MX2008007059A - Isoquinoline derivatives - Google Patents

Abstract

The invention relates to isoquinoline derivatives having the general Formula (I) wherein X is O, S or NH;Y is OH or NH2;m is 0, 1 or 2;n is 1 or 2;R1is H, when Y is NH2;or R1is H, (C1-4)alkyl or halogen, when Y is OH;R2and R3are independently H, (C1-4)alkyl or halogen;R is H or (C1-6)alkyl, optionally substituted with OH, (C1-4)- alkyloxy, (C1-4)alkyloxycarbonyl, (C3-7)cycloalkyl, which may optionally comprise a heteroatom selected from O and S, (C6-10)aryl, (C6-10)aryloxy or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms independently selected from O, N and S, each aryl or heteroaryl group being optionally substituted with 1-3 substituents independently selected from (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl and halogen;or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same as well as to the use of the isoquinoline derivatives in the treatment of ROCK-I related disorders such as hypertension, atherosclerosis and glaucoma.

Description

DERIVATIVES OF ISOQUINOLINE Field of the Invention The present invention relates to isoquinoline derivatives, to pharmaceutical compositions comprising the same, as well as to the use of these derivatives for the preparation of a medicament for the treatment of disorders related to ROCK-1. BACKGROUND OF THE INVENTION The vast majority of transduction pathway signals are controlled by reversible protein phosphorylation. There are currently approximately 500 known protein kinases, which are responsible for the phosphorylation of proteins and thus the control of cell signaling tests. Many diseases are associated with abnormal cell responses triggered by mediator-kinase protein tests and this has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. The protein kinase family was classified into tyrosine kinases and serine / threonine kinases, based on the phosphorylated amino acid residue. Histidine kinases (which are phosphorylated by the imidazole nitrogen in a histidine residue) have recently been discovered.

The AGC sub-family of kinases belongs to the septa and threonine family of kinases and participates in a variety of signaling processes This sub-family includes a Rho-associated coiled roll forming protein kinase (ROCK). Two isoforms have been reported ROCK ROCK-I / ROKß / p160ROCK and ROCKII / ROK / Rho-cmasa These two proteins divide by 65% similar to the amino acid level and 92% in a kinase domain. It was discovered that the ROCK-I and ROCKII were among the first to be carried out of the small GTPases of the Rho family. The Rho-ROCK controls the path of cell signaling form adhesion, contractility, mobility and cell invasion. The first generation of inhibitors Y-27632 and Fasudil have been used in a manner extensive to clarify the biological roles of ROCK-I and ROCK-II in various diseases and / or conditions As a result, ROCK inhibitors have been suggested to have therapeutic value in bronchial asthma, cerebral vasospasm, coronary vasospasm, erectile dysfunction, glaucoma , preterm labor, vascular smooth muscle proliferation, myocardial hypertrophy, malignoma, ischemia / reperfusion-induced injury, endotehal dysfunction, Crohn's disease and colitis, growth neurite, Raynaud's disease, angina, Alzheimer's disease, benign prostatic hyperplasia, cancer, neuropathic pain, hypertension and atherosclerosis (Mueller B K and associates, Nature Reviews Drug Discovery 4, 387-398 (2005); Hirooka Y. and Shimokawa H. Am. J. Cardiovasc. Drugs 5 (1). 31-39 (2005); Hu E. and Lee D. Current Opinion Ther. Targets 9 (4). 715-736 (2005)). 5-Substituted isoquinoline derivatives have been described as inhibitors of Rho / Rho kinase pathways in International Patent Application WO 2004/00955 (EP 1541559, Asahi Kasei Pharma Corporation). The N-substituted 5-isoquinolyl amine derivatives have been described as inhibitors of Rho kinase in International Patent Application WO 2004/024717 (EP 1550660, Kirin Brewerey Kabashiki Kaisha). There is a need for additional compounds useful in the treatment of Rho kinase mediating diseases such as hypertension, atherosclerosis and glaucoma. The present invention is directed to providing isoquinoline derivatives having the general formula I Formula I wherein X is O, S or NH; And it is OH or NH2; m is 0, 1 or 2; n is 1 or 2; R is H, wherein Y is NH2; or R-, is H, alkyl (C? -) or halogen, when Y is OH; R2 and R3 are independently H, a Iq u i I (C 1 -) or halogen; R is H or alkyl (C6), optionally substituted with OH, (C1-4) alkyloxy, alkyloxycarbonyl (C1.4), cycloalkyl (C3-7), which may optionally comprise a heteroatom selected from O and S , aril (C6-? o). aryloxy (C6-? o) or a 5- or 6-membered heteroaryl group comprising 1-3 heteroatoms independently selected from O, N and S, each aryl or heteroaryl group is optionally substituted with 1-3 substituents independently selected from alkyl ( C 4), alkyloxy (C 1 -), alkylsulfonyl (C 1-4) and halogen; or a pharmaceutically acceptable salt thereof, which are used in the treatment of diseases treated with Rho kinase such as hypertension, atherosclerosis and glaucoma.

The term (C 1-6) alkyl is used in the definition of the formula I, means a branched or unbranched alkyl group having from 1 to 6 carbon atoms, similar to hexyl, pentyl, butyl, isobutyl, tertiary butyl, propyl , isopropyl, ethyl and methyl. The term (C1-) alkyl is used in the definition of formula I, means a branched or unbranched alkyl group having from 1 to 4 carbon atoms, similar to butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. The term cycloalkyl (C3.) Means a cycloalkyl group having from 3 to 7 carbon atoms, similar to cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. The (C3-7) cycloalkyl group further comprises a heteroatom selected from O and S, as well as exemplified in tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, and tetrahydrothienyl. In the terms (1-4C) alkyloxy, alkyloxycarbonyl (C1-) and alkylsulfonyl (C1.4), alkyI (C1-4) have the meaning as defined above. The term halogen means F, Cl, Br or I. The term aryl (C6-? O) means phenyl or naphthyl. In the definition of Formula I the 5- or 6-membered heteroaryl group comprises from 1 to 3 heteroatoms independently selected from O, N and S, is exemplified by pyrrolyl, thienyl, furyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl. The 5- or 6-membered heteroaryl groups specified are 2-fluoro, 3-fluoro, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl , thiazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1, 2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1 , 3,4-oxadiazol-2-yl, 1,4-oxadiazol-5-yl, 1,4-oxadiazol-3-yl and 1,4-oxadiazol-5-yl. In one embodiment of the present invention isoquinoline derivatives having the General Formula I Formula I wherein X is O, S or NH; And it is OH or NH2; R ^ and R2 are H; R3 is H or alkyl (C -4); m is 0 or 1; n is 1 or 2; R is H or alkyl (C? _), Optionally substituted by (C3) cycloalkyl, which may optionally comprise a heteroatom selected from O and S, aryl (C6-? O) or a 5- or 6-membered heteroaryl group comprising from 1 to 3 heteroatoms independently selected from O, N and S, each aryl or heteroaryl group are optionally substituted with 1 to 3 substituents independently selected from (C1-) alkyl, (C1-) alkyloxy and halogen; or a pharmaceutically acceptable salt thereof. There is a preference for isoquinoline derivatives of Formula I where Y is OH. Further preferred compounds of Formula I are those wherein X is O. In the most preferred compounds of the present invention for Formula I, R3 is independently H, methyl or halogen, Ri and R2 are H. In addition, the preferred compounds of the present invention, R represents H, (C -4) alkyl, optionally substituted with phenyl or a 5- or 6-membered heteroaryl group comprising from 1 to 3 heteroatoms selected from O, N and S, the phenyl or heteroaryl group is optionally substituted with from 1 to 3 substituents selected from alkyl (C? -4), alkyloxy (C? -) and one or more halogens. Even more preferred are the isoquinoline derivatives of Formula I, wherein Y is OH, m is 1, n is 1 or 2, and R is H. The isoquinoline derivatives specifically preferred of the present invention are: - (S) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; - (S) -7-methyl-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; -6- (perhydroazepin-4-yloxy) -2H-isoquinolin-1-one; - (S) -6- [1- (1H-pyrrol-2-ylmethyl) -piperidin-3-yloxy] -isoquinolin-1-ylamine; - (S) -6- [1- (4-methylbenzyl) piperidin-3-yloxy] isoquinolin-1-ylamine; -6- (piperidin-4-yloxy) -2H-isoquinolin-1-one; - (R) -6- (1-Benzylpiperidin-3-yloxy) isoquinolin-1 -lamin; -6- [1- (2-phenoxyethyl) piperidin-3-yloxy] isoquinolin-1 -lamin; - (3S) -6- [1- (1-phenylethyl) piperidin-3-yloxy] isoquinolin-1-ylamine; -6- (piperidin-4-ylsulfanyl) -2H-isoquinolin-1-one; -6- (1-thiophen-2-methylmethylperidin-3-yloxy) isoquinolin-1 -lamin; - (S) -6- (1-benzylpiperidin-3-yloxy) isoquinolin-1-ylamine; - (R) -6- [1- (2-phenoxyethyl) piperidin-3-yloxy] -2H-isoquinolin-1-one; - (S) -6- [1- (4-Fluorobenzyl) -piperidin-3-yloxy] -isoquinolin-1-ylamine; - (S) -4-bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; -6- [1- (1H-pyrrol-2-ylmethyl) piperidin-4-yloxy] -2H-isoquinolin-1 -one; -6- [1- (4-methoxybenzyl) piperidn-3-loxy] -2H-isoquinolin-1-one; - (S) -6- [1-furan-3-ylmethylpiperidin-3-yloxy] isoquinolin-1-ylamine; -6- [1-Fe netylpiperidin-3-yloxy] isoquinolin-1 -lamin; -6- [1- (3-methoxybenzyl) piperidin-4-loxy] -2H-isoquinolin-1-one; - (S) -6- [1- (1H-pyrrol-3-ylmethyl) piperidin-3-yloxy] isoquinolin-1-ylamine; - (S) -6- [1- (2-Oxo-2-phenyl ethyl) piperidin-3-yloxy] -2H-isoquinolin-1-one; - (S) -6- (p? Rrol? D? N-3-? Lox?) - 2H-? Soqu? Nol? N-1-one, -6- (1-c? Clohex? Lmet? Lp? per? d? n-3-? lox?) - 2H-? soqu? nol? n-1-one, -6- (p? Per? D? N -3? Lsulfan? L)? Soqu? Nol? N-1-? Lam? Na, -6- (1-furan-2-? Lmet? Lp? Per? d? n-4-? lox?) - 2H-? soqu? nol? n-1-one, - (R) -6- (p? Rrol? D? N -3? Lsulfan? L)? Soqu? Nol? N-1-? Lam? Na, - (S) -4-met? L-6- (p? per? d? n-3-? lox?) - 2H-? soqu? nol? n-1-one, - (S) -6- (p? rrol? d? n -3? lsulfan? l)? soqu? nol? n-1-? lam? na, -6- (1-met? lp? per? d? n-4-? lox?) - 2H-? soqu? nol? n-1- ona, - (S) -6- (p? per? d? n-3-? lox?) -? soqu? nol? n-1-? lam? na, -6- (p? per? d? n -4-? Lsulfan? L)? Soqu? Nol? N-1-? Lam? Na, - (R) -6- (p? Per? D? N-3-? Lox?) - 2H-? Soqu? nol? n-1-one, - (S) -6- [1- (2-phenox? et? l) p? per? d? n -3? lox?] - 2H-? soqu? nol? n -1-one, -6- (1-benz? Lp? Per? D? N-3-? Lox?) - 7-met? L? Soqu? Nol? N-1-? Lam? Na, -6- [1- (3-hydroxypropylene) p? Per? D? N-4-? Lox?] - 2H-? Soqu? Nol? N-1-one, -6- [1- (2 -h? drox? et? l) p? per? d? n-4-? lox?] - 2H-? soqu? nol? n-1-one, - (R) -6- (p? rrol? d ? n-3-? lox?) - 2H-? soqu? nol? n-1-one, -6- [1- (3-met? lbenc? l) p? per? d? n-4-? lox ?] - 2H-? Soqu? Nol? N-1-one, -7-met? L-6- [1- (4-met? Lbenc? L) p? Per? D? N-3-? Lox? ]? so? nol? n-1-ylamine, - (S) -5-bromo-6- (p? per? d? n -3? lox?) - 2H-? soqu? nol? n-1- ona, -6- [1- (4-methox? benc? l) p? per? d? n-4-? lox?] -2H-? soqu? nol? n-1-one, and pharmaceutically acceptable salts of They were prepared the compounds of Formula I from the compounds of Formula II, wherein Y, X, Ri, R2, R3, n and m have pre-defined meanings, any reactive group in Y and X optionally carrying a protecting group, and Pg is a protecting group -? /, by removing said protecting group -? / (Pg) and alkylation -? / subsequent with an appropriate halide of the Formula R-Hal, or a reductive amination with an appropriate aldehyde derived from the group R, after which any group of remaining protection is eliminated.

The term protecting group -? / Means a group commonly used for the protection of an amino group, similar to the alloxycarbonyl group (Alloc), the tert-butyloxycarbonyl group (Boc), the benzyloxycarbonyl group (Z) or the 9-fluorenylmethyloxycarbonyl group (Fmoc). The protection groups eliminated can take place in different ways, depending on the nature of these protection groups. An overview of the amino protection groups and the methods for their elimination in T.W. Greene and P.G.M. Wuts, Protective Groups ¡n Organic Synthesis, 2nd. Edition, 1991, John Wiley & Sons, Inc.

