6-substituted isoquinolines and isoquinolinones effective as rho-kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

 

The present invention relates to novel isoquinoline and izohinolinove derivatives, their reception and their use for the treatment and/or prevention of diseases associated with inhibition of Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chains of myosin.

Activation of small GTP RhoA after agonist stimulation leads to the transformation of RhoA from the inactive GDP-bound form to the active GTP-bound form with the subsequent binding of Rho-kinase and its activation. There are two isoforms of Rho-kinase 1 and Rho-kinase 2. Rho-kinase 2 is expressed in the smooth muscle cells of blood vessels and endothelial cells. Activation of Rho-kinase 2 active GTP-bound RhoA leads to an increased sensitivity of smooth muscle cells to calcium mediated through phosphorylation inhibition of phosphatase activity light chains of myosin and to increase thereby the activity of the regulatory light chains of myosin (Uehata et al. Nature 1997, 389, 990-994).

It is known that Rho-kinase is actively involved in the narrowing of the blood vessels, including the formation of his own muscle tone and hyperactivity smooth muscles (Gokina et al. J. Appl. Physiol. 2005, 98, 1940-1948), the contraction of the smooth muscles of the bronchi (Yoshii et al. Am. J. Resp. Cell Mol. Biol. 1999, 20, 1190-1200), bronchial asthma (Setoguchi et al. Br. J. Pharmacol. 2001, 132, 111-118; Nakahara et al. Eur. J. Pharmac. 2000, 389, 103-106) and chronic obstructive the th lung disease (COPD, Maruoka et al. Nippon Rinsho, 1999, 57, 1982-1987), hypertension, pulmonary hypertension (Fukumoto et al. Heart 2005, 91, 391-392, Mukai et al. Nature 1997, 389, 990-994), intraocular hypertension and regulation of intraocular pressure (Honjo et al. Invest. Ophthalmol. Visual Sci. 2001, 42, 137-144), endothelial dysfunction (Steioff et al. Eur. J. Pharmacol. 2005, 512, 247-249), angina (Masumoto et al. Circulation 2002, 105, 1545-47, Shimokawa et al. J. Cardiovasc. Pharmacol. 2002, 40, 751-761), nefropatia, including nephropathy induced hypertension or other cause, and diabetes, renal failure and occlusive disease peripheral artery disease (PAOD) (Wakino et al. Drug News Perspect. 2005, 18, 639-643), myocardial infarction (Demiryurek et al. Eur. J. Pharmacol. 2005, 527, 129-140, Hattori et al. Circulation 2004, 109, 2234-2239), hypertrophy of the heart and heart failure (Yamakawa et al. Hypertension 2000, 35, 313-318; Liao et al. Am. J. Physiol. Cell Physiol. 2006, 290, C661-668; Kishi et al. Circulation 2005, 111, 2741-2747), coronary heart disease, arteriosclerosis, restenosis (Pacaud et al. Arch. Mal. Coeur 2005, 98, 249-254; Retzer et al. FEBS Lett. 2000, 466, 70-74; Negoro et al. Biochem. Biophys. Res. Commun. 1999, 262, 211 to 215), diabetes, complications of diabetes, glucose metabolism and metabolic syndrome (Sandu et al. Diabetes 2000, 49, 2178-2189; Maeda et al. Cell Metab. 2005, 2, 119-129), sexual dysfunction, for example, erectile dysfunction (Chitaley et al. Nature Medicine 2001, 7, 119-122), retinopathy, inflammation, immune diseases, AIDS, osteoporosis, endocrine dysfunctions, for example, hyperaldosteronism, disorders of the Central nervous system, such as not Rosalina degeneration and damage to the spinal cord (Hara et al. J. Neurosurg. 2000, 93, 94-101), cerebral ischemia (Uehara et al. Nature 1997, 389, 990-994; Satoh et al. Life Sci. 2001, 69, 1441-1453; Hitomi et al. Life Sci. 2000, 67, 1929-1939; Yamamoto et al. J. Cardiovasc. Pharmacol. 2000, 35, 203-211), cerebral vasospasm (Sato et al. Circ. Res. 2000, 87, 195-200; Kim et al. Neurosurgery 2000, 46, 440-447), pain, e.g. neuropathic pain (Tatsumi et al. Neuroscience 2005, 131, 491-498; Inoue et al. Nature medicine 2004, 10, 712-718), a bacterial infection of the gastrointestinal tract (WO 98/06433), the development and progression of cancer, neoplasia, where it was shown that inhibition of Rho-kinase inhibits growth and metastasis of tumor cells (Itoh et al. Nature Medicine 1999, 5, 221-225; Somlyo et al. Biochem. Biophys. Res. Commun. 2000, 269, 652-659), angiogenesis (Uchida et al. Biochem. Biophys. Res. Commun. 2000, 269, 633-640; Gingras et al. Biochem. J. 2000, 348, 273-280), proliferation and motility of smooth muscle cells of blood vessels (Tammy et al. Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al. Atherosclerosis 2001, 155, 321-327), proliferation of endothelial cells, contractility and motility of endothelial cells (Oikawa et al. Biochem. Biophys. Res. Commun. 2000, 269, 633-640), the formation of stress fibers (Kimura et al. Science 1997, 275, 1308-1311; Yamashiro et al. J. Cell Biol. 2000, 150, 797-806), thrombotic disorders (Kikkawa et al. FEBS Lett. 2000, 466, 70-74; Bauer et al. Blood 1999, 94, 1665-1672; Klages et al. J. Cell Biol. 1999, 144, 745-754; Retzer et al. Cell Signal 2000, 12, 645-648) and aggregation of cells (Kawaguchi et al. Eur. J. Pharmacol. 2000, 403, 203-208; Sanchez-Madrid et al. J. Immunol. 2003, 171, 1023-1034; Sanchez-Madrid, et al. J. Immunol. 2002, 168, 400-410), in biological processes related to stem cells and induced prepotent the mi stem cells, for example, in cell-cell interaction, cell proliferation, development, cell cycle, gene regulation, migration, modulation of actin cytoskeleton, and in related processes, such as viability, survival, recovery, growth, susceptibility to apoptosis, differentiation, development, modulation of genes, modulation of morphogenesis, implementation and hosting (Krawetz et al. BioEssay 2009, 31, 336-343; Claassen et al. Mol. Reprod. Dev. 2009, PMID: 19235204; Heng Tissue Cell 2009, PMID: 19261317; Arnsdorf et al. J. Cell. Sci. 2009, 122, 546-553, Kim et al. Stem Cells 2009, 27, 191-199), modulation of epithelial-mesenchymal transition (Royal et al. Mol. Biol. Cell 2000, 11, 1709-1725; Zondag et al. J. Cell Biol. 2000, 149, 775-782; Masszi et al. Am. J. Physiol. Renal. Physiol. 2003, 284, 911-924; Smallhorn et al. Development 2004, 131, 2641-2651; Wells et al. Cell Motil. Cytoskeleton 2005, 62, 180-194; Wu et al. Cancer Res. 2006, 66, 9527-9534; Fan et al. Mol Biol Cell. 2007, 18, 1083-1097; Cho et al. Cell Biol. Int. 2007, 31, 1225-1230; Giehl et al. Cells Tissues Organs. 2007, 185, 123-130; Rodrigues-Díez et al. Pharm. Res. 2008, 25, 2447-2461), bone resorption (Chellaiah et al. J. Biol. Chem. 2003, 278, 29086-29097), activation of Na/H exchange transport system (Kawaguchi et al. Eur. J. Pharmacol. 2000, 403, 203-208), Alzheimer's disease (Zhou et al. Science 2003, 302, 1215-1217), activation of adducin (Fukata et al. J. Biol. Chem., 1998, 273, 5542-5548) and in the signal transmission through the SREB (Sterol-induced element binding) and its effects on lipid metabolism (Lin et al. Circ. Res. 2003, 92, 1296-304).

Consequently, the compounds having inhibitory effect on Rho-kinase and/or mediated by Rho-kinase phosphorus is regulation phosphatase light chains of myosin, applicable for the treatment and/or prevention of cardiovascular and non-cardiovascular diseases with involvement of Rho-kinase as a primary or secondary cause of the disease, such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, impaired peripheral circulation, occlusive disease peripheral artery disease (PAOD), coronary heart disease, angina, cardiac hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end damage to the body), pneumovirus, liver fibrosis, liver failure, nephropathy, including nephropathy induced hypertension or other cause, and diabetes, renal failure, fibrosis of the kidney, renal glomerulosclerosis, hypertrophy of the organs, bronchial asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and its complications, metabolic syndrome, restenosis CROs is anenih vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, bacterial infection of the gastrointestinal tract, sepsis, development and progression of cancer, for example, malignant tumors of the breast, colon, prostate, ovarian, brain and lung and their metastases.

In addition, the compounds having inhibitory effect on Rho-kinase may also be applicable in approaches to treatment involving the use of stem cells or induced poly potent stem cells, to improve recognition or to treat or prevent fibrosis of the myocardium, depression, epilepsy, medullary necrosis renal, tubulo-interstitial dysfunction, multiple sclerosis, stenosis of blood vessels, such as stenosis of the carotid artery, or disorders of lipid metabolism.

In WO 2001/64238 described isoquinoline-5-sulfonamidnuyu derivatives, optionally substituted -(CH2)1-6-O-(CH2)0-6-, -(CH2)0-6-S-(CH2)0-6- or -(CH2)0-6-linked heterocyclic group, applicable as neuroprotective funds.

In WO 2004/106325 (Schering AG) describes prodrugs of inhibitors of Rho-kinase fasudil containing ether or ester group at the 1-position of the isoquinoline ring.

In WO 2001/039726 generally described-O-(C 0-C10)alkylglycerol-substituted tsiklogeksilnogo derivatives, applicable to the treatment of microbial infections.

In JP 10087629A described isoquinoline derivatives, applicable to the treatment of diseases caused byHelicobacter pylorisuch as, for example, gastritis, cancer or ulcer. Isoquinoline derivatives can be substituted by OH in the 1-position and preferably substituted X-[(C1-C6)alkylene]0-1-Y at the 5-position, where X can be an oxygen atom, and Y may represent an aryl or heterocyclic group.

In the work Hagihara et al. (Bioorg. Med. Chem. 1999, 7, 2647-2666) revealed 6-benzyloxyethanol for the treatment of infections caused byHelicobacter pylori.

In U.S. patent No. 5480883 as inhibitors of the receptors for EGF and/or PDGF applicable for inhibition of cell proliferation, generally disclosed compounds of formula ArI-X-ArII", where X can be a (CHR1)m-Z-(CHR1)nfor example, Z-CH2where Z may represent O, R1represents a hydrogen atom or alkyl, ArI, among others, can be an optionally substituted isohedron, and ArII additional area can be an optionally substituted C3-7-monocyclic saturated heterocyclic system.

In WO 2005/030791 (Merck & Co.) as inhibitors of potassium channels for the treatment of cardiac ar is TMI, stroke, congestive heart failure, and the like generally described izohinolinove derivatives, optionally substituted in the 6-position by the group (CReRf)pOR43where p can be 0, and R43represents, for example, (C3-C10)cycloalkenyl residue, optionally substituted by a group NR51R52where R51and R52can represent a hydrogen atom, (C1-C6)alkyl and the like; or R43represents a group R81defined as (4-6)-membered unsaturated or saturated monocyclic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms; and replaced by direct binding with optionally substituted aryl or heteroaryl ring in 4-position.

In WO 2005/030130 (Merck & Co.) as inhibitors of potassium channels for the treatment of cardiac arrhythmias, stroke, congestive heart failure, and the like generally described isoquinoline derivatives which may be substituted by a hydroxy-group in the 1-position and optionally substituted in the 6-position by the group (CReRf)pOR43where p can be 0, and R43represents, for example, (C3-C10)cycloalkenyl residue, optionally substituted by a group NR51R52where R51and R52what may be a hydrogen atom, (C1-C6)alkyl and the like; or R43represents a group R81defined as (4-6)-membered unsaturated or saturated monocyclic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms; and replaced by direct binding with optionally substituted aryl or heteroaryl ring in 4-position.

In WO 2003/053330 (Ube) is generally described izohinolinove derivatives of the formula

as inhibitors of Rho-kinase.

In WO 2007/012422 (Sanofi-Aventis) is generally described isoquinoline and izohinolinove derivatives of the formula

as inhibitors of Rho-kinase.

In WO 2008/020081 (Organon) described 6-substituted isoquinoline derivatives as inhibitors of Rho-kinase.

In particular, the selectivity against other kinases was identified as a necessary condition for the application of kinase inhibitors as therapeutic agents. For example, fasudil, widely advertised inhibitor of Rho-kinase, has only moderate selectivity against other kinases, such as protein kinase A and protein kinase G (see, e.g., Tamura et al., Biochimica et Biophysica Acta, Proteins and Proteomics (2005), 1754(1-2), 245-252). Another inhibitor of Rho-kinase, Y-27632, has only 20-fold selectivity relative to the protein kinase G.

So hot is some inhibitors of Rho-kinase and described, still remains the need for additional connections that are applicable for the treatment mediated by Rho-kinase diseases, in particular, with improved selectivity.

The embodiment of the present invention is a compound of formula (I)

in which

R1represents H, OH or NH2;

R3represents H, a halogen atom, CN, (C1-C6)alkyl, OH, NH2or other';

R4represents H, halogen atom, hydroxy, CN, (C1-C6)alkyl, R', or (C1-C6)alkylene-R';

R5represents H, a halogen atom, CN, (C1-C6)alkyl, or R';

R7represents H, halogen, CN, (C1-C6)alkyl, O-(C1-C6)alkyl, R' or SO2-NH2;

R8represents H, halogen atom or (C1-C6)alkyl;

R9represents R', OH, halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl, (C2-C6)quinil, (C1-C6)alkylen-O-R', (C1-C6)alkylene-CH[R']2, (C1-C6)alkylen-C(O)-R', (C1-C6)alkylen-C(O)NH2, (C1-C6)alkylen-C(O)NH-R', (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl, (C1-C6)alkylen-C(O)N[(C1-C6)alkyl]2/sub> , (C1-C6)alkylen-C(O)N[R']2, (C1-C6)alkylen-C(O)O-(C1-C6)alkyl, COOH, C(O)O-(C1-C6)alkyl, C(O)OR', C(O)(C1-C6)alkyl, C(O)R', C(O)NH2C(O)-NH-(C2-C6)alkenyl, C(O)-NH-(C2-C6)quinil, C(O)NH-(C1-C6)alkyl, C(O)other', C(O)-NH(C1-C6)alkylene-R', C(O)N[(C1-C6)alkyl]R', C(O)N[(C1-C6)alkyl]2C(O)-(C1-C6)alkylene-R' or C(O)O(C1-C6)alkylene-R';

R6no;

or is a (C1-C4)alkylen associated with cycloalkenyl ring, where (C1-C4)alkylene forms a second bond to a different carbon atom cycloalkyl ring with the formation of a bicyclic ring system,

where the bicyclic ring system optionally one or two carbon atoms replaced by a group independently selected from O, N-R15, S, SO or SO2;

or, if m and s are equal to 2, m is 3 and s is 1, or m is 4 and s is 0,

R6represents CH2-CH-(CH2)2associated one CH2with cycloalkyl ring, and the other two CH2linked to other carbon atoms cycloalkyl ring;

and, if m is 3 and s is 3,

R6represents two methylene groups connected to different carbon atoms cycloalkyl ring, where a methylene group which is the group CH 2-CH-(CH2)2linked to carbon atoms cycloalkyl ring in such a way that they form adamantanone system of equations

where L may be associated with any secondary or tertiary carbon atom, and

where the bicyclic ring system or adamantinoma system is unsubstituted or optionally substituted by R9;

R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C5-C10)heteroaryl, (C1-C6)alkylene-(C3-C8)heteroseksualci, C(O)NH-(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2C(O)NH-R', C(O)N-((C1-C6)alkyl)-R' or C(O)NH-(C1-C6)alkylene-R';

R11represents H, (C1-C6)alkyl, (C1-C6)alkylene-R', R',

or R11and R12form together with the carbon atom to which they are attached, (C3-C8)cycloalkyl or (C3-C8)geteroseksualnoe ring;

R12is a (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5-C10)heteroaryl, (C3-C8)hetero is cloacal or (C 6-C10)aryl;

or R12represents H, provided that r=2 and the other R12does not represent H;

or R11and R12form together with the carbon atom to which they are attached, (C3-C8)cycloalkyl or (C3-C8)geteroseksualnoe ring;

R13and R14independently of one another represent H, R', (C1-C6)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-R', (C1-C6)alkylene-CH[R']2, (C1-C6)alkylen-C(O)-R', (C1-C6)alkylen-C(O)NH2, (C1-C6)alkylen-C(O)NH-R', (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl, (C1-C6)alkylen-C(O)N[(C1-C6)alkyl]2, (C1-C6)alkylen-C(O)N[R']2, (C1-C6)alkylen-C(O)O-(C1-C6)alkyl, C(O)O-(C1-C6)alkyl, C(O)OR', C(O)(C1-C6)alkyl, C(O)R', C(O)NH-(C1-C6)alkyl, C(O)other', C(O)N[(C1-C6)alkyl]R', C(O)N[(C1-C6)alkyl]2C(O)-(C1-C6)alkylene-R', C(O)O(C1-C6)alkylene-R' or

R13and R14form together with the nitrogen atom to which they are attached, (C3-C8)heteroseksualci;

R15represents H or (C1-C6)alkyl;

n is 0, 1, 2, 3 or 4;

m is 1, 2, 3 Il is 4;

s is 0, 1, 2 or 3;

r is 1 or 2;

L represents O(CH2)pS(CH2)p, S(O)(CH2)p, SO2(CH2)p, NH(CH2)pN(C1-C6)alkyl-(CH2)pN(C3-C6)cycloalkyl-(CH2)p; or N[(C1-C3)alkylene-R']-(CH2)p;

p is 0, 1, 2, 3 or 4;

R' represents a (C3-C8)cycloalkyl, (C5-C10)heteroaryl, (C3-C8)heteroseksualci, (C6-C10)aryl;

where in the residues R3-R15alkyl or alkylene are unsubstituted or optionally substituted by one or more OH, OCH3C(O)OH, C(O)OCH3, NH2, NHCH3N(CH3)2C(O)NH2C(O)NHCH3or C(O)N(CH3)2;

where in the residues R3-R15cycloalkyl or heteroseksualci are unsubstituted or optionally substituted by one or more (C1-C6)alkilani, halogen atoms, OH, OCH3C(O)OH, C(O)OCH3, NH2, NHCH3N(CH3)2C(O)NH2C(O)NHCH3or C(O)N(CH3)2;

where in the residues R3-R15alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms;

where in the residues R3-R15(C6-C10)aryl and (C5-C10)heteroaryl are asamese the governmental or optionally substituted by one or more groups, independently selected from a halogen atom, OH, NO2N3, CN, C(O)-(C1-C6)alkyl, C(O)-(C6-C10)aryl, C(O)OH, C(O)O(C1-C6)alkyl, C(O)NH2C(O)NH(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2, (C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl, O-C(O)-(C1-C6)alkyl, PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl; SO-(C1-C6)alkyl, SO2-(C1-C6)alkyl, SO2-N=CH-N[(C1-C6)alkyl]2, SF5C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH-C(O)-(C1-C6)alkyl, NH-C(O)O-(C1-C6)alkyl, NH-SO2-(C1-C6)alkyl, NH-SO2-(C6-C10)aryl, NH-SO2-(C5-C10)heteroaryl, NH-SO2-(C3-C8)geterotsiklicheskie, N(C1-C6)alkyl-C(O)-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)-NH-(C1-C6)alkyl], (C6-C10)aryl, (C1-C6)alkylene-(C6 -C10)aryl, O-(C6-C10)aryl, O-(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C8)geterotsiklicheskie, (C1-C6)alkylene-(C5-C10)heteroaryl, (C1-C6)alkylene-(C3-C8)geterotsiklicheskie, O-(C1-C6)alkylene-(C5-C10)heteroaryl, O-(C1-C6)alkylene-(C3-C8)geterotsiklicheskie,

where indicated (C6-C10)aryl or (C5-C10)heteroaryl, or (C3-C8)heteroseksualci, or (C3-C8)cycloalkyl can be substituted one to three groups independently selected from a halogen atom, OH, NO2, CN, O-(C1-C6)alkyl, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, SO2CH3C(O)OH, C(O)O-(C1-C6)alkyl, C(O)NH2, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-(C6-C10)aryl, or O-(C1-C6)alkylene-(C6-C10)aryl;

or where (C6-C10)aryl is substituted vicinal group O-(C1-C4)alkylen-O, where (5-8)-membered ring is formed together with the carbon atoms to which are attached oxygen atoms; and

where the aryl substituents in (C6-C10)aryl, (C5-C10)heteroaryl, qi is alkiline or (C 3-C8)geteroseksualnoe groups can be optionally substituted by a group containing aryl, heteroaryl, cycloalkyl or heteroseksualci;

its stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

In another embodiment, the present invention also relates to the compound of formula (I) and/or its pharmaceutically acceptable salts for use as pharmaceuticals. It also relates to the use of at least one of the compounds of formula (I) and/or its pharmaceutically acceptable salts for the treatment and/or prevention mediated by Rho-kinase diseases such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, impaired peripheral circulation, occlusive disease peripheral artery disease (PAOD), coronary heart disease, angina, cardiac hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end damage to the body), pneumovirus, liver fibrosis, liver failure, nephropathy, renal failure, kidney fibrosis, renal glomerulosclerosis, hypertrophy of the organs, bronchial asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, insult, cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and its complications, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy, a bacterial infection of the gastrointestinal tract, sepsis or the development and progression of cancer. The present invention additionally relates to a medicinal product containing an effective amount of at least one of the compounds of formula (I) and/or its pharmaceutically acceptable salt. Another objective of the present invention is a method for obtaining compounds of formula (I).

The term "alkyl", as used in (C1-C2)alkyl, (C1-C4)alkyl or (C1-C6)alkyl and relevant alkilinity substituents, understood as a hydrocarbon residue, which may be linear, i.e. non-branched chain or branched and contains 1, 2, 3, 4, 5 or 6 carbon atoms, respectively. It is also used if an alkyl group is acting as a Deputy of another group, for example, in alkoxygroup (O-alkyl, S-alkyl or-O(C1-C6)alkylen-O-, aldoxycarb Niley group or arylalkyl group. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl, n-isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. Alkyl or alkylene groups can be optionally galogenirovannyie one or more times, for example, alkyl groups may be fluorinated, for example, perfluorinated. Examples of halogenated alkyl groups are CH2F, CHF2, CF3and CH2CF3, OCF3SCF3or-O-(CF2)2-O-.

The term "(C2-C6)alkenyl" means a hydrocarbon residue, the carbon chain of which is unbranched or branched and contains from 2 to 6 carbon atoms and, depending on chain length, 1, 2 or 3 double bonds, e.g. vinyl, 1-propenyl, 2-propenyl (= allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl. Where possible, the double bond may be E or Z orientation. The double bond can be internal or terminal.

(C2-C6)alkyline groups are hydrocarbon residues, the carbon chain of which is unbranched or branched and contains from 2 to 6 carbon atoms and, depending on chain length, 1 or 2 triple bond,for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL (= propargyl) or 2-butynyl. Triple bond can be internal or terminal.

The term "halogen atom" means a fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).

The term "(C1-C8)heteroalkyl or appropriate (C1-C8)heteroarenes assistants understand how (C1-C8)alkyl or (C1-C8)alkylene group, where at least one carbon atom, preferably one or two carbon atoms, more preferably one carbon atom replaced by a group selected from O, NH or S, and where the atoms of nitrogen and sulfur may be optionally oxidized. The heteroatom may be located in any position of the alkyl or alkilinity group. Examples (C1-C8)heteroalkyl groups include-CH2-O-CH3, -CH2-CH2-O-CH2-CH3, -CH2-NH-CH2-CH3, -CH2-N(CH2-CH3)2-CH2-CH2-CH2-O-CH3, -CH2-CH2-CH2-S-CH3, -CH2-O-CH(CH3)2, -CH2-O-CH2-CH2-O-CH3or O-CH2-CH3.

(C3-C8)cycloalkyl groups represent a cyclic alkyl group containing 3, 4, 5, 6, 7, or 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which also may be substituted and/or can contain 1 or 2 double bonds (unsaturated cycloalkyl group), such as, for example, cyclopentenyl or cyclohexenyl, which may be connected through any carbon atom.

The term "(C6-C10)aryl group" means an aromatic ring or ring system that contains two aromatic rings are condensed, or otherwise associated, or which contains two condensed aromatic rings, where one ring is saturated or partially saturated, i.e. contains at least one single C-C bond, for example, phenyl, naftalina, biphenylene, tetrahydronaphthalene, α - or β-tetralone, indanyl or indan-1-anilina group. Preferred (C6-C10)aryl group is phenyl.

