Title of Invention	"Novel isoquinoline derivatives useful in the treatment of diseases related to the inhibition of Rho kinase"
Abstract	The invention relates to 6-piperidinyl-substituted isoquinoline derivatives of the formula (I); useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.

Full Text

The present invention relates to novel isoquinoline derivatives, their preparation and their use in the treatment and/or prevention of diseases related to the inhibition of Rho-kinase and/or of Rho-kinase mediated phosphorylation of myosin light chain phosphatase. Activation of a small GTPase RhoA upon agonist stimulation results in conversion of RhoA from the inactive GDP-bound form to the active GTP-bound form with a subsequent binding to and activation of Rho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known. Rho-kinase 2 is expressed in vascular smooth muscle cells and endothelial cells. Activation of Rho-kinase 2 by the active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells through phosphorylation-mediated inhibition of the myosin light chain phosphatase activity and thereby up-regulation of the activity of myosin regulatory light chain (Uehata et al., Nature 1997, 389, 990-994). It is known that Rho-kinase is involved in vasoconstriction, including the development of myogenic tone (J. Appl. Physiol. 2005, 1940-8, 98), bronchial smooth muscle contraction (Am. J. Resp. Cell Mol. Biol. 20, 1190-1200), hypertension, i.e. pulmonary hypertension (Heart, 91, 391-2. 2005) and ocular hypertension (Invest. Ophthalmol. Visual Sci. 2001. 42, 137-144). endothelial dysfunction (Eur. J. Pharmacol. 2005. 512, 247-249). artherosclerosis, restenosis (Arch. Mai. Coeur 2005, 98. 249-254), glucose utilization, cardiac hypertrophy (Hypertension 2000, 35, 313-318). erectile dysfunction (Nature Medicine 2001, 7,119-122), retinopathy, inflammation, immune diseases, AIDS, osteoporosis, brain functional disorder, infection of digestive tracts with bacteria (WO 98/06433), cancer development, vascular smooth muscle proliferation and motility (Circ. Res. 1999, 84. 1186-1193; Atherosclerosis 2001, 155. 321-327). endothelial proliferation and motility (Biochem. Biophys. Res. Commun. 2000. 269, 633-640), stress fiber formation (Science 1997, 275. 1308-1311; J. Cell Biol. 2000. 150. 797-806). platelet aggregation (FEBS Lett. 2000, 466, 70-74; Blood 1999. 94. 1665-1672), Na/H exchange transport system activation (EMBO J. 1998, 17. 4712-4722), Alzheimer's disease (Science 2003, 302, 1215-1217). adducin activation (J. Biol. Chem.. 273, 5542-5548,1998). and in SREB (Sterol response binding element) signalling and its effects on lipid metabolism (Circ. Res., 92.1296-304. 2003). Therefore, a compound having inhibitory effect on Rho-kinase and/or on Rho-kinase mediated phosphorylation of myosin light chain phosphatase is useful for the treatment and/or prevention of diseases involving Rho-kinase as the primary disease cause, e.g. hypertension, i.e. pulmonary hypertension and ocular hypertension, peripheral circulatory disorder, angina pectoris, cerebral vasospasm, asthma, premature birth, hyperaggregability of platelets. Peripheral Occlusive Arterial Disease (PAOD), Chronic Obstructive Pulmonary Disease (COPD), cancer development, and erectile dysfunction, or as the secondary disease cause, e.g. arteriosclerosis, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, fibroid kidney, renal glomerulosclerosis, kidney failure, organ hypertrophy, prostatic hypertrophy, complications of diabetes, blood vessel restenosis, atherosclerosis, cancer, cardiac hypertrophy, heart failure; ischemic diseases; inflammation; autoimmune diseases; AIDS, osteopathy such as osteoporosis, brain functional disorder, infection of digestive tracts with bacteria, sepsis, adult respiratory distress syndrome, retinopathy, glaucoma and Alzheimer's disease. WO 01/64238 describes isoquinoline-5-sulfonamide derivatives optionally substituted by a -(CH2)1-6-O-(CH2)0.6-. a -(CH2)0-6-S-(CH2)0-6- or a -(CH2)0-6-linked heterocyclic group useful as neuroprotective agents. JP 10087629 A describes isoquinoiine derivatives useful for the treatment of infections caused by Heliobacter pylori such as for example gastritis or ulcer. The isoquinoiine derivatives are preferably 5-substituted by X-[(C1-C6)alkylene)]o-1-Y wherein X may be oxygen and Y may be an aryl or a heterocyclic group. Hagihara et al. (Bioorg. Med. Chem. 1999. 7, 2647-2666) disclose 6-benzyloxy-isoquinoline for the treatment of infections caused by Heliobacter pylori. US 5,480.883 generically discloses as EGF and/or PDGF receptor inhibitors useful for inhibiting cell proliferation compounds of the formula "Ar I - X - Ar H" wherein X may be (CHR-1)m-Z-(CHRi)n, eg. Z-CH2, wherein Z may be 0, R-j is hydrogen or alkyl, Ar I may be among others an optionally substituted C5-12 bicyclic heteroaryl ring system and Ar II may be among others an optionally substituted C3.7 monocyclic saturated heterocyclic system. wherein L2 is halogen and R10 may be C1-5alkylene-C1-5heterocyclic group as intermediates in the synthesis of GSK-3 inhibitors. wherein R1 is H. (C1-C6)alkyl. R' NH-(C1-C6)alkyl, NH-R' or N[(C1-C6)alkyl]2; R2 is hydrogen, halogen, or (C1-C6)alkyl; H, halogen, (C1-C6)alkyl, (C1-C6)alkylene-R', OH, 0-R", NH2, NHR", NR"R" or NH-C(0)-R", R4 is H, halogen, hydroxy, CN, (C1-C6)alkyl. R", (C1-C6)alkylene-R'; R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R'. (C1 -C6)alkylene-(C6-C10)aryl. (C1-C6)alkenylene-(C6-C10)afy'. (C1 -C6)alkylene-(C5-C10)heterocyclyl, CH(0H)-(C1-C6)alkyl. NH2. NH-R'. NH-SO2H, NH-S02-(C1-C6)alkyl. NH-S02-R", NH-C(0)-(C1-C6)aIkyl, NH-C(0)-R'. C{0)N[(C1-C6)alkyl]2. C(0)OH, or C(0)0-(C1-C6)alkyl; R6 is H, R'. (C1-C8)alkyl. (C1-C6)alkylene-R', (C1 -C6)alkylene-0-(C 1 -C6)alkyl, (C1-C6)alkylene-0-R', (C1-C6)alkylene-CH[R']2. (C1-C6)alkylene-C(0)-R*, (C1-C6)alkylene-C{0)NH2. (C1-C6)alkylene-C(0)NH-R', or (C1-C6)alkylene-C(0)N[R']2; R7 is H, halogen, CN, NO2, (C1-C5)alkyl. (C2-C6)alkenyl, R". (C1-C6)alkenylene-(C6-C10)afy'. (C1-C6)alkylene-R', CH(0H)-(C1-C6)alkyl, CH(OHHC6-C10)aryl. CH{0H)-(C5-C10)heterocyclyl, NH2, NH-R', NH-SO2H, NH-S02-(C1-C6)aIkyl. NH-SO2-R', SO2-NH2, SO2-NHR', NH-C(0HCi-C6)alkyl. NH-C(0)-R', C(0)N[(C1-C6)alkyl]2, C(0)OH, or C(0)0-(C1-C6)alkyl; R8 is H, halogen or (C1-C6)alkyl; n is 1, 2, 3 or 4; and L is O or 0-(C1-C6)alkylene; wherein R'is (C3-C8)cycloaIkyl, (C5-C10)heterocyclyl, (C6-C10)aryl;and R"is (C3-C8)cycloalkyl. (C5-C10)heterocyclyl, (C6-C10)aryl. (C1-C6)alkyl. (C1-C6)alkylene-R', (C1 -C6)alkylene-0-(C 1 -C6)alkyl, (C1-C6)alkylene-0-R', or (C1-C6)alkylene-NRxRy; and wherein Rx and Ry are independently of each other (C1-C6)alkyl. (C5-C10)heterocyclyl, (C6-C10)aryl, (C1 -C4)alkylene-(C5-C 1 o)heterocyclyl, (C1 -C4)aikylene-(C6-C 1 o)aryl, (C1 -C4)alkylene-NH(C 1 -C6)alkyl, (C1 -C4)a!kylene-N[(C 1 -C6)alkyl]2. {Ci-C4)alkylene-N[(C6-C10)aryl]2. or (Ci-C4)alkylene-N[(C5-C10)heterocyclyl]2; wherein in residues R4, R5, R7 and R8 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, F, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2. CONH2, CONHCH3 or CON(CH3)2; and their pharmaceutically acceptable salts and/or physiologically functional derivatives. Preferably. R-i is H. (C1-C6)alkyl. (C6"C10)aryl, NH-(C1-C6)alkyl. NH-(C6-C10)aryl or N[(C1-C6)alkyl]2. More preferably. R-| is H, halogen, (C1-C4)alkyl, NH-(C1-C4)alkyl, N[(C1-C4)alkyll2 or NH-phenyl. Most preferably. R-j is H. {C-|-C2)alkyl or NH-(C1-C2)alkyl. especially prefered H. Preferably. R2 is H, halogen or (C1-C4)alkyl. Preferably. R2 is H or (C1-C4)alkyl. More preferred. R2 is H, (C1-C2)alkyl. R2 may be bound to any carbon atom of the piperidine ring including the position where the linker group L is bound. R3 is preferably H. halogen. (C1-C4)alkylene-R' 0-R" or NHR". More preferred. R3 is H or NHR". Most preferred. R3 is H. NH-(C5-C6)heterocyclyl or NH-phenyl, especially preferred are H, NH-(C5-C6)heteroaryl containing one or more N atoms or NH-phenyl. Most especially preferred. R3 is H. Examples of R3 substituents are Preferably. R4 is H, halogen or (C1-C6)alkyl. More preferred, R4 is H, halogen or (C-|-C4)alkyl. Most preferred. R4 is H. Preferably. R5 is H. halogen. CN, (C1-C6)alkyl. R' NH-(C6-C-10)aryl or (C1-C6)alkylene-R' More preferably, R5 is H. halogen. (C1-C6)alkyl. R'. NH-(C6-C-10)317' or (C1-C6)alkylene-R' Most preferably, R5 is H, halogen, (C6-C10)aryl, NH.