The compounds of Formula I and II are prepared in which X is O or S from the coupling of a compound of Formula III, wherein Y, X, Ri, R2 and R3 have the same meanings as defined above, with a compound of Formula IV, wherein n, m and R have the same meanings as defined above, or Formula V, wherein n, m and Pg have the same meanings as defined above, and wherein L is OH, using standard Mitsunobu conditions (RL Elliot, H. Kopecka, DE Gunn, HN Lin and DS Garvey, Bioorg, Med.Chem.Lett., 6, 2283 (1996), K. Wisniewski, AS Koldziejczyk and B. Falkiewicz, J. Pept. Se. 4, 1 (1988).

IV Alternatively, the mediation shift SN2 Williamson of a suitable starting group of formula IV or Formula V (where L = OMs, OTs, I, Br or Cl) using phenols or thiols of Formula III (where X = O or S) and an appropriate base. The compounds of Formula I were prepared wherein X = S, by mediating displacement SN2 Williamson of a suitable starting group of Formula IV or Formula V (in where L = OMs, OTs, I, Br or Cl) using an appropriate base. The thiols of Formula III (where X = S) were prepared by the phenol treatment of Formula III (wherein X = O and Y = OH or a protected amino group such as urethane as well as Alloc, phthaloyl or amide such as benzoyl) with dimethylthiocarbamoyl chloride to produce the corresponding O-ester. Newman-Karnes (Newman, M. S. and Karnes, H.A. J. Org. Chem. 1966, 31_, 3980) the conversion of the O-ester to the S-ester was completed using microwave irradiation. Subsequently the hydrolysis of the S-ester produced thiols of the Formula III (wherein X = S and Y = OH or a protected amino group such as urethane as well as Alloc, phthaloyl or amide such as benzoyl). The compounds of Formula I were prepared where X = NH by the conversion of the phenolic OHs into the compounds of Formula III corresponding to the bromide, which is subsequently coupled to an amine derivative of Formula V (L = NH2 ) by the palladium-catalyzed amination reaction (Wolfe JP, Tomori H, Sadighi JP, Yin, J and Buchwald SLJ Org. Chem. 2000, 65, 1158-1174). The demethylation of aryl methyl esters of the Formula VI (wherein Y = OH or NH2) to the corresponding phenolic compounds of Formula III (wherein X = O and Y = OH or NH2) by reaction with BBr3 [J.F.W. McOmie and D.E. West, Org. Synth., Collect. Vol. V, 412 (1973)] or EtSNa [A.S. Kende and J.P. Rizzi, Tetrahedron Lett, 22, 1779 (1981)] or HBr.

A suitable starting material is a compound of Formula VIII for the preparation of compounds of Formula VII. The chlorine group of the compound VII was converted directly to an amine group by heating the former with ammonia under pressure. Alternatively, the chlorine group of the compound VII was converted to a phenoxy group by the reaction with phenol under alkaline conditions. The treatment of the phenoxy derivative (compound VI where Y = OPh) with ammonium acetate affords the amine derivatives of Formula VI (Y = NH2). Compound VI (Y = NH2) is also obtained by treating the compound VII with sodium azide and subsequent reduction of the aryl azide with PPh3.

Compound VII was obtained from compound VIII by treatment with phosphorus oxychloride. Compound VII was also prepared by the conversion of 6-methoxyisoquinoline (Hendrickson, J.B., Rodriguez, C; J. Org.

Chem. 1983, 48, 3344-3346) in the oxide- / V salt, for example with a similarity, such as m-chloroperbenzoic acid, followed by the HCl treatment, and the subsequent reaction this is oxide-α / with a chlorination reagent, similar to phosphoryl chloride (J. Robinson, J. Am. Chem. Soc, 69., 1941, 1939).

VIII 1-amino-6-bromoisoquinoline used in the preparation of compounds of Formula II wherein X = NH, Y = NH2 and R -? - R3 are H by knoevenagel condensation of 3-bromobenzaldehyde to provide the 3- bromo-cinnamic The acid was converted to the acyl chloride and subsequently transformed into the acyl azide, which undergoes a new Curtius adaptation in heating to provide the intermediate isocyanate. The intermediate isocyanate is heated resulting in an intramolecular ring closure to produce 6-bromoisoquinolinone. The formation of 1-amino-bromoisoquinoline was completed using the same procedures described for compound VI (where Y = NH2), using 1-chloro-6-bromoisoquinoline, which is generated by the treatment of 6-bromoisoquinolinone with POCI3.

In addition, the preparation of the compounds of Formula II wherein X = O, Y = NH2 and R3 = methyl require 6-methoxy-7-methyl-isoquinolin-1 -lamin which is prepared using similar procedures such as for the above 1-amino-6-bromoisoquinoline protocol. In general it was prepared in the compounds of Formula VI, wherein Y is OH, from the corresponding cinnamic acids of Formula IX. The acids were converted to acyl chlorides which were subsequently transformed into the acyl azides of Formula X, which undergo a new Curtius adaptation in heating to provide an intermediate isocyanates, in which in addition the heating results in a closing reaction of intramolecular ring to produce an isoquinolinone of Formula VI.

Formula IX Formula X In addition, the compounds of Formula I are converted and II (where Y = OH) in the compounds of Formula I and II (where Y = NH2) by treatment with POCI3 followed by additional treatment with ammonia. In addition, compounds of Formula II were prepared, wherein Y is OH, R2 and R3 are H and R is halogen, by halogenation with appropriate N-halosuccinamide. Alternatively, the compounds of Formula III were prepared, wherein Y is OH, X is O, R3 and R2 are H and Ri is halogen, by halogenation under acidic conditions with the appropriate dihalogen (i.e., Br2). In addition, the compounds of Formula VI were prepared, wherein Y is H, R-, and R3 are H and R2 is Br from 6-methoxyisoquinoline according to P. Chen et al., Bioorg. Med. Chem. Lett 13 (2003) 1345-1348. The bromide corresponding to the methyl derivative was converted by transmetallation and the subsequent reaction with a suitable electrophilic such as iodomethane. Alternatively, the formyl or keto derivative was formed from the appropriate electrophile and subsequently reduced to the appropriate alkyl derivative. Alternatively, palladium-catalyzed coupling-tracing with organostannanes was employed. It is understood that the compounds of the present invention wherein Y is OH can also occur in the O-form of the tautomeric amide and can therefore also be described as 2H-isoquinolin-1 -ones. 1-hydroxy-isoquinoline 2H-isoquinolin-1-one The isoquinoline derivatives of Formula I and their salts may contain at least one center of chirality, and therefore exist as stereoisomers, including enantiomers and diastereomers. The present invention includes the aforementioned stereoisomers within the scope and of each of the individual R and S enantiomers of the compounds of Formula I and their salts, which are substantially free, ie associated with at least 5%, preferably at least 2%, in particular at least 1% of the other enantiomer, and mixtures of said enantiomers in any proportions including the racemic mixtures containing substantially equal amounts of the two enantiomers. Methods for asymmetric synthesis or chiral separation whereby pure stereoisomers are obtained are well known in the art, for example, synthesis with chiral induction or starting from commercially available chiral substrates, or separation of stereoisomers, for example using chromatography in a chiral medium or by crystallization with a counter-chiral ion. The pharmaceutically acceptable salts of an isoquinoline derivative of the present invention were obtained by treating a free base of a compound of the Formula I with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, or an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acid acetic acid and methane sulfonic acid. There are the compounds of the present invention in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms equivalent to unsolvated forms are considered for the purpose of the present invention. The isoquinoline derivatives of the present invention were found to possess inhibitory activity in a human recombinant ROCK-1 in vitro, as well as being potentially useful in the treatment of ROCK-1 mediator of diseases such as hypertension, atherosclerosis and glaucoma. The present invention further provides pharmaceutical compositions comprising an isoquinoline derivative according to general Formula I, or a pharmaceutically acceptable salt thereof, in addition to a mixture with pharmaceutically acceptable auxiliaries, and other therapeutic agents optionally. The term "acceptable" means that it is compatible with the other ingredients of the composition and is not deleted from the same containers. The compositions include, for example, those suitable for oral, sublingual, subcutaneous, intravenous, epidural, intrathecal, intramuscular, transdermal, pulmonary, local, or rectal administration, and the like, all in unit dosage forms for administration. A preferred route of administration is the oral route. For oral administration, the active ingredient was presented as discrete units, such as tablets, capsules, powders, granules, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical composition of the present invention was presented in unit dose or multiple dose containers, for example liquid injections in predetermined amounts, for example in seal routes and ampoules, and are also stored in a drying condition by Freezing (lyophilized) requiring only the addition of the sterile liquid vehicle, ie, water, prior to use. Mixing with said pharmaceutically acceptable auxiliaries, ie, as described in the standard reference, Gennaro, A.R. and associates, Remington: The Science and Practice of Pharmacy (20th Edition, Lippincott Williams &Wilkins, 2000, see especially Part 5: Pharmaceutical Processing), the active agent may be comprised in solid dosage units, such as pills, tablets, or be processed into capsules, suppositories or patches. The active agent was applied by means of pharmaceutical fluids acceptable as a fluid composition, for example as an injection preparation, in the form of a solution, suspension, emulsion or as a sprayer, i.e. a nasal spray. For the preparation of solid dosage units, the use of conventional additives such as fillers, dyes, polymeric linkers and the like was contemplated. In general, any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the present invention can be administered such as solid compositions, include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. They can be used for parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions, containing pharmaceutically acceptable dispersing agents and / or wetting agents, such as propylene glycol or butyl eneol. The present invention further includes a pharmaceutical composition, as described above, in combination with suitable packaging material for said composition, said packaging material includes instructions for the use of the composition for use as described above.

The compounds of the present invention can be administered to humans in sufficient amounts and for a sufficient amount of time to alleviate the symptoms. By way of illustration, dosage levels for humans can be within the range of 0.001-50 mg per kg of body weight, preferably at a dose of 0.01-20 mg per kg of body weight. The present invention is illustrated by the following examples. General: The following abbreviations were used: Eluente was used: xy% solvent A in solvent B means the gradient of the eluent of x% (v / v) of solvent A in solvent B for y% (v / v) of the solvent A in solvent B. Example 1 (S) -6- (1-Benzylpyrrolidin-3-yloxy) -isoquinolin-1 -lamin 1 -amino-6-hydroxyisoquinoline (50 mg, 0.312 mmol), prepared as described in Publication WO 00/24718 (Akzo Nobel NV), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1, 3,2-diazaphosphorine in polystyrene (284 mg, -2.2 mmol.g. 1, -0.624 mmol) was stirred at room temperature in acetonitrile (4 ml) for 15 minutes, (R) methanesulfonic acid ester 1-benzylpyrrolidin-3-yl (0.312 mmol) and the mixture was heated to 110 ° C and The mixture was filtered and the precipitate was washed with acetonitrile.