The term "(C3-C8)heterocytolysine group" means a saturated (contains no double bonds) monocyclic carbon ring system containing 3, 4, 5, 6, 7, or 8 ring atoms in which one or more carbon atoms may be replaced by one or more heteroatoms, such as, for example, 1, 2 or 3 nitrogen atom, 1 or 2 oxygen atoms, 1 or 2 sulfur atom, or a combination of various heteroatoms. Heterocytolysine residues can be attached at any position, for example, in the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. Also citymouse corresponding N-oxides, the sulfoxidov or sulfones such compounds.

Examples (C3-C8)geterotsiklicheskikh groups are oxiranyl, oxetanyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, DIOXOLANYL, for example, 1,3-DIOXOLANYL, dioxane, for example, 1,4-dioxane, piperidinyl, pyrrolidinyl, imidazolidinyl, diazolidinyl, hexahydropyridine, piperazinil, triazinyl, for example, 1,3,5-triazinyl, 1,2,3-triazinyl or 1,2,4-triazinyl, tetrahydrothiophene, tetrahydrothiopyran, dithiolane, for example, 1,3-dithiolane, dithienyl, diazolidinyl, oxazolidinyl, oxathiolane, for example, 1,3-oxathiolane, morpholinyl or thiomorpholine, diazepan, for example, 1,4-diazepan.

Preferred (C3-C8)geteroseksualnoe group is morpholinyl, pyrrolidinyl, piperazinil, piperidinyl, oxetanyl or tetrahydropyranyl.

The term "(C5-C10)heteroaryl" means mono - or bicyclic ring system in which one or more carbon atoms may be replaced by one or more heteroatoms, such as, for example, 1, 2, or 4 nitrogen atom, 1 or 2 oxygen atoms, 1 or 2 sulfur atom, or a combination of various heteroatoms. Heteroaryl residues can be attached at any position, for example, in the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-state is, or 8-position. (C5-C10)heteroaryl group can be either (1) an aromatic monocyclic or bicyclic ring system, or (2) a bicyclic ring system where one ring is aromatic and another ring is at least partially saturated.

Also taken into account the corresponding N-oxides, sulfoxidov or sulfones such compounds.

Appropriate (C5-C10)heteroaryl groups are benzimidazolyl, benzofuran, benzothiazyl, isoindolyl, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, benzisoxazole, benzisothiazole, carbolines, cinnoline, bromanil, bromanil, naphthyridine, phthalazine, predominately, pteridinyl, purinol, hintline, honokalani, chinoline, ethenolysis, tetrahydroisoquinoline, tetrahydroquinoline, indoline, indolizinyl, indolyl, furyl, furutani, thienyl, imidazolyl, imidazolyl, 1H-indazole, pyrazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl.

Pyridyl is 2-, 3 - and 4-pyridyl. Thienyl means 2 - and 3-thienyl. Furyl means 2 - and 3-furyl. Also taken into account correspond to their N-oxides of these compounds, for example, 1-hydroxy-2-, 3 - or 4-pyridyl.

The substituents in (C5-C10)heteroaryl residues may contain free carbon atoms or nitrogen atoms.

Preferred examples of (C5-C10)heteroaryl residues are benzofuran, chinoline, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, triazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and tetrazolyl.

Preferred (C5-C10)heteroaryl is (C5-C6)heteroaryl group. Preferred (C5-C6)heteroaryl residues are furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, triazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl and pyridazinyl. Preferred examples of (C5-C6)heteroaryl residues are 2 - or 3-thienyl, 2 - or 3-furyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1-, -3 - or-5-yl, 2-, 4 - or 5-oxazolyl, 3-, 4 or 5 isoxazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-oxadiazol-2 - or-5-yl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 3 - or 4-pyridazinyl or pyrazinyl.

In the residues R3-R15(C6-C10)aryl and (C5-C10g is thereally residues are unsubstituted or unless otherwise specified, optionally substituted by one or more, preferably one to three groups independently selected from a halogen atom, OH, NO2N3, CN, C(O)-(C1-C6)alkyl, C(O)-(C6-C10)aryl, C(O)OH, C(O)O(C1-C6)alkyl, C(O)NH2C(O)NH(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2, (C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl, O-C(O)-(C1-C6)alkyl, PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, SO-(C1-C6)alkyl, SO2-(C1-C6)alkyl, SO2-N=CH-N[(C1-C6)alkyl]2, SF5C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH-C(O)-(C1-C6)alkyl, NH-C(O)O-(C1-C6)alkyl, NH-SO2-(C1-C6)alkyl, NH-SO2-(C6-C10)aryl, NH-SO2-(C5-C10)heteroaryl, NH-SO2-(C3-C8)geterotsiklicheskie, N(C1-C6)alkyl-C(O)-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O-(C1-C6)alkyl, N(Csub> 1-C6)alkyl-C(O)-NH-(C1-C6)alkyl], (C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, O-(C6-C10)aryl, O-(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C8)geterotsiklicheskie, (C1-C6)alkylene-(C5-C10)heteroaryl, (C1-C6)alkylene-(C3-C8)geterotsiklicheskie, O-(C1-C6)alkylene-(C5-C10)heteroaryl, O-(C1-C6)alkylene-(C3-C8)geterotsiklicheskie,

where indicated (C6-C10)aryl or (C5-C10)heteroaryl, or (C3-C8)heteroseksualci, or (C3-C8)cycloalkyl can be substituted one to three groups independently selected from a halogen atom, OH, NO2, CN, O-(C1-C6)alkyl, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, SO2CH3C(O)OH, C(O)O-(C1-C6)alkyl, C(O)NH2, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-(C6-C10)aryl, or O-(C1-C6)alkylene-(C6-C10)aryl;

or where (C6-C10)aryl is substituted vicinal group O-(C1-C4)alkylen-O, whereby is formed (5-8)-membered ring together with carbon atoms to which are connected inany oxygen atoms;

and where the aryl substituents in (C6-C10)aryl, (C5-C10)heteroaryl, cycloalkyl or (C3-C8)geterotsiklicheskikh groups can be optionally substituted by a group containing aryl, heteroaryl, cycloalkyl or heteroseksualci.

Preferred substituents for (C6-C10)aryl and (C5-C10)heteroaryl groups are OH, (C1-C4)alkyl, O-(C1-C4)alkyl, O-phenyl, phenyl, C(O)O-(C1-C6)alkyl, C(O)OH, C(O)-(C1-C4)alkyl, halogen atom, NO2, SO2NH2CN, SO2-(C1-C4)alkyl, SO2-N=CH-N[(C1-C6)alkyl]2, NH-SO2-(C1-C4)alkyl, NH2, NH-C(O)-(C1-C4)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkyl-OH, C(O)N[(C1-C4)alkyl]2C(O)NH(C1-C6)alkyl, C(O)NH2N[(C1-C4)alkyl]2, (C1-C4)alkylene-N[(C1-C4)alkyl]2, (C1-C4)alkylen-O-(C1-C4)alkyl, (C5-C6)heteroaryl, (C3-C8)heteroseksualci, (C1-C4)alkylene-(C6-C10)aryl, where (C6-C10)aryl may be optionally substituted one to three, preferably one, a halogen atom, (C1-C4)alkyl, O-(C1-C4)alkyl, (C1-C4)alkylen-O-(Csub> 1-C6)alkyl, (C6-C10)aryl, O-(C1-C6)alkylene-(C6-C10)aryl, or may be substituted vicinal group O-(C1-C4)alkylen-O, whereby is formed (5-8)-membered ring together with carbon atoms to which are attached oxygen atoms.

More preferred substituents for (C6-C10)aryl and (C5-C10)heteroaryl are OH, halogen atom, CN, phenyl, O-phenyl, NH-C(O)-(C1-C4)alkyl, C(O)-(C1-C4)alkyl, C(O)-O(C1-C4)alkyl, (C1-C4)alkyl, O-(C1-C4)alkyl, CONH2, SO2-NH2, SO2-(C1-C4)alkyl or SO2-N=CH-N[(C1-C4)alkyl]2, (C1-C4)alkalinity, (C1-C4)alkylen-O-(C1-C4)alkyl or (C5-C6)heteroaryl, where phenyl is unsubstituted or optionally substituted one to three, preferably one, OH, a halogen atom, (C1-C4)alkyl or O-(C1-C4)alkyl.

Even more preferred substituents for (C6-C10)aryl and (C5-C10)heteroaryl are OH, halogen atom, CN, phenyl, O-phenyl, NH-C(O)-(C1-C4)alkyl, especially NH-C(O)-CH3C(O)-(C1-C4)alkyl, especially C(O)-CH3C(O)-O(C1-C4)alkyl, especially C(O)-OCH3, (C1-C4)alkyl, the person is but CH 3or CF3, O-(C1-C4)alkyl, especially O-CH3, CONH2, SO2-NH2, SO2-(C1-C4)alkyl, especially SO2-CH3or SO2-CF3; or SO2-N=CH-N[(C1-C4)alkyl]2especially SO2-N=CH-N[(CH3)2,

where phenyl is unsubstituted or optionally substituted one to three, preferably one, OH, a halogen atom, (C1-C4)alkyl or O-(C1-C4)alkyl.

Particularly preferred substituents for (C6-C10)aryl and (C5-C10)heteroaryl groups are OH, CN, (C1-C4)alkyl, especially CH3or CF3, O(C1-C4)alkyl, especially O-CH3, halogen atom or phenyl, where phenyl may be optionally substituted one to three, preferably one, OH, a halogen atom, (C1-C4)alkyl, especially CH3or CF3or O-(C1-C4)alkyl, especially O-CH3.

The most preferred substituents for (C6-C10)aryl and (C5-C10)heteroaryl groups are OH, CN, halogen atom, (C1-C4)alkyl, especially CH3or CF3, O(C1-C4)alkyl, especially O-CH3or halogen atom.

In monosubstituted phenyl groups Deputy may be located in the 2-position, 3-position or 4-position, etc is than the 3-position and 4-position are preferred. If the phenyl group contains two Deputy, they can be located in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Phenyl groups containing three substituent, the substituents can be located in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.

The above explanations concerning phenyl groups, respectively, applicable to the divalent groups derived from phenyl groups, i.e. phenylene, which may be unsubstituted or substituted, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene. The above explanation is applicable to aryl subgroup comprising arylalkylamine groups. Examples arylalkylamine groups, which can also be unsubstituted or substituted in the aryl group, and also in alkalinous subgroup, are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropyl, 4-phenylbutyl, 1-methyl-3-phenylpropyl.

In the residues R3-R15alkyl or alkylene are unsubstituted or, if not specified otherwise, optionally substituted by one or more halogen atoms. In the presence of alkyl substituents or alkylen are preferably substituted by one to three halogen atoms selected from chlorine or bromine, but may be substituted by one or more tomonitor, for example, as perfluorinated. The preferred halogen is fluorine. Preferably alkylene is not halogenated. More preferably the alkyl or alkylen are not halogenated.

In the residues R3-R15alkyl or alkylene are unsubstituted or, if not specified otherwise, optionally substituted by one or more groups independently selected from OH, OCH3C(O)OH, C(O)OCH3, NH2, NHCH3N(CH3)2C(O)NH2C(O)NHCH3or C(O)N(CH3)2. In the presence of deputies, the number of substituents is preferably 1, 2, 3 or 4, more preferably 1 or 2, and more preferably is 1. Preferably alkylene is not replaced by one of the specified groups. More preferably the alkyl or alkylen are not replaced by one of the specified groups. Preferably the alkyl or alkylen R3, R4, R5, R7and R8are not substituted. In an additional embodiment, the alkyl or alkylen R4-R15are not replaced by one of the specified groups.

In the residues R3-R15cycloalkyl or heteroseksualci are unsubstituted or, if not specified otherwise, optionally substituted by one or more (C1-C6)alkilani, halogen atoms, OH, OCH3C(O)OH, C(O)OCH3, NH 2, NHCH3N(CH3)2C(O)NH2C(O)NHCH3or C(O)N(CH3)2. In the presence of deputies, the number of substituents is preferably 1, 2, 3 or 4, more preferably 1 or 2, and more preferably is 1. Preferably cycloalkyl or heteroseksualci R3-R9are not substituted. In an additional embodiment, cycloalkyl or heteroseksualci R3-R15are not substituted. In a preferred embodiment, heteroseksualci is not substituted. In another embodiment, cycloalkyl is not substituted.

Common and preferred substituents (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C8)geterotsiklicheskikh and (C3-C8)cycloalkyl groups, as defined above, can be combined with common and preferred definitions for R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, n, s, m, r, p and L, are described in subsequent versions of the implementation of the compounds of formula (I).

Further embodiments of the compounds of formula (I) further characterize the present invention and are a part of it.

In one embodiment, the compounds of formula (I) R1not only is et a H, and the compound is characterized by formula (II)

In another embodiment, the present invention R1represents OH, and the compound is characterized by formula (IIIa)

Isoquinoline derivative of the formula (I)in which R1represents OH, includes a corresponding tautomeric 1-izohinolinove derivative, which is characterized by the formula (IIIb)

This tautomeric form is a variant of implementation of the present invention.

In an additional embodiment, R1represents NH2and the compound is characterized by formula (IV)

Further additional embodiments of apply equally to compounds of formula (I), (II), (IIIa), (IIIb) and (IV).

In a preferred embodiment, R1represents H or OH; more preferably R1represents OH.

In one embodiment, R3preferably represents H, a halogen atom, (C1-C6)alkyl or NH-R'. In another more preferred embodiment, R3represents H, halogen atom, unsubstituted or substituted NH-(C5-C6)heteroaryl, unsubstituted or someseni the NH-(C 3-C8)heteroseksualci or unsubstituted or substituted NH-phenyl. In an even more preferred embodiment, R3represents an unsubstituted or substituted NH-(C5-C6)heteroaryl containing one or more nitrogen atoms, or unsubstituted or substituted NH-phenyl. In the most preferred embodiment, R3represents H.

Examples of substituents other' in R3are

The asterisk (*) indicates place of binding to C-atom rings.

In a preferred embodiment, R4represents H, a halogen atom, (C1-C6)alkyl or (C1-C2)alkenylphenol. In a more preferred embodiment, R4represents H, a halogen atom, or unsubstituted or substituted (C1-C4)alkyl or (C1-C2)alkenylphenol, preferably unsubstituted (C1-C4)alkyl or (C1-C2)alkenylphenol. Most preferably R4represents H.

In a preferred embodiment, R5represents H, CN, halogen atom, unsubstituted or substituted (C1-C6)alkyl, unsubstituted or substituted (C6-C10)aryl or unsubstituted or substituted (C5-C10)heteroaryl. Examples R5are ATO is hydrogen, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl, ethyl, phenyl, thienyl or pyridyl, nitrile, (p-methoxy)phenyl, N-aniline, cyclopropyl, tetrazole, 4-methoxyaniline. In a more preferred embodiment, (C1-C6)alkyl, (C6-C10)aryl or (C5-C10)heteroaryl are unsubstituted. In an even more preferred embodiment, R5represents H, halogen atom, methyl, ethyl, phenyl, thienyl or pyridyl, more specifically, H, halogen atom, methyl or ethyl. Most preferably R5represents H.

In a preferred embodiment, R7represents H, halogen atom, nitrile, unsubstituted or substituted (C1-C6)alkyl, unsubstituted or substituted O-(C1-C6)alkyl or unsubstituted or substituted R'. In a more preferred embodiment, R7represents H, halogen atom, nitrile, unsubstituted or substituted (C1-C4)alkyl, unsubstituted or substituted O-(C1-C4)alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted (C5-C6)heteroaryl or unsubstituted or substituted (C3-C6)cycloalkyl. Preferably, (C1-C6)alkyl, phenyl or (C5-C6)heteroaryl are unsubstituted.

In an even more preferred variant of the implementation of R 7represents H, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, methoxy, phenyl, nitrile, cyclopropyl or thienyl. More preferably R7represents H, fluorine atom, chlorine atom, bromine atom, methyl or methoxy, in particular H or chlorine atom. Most preferably R7represents a chlorine atom.

In a preferred embodiment, R8represents H, Cl, F, methyl or ethyl. In a more preferred embodiment, R8represents H.

In a preferred embodiment, R9represents R', OH, halogen atom, (C1-C6)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl, (C1-C6)alkylen-C(O)NH-R', (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl, C(O)OH, C(O)NH2C(O)NH-(C1-C6)alkyl, C(O)other', C(O)-NH-(C1-C6)quinil, C(O)-NH(C1-C6)alkylene-R' or C(O)N[(C1-C6)alkyl]2; where the alkyl, alkylene and R' are unsubstituted or substituted. In a more preferred embodiment, R9represents OH, a halogen atom, (C1-C6)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl, C(O)OH, C(O)NH2C(O)NH-(C1-C6)alkyl, C(O)other' or C(O)N[(C1-C6)alkyl]2where alkyl, alkylene and R' are unsubstituted or substituted. More PR is doctitle R 9represents OH, a halogen atom, (C1-C6)alkyl, C(O)OH, C(O)NH2or O-CH3where the alkyl is unsubstituted or substituted. In an even more preferred embodiment, R9represents an unsubstituted or substituted (C1-C6)alkyl, preferably R9represents unsubstituted (C1-C6)alkyl.

R9may be bonded to any carbon atom in the ring, including the position, which is associated linker group L.

As examples of these embodiments, R9represents methyl, ethyl, propyl, isopropyl,

The asterisk (*) indicates place of binding to C-atom rings.

In a preferred embodiment, R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C5-C10)heteroaryl, (C1-C6)alkylene-(C3-C8)heteroseksualci, C(O)NH-(C1-C6)alkyl, C(O)NH-(C6-C10)aryl, or C(O)NH-(C1-C6)alkylene-(C6-C10)aryl,

where (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3 -C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene, (C6-C10)aryl or (C5-C10)heteroaryl are unsubstituted or substituted.

In a more preferred embodiment, R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C5-C10)heteroaryl or (C1-C6)alkylene-(C3-C8)heteroseksualci,

where (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene, (C6-C10)aryl or (C5-C10)heteroaryl are unsubstituted or substituted.

In a particularly preferred embodiment, R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylether or (C1-C6)alkylene-(C5-C6)heteroaryl, (C1-C6)alkylene-(C5-C6)heteroseksualci,

where (C1-Csub> 6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene, phenyl or (C5-C10)heteroaryl are unsubstituted or substituted.

In an even more preferred embodiment, R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C2)alkalinity, (C1-C6)alkylene-(C5-C6)heteroseksualci, or

where (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, phenyl and (C5-C10)heteroaryl are unsubstituted or substituted, preferably phenyl is unsubstituted or optionally substituted by one or two groups independently from each other selected from halogen atom, (C1-C4)alkyl or O-(C1-C4)alkyl, where (C1-C4)alkyl may be optionally substituted by a fluorine atom. In a particularly preferred embodiment, (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C3-C8)heteroseksualci, phenyl and (C5-C10)heteroaryl are unsubstituted who passed.

In an even more preferred embodiment, R10represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, isopropylacrylamide, tetrahydrofuranyl, tetrahydropyranyl or benzyl, cyclohexyl, trifluoromethyl, 3,3,3-cryptochromes, methoxy, ethoxy, ethoxyethyl, tetrahydropyrimidine, dioxotetrahydrofuran.

In the most preferred embodiment, R10represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, isopropylacrylamide, tetrahydrofuranyl, tetrahydropyranyl or benzyl.

In a preferred embodiment, R11represents H, (C1-C6)alkyl, (C3-C8)cycloalkyl or (C5-C6)heteroaryl, preferably H or (C1-C6)alkyl, where (C1-C6)alkyl, (C3-C8)cycloalkyl or (C5-C10)heteroaryl are unsubstituted or substituted, preferably unsubstituted.

In a more preferred embodiment, R11represents H or (C1-C6)alkyl, where (C1-C6)alkyl is unsubstituted or substituted, preferably unsubstituted. Most preferably, R11represents H.

12is a (C1-C6)alkyl, where one or more hydrogen atoms optionally replaced by fluorine atom; and (C3-C8)cycloalkyl, (C5-C6)heteroaryl or (C6-C10)aryl, where (C3-C8)cycloalkyl, (C5-C10)heteroaryl and (C6-C10)aryl are unsubstituted or substituted, preferably (C3-C8)cycloalkyl and (C5-C6)heteroaryl are unsubstituted. Preferably (C6-C10)aryl represents phenyl, which is unsubstituted or optionally substituted by one or two groups independently from each other selected from halogen atom, (C1-C4)alkyl or O-(C1-C4)alkyl, where (C1-C4)alkyl may be optionally substituted by a fluorine atom.

In a preferred embodiment, R12represents methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, trifluoromethyl, pentafluoroethyl, thiazolyl or phenyl.

In an additional embodiment, R11and R12form together with the carbon atom to which they are attached, (C3-C8)cycloalkyl ring, which is unsubstituted or substituted, preferably unsubstituted.

In an additional embodiment, R11and R12form together with the carbon atom is, to which they are attached, (C3-C8)geteroseksualnoe ring, which is unsubstituted or substituted. Preferably formed heterocyclyl group is oxetanyl, morpholinyl, piperidinyl, pyrrolidinyl or piperazinil. More preferably heterocyclyl group represents morpholinyl or piperazinil. Educated heterocytolysine group is preferably unsubstituted.

In one embodiment, the compounds of formula (I) R13and R14independently of one another represent H, R', (C1-C6)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-R', C(O)NH-(C1-C6)alkyl, C(O)other', C(O)N[(C1-C6)alkyl]2where R', (C1-C6)alkyl and (C1-C6)alkylene are unsubstituted or substituted.

In an additional embodiment, R13and R14form together with the nitrogen atom to which they are attached, (C3-C8)-geteroseksualnoe ring, which is unsubstituted or substituted. Preferably, (C3-C8-heteroseksualci is unsubstituted.

In a preferred embodiment, the compounds of formula (I) R13and R14independently of one another represent H, C 1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heteroaryl, (C1-C4)alkylene-(C3-C8)heteroseksualci, (C1-C4)alkylene-(C6-C10)aryl, (C1-C4)alkylen-O-(C1-C6)alkyl, C(O)NH-(C1-C6)alkyl, or

R13and R14form together with the nitrogen atom to which they are attached, (C3-C8)geterotsyklicescoe group,

where (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene, (C5-C10)heteroaryl, (C3-C8)heteroseksualci, (C6-C10)aryl are unsubstituted or substituted.

Preferably formed R13and R14heterocyclyl group represents morpholinyl, piperidinyl, pyrrolidinyl or piperazinil. More preferably heterocyclyl group represents morpholinyl or piperazinil.

In a more preferred embodiment, compounds of formula (I) R13represents H, (C1-C6)alkyl, (C3-C8)cycloalkyl or (C1-C4)alkylene-(C3-C8)cycloalkyl; and

R14represents H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene-(C3 -C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heteroaryl, (C1-C4)alkylene-(C3-C8)heteroseksualci, (C1-C4)alkylene-(C6-C10)aryl, (C1-C4)alkylen-O-(C1-C6)alkyl or C(O)NH-(C1-C6)alkyl,

where (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene, (C3-C8)heteroseksualci, (C6-C10)aryl are unsubstituted or substituted.

In an even more preferred embodiment, compounds of formula (I)

R13represents H or (C1-C6)alkyl; and

R14represents H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heteroaryl, (C1-C4)alkylene-(C3-C8)heteroseksualci, (C1-C4)alkylene-(C6-C10)aryl or (C1-C4)alkylen-O-(C1-C6)alkyl,

where (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkylene, (C3-C8)heteroseksualci, (C6-C10)aryl are unsubstituted or substituted.

More preferably R13represents H, (C1-C6)alkyl, and

R14represents H, (C1-C6)al is silt or (C 3-C8)cycloalkyl, where (C1-C6)alkyl or (C3-C8)cycloalkyl are unsubstituted or substituted, preferably unsubstituted.

In an additional embodiment, R13represents H and R14represents H, (C1-C6)alkyl or (C3-C8)cycloalkyl, where (C1-C6)alkyl or (C3-C8)cycloalkyl are unsubstituted.

Most preferably R13and R14represent H.

As the above-mentioned embodiments, R13or R14independently from each other represent a hydrogen atom, methyl, ethyl, propyl, isopropyl, 3-methylbutyl, 2-methylpropyl, butyl, pentyl, 3,3,3-cryptochromes, 4,4,4-triptorelin or Deputy selected from the group consisting of

The asterisk (*) indicates place of the linking N-atom of the amine.

In one embodiment, R15represents H or (C1-C6)alkyl, which is unsubstituted or optionally substituted, more preferably R15represents H or (C1-C4)alkyl, most preferably H. Preferably, alkyl is unsubstituted.

