The mixture was filtered through celite while elution with methanol, then the filtrate was concentrated in vacuo, which gave a residue, which was purified preparative HPLC (basic method). This led to the number indicated in the title compound, as a white solid (17 mg, 16% in two stages).1H-NMR (methanol-d4) to 7.25 (1H, t), 7,17 (1H, s), 6,95-PC 6.82 (2H, m), 6,37 (1H,s), 4,89 (2H, users), a 4.83 (overlaps with H2O, users), to 4.16 (2H, users), 3,82 (2H, users), 3,66 (2H, users), 3,52 (2H, users), 3,39 of 3.28 (overlaps with MeOH, m), 3,20 (1H, Sept.), to 1.21 (6H, d). MS: [M+H]+416.

EXAMPLE 22

(2,4-Dihydroxy-5-isopropylphenyl)-[4-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano

A solution of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (189 mg, 0.50 mmol) and DMF (1 drop, catalytic) in DCM (5 ml) was cooled on ice, then treated with oxalylamino (112 μl, 1.28 mmol). After 2 hours the mixture was concentrated in vacuo, then azeotropic drove with toluene. The obtained acid chloride was dissolved in DCM (5 ml) was added to a solution of [2-(2,3-dihydro-1H-isoindole-4-yloxy)ethyl]dimethylamine (0.48 mmol, presumably quantitative output at the previous stage (C 17)) and triethylamine (and 0.50 ml, 3.6 mmol) in DCM (3 ml). After 16 hours, the mixture was diluted with ethyl acetate and washed with saturated potassium carbonate solution and saturated salt solution. The organic phase was dried (MgSO4) and concentrated, giving a residue that was partially purified flash chromatography on silica gel (gradient of 5-10% methanol/DCM, then 10% 2M methanolic ammonia/DCM)gave the contaminated sample of intermediate compounds (2,4-bis-benzyloxy-5-isopropylphenyl)-[4-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]methanone.

The solution (2,bis-benzyloxy-5-isopropylphenyl)-[4-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]methanone in methanol (5 ml) was first made at atmospheric pressure over 10% palladium on carbon (40 mg) for 22 hours. The mixture was filtered through celite while elution with methanol, then the filtrate was concentrated in vacuo, the resulting residue, which was purified preparative HPLC (acidic method). This led to formiate salt specified in the title compound, as a white solid (9 mg, 5% in two stages).1H-NMR (methanol-d4) charged 8.52 (0,7H, s), 7,29 (1H, t), 7,17 (1H, s), 6,98-6,86 (2H, m including of 6.90 (1H, d)), 6,37 (1H, s), 4,89 (2H, users), to 4.87 (2H, users), 4,28 (2H, users), 3,29-3,5 (3H, m including 3,20 (1H, Sept.)), 2,81 is 2.51 (6H, userd), to 1.21 (6H, d). MS: [M+H]+385.

EXAMPLE 23

(2,4-Dihydroxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano

A solution of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (210 mg, 0,56 mmol) and diisopropylethylamine (0.25 ml, 1.4 mmol) in DCM (5 ml) was treated with hexaphosphate postreperfusion (PyBrOP) (287 mg, of 0.62 mmol). After 1 hour, the solution was added 4-(3-morpholine-4-ylpropionic)-2,3-dihydro-1H-isoindole (0,56 mmol, presumably quantitative output at the previous stage (C18)in DCM (5 ml). After 4 hours the mixture was diluted with ethyl acetate and washed with water, 1N-sodium hydroxide solution and saturated salt solution. The organic phase was dried (MgSO4) and concentrated, giving a residue that was adsorbing on SCX-column. The column was washed with a mixture of 10% methanol/DCM, then the product of the t was suirable 25% 2M methanolic ammonia/DCM), that gave the contaminated sample of intermediate compounds (2,4-bis-benzyloxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano.

A solution of (2,4-bis-benzyloxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone in methanol (5 ml) was first made at atmospheric pressure over 10% palladium on carbon (45 mg) for 4 hours. The mixture was filtered through celite while elution with methanol, then the filtrate was concentrated in vacuo, which gave a residue, which was purified preparative HPLC (alkaline). This led to the number indicated in the title compound as a white solid (16 mg, 6% in two stages).1H-NMR (methanol-d4) of 7.24 (1H, t), 7,18 (1H, s), 6.89 in (1H, d), at 6.84 (1H, d), 6,37 (1H, s), to 4.87 (2H, users), 4,78 (2H, users), 4,11-Android 4.04 (2H, m), 3.72 points-3,66 (4H, m), 3,21 (1H, Sept.), 2,60-to 2.42 (6H, m), 2.05 is-of 1.92 (2H, m)to 1.21 (6H, d). MS: [M+H]+441.

EXAMPLES 24-47

Connection examples 24-47 was obtained by following the above methods.

The other roomConnectionChemical nameMethodThese NMRMass spectrum
24(3-terbutyl-4-hydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon A2 and A5. From (Z)-4-benzyloxy-3-(1-methylpropenyl)benzoic acid and isoindoline1H NMR (DMSO-d6) 9,73 (1H, users), 7,37 (1H, d), 7,32 (1H, DD), 7,30 (4H, users), 6,86 (1H, d), to 4.87 (2H, s), 4,82 (2H, s), 3,03 (1H, m), and 1.63 (1H, m), of 1.57 (1H, m)to 1.19 (3H, d), of 0.82 (3H, t)[M+H]+296
25(5-tert-Butyl-2,4-dihydroxyphenyl-2,4-dihydroindol-2-yl)methanonA2 and A5. From 2,4-bis-benzyloxy-5-tert-butylbenzoic acid and isoindoline1H NMR (DMSO-d6) 7,34 (2H, m), 7,29 (2H, m), 7,10 (1H, s), 6,33 (1H, s), a 4.83 (4H, s)of 1.35 (9H, s)MS: [M+H]+312
26(5-Chloro-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanonA2 and A3. From 2,4-bis-benzyloxy-5-chlorbenzoyl acid and isoindoline1H NMR (DMSO-d6) 10,42 (1H, s), 10,33 (1H, s), 7,38 (2H, m), 7,30 (2H, m), 7,24 (1H, s), 6,60 (1H, s), 4,78 (2H, users), 4,72 (2H, users)MS: [M+H]+290
27(1,3-Dihydroindol-2-yl)-(2-hydroxy-5-isopropyl-4-methoxy who enyl)metano A2, A5 and A7. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid and isoindoline1H NMR (DMSO-d6) of 10.21 (1H, users), 7,33 (2H, users), 7,28 (2H, users), 7,13 (1H, s), 6,50 (1H, s), 4,80 (4H, users), with 3.79 (3H, s)and 3.15 (1H, m)to 1.14 (6H, d)MS: [M+H]+312
28(4,7-debtor-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)metanoA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid and 4,7-depersonalise1H NMR (DMSO-d6) becomes 9.97 (1H, users), to 9.66 (1H, users), 7,22 (2H, DD), 7,03 (1H, s), 6.42 per (1H, s), 4,84 (4H, users), 3,10 (1H, m)of 1.13 (6H, d)MS: [M+H]+334
29(2,4-dihydroxy-5-isopropylphenyl)-(5-fluoro-1,3-dihydroindol-2-yl)methanonA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid and 5-fluoro-isoindoline [U.S. patent 5026856]1H NMR (DMSO-d6) 10,02 (1H, users), 9,58 (1H, s), 7,37 (1H, osirm), 7,20 (1H, osirm), 7,12 (1H, TD),? 7.04 baby mortality (1H, s)6,41 (1H, s), 4,78 (2H, users), and 4.75 (2H, users), 3,11 (1H, m)of 1.16 (6H, d)MS: [M+H]+316
30 (1,3-dihydroindol-2-yl)-(3-fluoro-2,4-dihydroxy-5-isopropylphenyl)metanoA8. From (1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanone1H NMR (DMSO-d6) 12,23 (1H, users), 7,39 (1H, m), 7,35-of 7.25 (3H, m), at 6.84 (1H, d), of 5.53 (1H, s), 4-74 (2H, s), 4,59 (2H, s), 2,52 (1H, m), is 1.11 (3H, d), is 0.84 (3H, d);19F NMR (DMSO-d6) to 19.3MS: [M+H]+316
31(1,3-dihydroindol-2-yl)-(2-fluoro-4,6-dihydroxy-3-isopropylphenyl)metanoA8. From (1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanone1H NMR (DMSO-d6) a 12.03 (1H, users), 7,40-to 7.35 (2H, m), 7,33-7,28 (2H, m), 6,53 (1H, userd), of 5.53 (1H, s), 5, 07 (1H, userd), to 4.98 (1H, userd), 4,79 (2H, s), 2,90 (1H, m)of 1.03 (6H, m);19F1H NMR (DMSO-d6) 24,9MS: [M+H]+316
32hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-(4-fluoro-1,3-dihydroindol-2-yl)methanoneFrom 2,4-bis-benzyloxy-5-isopropylbenzoic acid (B10) and 4-fluoro-2,3-dihydro-1H-isoindole1H NMR (DMSO-d6) 735 (2H, m), 7,20 (1H, m)and 7.1 (1H, t), of 7.0 (1H, s)of 6.4 (1H, s), 4,80 (4H, users), of 1.20 (6H, s)MS: [M+H]+316
33(5-chloro-6-methoxy-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)metanoA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (B10) and 5-chloro-6-methoxy-2,3-dihydro-1H-isoindole1H NMR (Me-d3-OD) to 7.32 (1H, s), 7,17 (1H, s), 7,05 (1H, s), 6,37 (1H, s), 4,89 (2H, s)to 3.89 (3H, s)to 3.36 (3H, m)of 1.23 (6H, d)MS: [M+H]+362
34(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-methoxyethoxy)-1,3-dihydroindol-2-yl]metanoA5. From (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(2-methoxyethoxy)-1,3-dihydroindol-2-yl]methanone1H NMR (DMSO-d6) 10,02 (1H, s), a 9.60 (1H, s), 7,22 (1H, users), 7,03 (1H, s), make 6.90 (1H, users), 6,85 (1H, d), to 6.4 (1H, s), 4,74 (4H, userd), 4,08 (2H, users), the 3.65 (2H, t), 3, 18-3,03 (1H, m)and 1.15 (6H, s), 3,30 (3H, s)MS: [M+H]+372
35(2,4-dihydroxy-5-isopropylphenyl)-[5-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano A5. From (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone1H NMR (DMSO-d6) 10,02 (1H, s), a 9.60 (1H, s), 7,22 (1H, users), 7,03 (1H, s), make 6.90 (1H, users), 6,85 (1H, d), to 6.4 (1H, s), 4,74 (4H, userd), 4,08 (2H, users), 3,55 (4H, users), 3, 18-3,03 (1H, m), 2.40 a (2H, s), of 2.38 (4H, users), of 1.85 (2H, t)and 1.15 (6H, s)MS: [M+H]+441
36(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metanoA5. From (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]methanone1H NMR (DMSO-d6) 10,02 (1H, s), a 9.60 (1H, s), 7,22 (1H, users), 7,03 (1H, s), make 6.90 (1H, users), 6,85 (1H, d), 6,40 (1H, s), 4,74 (4H, userd), 4,08 (2H, users), 3,18-3,03 (1H, m), 2,71 (2H, users), is 2.30 (6H, s)and 1.15 (6H, s)MS: [M+H]+385
37(2,4-dihydroxy-5-isopropylphenyl)-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanonA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and 2-oxa-5-azabicyclo[2.2.1]heptane1H NMR (DMSO-d6) for 9.64 (1H, s), 7,02 (1H, s), of 6.31 (1H, s)and 4.65 (2H, s), of 3.78 (2H, DD), and 3.31 (2H, s), of 3.07 (1H, m), 1.77 in (2H, m), 1,10 (6H, m)MS: [M+H]+278
38(3,4-dihydro-1H-isoquinoline-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)metanoA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and 1,2,3,4-tetrahydroisoquinoline1H NMR (Me-d3-OD) 7,19 (1H, s), 7,14-to 7.09 (1H, users), 7,02 (1H, s), 6,37 (1H, s), and 4.75 (2H, s), 3,80 (2H, t), 3,24 is 3.15 (1H, m), 2,95 (2H, t)to 1.19 (6H, d)MS: [M+H]+312
39(5-amino-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)metanoA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and TFA-salt 5-nitroisoquinoline (C5, but omitting the stage of hydrogenation)1H NMR (DMSO-d6) 7,05 (1H, s), 6,95-6,85 (1H, m), 6,60-6,50 (2H, m), and 6.25 (1H, s), 4.6 to 4.5 (4H, m), 3,10 (1H, H), of 1.10 (6H, d)MS: [M+H]+313
40(2,4-dihydroxy-5-isopropylphenyl)-(5-methoxy-1,3-dihydroindol-2-yl)methanonA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid obtaining B5) and 5-methoxyindole 1H NMR (DMSO-d6) of 10.05 (1H, s), a 9.60 (1H, s), 7,30-to 7.15 (1H, m), 7,05 (1H, s), 7,00-6,85 (1H, m), PC 6.82 (1H, d), 6,40 (1H, s), and 4.75 (2H, s) 4,70 (2H, in), 3.75 (3H, s), 3,10 (1H, m)of 1.13 (6H, d)MS: [M+H]+328
41(2,4-dihydroxy-5-isopropylphenyl)-(5-morpholine-4-yl-1,3-dihydroindol-2-yl)methanonA5. From (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-morpholine-4-yl-1,3-dihydroindol-2-yl)methanone (D5)1H NMR (DMSO-d6) 9,60 (1H, users), 7,30-to 7.15 (1H, m), 7,05 (1H, s), 7,00-of 6.90 (2H, m), 6,40 (1H, s), and 4.75 (2H, s)4,70 (2H, in), 3.75 (4H, m), 3.15 and was 3.05 (5H, m)and 1.15 (6H, d)MS: [M+H]+383
42(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metanoAs in example 41, but using the hydrochloride of bis(2-chloroethyl)methylamine in stage 21H NMR (DMSO-d6) 7,30-to 7.15 (1H, m), 7,05 (1H, s), 6,95-6,85 (2H, m), 6,40 (1H, s), 4-70 (2H, users) the 4.65 (2H, users), 3,15 was 3.05 (5H, m), of 2.45 (4H, m), of 2.20 (4H, s), of 1.85 (3H, s)and 1.15 (6H, d)MS: [M+H]+396
43IU the silt ester 2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid A2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and TFA-salt of methyl ester of 2,3-dihydro-1H-isoindole-5-carboxylic acid (getting C21)1H NMR (DMSO-d6) of 10.05 (1H,users), a 9.60 (1H, s), 8,00-a 7.92 (1H, m), of 7.90 (1H, s), 7,55-7,42 (1H, m), 7,05 (1H, d), 6,40 (1H, s), is 4.85 (4H, users) of 3.85 (3H, s), 3,10 (1H, m)of 1.13 (6H, d)MS: [M+H]+356
442-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acidA5. From 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid1H NMR (DMSO-d6) 12,90 (1H, users), of 10.05 (1H, users), a 9.60 (1H, s), 8,00-a 7.92 (1H, m), of 7.90 (1H, d), 7,55-7,40 (1H, m), 7,05 (1H, d), of 6.45 (1H, s), is 4.85 (4H, users) 3,10 (1H, m)and 1.15 (6H, d)MS: [M+H]+342
45hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-(5-morpholine-4-ylmethyl-1,3-dihydroindol-2-yl)methanoneA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and DATEFORMAT 5-morpholine-4-ylmethyl-2,3-dihydro-1H-isoindole (C6)1H NMR (DMSO-d6) 11,03 1H, users), of 10.05 (1H, users), 9,78 (1H, users), 7,60-7,38 (3H, m), 7,05 (1H, s), of 6.45 (1H, s), 4,80 (4H, m)to 4.33 (2H, d), 3.95 to of 3.85 (2H, m), 3,32-up 3.22 (2H, m), 3,28-of 3.00 (5H, m)and 1.15 (6H, d)MS: [M+H]+397
46tert-butyl ether {3-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]propyl}carbamino acidAs in example 34, A2 (benzyloxy-5-isopropylbenzoic acid (receiving B5) and 5-hydroxyisoquinoline), alkylation using 3-(BOC-amino)propyl bromide, then A51H NMR (DMSO-d6) of 10.05 (1H, users), a 9.60 (1H, s), 7,30-to 7.15 (1H, m), 7,05 (1H, s), 6,98-to 6.80 (3H, m), 6,40 (1 H, s), and 4.75 (2H, users) 4,70 (2H, users), of 3.95 (2H, s), 3, 15-3,05 (3H, m), of 1.80 (2H, TT), to 1.37 (9H, s)and 1.15 (6H, d)MS: [M+H]+471
47(2,4-dihydroxy-5-isopropylphenyl)-(5-methyl-1,3-dihydroindol-2-yl)methanonA2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and DATEFORMAT 5-morpholine-4-ylmethyl-2,3-dihydro-1H-isoindole (C6), a byproduct from example 451H NMR (DMSO-d6) of 10.05 (1H, s), a 9.60 (1H, s), 7,25-was 7.08 (3H, m), 7,05 (1H, s)6,40 (1H, s), and 4.75 (4H, m), 3,10 (1H, m), 2,30 (1H, s)and 1.15 (6H, d) MS: [M+H]+312