Concentrate the filtrate and then purify by prep-HPLC to yield (S) -6- (1-Benzylpyrrolidin-3-yloxy) -isoquinolin-1-ylamine (40 mg), EI-MS: m / z = 320.3 [M + H] +. Example 2 (R) -6- (1-Benzylpyrrolidin-3-yloxy) -isoquinolin-1-lamine The methanesulfonic acid ester compound- (S) 1 -benzylpyrrolidin-3-yl and 1-amino-6 was prepared -hydroxyisoquinoline by the procedure described in Example 1_ to produce the product (R) 6- (1-benzylpyrrolidin-3-yloxy) -isoquinolin-1 -lamin, EI-MS: m / z = 320.3 [M + H] +. Example 3 (S) -6- (Piperidin-3-yloxy) -isoquinolin-1 -lamin A: tert-butyl ester of (R) -3-Hydroxy-piperidine-carboxylic acid Di-tert-butyl was added dicarbonate (8.7 g, 11.6 mmol) to the suspension of (R) -3-hydroxypiperidine hydrochloride (5.0 g, 40.0 mmol) and sodium hydrogen carbonate (24.2 g, 29.0 mmol) in methanol (70 ml). Following the addition, the reaction was sonic at room temperature for 1.5 hours during which the temperature time was reached at 40 ° C. The solvent was removed under reduced pressure and the crude material was partitioned between ethyl acetate (200ml) and water (200ml). After separation of the layers, the organic material was washed in sequences with sodium hydrogen carbonate (100ml), water (100ml), brine (100ml) and water (100ml) before starting the dried with magnesium sulfate and evaporated on drying under reduced pressure. The (R) -3-hydroxy-piperidine carboxylic acid tert-butyl ester was obtained in the form of a colorless oil that solidified. Bj. (R) -3-Methanesulfonyloxy-piperidin-1-carboxylic acid tert-butyl ester Methanesulfonyl chloride (1.73ml, 22.5mmol) was added to be cooled (ice bath, 0-4 ° C), the stirred solution of tert-butyl ester of (R) -3-hydroxy-piperidine-carboxylic acid (3.0g, 15mmol) and triethylamine (3.12ml, 22.5mmol) in dichloromethane (30ml). The reaction was stirred followed by addition at its temperature for 30 minutes before allowing to be warmed to room temperature. After stirring at room temperature for 2 hours, aqueous sodium hydrogen carbonate (50ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (300ml) and aqueous sodium hydrogen carbonate (300ml) and after separation the organic phase was washed with water (200ml), dried with magnesium sulfate and evaporated by drying under reduced pressure to remove producing tert-butyl ester of (R) -3-methanesulfonyloxypiperidine-1-carboxylic acid, in the form of a semi-crystalline solid. C: (S) -3- (1-amino-isoauinolin-6-yloxy) piperidin-1-carboxylic acid tert-butyl ester added to a solution of tert-butyl acid ester (R) -3-hydroxypiperidin-1 -carboxylic acid (209 mg, 1.04 mmol), triphenylphosphine (327 mg, 1249 mmol), 1-amino-isoquinolin-6-ol (200 mg, 1249 mmol) in THF (4 ml) and DMF (394μL) at a temperature of 0 ° C, under argon, in the form of diethylazodicarboxylate drops (197 mL) for 5 minutes. The mixture was then warmed to room temperature and stirred for 48 hours. Then water and the mixture based on dilute NaOH were added. The mixture was extracted with ethyl acetate (X3), dried (sodium sulfate), filtered and evaporated under reduced pressure to produce a residue. Flash chromatography of the residue on silica (eluent: 2-10% methanol in dichloromethane with 1% aqueous ammonia) yields (S) 3- (1-amino-isoquinolin-6 -loxy) piper tert-butyl ester. Din-1-carboxylic acid (72 mg), EI-MS: m / z = 344.1 [M + H] +. For the preparation of an alternate procedure of (S) -3- (1-amino-isoquinolin-6-yloxy) piperidin-1-carboxylic acid tert-butyl ester, a suspension of 1-amino-6-hydroxyisoquinoline (0.8 g , d.Ommol), tert-butyl ester of (R) -3-methanesulfonyloxypiperidine-1-carboxylic acid (1.76 g) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3, 2-diazaphosphorine in polystyrene (loading 3.4g, ~ 2.2mmol / g) in acetonitrile (10ml) was heated at a temperature of 160 ° C for a period of 15 minutes using a microwave. The excess of the supported reagent was removed by filtration, washing with acetonitrile followed by methanol, and the filtrate evaporated to dry under reduced pressure. Purification was carried out by chromatography on silica (eluent: 2-10% methanol in ethyl acetate) to give (S) 3- (1-amino-isoquinolin-6-yloxy) piperidin-1-carboxylic acid tert-butyl ester. (72 mg), EI-MS: m / z = 344.1 [M + H] +. D: (S) -6- (Piperidin-3-yloxy) -isoquinolin-1-lamine A mixture of tert-butyl ester of (S) -3- (1-amino-isoquinolin-6-yloxy) acid was stirred. piperidin-1-carboxylic acid (72 mg) in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) at room temperature for 1.5 hours. The mixture was concentrated in vacuo then flash chromatography of the residue (eluent: 2-10% methanol in dichloromethane with 1% aqueous ammonia) yielded (S) -6- (piperidin-3-yloxy) isoquinolyl-1 - Lamina, EI: MS: m / z = 244.4 [M + H] +. Example 4 6- (Piperidin-4-yloxy) -isoquinolin-1 -lamin The compound was prepared from 4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (455 mg, 2.26 mmol) and 1- amino-6-hydroxyisoquinoline (435 mg, 2.71 mmol) by the Mitsunobu procedure described in 3C_. Subsequent Boc deprotection according to the procedure described in 3_D to yield 6- (piperidin-4-yloxy) -isoquinolin-1 -lamin (140 mg), EIMS: m / z = 244.6 [M + H] +. Example 5 6- (Piperidin-3-yloxy) -isoquinolin-1 -lamina The compound was prepared from racemic 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (207 mg, 1.02 mmol) and 1-amino-6-hydroxysoquinoline (198 mg, 1.23 mmol) by the Mitsunobu procedure described in 3_C. , the subsequent Boc deprotection according to the procedure described in 3_D to produce 6- (piperidin-3-yloxy) -soquinolin-1-racemic lamella (30 mg), EI-MS: m / z = 244.4 [M + H] +. Example 6 (S) -6- (Pyrrolidin-3-yloxy) -isoquinolin-1-lamine The compound was prepared from (S) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (195 mg, 1.04 mmol) and 1-amino-6-hydroxyisoquinoline (200 mg, 1.25 mmol) by the Mitsunobu procedure described in 3C, the subsequent Boc deprotection according to the procedure described in 3D to produce (S) -6- (pyrrolidin- 3-yloxy) -isoquinolin-1 -lamin, EI: MS: m / z = 230.3 [M + H] +. Alternate procedure: A solution of (R) -3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (2.95 g) in N, N-dimethylformamide (2 ml) was added dropwise to a stirred solution of 1 - amino-6-hydroxyisoquinoline (1.2 g, 7.4 mmol) and K2CO3 (1.02 g, 7.4 mmol) in N, N-dimethylformamide (10 ml) at a temperature of 100 ° C. The mixture was stirred for 1 hour then cooled and water was added. The mixture was acidified with glacial acetic acid and subsequently diluted with methanol The mixture was loaded on a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to yield (S) -6- (pyrrolidin-3-yloxy) isoquinolin-1-crude lamin, which was purified by flash chromatography on silica (eluent: 10% methanol in DCM with 1% ammonium hydroxide), EI-MS: m / z = 230.3 [M + H] +. Example 7 (S) -6- (1-Benzylpiperidin-3-yloxy) isoquinolin-1-yl amine A: (S) -3- [1 - (1,3-Dioxo-1, 3-tert-butyl ester -dihydroisoindol-2-yl) isoquinolin-6-yloxy-1-piperidin-1-carboxylic acid It was added to a solution of (S) -3- (1-amino-isoquinolin-6-yloxy) piperidin-1-carboxylic acid tert-butyl ester. (380 mg, 1.11 mmol) and triethylamine (1.5 mL, 11.1 mmol) in anhydrous tetrahydrofuran (1.5 mL) phthaloyl dichloride (170 μL, 1.16 mmol). The mixture was stirred at room temperature for 2 hours and then stirred water was quickly emptied. The mixture was extracted with dichloromethane (3 x 50 ml) and concentrated in vacuo to yield a residue. Flash chromatography of the residue on silica (eluent: 0-100% ethyl acetate in heptane) yielded (S) -3- [1- (1,3-dioxo-1,3-dihydroisoindole) -butyl ester. 2-yl) isoquinolin-6-yloxy] piperidine-1-carboxylic acid (390 mg) EI-MS: m / z = 474.3 [M + H] +. B: (S) -2- (6-piperidin-3-yloxy) isoquinolin-1-insoisoindole-1,3-dione A mixture of tert-butyl ester of (S) -3- [1-] acid was stirred. (1,3-dioxo-1,3-dihydro-indol-2-yl) isoquinolyl-6- iloxy] piperidin-1-carboxylic acid (340 mg) in dichloromethane (14 ml) and trifluoroacetic acid (2.8 ml) at room temperature for 1 hour. The mixture was concentrated in vacuo followed by flash chromatography of the residue on silica (eluent: 2-10% methanol in dichloromethane) to yield (S) -2- (6-piperidin-3-yloxy) -soquinolin-1-yl. ] Isoindol-1,3-dione (310 mg), EIMS: m / z = 374.3 [M + H] \ C: (S) -2-y6- (1-Benzylpiperdin-3-yloxy) isoquinolin-1 -Issisoindole-1, 3-dione It was added to a solution of (S) -2- (6-piperidin-3-yloxy) isoquinolin-1 -i Ijisoi ndo I-1, 3-dione (30mg, 62 μmol) in DMF (3 ml) potassium carbonate (10 mg, 74 μmol) and benzyl bromide (9 μL, 74 μmol). The mixture was stirred for 4 hours at room temperature, and then the solvent was removed in vacuo and water was added. The mixture was extracted with dichloromethane, dried (magnesium sulfate) and concentrated in vacuo to yield a residue. Flash chromatography of the residue on silica (eluent: 0-100% ethyl acetate in heptane) to yield (S) -2- [6- (1-benzylpiperidin-3-yloxy) isoquinolyl-1-yl] isoindole -1, 3-dione, EI-MS: m / z = 464.3 [M + H] +. D: (S) -6- (1-Benzylpiperidin-3-yloxy) isoquinolin-1-yl-amine was added to a solution of (S) -2- [6- (1-benzylpiperidin-3-yloxy) isoquinoline- 1 -yl] -isoindole-1,3-dione above (20 mg, 43 μmol) in ethanol (2 ml) hydrazine monohydrate (-3 μL, 65 μmol). The mixture was heated at a temperature of 50 ° C for 2 hours and then concentrated in vacuo to yield a residue. The residue was purified by prep-HPLC to yield (S) -6- (1-benzylpiperidine-3-yloxy) isoquinolin-1-yl-amine EI-MS: m / z = 334.3 [M + H] +. E_: Alternate Procedure A couple of drops of glacial acetic acid was added to a solution of 6- (piperidin-3-yloxy) -isoquinolin-1-racemic lamella (52 mg, 0.214 mmol) and benzaldehyde (26 mL, 0.256 mmol) ) in acetonitrile (2 ml). The mixture was stirred for 20 minutes and then sodium triacetoxyborohydride (68 mg, 0.321 mmol) was added in portions. The mixture was stirred at room temperature for 20 hours and then concentrated in vacuo. The mixture was separated in saturated aqueous sodium hydrogencarbonate dichloromethane. The organic layer was separated and then concentrated in vacuo to yield a residue. The residue was purified by prep-HPLC to yield 6- (1-benzylpyperidin-3-yloxy) isoquinolin-1-yl amine (73 mg) EI-MS: m / z = 334.3 [M + H] +. The following compounds were prepared by the procedure described in 7_E using the appropriate aldehyde and a 6- (piperidin-3-yloxy) isoquinolin-1-lamel or 6- (pyrrolidin-3-yloxy) isoquinolin-1-yl-amine racemic or enantiopura: 7F: 6-M- (1H-Pyrrol-2-ylmethyl) piperidin-3-loxi-1-isoquinolin-1 -lamina Via 1H-Pyrrole-2-carbaldehyde: EI-MS: m / z = 323.5 [M + H] +. 7G: 6- (1-thiophen-2-ylmethylpiperidin-3-yloxy) isoquinolin-1-ylamine Via Thiophene-2-carbaldehyde: EI-MS: m / z = 340.1 [M + H] +. 7H: (S) -6-f1- (4-Fluorobenzyl) piperdin-3-yloxy-isoquinolin-1 -amine Via 4-Fluorobenzaldehyde: EI-MS: m / z = 352.5 [M + H] +. 71: (S) -6- [1-Fenethylpiperidin-3-yloxy-1-isoquinol-1 -lamina Via Phenylacetaldehyde: EI-MS: m / z = 348.3 [M + H] \ 7J: (S) -6- [1-Furan-3-ylmethylpiperidin-3-yloxy] isoquinolin-1-ylamine Via Furan-3-carbaldehyde : EI-MS: m / z = 324.5 [M + H] +. 7K: (S) -6-ri- (1H-Pyrrol-2-ylmethyl) piperidin-3-yloxylisoquinolin-1 -lamin Via 1H-Pyrrole-2-carbaldehyde: EI-MS: m / z = 323.5 [M + H] +. 7L: (S) -6-p- (1H-Pyrrol-3-ylmethyl) piperidin-3-yloxylisoquinoline-l-lamine Via 1H-Pyrrole-3-carbaldehyde: EI-MS: m / z = 323.5 [M + H] +. 7M: (S) -6-f1- (3-Methylbenzyl) pyrrolidin-3-yloxy-isoquinolin-1-ylamine Via 3-Methylbenzaldehyde: EI-MS: m / z = 334.5 [M + H] +. 7N: (S) -6- [1- (3-Fluorobenzyl)) pyrrolidin-3-yloxy-isoquinolin-1-lamine Via 3-Fluorobenzaldehyde: EI-MS: m / z = 338.4 [M + H] +. 7O: (S) -6-M- (4-methanesulfonylbenzyl) pyrrolidin-3- iloxylisoquinolin-1 - Via 4-methanesulfonylbenzaldehyde lamine: EI-MS: m / z = 398.4 [M + H] + . 7P: (S) -6- (1-Benzylpyrrolidin-3-yloxy) isoquinolin-1 -lamin Via 1-Benzaldehyde: EI-MS: m / z = 320.1 [M + H] +. 7Q: (S) -6- [1- (3-Methoxybenzyl) pyrrolidin-3-yloxy-isoquinolin-1 -amine 3-Methoxybenzaldehyde: EI-MS: m / z = 350.5 [M + H] +. 7JR: (S) -6-i1- (1 H-Pyrrol-3-ylmethyl) pi rro I idin-3-yloxylisoquinolin-1 -lamin Via 1H-Pyrrole-3-carbaldehyde: EI-MS: m / z = 309.4 [M + H] +. 7S: 6- (1-Furan-2-methyl-piperidin-3-yloxy) isoquinolin-1-ylamine Via furan-2-carbaldehyde: EI-MS: m / z = 324.1 [M + H] +. 7T: 6-i1- (Tetrahydropyran-4-ylmethyl) piperidin-3-yloxylisoquinolin-1 -lamin Via tetrahydro-pyran-4-carbaldehyde: EI-MS: m / z = 341.9 [M + H] +. 7U: 6- [1- (4-tert-Butylbenzyl) -piperidin-3-yloxylisoquinolin-1-ylamine Via 4-tert-Butylbenzaldehyde: EI-MS: m / z = 390.4 [M + H] \ 7V: ( R) -6- (1-Benzylpiperin-3-yloxy) isoquinolin-1 -lamin Via 1-Benzaldehyde: EI-MS: m / z = 334.3 [M + H] +. Example 8 The following compounds were prepared by procedure described in 7_C and 7_D using the benzylbromide suitably substituted 8A: (S) -6-M- (3,4-D? clo steal c?) pipepd? n -3? lox? l? soqu? nol ? n-1-? lam? na Via 3,4-D? chlorobenz? lbromide EI-MS m / z = 402 3 [M + H] + 8B: (S) -6- [1- (4-Met? lbenc? l) p? per? d? n? 3-? lox?]? soqu? nol? n-1-ylamine Via 4-Met? lbenc? lbromide EI-MS m / z = 348 5 [M + H] + Example 9 6-f1- (3-Fen? Lprop? L) p? Pepd? N -3? Lox? L? Soqu? Nol? N-1-? Lam? Na This compound was prepared by the procedure described in 7C_ and 7_p_ using 3-phenolprop Lbromide EI-MS m / z = 362 5 [M + H] + Example 10 10A 6- (1-Met? Lp? Per? N-4-? Lox?)? Soqu ? nol? n-1-? lam? na Three drops of glacial acetic acid were added to a solution of 6- (p? per? d? n-4-? lox?) -? soqu? nol? n-1 - Ilamine (35 mg, 0 14 mmol) in N, N-dimethylformamide (1 mL), followed by the addition of formaldehyde (37% aqueous solution, 200 mL). Tath-ta-butoxide sodium hydride (150 mg) was added to the mixture, which was stirred for 72 hours. Hydrogen carbonate was added. aqueous saturated and subsequently the mixture acidified with acetic acid. The mixture was loaded on a pre-acidified SCX column, washed with methanol and subsequently eluted with 2M ammonia in methanol. the crude product and in addition it was purified using prep-HPLC to produce 6- (1-methylpiperidin-4-yloxy) -isoquinolin-1 -lamina (19 mg), EIMS: m / z = 258.5 [M + H] +. 1 OB: 6- (1-Ethylpiperidin-4-yloxy) isoquinolin-1-ylamine 6- (1-Ethylpiperidin-4-yloxy) isoquinolyl-1-lamine was prepared in the above manner using acetaldehyde, EIMS: m / z = 272.6 [M + H] + Example 11 6- (1-Benzylpiperidin-4-yloxy) isoquinolin-1 -lamin A drop of glacial acetic acid was added to a solution of 6- (piperidin-4-yloxy) -isoquinolin-1. -lamin (20 mg, 0.082 mmol) in N, N-methylformamide (0.5 ml), followed by the addition of benzaldehyde (20 ml). The mixture was then treated with sodium triacetoxyborohydride (50 mg) and stirred for 2 hours. Water (0.5 ml) was added, the mixture was stirred overnight and then purified by prep-HPLC to yield 6- (1-benzyl-p-peridin-4-yloxy) -isoquinol-1. -lamin (28 mg), EI-MS: m / z = 334.3 [M + H] +. Example 12 6- (Piperidin-3-ylsulfanyl) isoquinol-1-ylamine A: N- (6-Hydroxyisoquinolin-1-M) -benzamide Benzoic anhydride (10.27 g) was added to a solution from 1 - . 1-aminoquinquinoline-6-ol (3.312 g) in pyridine (53 ml) at room temperature. The mixture was heated at a temperature of 125 ° C for 1 hour, the pyridine was removed under pressure reduced and excess pyridine by azeotroping with toluene (X2). Water was added and the mixture was extracted with dichloromethane (X3), dried (sodium sulfate) and concentrated in vacuo to yield a solid precipitate. Recrystallization with dichloromethane-diethyl ester to yield benzoic acid ester 1-benzylaminoisoquinolin-6-yl (6 g), EIMS: m / z = 369.1 [M + H] +. A solution of NaOH (981 mg) in H2O water (65 ml) was added to a solution of benzoic acid ester 1-benzylaminoisoquinolin-6-yl (6 g) in methanol (65 ml) and tetrahydrofuran (65 ml). The mixture was stirred for 1.5 hours at room temperature and then the organics were removed in vacuo. The mixture was diluted with water and then extracted with ethyl acetate (x1). Subsequently, the aqueous phase was acidified with dilute hydrochloric acid (pH-3.5). The addition of ethyl acetate resulted in a solid precipitate which was filtered and washed with cold MeOH and then heptane to yield N- (6-hydroxyisoquinolyl-1-yl) -benzamide (3.6 g), EIMS: m / z = 265.1 [M + H] +. B_j_ N- (6-Mercaptoisoquinolin-1-yl) -benzamide It was added to a solution of N- (6-hydroxyisoquinolin-1-yl) -benzamide (100 mg, 0.379 mmol), triethylamine (105 mL, 0.758 mmol ) and pyridine (306 mL, 3.79 mmol) in anhydrous tetrahydrofuran (2 mL), N, N-dimethylthiocarbamoyl chloride (70 mg, 0.568 mmol) at a temperature of 0 ° C, under nitrogen. The mixture at a temperature of 65 ° C and stirred for 48 hours. Organics were removed under reduced pressure and excess pyridine was removed by azeotropin with toluene (x2). Saturated aqueous NaHCO3 was added and the mixture was extracted with dichloromethane (x2), it was extracted (magnesium sulfate) and concentrated in vacuo to yield a residue. Flash chromatography of the residue (eluent: 5-50% ethyl acetate in heptane) to yield dimethylthiocarbamic acid ester O- (1-benzoylaminoisoquinolin-6-yl) (70 mg), EIMS: m / z = 352.7 [M + H] +. A solution of dimethylthiocarbamic acid ester O- (1-benzoylaminoisoquinolin-6-yl) (70 mg) in o-dichlorobenzene (3 ml) was irradiated in a microwave at a temperature of 230 ° C for 30 minutes. Flash chromatography of the mixture (eluent: 5-50% ethyl acetate in heptane) to yield dimethylthiocarbamic acid ester S- (1-benzoylaminoisoquinolin-6-yl) (70 mg), EIMS: m / z = 352.7 [ M + H] +. A solution of NaOH (92 mg) in H2O water (1 ml) was added to a solution of dimethylthiocarbamic acid ester S- (1-benzoylaminoisoquinolin-6-yl) (70 mg) in MeOH (1 ml) and THF (1 mg). ml). The mixture was stirred for 1 hour at room temperature and then for an additional 1 hour at a temperature of 56 ° C. The organics were removed in vacuo and then the mixture was diluted with water and acidified with dilute hydrochloric acid (pH-3.5).