In one embodiment, the compounds of formula (I) R6missing or formed with R6Bicycle or Adam the tan is chosen from the group consisting of

(communication with dashed line indicates the position of the residue(CR11R12)rNR13R14)

or

which is unsubstituted or optionally substituted by R9. Preferably, Bicycle or adamantane are unsubstituted (n = 0) or substituted once (n = 1).

Preferably, the adamantane has the following structure

Also include CIS - and TRANS-isomers of these adamantanone residues, such as, for example, in structures

In one embodiment, the compounds of formula (I) R6missing, i.e. Bicycle or adamantane not formed.

In one embodiment, m is 2 and s is 2, which leads to the formation comprising the compounds of formula (I) residue of the formula

all stereochemical forms.

In another embodiment, m is 3 and s is 1, which leads to the formation comprising the compounds of formula (I) residue of the formula

In an additional embodiment, m is 2 and s is 1. In still another embodiment, m is 3 and s is 0. In another embodiment, m is equal to 4 and s is 0.

In one embodiment, with the organisations of the formula (I) n is 0, 1 or 2. More preferably, n is 0 or 1. Most preferably, n is 0.

In a preferred embodiment, r is 1.

In another embodiment, L represents O(CH2)p. In an additional embodiment, L is a S(CH2)p, S(O)(CH2)por SO2(CH2)p. In another embodiment, L represents NH(CH2)pN[(C1-C6)alkyl](CH2)pN[(C3-C6)cycloalkyl](CH2)pN[(C1-C3)alkylene](CH2)por N[(C1-C3)alkylene-(C5-C6)heteroaryl](CH2)pand more preferred are NH(CH2)pN(C1-C6)alkyl-(CH2)p. Preferably N(C1-C6)alkyl is an N(C1-C4)alkyl, more preferably NCH3or NCH2CH3and NCH3is more preferable. In a preferred embodiment, L represents O(CH2)p. In another preferred embodiment, L is a S(CH2)p. In an additional embodiment, L represents NH(CH2)p. Most preferably, L represents O, S or NH, and O is especially preferred.

Preferably, p is avno 0, 1, 2 or 3, more preferably 0 or 1, and most preferably is 0.

More preferably, m is 2 and s is 2, and L represents O, S or NH, preferably O.

In an additional embodiment, the present invention relates to the compound of formula (I)selected from the group consisting of

6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-propylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

6-[4-(aminocyclopropane)-4-propylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-ethyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminobutyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-2-methylpropyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-isopropoxybenzonitrile]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-ethyl)-4-cyclobutanecarboxylic]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-cyclobutyl is clohexane]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-cyclopentanecarboxylate]-7-chloro-2H-isoquinoline-1-it,

6-[4-(aminophenylamino)-4-cyclopentanecarboxylate]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-isobutyrylacetate]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-benzylacetone]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminobutyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminobutyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,

6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-2,2,2-triptorelin)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-2,2,2-triptorelin)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-2,2,3,3,3-pentafluoropropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

6-[4-(aminothiazol-2-ylmethyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it

6-[4-(aminothiazol-5-ylmethyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

their stereoisomeric and/or tautomeric forms and/or their pharmaceutically when mimih salts.

In an additional embodiment, the compound is chosen from the group consisting of

CIS-6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminobutyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminobutyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it

CIS-6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-it,

their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

In an additional embodiment, the compound is chosen from the group consisting of

CIS-6-[4-((S)-1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-((R)-1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-((S)-1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-((R)-1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-((R)-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-((S)-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[-((S)-aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it

CIS-6-[4-((R)-aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

their tautomeric forms and/or their pharmaceutically acceptable salts.

In an additional embodiment, the compound is chosen from the group consisting of

CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-fluoro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-fluoro-5-methyl-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-5,7-dimethyl-2H-isoquinoline-1-it,

CIS-6-[-4-(1-aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-it,

TRANS-6-[4-(1-aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-aminopropyl)-4-toxicologically]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminophenylamino)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminobutyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminophenylamino)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-3-methylbutyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-2-methylpropyl)-4-cyclohexylcyclohexanes]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-(4,4,4-afterbody)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-ylmethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminocyclopropane)-4-(tetrahydropyran-4-ylmethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminocyclopropane)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminocyclopropane)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethoxyethylacetate]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-ethyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminocyclopropane)-4-(4,4,4-trifloromethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-(tetrahydrothiopyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-ethyl)-4-propylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-fluoro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-fluoro-5-methyl-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-it,

CIS-7-chloro-6-{4-[1-(cyclopropylamino)propyl]-4-ethylcyclohexylamine}-2H-isoquinoline-1-it,

CIS-6-[4-(1-benzylaminopurine is)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

CIS-7-chloro-6-[4-ethyl-4-(1-isobutylamino)cyclohexyloxy]-2H-isoquinoline-1-it,

CIS-6-[4-(1-butylaminoethyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-2-methylpropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-7-chloro-4-fluoro-2H-isoquinoline-1-it (90),

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-4-fluoro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-4-bromo-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile,

CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-4-bromo-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

TRANS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

6-[4-(1-amino-3-methoxypropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,

CIS-6-[4-(1-aminopropyl)-4-(1,1-dioxotetrahydrofuran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,

6-[3-(1-aminopropyl)-3-propylcyclohexyl]-7-chloro-2H-isoquinoline-1-it

6-[4-(1-aminopropyl)-4-triftormetilfullerenov]-7-chloro-2H-isoquinoline-1-it,

their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

In an additional embodiment, the connection select the C group, consisting of

CIS-1-[4-(5,7-dimethylisoxazole-6-yloxy)-1-ethylcyclohexyl]Propylamine,

CIS-1-[1-ethyl-4-(7-forsakenly-6-yloxy)cyclohexyl]Propylamine,

CIS-1-[1-ethyl-4-(7-methylisoquinoline-6-yloxy)cyclohexyl]Propylamine,

CIS-1-[1-ethyl-4-(7-fluoro-5-methylisoquinoline-6-yloxy)cyclohexyl]Propylamine,

CIS-1-[1-ethyl-4-(7-fluoro-5-methylisoquinoline-6-yloxy)cyclohexyl] - ethylamine,

CIS-1-[4-(7-bromoisoquinoline-6-yloxy)-1-ethylcyclohexyl]ethylamine,

CIS-1-[4-(7-methylisoquinoline-6-yloxy)-1-ethylcyclohexyl]ethylamine,

CIS-1-[4-(5-chloroisoquinoline-6-yloxy)-1-ethylcyclohexyl]ethylamine,

CIS-6-[4-(1-amino-ethyl)-4-propylcyclohexanone]-7-chloroisoquinoline-1-ylamine and

[4-(1-aminopropyl)-4-methylcyclohexyl]isoquinoline-6-ylamine,

and their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

In any variants of implementation of the present invention one or more or all of the groups contained in the compounds of formula (I)may independently from each other to have any of the preferred, more preferred or most preferred definitions of the groups listed above, or any one or more of the specific exact values covered by the definitions of the groups mentioned above, and all combinations of the preferred definitions, more preferred or most predpochtitelnye/or specific exact values are the subject of the present invention. Furthermore, with respect to all preferred options for implementation of the present invention includes compounds of formula (I) in all stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their pharmaceutically acceptable salts.

The circuit in the isoquinoline are numbered according to the IUPAC rules:

The terms "isohedron and athinaikon" are used as synonyms.

All references to "compound(I) of the formula (I)" in this document refer to the compound(s) of formula (I), (II), (IIIa), (IIIb) and (IV)described above, and their pharmaceutically acceptable salts and/or their stereoisomeric forms, polymorphs and solvate. Also included physiologically active derivatives described in this document.

The term "pharmaceutically acceptable salts of compounds of formula (I)" means both organic and inorganic salts, described in Remington''s Pharmaceutical Sciences (17th edition, page 1418 (1985)). Because of the physical and chemical stability and solubility of the preferred acidic groups, in particular, salts of sodium, potassium, calcium and ammonium; preference is given to major groups, in particular, salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, f is sforno acids or carboxylic acids or sulfonic acids, for example, such as hydrochloride, hydrobromide, phosphates, sulphates, methansulfonate, acetates, lactates, maleate, fumarate, malate, gluconate and salts of amino acids, natural substrates or carboxylic acids. Getting pharmaceutically acceptable salts of the compounds of formula (I), which are capable of forming salts, including their stereoisomeric forms, perform a method known per se. The compounds of formula (I) form stable salts of alkali metals, salts of alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholate and ammonia or organic bases, for example trimethyl - or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or other basic amino acids, for example lysine, ornithine or arginine. If the compounds of formula (I) contain basic groups, there can be obtained a stable acid additive salts with strong acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention are salts of inorganic acids such as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, is tursultanova, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate and tartaric acid. Salt of hydrochloric acid is the preferred salt.

Salts with a pharmaceutically unacceptable anion, such as, for example, triptorelin, also included in the scope of the invention as suitable intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic purposes, for example,in vitro.

The present invention also includes a physiologically active derivatives of the compounds of formula (I). Used in this document, the term "physiologically active derivative" refers to any physiologically acceptable derivative compounds of formula (I) according to the present invention, for example, N-oxide, which when introduced mammals, such as, for example, people are able to form (directly or indirectly) a compound of formula (I) or its active metabolite.

Physiologically active derivatives include prodrugs of the compounds of the present invention, as described, for example in the publication of H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized byin vivobefore joining the present invention. By themselves, these prodrugs can be the act of the ate or inactive.

The present invention relates to compounds of formula (I) in the form of their stereoisomeric forms, which include the racemates, enriched mixture of enantiomers, pure enantiomers and diastereoisomers and their mixtures in any proportion.

Compounds of the present invention may also exist in different polymorphic forms, such as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the present invention are within the scope of the present invention and are a further aspect of the present invention.

If radicals or substituents may be present in compounds of formula (I) more than one, all of them, independently from each other, have a certain value and are the same or different.

The present invention also relates to compounds of formula (I) and/or their pharmaceutically acceptable salts for use as pharmaceuticals (or drugs), to the use of compounds of formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs for obtaining pharmaceuticals for the treatment and/or prevention of diseases associated with Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chains of myosin, i.e. for the treatment and/or prevention of hypertension, agonoy hypertension, intraocular hypertension, retinopathy and glaucoma, peripheral circulatory disorders, occlusive peripheral artery disease (PAOD), coronary heart disease, angina, hypercardia, heart failure, ischemic diseases, ischemic organ failure (end damage to the body), pneumovirus, liver fibrosis, liver failure, nephropathy, including nephropathy induced hypertension or other cause, and diabetes, renal failure, fibrosis of the kidney, renal glomerulosclerosis, hypertrophy of organs, bronchial asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostate hypertrophy, diabetes mellitus and its complications, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, bacterial infection of the gastrointestinal tract, sepsis, development and progression of cancer, for example, malignant tumors of the breast, colon, prostate, ovarian, brain and lung and their metastases.

In an additional embodiment, the present invention also relates to the use of compounds of formula (I) and/or its pharmaceutically acceptable salts for the treatment and/or prevention of hypertension, pulmonary hypertension, liver fibrosis, liver failure, nephropathy, renal failure, chronic obstructive pulmonary disease (COPD), cerebral vasospasm, pain, spinal cord injury, erectile dysfunction, restenosis of blood vessels or the development and progression of cancer.

In an additional embodiment, the present invention relates to the use of compounds of formula (I) and/or its pharmaceutically acceptable salts in the treatment approaches involving the use of stem cells or induced poly potent stem cells, to improve recognition or to treat or prevent fibrosis of the myocardium, depression, epilepsy, medullary necrosis renal, tubulo-interstitial dysfunction, multiple sclerosis, stenosis of blood vessels, such as stenosis of the carotid artery, or disorders of lipid metabolism.

The present invention also relates to pharmaceutical preparations (or farmace the political songs), which contain an effective amount of at least one of the compounds of formula (I) and/or its pharmaceutically acceptable salts and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable substances-carriers or solvents and/or excipients or excipients). Drugs can be administered orally, for example in the form of pills, tablets, glazed tablets, coated tablets, granules, hard or soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously in the form of injection or infusion solutions, microcapsules, implants or rods, or subcutaneously, or topically, e.g. in the form of ointments, solutions or tinctures, or in other ways, for example, in the form of aerosols or nasal sprays.

Pharmaceutical preparations in accordance with the present invention is produced by way known per se and familiar to the person skilled in the technical field, in addition to the compound(s) of formula (I) and/or their pharmaceutically acceptable salts and/or its (their) prodrugs, using pharmaceutically acceptable inert inorganic and/or the content of inorganic fillers substance-carriers and/or additives. For the preparation of pills, tablets, coated tablets and hard gelatin capsules may use, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Substances-carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid or liquid polyols, natural or hydrogenated oils, etc. with Suitable substances-carriers for the preparation of solutions, for example injection solutions, or emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. with Suitable substances-carriers for microcapsules, implants or rods are, for example, copolymers of glycolic and lactic acid. The pharmaceutical preparations generally contain from about 0.5 to about 90% by weight of compounds of formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs. The amount of active ingredient of formula (I) and/or its pharmaceutically acceptable salts and/or prodrugs is usually from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of formula (I) and/or their pharmaceutically acceptable Sol is m and substances-media the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrating agents, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, perfumes, fragrances, thickeners, diluents, buffer substances, solvents, soljubilizatory, means to achieve a depot effect, salts regulators of osmotic pressure, enrobing means or antioxidants. They can also contain two or more compounds of the formula (I) and/or their pharmaceutically acceptable salts. In that case, when the pharmaceutical preparation contains two or more compounds of the formula (I), the compounds can be targeted at specific total pharmacological profile of a pharmaceutical product. For example, a high-performance connection to the short duration of action may be combined with the connection prolonged action with low efficiency. The flexibility provided by the choice of substituents in the compounds of formula (I), allows to regulate the biological and physico-chemical properties of compounds, allowing, thus, to choose the desired connection. In addition, in addition, at least one compound of formula (I) and/or its pharmaceutically acceptable is the ol, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

When using compounds of formula (I), the dose can vary within wide limits and that is commonly known to doctors, must be consistent with the specific conditions in each case. It depends on exactly which connection to use, from the nature and gravity of the subject to treatment of the disease, method and mode of administration, or from chronic or acute condition being treated or is prevention. A suitable dose can be assigned using clinical approaches that are well known in the field of medicine. As a rule, the daily dose to achieve the desired results in an adult weighing about 75 kg is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg, in particular from about 0.1 to about 10 mg/kg (in each case in mg per kg of body weight). The daily dose may be divided, in particular, in the case of the introduction of relatively large amounts, for a few, such as 2, 3 or 4, partial injections. Typically, depending on the individual reactions may be necessary to increase or decrease the daily dose indicated.

in Addition, the compounds of formula (I) can be used as intermediate products of synthesis for the preparation of other compounds, in particular, other pharmaceutically active ingredients that can be obtained from compounds of the formula I, for example, by introduction of substituents or modification of functional groups.

The compounds of formula (I) can be obtained as follows:

Compounds of General formula (I) can be constructed from appropriately substituted isoquinoline fragment and replaced with appropriately cyclooctylamino fragment.

Isoquinolines and ishinomori type (i) or (ii)bearing a suitable balance for combination in the 6-position can be obtained from a wide variety of ways, for example, described in the publication of Alvarez et al. Science of Synthesis 2005, 15, 661-838 and 839-906 and there in the reference materials. Isoquinolines can also be converted into ishinomori the methods described in the literature, for example, in WO 2007/012421 or WO 2007/012422 as the conversion right in the corresponding isoquinoline N-oxide oxidant, such as hydrogen peroxide or metachlorobenzoic acid and subsequent conversion into the corresponding 1-chlorinated using glorieuses agent such as phosphorus oxychloride, followed by substitution of chlorine alcohol in basic conditions, such as metox the d sodium in methanol, or conversion to the corresponding 2H-isohedron, for example, by treatment with ammonium acetate in acetic acid at elevated temperature. Also the N-oxide can be directly converted into the corresponding 1-alkoxybenzenes by its interaction with a suitable chloroformate in an alcohol solvent such as methanol, in the presence of a base such as triethylamine. It is clear that the hydroxyl group in 6-position of formula (ii) may be released at a suitable stage of the synthesis, for example, when processing the corresponding 6-methoxypropanol Lewis acids such as aluminum chloride or tribromide boron. In addition, it is clear that 2H-ishinomori can be converted to protected appropriately 1-alkoxyethanol in various ways, for example, by treating the corresponding 2H-athinodorou alkylating agents, such as benzylbromide or mutilated, in the presence of a suitable base such as silver carbonate or triethylamine, in a suitable solvent, such as toluene or THF, or by converting the specified 2H-athinodorou in their 1-chlorinated by treatment gloriouse agent such as phosphorus oxychloride, followed by substitution of the chloride with an alcohol, for example, in basic conditions such as sodium methoxide in the methanol. It is clear that the residues R3, R4 , R5, R7and/or R8can either be included in the composition of the starting materials for the synthesis of the corresponding isoquinolines or athinodorou, or can be introduced at an appropriate later stage, for example, by halogenation, such as bromination or chlorination, followed by the replacement of the specified halogen method, are well represented in the literature, such as the combination by Suzuki or Buchwald-Hartwig using appropriate catalysts and agents of the combination, such as boranova acids, amines or anilines.

One of the possible routes of synthesis for cycloalumination of athinaikon with L=O (v) described below as an illustration, without limiting the present invention.

Cycloalumination athinaikon (for example, compound (v) can be synthesized in various ways. The following General scheme 1 illustrates some of the possible ways to obtain izohinolinove without limiting the present invention.

Scheme 1

6-Foreskinlacy (i), for example, substituted R3, R4, R5, R7and/or R8that, for example, independently from each other, represent substituents such as hydrogen, alkyl, alkoxy or halide, can be subjected to interaction with the appropriate R /R14substituted aminoalcohols, where R13/R14independently of one another are, for example, hydrogen, alkyl or a protective group such as, for example Boc or Cbz in the presence of a base, such as DBU, cesium carbonate or sodium hydride, at temperatures ranging from ambient temperature to 100°C, to obtain the corresponding derivative (iv). Optional, this conversion can be performed already at earlier stages of the synthesis (for example, by entering into the reaction of a suitable intermediate product). While I believe that in the case of unprotected athinodorou may need protection of nitrogen or oxygen izohinolinove fragment suitable means, such as interaction with appropriately substituted alkyl or benzylchloride in the presence of a base.

Alternatively, the aminoalcohols can be combined with 6-hydroxyisoquinoline, such as (ii), under conditions of inversion carrying the hydroxyl carbon centre of compounds of type (iii), or protected with suitable protecting group Q, or unprotected by the reaction of Mitsunobu using triphenylphosphine and dialkyldithiocarbamato, such as diethylazodicarboxylate or diisopropylethylamine, in a suitable solvent, such as tetrahydrofuran or toluene.

Products of type (iv), the floor is built of these methods, can either be isolated in the free state with the formation of compounds of type (v), or, if there is a suitable functional amino groups, may be exercised their interaction with the appropriate aldehydes or ketones in the presence of a reducing agent, such as triacetoxyborohydride sodium, sodium borohydride or cyanoborohydride sodium in a suitable solvent and in the presence of blagodaryaschih agent such as molecular sieves or suitable complex orthoepy. This amino group may need to be released at the initial stage, such as, for example, acidic removal of the Boc-group. In addition, the amino group may be allerban by its interaction with a suitable acid chloride in the presence of a base such as triethylamine or base Hunya, or by its interaction with a suitable carboxylic acid in the presence of a base such as triethylamine or base Hunya, and condensing reagent such as EDC, PyBOP or TOTU.

When using secure athinodorou for release search of athinodorou type (v) requires the removal of used protective groups. This release, however, may be performed before or after the stage of recovery amination, depending on the nature of the aldehyde/ketone and used protective group.

Izohinolinove production is adnie type (v) can be obtained as free bases or in the form of various salts, for example, such as hydrochloride, hydrobromide, phosphates, triptoreline, sulfates or fumarate. The salts can be converted into the corresponding free base or by carrying out ion-exchange chromatography, or, for example, by treating them with aqueous alkali solution, followed by extraction with suitable organic solvents, such as methyl tert-butyl ether, chloroform, ethyl acetate, or a mixture of isopropanol/dichloromethane, and subsequent evaporation to dryness.

Cyclooctylamine fragments, for example, of type (iii)can be synthesized in various ways. The following General schemes illustrate some of the possible ways to obtain amines without limiting the present invention. Within the competence of the specialist in this field of technology is replacing the typical connection diagram and typical reagent given in the text, suitable alternative compounds or reagents, or the exclusion or adding stages of synthesis, if necessary.

Synthesis of cycloalumination (iii) illustrative described in schemes 2 and 3 without limiting the range of substituents of the present invention.

Cycloalkenyl fragment of (iii) with a subgroup of the secondary or tertiary amine can be obtained, for example, from substituted with a suitable education is om cycloalkenyl (vi), which may be substituted by functional groups such as alkyl, alkoxy or acetals. The NITRILES can be functionalized in the alpha position by engagement with suitable electrophiles (e.g., alkylhalogenide, cycloalkyl-p-toluensulfonate, alkoxylated or aldehydes) using a suitable base, such as hexamethyldisilazide lithium, diisopropylamide lithium or metal hydrides in inert solvents, such as tetrahydrofuran, toluene or heptane.

Scheme 2

Then functionalized nitrile (vii) may be subjected to direct interaction with suitable nucleophiles for the introduction of functional groups, R11and R12for example, organolithium compounds or Grignard reagent, to obtain the compounds of type (viii). After this stage, depending on the nature of the original nitrile and complexity of the subsequent reactions can be attached or not attached a suitable protective group such as tert-butyloxycarbonyl or benzyloxycarbonyl. If R11=R12then organolithium compounds can be used as nucleophiles, activated by the addition of Lewis acids, such as isopropoxide titanium and cerium chloride.

If R11represents a hydrogen (H), something about eroticly Imin, formed by the addition of nucleophiles can be selected and restored with suitable reducing agents, such as cyanoborohydride or borhydride, in solvents such as tetrahydrofuran or alcohols. Alternatively, the nitrile (vii) can be restored to the aldehyde (x) suitable hydride-donor reagents, such as diisobutylaluminium, in cold organic solvents, such as diethyl ether or toluene, and converted into the corresponding imine (xi), such as benzylamine or N-tert-butanesulfinamide, the reaction catalyzed by Lewis acids, functionalized with appropriate amines. These imine (xi) can then be subjected to interaction with a suitable nucleophilic reagent such as an organolithium compounds, Grignard reagents or trimethylsilane, in combination with tetraalkyllead for the introduction of different substituents, such as alkyl, cycloalkyl or heterocyclyl group. Functional ketogroup can then be released by methods known to the person skilled in the technical field, for example, by treatment with aqueous acids such as acetic acid or hydrochloric acid in a mixture with acetone, and then restored to the corresponding alcohols (iii), usually in the form of mixtures of CIS/TRANS-isomers, appropriate what ostanovitesj, such as borhydride in alcohols, tetrahydrofuran or toluene, at very low temperatures.

This release, however, can also be carried out after stage functionalization nitrile (scheme 3), depending on the nature of the nitrile and circuits. If the ketone is restored to the functionalization of the nitrile, as a rule, with high selectivity get only one isomer (CIS or TRANS). For the conversion of NITRILES of type (xiii) in the amines (iii) can be useful the use of suitable protective groups for alcohol functional groups. Suitable protective groups known to the person skilled in the technical field, and it can be ethers, such as tetrahydropyrrole, methoxyethylamine or Silovye esters.

Scheme 3

To obtain cycloalkyl aminecontaining fragments other than cycloalkyl aminoalcohols, you can apply different ways. The following General scheme (scheme 4) illustrates some of the possible ways of obtaining the above amines, but does not limit the present invention.

Scheme 4

For example, the functional hydroxy-group of the compound (iii) can be converted to a thiol by reaction of Mitsunobu using thioacetate and subsequent primary redeploys a suitable base, leading to the formation of aminecontaining fragments of type (xiv). These thiols can be then - after combination with suitable izohinolinove in acceptable reaction conditions, for example, similar to that described above in scheme 1 for a combination of (iii) is used to obtain the compounds of formula (I) with the linker element L=S or optional can be oxidized by methods known to the person skilled in the technical field relevant to sulfoxidov and sulfones (for compounds of formula (I) with the linker element L=SO and SO2). The corresponding amines can be obtained by using the stage of recovery amination based on ketones, such as compound (ix or xii), using the appropriate amines in the presence of a reducing agent, such as triacetoxyborohydride sodium, sodium borohydride or cyanoborohydride sodium, in the presence of blagodaryaschih agent such as molecular sieves or suitable complex orthoepy.