EXAMPLE 48

Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(2-isopropylaminoethyl)-1,3-dihydroindol-2-yl]methanone

To a suspension of the hydrochloride [5-(3-aminoethoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanone (example 57) (250 mg, 0,702 mmol) in 1,2-dichloroethane (10 ml) was added acetone (62 μl, 0,842 mmol), triacetoxyborohydride sodium (178 mg, 0,842 mmol) and acetic acid (48 μl, 0,842 mmol), then heated at 60ºC for 24 hours. To the reaction mixture was further added acetone (52 μl, 0,702 mmol), triacetoxyborohydride sodium (149 mg, 0,702 mmol), acetic acid (40 μl, 0,702 mmol) and was heated at 60ºC for another 2 hours. The reaction mixture is then filtered and the mother liquor was purified flash chromatography [Biotage SP4: 25 m, flow rate 25 ml/min, gradient 20%-100% DMAW 90 in DCM)gave (2,4-dihydroxy-5-isopropylphenyl)-[5-(2-isopropylaminoethyl)-1,3-dihydroindol-2-yl]metano in the form of a light brown viscous oil (140 mg, 50%).1H-NMR (DMSO-d6) of 10.05 (1H, users); a 9.60 (1H, users); of 7.23 (1H, users); 7,05 (1H, s); 6,93 (1H, users); 6,85 (1H, userd); 6,40 (1H, s); 4,70 (4H, osirm); 4,00 (2H, t); 3,10 (1H, m); 2,90 (2H, t); 2,80 (1H, m); to 1.15 (6H, d); 1,00 (6H, d). MS: [M+H]+399.

EXAMPLE 49

Synthesis of N-{2-[2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]ethyl}-2-morpholine-4-ylacetamide

To a solution of hydrochloride [5-(3-aminoethoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanone (100 mg, 0,255 mmol) in DMF (10 ml) was added EDC (59 mg, 0,306 mmol), HOBt (41 mg, 0,306 mmol), morpholine-4-luksusowe acid (37 mg, 0,255 mmol) and triethylamine (43 μl, 0,306 mmol) and stirred at ambient temperature for one hour. To the reaction mixture was further added EDC (20 mg, 0.104 g mmol), HOBt (14 mg, 0.104 g mmol), morpholine-4-luksusowe acid (12 mg, 0,083 mmol) and triethylamine (14 μl, 0,100 mmol) and stirred at ambient temperature for another 2 hours. The solvent was removed in vacuum. The residue was purified flash chromatography [Biotage SP4: 25S, flow rate 25 ml/min, gradient from 20% DMAW 90 in DCM to 100% DMAW 90], then preparative HPLC, which gave N-{2-[2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]ethyl}-2-morpholine-4-ylacetamide in the form of a colorless viscous oil (40 mg, 33%).1H-NMR (Me-d3-OD) 7,20 (1H, users); to 7.18 (1H, s); make 6.90 (2H, osirm); 6,40 (1H, s); 4,10 (2H, t); to 3.73 (4H, m), 3,63 (2H, t); 3,20 (1H, m); 3,18 (2H, s); 2,60 (4H, m); 1,25 (6H, d). MS: [M+H]+484.

EXAMPLE 50

Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone

50A. Synthesis of tert-butyl ester 5-bromo-1,3-dihydroindol-2-carboxylic acid

A mixture of 5-bromo-2,3-dihydro-1H-isoindole (1.26 g; 6 mmol), di-tert-BUTYLCARBAMATE (1,53 g; 1.1 equiv.) and 4-dimethylaminopyridine (catalytic amount) in DMF (20 ml) was stirred at room temperature overnight, then evaporated. The residue was distributed between EtOAc and a saturated solution of salt, separated EtOAc layer was dried (MgSO4) and was evaporated. Purification column flash chromatography using a Biotage SP4 (4OS, 40 ml/min), while elution 0%-5% MeOH/DCM, to give 695 mg tert-butyl ester 5-bromo-1,3-dihydroindol-2-carboxylic acid as a brown resin.1H-NMR (DMSO-d6) of 7.55 (1H, d), of 7.48 (1H, d), 7,30 (1H, DD), 4,63-4,51 (4H, m)of 1.46 (9H, s).

50B. Synthesis of tert-butyl ester 5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-carboxylic acid

0,69 ml n-Utility (2.5m solution in hexane) was added dropwise to a stirred solution of tert-butyl ester 5-bromo-1,3-dihydroindol-2-carboxylic acid (429 mg; 1.44 mmol) in anhydrous THF (10 ml) at-78ºC under nitrogen atmosphere. The reaction mixture was stirred for 50 minutes, then was added 1-methyl-4-piperidone (212 μl; 1.2 equiv.) and was stirred at-78ºC for another 60 minutes, then heated to room temperature. The reaction was suppressed with a saturated solution of ammonium chloride, then was extracted with EtOAc. The EtOAc layer was washed with saturated NaHCO3, a saturated solution of salt, dried (MgSO4) and was evaporated. Purification column flash chromatography on SO 2when a gradient elution from 0% to 10% 2M methanolic ammonia in DCM, gave 111 mg tert-butyl ester 5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-carboxylic acid as a colourless oil.

50C. Synthesis of 4-(2,3-dihydro-1H-isoindole-5-yl)-1-methylpiperidin-4-ol

A solution of tert-butyl ester 5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-carboxylic acid (107 mg; 0.32 mmol) in THF (4 ml) was treated with concentrated hydrochloric acid (1.5 ml), then heated at the boil under reflux for 4 hours, then evaporated and re-evaporated with toluene, which gave the dihydrochloride of 4-(2,3-dihydro-1H-isoindole-5-yl)-1-methylpiperidin-4-ol as a brown resin.

50D. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-inmatea

A solution of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (145 mg; 1.2 equiv.) in DCM (5 ml) was treated with EDC (80 mg, 1.3 equiv.) and HOAt (66 mg; 1.5 equiv.), then was stirred at room temperature for 30 minutes. The resulting solution was then added to the mixture of the dihydrochloride of 4-(2,3-dihydro-1H-isoindole-5-yl)-1-methylpiperidin-4-ol (112 mg; 0.32 mmol) and triethylamine (90 μl; 2 equiv.) in THF (5 ml) and DMF (2 ml), then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, p is washed with water, 1N NaOH and saturated salt solution, was separated EtOAc layer was dried (MgSO4) and was evaporated. Purification column flash chromatography on SiO2when a gradient elution from 0% to 5% 2M methanolic ammonia in DCM resulted in 104 mg (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone as a yellow glassy substance.

50E. Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone

Hydrogenation of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone (as described in method A5) led to 72 mg specified in the title compound, in the form of a cream solid.1H-NMR (Me-d3-OD) to 7.35 (2H, m), 7,18 (1H, osirm) was 7.08 (1H, s), and 6.25 (1H, s), 4,78 (4H, m), 3,10 (1H, m), 2,65 (2H, m), of 2.45 (2H, m), of 2.25 (3H, s), from 2.00 (2H, m), of 1.65 (2H, m), 1,10 (6H, d). MS: [M+H]+411.

EXAMPLE 51

Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}methanone

51A. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-bromo-1,3-dihydroindol-2-yl)methanone

A solution of benzyloxy-5-isopropylbenzoic acid (2.85 g; 7.6 mmol), 5-bromo-2,3-dihydro-1H-isoindole (1.5 g; 1 equiv.), EDC (1,75 g; 1.2 equiv.) and HOBt (1.25 g; 1.2 equiv.) in DMF (25 ml) was stirred at room the temperature during the night, then was evaporated. The residue was dissolved in EtOAc, washed with 2M HCl, then with saturated NaHCO3, dried (MgSO4) and was evaporated. Purification using a Biotage SP4 (4OS, 40 ml/min), while elution systems 1:4-1:3-1:2 EtOAc/petroleum ether, gave of 2.45 g of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-bromo-1,3-dihydroindol-2-yl)methanone in the form of a light brown solid.