The mixture was extracted with ethyl acetate (X3), dried (sodium sulfate) and concentrated in vacuo to yield a residue. Flash chromatography of the residue (eluent: 1-5% ethyl acetate in heptane) to yield N- (6-mercaptoisoquinolin-1-yl) -benzamide in the form of a yellow residue (30 mg). C: 6- (Piperidin-3-ylsulfanyl) isoquinolin-1-ylamine. Potassium carbonate (44 mg, 0.32 mmol) and 3-methanesulfonyloxypiperidin-1-carboxylic acid tert-butyl ester (70 mg, 0.264 mmol) were added. a solution of the above N- (6-mercaptoisoquinolin-1-yl) -benzamide residue in DMF (2 ml). The mixture was irradiated in a microwave at a temperature of 160 ° C for 600 seconds and then concentrated in vacuo to yield the residue. The residue was purified by a preparative HPLC to produce 3- (1-benzoylaminoisoquinolin-6-l-sulfanyl) p -peridine-1-carboxylic acid tert -butyl ester (18 mg), EIMS: m / z = 464.3 [M + H] + and m / z = 486.5 [M + Na] +. Glacial acetic acid (2 ml) and 6M hydrochloric acid (4.25 ml) were added to the 3- (1-benzoylaminoisoquinolin-6-ylsulfanyl) piperidine-1-carboxylic acid tert-butyl ester (18 mg, 0.039 mmol) and the mixture was subjected to at reflux for 24 hours. The mixture was concentrated in vacuo to yield a residue. The residue was loaded onto a pre-acidified SCX column using methanol and subsequently eluted with 2M ammonia in methanol to yield 6- (piperidin-3-ylsulfanyl) isoquinolin-1-said ester which was purified also using prep-HPLC, EIMS: m / z = 260.3 [M + H] +. Example 13 13A: (S) -6- (Pyrrolidin-3-ylsulfanyl) isoquinolin-1-ylamine This compound was prepared by the procedure described in 12C using (R) -3-methanesulfonyloxy-pyrrolidine-1-tert-butyl ester. -carboxylic to produce (S) -6- (pyrrolidin-3-ylsulfanyl) isoquinolin-1-ylamine, EI: MS: m / z = 246.4 [M + H] +. 13B: (R) -6- (Pyrrolidin-3-ylsulfanyl) isoquinolin-1-ylamine This compound was prepared by the procedure described in 12C using (S) -3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester. to produce (R) -6- (pyrrolidin-3-ylsulfanyl) isoquinolin-1-ylamine, EI-MS: m / z = 246.4 [M + H] +. 13C: 6- (Piperidin-4-ylsulfanyl) isoquinolin-1-ylamine This compound was prepared by the procedure described in 12C using 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester to produce 6- (piperidin-4-ylsulfanil ) isoquinolin-1-alamine, EI-MS: m / z = 260.3 [M + H] +. EXAMPLE 14 6- (Piperidin-3-ylamino) isoquinolin-1-lamin For a degassed solution of 1-amino-6-bromoisoquinoline (554 mg), prepared as described in WO 98/47876 (Akzo Nobel NV), ester was added 3-aminopiperidine-1-carboxylic acid tert-butyl ester (823mg), 2- (di-tert-butylphosphino) biphenyl and sodium tert -butoxide (367 mg) in dioxane (10 ml) under argon, tris (dibenzylidene) -acetone) dipal-ladium (O). The mixture was further degassed with argon then heated to a temperature of 120 ° C for 90 minutes. The mixture was cooled to room temperature and subsequently diluted with methanol. The crude mixture was loaded onto a pre-acidified SCX column and the basic product eluted with 2M ammonia in methanol to yield a crude residue (700 mg). The residue was purified by preparative HPLC to give 3- (1-aminoisoquinolin-6-ylamino) piperidin-1-carboxylic acid tert-butyl ester. A mixture of 3- (1-aminoisoquinolin-6-ylamino) -piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) was stirred at room temperature for 3 hours. The mixture was concentrated and then purified by preparative HPLC followed by loading on a pre-acidified SCX column and a free base eluted with 2M ammonia in methanol to yield 6- (piperidin-3-ylamino) -isoquinolin-1-ylamine, EI: MS: m / z = 243.7 [M + H] +. Example 15 7-Methyl-6- (piperidin-3-yloxy) -isoquinolin-1 -lamin A: 1-amino-7-methyl-isoquinolin-6-ol hydrobromide A mixture of 3-methoxy was refluxed. -4-methylbenzaldehyde (19.3 g, 0.129 mol), triphenylphosphorane methylene of carbomethoxy (51 g) in toluene (250 ml) for 24 hours. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate and concentrated in vacuo to yield a residue. The residue was purified by flash chromatography using ethyl acetate-heptane (1: 1) to give methyl 3- (3-methoxy-4-methyl-phenyl) acrylic acid ester (27 g, 0.126 mol). A mixture of 3- (3-methoxy-4-methylphenyl) acrylic acid methyl ester (27 g), sodium hydride (14 g), water (70 ml), methanol (140 ml) and tetrahydrofuran (Ref. 70 ml) at a temperature of 50 ° C for 1 hour. The mixture was concentrated in vacuo and then water was added. The mixture was filtered and 5 M HCl was added until precipitation occurred. The mixture was filtered and the solid precipitate was washed with water and dried in vacuo to yield 3- (3-methoxy-4-methylphenyl) acrylic acid (23.5g, 0.122 mol). Toluene (750 ml) and thionyl chloride (11 ml) were subsequently added to a 3- (3-methoxy-4-methylphenyl) acrylic acid (20 g, 0.104 mol) at room temperature. The suspension was refluxed for 2 hours and then stirred vigorously to produce a clear yellow solution. The reaction of the mixture was concentrated in vacuo, and then toluene was added and the mixture was re-concentrated in vacuo to yield 3- (3-methoxy-4-methylphenyl) acryloyl chloride for use in the next step. 3- (3-Methoxy-4-methylphenyl) acryloyl chloride was dissolved in acetone (800 ml). Slowly added resulting solution (15 min) at a temperature of 0 ° C to a mixture of sodium azide (13 g) in water (100 ml) and acetone (100 ml) after vigorous stirring and cooling in an ice bath . After the addition was complete, the reaction mixture was stirred at a temperature of 0 ° C for 90 minutes after vigorous stirring. The reaction mixture was then emptied in an ice water (300 ml). The mixture was filtered for 15 minutes after stirring and the solid residue was washed with excess water. The remaining solid residue was dissolved in dichloromethane (45 ml). The liberated water was removed with a separating funnel. The dichloromethane layer was dried with Na2SO and the filtrate to produce a dichloromethane solution of 3- (3-methoxy-4-methyl-phenyl) acryloyl azide for immediate use in the next step. The dichloromethane azide solution was added in portions (Carefully!) Using a dropping funnel for the preheating of diphenyl ether (50 ml) at a temperature of 50 ° C, after gentle stirring, in a three-round bottom flask. -collars, equipped with a Dean-Severe hatch. During the addition of nitrogen gas the evolution takes place under the formation of the isocyanate. The added dichloromethane was evaporated and collected with the Dean-Severa hatch. After the addition was complete (~ 30 min) and the evolution was observed without gas, the mixture was heated to reflux (-250 ° C) after stirring (evaporated in no. more than ~ 200 ° C dichloromethane and the Dean-Severa hatch was removed quickly). The reaction mixture was maintained at a temperature of ~ 250 ° C for 1 hour then it was cooled to a temperature of 125 ° C and poured into a mixture of acetone and heptane (1:10). A precipitated solid was filtered and dried in vacuo to yield 6-methoxy-7-methyl-2H-isoquinolin-1 -one (12 g, 63.49 mmol). A suspension of 6-methoxy-7-methyl-2H-isoquinolin-1 -one (5 g, 26.45 mmol) was treated at room temperature with phosphorus oxychloride (22 ml). The mixture was heated at a temperature of 100 ° C for 1 hour with stirring then concentrated in vacuo to yield a residue. Toluene was added to the residue which was further concentrated in vacuo to produce a residue which forms a toluene and is slowly added to a saturated aqueous sodium carbonate. Subsequently, the toluene layer was separated. The aqueous layer was further mixed and extracted with toluene. The combined toluene layers were dried (MgSO4) and concentrated in vacuo to yield a residue. The residue was triturated with diethyl ether and subsequently dried and filtered in vacuo to yield 1-chloro-6-methoxy-7-methyl-isoquinoline (4 g, 19.32 mmol). A mixture of 1-chloro-6-methoxy-7-methyl-isoquinoline (9 g, 43.48 mol), phenol (16.3 g), potassium hydroxide (9.45 g) and xylene (100 ml) was refluxed for 4 days . The reaction mixture was poured into an aqueous sodium hydroxide (4 M) and the xylene layer was separated. The aqueous layer was extracted twice with toluene. The combined organic layers were dried (Na2SO4) and concentrated vacuo to yield a residue. The residue was purified by flash chromatography using dichloromethane to produce 6-methoxy-7-methyl-1-phenoxy-isoquinolma ( 9 g, 33 96 mmol) A mixture of crude 6-methoxy-7-methyl-1-phenoxoisoquinoline (9 g, 33 96 mmol) and ammonium acetate (26 g) was melted with stirring at a temperature of 170 ° C for 5 hours The mixture was partitioned between aqueous sodium hydroxide (2M) and ethyl acetate. The phases were separated and the organic phase was extracted with dilute aqueous hydrochloric acid. The acidic aqueous phase was neutralized to a pH of 12 using hydroxydehydroxide. Sodium (2M) was extracted with ethyl acetate, dried (MgSO) and then dried m vacuo to yield 6-methoxy-7-methoxy-so-quinol-1-alamine (511 g, 27 18 mmol) A mixture of 6-methoxy? -7-met? L-? Soqu? Nol? N-1-amine (511 g, 27.18 mmol) and 48% aqueous hydrobromic acid (150 ml) was heated. to a temperature of 125 ° C for 2 days. The mixture was concentrated in vacuo and triturated with diethyl ether, dried in vacuo to yield 1 -am? no-7-methyl? -soquinol-6-ol bromhydride (5 g), EIMS m / z = 175 1 [M + H] + B: 7-Met? L-6- (p? Pepd? N-3-? Lox?) -? Soqu? Nol? N-1 -? lam? na It was added to a solution of 3-hydroxypyridin-1-carboxylic acid tert-butyl ester (231 mg, 1 15 mmol), tphenylphosphine (301 mg, 1 15 mmol) , 1 -am? No-7-met? L? Soqu? Nol? N-6-ol (200 mg, 1 15 mmol) in DMF (5 ml) at a temperature of 0 ° C, under argon, in the form of drops diethylazodicarboxylate (181 μL, 1.15 mmol). The mixture was warmed to room temperature and stirred for 24 hours. Methanol was added and the mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to produce 3- (1-amino-7-methylisoquinolin-6-yloxy) piperidine-1-carboxylic acid tert-butyl ester. A mixture of (3- (1-amino-7-methylisoquinolin-6-yloxy) piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml), and trifluoroacetic acid (3 ml) was stirred at room temperature The mixture was concentrated in vacuo to yield a residue The residue was loaded onto a pre-acidified SCX column, washed with methanol and subsequently eluted with 2M ammonia in methanol The crude product was isolated and further purified using prep. -HPLC to produce 7-methyl-6- (piperidin-3-yloxy) isoquinolin-1-ylamine, EIMS: m / z = 258.3 [M + H] + Example 16 7-Methyl-6- (piperidin-4-) ilox!) isoquinolin-1-ylamine A suspension of 1-amino-7-methylisoquinolin-6-ol (430 mg, 2.4 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g) and K2CO3 (510 mg, 3.7 mmol) in anhydrous N, N-dimethylformamide (8 ml) in a microwave at a temperature of 100 ° C for 10 minutes. added an additional equivalent of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester in N, N-dimethylformamide (4 ml) and the microwave mixture at a temperature of 100 ° C for an additional 10 minutes. The mixture was diluted with water, acidified with acetic acid and further diluted with methanol. The mixture was loaded on a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using flash chromatography on silica (eluent: 9: 1: 0.1 dichloromethane methanol ammonium hydroxide) to produce 4- (1-amino-7-methylisoquinolin-6-yloxy) -butyl ester. ) piperidine-1-carboxylic acid (327 mg). A mixture of 4- (1-amino-7-methylisoquinolin-6-yloxy) -piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stirred at room temperature night. The mixture was concentrated in vacuo to yield a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol to yield 7-methyl-6- (piperidin-4-yloxy) isoquinolin-1-ylamine (270 mg), EI: MS: m / z = 258.4 [M + H] +. Example 17 The following compounds were prepared by the procedure as described in Example 16 using (R) - or (S) -3-methanesulphoryloxypyrrolidine-1-carboxylic acid tert-butyl ester: 17A: (R) -7-Methyl-6- (pyrrolidin-3-yloxy) isoquinolin-1-ylamine EI-MS: m / z = 244.1 [M + H] +. 17B: (S) -7-Methyl-6- (pyrrolidin-3-yloxy) -soquinolin-1-ylamine EI-MS: m / z = 244.3 [M + H] +. Example 18 18A: 6- (1-Benzylpiperidin-4-yloxy) -7-methylisoquinolin-1-ylamine A pair of drops of glacial acetic acid was added to a solution of 7-methyl-6- (piperidin-4) -loxy) isoquinolin-1-ylamine (30 mg, 0.117 mmol) in N, N-dimethylformamide (1 ml), followed by the addition of benzaldehyde (50 μL). The mixture was then treated with sodium triacetoxyborohydride (100 mg) and stirred for 2 hours. Water (1 ml) was added, the mixture was stirred for 30 minutes and then purified by prep-HPLC to yield 6- (1-benzyl-piperidin-4-yloxy) -7-methylisoquinolin-1-ylamine (24 mg). , EI: MS: m / z = 348.3 [M + H] +. The compounds were then prepared by the procedure as described above using the appropriate aldehyde: 18B: 7-Methyl-6- (1-methyl-piperidin-4-yloxy) -soquinolin-1-ylamine Via formaldehyde: EI-MS : m / z = 272.3 [M + H] +. 18C: 6-M- (4-Chlorobenzyl) p.peridin-4-yloxy-1-7-methylisoquinolin-1-ylamine Via Chlorobenzaldehyde: EI-MS: m / z = 381.9 [M + H] +. 18D: 7-Methyl-6-M- (4-methylbenzyl) piperidin-4-yloxylisoquinolin-1-ylamine Via 4-methylbenzaldehyde: EI-MS: m / z = 362.3 [M + H] +. Example 19 The following compounds were prepared by the procedure as described in Example 18 using 7-methyl-6- (piperidin-3-yloxy) isoquinolin-1 -lamin and the appropriate aldehyde: 19A: 6- (1- Benzylpiperidin-3-yloxy) -7-methylisoquinolin-1-ylamine Via 1-benzaldehyde: EI-MS: m / z = 348.0 [M + H] +. 19B: 7-Methyl-6-f1- (4-methylbenzyl) piperidin-3-yloxMisoquinolin-1-ylamine Via 4-methylbenzaldehyde EI-MS: m / z = 362.3 [M + H] +. Example 20 The following compounds were prepared by the procedure as described in Example 18 using (R) - or (S) -7-Methyl-6- (pyrrolidin-3-yloxy) isoquinolin-1-ylamine and benzaldehyde 20A: (R) -6- (1-Benzylpyrrolidin-3-yloxy) -7-methylisoquinolin-1-ylamine EI-MS: m / z = 334.0 [M + H] +. 20B: (S) -6- (1-Benzylpyrrolidin-3-yloxy) -7-methylisoquinolin-1-ylamine EI: MS: m / z = 334.3 [M + H] +.