(C6-C10)aryl. (C1-C2)alkyKC6-C10)aryl. (C1-C6)alkyl or (C5-C10)heteroaryl. Especially preferred, R5 is H, halogen, phenyl. (C1-C5)alkyl or (C5-C6)heteroaryl. Examples of R5 are hydrogen, fluoro, chloro, bromo, iodo, nitrile. nitro. (p-methoxy)-phenyl. N-aniline. phenyl, benzyl, methyl, ethyl, vinyl, 2-propenyl. s-butenyl, cyclopropyl, thienyl, tetrazol, amino, 4-methoxy-anilin, N-acetyl or a substituent of the group consisting of Preferably, R6 is H, (C1-C6)alkyl, R', (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-C{0)-(C5-C10)heterocyclyl, (C1-C4)alkylene-C(0)-(C6-C10)afyl or (C1-C6)alkylene-(C6-C10)ary- More preferred, R6 is H, (C1-C6)alkyl, (C5-C10)heterocyclyl, (C1-C4)aikylene-(C5-C10)heterocyclyl or (C1-C6)alkylene-(C6-C-10)aryl- Examples of R6 are H. methyl, ethyl, propyl, butyl, s-butyl, pentyl, 3-methyl-butyl, isopropyl, trifluoromethyl, 3,3.3-trifluorobutyl. cycJopropyl. methylene cyclopropyl. 2-pyrimidinyl, benzyl or a substituent of the group consisting of Preferably, R7 is H, halogen. CN, (C1-C6)alkyl. (C2-C6)alkenyl, R' or (C1-C6)alkylene-(C3-C8)cycloaIkyL More preferred, R7 is H, halogen. CN. {C-i-C4)alkyl. (C1-C4)alkenyl, phenyl, cyclopropyl or (C5-C6)heteroaryl. Most preferably. R7 is H. fluoro. chloro. bromo, methyl, ethyl, phenyl, nitrile. cyclopropyl, thienyl or vinyl. R8 is preferably H, halogen or (C1-C4)alkyl. More preferred. R8 IS H, CI. F. methyl or ethyl. Preferably, n is 1. 2 or 3. More preferred, n is 1. The linker group L may be bound to the piperidine ring in any position via a piperidine ring carbon atom. In a preferred embodiment, L is attached to the 4-position of the piperidine ring L is attached to the 3-position of the piperidine ring In an especially preferred embodiment, L is attached to the 4-position of the piperidine ring. In a further preferred embodiment, L is O-methylene, 0-ethylene or preferably O. More preferably, L is O-methylene, 0-ethylene or O attached to the 4-position of the piperidine ring. In preferred embodiments of the present invention one or more or ail of the groups contained in the compounds of fomiula (I) can independently of each other have any of the preferred, more preferred or most preferred definitions of the groups specified above or any one or some of the specific denotations which are comprised by the definitions of the groups and specified above, all combinations of preferred definitions, more preferred or most preferred and/or specific denotations being a subject of the present invention. Also with respect to all preferred embodiments the invention includes the compounds of the formula (I) in all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and their physiologically acceptable salts. The term "*-" in the exemplified substituents vide supra marks the point where the substituent is attached, which means, for example, for a R3 substituent a compound of the fomiula A preferred embodiment is a compound of the formula (I) wherein R1 is H, (C1-C6)alkyl, (C6-C10)aryl, NH-(C1-C6)aikyl. NH-(C6-C10)aryl. or N[(C1-C6)alkyl]2; R2 is hydrogen, halogen, or (C1-C6)alkyl; R3 is H, halogen, (C1-C4)alkylene-R', O-R" or NHR", wherein R" and R" are defined as above; R4 is H, halogen or (C1-C6)aikyl; R5 is H, halogen. (C1-C6)alkyl, CN. (C6-C10)aryl, NH-(C6-C-10)aryl. (C1-C6)alkylene-(C6-C10)aryl. (C5-C10)'^6terocyclyl or (C1-C6)alkylene-(C5-C10)heterocyclyl; R6 is H, R', (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C6)alkylene-C(0)-(C6-C10)aryl. (C1-C4)alkylene-C(0)-(C5-C10)heterocyclyl, (C1-C6)alkylene-{C6-C10)aryl or (C1-C6)alkyl. R7 is H, halogen, CN, (C1-C6)alkyl, (C2-C6)alkenyl or R'; ' R8 is H, halogen or (C1-C6)alkyl; n is 1, 2 or 3, and L is O, 0-methylene or 0-ethylene; and their pharmaceutically acceptable salts and/or physiologically functional derivatives. A further preferred embodiment is a compound of the formula (I) wherein R1 is H. (C1-C6)alkyl, (C6-C10)aryl. NH-(C1-C6)alkyl. NH-(C6-C10)aryl. or N[(C1-C6)alkyl]2; R2isH or(C1-4)alkyl; R3 is H. halogen or NHR". wherein R" is defined as above; R4 is H. halogen or (C1-C4)alkyl; R5 is H. halogen. (C1-C6)alkyl, (C6-C10)aryl, NH-(C6-C-io)aryl. (C1-C6)alkylene.(C6-C-10)aryl or (C5-C10)heterocyclyl; R6 is H. (C1-C6)alkyl. R'. (C-|-C4)alkylene-(C5-C10)heterocyclyl or (C1 -C6)alky lene-(C6-C 1 o)aryl; R7 is H. halogen. CN, (C1-C6)alkyl, (C2-C6)alkenyl or R'; R8 is H, halogen or (C1-C6)alkyl; n is 1, 2 or 3; and L is O; and their phamnaceutically acceptable salts and/or physiologically functional derivatives. An especially preferred ennbodiment is a compound of the fornnula (I) wherein Rl is H, (C1-C4)alkyl. NH-(C1-C4)alkyl, N[(C1-C4)alkyl]2 or NH-phenyi; R2isH, (C1-C4)alkyl; R3 is H, NH-(C5-C6)heteroaryl or NH-phenyl; R4 is H, halogen or (C-|-C4)alkyl; R5 is H, halogen. (C-|-C4)alkyl, (C6-C10)aryl, NH-(C6-C10)aryl. (C1-C2)alkyKC6-C10)aryl or (C5-C10)heteroaryl; R6 IS H. (C1-C6)alkyl. (C5-C10)heterocyclyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C6-C10)aryl or (C1-C6)alkylene-(C6-C10)aryl; R7 is H, halogen, CN, (C1-C4)alkyl, (C1-C4)alkenyl, phenyl, cyclopropyl, (C5-C5)heteroaryl; R8 is H. halogen or (C1-C4)alkyl; n is 1; and L is O; and their physiologically acceptable salts and/or physiologically functional derivatives. As in any embodiment of the invention, in the preceding embodiments which contain preferred, more preferred, most preferred or exemplary definitions of compounds according to the invention, one or more or all of the groups can have any of its preferred, more prefered. most preferred definitions specified above or any one or some of the specific denotations which are comprised by its definitions and are specified above. Isoquinoline and piperidyl substitution pattern are numbered text according to lUPAC rules: Physiologically acceptable salts of compounds of the formula (I) mean both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). Because of the physical and chemical stability and the solubility, preference is given for acidic groups inter alia to sodium, potassium, calcium and ammonium salts; preference is given for basic groups inter alia to salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates. malates, gluconates, and salts of amino acids, of natural bases or carboxylic acids. The preparation of physiologically acceptable salts from compounds of the formula (I) and (II) which are capable of salt fomation, including their stereoisomeric fomns, takes place in a manner known per se. The compounds of the fomiula (I) fomi stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanoiamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine. Where the compounds of the formula (I) have basic groups, stable acid addition salts can also be prepared with strong acids. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric. nitric and sulfuric acid, and of organic acids such as. for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic. lactic, lactobionlc. maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Salts with a physiologically unacceptable anion such as. for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic. for example in vitro, applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the fomiula (I) of the invention, for example an N-oxide, which on administration to a mammal such as. for example, a human is able to fonn (directly or indirectly) a compound of the formula (I) or an active metabolite thereof. Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al.. Chem. Pharm. Bull, 1994. 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not. The invention relates to compounds of the formula (I) in the form of their racemates, racemic mixtures and pure enantiomers and to their diastereomers and mixtures thereof. If radicals or substituents may occur more than once in the compounds of the formula (I), they may all, independently of one another, have the stated meaning and be identical or different The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention. All references to "compound(s) of fonnula (I)" hereinafter refer to compound(s) of the formula (I) as described above, and their physiologically acceptable salts, solvates and physiologically functional derivatives as described herein. The temns (C1-C2)alkyl. (C1-C4)alkyl. (C1-C6)alkyl. (C1-C8)alkyl and the corresposponding alkylene substituents are understood as a hydrocarbon residue which can be linear, i.e. straight-chain, or branched and has 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. This also applies if an alkyl group occurs as a substituent on another group, for example in an alkoxy group (O-alkyI), S-alkyI or a -0(Ci- C6)alkylene-0-, an alkoxycarbonyl group or an arylalkyi group. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl, the n-isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl. isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl. isohexyl, sec-butyl, tert-butyl or tert-pentyl. Alkyl groups may - if not othenvise stated - be halogenated once or more, i.e. alkyl groups may be fluorinated, i.e. perfluorinated. Examples of halogenated alkyl groups are CF3 and CH2CF3. OCF3. SCF3, or-0-(CF2)2-0-. Alkenyl are, for example, vinyl, 1-propenyl, 2-propenyl (= allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl. 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl. Alkynyl are. for example, ethynyl, 1-propynyl. 2-propynyl (= propargyl) or 2-butynyl. Halogen means fluoro, chloro, bromo or iodo, (C3-C8)cycloalkyl groups are cyclic alkyl groups containing 3, 4. 5, 6, 7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1 or 2 double bounds (unsaturated cycioatkyi groups) like, for example, cyclopentenyl or cyclohexenyl can be bonded via any carbon atom. A (CQ-C-io)aryl group means an aromatic ring or a ring system which comprises two aromatic rings which are fused or otherwise linked, for example a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon-. indanyl- or indan-1-on-yl group. A preferred (C6-C10)aryl group is phenyl. A (C5-C10)heterocyclyl group means a mono- or bicyclic ring system which comprises, apart from carbon, one or more heteroatoms such as, for example, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms. 1 or 2 sulfur atoms or combinations of different hetero atoms. The heterocydyl residues can be bound at any positions, for example on the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. (C5-C10)heterocydyl groups may be (1) aromatic [= heteroaryl groups] or (2) saturated or (3) mixed aromatic/saturated. Suitable (C5-C10)heterocyclyl group include acridinyl. azocinyl, benzimidazolyl. benzofuryl, benzomorpholinyl. benzothienyl, benzothiophenyl. benzoxazolyl. benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl. carbolinyl, furanyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, chromen-2-onyl, cinnolinyl, decahydroquinolinyl. 2H,6H-1,5.2-dithiazinyl, dihydrofuro[2.3"b]-tetrahydrofuran, furyl. furazanyl. homomorpholinyl, homopiperazinyl, imidazolidinyl. imidazolinyl, imidazolyl, 1 H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl. 1,2,3-oxadiazolyl. 1,2.4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl. oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl. phenanthrolinyi, phenazinyl, phenothiazinyl. phenoxathiinyl, phenoxazinyl. phthalazinyl, piperazinyl, piperidinyl, prolinyl, pterldinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiada2inyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadia2olyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl. Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2- and 3-thienyl. Furyl stands both for 2- and 3-furyl. Also included are the corresponding N-oxides of these compounds, for example, 1-oxy-2-, 3- or 4-pyridyl. Substitutions in (C5-C10)heterocyclyl residues can occur on free carbon atoms or on nitrogen atoms. Preferred examples of (C5-C10)heterocyclyl residues are pyrazinyl, pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl. benzofuryl, quinolinyl, tetrazolyl and triazolyl. (C5-C10)afy' and (C5-C10)heterocyclyl groups are unsubstituted or substituted one or more times by suitable groups independently selected from halogen, CF3, NO2, N3, CN, C(0)-(C1-C6)alkyl. C(0)-(C1-C6)aryl, COOH, COO(C1-C6)alkyl. CONH2, CONH(C1-C6)alkyl. CONI(C1-C6)alkyl]2. (C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-0H, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)alkynyl. 0-(C1-C6)alkyl. 0-C(0)-(C1-C6)alkyl, 0-C(0)-(C6-C10)aryl, 0-C(0)-(C5-C10)heterocyclyl, PO3H2, SO3H. SO2-NH2, S02NH(C1-C6)alkyl, S02N[(C1-C6)alkyl]2 . S-(C1-C6)alkyl: S-(C1-C6)alkylene-(C6-C10)aryl, S-(C1-C6)alkylene-(C5-C10)heterocyclyl, S0-(C1-C6)alkyl, SO-(C1-C6)alkylene-(C6-C-10)aryl. SO-(C1-C6)alkyIene-(C5-C10)heterocyclyl, SO2-(C1 -C6)alkyl. S02-{Ci -C6)alkylene-(C6-C 1 o)aryl, S02-(C1-C6)alkylene-(C5-C10)heterocyclyl, S02-NH(C1-C6)alkylene-(C6-C-10)aryl, S02-NH(C1-C6)alkylene-(C5-C10)heterocyclyl, S02-N[(C1-C6)alkyl3[(C1-C6)alkylene-(C6-C10)aryl],S02-N[(C1-C6)alkyl][(C1-C6)alkylene-(C5-C10)heterocyclyl], S02-N[(C1-C6)alkylene-(C6-C10)aryl]2. S02-N[(C 1 -C6)alky lene-(C5-C 1 o)heterocyclyl]2. C(NH)(NH2). NH2. NH-(C1-C6)alkyl. N[(C1-C6)alkyl]2. NH-C(0HCi-C6)alkyl, NH-C(0)0-(C1-C6)alkyl, NH-C(0)-(C6-C10)aryl. NH-C(0)-(C5-C10)heterocyclyl, NH-C(0)0-(C6-C10)aryl, NH-C(0)0-(C5-C10)heterocyclyl. NH-C(0)-NH-(C1-C6)alkyl, NH-C(0)-NH-(C6-C10)aryl, NH-C(0)-NH-(C5-C10)heterocyclyl, NH-S02-(C1-C6)alkyl, NH-S02-(C6-C10)aryl, NH-S02-(C5-C10)heterocyclyI, N(C1-C6)alkyl-C(0)-(C1-C6)alkyl, N(C1-C6)alkyl-C{0)0-(C1-C6)alkyl, N(C1-C6)alkyl-C(0)-(C6-C10)aryl, N(C1-C6)alkyl-C(0)-heterocyclyl, N(C1-C6)alkyl-C(0)0-(C6-C10)aryl. N(C1-C6)alkyl-C(0)0-(C5-C10)heterocyclyl, N(C1-C6)alkyl-C(0)-NH-(C1-C6)alkyl], N(C1-C6)alkyl-C(0)-NH-(C6-C10)aryl, N(C1-C6)alkyl-C(0)-NH-(C5-C10)heterocyclyl. N[(C1-C6)alkyl]-C(0)-N[(C1-C6)alkyl]2. N[(C1-C6)alkyl]-C(0)-N[(C1-C6)alkylHC6-C10)aryl, N[(C1-C6)alky!]-C(0)-N[(C1-C6)alkylHC5-C10)heterocyclyl. N[(C1-C6)alkyl]-C(0)-N[(C6-C10)aryl]2. N[(C1-C6)alkyl]-C(0)-N[(C5-C10)heterocyclyl]2,N[(C6-C10)aryl]-C(OHCi-C6)alkyl. N[(C5-C10)heterocyclyl]-C(0)-(C1-C6)alkyl. N[(C6-C10)aryl]-C(0)0-(C1-C6)alkyl. N[(C5-C-10)heterocyclyl]-C(0)0-(C1-C6)alkyl, N(aryl)-C(0)-(C6-C10)aryl, N[(C5-C10)heterocyclyl]-C{0)-(C6-C10)aryI, N[(C6-C10)aryl]-C(0)0-(C6-C10)aryl. N[(C5-C10)heterocyclyl]-C(0)0-(C6-C10)aryl, N[(C6-C10)aryl]-C{0)-NH-(C1-C6)alkyl. N[(C5-C10)heterocyclyl]-C(0)-NH-(C1-C6)alkyl, N(aryl)-C(0)-NH-(C6-C10)aryl, N[(C5-C10)heterocyclyl]-C(0)-NH-(C6-C10)aryl, N[(C6-C10)aryl]-C(0)-NI(C1-C6)alkyl]2. N[(C5-C10)heterocyclyI]-C(0)-N[(C1-C6)alkyl]2.N[(C6-C-10)aryl]-C{0)-N[(C1-C6)aIkyl]- (Ce-C 1 o)aryl. N[(C5-C10)heterocycIyi]-C(0)-N[(C1 -C6)alkyl]- (C6-C10)aryl. N[(C6-C10)aryl]-C(0)-N[(C6-C10)aryl]2. N[(C5-C10)heterocyclyl]-C(0)-N[(C6-C10)aryl]2, (C6-C10)aryl, (C1 -C6)alkylene-(C6-C10)aryl, 0-(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl, (C1-C6)alkylene-(C5-C10)heterocyclyl, 0-(C1-C6)alkylene-(C5-C10)heterocyclyl, wherein the (C6-C10)aryl or (C5-C10)heterocyclyl may be substituted one to 3 times by halogen. OH, NO2. CN. 0-(C1-C6)aIkyl. (C1-C6)afkyl. NH2. NH(C1-C6)afkyl, N[(C1- C6)alkyl]2. SO2CH3, COOH, C(0)0-(Ci"C6)alkyl. CONH2. {Ci"C6)alkytene-0-(C1- C6)alkyl, (C1-C6)a(kyfene-0-(C6-C-10)aryf. 0-(C1-C6)afkylene-(C6-C10)aryl; or wherein (CQ'C^o)ary] is vIcJnalJy substituted by a 0-(C'i-C4)alkylene-0 group whereby a 5-8-memberecl ring is formed togetiier >with the carbon atoms the oxygen atoms are attached to. Aryl or heterocyclyl substituents of (CQ'C^Q)ary\ and (C5-C-to)heterocyclyl groups may not be further substituted by an aryl or heterocyclyl containing group. Preferred substituents.for (C5"C-io)ary' groups are (C-|-C4)alkyl, 0-(C-|-C4)alkyl, 0-phenyl, C{0)0"(C1-C6)alkyl. C(0)OH. C(OHCi-C4)alkyl, halogen, NO2. SO2NH2. CN. S02-(C1-C4)alkyl, NH-S02-(C1-C4)alkyl. NH2. NH-C(0HCi-C4)alkyl. (C3-C8)cycloalkyl. (C1-C4)alkyl-0H. C(0)Nl(C1-C4)aikyl]2. C(0)NH2. N[(C1-C4)a(kyfJ2, (C1-C4)alkenytene-(C6-C'(o)3ry(. wherein the (C6-C10)ary/ may be further substituted by (Ci'C4)a)kyl. (C1-C4)alky)ene«0-(C-j-Cs)alkyl. 0-(C-j-C6)alkyl-(C6-C10)aryl. or may be vicinally substituted by a 0-(C-i"C4)alkylene-O group whereby a 5-8-membered ring is fomied together with the carbon atoms the oxygen atoms are attached to. In monosubstituted phenyl groups the substituent can be located in the 2-position, the 3-position or the 4-position, with the 3-position and the 4-position being preferred. If a phenyl group carries two substituents. they can be located in 2.3-position, 2,4-position. 2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenyl groups carrying three substituents the substituents can be located in 2,3,4-position, 2,3,5*position, 2.3,6-position, 2,4,5-position, 2.4,6-position, or 3,4,5-position. The above statements relating to phenyl groups correspondingly apply to divalent groups derived from phenyl groups, i.e. phenylene which can be unsubstituted or substituted 1,2-phenylene, 1.3-phenylene or 1.4-phenylene. The above statements also correspondingly apply to the aryl subgroup in arylalkylene groups. Examples of arylalkylene groups which can also be unsubstituted or substituted in the aryl subgroup as well as in the alkylene subgroup, are benzyl. 1-phenylethylene, 2-phenylethylene, 3-phenyipropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene. Preferred substituents for (C5-C10)heterocyclyl groups are (C1-C4)alkyl. 