51B. (2,4-bis-benzyloxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}metano

A solution of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-bromo-1,3-dihydroindol-2-yl)methanone (200 mg; 0.36 mmol) and 1-methyl-4-(piperidine-4-yl)piperazine (80 mg; 1.2 equiv.) in toluene (5 ml) was treated with (2-biphenyl)di-tert-butylphosphino (6 mg; 5 mol.%), Tris(dibenzylidene)palladium(0) (10 mg; 2.5 mol%) and tert-piperonyl sodium (50 mg; 1.4 equiv.), then was heated at 120ºC for 30 minutes in a microwave synthesizer for CEM test experiments. The reaction mixture was diluted with DCM, washed with a saturated solution of salt, dried (MgSO4) and was evaporated. Purification column flash chromatography (Biotage SP4 - 25S, 25 ml/min) with elution DMAW 240-120-90 with subsequent evaporation containing the product fractions gave 105 mg (2,4-bis-benzyloxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}methanone in the form of acetate salt.

51C. Hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}methanone

The salt solution with acetic acid (2,4-bis-benzyloxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}methanone in methanol (10 ml) was treated with 10% palladium on carbon (wet), was first made at room temperature and pressure overnight, then filtered and evaporated. The crude compound was purified column flash chromatography (Biotage SP4 - 25S, 25 ml/min), while elution DMAW 240-120-90-60. The fractions containing the product was evaporated, and treated with saturated HCl in EtOAc, then was evaporated, re-evaporated with methanol and dried in high vacuum at 60ºC overnight. Hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl}methanone was isolated as a cream solid (62 mg).1H-NMR (DMSO-d6) 12,40-12,00 (2H, osirm), 9,75-of 9.55 (1H, osirm), 7,45-7,05 (3H, m), 7,03 (1H, s), of 6.45 (1H, s), 4,70-4,55 (4H, m), 3,85-the 3.65 (6H, m), 3,60 is 3.40 (5H, m), 3.15 and was 3.05 (1H, m), 3.0 to 2,78 (5H, m), 2,30-of 2.20 (2H, m), 2,05-1,90 (2H, m)and 1.15 (6H, d). MS: [M+H]+479.

EXAMPLE 52

Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-piperazine-1-ylphenyl)-1,3-dihydroindol-2-yl]methanone

52A. Synthesis of tert-butyl ester 4-{4-[2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yl]phenyl}piperazine-1-carboxylic acid

A mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-bromo-1,3-dihydroiso ndol-2-yl)methanone (240 mg, 0.43 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidinecarboxylate (210 mg, 1.25 equiv.), bis(tri-tert-butylphosphine)palladium(0) (12.5 mg, 2.5 mol%) and potassium carbonate (350 mg, 6 equiv.) in a mixture of toluene/water/ethanol (1 ml:1 ml:4 ml) was heated at 135ºC for 30 minutes in a microwave synthesizer for CEM test experiments. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, dried (MgSO4) and was evaporated. Purified column flash chromatography (Biotage SP4 - 25S, 25 ml/min), while elution of 1:3, then 1:1 EtOAc/petroleum ether. Evaporation of fractions containing product gave 85 mg of tert-butyl ester 4-{4-[2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yl]phenyl}piperazine-1-carboxylic acid. MS: [M+H]+736.

52B. Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-piperazine-1-ylphenyl)-1,3-dihydroindol-2-yl]methanone

Hydrogenation of tert-butyl ester 4-{4-[2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yl]phenyl]piperazine-1-carboxylic acid (as described in method A5), with subsequent removal of the BOC protection (as described in example 70) was led to 10 mg specified in the title compound, in the form of cleaners containing hydrochloride salt after column flash chromatography (Biotage SP4, 25S), while elution DMAW 240-120-90, and evaporation of a mixture of saturated HCl/EtOAc.1H-NMR (Me-d3-OD) 7,63 (2H, d), 7,55 (2H, m) 7,45-7,30 (1H, m), 7,2 (1H, C), 7,20 (2H, d), of 5.03 (4H, m), 3,55 (4H, m), 3,47 (4H, m), 3,23 (1H, m), 1,25 (6H, d). MS: [M+H]+458.

EXAMPLE 53

Synthesis of 2,4-dihydroxy-5-isopropylphenyl)-[5-(1-dimethylamino-5-hydroxyethyl)-1,3-dihydroindol-2-yl]methanone and dihydroxy-5-isopropylphenyl)-[5-(2-dimethylamino-1-hydroxyethyl)-1,3-dihydroindol-2-yl]methanone

53A. Synthesis of methyl ester of 5-bromo-2,4-dimethoxybenzoic acid

A solution of 5-bromo-2,4-dihydroxybenzoic acid (24,9 g, 107 mmol) in acetone (355 ml), was treated with methyliodide (39.9 ml, 640 mmol) and K2CO3(88 g, 640 mmol), then heated at the boil under reflux overnight. Salt was filtered and washed with acetone. The filtrate was evaporated to dryness and the product was purified column flash chromatography (100% DCM) to give the methyl ester of 5-bromo-2,4-dimethoxybenzoic acid as a colorless solid (28 g).1H-NMR (Me-d3-OD) 7,98 (1H, s), 6,74 (1H, s)to 3.99 (3H, s), of 3.94 (3H, s), 3,85 (3H, s). MS: [M+H]+275/277.

53B. Synthesis of methyl ester of 5-Isopropenyl-2,4-dimethoxybenzoic acid

To isopropylideneuridine potassium (4,87 g, to 32.7 mmol) and methyl ether of 5-bromo-2,4-dimethoxybenzoic acid (7.5 g, 27,3 mmol) in THF (195 ml) was added Cs2CO3(26,6 g, 81,8 mmol) in water (39 ml). The reaction mixture was degirolami and was added Pd(PPh3)4(1,58 g of 1.36 mmol). Reactionuses was heated at the boil under reflux for three days, then extinguished by the addition of water and was extracted with EtOAc (×2). The combined organic fractions were washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated to obtain an orange solid. Product re-suspended in EtOAc and the precipitate was filtered. The filtrate was evaporated to dryness to obtain methyl ester 5-isopropyl-2,4-dimethoxybenzoic acid (6.2 g).1H-NMR (Me-d3-OD) to 7.68 (1H, s), of 6.66 (1H, s), 5,10-5,08 (1H, m), 5,02-5,00 (1H, m), 3,93 (3H, s)to 3.92 (3H, s), of 3.84 (3H, s), 2,08 e 2.06 (3H, m). MS: [M+H]+237.

53C. Synthesis of methyl ester 5-isopropyl-2,4-dimethoxybenzoic acid

A solution of methyl ester 5-isopropyl-2,4-dimethoxybenzoic acid (6.0 g, and 25.4 mmol) in MeOH (85 ml) was shaken with 10% Pd/C in an atmosphere of H2at room temperature for 3 hours. The catalyst was filtered through a paper filter GF/A, but a small amount of fine powder passed through the filter. The filtrate was passed through a thin layer of silica gel and evaporated to dryness to obtain a colorless solid. The product was purified flash column-chromatography (DCM:petroleum ether, gradient elution) to give a colorless solid methyl ester 5-isopropyl-2,4-dimethoxybenzoic acid (5.5 g).1H-NMR (Me-d3-OD) to 7.68 (1H, s), only 6.64 (1H, s), of 3.94 (3H, s), 3,91 (3H, s), of 3.84 (3H, s), 3,23 (1H, Sept.), of 1.20 (6H, d). MS: [M+H]+239.

53D. Synthesis of 5-from the propyl-2,4-dimethoxybenzoic acid

Methyl ester 5-isopropyl-2,4-dimethoxybenzoic acid (5.5 g, 23,1 mmol) and NaOH (1,38 g, 34.6 mmol) in THF (46 ml) and water (46 ml) was heated at 50ºC during the night. The reaction mixture was cooled and was diluted with water and EtOAc. The aqueous layer was neutralized with HCl (1 n aq.). The product was extracted with EtOAc (×3) and the combined organic fractions were washed with saturated salt solution and dried over MgSO4. The product was filtered and was evaporated to dryness to obtain 5-isopropyl-2,4-dimethoxybenzoic acid as a pale peach solid (4.7 g).1H-NMR (DMSO-d6) to 12.1 (1H, users), a 7.62 (1H, s)of 6.71 (1H, s), of 3.95 (3H, s), 3,91 (3H, s), 3,19 (1H, Sept.), of 1.18 (6H, d). MS: [M+H]+225.

53E. Synthesis of (5-bromo-1,3-dihydroindol-2-yl)-[5-isopropyl-2,4-acid)methanone

To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2,45 g, 10.9 mmol), HOBt (1,61 g, to 11.9 mmol) and EDC (1.85 g, to 11.9 mmol) in anhydrous DMF (33 ml) in an atmosphere of N2was added 5-bromo-2,3-dihydro-1H-isoindole (1.97 g, for 9.95 mmol) and stirred at room temperature overnight. The reaction mixture was suppressed by dilution of NaOH (1M, aq.) and the product was extracted EtOAc (×2). The combined organic fractions were washed with saturated salt solution and dried over MgSO4. The product was filtered and was evaporated to dryness to obtain a brown oil. The product was purified flash column-chromatography with what ispolzovaniem gradient elution (ether/petroleum ether) to give (5-bromo-1,3-dihydroindol-2-yl)-(5-isopropyl-2,4-acid)methanone in the form of a beige solid (3 g). 1H-NMR (Me-d3-OD) 7,60-7,13 (3H, m), 7,14 (1H, s)of 6.71 (1H, s), 4,89 (2H, d), with 4.64 (2H, d), 3,93 (3H, s), 3,90 (3H, s), with 3.27 (1H, Sept.), of 1.20 (6H, d). MS: [M+H]+404/406.

53F. Synthesis of 5-isopropyl-2,4-acid)-(5-vinyl-1,3-dihydroindol-2-yl)methanone

To (5-bromo-1,3-dihydroindol-2-yl)-(5-isopropyl-2,4-acid)methanone (2.2 g, 5,44 mmol) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 ml, 6,53 mmol) in MeOH (25 ml) and toluene (25 ml) was added Na2CO3in water (25 ml). The reaction mixture was degirolami, was added Pd(PPh3)4(0,38 g, 0.05 mmol), then heated at 80ºC overnight. The reaction was stopped by addition of water and extraction EtOAc (×3). The combined organic fractions were washed with saturated salt solution and dried over MgSO4. The product was filtered and was evaporated to dryness, then purified column flash chromatography, gradient elution (ether:petroleum ether) to give 5-isopropyl-2,4-acid)-(5-vinyl-1,3-dihydroindol-2-yl)methanone in the form of a yellow oil (1.6 g).1H-NMR (Me-d3-OD) 7,47-to 7.15 (3H, m), to 7.15 (1H, s), 6,82-6,72 (1H, m), of 6.71 (1H, s), 5,79 (1H, DD), of 5.24 (1H, DD), of 4.90 (2H, d), with 4.64 (2H, d), 3,93 (3H, s), 3,91 (3H, s), with 3.27 (1H, Sept.), of 1.23 (6H, d). MS: [M+H]+352.

53G. Synthesis of (5-isopropyl-2,4-acid-(5-oxiranyl-1,3-dihydroindol-2-yl)methanone

To (5-isopropyl-2,4-acid)-(5-vinyl-1,3-dihydroindol-2-yl)methanone (0,80 who, 2.28 mmol) in DCM (22 ml) was added mCPBA (0,61 g, 2,73 mmol) at 0ºC. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with NaOH (1M, aq.) and the product was extracted EtOAc. EtOAc layer was washed again NaOH. The organic layer was washed with saturated salt solution and dried over MgSO4. The product was filtered and was evaporated to dryness to obtain the crude (5-isopropyl-2,4-acid)-(5-oxiranyl-1,3-dihydroindol-2-yl)methanone in the form of a pale yellow oil. MS: [M+H]+368.

53H. Synthesis of (2,4-dihydroxy-5-isopropylphenyl-[5-(1-dimethylamino-2-hydroxyethyl)-1,3-dihydroindol-2-yl]methanone (connection 121H-i) and (2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylamino-1-hydroxyethyl)-1,3-dihydroindol-2-yl]methanone (connection 121H-ii)

(5-Isopropyl-2,4-acid)-(5-oxiranyl-1,3-dihydroindol-2-yl)methanon (120 mg, crude) was dissolved in a solution of dimethylamine in EtOH (20 ml, ~33%, 5,6M) and heated at 60ºC overnight. The reaction mixture was evaporated to dryness, and the product was subjected to coarse purification column flash chromatography MeOH:DCM (1:5) to obtain the contaminated substance, which was used without further purification. To a mixture of [5-(1-dimethylamino-2-hydroxyethyl)-1,3-dihydroindol-2-yl]-(5-isopropyl-2,4-acid)methanone and [5-(2-dimethylamino-1-hydroxyethyl)-1,3-dihydroindol-2-yl]-(5-isopropyl-2,4-dimethoxy the Il)methanone (~100 mg) was added DCM (5 ml) and then tribromide boron (3 EQ.) in an atmosphere of N 2. The reaction mixture was allowed to mix at room temperature until completion of the reaction. The reaction was suppressed with ice and diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic fractions were washed with saturated salt solution, dried over MgSO4, was filtered and was evaporated to dryness, giving a yellow residue, which was purified preparative HPLC to obtain two resorcinol isomers.