EXAMPLE 21 6- [1- (2-Phenoxyethyl) piperidin-3-yloxy-isoquinolin-1-ylamine It was added to a solution of 6- (piperidin-3-yloxy) isoquinol i n-1-ylamine (30 mg, 123 mg). μmol) in DMF (1 ml) potassium carbonate (18 mg, 129 μmol) followed by a solution of (2-bromoethoxy) benzene (26 mg, 129 μmol) in acetonitrile (0.5 ml). The mixture was stirred for 16 hours at room temperature, then the solvent was removed in vacuo and aqueous sodium hydrogen carbonate was added. The mixture was extracted with chloroform / iso-propanol (3: 1), dried (magnesium sulfate) and concentrated in vacuo to yield a residue. The residue was purified by prep-HPLC to yield 6- [1- (2-phenoxyethyl) piperidin-3-yloxy] -isoquinolin-1-ylamine (12.5 mg) EI: MS: m / z = 364.8 [M + H] +. The compounds were then prepared by the procedure as described above using the bromide or chloride and 6- (piperdin-3-yloxy) isoquinolin-1-enylamide or racemic allyl or 6- (pyrrolidin-3-yloxy) isoquinolin-1-amine: 21A: (S) -6-M- (2-Phenoxyethyl) piperidin-3-yloxy-isoquinolyl-1-amine was prepared from the above procedure using (S) -6- ( Piperidin-3-yloxy) soquinolin-1-ylamine. EI-MS: m / z = 364.6 [M + H] +. 21 B: 3-f3- (1-Aminoisoquinolin-6-yloxy) piperidin-1-inpropan-1 -ol Via 3-bromo-propan-1-ol: EI-MS: m / z = 302.5 [M + H] +. 21 C: 6-f1- (2-Methoxyethyl) piperidin-3-yloxy-isoquinolyl-1-ylamine Via 1-bromo-2-methoxyethane: EI-MS: m / z = 302.5 [M + H] +. 21 D: f 3 - (1-Aminoisoquinolin-6-yloxy) piperidin-1-ylacetic acid methyl ester Via bromoacetic acid methyl ester: EI-MS: m / z = 316.3 [M + H] +. 21 E: 2- [3- (1-Aminoisoquinolin-6-yloxy) piperidin-1-ipetanol Via 2-bromoethanol: EI-MS: m / z = 288.1 [M + H] +. 21 F: 6- (1-Tazozol-4-methylmethylpiperidin-3-yloxy) isoquinolin-1-ylamine Via 4-chloromethylthiazole: EI-MS: m / z = 341.1 [M + H] +. 21G: (S) -6-ri- (1-Phenylethyl) piperidin-3-yloxy-isoquinolin-1-ylamine Via (l-bromoethyl) benzene: EI-MS: m / z = 348.1 [M + H] '21 H: (S) -2-r3- (1-Aminoisoquinolin-6-yloxy) pyrrolidin-1-ylelethanol Via 2-bromoethanol: EI-MS: m / z = 274.5 [M + H] +. Example 22 6- (Pperidin-3-yloxy) -2H-isoquinolin-1-one 22A: 3- (1-chloroisoquinolin-6-yloxy) piperidine-1-carboxylic acid butyl ester. 1-Chloro-6-methoxyisoquinoline was prepared as described in WO 00/24718 (Akso Nobel N.V.). It was prepared alternately from 3-methoxybenzaldehyde using the same procedure as in Example 15A (for the synthesis of 1-chloro-6-methoxy-7-methyl-isoquinoline). The 1-chloro-6-methoxyisoquinoline is demethylated according to the procedure described in WO 00/24718 to produce 1-chloro-6-hydroxyisoquinoline. A suspension of 1-chloro-6-hydroxysoquinoline (0.18 g, 1 mmol), 3-methanesulfonyloxy-piperidin-1-carboxylic acid tert-butyl ester (336 mg, 1.2 mmol) and 2-tert-butyl-2-diethylamino was heated. -1, 3-dimethyl-perhydro-1, 3,2-diazaphosphorine in polystyrene (loading 500 mg, ~ 2.2mmol / g) in acetonitrile (4 ml) at a temperature of 120 ° C over a period of 900 seconds using a microwave. The excess of supported reagent was removed by filtration, washing with methanol, and the filtrate evaporated to dry under reduced pressure. The design reaction was not completed, the previous procedure was repeated. Purification of the crude material has been achieved by chromatography on silica (eluent: 0-25% ethyl acetate in heptane) to produce 3- (1-chloroisoquinolin-6-yloxy) piperidin-1-carboxylic acid tert-butyl ester. (106 mg), El-MS: m / z = 363.7 [M + H] +. 22B: 6- (Piperidin-3-yloxy) -2H-isoquinolin-1-one Aqueous hydrochloric acid (5M, 2ml) was added to a flask containing 3- (1-chloro-isoquinoline-6-butyl) acid. iloxy) piperidine-1-carboxylic acid (20 mg, 0.055 mmol) and the resulting solution was stirred at room temperature for 5 hours. The mixture was refluxed for 2 days, then cooled to room temperature and directly loaded onto an ion exchange column (SCX, 500 mg) followed by standard procedures to elute the desired product such as a free base. The product was further purified by prep-HPLC to yield 6- (piperidin-3-yloxy) -2H-isoquinolin-1 -one (15.5 mg), EI-MS: m / z = 245.6 [M + H] +. Example 23 6- (1-Benzyl-piperidin-3-yloxy) -2H-isoquinolin-1-one 23A: 1-Chloro-6- (piperidin-3-yloxy) -soquinoline Trifluoroacetic acid (1ml) was added and dichloromethane (5 ml) was added to 3- (1-chloro-isoquinolin-6-yloxy) piperidine-1-carboxylic acid tert-butyl ester (370 mg) and the mixture was stirred at room temperature for 48 hours. The mixture was concentrated in vacuo and subsequently loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to yield 1-chloro-6- (piperidin-3-yloxy) isoquinoline (180 mg). 23JB: 6- (1-Benzyl-piperidin-3-yloxy) -2H-isoquinolin-1-one Sodium triacetoxyborohydride (100 mg, 3.9 mol eq) to a solution of 1-chloro-6- (piperidin-3-yloxy) isoquinoline (40 mg), acetic acid (1 drop) and benzaldehyde (40 μl) in N, N-dimethylformamide (0.5 ml) and stirred for 17 hours. The reactions were quenched with water (0.5 ml) and stirred for 1 hour then loaded onto a SCX pre-acidified column using methanol and eluted with 2M ammonia in methanol. The product was concentrated in vacuo to yield a residue which was treated with 5M aqueous hydrochloric acid and heated in the microwave at a temperature of 180 ° C for 60 minutes. The mixture was concentrated in vacuo to yield a residue which was purified by prep-HPLC to yield 6- (1-benzylpiperidin-3-yloxy) -2H-isoquinolin-1 -one, EI-MS: m / z = [M + H] +. The following compounds were prepared by the procedure as described above using the appropriate aldehydes. 23C: 6-M- (4-Fluorobenzyl) piperidin-3-yloxy] -2H-isoquinolin-1-one Via 4-Fluorobenzaldehyde: EI-MS: m / z = 353.5 [M + H] +. 23D: 6- [1- (4-Methoxybenzyl) piperidin-3-yloxy-2H-isoquinolin-1-one Via 4-methoxybenzaldehyde: EI-MS: m / z = 365.3 [M + H] +. Example 24 (S) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-one 24A: 6-Hydroxy-2H-isoquinolin-1-one 1-Chloroisoquinolin-6-ol (5g, 27.84 mmol ) with hydrochloric acid (5M, 40 ml), and heated to a temperature of 180 ° C for 40 minutes under microwave conditions. The mixture was allowed to cool and subsequently filtered. The brown solid was washed with diethyl ester and dried in vacuo at a temperature of 50 ° C to produce 6-hydroxy-2H-isoquinolin-1-one, 4.45g (98%), EI-MS: m / z = 162.4 [M + H] \ 24JB: (R) -3-Methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester It was added to a solution of (R) -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester ( 6.51g, 32.3mmol) and triethylamine (6.8ml, 1.5 mol eq) in dichloromethane (70 ml) at a temperature of 0 ° C a solution of methanesulfonyl chloride (3.73 ml, 1.5 mol) in dichloromethane (30 ml) for 30 minutes. minutes The reaction was stirred at a temperature of 0 ° C for 2 hours. Saturated sodium hydrogen carbonate (100 ml) was added slowly. The organic phase was separated, washed with brine and dried under magnesium sulfate. Evaporation occurred under reduced pressure of (R) -3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester, 9.03 g (100%). NMR (CDCI3 7.27d) m 4.73d (1H), m 3.63d (2H), m 3.44d (1H), m 3.32d (1H), s 3.05d (3H), m 1.95d (2H), m 1.83 d (1H), m 1.54d (1H), s 1.46d (9H). 24C: (S) -3- (Oxo-1, 2-dydrohydrazino-6-yloxy) piperidine-1-carboxylic acid tert-butyl ester 6-Hydroxy-2H-isoquinolin-1 -one was mixed (2g, 12.41 mmol) and potassium carbonate (3.43g, 2 mol) with N, N- dimethylformamide (40ml) at a temperature of 100 ° C. A solution of (R) -3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (5.2 g, 1.5 mol) in dimethylformamide (50 ml) was added dropwise over 15 minutes. The mixture was stirred at a temperature of 100 ° C for 3.5 hours and allowed to cool. The crude material was separated between ethyl acetate and water. The ethyl acetate layer was separated and washed with sodium hydroxide (2M) and the brine was dried over magnesium sulfate. The residue was purified by flash chromatography on silica (eluent: Heptane / Ethyl acetate 0-100% followed by 2% 2M ammonia in methanol / ethyl acetate) to produce (S) -3- butyl ether. (Oxo-1, 2-dihydroisoquinolin-6-yloxy) -piperidine-1-carboxylic acid (1.25 g, 29%), EI-MS: m / z = 345.3 [M + H] +. 24D: (S) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-one Tert-butyl ester of (S) -3- (Oxo-1,2-dihydroisoquinolin-6-yloxy) acid was mixed piperidine-1-carboxylic acid (1.25 g, 3. 6mmol) with dichloromethane (30ml) and trifluoroacetic acid (10ml) at room temperature for 15 minutes. It was removed in a volatile manner under reduced pressure and the excess of trifluoroacetic acid was azeotroped with toluene. The residue was dissolved in methanol and purified using an SCX cartridge. The concentration (S) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-one was produced (450mg, 51%), EI-MS: m / z = 245.4 [M + H] +. The following compounds were prepared by procedure described above using the mesylate synthesized suitably. 24E: (R) -6- (Piperidin-3-yloxy) -2H-isoquinolin-1-one Via (S) -3-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester: EI-MS: m / z = 245.3 [M + H] +. 24F: 6- (Piperidin-4-yloxy) -2H-isoquinolin-1-one Via 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester: EI-MS: m / z = 245.3 [M + H] +. 24G: (R) -6- (Pyrrolidin-3-yloxy) -2H-isoquinolin-1-one Via (S) -3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester: EI-MS: m / z = 231.1 [M + H] +. 24H: (S) -6- (Pyrrolidin-3-yloxy) -2H-isoauinolin-1-one Via tert-butyl ester of (R) -3-methanesulfonyloxypyrrolidine-1-carboxylic acid: EI-MS: m / z = 231.1 [M + H] +. 241: 6- (Perhydroazepin-4-yloxy) -2H-isoquinolin-1-one Via 4-methanesulfonyloxyperhydroazepin-1-carboxylic acid tert-butyl ester: EI-MS: m / z = 259. 1 [M + H] +. Example 25 6- (Piperidin-4-ylsulfanyl) -2H-isoquinolin-1-one A: 6-mercapto-2H-isoquinolin-1-one was added to a solution of 6-hydroxy-2H-isoquinolin-1 -one ( 500 mg, 3.10 mmol), triethyl amine (860 μL, 6.2 mmol) and pyridine (2.5 mL, 31 mmol) in anhydrous tetrahydrofuran (16 mL) N, N-dimethylthiocarbamoyl chloride (573 mg, 4.65 mmol) at temperature of 0 ° C. The mixture was heated to a temperature of 65 ° C and stirred for 24 hours. The mixture was concentrated in vacuo with the addition of toluene. Saturated aqueous NaHCO3 was added to the residue and the mixture was extracted with ethyl acetate (x3), dried (Na2SO) and concentrated in vacuo to yield a residue. Flash chromatography of the residue was performed using ethyl acetate-heptane (5% to 100% ethyl acetate) in an undesired side product (280 mg), followed by dimethylthiocarbamic acid ester 1-oxo-1,2-dihydroisoquinoline-6. -yl (300 mg). A solution of dimethylthiocarbamic acid ester 1 -oxo-1,2-dihydroisoquinolin-6-yl in dichlorobenzene (2.5 ml) was heated under the conditions of a microwave at a temperature of 230 ° C for 60 minutes. The mixture was loaded directly onto a column and chromatographed instantaneously using ethyl acetate: heptane (1: 9 to 99: 1) to yield dimethylthiocarbamic acid ester S- (1 -oxo-1,2-dihydro-isoquin). nolin-6-l) (140 mg). Methanol (7 ml) and potassium hydroxide (86 mg) were added to the dimethyl-thiocarbamic acid ester S- (1-oxo-1,2-dihydro-isoquinolin-6-yl) (140 mg) and refluxed. the mixture, under nitrogen, for 2 hours at a temperature of 80 ° C. The mixture was cooled and concentrated in vacuo to produce a residue. Water was added and the mixture was extracted with ethyl acetate (x2). The aqueous phase was acidified (pH -2) using dilute hydrochloric acid and the mixture was extracted with ethyl acetate (x3). HE The combined organics were dried (Na2SO) and concentrated in vacuo to yield crude 6-mercapto-2H-isoquinolin-1 -one (104 mg). B: 6- (piperidin-4-ylsulfanyl) -2H-isoquinolin-1-one A mixture of 6-mercapto-2H-isoquinolin-1 -one was heated (50 mg, 0.28 mmol), 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.42 mmol) and K2CO3 (64 mg, 0.46 mmol) in N, N-dimethylformamide (1.5 mL) ) at a temperature of 50 ° C later during the night at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the mixture which was extracted with ethyl acetate (x3). The combined organics were dried (Na2SO4) and concentrated in vacuo to yield a residue. Instant chromatography of the residue using ethyl acetate: heptane (1: 9 to 99: 1) to produce 4- (1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl) piperidine-1-carboxylic acid tert-butyl ester ( 15 mg). A solution of acetic acid dichloromethane: trifluoroacetic acid (7: 3.5 ml) was added to the 4- (1-Oxo-1,2-dihydroisoquinolin-6-ylsulfanyl) piperidine-1-carboxylic acid tert-butyl ester and stirred Mix for 2 hours, then concentrate in vacuo to produce a residue. The residue was loaded on a SCX pre-acidified column using methanol and eluted with 2M ammonia in methanol to yield crude 6- (piperidin-4-ylsulfanyl) -2H-isoquinolin-1 -one, which was purified by prep-HPLC ( 2 mg), EI-MS: m / z = 261.1 [M + H] +.