0-(C1-C4)alkyl, (C1-C4)alkylene-phenyl, halogen. (C-|-C4)alkylene-0-(C-|-C4)alkyl. (C5-C10)heterocyclyl, (C-|-C4)a!kylene-N[(C'j-C4)alkyl]2. or (C6-C10)aryl. wherein the (C6-C-10)3ryl may be further substituted by (C-|-C4)alkyl, (C1-C4)a!kyiene-0-(C1-C6)alkyl, 0-(C1-C6)alkyKC6-C10)aryl. or may be vicinally substituted by a 0-(C1-C4)alkylene-O group whereby a 5-8-nnembered ring is formed together with the carbon atoms the oxygen atoms are attached to. The general and preferred substituents of (C6-C10)aryl and (C5-C10)heterocyclyl groups may be combined with the general and preferred definitions of R1. R2, R3, R4. R5. R6- R7 R8 n and L as described above. The present invention therefore also relates to the compounds of the formula (I) and/or their physiologically acceptable salts and/or their prodrugs for use as phamrtaceuticals (or medicaments), to the use of the compounds of the formula (I) and/or their physiologically acceptable salts and/or their prodrugs for the production of pharmaceuticals for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, i.e. for the treatment and/or prevention of hypertension, i.e. pulmonary hypertension and ocular hypertension, peripheral circulatory disorder, angina pectoris, cerebral vasospasm, asthma, premature birth, hyperaggregability of platelets, Peripheral Occlusive Arterial Disease (PAOD). Chronic Obstructive Pulmonary Disease (COPD), cancer development, erectile dysfunction, arteriosclerosis, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, fibroid kidney, renal glomerulosclerosis, kidney failure, organ hypertrophy, prostatic hypertrophy, complications of diabetes, blood vessel restenosis, atherosclerosis, cancer, cardiac hypertrophy, heart failure; ischemic diseases; inflammation; autoimmune diseases; AIDS, osteopathy such as osteoporosis, brain functional disorder, infection of digestive tracts with bacteria, sepsis, adult respiratory distress syndrome, retinopathy, glaucoma and Alzheimer's disease. The present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one compound of the formula (I) and/or its physiologically acceptable salts and/or its prodrugs and a pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients). The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the fomi of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously. in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays. The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formula (I) and/or its (their) physiologically acceptable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carrier substances for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils. etc. Suitable carrier substances for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90 % by weight of the compounds of the formula (I) and/or their physiologically acceptable salts and/or their prodrugs. The amount of the active ingredient of the formula (I) and/or its physiologically acceptable salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg. In addition to the active ingredients of the formula (I) and/or their physiologically acceptable salts and/or prodrugs and to carrier substances, the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula (I) and/or their physiologically acceptable salts and/or their prodrugs. In case a pharmaceutical preparation contains two or more compounds of the formula (I) the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency. The flexibility permitted with respect to the choice of substituents in the compounds of the formula (I) allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds. Furthermore, in addition to at least one compound of the formula (I) and/or its physiologically acceptable salts and/or its prodrugs, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients. When using the compounds of the formula (I) the dose can vary within wide limits and. as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out. An appropriate dosage can be established using clinical approaches well known in the medical art. In general, the daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg. in particular from about 0.1 to about 10 mg/kg, (in each case in mg per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated. Furthermore, the compounds of the formula (I) can be used as synthesis intemiediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups. The compounds of the formula (I) can be prepared according to the following exemplified compounds without limiting the scope of the claims. In general, protective groups that may still be present in the products obtained in the coupling reaction are then removed by standard procedures. For example, tert-butyl protecting groups, in particular a tert-butoxycarbonyl group which Is a protected form of an amidino group, can be deprotected. i. e. converted into the amidino group, by treatment with trifluoroacetic acid. As already explained, after the coupling reaction also functional groups can be generated from suitable precursor groups. In addition, a conversion into a physiologically acceptable salt or a prodrug of a compound of the formula (I) can then be carried out by known processes. In general, a reaction mixture containing a final compound of the formula (I) or an intermediate is worked up and. if desired, the product is then purified by customary processes known to those skilled in the art. For example, a synthesized compound can be purified using well known methods such as crystallization, chromatography or I reverse phase-high performance liquid chromatography (RP-HPLC) or other methods of separation based, for example, on the size, charge or hydrophobicity of the compound. Similarly, well known methods such as amino acid sequence analysis. NMR. IR and mass spectrometry (MS) can be used for characterizing a compound of the invention. It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not limit the present invention. LCMS methods Method #1 Column: YMC J'shere 33x2 4pm gradient (AcN+0.05% TFA): H2O+0.05% TFA; 5:95 (Omin) to 95:5 (2.5 min) to 95:5 (3 min) Method #2 Column: YMC J'shere 33x2 4|jm gradient (AcN+0.05% TFA): H2O+0.05% TFA. 5:95 (Omin) to 95:5 (3.4min) to 95:5 (4.4min) Method #3 Column: YMC J'shere 33x2 4µm gradient AcN+0.08%FA : H2O+0.1%FA; 5:95 (Omin) to 95:5(2.5min) to 95:5(3min) Method #Top Column: YMC YMC J'sphere ODS H80 20X2 1 4µ gradient 0 min 96%H2O(0.05%TFA) 2.0min-95%ACN; 95%ACN bis 2.4min;4%ACN 2.45min Building block syntheses 7-Bromo-isoquinoline-6-ol (1) 25 g (116.3 mmol) of 3-bromo-4-methoxybenzaldehyde, 19.0 mL (18.3 g, 174.5 mmol) of aminoacetaldehyde dimethyl acetal and 250 mL of toluene were heated to reflux for 6 h using a Dean-Stark apparatus. Solvent and excess reagent were distilled off and the crude product ( approx. 37 g) was used for the next step without any additional purification. The imine was dissolved in 240 mL of THF. 11.1 mL(12.6g, 116.3 mmol) of ethyl chloroformate were added dropwise at O°C. After stirring for 5 minutes 24.3 mL (23.2 g, 139.2 mmol) triethylphosphite were added dropwise. The mixture was stirred for 18 h at room temperature. Then the solvents were distilled off. Excess reagent was removed by repeated addition of 100 ml toluene and evaporation of the solvents. The P,N-acetal (approx. 62 g ) was used for the next step without any additional purification. The P,N-acetal, 51.3 mL (88.2 g, 465.2 mmol) titanium tetrachloride and 300 mL chloroform were heated to reflux for 48 h. The mixture was poured on ice and the pH was adjusted to 9 by using aqueous ammonia. Repeated extraction with ethyl acetate followed by removal of the solvents gave 14,8 g (53%.) of 7-brom0-6- methoxyisoquinoline. 1H-NMR (de-DMSO): § = 9.16 (1H. s). 8.46 (1H, d. J = 5.9 Hz), 8.46 (1H, s). 7.76 (1H, d, J = 5.9 Hz), 7.51 (1H, s). 4.01 (3H. s). MS: m/2 = 238 (MH+). 3.6 mL (9.5 g. 37.8 mmol) of BBr3 were added at 0°C to a solution of 4.5 g (18.9 mmol) 7-brom0-6-methoxy isoquinoline in 30 mL dichloromethane and stirred for 18 h at room temperature. Aqueous NaHCOa-solution was added to adjust the pH to 8. Extraction with chloroform/isopropanol (3/1) followed by drying over sodium sulfate and removal of the solvents gave 2,7 g (64%) of compound 1. 1H-NMR (ds-DMSO): 5 = 9.19 (1H, s), 8.49 (1H, s), 8.38 (1H, d, J = 6.1 Hz), 7.78 (1H, d, J=6.1 Hz), 7.34(1 H,s). MS: m/z = 224 (MH+). The following intermediates were synthesized using this procedure: 1H-NMR (de-DMSO): 5 = 10.84 (1H, s), 9.21 (1H, s), 8.40 (1H, d, J = 5.8 Hz), 7.67 (1H, d, J = 5.8 Hz). 7.01 (2H, m). MS:m/z = 164(MH+). 