As a rule, protective groups that may still be present in the products obtained in the reaction mix, then remove using standard techniques. For example, tert-Budilnik protective groups, in particular, tert-butoxycarbonyl group, which is a protective form amino groups, can be unsecured, i.e. the group may be conversions the van into the amino group by treatment triperoxonane acid. As already mentioned, after the reaction of a combination of suitable groups precursor can also be formed functional groups. In addition, then known methods can be implemented conversion pharmaceutically acceptable salt or prodrug of the compounds of formula (I).

As a rule, from the reaction mixture containing the target compound of formula (I) or an intermediate product, produce a product, and then, if desired, purify the product by standard methods known to experts in this field of technology. For example, the synthesized compound can be purified using well known methods such as crystallization, chromatography or reversed-phase high-performance liquid chromatography, or other methods of separation based on, for example, on the size, charge or hydrophobicity of the compounds. By analogy, for the characterization of compounds of the present invention can be used well-known methods, such as NMR, IR and mass spectrometry (MS).

EXAMPLES

The following examples illustrate various embodiments of the present invention and are a part of the present invention. CIS and TRANS nomenclature in the name of the corresponding compounds indicates the relative configuration of the remainder -[CR11R12]rNR13 R14and L-residue in cycloalkene ring. This is true for the corresponding predecessors.

6,7-Debtor-5-methylisoquinoline (compound 25)

a) [1-(3,4-Debtor-2-were)methylidene]-2,2-dimethoxyethan (compound 22)

3,4-Debtor-2-methylbenzaldehyde (26,0 g, 166 mmol) was dissolved in toluene (182 ml) and subjected to interaction with dimethylacetal 2-aminoacetaldehyde (19.3 g, 183,2 mmol) and toluensulfonate acid (3.2 g) for 2 hours in the office of Dean-stark. The solution was left to cool, was extracted with saturated sodium bicarbonate solution, water and saturated salt solution, dried over sodium sulfate and evaporated to dryness obtaining of 40.4 g of a dark yellow oil which was used without further purification.

(b) 3,4-Debtor-2-methylbenzyl-2,2-dimethoxyethane (compound 23)

[1-(3,4-Debtor-2-were)methylidene]-2,2-dimethoxyethan (compound 22, 40,4 g) was dissolved in ethanol (225 ml). Portions was added sodium borohydride (4.8 g, 124 mmol). Stirring was continued over night. For separation of the reaction product was added acetic acid until the completion of the visible evolution of gas. Then the solution was evaporated to dryness, absorbed dichloromethane and washed with saturated sodium bicarbonate solution and twice with water. The organic layer about ivali saturated salt solution, was dried over magnesium sulfate and evaporated to dryness. The crude product (of 37.8 g) was used without purification.

c) N-(3,4-Debtor-2-methylbenzyl)-N-(2,2-dimethoxymethyl)-4-methylphenylsulfonyl (compound 24)

3,4-Debtor-2-methylbenzyl-2,2-dimethoxyethane (compound 23, of 37.8 g) was dissolved in dichloromethane (100 ml). Added pyridine (42 ml). Dropwise at 0°C was added a solution of p-toluensulfonate cases (36.8 g, 193 mmol) in dichloromethane. The reaction mixture was allowed to warm to room temperature and continued stirring until the conversion is complete. For separation of the reaction product, the reaction mixture was diluted with dichloromethane (100 ml) and was extracted twice 1,5M hydrochloric acid, twice with sodium bicarbonate solution and once with saturated salt solution. The organic layer was dried over magnesium sulfate, was evaporated to dryness to obtain the crude product as an orange oil (68,3 g). The oil was used without further purification.

d) 6,7-Debtor-5-methylisoquinoline (compound 25)

Trichloride aluminum (111,7 g, 838 mmol) suspended in dichloromethane (250 ml) at 0°C. was Added a solution of N-(3,4-debtor-2-methylbenzyl)-N-(2,2-dimethoxymethyl)-4-methylphenylsulfonyl (compound 24, 68,3 g) in dichloromethane (250 ml). The reaction mixture was heated at 50°C in those who tell 2 hours, after which it was cooled to 0°C and poured into ice. The organic layer was separated, and the aqueous layer was extracted twice with a mixture of dichloromethane/isopropanol (3:1). The combined organic phase was extracted twice with saturated sodium bicarbonate solution and dried over magnesium sulfate, then filtered and evaporated to obtain 63,5 g of the crude dark brown semi-solid product. This product was purified by chromatography on silica gel. Elution with a mixture of ethyl acetate/heptane (5%:95% to 35%:65%) gave 11.3 g specified in the title compound 25 as a yellow-brown solid. Rt=0,86 min (method G). Detected mass: 180,1 (M+H+).

The following isoquinolines synthesized from the corresponding benzaldehydes similar to the method described for compound 25.

ConnectionThe original connectionProductChemical name[M+H+]Rt[min]Method
263,5-dimethyl-4-fluoro-benzaldehyde5,7-dimethyl-6-forsakenly 176,11,06G
273,4-debtor-benzaldehyde6,7-debtor-isoquinoline166,11,07C
283-bromo-4-fluoro-benzaldehyde7-bromo-6-fluoro-isoquinoline226,0 228,30,91J
294-fluoro-3-methoxy-benzaldehyde6-fluoro-7-methoxy-isoquinoline178,10,90G
304-fluoro-3-methyl-benzaldehyde6-fluoro-7-methylisoquinoline161,90,90G

1-Benzyloxy-7-chloro-6-forsakenly (compound 1)

7-Chloro-6-fluoro-2H-isoquinoline-1-he is received in accordance with WO 2007/012422; of 52.2 g) was dissolved in THF (1 l). After you have added silver carbonate (145,5 g) and benzylbromide (40,6 ml) and the mixture was stirred at room temperature overnight. Was added 6.2 ml of benzylbromide and stirred the mixture at 70°C for 2 hours After cooling to room temperature the reaction mixture was diluted by adding 1 l of ethyl acetate and filtered through celite. The filter residue is thoroughly washed, the organic layer was evaporated and subjected to chromatography on silica gel (n-heptane:methyl tert-butyl ether) to obtain 27.8 g is specified in the header connection 1. Rt=to 3.73 min (method A). Detected mass: grass 288,1 (M+H+).

1-Benzyloxy-4-benzyl-7-chloro-6-forsakenly (compound 2)

As a by-product of obtaining 1-benzyloxy-7-chloro-6-vtoritchnaia (compound 1) by chromatography on silica gel can be allocated to 8.45 g of 1-benzyloxy-4-benzyl-7-chloro-6-vtoritchnaia. Rt=Android 4.04 min (method A). Detected mass: 378,1 (M+H+).

1-Benzyloxy-7-methyl-6-forsakenly (compound 3)

1-Benzyloxy-7-methyl-6-forsakenly (compound 3) was obtained in accordance with the procedure described for the synthesis of compound 1, from 7-methyl-6-fluoro-2H-isoquinoline-1-it (obtained in accordance with the method described in WO 2007/012421 or O 2007/012422). Rt=4,00 min (method A). Detected mass: 268,1 (M+H+).

7-Chloro-6-forsakenly-2-oxide (compound 31)

50 g of 7-chloro-6-vtoritchnaia (obtained in accordance with WO 2007/012422) was dissolved in dichloromethane and cooled to 5°C. Portions were added to 69.6 g of m-chloroperbenzoic acid (70%). The mixture was stirred at room temperature. After the conversion is complete, the mixture was diluted with 1.5 l of dichloromethane and was extracted three times with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated to dryness to obtain 47,6 g of the desired compound 31. Rt=0,98 min (method D). Detected mass: 198,1 (M+H+).

7-Chloro-6-fluoro-1-methoxyethanol (compound 4)

10 g of 7-chloro-6-forsakenly-2-oxide (compound 31) was dissolved in 100 ml of anhydrous methanol. Dropwise at -10°C was added 12 ml of ethylchloride. The mixture was left to mix for 15 minutes and then at -20°C for 1 h was added dropwise 28 ml of triethylamine, dissolved in 55 ml of methanol. Added 100 ml of 2 n sodium hydroxide solution and the precipitate was isolated by filtration. Additionally, the product was besieged by adding 2 n sodium hydroxide solution and water to the stock solution. The combined solids were dried to obtain 7.8 g we wish the th product. Rt=3,75 min (method A). Detected mass: 212,0 (M+H+).

The following compounds were obtained analogously to the method described for the synthesis of compounds 4, based on the corresponding isoquinolines.

Connection # The original connectionProductChemical name[M+H+]Rt[min]Method
325-chloro-6-fluoro-isoquinoline5-chloro-6-fluoro-1-methoxy-isoquinoline212,01,78G
33276,7-debtor-1-methoxy-isoquinoline196,13,53A

34256,7-debtor-1-methoxy-5-methyl-isoquinoline 210,13,85C
35306-fluoro-1-methoxy-7-methyl-isoquinolineUSD 192.13,44C
36266-fluoro-1-methoxy-5,7-dimethyl-isoquinoline206,13,74C
37296-fluoro-1,7-dimethoxy-isoquinoline208,13,1C

Example 1 and 2: 6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he

a) 8-(Tetrahydropyran-4-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (compound 5)

To a 2M solution of diisopropylamide lithium in a mixture of heptane/tetrahydrofuran/ethylbenzene (18 ml, compared with 35.9 mmol, 1.5 EQ.) at -78°C was added dropwise a solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (available commercially or poluchennogo is using techniques for example, as described in Becker et al. Synthesis 1992, 11, 1080-1082; 4.0 g, of 23.9 mmol) in tetrahydrofuran (40 ml). After stirring for 30 min at -78°C was carefully added 4-itetrahedra-2H-Piran (5,1 g of 23.9 mmol, 1 EQ.). The reaction mixture was left to warm to room temperature overnight, and then extinguished by successive slow addition of ethanol (10 ml) and water (20 ml). The resulting suspension was filtered through celite and was extracted three times with dichloromethane. The combined organic phase was concentrated in vacuum and purified by the method of flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to obtain 2,80 g of 8-(tetrahydropyran-4-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (compound 5). Rt=1,03 min (method B). Detected mass: 252,3 (M+H+).

b) Benzyl ether {1-[8-(tetrahydropyran-4-yl)-1,4-dioxaspiro[4.5]Dec-8-yl]propyl}carbamino acid (compound 6)

8-(tetrahydropyran-4-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (compound 5, 1.4 g to 5.57 mmol) was added a 2M solution of ethylmagnesium in THF (5.6 ml, 11.1 mmol, 2.0 EQ.) and boiling the reaction mixture under reflux for 72 hours, the resulting suspension was cooled to -20°C and treated with methanol (8 ml). After stirring for 10 min at 0°C portions) was added sodium borohydride (376 mg, 9,95 mmol, 2 EQ.) and stirred the reaction mixture at room temperature for 1 h The solution was diluted 1 N. aqueous sodium hydroxide solution (20 ml) and was extracted twice with diethyl ether. The combined organic phases were washed with saturated salt solution, dried over magnesium sulfate and concentrated in vacuum with the receipt of 1.46 g of the crude amine.

The crude product was dissolved in dichloromethane (15 ml)was cooled to -78°C and sequentially treated with triethylamine (0,79 ml, 5,67 mmol, 1.1 EQ.) and benzylchloride (0,87 ml of 5.15 mmol, 1 EQ.). After stirring for 1 h at room temperature the reaction was suppressed by addition of water (20 ml) and was extracted three times with dichloromethane. The organic phase was dried over magnesium sulfate, concentrated in vacuum and purified by the method of flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to give the 717 mg specified in the connection header. Rt=1,48 min (method B). Detected mass: 418,4 (M+H+).

c) 4-(1-Aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexanol (compound 7)

Benzyl ether of {1-[8-(tetrahydropyran-4-yl)-1,4-dioxaspiro[4.5]Dec-8-yl]propyl}carbamino acid (compound 6, 717 mg, 1,72 mmol) was dissolved in acetone (5 ml) was added 6 N. aqueous hydrochloric acid (2.5 ml). The solution was stirred for 16 h at room temperature, and then carefully dropwise introduced into saturated aqueous dissolve the sodium bicarbonate (100 ml). The mixture was extracted three times with dichloromethane, the organic phase was dried over magnesium sulfate and concentrated in vacuum to obtain 577 mg of the crude ketone.

The crude product was dissolved in tetrahydrofuran (10 ml), cooled to -30°C was added sodium borohydride (64,3 mg, 1.7 mmol, 1.1 EQ.). The reaction mixture was slowly heated to room temperature and was stirred for 2 h, and then extinguished with water (15 ml). The solution was acidified to pH 2 by adding 2 N. aqueous hydrochloric acid and was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuum to obtain 517 mg of the desired alcohol.

N-protected alcohol was dissolved in methanol (2 ml) and added to 14.6 mg of palladium on coal (10%). The mixture was stirred in an atmosphere of hydrogen until the conversion is complete. The catalyst was filtered and the reaction mixture is evaporated to dryness to obtain 370 mg specified in the title compounds as a mixture of diastereoisomers. Rt=0,36 min 0,60 min (method B). Detected mass: 242,3 (M+H+).

d) 1-[4-(1-Benzyloxy-7-chloroisoquinoline-6-yloxy)-1-(tetrahydropyran-4-yl)cyclohexyl]Propylamine (compound 8 and 9)

To a suspension of sodium hydride (60%, 167 mg of 4.17 mmol, 3 EQ.) in dimethylacetamide (8 ml) was added a solution of 4-(1-aminopropyl)-4-(tetrahed operan-4-yl)cyclohexanol (compound 7, 369 mg, 1.53 mmol, 1.1 EQ.) in dimethylacetamide (8 ml). After stirring for 60 min at room temperature was added a solution of 1-benzyloxy-7-chloro-6-vtoritchnaia (connection 1, 400 mg of 1.39 mmol) in dimethylacetamide (8 ml) and continued stirring at room temperature and then at 50°C to complete the reaction. The reaction was suppressed by addition of water (30 ml) and the reaction mixture was extracted three times with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated and the crude product was purified by the method of flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to give 83 mg (eluruumis previously isomer 1, compound 8) and 48 mg (eluruumis later isomer 2, compound 9) net diastereoisomers in the form of racemates. The relative stereochemistry was not determined. In addition, can be allocated 166 mg of the product as diastereoisomeric mixture. Rt=0,92 min (compound 8), 0,93 min (compound 9) (method B). Detected mass: 419,4 (M+H+).

e) 6-[4-(1-Aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he (compounds of examples 1 and 2)

A solution of 1-[4-(1-benzyloxy-7-chloroisoquinoline-6-yloxy)-1-(tetrahydropyran-4-yl)cyclohexyl]Propylamine (compound 8, 83 mg, 0.16 mmol) in 2-propanol (1 ml) was treated with 2 N. aqueous hydrochloric acid (0.5 ml, and stirred at room temperature until full conversion. The reaction mixture was evaporated and double-liofilizirovanny of water to obtain 68 mg specified in the title compound (compound of example 1) in the form of its hydrochloride. Rt=2,40 min (method A). Detected mass: 419,4 (M+H+).

45 mg of the second diastereoisomer (the compound of example 2) can be synthesized from 48 mg of compound (9), following the same methodology. Rt=2,40 min (method A). Detected mass: 419,4 (M+H+). The relative stereochemistry was not determined.

The following products were synthesized as racemic hydrochloride similar to the method described for the synthesis of compounds of example 1, based on the corresponding aminoalcohols (obtained according to the procedure described for the synthesis of compound 7) and 1-benzyloxy-7-chloro-6-vtoritchnaia (compound 1). If diastereoisomers could not be separated at an early stage of the synthesis, the products with removed protection was purified by the method of preparative HPLC and liofilizirovanny sequentially from 1 N. HCl and water.

Ave. No.ProductISO-MerChemical name[M+H+]Rt [min]Method
3 16-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he349,22,39C
426-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he349,22,47C
516-[4-(1-aminopropyl)-4-propylcyclohexyl-oxy]-7-chloro-2H-isoquinoline-1-he377,12,58A
616-[4-(amino-cyclopropylmethyl)-4-propylcyclohexyl-oxy]-7-chloro-2H-isoquinoline-1-he389,22,60A
726-[4-(amino-cyclopropylmethyl)-4-propylcyclohexyl-oxy]-7-chloro-2H-isoh the nolin-1-he 389,3, 372,3 [M-NH3+H+]3.04 fromD
816-[4-(1-aminopropyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he377,22,50A
926-[4-(1-aminopropyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he377,22,64A

1016-[4-(1-amino-ethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he375,22,55C
1126-[4-(1-amino-ethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he 375,22,64C
1216-[4-(1-aminopropyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he389,22,58A
1326-[4-(1-aminopropyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he389,22,61A
1416-[4-(1-aminobutyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he403,32,68A
1526-[4-(1-aminobutyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he403,32,64A
16-[4-(amino-cyclopropylmethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he401,22,62A

1726-[4-(amino-cyclopropylmethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he401,22,66C
181+26-[4-(1-amino-2-methylpropyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he403,2of 2.50 to 2.55A
1916-[4-(1-aminopropyl)-4-isopropoxyphenyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he407,22,56A
2026-[4-(1-aminopropyl)-4-isopropoxyphenyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he407,22,70A
2116-[4-(1-amino-ethyl)-4-cyclobutyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he375,22,46A
2216-[4-(1-aminopropyl)-4-cyclobutyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he389,2to 2.57A
2326-[4-(1-aminopropyl)-4-cyclobutyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he389,22,88A

24 16-[4-(1-aminopropyl)-4-cyclopentyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he403,22,88A
2516-[4-(AMINOPHENYL-methyl)-4-cyclopentyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he451,2, 434,2 [M-NH3+H+]2,87A

Getting 4-(1-aminopropyl)-4-Benzylalcohol (compounds 13 and 14)

a) tert-Butyl ether [1-(1-benzyl-4-oxocyclohexyl)propyl]carbamino acid (compound 10)

1 g of 8-benzyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile derived from 1,4-dioxaspiro[4.5]decane-8-carbonitrile and benzylbromide similar to the method described for compound 5, was dissolved in 6 ml of 1M solution of ethylmagnesium in diethyl ether. The mixture was heated at the boil under reflux for 2 days. The mixture was cooled to room temperature, was diluted by adding 100 ml of methyl tert-butyl ether was added 2 ml of saturated solution of sodium sulfate. The mixture was filtered through celite and washed precipitate tert-butyl epigrams was evaporated and the residue was absorbed 30 ml of ethanol.

Added 189 mg sodium borohydride and left the mixture is mixed until the conversion is complete. The mixture was evaporated and absorbed 100 ml of ethyl acetate. The organic layer was extracted with dilute hydrochloric acid. After demetalization the aqueous layer was brought to an alkaline pH by addition of 2M sodium hydroxide solution and was extracted twice with dichloromethane. The combined dichloromethane layer was washed with saturated salt solution and dried over sodium sulfate.

Added 2,05 g of di-tert-BUTYLCARBAMATE and 1.2 g of triethylamine and left the mixture was mixed for 2 days. The mixture was washed 1 N. sodium hydroxide, 1 N. hydrochloric acid, water and saturated salt solution, dried over sodium sulfate and evaporated to dryness. The remaining oil was subjected to chromatography with getting 286 mg of the desired product. Rt=3,57 min (method A). Detected mass: 290,2 (M-tert-butyl+H+).

b) tert-Butyl ether [1-(1-benzyl-4-hydroxycyclohexyl)propyl]carbamino acid (compounds 11 and 12)

280 mg of compound 10 was dissolved in 10 ml ethanol at -20°C was added 34 mg of sodium borohydride. The mixture was allowed to warm to room temperature and was stirred for 3.5 hours the Mixture was evaporated, the residue was dissolved in ethyl acetate and washed twice 2 N. chloris vodorodnoi acid and once with a saturated solution of salt. The organic layer was dried over sodium sulfate and evaporated to dryness to obtain the crude product, which was purified by chromatography on silica gel (heptane:ethyl acetate) to give 86 mg of isomer 1 (compound 11) and 105 mg of isomer 2 (compound 12). The relative stereochemistry was not determined. Rt=1,61 min (11), of 1.57 min (12) (method B). Detected mass: 274,2 (M+H+).

c) 4-(1-Aminopropyl)-4-Benzylalcohol (compounds 13 and 14)

86 mg of compound (11) was dissolved in 2 ml of isopropanol was added 1 ml of 6M hydrochloric acid in isopropanol. The mixture was left to mix overnight, then added water and isopropanol was removed under vacuum. The mixture three times liofilizirovanny of water to obtain 66 mg of compound 13 in the form of hydrochloride. The relative stereochemistry was not determined. Rt=2,34 min (method A). Detected mass: 248,2 (M+H+).

The other isomer (compound 14) was obtained, respectively, on the basis of the connection 12. Rt=2,34 min (method A). Detected mass: 248,2 (M+H+).

The following products were synthesized in the form of hydrochloride similar to the method described for the synthesis of compounds of example 1 (stage d and e)on the basis of the corresponding aminoalcohols (obtained in accordance with the procedure described for the synthesis of compounds 13 and 14) and accordingly protected 7-chloro-6-ftory is ohioline. If diastereoisomers could not be separated at an early stage of the synthesis, the products with removed protection was purified by the method of preparative HPLC and liofilizirovanny sequentially from 1 N. HCl and water.

Ave. No.ProductISO-MerChemical name[M+H+]Rt [min]Method
2616-[4-(1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-he349,2was 2.76D
2726-[4-(1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-he349,32,77D
2816-[4-(1-aminopropyl)-4-isobutyryloxy-oxy]-7-chloro-2H-isoquinoline-1-he 391,32,73C
2926-[4-(1-aminopropyl)-4-isobutyryloxy-oxy]-7-chloro-2H-isoquinoline-1-he391,2to 2.67A
3016-[4-(1-aminopropyl)-4-benzylacetone]-7-chloro-2H-isoquinoline-1-he425,23,20D

3126-[4-(1-aminopropyl)-4-benzylacetone]-7-chloro-2H-isoquinoline-1-he425,1was 2.76A

An alternative method of obtaining the compound of example 26: 6-[4-(1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-he

a) 1-Methyl-4-oxocyclohexanecarboxylate (compound 15)

5 g of 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile derived from 1,4-what dioxaspiro[4.5]decane-8-carbonitrile and methyliodide same way, described for compound 5, was dissolved in 100 ml of acetone, was added 25 ml of 1 N. HCl and left the mixture is mixed until the conversion is complete. The reaction was further added concentrated HCl. The mixture was neutralized by adding saturated sodium bicarbonate solution and was extracted three times with ethyl acetate.

The combined organic layer was washed with saturated salt solution, dried over sodium sulfate and evaporated to dryness. The crude substance was purified by filtration on silica gel to obtain 3.75 g of the desired product.

Alternatively, the connection may be obtained by heating at boiling under reflux 14.2 g of 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 190 ml of 80% acetic acid until the conversion is complete. The mixture was cooled and was poured into 1.2 l of cold saturated solution of sodium bicarbonate. Added 600 ml of saturated salt solution and several times was extracted with a mixture of ethyl acetate. United an ethyl acetate layers were washed with saturated salt solution, dried over magnesium sulfate and evaporated. The residue was absorbed water and acetonitrile and liofilizirovanny with the receipt of 6.75 g of the desired product, which could be used directly in subsequent transformations. Rt=0,63 min (method B). Detected mass: 138,2 (M+H+).

b) CIS-4-Hydroxy-1-m is teleklagenaevnet (compound 16)

1 g of compound 15 was dissolved in 50 ml of ethanol and portions at -65°C was added 303 mg sodium borohydride. The mixture was left to mix until the conversion is complete, was added 150 ml of water and brought the pH to 2 by adding 2 N. hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel to obtain 840 mg of compound 16 in the form of a single isomer. Rt=0,70 min (method B). Detected mass: 140,1 (M+H+).

c) CIS-4-(1-Aminopropyl)-4-methylcyclohexanol (compound 17)

400 mg of compound 16 was dissolved in 6 ml of a 3M solution of ethylmagnesium in diethyl ether and heated at boiling under reflux for 4 hours the Mixture was cooled to room temperature, was diluted by adding 200 ml of THF and filtered through celite. The filter residue washed with THF. The mixture was evaporated and absorbed the residue 50 ml of ethanol. Added 217 mg sodium borohydride and left the mixture is mixed until the conversion is complete. The mixture was evaporated and absorbed 50 ml of 1 N. HCl. The aqueous layer was extracted with ethyl acetate and was extracted with an ethyl acetate layer 30 ml of 1 N. HCl. The combined aqueous layer to which the Odile to alkaline pH by addition of 5M sodium hydroxide solution and twice was extracted with methyl tert-butyl ether. The combined ether layers were washed with saturated salt solution, dried over sodium sulfate and evaporated to dryness to obtain 225 mg of compound 17. Rt=0,47 min (method B). Detected mass: 172,2 (M+H+).

d) CIS-1-[4-(1-Benzyloxy-7-chloroisoquinoline-6-yloxy)-1-methylcyclohexyl]Propylamine (compound 18)

224 mg of compound 17 was twice subjected to distillation together with toluene, dissolved in 13 ml of anhydrous dimethylacetamide and added 132 mg of 95% sodium hydride. The mixture was left to mix for 10 minutes. Added 414 mg of 1-benzyloxy-7-chloro-6-vtoritchnaia (compound 1) and the mixture was stirred in an argon atmosphere for 3 h at 50°C. the Stirring was continued over night at room temperature. Was carefully added water (~20 ml). The mixture was extracted several times with a mixture of dichloromethane and isopropanol (3:1). The combined organic layer was thrice washed with water and saturated salt solution, dried over sodium sulfate and evaporated. To the residue was added water and the mixture liofilizirovanny. The crude product was subjected to chromatography on silica gel (dichloromethane:methanol) to give 395 mg of the desired product. Rt=1,40 min (method B). Detected mass: 439,2 (M+H+).

e) CIS-6-[4-(1-Aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-he (the compound of example 26)

400 mg of compound 18 was dissolved in 10 ml of a mixture of isopropanol/1 N. HCl (1:1). The mixture was stirred at room temperature until full conversion. The reaction mixture was evaporated and double-liofilizirovanny of water to obtain 300 mg specified in the title compound of example 26 in the form of its hydrochloride. Rt=2,37 min (method A). Detected mass: 349,2 (M+H+).