Example 26 (S) -7-Methyl-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one 26A: 6-Hydroxy-7-methyl-2H-isoquinolin-1-one A mixture was refluxed of 3-methoxy-4-methylbenzaldehyde (19.3 g, 0.129 mol), carbo-methoxy methylene triphenylphosphorane (51 g) in toluene (250 ml) for 24 hours. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate and concentrated in vacuo to yield a residue. The residue was purified by flash chromatography using heptane-ethyl acetate (1: 1) to give 3- (3-methoxy-4-methyl-phenyl) acrylic acid methyl ester (27 g, 0.126 mol). A mixture of 3- (3-methoxy-4-methyl-phenyl) acrylic acid methyl ester (27 g), sodium hydroxide (14 g), water (70 ml), methanol (140 ml) and the like were refluxed. tetrahydrofuran (70 ml) at a temperature of 50 ° C for 1 hour. The mixture was concentrated in vacuo and water was subsequently added. The mixture was filtered and 5 M HCl was added until precipitation occurred. The mixture was filtered and the precipitated solid was washed with water and dried in vacuo to yield 3- (3-methoxy-4-methylphenyl) acrylic acid (23.5g, 0.122 mol). Toluene (750 ml) and thionyl chloride (11 ml) were subsequently added to 3- (3-methoxy-4-methylphenyl) acrylic acid (20 g, 0.104 mol) at room temperature. The suspension was refluxed for 2 hours while stirring vigorously to produce a light yellow solution.