1H-NMR (de-DMSO): 5 = 11.06 (1H, s), 9.07 (1H, s), 8.33 (1H, d, J = 5.6 Hz), 7.88 (1H. d, J = 11.4 Hz), 7.64 (1H, d. J = 5.6 Hz), 7.31 (1H, d, J = 8.6 Hz). MS:m/z=164(MH+). 8-Methyl-isoquinoline-6-ol (4) 1H-NMR (de-DMSO): 5 = 11.55 (1H. s), 9.47 (1H, s), 8.42 (1H. d, J = 6.5 Hz), 8.11 (1H, d, J = 6.5 Hz), 7.31 (1H, s), 7.25 (1H, s), 2.76 (3H, s). MS:m/z=160(MH+). 1H-NMR (de-DMSO): 6 = 11.87 (1H, s), 9.58 (1H, s), 8.41 (1H, d, J = 6.5 Hz). 8.18 (1H. d, J = 6.5 Hz), 7.35 (1H, s), 7.25 (1H, s), 2.71 (3H. s), 2.35 (3H. s). MS:m/z=174(MH+). 1H-NMR (de-DMSO): 5 = 11.55 (1H. s), 9.52 (1H, s), 8.47 (1H, d, J = 6.8 Hz), 8.26 (1H, d, J = 6.8Hz), 7.42 (1H, s), 2.76 (3H, s), 2.42 (3H. s). MS:m/z=174(MH+). LCMS Method # 1, retention time 0.14 min, detected mass 146.08 [M+Hf 0.61 mL (1.02 g, 7.6 mmol) of sulfuryl chloride were added to a solution of 1.0 g (6,9 mmol) of compound 7 in 30 mL of dichloromethane. Three drops diethyl ether were added and the reaction was stirred at roonn temperature for 5 h. The solvents were removed by distillation and the remainder was treated with aqueous NaHCOs solution. The precipitate was filtered, washed with water and dried to give 1.1 g (89%) of compound 8 as a green-yellow solid. 1H-NMR (de-DMSO): 5 = 11.37 (IH, s), 9.18 (1H, s). 8.50 (1H. d, J = 6 Hz). 8.00 (1H. d. J= 8.8 Hz). 7.83 (IH. J = 6 Hz). 7.44 (IH. d. J = 8.7 Hz). MS:m/z=180(MH^). 7.9 mL (19.18 g, 120 mmol) of bromine were added dropwise to a suspension of 17.42 g (120 mmol) of compound 7 in 250 mL of chloroform at room temperature. After stirring for 2 h ethyl acetate was added. The precipitate was filtered, washed with ethyl acetate and dried. Aqueous NaHCOs solution was added carefully. The precipitate was filtered and washed with NaHCOs solution until the filtrate had a pH of 8. Drying gave 23.78 g (88%) of compound 9 as an off-white solid. 1H-NMR (de-DMSO): 5 = 11.30 (IH. s). 9.13 (IH. s). 8.48 (IH. d, J = 5.9 Hz). 8.02 (1H. d, J= 8.8 Hz). 7.78 (IH. J = 5.9 Hz), 7.40 (IH. d, J = 8.8 Hz). MS: m/z = 224 (MH^). Under argon atmosphere 1.77 g (12.2 mmol) of compound 7 were added to a solution of 5.0 g (13.5 mmol) bis(pyridin)iodonium tetrafluoroborate in 100 mL of dry dichloromethane. A solution of 2.4 mL (4 g. 26.8 mmol) trifluoromethane sulfonic acid in 20 mL dry dichloromethane was added dropwise at 0°C and the mixture was stirred for 3 hours at room temperature. The solvents were removed by distillation and the remainder was treated with aqueous NaHCOa solution. The precipitate was filtered, washed with water and dried to yield 3.2 g (97%) of compound 10 as a t)eige solid. 1H-NMR (de-DMSO): 5 = 9.09 (1H. s). 8.47 (1H. d, J = 6.1 Hz), 8.04 (1H. d, J= 8.8 Hz). 7.76 (1H. J = 6.1 Hz), 7.37 (1H. d, J = 8.8 Hz). MS: m/z = 272 (MH+). 3.75 mL (4.15 g, 23.8 mmol) of diethyl azo dicarboxylate were added to 12.7 g (19.9 mmol) of polymer-bound triphenylphosphine (PS-PPha, approx. 1.6 mmol/g. Argonaut) in 250 mL of dichloromethane at 0°C and stirred for 15 min. 4.45 g (19.9 mmol) 5-bromo isoquinoline-6-ol (9), 4.0 g (19.9 mmol) Boc-(4-hydroxy)piperidine and 4.1 mL (3.0 g, 29.8 mmol) triethyl amine were added. The mixture was shaken for 16h. The polymer was removed by filtration through Celite and the solvents were distilled off. 20 mL dichloromethane were added and the precipitate was isolated by filtration. The crude product (8 g) was purified by flash chromatography using ethyl acetate/n-heptane as eluent to give 4.78 g (60%) of compound 11, 1H-NMR (de-DMSO): 6 = 9.24 (1H, s), 8.97 (1H. s), 8.56 (1H. d. J = 6 Hz), 8.20 (1H, d, J = 9 Hz), 7.85 (1H. d. J= 6 Hz), 7.75 (1H, d. J = 9 Hz). 5.02 (1H, m). 3.58 (2H. m), 3.40 (2H, m). 1.91 (2H, m), 1.70 (2H, m), 1.41 (9H, s). MS: m/z = 407 (MH+). The following building blocks were synthesized according to this method: 4-(5-lodo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (12) using compound 10 as starting material 1H-NMR (CDCI3): 5 = 9.04 (1H. s), 8.55 (1H. d, J = 6 Hz). 7.93 (1H, d, J = 9 Hz). 7.86 (1H. d. J = 6 Hz). 7.27 (1H. d, J= 9 Hz). 4.87 (1H. m). 3.66 (4H. m), 1.93 (4H. m). 1.48 (9H, s). MS: m/z = 455 (MH+). using compound 1 as starting material LCMS Method #4, retention time 1.13 min. detected mass 407.4 [M+Hf A solution of 0.55 g (1.34 mmol) 4-(5-bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in 14 mL of DMSO was added to a mixture of 1.0 g (4.0 mmol) bis(pinacolato)diboron, 0.78 g (8.0 mmol) K2CO3 and 29 mg (0.03 eq.) Pd(dppf)Cl2. Argon was bubbled through the mixture for 30 min and then the reaction mixture was heated in a microwave reactor (CEM Discovery) to 100^*0 for 60 min. After cooling to room temperature water was added. The mixture was extracted with ethyl acetate. After removal of the solvent the product was isolated by flash chromatography (ethyl acetate/n-heptane) to yield; 269 mg (44%) of compound 14 as a white solid. LCMS Method # 4, retention time 1.30 min. detected mass 433.3 [M+Hf Under argon atmosphere 47 mg (0.4 mmol) of Zn(CN)2 and 23 mg of (0.02 eq) Pd(PPh3)4 were added to a solution 62 mg (0.4 mmol) of 4-(5-bromo-isoquinolln-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in DMF. The reaction was heated for 5 minutes to 150°C in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through celite. washed with ethyl acetate and concentrated to yield 176 mg of compound 15. MS: m/z = 354 (MH+). Under argon atmosphere 35 mg (0.3 mmol) of Zn(CN)2 and 17 mg (0.05 eq) of Pd(PPh3)4 were added to a solution of 122 mg (0.3 mmol) of 4-(7-bromO"isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (13) in DMF, The reaction was heated for 5 minutes to 150°C in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through Celite. washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to yield 77 mg of compound 16. LCMS Method #4, retention time 1.06 min, detected mass 354.5 [M+Hf Under argon atmosphere 40 pL (0.04 mmol) of 1N NaOH, 4.6 mg (0.04 mmol) of L-proline. 3.8 mg of (0.02 mmol) Cul and 15.6 mg (0.24 mmol) of NaNa were added to a solution of 91 mg (0.2 mmol) of 4-(5-iodo-isoquinoline-6-yloxy)-piperidin-1-carbbxylic acid tert-butyl ester (12) in 2 mL of DMSO. The mixture was heated to 60X for 18 h. NaN3. NaOH and L-proline were added in the same amounts again and the reaction was heated to 60X for 5 h. After cooling to room temperature water was added. The precipitate was filtered, washed with water and dried in vacuo to give 74 mg of compound 17. which was used without any additional purification. MS: m/z = 370 (MH+). Under argon atmosphere 600 pL (0.6 mmol) of IN NaOH, 13.8 mg (0.12 mmol) L-proline, 7.6 mg (0.04 mmol) of Cul and 52 mg (0.8 mmol) of NaNs were added to a solution of 163 mg (0.4 mmol) 4-(5-bromo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (11) in 0.6 mL of water The mixture was heated to 95°C for 3 h in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through Celite. washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to yield 42 mg of compound 18 (containing some 11 as impurity). LCMS Method # 4, retention time 0.97 min. detected mass 344.5 [M+H]+ Under argon atmosphere 340 mg tributyl-vinyl-stannane (1.07 mmol, 1.2 eq.) and 103 mg of Pd(PPh3)4 (0.1 eq.) were added to a solution of 364 mg of 4-(7-Bromo- isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyi ester (13) (0.98 mmol) in 4 ml of toluene. The reaction was heated to 100°C in a microwave reactor (CEM Discovery) for 1 h. After cooling to room temperature water and ethyl acetated were added. The mixture was filtered through a Celite cartridge, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to yield 256 mg (81 %) of compound 19. LCMS Method #4, retention time 1.19 min, detected mass 355.5 [M+H]+ The following building blocks were synthesized according to this method: using compound 11 as starting material LCMS Method # 4, retention time 1.11 min, detected mass 355.4 [M+H]+ 4-(7-Thiophen-2-yNsoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (20) using compound 13 and tributyl-thiophen-2-yl-stannane as starting materials. LCMS Method # 4, retention time 1.26 min, detected mass 411.5 [M+H]"" 12.4 g of 4-Fluoroben2aldehyde were dissolved in 100 mL of toluene and reacted with 10.5 g 2-Aminoacetaldehyde dimethylacetal and 1.90 g (10 mmol) p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 mL of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. Rt = 0.86 min (Method #1). Detected mass: 182.1 (M-OMel. 214.2 (M+H""). N-(2,2-Dimethoxy-ethyl)-N-(4"fluoro-benzyl)-4-methyl-ben2enesulfonamide (22) 20 g (2,2-Dimethoxy-ethyl)-(4-fluorO"benzyl)-amine (21) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine are added. At 0 **C a solution of 23.8 g p-toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95g of compound 22 as an orange oil. R1= 1.71 min (Method # 4). Detected mass: 336.1 (M-OMe"). 