By conducting NMR of the obtained product was identified as CIS-product. Therefore, it was concluded that the compounds 16-18 also exist in CIS-form.

The following products were synthesized in the form of hydrochloride similar to the method described for alternative synthesis of the compound of example 26, on the basis of the corresponding aminoalcohols (obtained in accordance with the procedure described for the synthesis of compound 17) and accordingly protected 6-vtoritchnaia. In the case of compound of example 38, the release of the final product was achieved by heating protected isoquinoline derivative, obtained as described above, in a mixture of isopropanol/1 N. hydrochloric acid for 1 h at 100°C in a microwave oven, releasing the final product is similar to the method described in the above method (for example, for compounds of example 26, step e).

Ave. No. ProductP. elem.Chemical name[M+H+]Rt [min]Method
341CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he363,22,42A

351CIS-6-[4-(1-aminobutyl)-4-isopropylcyclohexane-oxy]-7-chloro-2H-isoquinoline-1-heto € 391.11,12B
363CIS-6-[4-(1-aminobutyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-he357,21,08B
373CIS-6-[4-(1-aminoate is)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-he 329,20,98B
384CIS-6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he391,21,10B
392CIS-6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-he481,31,25B
4937CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-methoxy-2H-isoquinoline-1-he359,21,25G
5033CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-fluoro-2H-isoquinoline-1-he347,21,25G
5134CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-fluoro-5-methyl-2H-isoquinoline-1-he361,21,29G

5235CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-he343,21,29G
5326CIS-1-[4-(5,7-dimethyl-isoquinoline-6-yloxy)-1-ethylcyclohexyl]-Propylamine341,21,21G
5436CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-5,7-dimethyl-2H-isoquinoline-1-he357,31,29G
55 27CIS-1-[1-ethyl-4-(7-fluoro-isoquinoline-6-yloxy)cyclohexyl]-Propylamine331,21,17G
563CIS-1-[1-ethyl-4-(7-methyl-isoquinoline-6-yloxy)cyclohexyl]-Propylamine327,21,19G
5725CIS-1-[1-ethyl-4-(7-fluoro-5-methylisoquinoline-6-yloxy)cyclohexyl]-Propylamine345,21,13G

Example 58: CIS-6-[4-(1-Aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-he

a) (4,4-Dimethoxymethylsilyl)benzene (compound 38)

To a solution of 4-benzyloxyacetophenone in 20 ml of anhydrous methanol was added from 5.29 ml triethylorthoformate and 32 mg p-toluensulfonate acid and stirred the mixture overnight. Was added 20 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of dichloromethane, the aqueous layer several times ekstragirovaniem, the combined organic layers was dried and evaporated to dryness to obtain 1.50 g of the desired product which was used without further purification.

b) 4-Benzyloxy-1-methoxycyclohexanone (compound 39)

1.5 g (4,4-dimethoxymethylsilyl)benzene (compound 38) was dissolved in 20 ml of anhydrous dichloromethane and cooled to 0°C. was added dropwise 3,05 ml trimethylsilylacetamide and after stirring for 2 minutes was added dropwise 1.31 ml trimethylsilyltrifluoromethane. The mixture was stirred at 0°C for 2 h, and then was added dropwise 20 ml of a saturated aqueous solution of sodium bicarbonate. The phases were separated and several times were extracted aqueous layer with dichloromethane. The combined organic layer was dried and evaporated to dryness to obtain 1.5 g of the crude product, which was purified by chromatography on silica gel to obtain 1.3 g of the desired compound in the form of a CIS/TRANS mixture. Rt=4,68 min (method D). Detected mass: 246,1 (M+H+).

c) 1-(4-Benzyloxy-1-methoxycyclohexyl)Propylamine (compound 40)

In an argon atmosphere of 1.2 g of compound 39 was dissolved in 60 ml of absolute toluene. Then dropwise added to 2.9 ml of ethylmagnesium (3M in diethyl ether). The mixture was allowed to warm to room temperature. After the evershine conversion the reaction mixture was cooled to 5°C was added 2 ml of anhydrous ethanol. The mixture was filtered through celite and washed the residue on the filter with tetrahydrofuran. Volatiles were removed in vacuo, the residue was dissolved in 20 ml of anhydrous ethanol was added 331 mg sodium borohydride and the mixture was stirred for 2 h at 0°C. the Mixture was evaporated, was added 20 ml of methyl tert-butyl ether and 20 ml of water was added dropwise 1 N. aqueous hydrochloric acid until the completion of gas evolution. The organic layer was separated, washed with saturated salt solution, dried and evaporated to obtain 1 g of the desired product in the form of a CIS/TRANS mixture. Rt=0,96/0,99 min (method M). Detected mass: 278,3 (M+H+).

d) 4-(1-Aminopropyl)-4-methoxycyclohexanone (compound 41)

35 ml of ammonia are condensed in the vessel Slanka, cooled in a bath of dry ice and isopropanol. Was dissolved 170 mg of sodium was added 1.1 g of compound 40, dissolved in 3 ml of anhydrous tetrahydrofuran. After complete conversion the reaction was suppressed by the addition of methanol and the mixture was heated to room temperature. The solvents are evaporated, the crude substance was absorbed by the methanol and dilute hydrochloric acid and several times was evaporated to obtain 1.19 g of the crude product in the form of a CIS/TRANS mixture, which was used directly in the next stage, Rt=0,10 min (method P). Found ujena weight: 188,1 (M+H +).

e) 1-[4-(7-Chloro-1-methoxyethanol-6-yloxy)-1-methoxycyclohexyl]Propylamine (compound 42 and 43)

650 mg of compound 41 was dissolved in 40 ml of anhydrous dimethylacetamide. The mixture was cooled to 0°C and added 369 mg of sodium hydride (60% in mineral oil). After stirring for 10 minutes was added 536 mg of 7-chloro-6-fluoro-1-methoxyethylamine (compound 4), and the mixture was heated to 50°C. Stirring was continued at room temperature until completion of the reaction, if necessary, added a small additional amount of isoquinoline. The mixture was cooled to room temperature and was added 50 ml water and 50 ml of a mixture of dichloromethane/isopropanol (3:1). The organic layer was twice washed with water, dried over sodium sulfate and evaporated. The crude product was purified by the method of flash chromatography to obtain 100 mg of compound 42, 330 mg of compound 43 and 130 mg of a mixture of two compounds. The connection 42: Rt=1,03 min (method M). Detected mass: to 379.2 (M+H+). Compound 43: Rt=1,04 min (method M). Detected mass: to 379.2 (M+H+).

(f) CIS-6-[4-(1-Aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-he (the compound of example 58)

100 mg of compound 42 was dissolved in 8 ml of a mixture of 2-propanol/1 N. aqueous hydrochloric acid (1:1) and heated in a microwave the oven for 10 minutes at 120°C. The reaction mixture was evaporated and double-liofilizirovanny of water to obtain 100 mg specified in the title compound (compound of example 58) in the form of its hydrochloride. Rt=1,24 min (method G). Detected mass: 365,2 (M+H+).

Example 59: TRANS-6-[4-(1-Aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-he

TRANS-6-[4-(1-Aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-he (the compound of example 59) was obtained from compound 43 by analogy to the reaction described for the compound of example 58. Rt=1,22 min (method G). Detected mass: 365,2 (M+H+).

Example 60: 6-[4-(1-Aminopropyl)-4-toxicologically]-7-chloro-2H-isoquinoline-1-he

6-[4-(1-Aminopropyl)-4-toxicologically]-7-chloro-2H-isoquinoline-1-he (the compound of example 60) was obtained by following the same sequence of reactions described for the synthesis of the compound of example 58, from 4-benzyloxyacetophenone and using triethylorthoformate instead of triethylorthoformate on a stage. In this case, the isomers could not be separated at the stage with preservation of the protective groups, the product was obtained in the form of a CIS/TRANS mixture. Rt=1,27 min (method G). Detected mass: to 379.2 (M+H+).

Alternative connection example 1: CIS-6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy and]-7-chloro-2H-isoquinoline-1-he

a) 4-Oxo-1-(tetrahydropyran-4-yl)cyclohexanecarbonitrile (compound 44)

A solution of 10.3 g (of 40.8 mmol) 8-(tetrahydropyran-4-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (compound 5) in a mixture of 90 ml of acetic acid and 18 ml of water was heated at 100°C for 24 h the Mixture was cooled to room temperature and slowly poured into 1.2 l of cold saturated aqueous sodium bicarbonate solution. The mixture was diluted with 600 ml of saturated salt solution and six times was extracted with methyl tert-butyl ether. The combined organic phases are washed with water and saturated salt solution, dried over magnesium sulfate, filtered and concentrated in vacuum. The remainder liofilizirovanny of acetonitrile and water, absorbed water and again liofilizirovanny obtaining 5,95 g of the ketone, which was used directly in the next stage. Rt=0,82 min (method O). Detected mass: 208,1 (M+H+).

b) CIS-4-(tert-Butyldimethylsilyloxy)-1-(tetrahydropyran-4-yl)cyclohexanecarbonitrile (compound 45)

5,95 g (28.7 mmol) of ketone 44 was dissolved in 85 ml of absolute ethanol, cooled to -70°C and the portions was added 1.20 g (of 31.6 mmol) of sodium borohydride. The reaction mixture gave to slowly warm to room temperature and was stirred for 17 hours After completion of the reaction, the reaction is ionic mixture was diluted with 150 ml of water, brought the pH to pH 2 by addition of 2 N. aqueous hydrochloric acid and was extracted three times a mixture of ethyl acetate. The combined organic phases were washed with saturated salt solution, dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 4.5 g of alcohol, which was used directly in the next stage.

3.00 g (of 14.3 mmol) of the alcohol was dissolved in 15 ml of absolute dichloromethane, cooled to 0°C and treated to 4.17 ml (3,84 g, 35.8 mmol) of 2,6-lutidine and 3.95 ml (4,55 g, and 17.2 mmol) of tert-butyldimethylchlorosilane. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml dichloromethane, washed twice with 50 ml water, twice with 0.1 N. hydrochloric acid (50 ml each time), twice with saturated aqueous sodium bicarbonate solution and once with 50 ml of saturated salt solution, dried over magnesium sulfate, evaporated to dryness and purified by chromatography on silica gel (heptane/ethyl acetate) to obtain 2,12 g of the desired product. Rt=1,21 min (method P). Detected mass: 324,4 (M+H+).

c) CIS-4-(1-Aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexanol (compound 46)

In the atmosphere of argon 400 mg (1,24 mmol) of 4-(tert-butyldimethylsilyloxy)-1-(tetrahydropyran-4-yl)cyclohexanecarbonitrile (compound 45) dissolve the Yali in 0.5 ml of absolute toluene. Then was added dropwise 618 μl (of 1.85 mmol) ethylacetamide (3M in diethyl ether) and heated the reaction mixture to 90°C. After 16 h was further added 200 μl of ethylacetamide (3M in diethyl ether) and continued stirring to complete the reaction. The reaction mixture was cooled to room temperature, and was added 3 ml of anhydrous methanol. After 10 min was added br93.1 mg (2,46 mmol) sodium borohydride and the mixture was stirred for 16 h at room temperature. The reaction was suppressed by adding 50 ml of 1M aqueous sodium hydroxide solution and was extracted twice with diethyl ether each time (60 ml).

The combined organic phase was treated with 120 ml of 2 N. aqueous hydrochloric acid. A two-phase system was vigorously stirred at room temperature for 18 hours, the Phases were separated and the organic phase is extracted with 60 ml of 2 N. aqueous hydrochloric acid. The combined aqueous layer was washed with 50 ml of ethyl acetate, brought to pH 12 by adding 5 n sodium hydroxide solution and was extracted twice with a mixture of dichloromethane and 2-propanol (3:1, each 80 ml). The combined organic layers were evaporated to obtain 115 mg of the desired product which was used directly in the next stage. Rt=0,65 min (method O). Detected mass: 242,2 (M+H+).

d) CIS-1-[4-(7-Chloro-1-methoxyethanol--yloxy)-1-(tetrahydropyran-4-yl)cyclohexyl]Propylamine (compound 47)

To a suspension of sodium hydride (60%, 369 mg, which 9.22 mmol, 3 EQ.) in dimethylacetamide (8 ml) was added a solution of CIS-4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexanol (compound 46, 619 mg, to 3.38 mmol, 1.1 EQ.) in dimethylacetamide (8 ml). After stirring for 60 min at room temperature was added a solution of 1-methoxy-7-chloro-6-vtoritchnaia (compound 4, 650 mg of 3.07 mmol) in dimethylacetamide (8 ml) and continued stirring at room temperature to complete the reaction. The reaction mixture was concentrated in vacuo and was suppressed by addition of water (50 ml). The reaction mixture was extracted three times with 50 ml of a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers were evaporated and purified the crude product by the method of flash chromatography (SiO2, 0%→30% methanol in dichloromethane) to give the 701 mg of compound 47 in the form of a racemate. Rt=0,74 min (method P). Detected mass: 433,3 (M+H+).

e) CIS-6-[4-(1-Aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he (the compound of example 1)

A solution of 1-[CIS-4-(7-chloro-1-methoxyethanol-6-yloxy)-1-(tetrahydropyran-4-yl)cyclohexyl]Propylamine (compound 47, 701 mg of 1.62 mmol) in 2-propanol (2 ml) was treated with 1 N. aqueous hydrochloric acid (2 ml) and heated in a microwave, the reaction is ora, during the first 20 min at 100°C and then for 5 min at 120°C until complete conversion is complete. The reaction mixture was evaporated and double-liofilizirovanny from water getting 653 mg specified in the title compound (compound of example 1) in the form of its hydrochloride. Rt=2,34 min (method C). Detected mass: 419,2 (M+H+).

Alternative connection example 34: CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he

a) CIS-1-[4-(7-Chloro-1-methoxyethanol-6-yloxy)-1-ethylcyclohexyl]Propylamine (compound 48)

In accordance with the methodology described for alternative for obtaining compounds of example 1 (stage d), synthesized 1.47 g of compound 48, according to 1.16 g (of 5.50 mmol) 7-chloro-6-fluoro-1-methoxyethylamine, 927 mg (5.0 mmol) of CIS-4-(1-aminopropyl)-4-ethylcyclohexane (obtained from 8-ethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile and ethylacetamide using a technique similar to that described for the synthesis of compound 46) and 450 mg (15.0 mmol) of sodium hydride (80% in mineral oil). Rt=0,76 min (method P). Detected mass: 377,4 (M+H+).

b) CIS-6-[4-(1-Aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he (the compound of example 34)

1,25 g of CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it (connect the imposition of example 34) was synthesized as hydrochloride similar to the way, described for alternative synthesis of compounds of example 1 (stage e), on the basis of 1.47 g of CIS-1-[4-(7-chloro-1-methoxyethanol-6-yloxy)-1-ethylcyclohexyl]Propylamine (compound 48). Rt=2,43 min (method C). Detected mass: 363,2 (M+H+).

The following products were synthesized in the form of hydrochloride similar to the method described for alternative synthesis of compounds of example 1 (stage d and e)on the basis of the corresponding aminoalcohols (obtained in accordance with the procedure described for the synthesis of compound 46) and therefore protected 6-vtoritchnaia.

Ave. No.ProductP. elem.Chemical name[M+H+]Rt [min]Method
611CIS-6-[4-(amino-phenylmethyl)-4-methylcyclohexyl-oxy]-7-chloro-2H-isoquinoline-1-he397,22,42A
621CIS-6-[4-(1-is aminobutyl)-4-methylcyclohexyl-oxy]-7-chloro-2H-isoquinoline-1-he 363,21,76N

631CIS-6-[4-(amino-phenylmethyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he437,22,14H
641CIS-6-[4-(1-amino-3-methylbutyl)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he417,21,92J
654CIS-6-[4-(1-amino-propyl)-4-cyclohexyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he417,21,99K
664CIS-6-[4-(1-aminopropyl)-4-(4,4,4-Cryptor-butyl)cyclohexyl-oxy]-7-chloro-2H-isoquinoline-1-he 445,11,91K
674CIS-6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-ylmethyl)-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he433,21,74K

684CIS-6-[4-(amino-cyclopropyl-methyl)-4-(tetrahydropyran-4-ylmethyl)-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he445,21,76K
694CIS-6-[4-(amino-cyclopropyl-methyl)-4-methyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he361,21,73K
704CIS-6-[4-(amino-cyclopropyl-methyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he1,74K
714CIS-6-[4-(1-aminopropyl)-4-ethoxymethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he393,11,78N
724CIS-6-[4-(1-amino-ethyl)-4-cyclopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he361,21,65N

734CIS-6-[4-(amino-cyclopropyl-methyl)-4-(4,4,4-trifloromethyl)-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he457,21,89N
744CIS-6-[4-(1-aminopropyl)-4-cyclopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he375,2 1,73N
754CIS-6-[4-(amino-cyclopropyl-methyl)-4-cyclopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he387,21,76N
764CIS-6-[4-(1-aminopropyl)-4-(tetrahydro-thiopyran-4-yl)-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he434,21,24L
774CIS-6-[4-(1-amino-ethyl)-4-propyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he363,32,48C
7833CIS-6-[4-(1-amino-ethyl)-4-ethyl-cyclohexyloxy]-7-fluoro-2H-isoquinoline-1-heto 333.31,19J

7934CIS-6-[4-(1-amino-ethyl)-4-ethyl-cyclohexyloxy]-7-fluoro-5-methyl-2H-isoquinoline-1-he347,31,24G
8025CIS-1-[1-ethyl-4-(7-fluoro-5-methyl-isoquinoline-6-yloxy)-cyclohexyl]-ethylamine331,30,80M
812CIS-6-[4-(1-amino-ethyl)-4-ethyl-cyclohexyloxy]-4-benzyl-7-chloro-2H-isoquinoline-1-he439,21,42G
8228CIS-1-[4-(7-bromoisoquinoline-6-yloxy)-1-ethyl-cyclohexyl]-ethylamine377,11,11G
83 30CIS-1-[4-(7-methylisoquinoline-6-yloxy)-1-ethylcyclohexyl]-ethylamine313,21,10G
845-chloro-6-fluoro-ISO-quinolineCIS-1-[4-(5-chloroisoquinoline-6-yloxy)-1-ethyl-cyclohexyl]-ethylamine333,21,12G

Example 85: CIS-7-chloro-6-{4-[1-(cyclopropylamino)propyl]-4-ethylcyclohexylamine}-2H-isoquinoline-1-he

100 mg of the compound of example 34 was dissolved in 1.5 ml of methanol, was added 69 μl of triethylamine, 143 μl of acetic acid, 100 mg of powdered molecular sieves and 56 μl of cyclopropanecarboxaldehyde and left the mixture was mixed for 1 h was Added 47 mg cyanoborohydride sodium and the mixture was stirred at 40°C to complete the reaction. The reaction mixture was diluted with 10 ml of methanol, filtered and the solution was evaporated to dryness. The residue was dissolved in 50 ml of saturated sodium bicarbonate solution and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, evaporated and the crude was purified substance by the method of reversed-phase HPLC (water:acetonitrile) to give 95 mg of desire is on the product as a salt triperoxonane acid. Rt=1,39 min (method G). Detected mass: 417,2 (M+H+).

Compounds of the following examples was obtained similarly to the method described for the compound of example 85, using the compound of example 34 and the corresponding aldehydes as starting substances:

Ave. No.ProductAldehydeChemical name[M+H+]Rt [min]Method
86Benz-aldehydeCIS-6-[4-(1-benzylamino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he453,2the 1.44G
87Isobutyl-aldehydeCIS-7-chloro-6-[4-ethyl-4-(1-isobutylamino-propyl)-cyclohexyloxy]-2H-isoquinoline-1-he419,21,41G
88 ButanalCIS-6-[4-(1-butylamino-propyl)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he419,21,40G

Synthesis of 4-(1-amino-2,2,2-triptorelin)-4-cyclopropylmethanol (compound 21)

a) 1-(8-Cyclopropylmethyl-1,4-dioxaspiro[4.5]Dec-8-yl)methylidene 2-methylpropan-2-sulinowo acid (compound 19)

To a solution of 8-cyclopropylmethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (3.00 g, to 13.6 mmol), obtained from 1,4-dioxaspiro[4.5]decane-8-carbonitrile and cyclopropanemethylamine similar to the method described for compound 5, in tetrahydrofuran (40 ml) at -78°C was added 1M solution of diisobutylaluminium in toluene (20,3 ml, 20.3 mmol, 1.5 EQ.) and given the reaction mixture to warm to 0°C for 3 hours the Mixture was again cooled to -78°C, neutralized by adding dropwise a 10% aqueous solution of citric acid and was heated to room temperature. The mixture was distributed between methyl tert-butyl ether and water, the aqueous phase was twice extracted with methyl tert-butyl ether, the combined organic phases were dried over magnesium sulfate, filtered and evaporated to obtain 8-cyclopropylmethyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde.

The crude aldehyde was dissolved in Tetra is drofuran (40 ml) was added 2-methyl-2-propanesulfinamide (1,81 g, 14.9 mmol, 1.1 EQ.) and atoxic titanium (IV) (4,27 ml, 20.3 mmol, 1.5 EQ.). The resulting mixture was stirred for 5 h heating at boiling under reflux, and for 16 h at room temperature, then treated with water (10 ml) and filtered through celite. The filter residue was washed with ethyl acetate, the aqueous layer was separated and was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum. The crude product was purified by the method of flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to give 1.90 g specified in the connection header 19. Rt=1,58 min (method B). Detected mass: 328,3 (M+H+).

b) [1-(8-Cyclopropylmethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-2,2,2-triptorelin]amide 2-methylpropan-2-sulinowo acid (compound 20)

A solution of 1-(8-cyclopropylmethyl-1,4-dioxaspiro[4.5]Dec-8-yl)methylidene 2-methylpropan-2-sulinowo acid (compound 19, and 1.00 g of 3.05 mmol) in tetrahydrofuran was cooled to -40°C and sequentially processed by Tetramethylammonium (313 mg, to 3.36 mmol, 1.1 EQ.) and (trifluoromethyl)trimethylsilane (587 μl, of 3.97 mmol, 1.3 EQ.). The mixture was stirred for 2 h at 0°C, and then extinguished by adding a saturated aqueous solution of ammonium chloride and was extracted twice with ethyl acetate. Volume of the United organic layers were dried over magnesium sulfate, was filtered and concentrated in vacuum to obtain 960 mg specified in the connection header. Rt=1,63 min (method B). Detected mass: 398,3 (M+H+).

c) 4-(1-Amino-2,2,2-triptorelin)-4-cyclopropylmethanol (compound 21)

A solution of [1-(8-cyclopropylmethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-2,2,2-triptorelin]amide 2-methylpropan-2-sulinowo acid (compound 20, and 1.00 g, 2,52 mmol) in 80% acetic acid (10 ml) was heated in a microwave oven for 10 min at 130°C. Then the reaction mixture was slowly dropwise added to saturated sodium bicarbonate solution (150 ml)was stirred for 30 min at room temperature and was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the crude ketone which is absorbed by the ethanol (20 ml), cooled to 0°C and treated with sodium borohydride (190 mg, of 5.03 mmol, 2.0 EQ.). After completion of the reaction the mixture was poured into water (20 ml) and was extracted three times with dichloromethane. The organic layers were concentrated in vacuo and the residue was dissolved in a mixture of 2-propanol (15 ml) and 6 N. aqueous hydrochloric acid (5 ml). After stirring over night at room temperature was added 5 ml of 6 N. aqueous hydrochloric acid and the mixture was heated to 50 the C for 1 h The reaction mixture was concentrated in vacuum and double-liofilizirovanny out of the water with obtaining specified in the connection header 21 in the form of a racemic mixture of diastereoisomers as hydrochloride. Rt=0,73 min, 0,82 min (method B). Detected mass: 252,3 (M+H+).