(2,4-Dihydroxy-5-isopropylphenyl)-[5-(1-dimethylamino-2-hydroxyethyl)-1,3-dihydroindol-2-yl]metano (connection 121H-i).1H-NMR (Me-d3-OD) 7,42-7,30 (3H, m), 7,19 (1H, s), to 6.39 (1H, s), 4,98-to 4.87 (4H, m), a 4.03-of 3.97 (1H, m), 3,94-3,86 (1H, m), 3,68 (1H, users), up 3.22 (1H, Sept.), is 2.40 (6H, s)of 1.23 (6H, d). MS: [M+H]+384.

(2,4-Dihydroxy-5-isopropylphenyl)-[5-(2-dimethylamino-1-hydroxyethyl)-1,3-dihydroindol-2-yl]metano (connection 121H-ii).1H-NMR (Me-d3-OD) 7,39-of 7.25 (3H, m), 7,18 (1H, s)6,38 (1H, s), 6,94-to 6.88 (5H, m), up 3.22 (1H, Sept.), 2,77 of 2.68 (1H, m), 2,61 is 2.51 (1H, m), 2,42 (6H, s)of 1.23 (6H, d). MS: [M+H]+384.

EXAMPLE 54

Synthesis of hydrochloride of (2,4-dihydroxy-5-isopropylphenyl)-[5-(piperazine-1-carbonyl)-1,3-dihydroindol-2-yl]methanone

54A. Synthesis of tert-butyl ester 4-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbonyl]piperazine-1-carboxylic acid

A solution of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbon is acid (receiving D6) (0.5 g, 0.96 mmol), EDC (0,22 g, 1.15 mmol), HOBT (0,196 g, 1.15 mmol) and BOC-piperazine (0,117 ml, 1.06 mmol) in DMF (10 ml) was stirred at room temperature for 48 hours, then evaporated in vacuum. The crude substance was dissolved in ethyl acetate and was extracted twice with saturated NaHCO3. The organic fraction was washed with a saturated solution of salt, dried (MgSO4), filtered, then evaporated in vacuo, and purified flash column-chromatography (80% EtOAc-petroleum ether as eluent)gave 0.5 g of tert-butyl ester 4-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbonyl]piperazine-1-carboxylic acid. MS: [M+H]+688.

54B. Synthesis of hydrochloride of (2,4-dihydroxy-5-isopropylphenyl)-[5-(piperazine-1-carbonyl)-1,3-dihydroindol-2-yl]methanone

The hydrogenation according to the method A5 gave (0.2 g, 0.30 mmol) tert-butyl ester 4-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbonyl]piperazine-1-carboxylic acid [used raw], which was dissolved in EtOAc, then was treated with saturated EtOAc/HCl, stirred at ambient temperature for 3 hours, the reaction mixture was diluted with ether, filtered, the solid that was given to 0.19 g of the hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-[5-(piperazine-1-carbonyl)-1,3-dihydroindol-2-yl]methanone.1H-NMR (Me-d3-0D) 7,50-7,42 (3H, m), 7,18 (1H, s), to 6.39 (1H, is), 5,00-of 4.95 (4H, users), 3,92-with 3.79 (4H, users), 3,35 of 3.28 (4H, users), 3,26 is 3.15 (1H, m)of 1.23 (6H, d). MS: [M+H]+410.

EXAMPLE 55

Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]methanone

55A. Synthesis of methoxyethylamine 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid

A solution of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (receiving D6) (1,76 g, 3,39 mmol), EDC (0,78 g 4,06 mmol), HOBT (0.55 g, 4,06 mmol), Et3N (1 ml, of 6.78 mmol) and hydrochloride of N,O-dimethylhydroxylamine (0.36 g, 3.72 mmol) in DMF (20 ml) was stirred at room temperature for 48 hours, then evaporated in vacuum. The crude substance was dissolved in ethyl acetate and was extracted twice with saturated NaHCO3. The organic fraction was washed with a saturated solution of salt, dried (MgSO4), filtered, then evaporated, which gave 1.84 g of methoxyethylamine 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid. MS: [M+H]+563.

55B. Synthesis of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde

The solution methoxyethylamine 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (0,226 g, 0.4 mmol) in THF (5 ml) was cooled to 0ºC, was treated with 1M LiAlH4/THF (,3 ml, 0.3 mmol), stirred 1 hour, it was added LiAlH4(0.05 ml), then was stirred for 30 minutes. The reaction was suppressed with saturated solution of KHSO4, was extracted with EtOAc, dried (MgSO4), filtered and evaporated, giving 0.2 g of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde. MS: [M+H]+504.

55C. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]methanone

To a solution of 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (0,316 g to 0.63 mmol) and n-methylpiperazine (63 mg, 0,63 mmol) in CH2Cl2(10 ml) was added AcOH (38 mg, 0,63 mmol) and NaBH(OAc)3(0.28 g, of 1.33 mmol), then stirred at ambient temperature for 5 hours. The reaction is extinguished with water, the layers were separated and the aqueous layer was washed with CH2Cl2. The organic fractions were combined, washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated, which gave 0.32 g of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]methanone. MS: [M+H]+588.

55D. Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]methanone

The hydrogenation was carried out using the method A5, but with the addition of K2CO3(2 equiv.) in MeOH/H2O [9:1]. After evaporation met the Nola reaction mixture was diluted with water, neutralized using 1M HCl, and was extracted with CH2Cl2(×2). The organic fraction was dried (MgSO4), was filtered and was evaporated in vacuo, then purified preparative HPLC, which gave 21 mg (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]methanone. MS: [M+H]+410.1H-NMR (Me-d3-OD) 7,37-of 7.23 (3H, users), 7,19 (1H, s), to 6.39 (1H, s), 4,94-to 4.87 (4H, users), of 3.57 (2H, s), 3.27 to and 3.16 (1H, m), 2,67-2,39 (8H, m), 2,31 (3H, s)of 1.23 (6H, d).

EXAMPLE 56

Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone

56A. Synthesis hydrobromide 4-hydroxyisoquinoline

A suspension of dimethyl 3-methoxyflurane (69,45 g, 0.31 mol) [obtained as inJ. Chem. Soc, Perkin Trans. 1, 1989, 391] in water (300 ml) was treated with potassium hydroxide (43,7 g, 0.78 mol), the mixture was stirred and kept at the boiling point under reflux for 4 hours. After cooling to room temperature, the methanol released during the reaction was removed under vacuum, the mixture was acidified to pH 2 or below by the addition of 5M hydrochloric acid and gently evaporated in a vacuum to initiate crystallization. The solid was filtered off, washed with a small amount of ice-cold water have been pumped out on the filter to dryness under reduced pressure and dried in a vacuum oven at 50ºC in ECENA night, which gave 3-methoxyflavone acid (51,0 g, 84%) as a colourless solid.1H-NMR (DMSO-d6) of 13.05 (2H, users), of 7.48 (2H, m), 7,33 (1H, m), 3,82 (3H, s). MS: [M+H]+197.

Acetic anhydride (70 ml) was added to a mixture of 3-methoxyflavone acid (51,0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml), the mixture was stirred and kept at the boiling point under reflux for 4 hours. After cooling to room temperature the solvent was removed in vacuum and the resulting solid was dried in a vacuum oven at 50ºC during the night, which gave 3-methoxypoly anhydride (45,9 g, 99%) as a colourless solid.1H-NMR (DMSO-d6) of 7.97 (1H, DD), 7,63 (1H, d), 7,60 (1H, d), was 4.02 (3H, s). MS: [M+H]+179.

A mixture of 3-methoxyflavone anhydride (24,0 g, 134,8 mmol) and formamide (120 ml) was stirred and kept at 210ºC for 5 hours, then allowed to cool to room temperature overnight. Was added water (100 ml), and the solid was filtered under reduced pressure. The crude product was washed successively with 50% aqueous acetone (50 ml), diethyl ether (200 ml) and sucked out on the filter to dryness under reduced pressure, which gave 3-methoxyflavone (of 8.95 g, 37%) as not quite white solid.1H-NMR (DMSO-d6) 11,08 (1H, users), 7,78 (1H, DD), was 7.45 (1H, d), of 7.36 (1H, d), 3,93 (3H, s). MS: [M+H]+178.

Re exively a solution of 3-metoclopramide (of 8.95 g, 50,56 mmol) in anhydrous tetrahydrofuran (200 ml) at 0ºC was treated dropwise with a solution of borane in tetrahydrofuran (1M, 150 ml, 0.15 mol) and the resulting mixture was stirred and kept at the boiling point under reflux for 16 hours. The mixture was cooled to 0ºC was added dropwise methanol (60 ml), then 5M hydrochloric acid (60 ml), the mixture was stirred and kept at the boiling point under reflux for 4 hours. After cooling to room temperature, the organic solvent was removed in vacuo, the mixture was diluted with water (250 ml) and was extracted with methylene chloride (3×250 ml). The aqueous layer was podslushivaet to pH 12 or higher by the addition of 5M sodium hydroxide, extracted with methylene chloride (3×250 ml) and the combined extracts were evaporated to dryness in vacuo, which gave 4-methoxyindole (4.44 g, 59%) as a green oil which was used without further purification.1H-NMR (DMSO-d6) to 7.18 (1H, 1), 6,83 (1H, d), is 6.78 (1H, d), 4,07 (2H, s), was 4.02 (2H, s), of 3.78 (3H, s). MS: [M+H]+150.

4-Methoxyindole (4.4 g, 29,53 mmol) in 48% aqueous Hydrobromic acid (50 ml) was stirred and kept at the boiling point under reflux for 16 hours. After cooling to room temperature the solvent was removed in vacuo, giving the hydrobromide 4-hydroxyisoquinoline (5.0 g, 78%) as a pale orange is solid substances. 1H-NMR (DMSO-d6) 9,95 (1H, users), 9,37 (2H, users), 7,19 (1H, t), at 6.84 (1H, d), to 6.80 (1H, d), 4,48 (2H, t), and 4.40 (2H, t). MS: [M+H]+136.

56B. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-(4-hydroxy-1,3-dihydroindol-2-yl)methanone

A mixture of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (8.1 g, 21,65 mmol), hydrobromide 4-hydroxyisoquinoline (4,91 g, 22,73 mmol), hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (5.0 g, 25,98 mmol), 1-hydroxybenzotriazole (3.5 g, 25,98 mmol) and triethylamine (6 ml, to 43.3 mmol) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was treated with saturated aqueous sodium bicarbonate (200 ml). The mixture was filtered, the solid is abundantly washed with water have been pumped out on the filter to dryness under reduced pressure and dried in a vacuum oven at 50ºC during the night, which gave (2,4-bis-benzyloxy-5-isopropylphenyl)-(4-hydroxy-1,3-dihydroindol-2-yl)methanon (of 10.25 g, 96%) as pale yellow-brown solid.1H-NMR (DMSO-d6) (mixture of amide rotamers) 9,68 and a 9.60 (1H, 2×users), 7,45-of 7.25 (10H, m), 7,20-to 7.00 (3H, m), 6.82 and 6,72 (1H, 2×d), of 6.68 (1H, m), 5,23 and with 5.22 (2H, 2×s), is 5.18 (2H, s), 5,11 (1H, s), 5,09 (1H, s), 4,77 and 6.67 (2H, 2×s), 4,53 and of 4.44 (2H, 2×s), 2,04 (3H, s). MS: [M+H]+492.

56C. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-di is Itaitinga-2-yl]methanone

A mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-(4-hydroxy-1,3-dihydroindol-2-yl)methanone (2 g, 4.07 mmol), 4-(3-chlorpropyl)of the research (1.66 g; 2.5 equiv.) and cesium carbonate (8,3 g; 6,25 equiv.) in DMF was heated at 90ºC during the night, then was evaporated. The residue was dissolved in EtOAc, washed with saturated solution of salt, dried (MgSO4) and was evaporated. Purification of the crude substances on the Biotage SP4 (4OS, 40 ml/min)using a gradient elution from 0% to 10% MeOH/EtOAc, gave 1.8 g of (2,4-bis-benzyloxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone in the form of a pale yellow resin. MS: [M+H]+619.