41.6 g of AICI3 were suspended in 400 mL of dichloromethane. At room temperature, a solution of 22.95 g of N-(2,2-Dimethoxy-ethyl)--(4-fluoro-benzyl)-4-methyl-benzenesulfonamide (22) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice. the organic layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers are then extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained cmde product (8.75g) is purified by silica gel chromatography to yield 2.74 g of compound 23. Rt = 0.30 min (Method # 4). Detected mass: 148.1 (M+H^). 4-Chlor0-6-fluoro-isoquinoline (24) A solution of 1.5 g 6-fluoro-isoquinoline (23) in 4.5 ml sulfuryi chloride was heated to 60 °C in a microwave reactor (CEM Discovery) for 8 h. After cooling to room temperature the mixture was poured on ice and extracted three times with CHCI3. After drying over Na2S04 the solvent was distilled off and the crude product was purified by flash chromatography to yield 930 mg of compound 24. LCMS Method # 1. retention time 1.37 min. detected mass 182.01 [M+H]' 213 mg (5.6 mmol) of NaBH4 were added portionwise at 0°C to a solution of 1.0 g (4.7 mmol) 1-Boc-2-methyl-piperidin-4-on in 10 mL EtOH. The mixture was stirred at room temperature for another 2 h. The solvent was removed by distillation and the remainder was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetated and the combined organic layers were dried over Na2S04. After filtration the solvent was removed by distillation and the crude product was purified by column chromatography n-heptane/ethyl acetate (1/1) to yield 367 mg (36%) of the cis-isomer 25 and 205 mg (20%) of the trans-isomer 26 in addition to 97 mg (10%) mixture of both isomers. Cis-lsomer (25): 1H-NMR (CDCI3): 5= 4.28 (1H. m). 4.17 (1H. m). 3.82 (1H. m). 3.26 (1H, m), 1.85 (1H, ddd, J= 14.7, 6.6. und 3.4 Hz). 1.77 (1H, m), 1,66 (2H. m). 1.33 (3H. d, J = 7.1 Hz). Trans-lsomer (26): 1H-NMR (CDCI3): 5 = 4.50 (1H. m). 4.04 (1H. m). 3.95 (1H. m). 2.87 (1H. dt. J = 2.9 und 13.6 Hz). 1.93 (1H. m). 1.83 (1H. m). 1.53 (1H. m), 1.32 (1H. m). 1.14 (3H. d. J = 7.1 Hz). Under an argon atmosphere 81 mg (0.2 mmol) of 4-(5-bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) and 24 mg (0.26 mmol) of aniline were added to a solution of 27 mg (0.28 mmol) of NaOfBu in 3 mL of toluene. After stirring at room temperature for 10 min.. 9 mg (0.05 eq) of Pd2ba3were added and the mixture was heated to 100°C in a microwave reactor (CEM Discovery) for 1h. After cooling to room temperature water and ethyl acetate were added. The organic layer was. separated, dried over Na2SO and concentrated. HPLC purification gave the Boc protected intermediate which was treated with 2 mL 5-6 N HCI in isopropanol for 2 h. The hydrochloride was filtered and subjected to another HPLC chromatography to yield compound 27 as trifluoroacetate (31.3 mg). LCMS Method # 2. retention time 0.78 min. detected mass 320.26 [M+H]+ 5-Methyl-6-(piperidin-4-yloxy)-isoquinoline hydrochloride (28) Under an argon atmosphere a 2 M solution of dinnethyl zinc (0.5 mL. 93.7 mg, 4 eq.) in toluene was added to a solution of 100 mg (0.24 mmol) 4-(5-bronno-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (11) and 10 mg (1,1-bis(diphenylphosphino)ferrocen)palladium(ll)chlorid (0.056 eq. Pd(dppf)Cl2) in 3 mL of dioxane. Tine mixture was heated to 100 °'C for 5 h. After cooling the solvents were distilled off and the remainder was subjected to preparative HPLC to give the Boc-protected intermediate which was treated with 5-6 N HCI in isopropanol for 2 h at room temperature. Removal of the solvents gave 13.7 mg (18%) of compound 28. LCMS Method # 1, retention time 0.67 min, detected mass 243.24 [M+H]+ 0.3 mL of water were added to a solution of 81 mg (0.2 mmol) of 4-(5-bromo-isoquinoline-6-yloxy)-piperidin-1- carboxylic acid tert-butyl ester (11). 195 mg (0.6 mmol) of CS2CO3. 14.6 mg (0.02 mmol) of Pd(dppf)Cl2 and 51 mg (0.26 mmol) of potassium benzyltrifluoroborate in 3 mL of THF, Argon was bubbled through the mixture for 10 minutes and then the reaction was heated to reflux for 16 h (incomplete conversion). After cooling to room temperature water and ethyl acetate were added. The organic layer was separated, dried over Na2SO4. After removal of the solvents 2 mL 5-6 N HCI in isopropanol was added. After 2 h the solvents were distilled off and the remainder was subjected twice to preparative HPLC to give 3.5 mg compound 29 as trifluoroacetate. LCMS Method # 3. retention time 0.56 min, detected mass 319.23 [M+H]+ A solution of 200 mg (0.44 mmol) 4-(5-iodo-isoquinorme-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (12), 107 mg (0.88 mmol) of DMAP, 4,7 mg (0.1 eq) of Pd on charcoal (10%). 150 pL (0.88 mmol) of triethyl amine and 58 mg (0.22 mmol) of Mo(CO)6 in 3 mL of ethanol was heated to 135°C for 1 h in a microwave reactor (CEM Discovery). Then water and ethyl acetate were added and the mixture was filtered through a Celite cartridge. After removal of the solvents the remainder was subjected to preparative HPLC to give the 7.4 mg Boc-protected intermediate. To remove the Boc group the intermediate was treated with 2 mL 5-6 N HCl in isopropanol at room temperature for 2 h. Purification by preparative HPLC gave 2.5 mg of compound 30 as TFA salt. 60 yL of 1N NaOH-solution. 6.9 mg (0.3 eq) of L-proline. 3.8 mg (0.1 eq) of Cul and 26 mg (0.4 mmol) of NaNa were added to a solution of 82 mg (0.2 mmol) of 4-(5-BromO" isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in 2 mL of ethanol/water (7/3). The mixture was heated to 95°C for 3 h in a microwave reactor (CEM Discover). After cooling water and ethyl acetate were added and the mixture was filtered through a celite cartridge. After removal of the solvents by distillation the remainder was subjected to preparative HPLC. The N-Boc-protected intermediate was deprotected by treatment with 2 mL 5-6 N HCl in isopropanol for 2 h at room temperature. Then water was added and all solvents were removed by freeze drying to yield 18 mg of compound 31 as hydrochloride. 1H-NMR (de-DMSO): 5 = 9.60 (1H, s). 8.95 (2H. br s). 8.56 (1H. d. J = 7.1 Hz), 8,41 (1H, d. J = 7.1 Hz), 7.85 (1H. d. J = 9.0 Hz), 7.81(1H, d, J = 9.0 Hz), 5.03 (1H. m), 3.13 (1H. m). 2.92 (1H, m), 2.15 (2H, m). 1.99 (2H. m), 1.84 (IH. m), 1.55 (1H, m). LCMS Method # 1. retention time 0.35 min, detected mass 244.25 [M+H]+ Under argon atmosphere 78 mg (1.2 mmol) of NaNs and 64 mg (1.2 mmol) of NH4CI were added to a solution of 35 mg (0.1 mmol) 4-(5-Cyano-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (15) in 1 mL of DMF. The mixture was heated to approximately 160°C and 7 bar pressure for 3 h in a microwave reactor (CEM Discovery). After cooling to room temperature aqueous NH4CI-solution and dichloromethane was added. The mixture was filtered through a phase separation cartridge and the aqueous layer was washed twice with dichloromethane. The organic layers were combined and the solvents were distilled off. The remainder was subjected to preparative HPLC to yield 4 mg (8%) of compound 32 as trifluoroacetate. LCMS Method # 3, retention time 0.90 min, detected mass 297.04 [M+H]+ 4 mg (0.1 eq.) of sodium ascorbate and 0.5 mg (0.01 eq.) of Copper(II)sulfate-hydrate were added to a solution of 73 mg (0.2 mmol) of 4-(5-Azido-isoquinoline-6-yloxy)- piperidin-1- carboxylic acid tert-butyl ester (17) and 14 mg (0.2 mmol) of methyl propargy! ether in 4 ml of water/tert-butanol (1/1). The mixture was stirred for 18 h at room temperature. Then ethyl acetate was added and the mixture was filtered through a Celite cartridge. After removal of the solvents the remainder was subjected to preparative HPLC. The N-Boc-protected intermediate was deprotected by treatment with 2 mL 5-6 N HCI in isopropanol for 2 h at room temperature. Then the solvent was evaporated and the product was isolated by preparative HPLC to yield 2.8 mg compound 33 as trifluoroacetate. LCMS Method # 3, retention time 0.08 min, detected mass 340.17 [M+H]+ According to the procedure described for compound 33 the title compound was obtained using 20 mg (0.2 mmol) phenylacetylene. Yield 2.5 mg of compound 34 as trifluoroacetate. LCMS Method # 3. retention time 0.14 min. detected mass 372.2 [M+H]+ 1 mg of 5 % Palladium on charcoal (0.02 eq.) was added to a solution of 174 mg 4-(7-Vinyl-isoquinolin-6-yloxy)"piperidine-1-carboxylic acid tert-butyl ester (19) (0.49 mmol, 1 eq.) in 15 mL