The following products were synthesized in the form of hydrochloride in accordance with the method described for the compound of example 1 (stage d and e)on the basis of the corresponding aminoalcohols (obtained using the techniques described for the synthesis of compound 21) and 1-benzyloxy-7-chloro-6-vtoritchnaia (compound 1). The aminoalcohols of the compounds of examples 46 and 47 was obtained from 2-(trimethylsilyl)thiazole, using the procedure described for the synthesis of compound 21. The regioisomers formed at the stage of alkylation (similar to connection 20), divided by the method of flash chromatography. The stereochemistry of the products was not determined.

Ave. No.ProductIsomerChemical name[M+H+]Rt [min]Method
401 6-[4-(1-amino-2,2,2-triptorelin)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he429,12,55A
4126-[4-(1-amino-2,2,2-triptorelin)-4-cyclopropylmethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he429,33,63D
4216-[4-(1-amino-2,2,2-triptorelin)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he417,12,49A
4326-[4-(1-amino-2,2,2-triptorelin)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he417,12,58A

4416-[4-(-amino-2,2,3,3,3-pentafluoropropyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he 467,13,24A
4526-[4-(1-amino-2,2,3,3,3-pentafluoropropyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he467,1with 3.27A
461+26-[4-(aminothiazol-2-ylmethyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he432,11,05, 1,13F
4716-[4-(aminothiazol-5-ylmethyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he432,30,64F
4826-[4-(aminothiazol-5-ylmethyl)-4-isopropyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he432,30,67 F

Example 89: 6-[4-(1-amino-2-methylpropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-he

11 mg of the compound of example 89 was synthesized as hydrochloride according to the procedure described for the compound of example 1 (stage d and e)on the basis of 137 mg (642 μmol) of the corresponding amerosport (obtained from 1-(8-isopropyl-1,4-dioxaspiro[4.5]Dec-8-yl)methylidene 2-methylpropan-2-sulinowo acid using methods similar to the method of obtaining compounds of 21, but using isopropylate as a nucleophile) and 168 mg (584 mmol) of 1-benzyloxy-7-chloro-6-vtoritchnaia (compound 1). Rt=1,84 min (method J). Detected mass: 391,2 (M+H+).

Example 90: CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-7-chloro-4-fluoro-2H-isoquinoline-1-he

a) tert-Butyl ether CIS-{1-[4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)-1-isopropylcyclohexane]propyl}carbamino acid (compound 49)

To a solution 1,71 g (4.14 mmol) of the compound of example 8 in 200 ml of absolute dichloromethane was added triethylamine (0,86 ml, 6.21 mmol) and di-tert-BUTYLCARBAMATE (1.35 g, 6.21 mmol). After stirring over night the reaction mixture was diluted with 100 ml dichloromethane and washed with 1 N. aqueous sodium hydroxide solution, twice 1 N. water chlorotoluron the acid, twice with water and once with saturated salt solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to obtain the crude product, which was purified by chromatography on silica gel (dichloromethane:methanol) to obtain 1,00 g of the desired product. Rt=0,89 min (method Q). Detected mass: UAH 421,2 ([M-tert-butyl]+H+).

b) CIS-6-[4-(1-Aminopropyl)-4-isopropylcyclohexane]-7-chloro-4-fluoro-2H-isoquinoline-1-he (the compound of example 90)

250 mg of compound 49 was dissolved in 3.6 ml of a mixture of acetonitrile and methanol (1:1). Was added N-fluoro-N'-chlorotetracycline-bis(tetrafluoroborate) (204 mg) and left the mixture was mixed for 5 days. The mixture was diluted with dichloromethane, was extracted several times with water, and then 2 N. hydrochloric acid and saturated salt solution. The organic layer was evaporated to dryness, the residue was dissolved in 10 ml of a mixture of isopropanol and 1 N. hydrochloric acid and heated for 45 minutes in a microwave oven at 110°C.

The mixture was diluted with water, and was twice extracted with methyl tert-butyl ether and liofilizirovanny. The crude substance was absorbed water and twice liofilizirovanny to obtain 177 mg of the desired product as hydrochloride. Rt=2,59 min (method C). Detected mass: 395,2 (M+H+).

Example 91: CIS-6-[4-(1-amino the filing)-4-ethylcyclohexylamine]-7-chloro-4-fluoro-2H-isoquinoline-1-he

a) tert-Butyl ether CIS-{1-[4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)-1-isopropylcyclohexane]propyl}carbamino acid (compound 50)

To a solution of 1.8 g of the compound of example 34 in 20 ml of absolute dichloromethane was added triethylamine (0.75 ml) and di-tert-BUTYLCARBAMATE (1.18 g). After stirring over night the reaction mixture was diluted with 100 ml dichloromethane, washed twice 1 N. aqueous solution of sodium hydroxide, 1 N. aqueous hydrochloric acid and with water and once with saturated salt solution. The organic phase was dried over magnesium sulfate, filtered and evaporated obtaining of 2.05 g of the desired product. Rt=1,86 min (method G). Detected mass: 407,2 ([M-tert-butyl]+H+).

b) CIS-6-[4-(1-Aminopropyl)-4-ethylcyclohexylamine]-7-chloro-4-fluoro-2H-isoquinoline-1-he (the compound of example 91)

200 mg of compound 50 was dissolved in 3 ml of a mixture of acetonitrile and methanol (1:1). Was added N-fluoro-N'-chlorotetracycline-bis(tetrafluoroborate) (168 mg) and left the mixture was mixed for 6 days. The mixture was diluted with dichloromethane, was extracted several times with water, then 2 N. hydrochloric acid and saturated salt solution. The organic layer was evaporated to dryness, the residue was dissolved in 10 ml of a mixture of isopropanol and 1 N. hydrochloric acid is heated for 30 minutes in a microwave oven at 100°C.

The mixture was diluted with water, and was twice extracted with methyl tert-butyl ether and liofilizirovanny. The crude substance was absorbed water and twice liofilizirovanny to obtain 106 mg of the desired product as hydrochloride. Rt=1,31 min (method G). Detected mass: 381,2 (M+H+).

Example 92: CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-4-bromo-7-chloro-2H-isoquinoline-1-he

a) tert-Butyl ether CIS-{1-[4-(4-bromo-7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)-1-ethylcyclohexyl]propyl}carbamino acid (compound 51)

1.5 g of compound 50 was dissolved in 25 ml of chloroform and added dropwise at 0°C was added to 3.8 ml of a 1M solution of bromine in chloroform. The mixture was allowed to warm to room temperature. After the conversion is complete, the mixture was suppressed by adding a 20% solution of ditosylate sodium was extracted with 1 N. hydrochloric acid and saturated salt solution, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by chromatography on silica gel to give the desired product. Rt=2,02 min (method G). Detected mass: 485,1/487,1 ([M-tert-butyl]+H+).

b) CIS-6-[4-(1-Aminopropyl)-4-ethylcyclohexylamine]-4-bromo-7-chloro-2H-isoquinoline-1-he (the compound of example 92)

70 mg of compound 51 was dissolved in 6 ml of a mixture of isopropanol and 1 N. hydrochloric key is lots and heated for 33 minutes in the microwave at 120°C. The mixture was diluted with water and liofilizirovanny. The crude substance was absorbed water and twice liofilizirovanny to obtain 177 mg of the desired product as hydrochloride. Rt=1,36 min (method G). Detected mass: 441,2/443,1 (M+H+).

Example 93: CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-1-oxo-1,2-dihydroisoquinoline-4-carbonitril

150 mg of compound 51 was dissolved in 9 ml of degassed dimethylformamide in an argon atmosphere was added 43 mg of cyanide of zinc and 32 mg of tetrakis(triphenylphosphine)palladium(0). The mixture was heated in a microwave oven for 90 minutes at 150°C. the Mixture was filtered, the solvent evaporated and the crude product is purified by HPLC. The purified product was absorbed 2 ml of isopropanol and 2 ml of 1 N. hydrochloric acid and heated in a microwave oven at 100°C for 1 hour. Added water, the solution was twice extracted with methyl tert-butyl ether and liofilizirovanny water layer. The residue was absorbed water and again liofilizirovanny obtaining by 115.7 mg of the desired product in the form of its hydrochloride. Rt=2,55 min (method F). Detected mass: 388,2 (M+H+).

Example 94: CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-4-bromo-7-chloro-2H-isoquinoline-1-he

Following the procedure described for the synthesis of the compound of example 92 synthesis is believed CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-4-bromo-7-chloro-2H-isoquinoline-1-it is based on tert-butyl ether CIS-{1-[4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)-1-isopropylcyclohexane]propyl}carbamino acid (compound 49), and bromine. Rt=1,14 min (method O). Detected mass: 455,1/457,2 (M+H+).

Examples 95 and 96: CIS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he (the compound of example 95) and TRANS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he (the compound of example 96)

a) [2-Benzazolyl-1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-2-feratel]amide 2-methylpropan-2-sulinowo acid (compound 52)

To a solution of 1.70 g (5,64 mmol) 1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)methylidene 2-methylpropan-2-sulinowo acid (obtained from 8-ethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile using the techniques described for the synthesis of compound 19) and 982 mg (5,64 mmol) of pharmacyfertility in 60 ml of absolute tetrahydrofuran at -78°C was added of 5.92 ml (of 5.92 mmol) of 1M solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran. The mixture was stirred for 1 h at -78°C, and then extinguished by adding a saturated aqueous solution of ammonium chloride and was extracted twice with 100 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 2.65 g of the crude specified in the connection header. Rt=0,91 min (method P). Detected mass: 476,4 (M+H+).

b) [1-(8-Ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-2-forat the l]amide 2-methylpropan-2-sulinowo acid (compound 53) and [2-benzazolyl-1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)ethyl]amide 2-methylpropan-2-sulinowo acid (compound 54)

1.0 g (2.10 mmol) [2-benzazolyl-1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-2-feratel]amide 2-methylpropan-2-sulinowo acid (compound 52) was dissolved in 30 ml of anhydrous methanol was added 895 mg (of 6.31 mmol) secondary acid phosphate. The suspension was cooled to -20°C and treated 1,41 g of sodium-mercury amalgam (5% mercury). The reaction mixture was stirred at 0°C for 16 h and was added 470 mg sodium amalgam. After stirring for 7 h at room temperature the solution was separated (decantation), the solids were evaporated to dryness and divided the remainder between 50 ml of saturated salt solution and 100 ml of diethyl ether. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. By cleaning method flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) received 296 mg of compound 53 [Rt=0,81 min (method P). Detected mass: 336,4 (M+H+)] and 96 mg of compound 54 [Rt=0,82 min (method P). Detected mass: 458,3 (M+H+)].

c) 4-(1-Amino-2-foradil)-4-ethylcyclohexane (compound 55)

99 mg of compound 55 was synthesized as a mixture of stereoisomers, in the form of hydrochloride of 236 mg (704 mmol) of compound 53, using the procedure described for the synthesis of compound 21. Rt=0,09, of 0.14 min (method P). Obnarujennaya: 190,3 [M+H +).

The following products were synthesized in the form of their respective hydrochloride similar to the method described for alternative synthesis of compounds of example 1 (stage d and e)on the basis of the corresponding aminoalcohols, obtained as described above, and 7-chloro-6-fluoro-1-methoxyethylamine (compound 4).

Ave. No.ProductChemical name[M+H+]Rt [min]Method
95CIS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he367,11,64N
96TRANS-6-[4-(1-amino-2-foradil)-4-ethyl-cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he367,11,66N

Example 98: 6-[4-(1-amino-3-methoxypropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he

a) [1-(8-Ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)allyl]amide 2-methylpropan-2-sulinowo acid (compounds is of 57)

In an argon atmosphere of 2.00 g (6,64 mmol) 1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)methylidene 2-methylpropan-2-sulinowo acid (obtained from 8-ethyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile using the techniques described for the synthesis of compound 19) was dissolved in 5 ml of absolute tetrahydrofuran. Then at 0°C was added dropwise 7,30 ml (7,30 mmol) vinylmania (1M in tetrahydrofuran) and stirred the reaction mixture for 17 h at room temperature. Was added to 16.6 ml (16,6 mmol) vinylmania (1M in tetrahydrofuran) and the mixture was stirred for 2 h at room temperature. The reaction mixture was cooled to 0°C and was added 15 ml of a saturated aqueous solution of sodium sulfate. The suspension was filtered through celite, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The crude product was purified by the method of flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to give 1.30 grams specified in the header connection 57 in the form of a mixture of diastereoisomers. Rt=2,19, and 2.26 min (method N). Detected mass: 330,2 (M+H+).

b) [1-(8-Ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-3-methoxypropyl]amide 2-methylpropan-2-sulinowo acid (compound 58)

To a solution of 600 mg (1.82 mmol) of [1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)allyl]amide is 2-methylpropan-2-sulinowo acid (compound 57) in 5 ml THF at 0°C was added 10.9 ml (5.46 mmol) of 0,5M solution of 9-BBN in tetrahydrofuran. The reaction mixture was left to warm to room temperature overnight, then was cooled to 0°C. and Then slowly added to 13.5 ml of 3M aqueous sodium hydroxide and 13.5 ml of 30% aqueous hydrogen peroxide and the mixture was stirred for 16 h at room temperature. The mixture was twice extracted with 50 ml ethyl acetate, washed with water (30 ml) and a saturated solution of sodium chloride (30 ml), dried over magnesium sulfate and concentrated in vacuum.

The crude alcohol was dissolved in 9 ml of tetrahydrofuran and, at 0°C was slowly added to a suspension of 145 mg (3.63 mmol) of sodium hydride (60%) in 9 ml of tetrahydrofuran. The suspension was stirred for 30 min, then was added 339 μl (of 5.45 mmol) of iodomethane. The reaction mixture was stirred at room temperature for 20 h and twice was additionally added 339 μl (of 5.45 mmol) of iodomethane. Then added 30 ml of methanol and 15 ml of an aqueous solution of ammonium hydroxide (33%). The reaction mixture was evaporated to dryness to obtain 655 mg specified in the header connection 58 with a purity sufficient for further conversion. Rt=0,85 min (method P). Detected mass: 362,3 (M+H+).

c) 4-(1-Amino-3-methoxypropyl)-4-ethylcyclohexane (compound 59)

60 mg of 4-(1-amino-3-methoxypropyl)-4-ethylcyclohexane (compound 59) in the form of a mixture of diastereoisomers received in VI is e hydrochloride using a similar methodology, described for the synthesis of compound 21 on the basis of 315 mg of [1-(8-ethyl-1,4-dioxaspiro[4.5]Dec-8-yl)-3-methoxypropyl]amide 2-methylpropan-2-sulinowo acid (compound 58). Rt=0,20, 0,39 min (method P). Detected mass: to 216.2 (M+H+).

d) 6-[4-(1-Amino-3-methoxypropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he (the compound of example 98)

The compound of example 98 was synthesized using the sequence of reactions described for alternative synthesis of compounds of example 1 (stage d and e). Used 60 mg of 4-(1-amino-3-methoxypropyl)-4-ethylcyclohexane (compound 59) and 53,9 mg 7-chloro-6-fluoro-1-methoxyethylamine (compound 4) to give 43 mg of the compound of example 98 in the form of hydrochloride. The stereochemistry was not determined. Rt=1,78 min (method N). Detected mass: to 393.3 (M+H+).

Example 99: CIS-6-[4-(1-aminopropyl)-4-(1,1-dioxotetrahydrofuran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he

a) tert-Butyl ether CIS-{1-[4-(7-chloro-1-methoxyethanol-6-yloxy)-1-(tetrahydrothiopyran-4-yl)cyclohexyl]propyl}carbamino acid (compound 60)

To a solution of 61 mg (136 mmol) of CIS-1-[4-(7-chloro-1-methoxyethanol-6-yloxy)-1-(tetrahydrothiopyran-4-yl)cyclohexyl]Propylamine [derived from CIS-4-(1-aminopropyl)-4-(tetrahydrothiopyran-4-yl)cyclohexanol and 7-chloro-6-photo the-1-methoxyethylamine (compound 4) similar to the way, described for alternative synthesis of compounds of example 1] in 2 ml of dichloromethane was added to 28.2 μl (20.6 mg, 204 μmol) of triethylamine and 44.4 mg (204 mmol) of di-tert-BUTYLCARBAMATE and stirred the mixture overnight at room temperature. The reaction mixture was evaporated, absorbed in diethyl ether, filtered through celite and the filtrate was concentrated in vacuum to obtain 76 mg specified in the title compound with a purity sufficient for further conversion. Rt=1,06 min (method Q). Detected mass: 549,2 (M+H+).

b) CIS-6-[4-(1-Aminopropyl)-4-(1,1-dioxotetrahydrofuran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he (the compound of example 99)

A solution of 76 mg (138 mmol) tert-butyl ether CIS-{1-[4-(7-chloro-1-methoxyethanol-6-yloxy)-1-(tetrahydrothiopyran-4-yl)cyclohexyl]propyl}carbamino acid (compound 60) in 3 ml of absolute dichloromethane was treated at 0°C a solution of 102 mg (415 mmol) m-chloroperbenzoic acid in 1 ml dichloromethane and stirred the reaction mixture at room temperature for 2 hours Then added 25 ml of water and was extracted three times a mixture of dichloromethane. The combined organic layers were washed in 0,1M aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate and saturated salt solution, dried over sulfate is magnesium, filtered and evaporated. After cleaning method flash chromatography (SiO2, 0%→30% methanol in dichloromethane) received 36 mg of tert-butyl methyl ether {1-[CIS-4-(7-chloro-1-methoxyethanol-6-yloxy)-1-(1,1-dioxotetrahydrofuran-4-yl)cyclohexyl]propyl}carbamino acid, the product was dissolved in 2 ml of a mixture of 2-propanol and 1 N. aqueous hydrochloric acid (1:1) and heated in a microwave oven for 30 min at 100°C. the Reaction mixture was evaporated and double-liofilizirovanny out of the water with obtaining 21 mg specified in the title compound (compound of example 99) in the form of its hydrochloride. Rt=1,17 min (method G). Detected mass: 467,2 (M+H+).

Example 100: CIS-6-[4-(1-amino-ethyl)-4-propylcyclohexanone]-7-chloroisoquinoline-1-ylamine

a) tert-Butyl-(7-chloro-6-forsakenly-1-yl)amine (compound 61)

A solution of 5.0 g (to 25.3 mmol) 7-chloro-6-forsakenly-2-oxide (compound 9) in 120 ml of benzotrifluoride were treated to 15.9 ml (11.1 g, 152 mmol) of tert-butylamine and cooled to 0°C. Then, when the control temperature (<10°C) slowly portions was added 17.3 g (53,1 mmol) p-toluensulfonate anhydride. The reaction mixture was stirred at room temperature for 16 h, then was cooled to 0°C and was added to 8.0 ml (76,1 mmol) of tert-butylamine and compared to 8.26 g (to 25.3 mmol) p-toluensulfonate anhydride. The reaction mixture plumage is shivali for 24 h at room temperature, then concentrated and distributed between 120 ml of water and 150 ml of dichloromethane. The phases were separated, the organic phase is washed 8 times 3 N. aqueous sodium hydroxide, dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified twice by chromatography on silica gel (dichloromethane:methanol) to obtain 277 mg of pure desired product (compound 61) and 714 mg of the product slightly contaminated p-toluensulfonate acid. Rt=2,35 min (method C). Detected mass: 253,1 (M+H+).

b) CIS-6-[4-(1-amino-ethyl)-4-propylcyclohexanone]-7-chloroisoquinoline-1-ylamine (compound of example 100)

28 mg of the compound of example 100 was received in accordance with the sequence of reactions similar to the sequence used for the synthesis of compounds of example 1 (stage d and e), based on 73,4 mg (396 mmol) of 4-(1-amino-ethyl)-4-propylcyclohexane and 100 mg (0.40 mmol) of tert-butyl(7-chloro-6-forsakenly-1-yl)amine (compound 61). Rt=of 2.26 min (method C). Detected mass: 362,3 (M+H+).

Examples 101 and 102: 6-[3-(1-aminopropyl)-3-propylcyclohexyl]-7-chloro-2H-isoquinoline-1-he

a) 1-Cyano-1-propylthiophene-3-ene (compound 62)

To a stirred solution of valeronitrile (20 g, to 25.3 ml, 241 mmol) in THF (250 ml) at -78°C under argon atmosphere was added dropwise LDA(276 ml, 553 mmol, 2M in THF), and then was stirred for 15 minutes. The reaction mixture then was heated to room temperature and was further stirred for 20 minutes. After cooling to -78°C is added dropwise within 10 minutes was added CIS-1,4-dichlorobutene (30.1 g, 25,3 ml) and the mixture was stirred for 10 minutes. The mixture was allowed to warm to room temperature and then was stirred overnight. The reaction extinguished cautious addition of 150 ml of ice water, and then was extracted with methyl tert-butyl ether. In the evaporation was received and 47.5 g of orange oil. By vacuum distillation (0.2 to 16 mbar, 55-105°C) was obtained 2.3 g of a yellow oil which was used without further purification.

b) 1-(1-Aminopropyl)-1-propylthiophene-3-ene (compound 63)

1-Cyano-1-propylthiophene-3-ene (compound 62, 2.3 g, to 16.9 mmol) was dissolved in toluene (15 ml) was added ethylmagnesium (11.2 ml, or 33.7 mmol, 3M in ether). After stirring for 30 minutes at 90°C the reaction mixture was cooled and was added dropwise to ice-cold methanol (66 ml)was then added sodium borohydride (638 mg, 17 mmol). The mixture was heated to room temperature and was stirred overnight. The white suspension was treated with sodium hydroxide solution (water, 1M), filtered through celite, and then was extracted with a mixture of dichloromethane/isopropanol (3/1). Phil is spending washed with dichloromethane. The organic phase is washed with saturated salt solution, dried over sodium sulfate and evaporated to obtain 3.8 g of a yellow oil. This oil is absorbed dichloromethane and twice was extracted with hydrochloric acid (2M). The aqueous layer was podslushivaet solution of sodium hydroxide (6M) and extracted with dichloromethane. By evaporation got to 1.38 g of the desired product as a yellow oil which was used without further purification.

c) 1-(1-Aminopropyl)-1-propylthiophene-3-ol (compound 64)

1-(1-Aminopropyl)-1-propylthiophene-3-ene (compound 63, 1.4 g, 8.25 mmol) was dissolved in THF (15 ml) at 0°C in an argon atmosphere. Dropwise within 10 minutes was added borane (9.1 ml, 9,07 mmol, 1M in THF). The reaction mixture was allowed to warm to room temperature, then stirred overnight. After cooling to 0°C was added water (4 ml)and then hydrogen peroxide (5.8 ml, 30% solution in water) and sodium hydroxide solution (9.1 ml, 1M aqueous solution). After stirring for 5 minutes, the mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated to obtain 1.54 g of the desired product as a mixture of isomers. Rt=0,81, 0,84, 0,88 min (method M). Detected mass: 186,2 (M+H+).

d) 1-[3-(7-Chloro-1-methoxyethanol-6-yloxy)cyclopentyl]-1-propylpiperidine (connections 65 and 66)

1-[3-(7-Chloro-1-methoxyethanol-6-yloxy)cyclopentyl]-1-propylpiperidine (connections 65 and 66) was obtained as a mixture of isomers of 1-(1-aminopropyl)-1-propylthiophene-3-ol (compound 64) and 7-chloro-6-fluoro-1-methoxyethylamine (compound 4)as described for alternative synthesis of compounds of example 1, step d. Rt=1,51 min (method G). Detected mass: 377,2 (M+H+and Rt=1,56 min (method G). Detected mass: 377,2 (M+H+).

e) 6-[3-(1-Aminopropyl)-3-propylcyclohexyl]-7-chloro-2H-isoquinoline-1-he (compounds of examples 101 and 102)

6-[3-(1-Aminopropyl)-3-propylcyclohexyl]-7-chloro-2H-isoquinoline-1-ones of example 101 example 102 was obtained from 1-[3-(7-chloro-1-methoxyethanol-6-yloxy)cyclopentyl]-1-popypropylene 65 and 66, as described for alternative synthesis of compounds of example 1, step e. Rt=1,33 min (method G). Detected mass: 363,2 (M+H+and Rt=0,94 min (method M). Detected mass: 363,3 (M+H+).

Connect both of the examples given in the form of a mixture of isomers, the relative stereochemistry was not determined.