56D. Synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone

Hydrogenation of (2,4-bis-benzyloxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]methanone (as described in method A5), followed by treatment with saturated HCl/EtOAc and rubbing in hot acetone gave 890 mg specified in the connection header (cleaners containing hydrochloride salt) in the form of a cream solid.1H-NMR (DMSO-d6) 10,78 (1H, users), of 10.05 (1H, users), of 9.55 (1H, users), 7,30 (1H, t), was 7.08 (1H, s) 6,98-of 6.90 (2H, m), of 6.45 (1H, s), 4,80 (2H, s), and 4.75 (2H, s), is 4.15 (2H, t), of 3.95 (2H, osirm), 2,80 (2H, osirm), 3,50-to 3.35 (2H, osirm)at 3.25 (2H, users), 3,18-to 3.02 (3H, osirm), of 2.20 (2H, osirm)and 1.15 (6H, d). MS: [M+H]+441.

EXAMPLES 57-74

the following compounds were obtained by the above methods.

The other roomConnectionChemical nameMethodThese NMRMass spectrum
57[5-(2-Aminoethoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)metanoAs for example 34, A2 (2,4-bis-benzyloxy-5-isopropylbenzoic acid (receiving B5) and 5-hydroxyisoquinoline), alkylation using 3-(BOC-amino)tiltability, then A5. The final removal of the BOC protection effect of saturated HCl/EtOAc (example 18)1H NMR (Me-d3-OD) 8,55 (1H, s), 7,30-7,20 (1H, m), to 7.15 (1H, s), 7,05-to 6.95 (2H, m), 6,40 (1 H, s), 4,95-4,80 (4H, m)of 4.25 (2H, t), at 3.35 (2H, t), 3.25 to a 3.15 (1H, m), 1,25 (6H, d)MS: [M+H]+357
58(2,4-Dihydroxy-5-isopropylphenyl)-(5-hydroxy-1,3-dihydroindol-2-yl)methanonWas isolated as a side product of the synthesis in example 571H NMR (Me-d3-OD) 7,20 (1H, s), 7,15-7,05 (1H, m), 6,80-6,70 (2H, m), 6,40 (1H, s), 4,95-4,80 (4H, m), 3.25 to a 3.15 (1H, m), 1,25 (6H, d) MS: [M+H]+314
59(2,4-Dihydroxy-5-isopropylphenyl)-{5-[4-(2-hydroxyethyl)piperazine-1-yl]-1,3-dihydroindol-2-yl}metanoAs in example 51, using N-(2-hydroxyethyl)piperazine in a reaction Buchwald (Buchwald)1H NMR (DMSO-d6) the 10.40 (1H, users), 9,65 (1H, users), 7,40-to 7.15 (1H, m), 7,05 (1H, s), 7,05-of 6.90 (2H, m), of 6.45 (1H, s), 4.80 to 4,60 (4H, m), 3,85-3,70 (4H, m), 3,65-3,55 (2H, m), 3.25 to 3,05 (7H, m)and 1.15 (6H, d)MS: [M+H]+426
60(2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-(morpholine-4-reparacin-1-yl)-1,3-dihydroindol-2-yl]metanoAs in example 51, using 4-morpholinopropan in the Buchwald reaction (Buchwald)1H NMR (DMSO-d6) 11,10 (1H, users), 9,65 (1H, users), 7,30-7,05 (3H, m), 7,03 (1H, s), of 6.45 (1H, s), 4.80 to the 4.65 (4H, m), 4,0-of 3.95 (2H, m), 3,90 of 3.75 (4H, m), 3,50 is 3.40 (2H, m), 3,40-3,30 (1H, m), 3,15-3,03 (3H, m), 2,90 is 2.75 (2H, m), 2,25-of 2.15 (2H, m), 1,95-of 1.80 (2H, m)and 1.15 (6H, d)MS: [M+H]+466
61(2,4-Dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,3-dihydroindol-2-the l]metano As in example 51, using 4-amino-1-methylpiperidine in the Buchwald reaction (Buchwald)1H NMR (DMSO-d6) or 10.60 (1H, users), 9,65 (1H, users), 7,20 (1H, m), 7,03 (1H, s), 6,95-to 6.80 (2H, m), of 6.45 (1H, s), 4.80 to the 4.65 (4H, m), of 3.45 (2H, m)of 3.25 (1H, m), 3,10 (1H, m)of 3.00 (2H, m), 2,70 (3H, d), 2, 15-2,05 (2H, m), 1,90 is 1.75 (2H, m)and 1.15 (6H, d)MS: [M+H]+410
62(2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-isopropylpiperazine-1-yl)-1,3-dihydroindol-2-yl]metanoAs in example 51, using isopropylpiperazine in the Buchwald reaction (Buchwald)1H NMR (DMSO-d6) 10,70 (1H, users), 9,65 (1H, users), 7,25-7,10 (1H, m), 7,05 (1H, s), 7,00-of 6.90 (2H, m), of 6.45 (1H, s), 4.80 to 4,60 (4H, m), 3,80 (2H, m), 3,55 is 3.40 (3H, m), 3,23 was 3.05 (5H, m)of 1.33 (6H, d)and 1.15 (6H, d)MS: [M+H]+424
63(2,4-Dihydroxy-5-isopropylphenyl)-(5-piperazine-1-yl-1,3-dihydroindol-2-yl)methanonAs in example 51, using Boc-piperazine in a reaction Buchwald (Buchwald). Removal of the Boc protection effect of saturated HCl/dioxane (example 18)1H NMR (DMSO-d6) to 9.70 (1H, users), a 9.25 (2H, users), of 7.23 (1H, is IRM), 7,05 (1H, s), 7,00-of 6.90 (2H, m), of 6.45 (1H, s), 4.80 to 4,60 (4H, m)to 3.35 (4H, m), 3,20 (4H, m), 3,10 (1H, m)and 1.15 (6H, d)MS: [M+H]+382
64tert-Butyl ester 4-[2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-ylamino]piperidine-1-carboxylic acidAs in example 51, using 1-Boc-4-aminopiperidine in the Buchwald reaction (Buchwald)1H NMR (Me-d3-OD) 7,20 (1H, s), 7,05 (1H, m), 6,65-6,55 (2H, m), 6.35mm (1H, s), 4,85-of 4.75 (4H, m), of 4.05 (2H, m), 3,50 (1H, m), 3,20 (1H, m)of 3.00 (2H, m), from 2.00 (2H, m), and 1.5 (9H, s)of 1.30 (2H, m)and 1.15 (6H, d)MS: [M+H]+496
65(2,4-dihydroxy-5-isopropylphenyl)-[5-(piperidine-4-ylamino)-1,3-dihydroindol-2-yl]metanoRemoval of the BOC protection using a mixture of saturated HCl/EtOAc (example 18)1H NMR (DMSO-d6) 7,05 (1H, s), 7,00 (1H, m), 6,55-of 6.45 (2H, m), 6,40 (1 H, s), 4,70-4,60 (4H, m)of 3.25 (1H, m), 3,10 (1H, m), 2,95 (2H, m), of 2.45 (2H, m), of 1.85 (2H, m)of 1.75 (3H, s)of 1.20 (2H, m)and 1.15 (6H, d)MS: [M+H]+396
66(2,4-dihydroxy-5-isopropylphenyl)-[4-(4-methylpiperid the Zin-1-yl)-1,3-dihydroindol-2-yl]metano As in example 51, using (2,4-bis-benzyloxy-5-isopropylphenyl)-(4-bromo-1,3-dihydroindol-2-yl)methanone (obtain: A2 using 2,4-bis-benzyloxy-5-isopropylbenzoic acid and 4-bromo-1,3-dihydro-1H-isoindoline) and N-methylpiperazine in the Buchwald reaction (Buchwald)1H NMR (Me-d3-OD) 7,35-to 7.18 (2H, m), 7,1 0-6,95 (2H, m), 6,95-6,85 (2H, m), 6,40 (1H, s), 4,95-4,85 (4H, m)of 3.25 (1H, m), 3,20-3, 05 (4H, m), 3,05 is 2.80 (4H, m)2,60 (3H, m), from 2.00 (3H, s), 1,25 (6H, d)MS: [M+H]+396
67(2,4-dihydroxy-5-isopropylphenyl)-[4-(piperidine-4-ylamino)-1,3-dihydroindol-2-yl]metanoAs in example 65, using 1-Boc-4-aminopiperidine in the Buchwald reaction (Buchwald), with subsequent removal of the Boc protection using a mixture of saturated HCl/EtOAc (example 18)1H NMR (DMSO-d6) 7,05 (1H, s), 7,00 (1H, m), 6,55-of 6.45 (2H, m), 6,40 (1H, s);4,70-4,60 (4H, m)of 3.25 (1H, m), 3,10 (1H, m), 2,95 (2H, m), of 2.45 (2H, m), of 1.85 (2H, m)of 1.75 (3H, s)of 1.20 (2H, m)and 1.15 (6H, d)MS: [M+H]+396
68(2,4-Dihydroxy-5-isopropylphenyl)-(5-dimethylaminomethyl-1,3-dihydroindol-2-yl)methanon A2 and A5. From 2,4-bis-benzyloxy-5-isopropylbenzoic acid (B5), and (2,3-dihydro-1H-isoindole-5-ylmethyl)dimethylamine (obtaining A1))1H NMR (Me-d3-OD) 7,26 for 7.12 (3H, m), 7,07 (1H, s), 6,27 (1H, s), 4,85-of 4.77 (4H, users), 3,40 (2H, s), 3.15 and was 3.05 (1H, m), of 2.15 (6H, s)a 1.11 (6H, d)MS: [M+H]+355
69(2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-carbonyl)-1,3-dihydroindol-2-yl]metanoA2 and A5. From 2-(2,4-bis-benzyloxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (D6) and N-methylpiperazine1H NMR (Me-d3-OD) 7,60-7,38 (3H, m), 7,19 (1H, s), to 6.39 (1H, s), 4,96 (4H, m), 3,85-3,71 (2H, users), 3,54-3,4 (2H, users), 3,26 is 3.15 (1H, m), 2,59-2,39 (4H, userd), was 2.34 (3H, s)of 1.23 (6H, d)MS: [M+H]+424
70(2,4-Dihydroxy-5-isopropylphenyl)-{5-[2-(2,2-dimethylpropylene)ethoxy]-1,3-dihydroindol-2-yl}metanoAs for the synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(2-isopropylaminoethyl)-1,3-dihydroindol-2-yl]methanone, except for the use of trimethylacetaldehyde instead of acetone. Was purified preparative HPLC1The NMR (Me-d 3-OD) 7,28 (1H, users); 7,20 (1H, s); 7,00 (2H, osirm); 6,40 (1H, s); of 4.35 (2H, t); 3,50 (2H, t); 3,20 (1H, m); 3,00 (2H, s); of 1.23 (6H, d); 1,10 (9H, s)MS: [M+H]+427
71[5-(2-Cyclopentylamine)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)metanoAs for the synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(2-isopropylaminoethyl)-1,3-dihydroindol-2-yl]methanone, except for the use of Cyclopentanone instead of acetone. Was purified preparative HPLC1H NMR (DMSO-d6) of 10.05 (1H, users); a 9.60 (1H, users); of 7.23 (1H, users); 7,05 (1H, s); 6,95 (1H, users); to 6.88 (1H, userd); 6,40 (1H, s); 4,72 (4H, osirm); was 4.02 (2H, t); 3,10 (2H, m); at 2.93 (2H, t); of 1.78 (2H, m), and 1.63 (2H, m); to 1.48 (2H, m); 1,35 (2H, m); to 1.15 (6H, d)MS: [M+H]+425
72(2,4-Dihydroxy-5-isopropylphenyl)-(5-piperidine-1-ylmethyl-1,3-dihydroindol-2-yl)methanonAs for the synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl-1,3-dihydroindol-2-yl]methanone (example 56) except for using piperidine instead of N-methylpiperazine1H NMR (Me-d3-OD) 7,35-7,24 (3H, m), 7,19 (1H, s), to 6.39 (1H, s), 4,94 of 4.9 (4H, users), of 3.54 (2H, s), 3.27 to 3,18 (1H, m), of 2.51-to 2.41 (4H, users), 1,66-1, 58 (4H osirm), 1,53-of 1.42 (2H, users), of 1.23 (6H, d)MS: [M+H]+395
73(2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-hydroxypiperidine-dihydroindol-2-yl]metanoAs for the synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone (example 50), except for using N-benzyloxycarbonylamino-4-it is in stage 21H NMR (Me-d3-OD) 7,47 (2H, m), 7,30 (1H, osirm), 7,20 (1H, s)6,40 (1H, s)4,90 (4H, d), up 3.22 (1H, m)and 3.15 (2H, m), 2,95 (2H, m), is 2.05 (2H, m)of 1.75 (2H, m), 1,25 (6H, d)MS: [M+H]+397
74(5-chloro-6-hydroxy-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)metanoWas isolated as a side product when getting in example 331H NMR (DMSO-d6) 10,00 (1H, s), 9,58 (1H, s)of 7.48-7,38 (1H, m), 7,02 (1H, s), 7,97-6,85 (1H, m), 6,40 (1H, s), and 4.68 (4H, users), 3,10 (1H, m)and 1.15 (6H, d)MS: [M+H]+348

EXAMPLE 75

(5-Chloro-2,4-dihydroxyphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano

75A. t is et-Butyl ester 5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-carboxylic acid

tert-Butyl ester 5-bromo-1,3-dihydroindol-2-carboxylic acid (2,97 g, 10 mmol) azeotrope dried by evaporation with toluene. Added Tris(dibenzylideneacetone)dipalladium(0) (228 mg, 0.25 mmol), 2-(di-tert-butylphosphino)biphenyl (149 mg, 0.50 mmol) and tert-piperonyl sodium (1,34 g, a 13.9 mmol) and the flask was purged with nitrogen. Was added toluene (25 ml), then N-methylpiperazine (1,33 ml, 12 mmol) and the mixture was heated to 80ºC for 2 hours. After cooling to room temperature the mixture was diluted with ether, filtered through celite and concentrated, giving a residue that was purified flash chromatography on silica gel (2M methanolic ammonia in methylene chloride, gradient 1%-3%). This led to the number indicated in the title compound, as a brown solid (1.45 g, 46%).1H-NMR (MeOH-d4) to 7.15 (1H, m), 6,94-to 6.88 (2H, m), 4,60-of 4.54 (4H, m), 3,20-3,17 (4H, m), 2,63-2,60 (4H, m), of 2.34 (3H, s), of 1.52 (9H, s). MS: [M+H]+318.