The reaction mixture was concentrated in vacuo, then toluene was added and the mixture was re-concentrated in vacuo to yield 3- (3-methoxy-4-methylphenyl) acryloyl chloride for use in the next step. The 3- (3-methoxy-4-methylphenyl) acrylic acid chloride was dissolved in acetone (800 ml). The resulting solution (15 minutes) was slowly added at a temperature of 0 ° C to the mixture of sodium azide (13 g) in water (100 ml) and acetone (100 ml) while stirring vigorously and cooling with a bath -ice. The addition was completed after the reaction mixture and stirred at a temperature of 0 ° C for 90 minutes while stirring vigorously. The reaction mixture was poured into ice water (300ml). The mixture was filtered after stirring for 15 minutes and the solid residue was washed with excess water. The remaining solid residue was dissolved in dichloromethane (45 ml). The liberated water was removed with a separating funnel. The dichloromethane layer was dried with Na 2 SO 4 and filtered to give a dichloromethane solution of 3- (3-methoxy-4-methylphenyl) acryloyl azide for immediate use in the next step. A solution of dichloromethane azide (Carefully!) Was added in portions using a dropping funnel for the preheating of diphenyl ether (50 ml) at a temperature of 150 ° C, while stirring gently, in a round bottom flask of three necks, equipped with a hatch Dean-Severe. During the addition of the nitrogen gas, evolution takes place under the formation of isocyanate. The added dichloromethane was evaporated and collected with the Decano-Severo hatch. It was completed after the addition (~ 30 min) and evolution was observed without gas, the mixture was heated to reflux (~ 250 ° C) while stirring (dichloromethane was evaporated at no more than ~ 200 ° C and the Dean-Sever hatch quickly). The reaction mixture is stored at a temperature of ~ 250 ° C for 1 hour and cooled to a temperature of 125 ° C and poured into a mixture of acetone and heptane (1:10). A precipitated solid was filtered and dried in vacuo to yield 6-methoxy-7-methyl-2H-isoquinolin-1 -one (12 g, 63.49 mmol). A 1M solution of boron tribromide (2.9 ml, 2.91 mmol) in the form of drops was added to a stirred suspension of 6-methoxy-7-methyl-2H-isoquinolin-1 -one (100 mg, 0.53 mmol) in 1 ml. of dichloromethane at a temperature of 0-4 ° C (in an ice bath). After stirring for 1 day at room temperature, the reaction mixture was poured into ice and the pH was adjusted to 9 by the addition of concentrated aqueous ammonia. The precipitated material was collected by filtration, washed with water, and dried in vacuo to yield 6-Hydroxy-7-methyl-2H-isoquinolin-1-one (51 mg, 55%), EI-MS: 176.6 [M + H] \ 26B: (S) -7-Methyl-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one The preparation according to Example 24C and 24D using (R) -3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester and 6-hydroxy-7-methyl-2H-isoquinolin-1 -one to produce 7-methyl -6- (piperidin-3-yloxy) -2 H -soquinolin-1 -one EIMS: m / z = 259.1 [M + H] +. Example 27 (S) -4-Bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one A solution of (S) -3- (oxo-1,2-dihydroisoquinolin-6-yloxy) piperidin-1-carboxylic acid tert-butyl ester (1 g, 2.9 mmol) and N-bromosuccinamide (516) was stirred. mg, 2.9 mmol) in acetonitrile overnight at room temperature. The mixture was absorbed in flash chromatography and silica (eluent: ethyl acetate) to produce (S) -3- (4-bromo-1-oxo-1,2-dihydroisoquinolin-6-yloxy) tert-butyl ester piperidin -1-carboxylic acid (700 mg). Dichloromethane and trifluoroacetic acid (3: 1, 20 ml) were added to tert-butyl ester of (S) -3- (4-bromo-1-oxo-1,2-dihydroisoquinolin-6-yloxy) piperidin-1-carboxylic acid and the mixture was stirred for 2 hours, then concentrated in vacuo to produce a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to yield crude (S) -4-bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1 -one (530) mg), which was purified by prep-HPLC, EI: MS: m / z = 325.5 [M + H] +. The following compounds were prepared by the procedure as described above using the appropriate building block. 27A: (R) -4-Bromo-6- (pyrrolidin-3-yloxy) -2H-isoquinolin-1-one EI-MS: m / z = 309.3 and 311.0 [M + H] +. 27B: (S) -4-Bromo-6- (pyrrolidin-3-yloxy) -2H-isoquinolin-1-one EI-MS: m / z = 309.3 and 311.0 [M + H] +. Example 28 (S) -4-Met6- (piperidin-3-yloxy) -2H-isoquinolin-1-one A: 3- (3-Methoxyphenyl) -but-2-enoic acid metester Heated 1 - (3-Methoxyphenyl) ethanone (15 g, 0.1 mmol) and met(triphenylphosphoranylidene) acetate (62 g, 0.186 mmol) in toluene (75 ml) at a temperature of 100 ° C for 2 days. After allowing cooling to room temperature, the solvent was removed under reduced pressure to produce a crude product. Precipitation was provided with EtOAc and heptane followed by flash chromatography of the liquor. mother concentrated on silica (eluent: 20% EtOAc in heptane) of the product as a mixture of geometric isomers (21.8 g, 86%). B: 3- (3-Methoxyphenyl) -but-2-enoic acid 3- (3-Methoxy-phenyl) -but-2-enoic acid methyl ester (2 g, 7.9 mmol) and sodium hydroxide (0.78) were dissolved. g, 19.4 mmol) in a mixture of water (50 ml), methanol (50 ml) and THF (50 ml). The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The ining aqueous solution was diluted with water and extracted with EtOAc twice. The aqueous was collected and acidified to a pH of 4 and extracted with EtOAc three times. The organics were combined, dried (magnesium sulfate) and concentrated in vacuo to yield 3- (3-methoxy-phenyl) -but-2-enoic acid in the form of a white crystalline solid (1 g, 55%). . C: 6-Hydroxy-4-methyl-2H-isoquinolin-1-one A solution of 3- (3-methoxy-phenyl) -but-2-enoic acid (1.54 g, 7.8 mmol) was stirred, d ifen i If osf oryl azide (2.15 g) and triethylan (1.1 ml) in toluene at room temperature for 1 hour. The mixture was filtered through a plug of silica, washing with toluene, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diphenylmethane (6 ml) and heated at a temperature of 200 ° C for 3 hours. After allowing cooling to room temperature, the solid precipitate was collected by filtration, washed with toluene and subsequently dried to produce 6-methoxy-4-methyl-2H-isoquinolin-1 -one in the form of a solid (0.22 g). A suspension of 6-methoxy-4-methyl-2H-isoquinolin-1 -one (215 mg, 1.1 mmol) in 5 N hydrochloric acid (1 ml) was irradiated in a microwave at a temperature of 180 ° C for 40 minutes. After val of the solvent in vacuo, the crude residue was purified by flash chromatography on silica (eluent: 1% methanol in DCM) to give 6-hydroxy-4-methyl-2H-isoquinolin-1-one (130 mg, 67%). %), EI-MS: m / z = 174.3 [M + H] +. D: (S) -4-Methyl-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one A suspension of 6-hydroxy-4-methyl-2H-isoquinolin-1 -one was heated ( 60 mg, 0.34 mmol) and potassium carbonate (70 mg, 0.51 mmol) in DMF (2.5 ml) at a temperature of 110 ° C and a solution of (R) -3-methanesulfonyloxypiperidine-tert-butyl ester was added. 1-carboxylic acid (138 mg, 0.51 mmol) in DMF (1.5 ml) in the form of drops. Heating was continued at a temperature of 110 ° C for 16 hours and the solvent was ved in vacuo. A sample of the residue was taken in chloroform / isopropanol (3: 1) and washed with aqueous sodium hydrogen carbonate. The organics were collected through a hydrophobic frit and the concentrate to allow the (S) -3- (4-methyl-1-oxo-1,2-dihydroisoquinolin-6-yloxy) piperidine-1-tert-butyl ester. -carboxylic crude. The (S) -3- (4-Methyl-1 - tert-butyl ester) was dissolved oxo-1, 2-dihydroisoquinolin-6-yloxy) piperidin-1-carboxylic acid in 2 ml of DCM and an excess of TFA (0.2 ml) was added. The solvent was ved after stirring for 2 hours under reduced pressure and the residue was dissolved in methanol and partially purified by ion exchange chromatography. Further purification by prep-HPLC yielded (S) -4-methyl-6- (piperidin-3-yloxy) -2H-isoquinolin-1 -one, EI-MS: m / z = 259.1 [M + H] +. Example 29 (S) -5-Bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one A: 5-Bromo-6-hydroxy-2H-isoquinolin-1-one It was added to a solution of 6-methoxyisoquinoline (2.38 g, 14.9 mmol) in dichloromethane (55 ml) ACI3 (4.4 g, 33 mmol) under nitrogen at room temperature. The mixture was stirred for 30 minutes then Br2 (0.92 ml, 18 mmol) was added at a temperature of 0 ° C. The mixture was stirred for 2 hours, then it was poured into water and neutralized with solid Na2CO3. The mixture was filtered through celite and the filtrate was extracted with dichloromethane and chloroform. The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield a residue. Flash chromatography of the residue on silica (eluent: 50-100% ethyl acetate in heptane) afforded 5-bromo-6-methoxy-quinoline (1.2 g, 34% yield). M-Chloroperbenzoic acid (1.4 g, 75%) was added in portions to a stirred solution of 5-bromo-6-methoxyisoquinoline (1.2 g, 5.04 mmol) in dichloromethane (12 ml). The mixture was stirred for 1 hour then dichloromethane (10 ml) was further added and the mixture was stirred for an additional 2 hours. Methanol (12 ml) was added and the mixture was concentrated in vacuo for ~ 9 ml, then 1M hydrochloric acid in diethyl ether (10 ml) was added. The mixture was diluted with ether and filtered, the precipitated solid was washed with diethyl ether and dried in vacuo to yield 5-bromo-6-methoxyisoquinoline-N-oxide hydrochloride (1.22 g). POCI3 (6.5 ml) was added to the 5-bromo-6-methoxyisoquinoline-N-oxide hydrochloride (1.22 g) and the mixture was heated at a temperature of 90 ° C for 6 hours. Excess POCI3 was removed in vacuo and the remaining solid was washed with water, filtered and dried in vacuo to yield 5-bromo-1-chloro-6-methoxyisoquinoline (1.26 g). A solution of 1M BBr3 in dichloromethane (25.5 ml) was added dropwise to a stirred solution of 5-bromo-1-chloro-6-methoxyisoquinoline (1.26 g) in dichloromethane at a temperature of 10 ° C. The mixture was stirred at room temperature for 48 hours then it was emptied into ice water and the pH adjusted to 8 by the addition of concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (x2) and then the aqueous phase was acidified to a pH ~ 4 using dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (x2), the combined organics were dried (Na2SO) and concentrated in vacuo to yield 5-bromo-1-chloro-6-hydroxyisoquinoline (1.1 g), EI-MS; m / z = 257.9, 260.0 and 261.6 [M + H] +. B _ (S) -5-Bromo-6- (piperidin-3-yloxy) -2 H -soquinolin-1-one 5-Bromo-1-chloro-6-hydroxyisoquinoline (108 mg, 0.42 mmol) was mixed with hydrochloric acid (5M, 2 ml) and heated under microwave conditions at a temperature of 150 ° C for 40 minutes. The cooled residue was mixed with methanol and azeotroped to dry under reduced pressure to yield 5-bromo-6-hydroxy-2H-isoquinolin-1 -one EI-MS: m / z = 240 and 242 [M + H] +. The crude 5-bromo-6-hydroxy-2H-isoquinolin-1-ene (93 mg) was mixed with (R) -3-methanesulfonyloxypiperidin-1-carboxylic acid tert-butyl ester (500 mg, 4.3 mol eq), potassium carbonate (700mg, 12 mol eq) and N, N-dimethylformamide (2 ml). The mixture was irradiated in a microwave at a temperature of 150 ° C for 20 minutes. Water was added to the mixture and the crude product was extracted into ethyl acetate. The organic phase was washed with brine and dried (MgSO4). The organics were concentrated in vacuo and subsequently purified by prep-HPLC. Dichloromethane and trifluoroacetic acid (3: 1, 2 ml) were added and the mixture was stirred for 1 hour then concentrated in vacuo to yield a residue. The residue was loaded onto a SCX pre-acidified column using methanol and eluted with 2M ammonia in methanol to yield (S) -5-bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1 -one. The residue was purified by prep-HPLC (1.8mg), EI-MS: m / z = 323.5 and 323.5 [M + H] \ Example 30A: 6-f1- (4-Methylbenzyl) piperidin-4-yloxy1-2H -isoquinolin-1-one Sodium triacetoxyborohydride (100 mg, 3.9 mol eq) was added to a solution of 6- (piperidin-4-yloxy) -2H-isoquinolin-1 -one (30mg, 0.12mmol), acetic acid (2 drops) and 4-methylbenzaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (700 μl) and stirred for 17 hours. The reaction was quenched with water and methanol and the semi-purified product using an SCX cartridge. The product was further purified by prep-HPLC to yield 6- [1- (4-Methylbenzyl) piperidin-4-yloxy] -2H-isoquinolin-1-one: EI-MS: m / z = 349.4 [M + H] +. The following compounds were prepared by the procedure described above using the appropriate aldehyde. 30B: 6- [1- (3-Methylbenzyl) piperdin-4-yloxM-2H-isoquinolin-1-one Via 3-Methylbenzaldehyde: EI-MS: m / z = 349.4 [M + H] +. 30C: 6-f1- (4-Methoxybenzyl) piperidin-4-yloxy1-2H-isoquinolin-1-one Via 4-Methoxybenzaldehyde: EI-MS: m / z = 365.1 [M + H] +. 30D: 3- [4- (1-Oxo-1,2-dihydroisoquinolin-6-yloxy) piperidin-1-ylmethylbenzonitrile Via 3-Cyanobenzaldehyde: EI-MS: m / z = 360.5 [M + H] +. 30E: 6- (1-Furan-2-ylmethylpiperidin-4-yloxy) -2H-isoquinolin-1-one Via 1-Furan-2-carbaldehyde: EI-MS: m / z = 325.5 [M + H] +. 30F: 6- (1-Furan-3-methyl-piperidin-4-yloxy) -2H-isoquinolin-1-one Via 1-Furan-3-carbaldehyde: EI-MS: m / z = 325.5 [M + H ] +. 30G: 6- (1-Methylpiperidin-4-yloxy) -2H-isoquinolin-1-one Via formaldehyde: EI-MS: m / z = 259.1 [M + H] +. 30H: 6-f1- (1H-Pyrrol-3-ylmethyl) piperidin-4-yloxy1-2H-isoquinolin-1-one Via 1H-Pyrrole-3-carbaldehyde: EI-MS: m / z = 324.6 [M + H] +. 301: 6- (1-Benzylpiperidin-4-yloxy) -2H-isoquinolin-1-one Via Benzaldehyde: EI-MS: m / z = 335.5 [M + H] +. Example 31 31 A: 6- [1- (2-Phenoxyethyl) piperidin-4-yloxy] -2H-isoquinolin-1-one 2-phenoxyethyl bromide (1 mol eq) was added to a suspension of 6- ( piperidin-4-yloxy) -2H-isoquinolin-1 -one (30 mg, 0.12 mmol) and potassium carbonate (50 mgs, 3 mol) in N, N-dimethylformamide (1 ml) and stirred for 17 hours. The reaction was quenched with hydrochloric acid (2M) and methanol and passed into an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean product was isolated by evaporation under reduced pressure to yield 6- [1- (2-phenoxyethyl) piperidin-4-yloxy] -2H-isoquinolin-1-one: EI-MS: m / z = 365.1 [M + H ] +. The following compounds were prepared by the procedure described above using the bromides Suitable 31 B: 6- [1- (Metox? et? l) p? per? d? n-4-? lox?] - 2H-? soqu? nol? n-1-one Via 2-Methoxyethyl Bromide EI -MS m / z = 303 1 [M + H] + 31 C: 6-M- (3-H? Drox? Prop? L) p? Per? D? N-4-? Lox? 1-2H-? Soqu Nol? n-1-one Via 2-3-hydroxyl Bromide Prop EI-MS m / z = 303 1 [M + H] + 31 D: 6- (1-C? cloprop? lmet ? lp? per? d? n-4-? lox?) - 2H-? soqu? nol? n-1-ona Via (bromomet? l) c? cloprop? el EI-MS m / z = 299 5 [M + H] + 31 E: 6-f1- (2-H? Drox? Et? L) p? Per? D? N-4-? Lox?] - 2H-? Soqu? Nol? N-1-one Via 2-bromoethanol EI-MS m / z = 289 3 [M + H] + 31 F: 6-f1- (3-Methoxy? Benc? L) p? Per? D? N-4-? Lox?] - 2H -? soqu? nol? n-1-ona Via 3-Methox? benzaldehyde EI-MS m / z = 365 5 [M + H] + 31G: 6-M- (1H-P? rrol-2-? lmet? l) p? per? d? n? 4-? lox? 1-2H-? soqu? nol? n-1-ona Via 1H-P? rrol-2-carbaldeh? do EI-MS m / z = 324 5 [M + H] + Example 32 32A (S) 6-M- (2-Benzyl) et? L) p? Per? D? N -3? Lox? L-2H-? Soqu? Nol? N -1-one 2-Benzylloxyl bromide (1 mole) was added to a suspension of (S) -6- (p? Per? D? N -3? Lox?) - 2H-? soqu? nol? n-1 -one (30 mg, 0 12 mmol) and potassium carbonate (70mg, 4 2 mol), in N, N-dimethylformamide (500μl) and stirred for 17 hours. The reaction was quenched with hydrochloric acid (2M) and methanol and passed to an SCX cartridge. The products were purified by preparative HPLC under basic conditions. The clean product was isolated by evaporation. under reduced pressure for produce (S) -6- [1- (2-benz? lox? et? l) p? per? d? n? 3-? lox?] - 2H-? soqu? nol? n-1-one EI- MS m / z = 379 4 [M + H] + The following compounds were prepared by the procedure as described above using the appropriate bromides, (R) - or (S) -6-p? Per? D? N- 3-? Lox?) - 2H-? Soqu? Nol? N-1-one and (R) -6- (p? Rrol? D? N-3-? Lox?) - 2H-? Soqu? Nol? N -1-ona 32B: (S) -6-M- (2-Oxo-2-phen? Let? L) piper? D? N-3-? Lox? L-2H-? Soqu? Nol? N- 1 -one Via 2-bromideacetophenone EI-MS m / z = 363 5 [M + H] + 32 C: (S) -6-M- (2-Phenoxy et? l) p? per? d? n -3 ? -lox? l-2H-? soqu? nol? n-1-ona Via beta-bromofenetol EI-MS m / z = 365 1 [M + H] + 32 D: (R) -6-M- (3-H hydroxypropyl bromide hydroxypropyl bromide EI-MS m / z = 289 3 [M +? H] + 32E: (R) -6-M- (2-Phenoxy et? L) p? Per? D? N -3? Lox? L-2H-? Soqu? Nol? N-1-one Via beta-bromophenetol EI-MS m / z = 365 5 [M + H] + Example 33 33A 6- (1-Et? lp? per? d? n-3-? lox?) - 2H-? soqu? nol? n-1-one Sodium tpacethoxyborohydride (45 mg, 1 8 mol) was added to a solution of 6- (p? per? d? n-3) -? lox?) - 2H-? soqu? nol? n-1 -one (30mg, 0 12mmol), acetic acid (10Oμl) and acetaldehyde (50μl or 50mg) in N, N-dimethylformamide (500μl) and stirred for 17 minutes. hours. The reaction was quenched with water and methane and passed in an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean products were isolated by evaporation under reduced pressure to yield 6- (1-ethyl-piperidin-3-yloxy) -2H-isoquinolin-1 -one: EI-MS: m / z = 273.5 [M + H] +. The following compounds were prepared by the procedure as described above using the appropriate aldehyde, (R) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-a racemic and (R) -6- (pyrrolidin-3-yloxy) -2H-isoquinolin-1 -one: 33B: 6- f1- (2-Ethylbutyl) piperidin-3-yloxy] -2H-isoquinolin-1-one Via 2-ethylbutyraldehyde: EI-MS: m / z = 329.5 [M + H] +. 33C: 6- (1-Cyclohexylmethyl-piperidin-3-yloxy-2H-isoquinolin-1-one Via cyclohexanecarboxaldehyde: EI-MS: m / z = 341.1 [M + H] +. 33D: (R) -6- (1-Benzylpiperidin-3-yloxM-2H-isoquinolin-1-one Via Benzaldehyde: EI-MS: m / z = 335.1 [M + H] +. 31 E: (R) -6- ( 1-Methylpyrrolidin-3-yloxy] -2H-isoquinolin-1-one Via Formaldehyde: EI-MS: m / z = 245.6 [M + H] + Example 34 In-vitro determination of the inhibitory activity of the compounds of the present invention in a human ROCK-1 recombinant. A 38 μm 5 μl of a 250 μM solution of a test compound was added to a reservoir microtitre plate in a test regulator (20 mM Hepes pH7.4, 0.01 % tween) with 4% dimethylsulfoxide (DMSO), plus 5 μl of a mixture containing 100nM of fluorescence-tagged peptide (AKRRRLSSLRAK-fluorescence from the Peptide Institute, Japan), 20μM ATP, 10mM MgCl2 diluted in an assay buffer containing 2mM of dithiothreitol. 10 μl of a 0.1ng / μl solution of recombinant human ROCK-I was subsequently added to a test buffer containing 2mM of dithiothreitol, to each reservoir, yield of a final test compound concentration of 10μM. Following one hour of incubation at room temperature in the dark, enzyme activity was detected by the addition of 60μl of the IMAP binding reagent (Molecular Apparatus) to each reservoir. The plate was incubated for an additional 30 minutes at room temperature in the dark and the resulting change in fluorescence polarization was measured in Analyst HT (Molecular Apparatus) at a wavelength excitation of 485nM and an emission wavelength of 530nM. The percentage of enzyme activity was calculated by comparing this activity to contain a solution of 30μM Y-27632 from Tocris (generated from maximum inhibition of ROCK-I activity). The compounds are subsequently subjected to a curved analysis response dose in order to determine IC 50 values for active compounds (wherein IC 50 is the concentration of the test compounds causing 50% inhibition of the enzymatic activity) All exemplified compounds have plC50 values greater than 5 0 The prepared compounds of the present invention are characterized by a plC50 > 6 0 Table 1 shows the plC50 values obtained for the same representative compounds of the same Table I EXAMPLE 35 m-vitro determination of the inhibitory activity of monocyte migration of the compounds of the present invention Human monocytic cells (THP-1) were suspended in a migration medium (containing RPMI 1640 BSA 1%) in a concentration of 2x106 cells / ml in the presence and absence of the inhibitory test compound. The cell suspension was subsequently incubated for 30 minutes at a temperature of 37 ° C. A solution of Human Monocyte Chemotactic Protein 1 (MCP-1) was added in a concentration of 10ng / ml in a migration medium to the lower chamber of Qimiotaxis QCMTM 5μM 96-Depot Cell Migration Equipment (ECM512, International Chemistry) Followed by introduction of the migration insert and a pre-equilibration step in 10min, then a 100μl cell suspension was added to the upper chamber and the equipment was incubated for 4 hours at a temperature of 37 ° C under 5% carbon dioxide . Also included are White and Basic Migration reservoirs that contain and not MCP-1 cells, respectively. The number of migratory cells was determined by the application of a regulator lysis and a nucleic acid sensitive to dry fluorescence (CyQuant GR dry, Molecular Tests). Fluorescence was determined using the FlexStation Plate Reader. The percentage of migration inhibition was calculated using the following equation: (%) of Specific Migration Inhibition = (1- ({. (Cells migrated in the presence of test compounds-Basal Migrated Cells) / (Cells migrated in the absence of Test Compounds-Migrated Basal Cells).}.) x 100.