Example 103: 6-[4-(1-aminopropyl)-4-triftormetilfullerenov]-7-chloro-2H-isoquinoline-1-he (isomer 1)

a) N-Methoxy-N-methyl-2-triptoreline (compound 67)

16.6 g (167 mmol) of the hydrochloride of N,O-dimethylhydroxylamine suspended in 90 ml of CH 2Cl2and dropwise at 0°C was added to 29.1 ml (167 mmol) of N,N-diisopropylethylamine. The resulting solution at -40°C was added dropwise to a solution of 20.0 g (143 mmol) of 2-(trifluoromethyl)propanolol acid in 500 ml of CH2Cl2. After this was added to 34.5 g (167 mmol) of N,N'-dicyclohexylcarbodiimide and the mixture was stirred at 0°C for 16 h, the resulting suspension is then filtered and carefully evaporated the filtrate (the desired product is volatile!). After this was added 100 ml of n-pentane and stirred suspension for 30 minutes at ambient temperature. The precipitate was removed by filtration, the filtrate was carefully evaporated. By chromatography on silica gel using a mixture of ethyl acetate/n-pentane (1:4) was received of 22.8 g of the desired product. Rt=0,56 min (method P).

b) Methoxymethane 4-oxo-1-triftormetilfullerenov acid (compound 68)

21.8 g (119 mmol) of N-methoxy-N-methyl-2-triptoreline (compound 67) and the 36.1 ml (29.6 mmol) of 2-(trimethylsiloxy)-1,3-butadiene were mixed and divided into 3 portions. Each portion was treated at 120°C with microwave radiation for 2 hours combined reaction products were then diluted using 150 ml of THF, was added 100 ml of 5% aqueous HCl and was stirred for 1 h at ambient temperature. After this mixture three times the extras who were garofali using each time with 200 ml of ethyl acetate, dried using MgSO4and was evaporated to obtain 18.0 g, used without further purification. Rt=0,72 min (method P).

c) Methoxymethane 4-hydroxy-1-triftormetilfullerenov acid (compound 69)

18.0 g (71,1 mmol) methoxyethylamine 4-oxo-1-triftormetilfullerenov acid (compound 68) was dissolved in 350 ml of anhydrous ethanol and portions at -70°C was added 2,96 g (78.2 mmol) NaBH4. The mixture then was stirred for 1 h at ambient temperature, then added to 500 ml of water. First, the value of pH was brought to pH=4-5 with 10% aqueous HCl solution to remove any remaining NaBH4. Then the pH was brought to pH=8 with saturated aqueous NaHCO3and the ethanol evaporated. The residual solution was extracted three times using each time with 300 ml of ethyl acetate. After that, the organic layer was washed using 300 ml saturated aqueous NaCl, dried over MgSO4and was evaporated. By chromatography on silica gel using a mixture of ethyl acetate/n-heptane received 6,00 g of compound 69 in the form of a colorless oil containing only one of CIS/TRANS isomer of unknown configuration. Rt=0,66 min (method P).

d) Methoxymethane 4-(tert-butyldimethylsilyloxy)-1-trifloromethyl agexanorhoole acid (compound 70)

6,00 g (23.5 mmol) of methoxyethylamine 4-hydroxy-1-triftormetilfullerenov acid (compound 69) was dissolved in 20 ml of CH2Cl2and added 6.8 ml of 2,6-lutidine. Then at 0°C was added 6,48 ml (28,2 mmol) of tert-butyldimethylchlorosilane and leave the mixture to stand at ambient temperature for 16 hours Then the mixture was diluted with 30 ml of CH2Cl2and then washed twice with 30 ml water, twice with 30 ml of 0.1 G. of an aqueous solution of HCl and once with 30 ml of a saturated aqueous solution of NaHCO3. The organic layer then was dried over MgSO4and evaporated obtaining of 8.40 g of compound 70. Rt=0,99 min (method Q).

e) 4-(tert-Butyldimethylsilyloxy)-1-triftormetilfullerenov (compound 71)

4.15 g in (11.2 mmol) of methoxyethylamine 4-(tert-butyldimethylsilyloxy)-1-triftormetilfullerenov acid (compound 70) was dissolved in 40 ml of anhydrous THF. Then at 0°C was added to 28.1 ml (28.1 mmol) of 1M solution of diisobutylaluminium in CH2Cl2and the mixture was stirred at 0°C for 30 minutes. Added 40 ml of 10% aqueous solution of tartrate tetrahydrate potassium-sodium and the mixture was stirred for 1 h at ambient temperature. Then the reaction mixture was twice extracted with use the reattaching each 50 ml of ethyl acetate. The organic layer was dried over MgSO4and was evaporated to obtain 3,40 g of compound 71. Rt=0,98 min (method Q).

f) 1-[4-(tert-Butyldimethylsilyloxy)-1-tripterocalyx]methylidene 2-methylpropan-2-sulinowo acid (compound 72)

3,20 g (10.3 mmol) of 4-(tert-butyldimethylsilyloxy)-1-triftormetilfullerenov (compound 71) was dissolved using 25 ml of anhydrous THF. Added 1.31 g (10,8 mmol) of 2-methyl-2-propanesulfinamide and 4,32 ml (to 20.6 mmol) ethoxide titanium (IV) and the mixture was heated at the boil under reflux for 4 hours, the Reaction mixture was poured into 75 ml of saturated aqueous NaHCO3and the precipitate was removed by filtration. The filtrate was extracted three times using each time 50 ml of ethyl acetate. The organic layer was dried using MgSO4and was evaporated to obtain 3,90 g of compound 72. Rt=1,02 min (method Q).

g) {1-[4-(tert-Butyldimethylsilyloxy)-1-tripterocalyx]propyl}amide 2-methylpropan-2-sulinowo acid (compound 73)

13.4 ml (26.8 mmol) of a 2M solution of ethylmagnesium in diethyl ether was diluted with 8 ml of anhydrous diethyl ether and cooled to -78°C. At this temperature was added dropwise a solution of 3.7 g (of 8.95 mmol) 1-[4-(tert-butyldimethylsilyloxy)1-tripterocalyx]methylidene 2-methylpropan-2-sulinowo acid (compound 72) in anhydrous diethyl ether. After that, the mixture was allowed to warm to ambient temperature and was stirred for 2 h at ambient temperature. Added 100 ml of a saturated aqueous solution of Na2SO4, the organic layer was separated, dried using MgSO4and was evaporated to obtain 3,22 g of compound 73 in the form of oil, which was used without further purification. Rt=1,09 min (method Q).

h) 4-(1-Aminopropyl)-4-cryptometrics (compound 74)

3,22 g (7,26 mmol) {1-[4-(tert-butyldimethylsilyloxy)-1-tripterocalyx]propyl}amide 2-methylpropan-2-sulinowo acid (compound 73) was dissolved using 200 ml of 2-propanol. Added 60 ml of 10% aqueous HCl, the mixture was stirred for 5 h at ambient temperature and leave the mixture to stand at ambient temperature for 16 hours then was added 300 ml of a saturated aqueous solution of K2HPO4and evaporated 2-propanol. The resulting mixture was extracted twice using each time 100 ml of ethyl acetate. The organic layer was dried using MgSO4and was evaporated to obtain 1.50 g of compound 74 in the form of oil, which was used without further purification. Rt=0,82 min (method P).

i) 1-[4-(7-Chloro-1-methoxyethanol-6-yloxy)-1-tripterocalyx]prop the Lamin (compound 75)

160 mg (4.00 mmol) NaH suspended with 3 ml of DMA was added a solution of 300 mg (of 1.33 mmol) of 4-(1-aminopropyl)-4-triftormetilfullerenov (compound 74) in 3 ml of DMA. The mixture was stirred for 1 h at ambient temperature. After this was added a solution of 282 mg (1,33 mmol) 7-chloro-6-fluoro-1-methoxyethylamine in 4 ml of DMA and the mixture was stirred for 3 h at ambient temperature. Then the mixture was poured into 100 ml saturated aqueous solution of NaHCO3and was extracted three times using each time 50 ml of ethyl acetate. The organic layer was twice washed with 50 ml water, dried using MgSO4and was evaporated. By chromatography on silica gel using a mixture of ethyl acetate/n-heptane, and then by chromatography on silica gel using a mixture of tert-butyl methyl ether/n-heptane (1:1 + 1% acetic acid) received 162 mg of the desired product in the form of acetate. Rt=0,77 min (method P).

k) 6-[4-(1-Aminopropyl)-4-triftormetilfullerenov]-7-chloro-2H-isoquinoline-1-he (isomer 1) (compound of example 103)

229 mg (480 mmol) of 1-[4-(7-chloro-1-methoxyethanol-6-yloxy)-1-tripterocalyx]Propylamine (compound 75) was dissolved with 2 ml of 2-propanol and 2 ml of 1 N. aqueous HCl. The mixture was treated at 100°C for 1 h with a MIC is wave irradiation. After that, the mixture was diluted using 50 ml of water and liofilizirovanny to obtain 195 mg of the compound of example 103 in the form of hydrochloride. Rt=0,64 min (method P). Detected mass: 403,10 (M+H+).

Example 104: 6-[4-(1-aminopropyl)-4-triftormetilfullerenov]-7-chloro-2H-isoquinoline-1-he (isomer 2)

a) 7-Chloro-6-hydroxy-1-methoxyethanol (compound 81)

To a solution of 7-chloro-6-fluoro-1-methoxyethylamine (compound 4, 10 g, or 47.2 mmol) in DMA (200 ml) in an argon atmosphere was added a solution of trimethylsilanol sodium (149,2 ml, 1M in THF). After stirring at 60°C for 24 hours, the solution was evaporated under reduced pressure, and then liofilizirovanny to obtain the crude product (20.4 g). This product was dissolved in water and brought the pH up to pH=6,5. Light brown precipitate was collected by filtration and purified by the method of reversed-phase chromatography (0-4 min, 15% acetonitrile/water, 4-24 min 15-90% mixture of acetonitrile/water, and then 100% acetonitrile) to give 7 g of the desired product. Rt=2,60 min (method C). Detected mass: 210,0 (M+H+).

b) 1-[4-(7-Chloro-1-methoxyethanol-6-yloxy)-1-tripterocalyx]Propylamine (compound 76)

790 mg (3,51 mmol) of 4-(1-aminopropyl)-4-triftormetilfullerenov (compound 74) was dissolved using an 8.0 ml anhydrous is GF. Added 1.20 g (4,56 mmol) of triphenylphosphine, of 0.58 ml (3,51 mmol) of N,N-diisopropylethylamine and 735 mg (3,51 mmol) 7-chloro-1-methoxyethanol-6-ol (compound 81) and cooled the mixture to 0°C. At this temperature was added 0,83 ml (5,26 mmol) of diethylazodicarboxylate and the mixture was stirred for 16 h at ambient temperature. After that, the mixture was diluted with 20 ml of CH2Cl2and successively washed with 20 ml of 1 N. aqueous solution of NaOH, 20 ml of a saturated aqueous solution of NH4Cl, 20 ml of water and 20 ml saturated aqueous NaCl, respectively. Then the organic layer was treated with 20 ml of 1 N. aqueous HCl. The crude product was besieged, was filtered and re-suspended in 20 ml of 1 N. aqueous solution of NaOH. This suspension was extracted three times with 20 ml of CH2Cl2. Then the organic layer was dried using MgSO4and was evaporated. The residue was subjected to chromatography on silica gel using a mixture of tert-butyl methyl ether/n-heptane (1:1 + 1% acetic acid)to give 160 mg of the desired product in the form of acetate. Rt=0,79 min (method P). Detected mass: 417,2 (M+H+).

c) 6-[4-(1-Aminopropyl)-4-triftormetilfullerenov]-7-chloro-2H-isoquinoline-1-he (isomer 2) (compound of example 104)

160 mg (336 mmol) of 1-[4-(7-chloro-1-methoxyethanol-6-yloxy)-1-tripterocalyx]the cuts is a (compound 76) was dissolved with 2 ml of 2-propanol and 2 ml of 1 N. aqueous HCl. The mixture was treated at 100°C for 1 h under microwave irradiation. After that, the mixture was diluted using 50 ml of water and liofilizirovanny to obtain 154 mg of the desired product. Rt=0,66 min (method P). Detected mass: 403,2 (M+H+).

Example 111: [4-(1-aminopropyl)-4-methylcyclohexyl]isoquinoline-6-ylamine

a) Benzyl ester [1-(8-methyl-1,4-dioxaspiro[4.5]Dec-8-yl)propyl]carbamino acid (compound 77)

7.50 g (41,4 mmol) of 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbonitrile (synthesized from 1,4-dioxaspiro[4.5]decane-8-carbonitrile and methyliodide similar to the method described for compound 5) was dissolved in 17 ml of absolute tetrahydrofuran. Then was added dropwise to 20.7 ml (62,1 mmol) ethylaniline (3M in diethyl ether) and the reaction mixture is heated at the boil under reflux for 8 hours After cooling to 0°C was added 20 ml of anhydrous methanol. After 10 min at 0°C portions were added 2,56 g (+67.7 mmol) of sodium borohydride and the mixture was stirred for 16 h at room temperature. The reaction was suppressed by addition of 1M aqueous sodium hydroxide solution (200 ml) and was extracted twice with diethyl ether each time (150 ml). The combined organic phases were dried over magnesium sulfate, filtered and the solvent evaporated.

Not the shelled Amin (8,20 g) was dissolved in 115 ml of anhydrous dichloromethane, was cooled to -78°C and added of 5.89 ml (4,28 g of 42.3 mmol) of triethylamine and of 6.49 ml (6,56 g, 38.4 mmol) benzylphosphonate. The reaction mixture was heated to room temperature and was stirred for 2 h Then was added 100 ml of water three times and was extracted with a mixture of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to obtain the crude compound 77, which was purified by chromatography on silica gel (heptane:ethyl acetate) to give 5.50 g of the pure desired product (compound 77). Rt=1,03 min (method P). Detected mass: 348,2 (M+H+).

b) Benzyl ester [1-(1-methyl-4-oxocyclohexyl)propyl]carbamino acid (compound 78)

5.50 g of benzyl ether [1-(8-methyl-1,4-dioxaspiro[4.5]Dec-8-yl)propyl]carbamino acid (compound 77) was dissolved in 15 ml of a mixture of acetone and 6 N. aqueous hydrochloric acid (2:1). The reaction mixture was stirred for 16 h at room temperature, then was added dropwise to 150 ml of a saturated aqueous solution of sodium bicarbonate. The mixture was extracted three times with dichloromethane (each 100 ml), the combined organic phases were dried over magnesium sulfate, filtered and concentrated to obtain ketone 78, which was used directly in the next stage. Rt=0,59 min (pic is b P). Detected mass: 304,2 (M+H+).

c) Benzyl ester [1-(4-amino-1-methylcyclohexyl)propyl]carbamino acid (compound 79)

2.10 g (6,92 mmol) of ketone (compound 78) was dissolved in 21 ml of absolute methanol, then added 5.34 g (69,2 mmol) of ammonium acetate and 435 mg (6,92 mmol) cyanoborohydride sodium and the mixture was stirred at room temperature for 16 hours, the Reaction mixture was evaporated, the residue was dissolved in 50 ml of 1 N. aqueous sodium hydroxide and was extracted twice with 100 ml dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated to obtain 1.70 g is specified in the header connection 79 with a purity sufficient for use directly in the next stage. Rt=0,75 min (method P). Detected mass: 305,2 (M+H+).

(d) Benzyl ether {1-[4-(isoquinoline-6-ylamino)-1-methylcyclohexyl]propyl}carbamino acid (compound 80)

In 2 ml of absolute toluene were dissolved 100 mg (481 mmol) of 6-bromoisoquinoline, 176 mg (577 mmol) of benzyl ester [1-(4-amino-1-methylcyclohexyl)propyl]carbamino acid (compound 79) and 235 mg (721 mmol) of cesium carbonate. The solution was twice degirolami, then added 3.24 mg (14.4 mmol) of palladium acetate and 13.5 mg (21.6 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and heated the reaction mixture to 100°C until there was complete conversion. The mixture was evaporated, the residue was dissolved in 50 ml dichloromethane and washed twice with 50 ml saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered, concentrated and purified by chromatography on silica gel (dichloromethane:methanol) to give 66 mg of pure desired product. Rt=1,32 min (method O). Detected mass: 432,3 (M+H+).

e) [4-(1-Aminopropyl)-4-methylcyclohexyl]isoquinoline-6-ylamine (compound of example 111)

66 mg (153 mmol) of benzyl ether {1-[4-(isoquinoline-6-ylamino)-1-methylcyclohexyl]propyl}carbamino acid (compound 80) was dissolved in 500 μl of anhydrous methanol was added 5 mg of palladium on charcoal (10%). The mixture was stirred in an atmosphere of hydrogen until the conversion is complete. The catalyst was filtered and the reaction mixture is evaporated to dryness to obtain specified in the title compound, which was purified by the method of reversed-phase HPLC (water/acetonitrile) to give 30 mg of pure compound of example 111 in the form of a salt triperoxonane acid. Rt=1,02 min (method L). Detected mass: 298,2 (M+H+).

Following the racemate was separated by HPLC using a chiral column. The absolute stereochemistry was not determined, eluruumis first enantiomer was identified as "enantiomer 1".

Example No.The racemateEnantiomerMethodRt [min], chiral column
32Example 261E8,68
33Example 262E9,98
105Example 11T8,33
106Example 12T11,3
107Example 341Rof 6.31
108Example 342R8,30
109Example 161S6,56
110Example 162S10,6

The enantiomers obtained in these examples by separation of the racemate, are

CIS-6-[4-((S)-1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-he,

CIS-6-[4-((R)-1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-he,

CIS-6-[4-((S)-1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he,

CIS-6-[4-((R)-1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-he,

CIS-6-[4-((R)-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he,

CIS-6-[4-((S)-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-he,

CIS-6-[4-((S)-aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-he

CIS-6-[4-((R)-aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it.

(The enantiomers was not named "enantiomer 1" or "enantiomer 2", respectively).

Methods HPLC

td align="justify"> Stationary phase:
Method A:
Stationary phase:Waters XBridge C18
Gradient:ACN+0.05% TFUCK:H2O+0.05% TFUK 5:95 (0 min) → :95 (0,3 min) → 95:5 (3, 5 min) → 95:5 (4 min)
Flow rate:1.3 ml/min
Method:
Stationary phase:Col YMC Jsphere ODS H80 20×2
Gradient:ACN:H2O+0.05% TFUK 4:96 (0 min) → 95:5 (2,0 min) → 95:5 (2,4 min)
Flow rate:1 ml/min
Method:
Stationary phase:Col YMC Jsphere 33×2,1
Gradient:ACN+0.05% TFUCK:H2O+0.05% TFUK 2:98 (0 min) → 2:98 (1 min) → 95:5 (5 min) → 95:5 (6,25 min)
Flow rate:1 ml/min
Method D:
Stationary phase:Waters XBridge C18
Gradient:ACN+0.1% of FA:H2O+0,08% FA 3:97 (0 min) → 60:40 (3.5 minutes) → 98:2 (4,0 min) → 98:2 (5,0 min) → 3:97 (5,2 min) → 3:97 (6.5 minutes)
Flow rate:1.3 ml/min
Method E:
Chiralpak IA 250×4.6 mm

Eluent:Heptane:EtOH:MeOH 5:1:1+0.1% diethylamine
Flow rate:1 ml/min
Method F:
Stationary phase:Luna 3 μm C18(2) 10×2.0 mm
Gradient:ACN:H2O+0.05% TFUK 7:93 (0 min) → 95:5 (1,2 min) → 95:5 (1,4 min)
Flow rate:1.1 ml/min
Method G:
Stationary phase:Merck Chromolith fast Grad
Gradient:H2O+0.05% TFUCK:ACN+0.035% of TFWC 98:2 (0 min) → 98:2 (0,2 min) → 2:98 (2,4 min) → 2:98 (3.2 min) → 98:2 (3,3 min) → 98:2 (4 min)
Flow rate:2 ml/min
Method H:
Stationary phase:Waters XBridge C18
Gradient:H2O+0.05% of TFU is:ACN+0.05% TFUK 95:5 (0 min )→ 5:95 (3,3 min) → 5:95 (3,85 min) → 95:5 (4,3 min)
Flow rate:1.7 ml/min
Method I:
Stationary phase:Waters XBridge C18
Gradient:H2O+0.05% TFUCK:ACN+0.05% TFUK 95:5 (0 min) → 5:95 (3,3 min) → 5:95 (3,85 min) → 95:5 (4 min)
Flow rate:1.7 ml/min
Method J:
Stationary phase:Waters XBridge C18

Gradient:H2O+0.05% TFUCK:ACN+0.05% TFUK 95:5 (0 min) → 5:95 (2,6 min) → 5:95 (3,0 min) → 95:5 (3,1 min) → 95:5 (4,0 min)
Flow rate:1.7 ml/min
Method K:
Stationary phase:Waters XBridge C18
Gradient:H2O+0.05% TFUCK:ACN+0.05% TFUK 95:5 (0 min) → 95:5 (0,2 min) → 5:95 (2,4 min )→ 5:95 (3.2 min) → 95:5 (3,3 min) → 95:5 (4,0 min)
Flow rate:the 1.7 is l/min
Method L:
Stationary phase:Merck Chromolith fast Grad
Gradient:H2O+0.05% TFUCK:ACN+0.05% TFUK 98:2 (0 min) → 98:2 (0,2 min) → 2:98 (2,4 min) → 2:98 (3.2 min) → 98:2 (3,3 min) → 98:2 (4 min)
Flow rate:2.4 ml/min
Method M:
Stationary phase:Waters Aquity SDS
Gradient:H2O of+0.1% FA:ACN+0,08% FA 95:5 (0 min) → 5:95 (1,1 min) → 5:95 (1,7 min) → 95:5 (1,8 min) → 95:5 (2,0 min)
Flow rate:0.9 ml/min
Method N:
Stationary phase:Waters XBridge C18

Gradient:H2O+0.05% TFUCK:ACN+0.05% TFUK 95:5 (0 min) → 95:5 (0,2 min) → 5:95 (2,4 min) → 5:95 (3,5 min) → 95:5 (3,6 min) → 95:5 (4.5 min)
Flow rate:1.7 ml/min
Method O:Stationary phase:Col YMC Jsphere ODS H80 20×2
Gradient:ACN:H2O+0.05% TFUK 4:96 (0 min) → 95:5 (2,0 min) → 95:5 (2,4 min) → 4:96 (2,45 min)
Flow rate:1 ml/min
Method P:
Stationary phase:Luna 3 μm C18(2) 10×2.0 mm
Gradient:ACN:H2O+0.05% TFUK 7:93 (0 min) → 95:5 (1,2 min) → 95:5 (1,4 min) → 7:93 (1,45 min)
Flow rate:1.1 ml/min
Method Q:
Stationary phase:Luna 3 μm C18(2) 10×2.0 mm
Gradient:ACN:H2O+0.05% TFUK 20:80 (0 min) → 95:5 (0,8 min) → 95:5 (1,4 min) → 20:80 (1,45 min)
Flow rate:1.1 ml/min
Method R:
Stationary phase:Chiralpak AD-H/83, 250×4.6 mm
Eluent:MOH:EtOH (1:1)+0.1% diethylamine
Flow rate:1 ml/min
Detection:249 nm

Method S:
Stationary phase:Chiralpak AD-H/55, 250×4.6 mm
Eluent:MeOH:EtOH (1:1)+0.1% diethylamine
Flow rate:1 ml/min
Detection:249 nm
Method T:
Stationary phase:IA 250×4.6 mm
Eluent:Heptane:EtOH:MeOH(1:1:1)+0,1% diethylamine
Flow rate:1 ml/min
Detection:249 nm
Method U:
Stationary phase:Merck Chromolith fast Grad
Gradient:Water+0.05% TFUCK:ACN+0.05% TFUK 98:2 (0 min) → 98:2 (0,2 min)→ 2:98 (2,4 min)
Flow rate:1.3 ml/min

1)Determination of the inhibition of Rho-kinase

To measure inhibition of Rho-kinase values IC50determined in accordance with the following Protocol:

Active recombinant human ROCK-II (N-terminal residues 11-552 His6-tagged recombinant human ROCK-II) was purchased from Millipore GmbH, Schwalbach, Germany. The peptide substrate, Fluorescein-AKRRRLSSLRA-COOH, were purchased from JPT Peptide Technologies, Berlin, Germany. Adenosine-5'-triphosphate (ATP), bovine serum albumin (BSA), dimethylsulfoxide DMSO), 4-(2-hydroxyethyl)piperazine-1-econsultancy acid (Hepes), Brij-35, dithiothreitol (DTT) and Pluronic F-68 was purchased from Sigma-Aldrich, Munich, Germany. Tris(hydroxymethyl)aminomethan (Tris), magnesium chloride, NaOH, 1M HCl, and EDTA were purchased from Merck Biosciences, Darmstadt, Germany. Cocktail of protease inhibitors “Complete” was the production of Roche Diagnostics, Mannheim, Germany.