75B. The dihydrochloride of 5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-isoindole

tert-Butyl ester 5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-carboxylic acid (247 mg, 0.78 mmol) was treated with 4M HCl in dioxane (4 ml, 4 mmol) for 24 hours. Concentration in vacuum quantitatively resulted specified in the title compound, which was used directly in the reaction combinations.1H-NMR (who MCO-d 6) 11,13 (1H, users), 9,99 (2H, users), 7,27 (1H, d), 7,02-7,00 (2H, m), 4,43-4,37 (4H, m), 3,82 of 3.75 (2H, m), 3,49-of 3.43 (2H, m), 3,15-3,10 (4H, m), 2,79-2,78 (3H, s), of 1.52 (9H, s). MS: [M+H]+218.

75C. (5-Chloro-2,4-dihydroxyphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano

A solution of 5-chloro-2,4-dihydroxybenzoic acid (176 mg, of 0.93 mmol) in DMF (5 ml) was treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (179 mg, of 0.93 mmol), then HOBt (126 mg, of 0.93 mmol). After 45 minutes the solution was added the activated acid to the mixture of the dihydrochloride of 5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-isoindole (290 mg, 0.78 mmol) and triethylamine (of 0.28 ml, 2 mmol), the mixture is then stirred at room temperature for 3 hours. The solvent was removed in vacuo, then the residue was distributed between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and saturated salt solution, then dried (MgSO4), were combined and concentrated. Remained a certain amount of the insoluble substance was dissolved in 1 N. hydrochloric acid and methanol, and then combined with organic extracts. pH brought up to 14 solid sodium hydroxide and the mixture was allowed to stand over night. the pH was brought to 7 1 N. hydrochloric acid and the resulting precipitate was filtered, then purified preparative HPLC, which gave the decree is Noah in the title compound as a red solid. It was turned into a hydrochloric salt processing 4M HCl in dioxane, concentrated in vacuum and friction in the air, which gave a brown solid (91 mg, 27%).1H-NMR (DMSO-d6) 11,10 (1H, users), 10,50 (1H, users), 7,26-to 7.15 (2H, m), 7,02-6,93 (2H, m), 6,69 (1H, s), 4.72 in-br4.61 (4H, m), 3,78-and 3.72 (2H, m), of 3.45 (2H, users), of 3.12 (4H, users), 2,78 (3H, s). MS: [M+H]+386/388.

EXAMPLE 76

(2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl)methanon

76A. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-bromo-1,3-dihydroindol-2-yl)methanone

The combination of 2,4-bis-benzyloxy-5-isopropylbenzoic acid (5.0 g, a 13.4 mmol) (obtaining B9) and 5-bromo-2,3-dihydro-1H-isoindole (getting C20) were performed according to the method of A4, using CH2Cl2as the reaction solvent, which gave specified in the header connection (to 8.34 g) as a beige solid.

76B. Synthesis of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]methanone

To a mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-bromo-1,3-dihydroindol-2-yl)methanone (8,30 g, 15.0 mmol), 2-(di-tert-butylphosphino)biphenyl (223 mg, 0.75 mmol), Tris(dibenzylideneacetone)diplegia (344 mg, 0.38 mmol), tert-butoxide sodium (2.17 g of 22.5 mmol) and 1-methylpiperazine (2,16 ml, 19,5 mm is l) in the atmosphere N 2added anhydrous toluene (100 ml). The mixture is brought up to 80ºC and was heated at this temperature for 16 hours. The mixture was allowed to cool to ambient temperature, diluted with ether (150 ml) and filtered through a layer of celite was washed with ether. The filtrate was evaporated in vacuum and the residue was purified column chromatography using as eluent CH2Cl2-DMAW 120 (1:0-0:1), which gave specified in the header connection (9,39 g) in the form of a red resin.

76C. (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano

A mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]methanone (8,61 g, 15.0 mmol) and 10% Pd/C (1.0 g) in methanol (200 ml) was intensively stirred in hydrogen atmosphere (~1 ATM) for 18 hours at ambient temperature. The mixture was filtered through a layer of celite and was evaporated in vacuo, which gave a purple oil. The obtained residue was purified column chromatography using as eluent DMAW 120, which gave specified in the title compound in the form of its acetate salt.

The obtained salt was dissolved in MeOH (30 ml) and to the solution was added saturated HCl in EtOAc (20 ml). The resulting mixture was stirred at ambient temperature for 2 hours and the resulting solid was isolated what filtrowanie and dried in vacuum, what gave you specified in the title compound in the form of cleaners containing hydrochloride salt (2.64 g) as a white solid.

EXAMPLE 77

(5-Chloro-2,4-dihydroxyphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano

A solution of 5-chloro-2,4-dihydroxybenzoic acid (176 mg, of 0.93 mmol) in DMF (5 ml) was treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (179 mg, of 0.93 mmol), then HOBt (126 mg, of 0.93 mmol). After 45 minutes the solution was added the activated acid to the mixture of the dihydrochloride of 5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-isoindole (290 mg, 0.78 mmol) and triethylamine (of 0.28 ml, 2 mmol), the mixture is then stirred at room temperature for 3 hours. The solvent was removed in vacuo, then the residue was distributed between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and saturated salt solution, then dried (MgSO4), were combined and concentrated.

Remained a certain amount of insoluble matter, and it was dissolved in 1 N. hydrochloric acid and methanol, and then was combined with the organic extracts; pH brought up to 14 solid sodium hydroxide and the mixture was allowed to stand over night; the pH was brought to 7 1 N. hydrochloric acid and the resulting precipitate was filtered, then purified preparative HPLC, which gave the decree is Noah in the title compound as a red solid. The resulting compound was converted into its cleaners containing hydrochloride salt by treatment of 4M HCl in dioxane, concentrated in vacuo and triturated in ether, which gave a brown solid (91 mg, 27%).1H-NMR (DMSO-d6) 11,10 (1H, users), 10,50 (1H, users), 7,26-to 7.15 (2H, m), 7,02-6,93 (2H, m), 6,69 (1H, s), 4.72 in-br4.61 (4H, m), 3,78-and 3.72 (2H, m), of 3.45 (2H, users), of 3.12 (4H, users), 2,78 (3H, s). MS: [M+H]+386/388.

EXAMPLE 78

Alternative synthesis of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]methanone

78A. 5-Bromo-2-trityl-2,3-dihydro-1H-isoindole

Trailhead (2.30 g, 8,23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (1.64 g, 8,23 mmol) and triethylamine (1.4 ml, 9.9 mmol) in methylene chloride (20 ml). After 18 hours the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and washed with water (×2) and saturated salt solution, dried (MgSO4) and concentrated. The crude substance was purified flash chromatography on silica gel with elution by 1% triethylamine/10% ethyl acetate/petroleum ether gave 5-bromo-2-trityl-2,3-dihydro-1H-isoindole as a reddish brown solid (3,10 g, 85%).1H-NMR (CDCl3) to $ 7.91-to 7.84 (1H, m), EUR 7.57 (6H, d), 7,45-7,41 (1H, m), 7,33-7,14 (9H, m), to 6.95 (1H, d), 3,90 (2H, s), 3,86 (2H, s). MS: Ph3C+243.

78B. 1-Methyl-4-(2-trityl-2,3-dihydro-1H-isoindole-5-yl)piperidine-ol

Under nitrogen atmosphere a solution of 5-bromo-2-trityl-2,3-dihydro-1H-isoindole (2,03 g, 4.6 mmol) in THF (20 ml) was cooled to-78ºC. Solution was added n-utility (2.5m in hexane, 2.0 ml, 5 mmol) for 5 minutes, then after 10 minutes, was added dropwise 1-methyl-4-piperidone. After another hour the cooling bath was removed and the reaction was suppressed by sodium bicarbonate solution. The mixture was extracted with ethyl acetate, then the organic phase was washed with a saturated solution of salt, dried (MgSO4) and concentrated. The residue was purified flash chromatography on silica gel (gradient elution 2M methanolic ammonia in methylene chloride, 0%-5%) gave 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindole-5-yl)piperidine-4-ol in the form of a pink foam (1.25 g, 57%).1H-NMR (MeOH-d4) 7,56 (6H, DD), 7,28 (6H, t), 7,25-7,21 (2H, m), 7,15 (3H, t), 7,03 (1H, d), to 3.92 (2H, s), 3,91 (2H, s), 2,70 (2H, d), of 2.53 (2H, dt), of 2.33 (3H, s)to 2.06 (2H, TD), to 1.70 (2H, d). MS: [M+H]+475.

78C. The dihydrochloride of 4-(2,3-dihydro-1H-isoindole-5-yl)-1-methylpiperidin-4-ol

A mixture of 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindole-5-yl)piperidine-4-ol (1.42 g, 3.0 mmol), 5 N. hydrochloric acid (5 ml) and methanol (10 ml) was placed in a nitrogen atmosphere, then heated at the boil under reflux for 80 minutes. After cooling, the mixture was concentrated in vacuo to remove methanol, diluted with water and washed the and ethyl acetate (×2). The aqueous phase was concentrated to dryness, which gave with a quantitative yield specified in the title compound as a black solid.1H-NMR (MeOH-d4) a 7.62 (1H, s), EUR 7.57 (1H, d), was 7.45 (1H, d), with 4.64 (2H, s), 4,63 (2H, s), 3,49-of 3.46 (4H, m), 2,95 (3H, s), 2,40 of-2.32 (2H, m)of 1.97 (2H, DD).

78D. (2,4-Bis-benzyloxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl)-methanon

2,4-Bis-benzyloxy-5-isopropylbenzoic acid (1.65 g, 4.4 mmol), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (843 mg, 4.4 mmol) and 1-hydroxybenzotriazole (595 mg, 4.4 mmol) was dissolved in DMF (20 ml). After 35 minutes the solution was added to the suspension dihydrochloride 4-(2,3-dihydro-1H-isoindole-5-yl)-1-methylpiperidin-4-ol (1.22 g, 4.0 mmol) and triethylamine (1.4 ml, 10 mmol in DMF (5 ml)). The mixture was stirred for 3 hours, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with a mixture of water (brought to pH 14 2 N. a sodium hydroxide solution and saturated salt solution. The aqueous phase was extracted twice more with ethyl acetate, then the combined organic extracts were washed with sodium bicarbonate solution and a saturated solution of salt, dried (MgSO4) and concentrated. The crude product was purified flash chromatography (gradient elution 2M methanolic ammonia in methylene chloride, 2%-10%), which was given is shown in the title compound as a brown foam (1,62 g, 69%).1H-NMR (methanol-d4) 7,51-7,14 (14H, m), 6,85 (0,5H, C)6,84 (0,5H, s), 5,16 (2H, s), of 5.15 (2H, s), 5,10-5,08 (1H, m), 5,07-of 5.05 (1H, m), to 4.87 (1H, s), a 4.86 (1H, s), br4.61 (2H, users), 2,78-2,70 (2H, m), 2.57 m (1H, dt), of 2.54 (1H, etc), 2,36 (1,5H, s), 2,34 (1,5H, s), 2,16-2,05 (5H, m, including of 2.09 (3H, s)), 1,78 is 1.70 (2H, m). MS: [M+H]+589.