of methanol. The olefin was hydrogenated under 5 bar H2 at ambient temperature over night. Only partial conversion was observed, thus the catalyst was removed by filtration and fresh catalyst was added. Another treatment under the same hydrogenation conditions completed the reaction. Then the catalyst was removed by filtration and the crude product was purified by preparative HPLC to give 97 mg of the Boc protected intermediate. The protecting group was removed by treatment with 5-6 N HCI in isopropanol for 2 h at room temperature. The solvent was distilled of and water and acetonitrile were added. Freeze drying of the mixture gave 53 mg of compound 35. LCMS Method #1, retention time 0.71 min. detected mass 257.18 [M+H]+ The following example compound was synthesized according to this method: using compound 19A as the starting material LCMS Method # 2, retention time 0.17 min. detected mass 257.21 [M+H]* At -78°C 0.6 mL (0.98 mmol. 1.6 M in hexane) n-butyl lithium were added to a solution of 200 mg (0.49 nnmol, 1 eq.) 4-(5-Bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in 3 mL of THF. After 30 min 110 pL (115 mg. 1.08 mmol) of benzaldehyde were added and the mixture was allowed to warm to ambient temperature. After 2 h of stirring at room temperature water and ethyl acetate were added. The layers were separated and the organic layer was washed with water and brine. After drying over Na2SO4 and evaporation of the solvent the remainder was subjected to preparative HPLC to yield the Boc protected intermediate. The Boc group was removed by dissolving the intermediate in isopropanol and addition of 5-6 N HCI in isopropanol. The precipitated hydrochloride was isolated by filtration to yield 5.2 mg of compound 37 (3 %). 1H-NMR (de-DMSO): 5 = 9.43 (1H. s), 8.50 (1H, br s), 8.40 (1H, br s). 8.30 (3H, m). 7.87 (1H, d, J = 9.2 Hz), 7.33 (2H. d. J = 7.4 Hz). 7.28 (2H. t. J= 7.4 Hz). 7.19 (1H, t, J = 7.4 Hz). 6.74 (1H. s). 6.34 (1H. s). 5.10 (1H. m), 3.25 (2H. m). 3.15 (2H. m), 2.19 (2H, m), 1.93 (2H.m). LCMS Method #1. retention time 0.80 min, detected mass 335.22 [M+H]+ The following example compound was also synthesized according to this method: LCMS Method # 1, retention time 0.55 min. detected mass 273.2 [M+H]+ 2.2,2-Trifluoro-N-[6-(piperidin-4-yloxy)-isoquinolin-5-yI]-acetamidetrifluoro-acetate (39) 62.8 mg of potassium carbonate (0.46 mmol, 4 eq.) and 10.7 pL of methanesulfonyl chloride (0.13 mmol. 1.2 eq.) were added to a solution of 39 mg (0.11 mmol) of 4-(5-AminO"isoquinoline-6-yloxy)- piperidin-1- carboxylic acid tert-butyl ester (18) (containing some compound 11) in 3 mL DMF. The reaction was stirred for 4 h at room temperature. Then water and ethyl acetate were added. The mixture was filtered through Celite. washed with ethyl acetate and concentrated to yield a single product. The N-Boc-protected intermediate was deprotected by treatment with 2 mL 5-6 N HCI in isopropanol for 2 h at room temperature. Then the solvent was evaporated and the product was isolated by preparative HPLC to yield 18.5 mg of compound 39. LCMS Method # 1. retention time 0.39 min, detected mass 340.15 [M+H]+ Under argon atmosphere 81.5 mg (0.2 mmol) of 4-(5-bromo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (11) and 14.2 mg of acetamide (0.24 mmol, 1.2 eq.) were added to a solution of 27 mg (0.28 mmol, 1.4 eq) of NaOtBu in 3 mL toluene. After stirring for 10 minutes at room temperature 9.1 mg (0.01 mmol, 0.05 eq) Pd2(dba)3 and 11.9 mg (0.04 mmol. 0.2 eq) of 2-(dt-butylphosphino)biphenyl were added. The reaction was heated to 120 °C for 2 h in a microwave reactor (CEM Discovery). Then water and ethyl acetate were added. The mixture was filtered through Celite. washed with ethyl acetate and concentrated. The remainder was subjected twice to preparative HPLC to yield the N-Boc-protected intermediate. The N-Boc-protected intermediate was deprotected by treatment with 2 mL 5-6 N HCI in isopropanol for 2 h at room temperature. Then the solvent was evaporated and the product was isolated by preparative HPLC to yield 2.5 mg of compound 40. LCMS Method # 3. retention time 0.15 min, detected mass 286,15 [M+H]* General procedure for Boc-deprotection of building blocks: The corresponding N-Boc-protected compounds were treated with 5-6 N HCI in isopropanol for 2 h at room temperature. The precipitated hydrochlorides weR6 isolated by filtration and dried. If necessary, additional purification by preparative HPLC was performed. General procedure for Suzuki-coupling with 4-(5-Bromo-isoquinoline-6-yloxy)-piperidin-1- carboxyjic acid tert-butyl ester (11) Aqueous Na2CO3 solution (0.2 ml, 0.4 mmol, 2 eq. 2M) was added to a solution of 81 mg (0.2 mmol, 1 eq.) of 4-(5-Bromo-isoquinoline-6-yloxy)-piperidin-1- carboxyiic acid tert-butyl ester (11) and 1.5 eq. (0.3 mmol) of the con"esponding boronic acid (reagent 2) in 3 mL of DME. Argon was bubbled through the reaction mixture for 10 min. Then 23 mg (0.1 eq.) Pd(PPh3)4 were added and the reaction was stired at 95 **C overnight under Argon atmosphere. After cooling 2 mL of water and 10 mL of ethyl acetate were added. The organic layer was separated, dried and the solvent was distilled off. The remainder was subjected to preparative HPLC. The Boc group was removed by dissolving the intermediate in isopropanol and addition of 5-6 N HC! in isopropanol. The precipitate was isolated by filtration. In some reactions no hydrochloride precipitated or the purity of the precipitate was unsatisfactory. In these cases the solvent was distilled off and the remainder was purified by preparative HPLC. The following examples were synthesized using this method: Suzuki coupling procedure for variation in the 5- and 7-position The base was added to a solution of reagent 1 (typically 0.2 mmol) and reagent 2 in DME. Argon was bubbled through the reaction mixture for 10 min. Then the catalyst was added and the reaction was stirred at reflux temperature overnight under Argon atmosphere. After cooling 2 mL of water and 10 mL of ethyl acetate were added. The mixture was filtered through a celite cartridge. The solvents were removed by distillation and the remainder was subjected to preparative HPLC. The isolated intermediate was deprotected by treatment with 2 mL 5-6 N HCI in isopropanol for 2 h at room temperature. The solvent was distilled of and the precipitate was isolated by filtration. In some reactions no hydrochloride precipitated or the purity of the precipitate was unsatisfactory. In these cases the solvent was distilled off and the remainder was purified by preparative HPLC. Using this method the following examples were prepared: 85 mg (0.62 mmol) of K2CO3 and 70 mg (0.15 mmol) of 4-[5-(4,4,5.5-Tetramethyl-[1,3.2]dioxaborolan-2-yl)-isoquinoIine-6-yloxyl-piperidin-1- carboxylic acid tert-butyl ester (14) were added to a solution of 22 mg (0.18 mmol) 2-Bromo-propene in 2mL of DMF. Under argon atmosphere 5.6 mg (0.05 eq) of Pd(dppf)Cl2 were added and the mixture was heated to 100°0 for 16 h. After cooling to room temperature water and dichloromethane were added. The mixture was filtered through a Celite cartridge. The solvents were removed by distillation and the remainder was subjected to preparative HPLC. The isolated intemiediate was deprotected by treatment with 2 mL 5-6 N HCI in isopropanol for 2 h at room temperature. The solvent was distilled of and compound 83 was isolated by preparative HPLC to give 3.2 mg as the trifluoroacetate, LCMS Method # 3. retention time 0.15 min, detected mass 269.15 [M+H]+ Using this method the following examples were prepared: 2 g 6-Methoxy-isoquinoline were dissolved in 25 mL of dry tetrahydrofuran. 12.56 mL of a 1 M solution of potassium triethyl borohydrate were added dropwise. The solution was allowed to stir at room temperature for 2 h, then 3.29 g of 4,4,4-Trifluoro-1-iodobutane were added dropwise. The solution was allowed to stir overnight, then 32 mL of 1M sodium hydroxide and 12 mL of sodium peroxide solution (35%) were added. Stirring was continued for another 3 hrs. then the solution was diluted with dichloromethane, extracted with water and brine and the organic layer was dried over sodium sulfate and evaporated to dryness. Silica gel chromatography yields 1.03 g of the desired product. LCMS Method # 1. retention time 1.20 min. detected mass 270.06 [M+H]" 1.02 g of 6-Methoxy-4-(4.4.4-trifluoro-butyl)-isoquinoline (87) were treated with boron tribromide as described for the synthesis of compound 1 to give 410 mg of the desired product 88. LCMS Method # 1. retention time 1.04 min, detected mass 256.00 [M+H]+ 4-[4-(4.4.4-Trifluoro-butyl)-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert- butyl ester (89) 100 mg of compound 88, 118 mg of Boc-(4-hydroxy)piperidine and 416 mg of Diphenyl-[4-[1H.1H,2H.2H-perfluorodecyl]phenyl]phosphine were dissolved in 5 mL of dry tetrahydrofurane. 