Test compounds were diluted to the appropriate concentrations of buffer 1 (25 mm Tris-HCl, pH of 7.4, 5 mm MgCl2, 2 mm DTT, 0.02 percent (wt./about.) BSA, 0.01% Pluronic F-68 and 3% DMSO). The enzyme ROCK II was diluted to a concentration of 100 ng/ml of buffer 2 (25 mm Tris-HCl, pH of 7.4, 5 mm MgCl2, 2 mm DTT and 0.02% (wt./about.) BSA). The peptide substrate and ATP was diluted to concentrations of 3 μm and 120 μm, respectively, the buffer 2. Two μl of a solution of the compound was mixed with 2 ál of diluted enzyme in 384-well titer is operating microplate (Greiner, Bio-One, Frickenhausen, Germany) and initiated the kinase reaction by adding 2 ál of a solution containing the peptide substrate and ATP. After 60 minutes incubation at a temperature of 32°C the reaction was stopped by adding 20 μl of solution containing 100 mm Hepes-NaOH, pH 7,4, 0,015% (vol./about.) Brij-35, 45 mm EDTA and 0,227% chip coating reagent 1 reagent to cover the chip (Caliper Lifescience Inc, Hopkinton, MA). Phosphorylation of the peptide substrate was determined on the Caliper device 3000, essentially as described in the publication Pommereau et al (J. Biomol. Screening 2004, 9(5), 409-416). The separation conditions were as follows: pressure is 1.3 pounds/inch2increasing the voltage-V lowering the voltage of - 500V, sample sip time 200 MS. The positive control (buffer 1 instead of the connection) and the negative control (buffer 1 instead of the compound and buffer 2 instead of ROCK II) were placed in parallel on each tablet.

The following products/compounds were tested using the above method of analysis using the appropriate form (salt or free base), obtained as in the examples described above, and were measured following activity values.

Example No.pIC50
1+++++++
2+++++
34++++++
5+++++++
6+++++++
7++++++
8+++++++
9++++++
10+++++++
11++++++
12+++++++
13++++++
14+++++++
15++++++
16+++++++
17++++++
18+++++++
19++++++
20+++++
21++++++
22++++++
23+++++
24++++++
25++++++
26+++++++
27++++++

28+++++
29++++++
30++++++
31++++++
32+++++++
33+++++++
34+++++++
35++++++
37++++++
38+++++++
39+++++
40+++++
41+++++
46+++++
47++++++
5 ++++++
51+++++
52+++++
53+++++
54+++++
56+++++
57+++++
58++++++
59++++++
60++++++
61++++++
62+++++++
63+++++
64+++++++
65++++++
66+++++++
67++++++
68+++++++
69+++++++

70++++++
71+++++++
72++++++
73+++++++
74+++++++
75+++++++
76+++++++
77+++++++
78++++++
79+++++
80+++++
81+++++
82+++++
84+++++
85+++++
86+++++
87+++++
88+++++
89+++++
90++++++
95+++++++
96++++++
97+++++
98++++++
99+++++++
100+++++
103+++++++
104+++++
105++++++
106+++++++
107+++++++
108+++++++

The activity is presented as a negative logarithm of the values of the IC50(pIC50as follows:

+:pIC50≤ 3,0
++:3,0 ≤ pIC50< 4,0
+++:4,0 ≤ pIC50< 5,0
++++:5,0 ≤ pIC50< 6,0
+++++ :6,0 ≤ pIC50< 7,0
++++++ 7,0 ≤ pIC50< 8,0
+++++++:8,0 ≤ pIC50

2) determination of the inhibition of protein kinase A and protein kinase G

To measure inhibition of PKA and PKG1β values IC50determined in accordance with the following Protocol:

Active human recombinant PKG1β (the primary product of translation, with N-terminal His-tagging) was purchased from Millipore GmbH, Schwalbach, Germany. Active human recombinant PKA (residues 1-351, with N-terminal His-tagging) was purchased from Invitrogen, KKarlsruhe, Germany. The peptide substrate, Fluorescein-AKRRRLSSLRA-COOH, were purchased from JPT Peptide Technologies, Berlin, Germany. Adenosine-5'-triphosphate (ATP), bovine serum albumin (BSA), dimethylsulfoxide DMSO), 4-(2-hydroxyethyl)piperazine-1-econsultancy acid (Hepes), Brij-35, dithiothreitol (DTT) and Pluronic F-68 was purchased from Sigma-Aldrich, Munich, Germany. Tris(hydroxymethyl)aminomethan (Tris), magnesium chloride, NaOH, 1M HCl, and EDTA were purchased from Merck Biosciences, Darmstadt, Germany. Cocktail of protease inhibitors “Complete” was the production of Roche Diagnostics, Mannheim, Germany.

Test compounds were diluted to the appropriate concentrations of buffer 1 (25 mm Tris-HCl, pH of 7.4, 5 mm MgCl2, 2 mm DTT, 0.02 percent (wt./about.) BSA, 0.01% Pluronic F-68 and 3% DMSO). PKG1β and PKA was diluted to a concentration of 150 ng/ml and 30 ng/ml, respectively, buffer 2. The peptide substrate and ATP was diluted to concentrations of 3 the km and 120 μm, accordingly, the buffer 2. Two μl of a solution of the compound was mixed with 2 ál of diluted enzyme in 384-well titration the microplate (Greiner, Bio-One, Frickenhausen, Germany) and initiated the kinase reaction by adding 2 ál of a solution containing the peptide substrate and ATP. After 60 minutes incubation at a temperature of 32°C the reaction was stopped by adding 20 μl of solution containing 100 mm Hepes-NaOH, pH 7,4, 0,015% (vol./about.) Brij-35, 45 mm EDTA and 0,227% chip coating reagent 1 reagent to cover the chip (Caliper Lifescience Inc, Hopkinton, MA). Phosphorylation of the peptide substrate was determined on the Caliper device 3000, essentially as described in the publication Pommereau et al. (J. Biomol. Screening 2004, 9(5), 409-416). The separation conditions were as follows: pressure is 1.3 pounds/inch2increasing the voltage-V lowering the voltage of - 500V, sample sip time 200 MS. The positive control (buffer 1 instead of the connection) and the negative control (buffer 1 instead of the compound and buffer 2 instead of kinase solution) were placed in parallel on each tablet.

The following products/compounds were tested using the above method of analysis using the appropriate form (salt or free base), obtained as in the examples described above, and were measured following activity values.

Example No.Selectivity against PKA/td> The selectivity in respect PKG
1>1000-fold>300-fold
2>10-fold>1-fold
3>1000-fold>1000-fold
4>300-fold>100-fold
5>1000-fold>1000-fold
6>1000-fold>1000-fold
7>300-fold>100-fold
8>100-fold>100-fold
9>10-fold>10-fold
10>1000-fold>300-fold
11>100-fold>300-fold
12>1000-fold>300-fold
13>10-fold>10-fold
14>1000-fold>100-fold
15>10-fold>10-fold
16>300-fold>300-fold
17>10-fold>10-fold
18>300-fold>300-fold
19>1000-fold>300-fold
21>300-fold>100-fold
22>300-fold>100-fold
23>10-fold>10-fold
25>300-fold>00-fold
27>1000-fold>1000-fold
28>10-fold>10-fold
30>300-fold>10-fold
31>10-fold>100-fold
32>1000-fold>300-fold

33>1000-fold>1000-fold
34>1000-fold>300-fold
35>300-fold>10-fold
37>300-fold>100-fold
38>1000-fold>300-fold
47>300-fold>300-fold
50>300-fold>10-fold
52>100-fold>10-fold
54>10-fold>10-fold
58>300-fold>300-fold
59>100-fold>100-fold
61>100-fold>300-fold
62>1000-fold>100-fold
64>1000-fold>300-fold
65>300-fold>100-fold
68>1000-fold>300-fold
69>1000-fold>300-fold
70>1000-fold
72>300-fold>100-fold
73>1000-fold>300-fold
74>1000-fold>1000-fold
75>1000-fold>1000-fold
76>1000-fold>1000-fold
77>1000-fold>300-fold
78>300-fold>100-fold
90>300-fold>100-fold
95>1000-fold>300-fold
96>300-fold>100-fold
99>1000-fold>300-fold
103 >1000-fold>1000-fold

106>1000-fold>1000-fold
107>1000-fold>1000-fold
108>1000-fold>10-fold
109>300-fold>100-fold
110>1000-fold>1000-fold

1. The compound of formula (I)

in which
R1represents H, HE or NH2;
R3represents H;
R4represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl;
R5represents H, a halogen atom, (C1-C6)alkyl;
R7represents H, a halogen atom, (C1-C6)alkyl, (C1-C6)alkyl;
R8represents H;
R9no;
R6no;
R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycle is alkyl, (C6)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heteroseksualci;
R11represents H;
R12is a (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl;
R13and R14independently of one another represent H, (C1-C6)alkyl, (C1-C6)alkylene-R';
n is 0;
m is 2 or 3;
s is 1 or 2;
r is 1;
L represents O or NH;
R' represents a (C3-C8)cycloalkyl, (C6-C10)aryl;
where in the residues R10, R12-R14alkyl or alkylene are unsubstituted or optionally substituted by one or more co3;
where in the residues R10, R12-R14alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms;
where (C1-C8)heteroalkyl group means (C1-C8)alkyl groups, where at least one carbon atom is replaced by O;
(C6)heterocytolysine group means a monocyclic carbon ring system containing 6 ring atoms, where one carbon atom may be replaced with 1 oxygen atom or 1 at the IOM sulfur, which may be optionally oxidized;
(C5)heteroaryl means monocalcium system in which one or more carbon atoms may be replaced by 1 nitrogen atom or 1 sulphur atom, or by a combination of different heteroatoms;
its stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

2. The compound of formula (I) according to claim 1, in which R1represents h, and which is characterized by formula (II)

3. The compound of formula (I) according to claim 1, in which R1HE is a and which is characterized by the formula (IIIa)

or formula (IIIb)

4. The compound according to claim 1, in which R1represents NH2.

5. The compound according to claim 1, in which R4represents H, halogen atom or (C1-C2)alkylether.

6. The compound according to claim 1, in which R4represents N.

7. The compound according to claim 1, in which R5represents H, a halogen atom, (C1-C6)alkyl.

8. The compound according to claim 1, in which R5represents N.

9. The compound according to claim 1, in which R7represents H, a halogen atom, (C1-C6)alkyl, (C1-C6)alkyl.

10. The compound according to claim 1, in which R7represents a hydrogen atom, methyl or a chlorine atom.

11. The compound according to claim 1, in which R10is a (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)heteroseksualci, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C8)alkylether or (C1-C6)alkylene-(C6)heteroseksualci,
where (C1-C6)alkyl is unsubstituted or substituted.

12. The compound according to claim 1, in which R10represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, isopropylacrylamide, tetrahydropyranyl or benzyl.

13. The compound according to claim 1, in which R12is a (C1-C6)alkyl, where one or more hydrogen atoms optionally are replaced by fluorine atoms; and (C3-C8)cycloalkyl, (C5)heteroaryl.

14. The compound according to claim 1, in which R12represents methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, pentafluoroethyl, thiazolyl or phenyl.

15. The compound according to claim 1, in which R13and R14independently of one another represent H, (C1-C6)alkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C6-C10)aryl,
where (C1-C6)alkyl is unsubstituted or substituted.

16. The connection is about to claim 1, in which
R13represents H, (C1-C6)alkyl or (C1-C4)alkylene-(C3-C8)cycloalkyl; and
R14represents H, (C1-C6)alkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl or (C1-C4)alkylene-(C6-C10)aryl, where (C1-C6) alkyl or (C1-C4)alkylene are unsubstituted or substituted.

17. The compound according to claim 1, in which
R13represents H or (C1-C6)alkyl; and
R14represents H, (C1-C6)alkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C6-C10)aryl or
where (C1-C6)alkyl or(C1-C4)alkylene are unsubstituted or substituted.

18. The compound according to claim 1, in which
R13represents H, (C1-C6) alkyl; and
R14represents H or (C1-C6) alkyl,
where (C1-C6)alkyl are unsubstituted or substituted.

19. The compound according to claim 1, in which R13and R14represent N.

20. The compound according to claim 1, in which m is 2 and s is 2.

21. The compound according to claim 1, in which m is 3 and s is 1.

22. The compound according to claim 1, selected from the group consisting of
6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-from inolin-1-it,
6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-propylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
6-[4-(aminocyclopropane)-4-propylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-ethyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminobutyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
6-[4-(aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-2-methylpropyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-isopropoxybenzonitrile]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-ethyl)-4-cyclobutanecarboxylic]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-cyclobutanecarboxylic]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-cyclopentanecarboxylate]-7-chloro-2H-isoquinoline-1-it,
6-[4-(aminophenylamino)-4-cyclopentanecarboxylate]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-isobutyrylacetate]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-benzylacetone]-7-chloro-2H-isoquinoline-1-it,
6-[4-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminobutyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminobutyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,
6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-2,2,2-triptorelin)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-2,2,2-triptorelin)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-2,2,3,3,3-pentafluoropropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
6-[4-(aminothiazol-2-ylmethyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-or
6-[4-(aminothiazol-5-ylmethyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

23. The compound according to claim 1, selected from the group consisting of
CIS-6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminobutyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminobutyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it, CIS-6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it, and
CIS-6-[4-(1-aminopropyl)-4-butylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-it,
their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

24. The compound according to claim 1, selected from the group consisting of
CIS-6-[4-((S)-1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-((R)-1-aminopropyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-((S)-1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-((R)-1-aminopropyl)-4-(tetrahydropyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-((R)-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-((S)-1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-((S)-aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it
CIS-6-[4-((R)-aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
their tautomeric forms and/or their pharmaceutically acceptable salts.

25. The compound according to claim 1, selected from the group consisting of
CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-fluoro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-fluoro-5-methyl-2H-isoh the nolin-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-methyl-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-5,7-dimethyl-2H-isoquinoline-1-it,
CIS-6-[-4-(1-aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-it,
TRANS-6-[4-(1-aminopropyl)-4-methoxycyclohexyl]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-aminopropyl)-4-toxicologically]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminophenylamino)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminobutyl)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminophenylamino)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-3-methylbutyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1 - it,
CIS-6-[4-(1-amino-propyl)-4-cyclohexylcyclohexanes]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-(4,4,4-trifloromethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-(tetrahydropyran-4-ylmethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminocyclopropane)-4-(tetrahydropyran-4-ylmethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminocyclopropane)-4-methylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminocyclopropane)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
CIS-6- [4-(1-aminopropyl)-4-ethoxyethylacetate]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-ethyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminocyclopropane)-4-(4,4,4-trifloromethyl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(aminocyclopropane)-4-cyclopropylmethoxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-(tetrahydrothiopyran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-ethyl)-4-propylcyclohexanone]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-fluoro-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-7-fluoro-5-methyl-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-ethyl)-4-ethylcyclohexylamine]-4-benzyl-7-chloro-2H-isoquinoline-1-it,
CIS-7-chloro-6-{4-[1-(cyclopropylamino)propyl]-4-ethylcyclohexylamine}-2H-isoquinoline-1-it,
CIS-6-[4-(1-benzylaminopurine)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
CIS-7-chloro-6-[4-ethyl-4-(1-isobutylamino)cyclohexyloxy]-2H-isoquinoline-1-it,
CIS-6-[4-(1-butylaminoethyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-2-methylpropyl)-4-isopropylcyclohexane]-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-7-chloro-4-fluoro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-4-fluoro-2H-isoquinoline-1-it,
CIS-6-[4-(1-and isopropyl)-4-ethylcyclohexylamine]-4-bromo-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-aminopropyl)-4-ethylcyclohexylamine]-7-chloro-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile,
CIS-6-[4-(1-aminopropyl)-4-isopropylcyclohexane]-4-bromo-7-chloro-2H-isoquinoline-1-it,
CIS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
TRANS-6-[4-(1-amino-2-foradil)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1-it,
6-[4-(1-amino-3-methoxypropyl)-4-ethylcyclohexylamine]-7-chloro-2H-isoquinoline-1 - it,
CIS-6-[4-(1-aminopropyl)-4-(1,1-dioxotetrahydrofuran-4-yl)cyclohexyloxy]-7-chloro-2H-isoquinoline-1-it,
6-[3-(1-aminopropyl)-3-propylcyclohexyl]-7-chloro-2H-isoquinoline-1-it
6-[4-(1-aminopropyl)-4-triftormetilfullerenov]-7-chloro-2H-isoquinoline-1-it,
their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

26. The compound according to claim 1, selected from the group consisting of
CIS-1-[4-(5,7-dimethylisoxazole-6-yloxy)-1-ethylcyclohexyl]Propylamine,
CIS-1-[1-ethyl-4-(7-forsakenly-6-yloxy)cyclohexyl]Propylamine,
CIS-1-[1-ethyl-4-(7-methylisoquinoline-6-yloxy)cyclohexyl]Propylamine,
CIS-1-[1-ethyl-4-(7-fluoro-5-methylisoquinoline-6-yloxy)cyclohexyl]Propylamine,
CIS-1-[1-ethyl-4-(7-fluoro-5-methylisoquinoline-6-yloxy)cyclohexyl] - ethylamine,
CIS-1-[4-(7-bromoisoquinoline-6-yloxy)-1-ethylcyclohexyl]ethylamine,
CIS-1-[4-(7-methylisoquinoline-6-yloxy)-1-ethylcyclohexyl]ethylamine,
CIS-1-[4-(5-chloroisoquinoline-yloxy)-1-ethylcyclohexyl]ethylamine,
CIS-6-[4-(1-amino-ethyl)-4-propylcyclohexanone]-7-chloroisoquinoline-1-ylamine and
[4-(1-aminopropyl)-4-methylcyclohexyl]isoquinoline-6-ylamine,
and their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.

27. The compound of formula (I) and/or its pharmaceutically acceptable salt according to any one of claims 1 to 26 for use as a drug for the treatment and/or prevention of diseases associated with inhibition of Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chains of myosin.

28. The use of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to any one of claims 1 to 26 for obtaining a medicinal product for the treatment and/or prevention of diseases associated with inhibition of Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chains of myosin.

29. The use of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to any one of claims 1 to 26 for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorders, occlusive peripheral artery disease (PAOD), coronary heart disease, angina, hypercardia, heart failure, ischemic diseases, ischemic organ failure (end is offered by the damage to the body), pneumovirus, liver fibrosis, liver failure, nephropathy, renal failure, fibrosis of the kidney, renal glomerulosclerosis, hypertrophy of organs, bronchial asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostate hypertrophy, diabetes mellitus and its complications, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy bacterial infections of the gastrointestinal tract, sepsis or the development and progression of cancer.

30. The use of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to any one of claims 1 to 26 for the treatment and/or prevention of hypertension, pulmonary hypertension, liver fibrosis, liver failure, nephropathy, renal failure, chronic obstructive pulmonary disease (COPD), cerebral vasospasm, pain, spinal cord injury, erectile dysfunction, restenosis of blood vessels or the development and progression of cancer.

31. PR is the application of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to any one of claims 1 to 26 in approaches to treatment associated with the use of stem cells or induced poly potent stem cells, to improve recognition or to treat or prevent fibrosis of the myocardium, depression, epilepsy, medullary necrosis renal, tubulo-interstitial dysfunction, multiple sclerosis, stenosis of the blood vessels or disorders of lipid metabolism.

32. Medicinal product for the treatment and/or prevention of diseases associated with inhibition of Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chains of myosin containing an effective amount of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to any one of claims 1 to 26, pharmaceutically acceptable excipients and carriers.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining N-(1,5,3-dithiazonan-3-yl)amides of general formula (1): where R=p-C5H4N (a), (CH3)3CO (b), m-C5H4N (c), which consists in the following: hydrazides of general formula RC(O)NHNH2 (R=mentioned above) undergo interaction with 1,4-butanedithiol, preliminarily mixed at 20°C with water formaldehyde solution, in presence of catalyst crystallohydrate of copper chloride CuCl2·2H2O with molar ration 1,4-butanedithiol: CH2O : RC(O)NHNH2 : CuCl2·2H2O = 10:20:10:(0.3-0.7) at 75-85°C and atmospheric pressure for 44-52 h.

EFFECT: elaborated is method of obtaining novel compounds, which can be applied as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acyl thiourea derivatives of formula or a pharmaceutically acceptable salt thereo, where R1 is a hydrogen atom or a C1-3 alkyl group; R2 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C6-14 aromatic hydrocarbon group or an optionally substituted saturated or unsaturated 5-7-member heterocyclic group containing 1 or 2 nitrogen or sulphur atoms, or R1 and R2, together with the nitrogen atom which they are bonded, can form an optionally substituted nitrogen-containing saturated heterocyclic group selected from a group comprising pyrrolinyl, piperidinyl, piperazinyl or morpholino group; where the substitute is selected from a group comprising a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-6 alkanoyl group, a C1-6 alkyl group, a C3-10 cycloalkyl group, a C2-6 alkenyl group, C1-6 alkoxy group, an amino group, a C1-6 alkylamino group, a C1-6 alkanoylamino group, a C1-6 alkylaminocarbonyl group, a C1-6 alkylsulphonyl group, a C6-14 aromatic group, a saturated or unsaturated 5-7-member heterocyclic group containing 1-4 nitrogen and/or oxygen atoms, a saturated or unsaturated 5-7-member heterocycyl-carbonyl group containing 1 or 2 nitrogen and/or oxygen atoms, and an oxo group; R3 is a C1-6 alkyl group; and R4 is a halogen atom; R5 and R6, which can be identical or different from each other, denote a hydrogen atom, a halogen atom, a C1-3 alkyl group which can be substituted with a halogen atom, or a C1-6 alkoxy group. The invention also relates to a pharmaceutical or anti-tumour agent based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel acetyl thiourea derivatives having c-Met inhibiting activity are obtained.

11 cl, 2 dwg, 4 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to sulphonamide compounds of formula or pharmaceutically acceptable salts thereof, wherein A is phenyl, optionally substituted with 1 or 2 halogen atoms, C1-6 alkyl group, trifluoromethyl group, C1-6 alkoxy group or -SCH3 group, thiophenyl, optionally substituted with a C1-C6 alkyl group or a halogen atom, pyridinyl, optionally substituted with a halogen atom, naphthalenyl or dihydroindenyl; R1 denotes the following formulae or [in formulae (R1a) and (R1b) Ar1 denotes the following formulae , or (each R5 and R6 independently denotes a hydrogen atom, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms, C1-6 lower alkoxy group optionally substituted with up to three halogen atoms); Ar2 denotes the following formulae , or (each R7 and R8 independently denotes a hydrogen atom, a hydroxyl group, a halogen atom, a C1-6 alkyl group optionally substituted with up to three halogen atoms or a C1-6 lower alkoxy group optionally substituted with up to three halogen atoms, an amine group, a nitro group, a C2-6 acyl group, or R7 and R8 together form -CH2CH2O-; R9 is a hydrogen atom or - J-COOR10; J is a covalent bond, alkylene containing 1 to 5 carbon atoms, alkenylene containing 2 to 5 carbon atoms or alkynylene containing 2 to 5 carbon atoms, where one carbon atom in said alkylene groups can be substituted with an oxygen atom, a sulphur atom, NR11, CONR11 or NR11CO in any chemically acceptable position; R11 is a hydrogen atom; and R10 is a hydrogen atom); and p equals 0 or 1]; R2 is a C1-6 alkyl group; each R3 and R4 is independently a C1-6 alkyl group; * denotes an asymmetric carbon atom; and m equals an integer from 1 to 3. The invention also relates to a medicinal agent for stimulating PTH secretion.

EFFECT: obtaining novel compounds which can be used in medicine to prevent or treat primary or secondary osteoporosis.

29 cl, 15 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula or to its therapeutically acceptable salt, where A1 represents N or C(A2); A2 represents H; B1 represents H, OR1 or NHR1; D1 represents H; E1 represents H; Y1 represents CN, NO2, F, Cl, Br, I, R17 or SO2R17; R1 represents R4 or R5; Z1 represents R26 or R27; Z2 represents R30; Z1A and Z2A both are absent; L1 represents R37; R26 represents phenylene; R27 represents indolyl; R30 represents piperasinyl; R37 represents R37A; R37A represents C2-C4 alkylene; Z3 represents R38, R39 or R40; R38 represents phenyl; R39 represents benzodioxilyl; R40 represents C4-C7cycloalkenyl, heterocycloalkyl, which represents monocyclic six- or seven-member ring, containing one heteroatom, selected from O, and zero of double bonds, or azaspiro[5.5]undec-8-ene; the remaining values of radicals are given in i.1 of invention formula. Invention also relates to pharmaceutical composition, based on claimed compound.

EFFECT: novel compounds, which can be applied in medicine for treatment of diseases, in the process of which anti-apoptotic Bcl-2 protein is expressed, are obtained.

8 cl, 2 tbl, 411 ex

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