78E. (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano

(2,4-Bis-benzyloxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano (example 50F) (1,62 g, a 2.75 mmol) was dissolved in methanol (50 ml) and was first made at 50ºC 10% palladium on carbon using the apparatus for hydrogenation by controlling the concentration of hydrogen, under conditions of free flow of hydrogen. Concentration led to headline the compound (1,14 g, 100%) as a yellow solid, for which the data of NMR and mass spectrometry match those specified in example 50E.

EXAMPLE 79

(2,4-Dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-7-methyl-1,3-dihydroindol-2-yl]metano

79A. The hydrobromide 7-methyl-2,3-dihydro-1H-isoindole-5-ol

Using the way to obtain C2, dimethyl 5-methoxy-3-methylphthalic acid (obtained byTarn and Coles, Synthesis 1988, 383) hydrolyzed to 5-methoxy-3-methylphthalic acid.1H-NMR (DMSO-d612,95 (2H, users), to 7.15 (1H, d),? 7.04 baby mortality (1H, d), of 3.80 (3H, s)to 2.29 (3H, s). MS: [M-H]+209.

5-Methoxy-3-methylphthalic acid was converted into 5-methoxy-3-methylphthalic anhydride.1H-NMR (DMSO-d6) 7,40 (1H, d), 7,34-7,33 (1H, m), of 3.94 (3H, s), 2,58 (3H, s).

5-Methoxy-3-methylphthalic anhydride was used to obtain 6-methoxy-4-meteosound-1,3-dione.1H-NMR (DMSO-d6) 11,05 (1H, users), 7,13 (1H, d), 7,10 (1H, d), 3,88 (3H, s)to 2.55 (3H, s).

Recovery of 6-methoxy-4-meteosound-1,3-dione according to the method of obtaining C2 resulted in 6-methoxy-4-methylisoxazole.1H-NMR (DMSO-d6) only 6.64 (1H, s), to 6.57 (1H, s), of 4.05 (2H, s), of 3.96 (2H, s), 3,70 (3H, s)of 2.16 (3H, s). MS: [M+H]+164.

6-Methoxy-4-meteosound has Demetrashvili that gave specified in the title compound in the form of his hydrobromide salt.1H-NMR (DMSO-d6) 9,52 (1H, users), 9,29 (2H, users), 6,59 (1H, s), 6,56 (1H, s)to 4.41 (2H, t), 4,34 (2H, t), 2,17 (3H, s).

79B. (2,4-Bis-benzyloxy-5-isopropylphenyl)-(5-hydroxy-7-methyl-1,3-dihydroindol-2-yl)methanon

2,4-Bis-benzyloxy-5-isopropylbenzoic acid (248 mg, 0.66 mmol), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (127 mg, 0.66 mmol) and 1-hydroxybenzotriazole (89 mg, 0.66 mmol) was dissolved in DMF (5 ml). After 20 minutes was added hydrogen bromide 7-methyl-2,3-dihydro-1H-isoindole-5-ol (152 mg, 0.66 mmol) and triethylamine (0,14 ml of 0.99 mmol). After another 3.5 hours the mixture was concentrated in HAC is the mind and the residue was treated with 1 N. hydrochloric acid and ethyl acetate. The aqueous phase was removed, was added a saturated solution of salt and indicated in the title compound was isolated by filtration as a gray solid (168 mg, 57%).1H-NMR (DMSO-d6) of 9.30 (0,47H, C), 9,24 (0,53H, C)of 7.48-of 7.25 (10H, m), 7,09 (0,47H, C)7,08 (0,53H, C), 6,99 (0,47H, C), 6,98 (0,53H, C), 6,56 (0,47H, C)6,50 (0,53H, s), 6.48 in (0,47H, C), 6,44 (0,53H, s), 5,24 (0,47H, C)5,22 (0,53. C), by 5.18 (2H, s), 5,10 is 5.07 (2H, m), 4,70 (0,47H, C), br4.61 (0,53H, C), 4,46 (0,47H, C)4,36 (0,53H, C)2,17 (1,41H, C)2,04 (3H, s), 1,99 (1,59H, with). MS: [M+H]+506.

79 ° C. (2,4-Bis-benzyloxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-7-methyl-1,3-dihydroindol-2-yl]metano

A mixture of (2,4-bis-benzyloxy-5-isopropylphenyl)-(5-hydroxy-7-methyl-1,3-dihydroindol-2-yl)methanone (164 mg, 0.32 mmol), potassium carbonate (112 mg, 0.81 mmol) and hydrochloride of 2-(dimethylamino)ethylchloride (93 mg, 0.64 mmol) in DMF (5 ml) was heated at 60ºC for 17 hours, then at 90ºC for 6 hours. Added additional portion of potassium carbonate (112 mg, 0.81 mmol) and hydrochloride of 2-(dimethylamino)ethylchloride (93 mg, 0.64 mmol) and the mixture was stirred at 60ºC for 72 hours and, finally, another 24 hours at 90ºC. The mixture was concentrated in vacuo, then the residue was distributed between ethyl acetate and 0.5 N. aqueous sodium hydroxide. The organic phase is washed with saturated salt solution (×2), dried (MgSO4) and concentrated, causing the OS is ATCO, which was purified preparative HPLC (acidic method), which gave specified in the title compound in the form of formiate salt (37 mg, 20%).1H-NMR (MeOH-d4) 8,51 (1H, users), 7,43-7,27 (7H,m), 7,24-7,20 (3H, m), 7,17 (0,5H, s), 7,16 (0,5H, s), 6,85 (0,5H, C)6,84 (0,5H, s), for 6.81 (0,5H, s), 6,77 (0,5H, s), 6,74 (0,5H, s), 6,62 (0,5H, s), 5,16 (1H, s), 5,14 (3H, s), 5,09 (1H, m), is 5.06 (1H, m), a 4.83 (1H, s), 4,74 (1H, s), 4,60 (1H, s), 4,48 (1H, s), 4,28 (1H, t), to 4.23 (1H, t), is 3.41 (1H, t), 3,37 (1H, t), 2,84 (3H, s), of 2.81 (3H, s), and 2.27 (1,5H, s), is 2.09 (3H, s)2,07 (1,5H, s). MS: [M+H]+577.

79D. (2,4-Dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-7-methyl-1,3-dihydroindol-2-yl]metano

(2,4-Bis-benzyloxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano (37 mg, 0.06 mmol) was first made in methanol at 50ºC 10% palladium on carbon using the apparatus for hydrogenation by controlling the concentration of hydrogen, under conditions of free flow of hydrogen. The product was purified preparative HPLC (alkaline), which gave specified in the title compound in the form of not-quite-white solid (9 mg, 35%).1H-NMR (MeOH-d4) to 7.18 (1H, s), 6,77-of 6.65 (2H, osirm), 6,37 (1H, s)4,85 (water blocks the signal CH2), of 4.77 (2H, s)4,08 (2H, t), 3,20 (1H, Sept.), of 2.81 (2H, t), 2,39 (6H, s), 2,22 (3H, users), to 1.21 (6H, d). MS: [M+H]+399.

Biological activity

EXAMPLE 80

Calorimetry isothermal titration

Ability is soedinenii according to the invention to contact Hsp90-protein man was determined using calorimetry isothermal titration.

Experiments on calorimetry isothermal titration (ITC) was performed by titration calorimeter VP-ITC (Microcal Inc., Northampton, MA, USA). Cloning, expression and purification of N-terminal domain of Hsp90α were performed according to published methods (Jez, J.M. et al., Chem Biol. 2003 Apr;10(4):361-8). A solution of N-terminal domain of human Hsp90α and the solution of the compounds were obtained in buffer containing 25 mm Tris, 100 mm NaCl, 1 mm MgCl2, 1 mm TCEP, 5% DMSO, pH of 7.4. All the solutions were filtered and were degirolami before titration. The enthalpy change that occurs from each injection of ligand, obtained through integration of the calorimetric signal. Data were analyzed using Origin 7.0 (Microcal Software Inc., Northampton, MA). The heat of dilution was evaluated using the end of injection for each individual titration, and subtracted before the data approximation. Used various ITC-experimental formats in order to obtain the dissociation constants of the compounds (Kd) in a wide range of affinely. For weakly binding compounds used method ITC low P-value (W.B. Turnbull and Daranas A.H. J. Am. Chem. Soc. 2003 Dec 3; 125(48):14859-66), in which the protein is present in a concentration of 10-20 μm in the calorimetric cell and the concentration of the compounds was 1-20 mm in the syringe for injection. In this type of experiment parameter stoichiometry (N) was fixed as 1 with the compatibility data. For constant Kd in the range of 20-0,004 microns experiment was changed so that bind the concentration of customers, divided by the Kd (C-value), ranged from 5 to 1000. For most of these experiments, the protein concentration in the calorimetric cell was in the range of 4-100 μm and the concentration of ligand in the syringe for injection was varied in the range of 50-1500 microns. In rare cases where the solubility of the compounds was limited, the solution of the compound was placed in the calorimetric cell was titrated protein from a syringe for injection, while maintaining the C-value of from 5 to 1000. To obtain the constants Kd<4 mm used competitive ITC experiments by carrying out the titration in the presence of more weakly competitive binding compound according to the method described inB.W. Sigurskjold Anal Biochem. 2000 Jan 15; 277(2):260-6.

Were tested compounds examples 5, 10, 11, 12, 13, 14, 16, 17, 18, 19, 21, 22, 23, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 48, 49, 50, 51, 52, 53, 54, 55, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 and 75 and it was found that they have Kdvalues less than 1 micromoles.

Connection examples 5, 10, 12, 13, 14, 16, 17, 18, 19, 21, 22, 23, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 48, 49, 50, 51, 53, 54, 55, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 and 75 had Kdvalues less than 0.1 micromoles, and most of these compounds had the Kdvalues less than 0.01 micromoles.

EXAMPLE 81

Antiproliferative activity

Antiproliferative activity of the compounds according to the invention can be determined by measuring the ability of compounds for inhibition of cell growth in several cell lines, such as cell line HCT116 colon cancer person. Inhibition of cell growth was measured using samples of Alamar Blue (Nociari, ETC, Shalev, A., Benias, P., Russo, C. Journal of Immunological Methods 1998, 213, 157-167). The method is based on the ability of viable cells to restore resazurin to its fluorescent product resorufin. For each analysis cell proliferation was placed in a 96-well plate and left to adapt for 16 hours before the addition of inhibitory compounds within the next 72 hours. Upon completion of the incubation period was added 10% (vol./vol.) Alamar Blue, and incubated in the next 6 hours before detection of the fluorescent product at 535 nm excitation/59O nm emission. In the case of the analysis of nonproliferative cells, the cells were kept when confluently within 96 hours before adding inhibitory connections within the next 72 hours. The number of viable cells was determined by examining Alamar Blue as described above. Cell lines can be obtained from ECACC (European collection of cell cultures).

Connection examples 5, 12, 13, 14, 17, 18, 19, 21, 22, 23, 25, 28, 29, 3, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 48, 49, 50, 51, 52, 53, 54, 55, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 74 and 75 were tested and it was found that they have the IC50values less than 1 micromoles against cell line HCT116.

Pharmaceuticals

EXAMPLE 82

(i) the Drug is in tablet form

The composition of the tablets containing the compound of formula (I), was obtained by mixing 50 mg of the compounds with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as lubricant and pressing with obtaining tablets in a known manner.

(ii) the Drug is in the form of capsules

The drug is in the form of capsules was obtained by mixing 100 mg of the compounds of formula (I) with 100 mg of lactose, and placing the mixture in a standard matte hard gelatin capsules.

(iii) the Drug is in the form of injections I

Parenteral composition for administration by injection was obtained by dissolving the compounds of formula (I) (e.g. in a salt form) in water containing 10% propylene glycol, which gave the concentration of the active compounds of 1.5% by weight. The solution is then sterilized by filtration, was placed in a vial and sealed.

(iv) Preparation for injection II

Parenteral composition for injection was obtained by dissolution in water of the compounds of formula (I) (e.g. in a salt form) (2 mg/ml) and mannitol (50 mg/ml), sterile filtering the solution of the premises in zapaivanie 1 ml vials or ampoules.

(v) the Preparation for injection III

Preparation for intravenous (i.v.) delivery by injection or infusion can be obtained by dissolving the compounds of formula (I) (e.g. in a salt form) in water at a concentration of 20 mg/ml of the Vial was then sealed and sterilized in an autoclave.

(vi) the Preparation for injection IV

Preparation for intravenous (i.v.) delivery by injection or infusion can be obtained by dissolving the compounds of formula (I) (e.g. in a salt form) in water containing a buffer (for example, 0,2M acetate at pH 4.6) at a concentration of 20 mg/ml test Tube was then sealed and sterilized in an autoclave.