Claims (5)

1. CLAIMS 1. An isoquinoline derivative having the general Formula I
2. Formula I wherein X is O, S or NH; And it is OH or NH2; m is 0, 1 or 2; n is 1 or 2; Ri is H, where Y is NH2; or Ri is H, alkyl (C1-) or halogen, when Y is OH; R2 and R3 are independently H, (C1-4) alkyl or halogen;
3. R is H or C 1-6 alkyl, optionally substituted with OH, (C 1-4) alkyloxy, C 1-4 alkyloxycarbonyl, C 3-7 cycloalkyl, which may optionally comprise a heteroatom selected from O and S , aril (C6-? o). aryloxy (C6-? o) or a heteroaryl group of 5- or 6 members comprising 1-3 heteroatoms independently selected from O, N and S, each aryl or heteroaryl group is optionally substituted with 1-3 substituents independently selected from (C 1) alkyl.
4. 4), (C 1-4) alkyloxy, (C 1-4) alkylsulfonyl and halogen; or a pharmaceutically acceptable salt thereof. 2. The isoquinoline derivative as described in claim 1, characterized in that X is O, S or NH; And it is OH or NH2; RT and R2 are H; R3 is H, alkyl (C? -4); m is 0 or 1; n is 1 or 2; R is H or alkyl (C -? - 4), optionally substituted (C3-7) cycloalkyl, which may optionally comprise a heteroatom selected from O and S, aryl (C6-? O), or a heteroaryl group of or 6 members comprising 1-3 heteroatoms independently selected from O, N and S, each aryl or heteroaryl group is optionally substituted with 1-3 substituents independently selected from (C 1-4) alkyl, (C 1) alkyloxy, and halogen; or a pharmaceutically acceptable salt thereof. 3. The isoquinoline derivative as described in claim 1 or 2, characterized in that Y is OH. 4. The isoquinoline derivative as described in any of claims 1 to 3, characterized in that X is O. 5. The isoquinoline derivative as described in claim 1, characterized in that R3 is independently H, methyl or halogen, Ri and R2 are H, and R is H, (C1-4) alkyl, optionally substituted with phenyl or a heteroaryl group (C2.
5. 5) of 5- or 6 members comprising from 1 to 3 heteroatoms selected from O, N and S, the phenyl or heteroaryl group is optionally substituted with from 1 to 3 substituents selected from alkyl (C1-), alkyloxy (C- | .4) and one or more halogens. 6. The isoquinoline derivative as described in any of claims 1 to 5, characterized in that Y is OH, m is 1, n is 1 or 2, and R is H. 7. The isoquinoline derivative is which is selected from: - (S) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; - (S) -7-methyl-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; -6- (perhydroazepin-4-yloxy) -2H-isoquinolin-1-one; - (S) -6- [1- (1H-pyrrol-2-ylmethyl) -piperidin-3-Moxy] -isoquinolin-1-ylamine; - (S) -6- [1- (4-methylbenzyl) piperidin-3-yloxy] isoquinolin-1-ylamine; -6- (piperidin-4-yloxy) -2H-isoquinolin-1-one; - (R) -6- (1-Benzylpiperidin-3-yloxy) isoquinolin-1-ylamine; -6- [1- (2-phenoxyethyl) piperidin-3-yloxy] isoquinolin-1-ylamine; - (3S) -6- [1- (1-phenylethyl) piperidin-3-yloxy] isoquinolin-1-ylamine; -6- (piperidin-4-ylsulfanyl) -2H-isoquinolin-1-one; -6- (1-thio-n-2-ylmethylpiperidin-3-yloxy) isoquinolin-1-ylamine; - (S) -6- (1-benzylpiperidin-3-yloxy) isoquinolin-1 -lamin; - (R) -6- [1- (2-phenoxyethyl) piperidin-3-yloxy] -2H-isoquinolin-1-one; - (S) -6- [1- (4-Fluorobenzyl) -piperidin-3-yloxy] -isoquinolin-1-alamine; - (S) -4-bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; -6- [1- (1H-pyrrol-2-ylmethyl) piperidin-4-yloxy] -2H-isoquinolin-1-one; -6- [1- (4-methoxybenzyl) piperidin-3-yloxy] -2H-isoquinolin-1-one; - (S) -6- [1-furan-3-ylmethylpiperidin-3-yloxy] isoquinolin-1-ylamine; -6- [1-Fe-netylpiperidin-3-yloxy] -isoquinolin-1-ylamine; -6- [1- (3-methoxybenzyl) piperidin-4-yloxy] -2H-isoquinolin-1-one; - (S) -6- [1- (1H-pyrrol-3-ylmethyl) piperidin-3-yloxy] isoquinolin-1-ylamine; - (S) -6- [1- (2-Oxo-2-phenyl ethyl) piperidin-3-yloxy] -2H-isoquinolin-1 -one; - (S) -6- (pyrrolidin-3-yloxy) -2H-issoquinolin-1-one; -6- (1-cyclohexylmethyipiperidin-3-yloxy) -2H-isoquinolin-1-one; -6- (piperidin-3-ylsulfanyl) isoquinolin-1-ylamine; -6- (1-furan-2-ylmethylpiperidin-4-yloxy) -2H-isoquinolin-1-one; - (R) -6- (pyrrolidin-3-ylsulfanyl) isoquinolin-1-ylamine; - (S) -4-methyl-6- (piperidin-3-yloxy) -2H-isoquinolyl-1-one; - (S) -6- (pyrrolidin-3-ylsulfanyl) isoquinolin-1-ylamine; -6- (1-methylpiperidin-4-yloxy) -2H-isoquinolin-1-one; - (S) -6- (piperidin-3-yloxy) -isoquinolin-1-ylamine; -6- (piperidin-4-ylsulfanyl) isoquinolin-1-ylamine; - (R) -6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; - (S) -6- [1- (2-phenoxyethyl) piperidin-3-yloxy] -2H-isoquinolin-1-one; -6- (1-benzylpiperidin-3-yloxy) -7-methylisoquinolin-1-ylamine; -6- [1- (3-hydroxypropyl) piperidin-4-yloxy] -2H-isoquinolin-1-one; -6- [1- (2-hydroxyethyl) p.peridin-4-yloxy] -2H-isoquinolin-1-one; - (R) -6- (pyrrolidin-3-yloxy) -2H-isoquinolin-1-one; -6- [1- (3-methylbenzyl) picperidin-4-yloxy] -2H-isoquinolin-1-one; -7-methyl-6- [1- (4-methylbenzyl) piperidin-3-yloxy] isoquinolin-1-ylamine; - (S) -5-Bromo-6- (piperidin-3-yloxy) -2H-isoquinolin-1-one; -6- [1- (4-methoxybenzyl) piperidin-4-yloxy] -2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. 8. An isoquinoline derivative as described in any one of claims 1 to 7 for use in therapy. 9. A pharmaceutical composition comprising an isoquinoline derivative as described in any of claims 1 to 7, characterized in that a pharmaceutically acceptable salt thereof is the addition of a mixture with pharmaceutically acceptable auxiliaries. The use of an isoquinoline derivative as described in any of claims 1 to 7, characterized in that for the preparation of a medicament for the treatment of disorders related to ROCK-1 such as hypertension, atherosclerosis and glaucoma.