(vii) Preparation for subcutaneous injection

Composition for subcutaneous injection was prepared by mixing the compounds of formula (I) with corn oil pharmaceutical purity, which gave a concentration of 5 mg/ml of the Composition is sterilized and placed in an acceptable container.

(viii) Lyophilized drug

Aliquots of the compounds of formula (I) in the form of the drug was placed in 50 ml test tubes and liofilizirovanny. During lyophilization, the composition froze with the use of one-stage Protocol freezing when (-45ºC). The temperature was raised up to-10ºC for annealing, and then lowered to freezing down to-45ºC, followed by primary drying at+25ºC for approximately 3400 minutes, and then secondary drying with Uwe is echenim the number of stages, at temperatures below 50ºC. The pressure within the primary and secondary drying was kept at 80 millitorr.

Equivalents

The above examples are provided to illustrate the invention and should not be discussed as imposing any limitation on the scope of the invention. It will be obvious that numerous modifications and changes may be made in the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and changes are intended to include in the scope of the present invention.

1. The compound of formula (VI):

or its pharmaceutically acceptable salt;
where n is 0, 1, 2 or 3;
R1represents a hydroxy-group or hydrogen;
R2arepresents a hydroxy-group or a methoxy group, provided that at least one of R1and R2ais a hydroxy-group;
R3selected from chlorine, bromine, cyclopropyl and branched C3-5of alkyl;
R4arepresents hydrogen;
R8represents hydrogen; and
where the fragment:

can be one of the groups B8, V, W, V, W, V, in40, B41 content, W, W, W, V46, V, W, V, W, V, W, V, W, V, W, V, W, V, W, V, B80, V, W, V, W, V, W, V, W,V, V, W, B95, B96, V, W, B99, B100 and V presented in the table below:



2. The compound according to claim 1, where R1and R2aboth represent a hydroxy-group.

3. The compound according to claim 2, where R3represents isopropyl or tert-butyl.

4. The compound according to claim 1, which is:
(1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;
(1,3-dihydroindol-2-yl)-(4-hydroxy-3-isopropylphenyl)methanon;
(5-cyclopropyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;
(5-sec-butyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;
(5-chloro-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;
[5-(3-aminopropoxy)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanon;
(5-bromo-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-isopropylphenyl)-{4-[2-(2-methoxyethoxy)ethoxy]-1,3-dihydroindol-2-yl}meanon;
(2,4-dihydroxy-5-isopropylphenyl)-[4-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[4-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano;
(5-tert-butyl-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;
(5-chloro-2,4-dihydroxyphenyl)-(1,3-dihydroindol-2-yl)methanon;
(1,3-dihydroindol-2-yl)-(2-hydroxy-5-isopropyl-4-methoxyphenyl)methanon;
(4,7-debtor-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-(5-fluoro-1,3-dihydroindol-2-yl)methanon;
hydrochloride(2,4-dihydroxy-5-isopropylphenyl)-(4-fluoro-1,3-dihydroindol-2-yl)methanone;
(5-chloro-6-methoxy-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-methoxyethoxy)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(3-morpholine-4-ylpropionic)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano;
(5-amino-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl) methanon;
(2,4-dihydroxy-5-isopropylphenyl)-(5-methoxy-1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-(5-morpholine-4-yl-1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;
methyl ester of 2-(2,4-di is hydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid;
2-(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid;
(2,4-dihydroxy-5-isopropylphenyl)-(5-morpholine-4-ylmethyl-1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-isopropylaminoethyl)-1,3-dihydroindol-2-yl]metano;
N-{2-[(2,4-dihydroxy-5-isopropylbenzyl)-2,3-dihydro-1H-isoindole-5-yloxy]ethyl}-2-morpholine-4-ylacetamide;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-1,3-dihydroindol-2-yl} meanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-piperazine-1-ylphenyl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-dimethylamino-2-hydroxyethyl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylamino-1-hydroxyethyl)-1,3-dihydroindol-2-yl]metano;
hydrochloride (2,4-dihydroxy-5-isopropylphenyl)-[5-(piperazine-1-carbonyl)-1,3-dihydroindol-2-yl]methanone;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-{5-[4-(2-hydroxyethyl)piperazine-1-yl]-1,3-dihydroindol-2-yl}meanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-(morpholine-4-yl-piperidine-1-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-isopropylpiperazine-1-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-(5-piperazine-1-yl-1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(piperidine-4-ylamino)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[4-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[4-(piperidine-4-ylamino)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-(5-dimethylaminomethyl-1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-carbonyl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-{5-[2-(2,2-dimethylpropylene)ethoxy]-1,3-dihydroindol-2-yl}meanon;
[5-(2-cyclopentylamine)-1,3-dihydroindol-2-yl]-(2,4-dihydroxy-5-isopropylphenyl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-(5-piperidine-1-ylmethyl-1,3-dihydroindol-2-yl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxypiperidine-4-yl)-1,3-dihydroindol-2-yl]metano;
(5-chloro-6-hydroxy-1,3-dihydroindol-2-yl)-(2,4-dihydroxy-5-isopropylphenyl)methanon;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;
(5-chloro-2,4-dihydroxyphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;
or its pharmaceutically acceptable salt.

5. Soy is inania according to claim 4, which is;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(2-dimethylaminoethoxy)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-(5-piperazine-1-yl-1,3-dihydroindol-2-yl)methanon or
(2,4-dihydroxy-5-isopropylphenyl)-(5-dimethylaminomethyl-1,3-dihydroindol-2-yl)methanon;
or its pharmaceutically acceptable salt.

6. The compound according to claim 5, which is:
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-hydroxy-1-methylpiperidin-4-yl)-1,3-dihydroindol-2-yl]metano;
(2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]metano or
(2,4-dihydroxy-5-isopropylphenyl)-[5-(1-methylpiperidin-4-ylamino)-1,3-dihydroindol-2-yl]metano;
or its pharmaceutically acceptable salt.

7. The connection according to claim 6, representing (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroindol-2-yl]metano.

8. The compound according to any one of claims 1 to 7 in the form of a pharmaceutically acceptable the salt.

9. Pharmaceutical composition having Hsp90 inhibitory activity containing a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. The compound according to any one of claims 1 to 8 for use in the prevention or treatment of the disease condition mediated by Hsp90 activity.

11. The compound according to any one of claims 1 to 8 for use in the treatment of a disease or condition comprising or arising from abnormal cell growth in a mammal.

12. The compound according to any one of claims 1 to 8 for use in the treatment of proliferative disorders.

13. The connection section 12, where the proliferative disease is a cancer.

14. The connection indicated in paragraph 13, where the proliferative disease is selected from carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin; hematopoietic tumors of lymphoid origin; hematopoietic tumors of myeloid origin; follicular thyroid cancer; a tumour of mesenchymal origin; a tumour of the Central or peripheral nervous system; melanoma; seminomy; teratocarcinoma; osteosarcoma; pigment xeroderma; keratoacanthoma or Kaposi's sarcoma.

15. The connection p is item 13, where the cancer is selected from colorectal carcinoma, colon adenocarcinoma, adenoma of the colon, adenocarcinoma, small-cell lung cancer, non-small cell lung carcinoma, exocrine pancreatic carcinoma, gastrointestinal stromal tumors, squamous cell carcinoma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, b-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, lymphoma of Burket, acute and chronic myelogenous leukemia, imatinib sensitive and refractory chronic myelogenous leukemias, myelodysplasias syndrome, bortezomib sensitive and refractory multiple myeloma, myeloproliferative disease, promyelocytes leukemia, fibrosarcoma, rabdomyosarcoma, astrocytoma, neuroblastoma, glioma or neurinomas.

16. The connection indicated in paragraph 13 where the cancer is a cancer of the breast person, selected from primary tumors of the breast, newscoverage breast cancer, invasive adenocarcinoma of the ducts of the breast, endometrioid breast cancer; or lymphoma epithelial cells.

17. The connection indicated in paragraph 13, where the cancer is selected from leukemia, chronic lymphocytic leukemia, lymphoma cells of the mantle tissue b-cell lymphoma and optional extras selected from chronic myelogenous LEU is emii and multiple myeloma.

18. The connection indicated in paragraph 13, where the cancer is selected from ErbB2-positive breast cancer, prostate, lung and stomach; chronic myeloid leukemia; cancer of the prostate is dependent on receptor androgen hormone; Flt3-dependent acute myeloid leukemia; melanoma associated with mutation of skin disease; multiple myeloma; Velcade-resistant multiple myeloma; and gastrointestinal stromal tumors (GIST).

19. The connection indicated in paragraph 13, where the cancer is selected from multiple myeloma and walked-resistant tumor types.

20. The use of compounds according to any one of claims 1 to 8 in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders, as defined according to any one of PP-19.

21. The method of obtaining the compounds of formula (VI)as defined in any one of claims 1 to 8, which includes the interaction of the compounds of formula (X):

or activated and/or protected form with an amine of the formula HNR5R6where HNR5R6has the structure:

in conditions suitable for the formation of amide linkages,
where R1, R3and R8have the meanings defined in claim 1, R2is an R2aas defined in claim 1, R4is an R4aas defined in claim 1,
and R10T and Q in connectioncorrespond to R10/sup> T and Q in any of the fragmentsas defined in claim 1.

22. The connection, which is 2,4-bis-benzyloxy-5-isopropylbenzoic acid.

23. The compound that is represented by formula (XXI):

where n is 0 or 1; M represents a nitrogen atom or SNON, and R25represents hydrogen or methyl; provided that when n is 0 and R25represents methyl, then M is NON.

24. Connection item 23, which is selected from formula (XXI), (XXII) and (XXIV):

25. The method of obtaining the compounds of formula (VI), as defined in p, 1, which includes the interaction of the compounds of formula (X):

with the compound of the formula

in conditions suitable for the formation of amide linkages, and further, if necessary, removing the protective groups,
where R1, R2a, R3, R4aand R8have the meanings defined in claim 1,
and R10bin connectioncorresponds to R10in any of the fragmentsas defined in claim 1.

26. The method of obtaining the compounds of formula (VI), as defined in claim 2 or any dependent from him the item, which includes the interaction of the compounds of formula (XIX) or its protected production is underwater with the compound of the formula (XX):

in conditions suitable for the formation of amide linkages, and further, if necessary, removing the protective groups,
where R3, R4aand R8have the meanings defined in claim 1, and R10ccin connectioncorresponds to R10in any of the fragmentsas defined in claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 or pharmaceutically acceptable derivatives thereof, where values of radicals X, W, R4, Ar1, Ar2, R3, R4, R20 are as described in paragraph 1 of the claim. The invention also describes a composition for treating or preventing pain, UI, ulcers, inflammatory bowel disease or irritable bowel syndrome.

EFFECT: compound which can be used in medicine is obtained and described.

46 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing an amide compound of formula (3). The disclosed method involves reaction of an aniline compound of formula (1) and an aldehyde compound of formula (2) in a solvent in the presence of an oxidant such as oxygen, peroxide, chromic acid or salt thereof. In the given formulae, R1, R2, R3, R4, R5, R6 and R7 assume values given in the claim. In particular, R1, R2 and R3 independently denote a C1-C6 alkyl group which can be substituted with a halogen atom or similar; R4, R5, R6 and R7 independently denote a halogen atom or similar.

EFFECT: disclosed method enables to obtain compounds of formula (3), which have excellent regulating activity on harmful arthropods.

3 cl, 5 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds of general formula (I)

, where the value of each symbol is defined in the claim, which are ORL-1 receptor agonists.

EFFECT: improved bioavailability, based on improved metabolic stability, strong and high selectivity and can be used in medicine.

7 cl, 148 ex, 35 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: copolycarbonate contains an isomeric mixture of the following formulae as a repeating monomer unit:

,

where R1 is hydrogen or alkyl with 1-10 carbon atoms and R2 is an alkyl with 1-10 carbon atoms or, if needed, a phenyl or benzyl substituted with hydrogen and/or an alkyl with 1-10 carbon atoms, respectively; and diphenol of formula:

, where R3 and R4 denote hydrogen, an alkyl with 1-18 carbon atoms, an alkoxy with 1-18 carbon atoms, a halogen, respectively, if needed, a substitued aryl or arylalkyl, and X is a single bond, -SO2-, -CO-, -O-, -S-, an alkylene with 1-6 carbon atoms, an alkyidene with 2-5 carbon atoms or a cycloalkylidene with 5-6 carbon atoms, which can be substituted with an alkyl with 1-6 carbon atoms, an arylene with 6-12 carbon atoms, which, if needed, is condensed with aromatic ring groups containing heteroatoms.

EFFECT: high glass transition temperature, high operating temperature and improved adhesion to metal.

9 cl, 9 ex

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