208 mg of Bis (1H, 2H, 2H. 3H. 3H-perflourononyl)-azodicarboxylate were added and the reaction was allowed to stir overnight. The mixture was evaporated to dryness and filtered over a 5 g Fluoro-Flash cartridge. The obtained crude product was purified by preparative HPLC to yield 46 mg of the desired product, LCMS Method # 1, retention time 1.51 min, detected mass 439.13 [M+H]+ 42 mg of compound 89 were dissolved in 5M hydrochloric acid in isopropanol. The solution was stirred at room temperature for 2hrs and another 2 hrs at 40°C. evaporated to dryness and taken up in water and lyophilized three times to give 32 mg of the desired product as the hydrochloride salt. LCMS Method # 1, retention time 0.98 min. detected mass 338.16 [M+H]+ The following isoquinolines were synthesized in a similar fashion as described for compound 90, using appropriate alkyl halides: General procedure for reductive amination: 1.5 eq of aldehyde was dissolved in 1 mL of methanol and 50 mg of compound 124 and 27 mg of anhydrous sodium acetate, dissolved in methanol, were added. 0.250 mL of a solution of 1M sodium cyanoborohydride in THF was added. The reaction was allowed to run overnight, then the solution was filtered, evaporated to dryness and the residue was taken up in ethyl acetate. The organic layer was extracted with a solution of 5% sodium carbonate in water, then with 5% sodium chloride in water. The organic layer was dried, evaporated to dryness and purified by RP chromatography. This procedure was used to obtain compounds 93 to 123: General procedure for the reaction of boc-protected aminoalcohols with 6-hydroxy isoquinolines(Mitsunobu-reaction): AAV1: To 500 mg (1.5 mmol) of triphenylphosphine (bound to polystyrene, 3mmol/g) and 10 ml of dichloromethane 0.195 mL (1.2 mmol) of diethylazodicarboxylate (or alternatively diisopropylazodicarboxylate) were added. The reaction mixture was allowed to shake for 10 min. and then 0.14 mL of triethylamine. 145 mg of 6-hydroxyisoquinoline (7) (or an equivalent amount of a different suitable isoquinol) (reagent 1) and 1 mmol of the desired, boc-protected aminoalcohol (reagent 2) was added. The reaction was shaken at room temperature until no further conversion could be observed by LCMS. For workup, the solution was filtered, the residue was washed with dichloromethane and the organic layer was washed twice with IN sodium hydroxide, twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC to yield the boc protected coupled product. General procedure for removal of the boc-group (AAV2): The starting material was dissolved in 2M hydrochloric acid and reacted overnight. To compounds with poor aqueous solubility, methanol or dioxane was added until a homogenous solution was obtained. Alternatively, 4M hydrochloric acid in isopropanol was used to react the compound. The reaction mixture was lyophilised and the deprotected product is obtained as the corresponding hydrochloride of the free amine. Chromatographic resolution of compounds 140 and 143: The N-Boc protected intennediate, obtained as an enantiomeric mixture of compound 140 and compound 143. was separated into the enantiomers on a chiral column (Chiralcel OD-H/56 250 x 4.6 mm). The removal of the protection group as the final step was performed as described in the general procedure. The absolute configuration of the stereo centers has not been determined. Compound 140: earlier eluting Boc-protected intermediate; Compound 143: later eluting Boc-protected intemriediate Chromatographic resolution of compounds 141 and 142: The N-Boc protected intermediate, obtained as an enantiomeric mixture of compound 141 and compound 142. was separated into the enantiomers on a chiral column (Chiralpak AD-H/40 250 x 4.6 mm). The removal of the protection group as the final step was performed as described in the general procedure. The absolute configuration of the stereo centers has not been determined. Compound 141: earlier eluting Boc-protected intermediate; Compound 142: later eluting Boc-protected intermediate. 7-Chlor0-6-fluoro-isoquinoline is obtained by the same reaction sequence, used for the synthesis of 6-Fluoro-isoquinoline (23), starting from 3-Chloro-4-fluoro-ben2aldehyde. Rt = 0.77 min (Method #2). Detected mass: 182.1/184,1 (M+H"). 5-Chlor0-6-fluoro-isoquinoIine-trifluoro acetate (151) 7.0 g (38.1 mmol) of 6-FluoroisoquinoIine (23) are dissolved in 60 mL of concentrated sulfuric acid. At 0°C 10.18 g of N-Chlorosuccinimide are added. After 1h another 5.2g of N-Chlorosucciminide are added and the solution is warmed to 50**C. Two more portions of 5.2 g N-Chlorosuccinimide are added successively and stirring is continued at 50 °C until the reaction is complete. The reaction mixtuR6 is cooled to room temperature, is poured on ice and adOPJusted to pH 10 by addition of sodium hydroxide. The precipitate is filtered off, taken up in dichloromethane and washed with aqueous sodium hydroxide. The organic layer is dried over magnesium sulfate, evaporated and the crude product is purified by preparative HPLC to yield 4.04 g of 5-Chlor-6-fluor-isoquinoline (151) as trifluoroacetate. Rt = 0.97 min (Method #2). Detected mass: 182.0/184.0 (M+H*). Under cooling 2.0 mL of concentrated nitric acid are added to 2.8 mL of sulphuric acid. Subsequently 350 mg of 6-fluoroisoquinoline (23) are added, the reaction is wanned up to room temperature and allowed to stir overnight. The reaction mixtuR6 is poured on ice, extracted with dichloromethane and adOPJusted to alkaline pH by addition of sodium hydroxide. The aqueous layer is extracted again with dichloromethane. The dichloromethane layer is dried over magnesium sulfate and evaporated to give 90 mg of 6-Fluoro-5-nitro-isoquinoline, which can be used without further purification, Rt = 1.03 min (Method #1). Detected mass: 193.0 (M+H+). 4-(lsoquinolin-6-yloxy)-plperidine-1-carbocyclicacid-tert-butylester(154) 7.49 g of 4"Hydroxy-piperidine-1-carboyciic acid-tert-butylester are dissolved in 20 mL of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) are added. Then a solution of 3.65 g 6-Fluoroisoquinoline (23) is added dropwise. The solution is heated at 80 °C for 2 hours, then the solvent is removed and the residue is taken up in dichloromethane. The organic layer is extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by silica gel chromatography to yield 6.22g of 4-(lsoquinolin-6-yloxy)-piperidine-1-carbocyclic acid-tert-butylester. Rt = 1.32 min (Method #1). Detected mass: 329.1 (M+H*). 4"(lsoquinolin-6-yloxy)-piperidine-1-carbocyclic acid-tert-butylester (154) is deprotected by the general procedure described in AAV2 to yield the title compound as HCI-salt. Rt = 0.20 min (Method #2). Detected mass: 229.1 (M+H*). The following example was synthesized according to this method: using 4-chlor0-6-fluoro-isoquinoline (24) as starting material LCMS Method # 2, retention time 0.56 min, detected mass 263,12 [M+H]+ 150 mg of 6-(Piperidine-4-yloxy)-isoquinoline hydrochloride (124) are dissolved in 10 mL of dry pyridine. 177 mg of triethylamine and 69 mg of 4-chloropyrimidine are added and the solution is stirred at 65°C for 6 hours. The reaction mixtuR6 is poured on brine and extracted three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate, evaporated to dryness and the crude product is purified by preparative HPLC. The product is converted into the corresponding HCI salt by taking up the product in 20 mL of 1 N hydrochloric acid followed by lyophilization. Yield; 47 mg. Rt = 1.05 min (Method #2). Detected mass: 307.1 (M+H*). 75 mg of 6-(Piperidine-4-yloxy)-isoquinoline-Hydrochloride (124) are dissolved in 5 mL of dry pyridine and 5 mL of DMF. 55 mg 2-Chlor-4-trifIuoromethyl-pyrimidine are added and the solution is stirred at 60'*C for 3 hours. The solvents are removed in vacuo and the residue is taken up in brine and extracted three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate, evaporated to dryness and the crude product is purified by preparative HPLC. The product is converted into the corresponding HCI salt by taking up the product in 20 mL of 1 N hydrochloric acid followed by lyophilization. Yield: 29 mg. Rt = 1.69 min (Method #2). Detected mass: 375.1 (M+H*). 6-(1-Cyclopropyl-piperidin-4-yloxy)-isoquinoline-hydrochlorlde(159) 300 mg (1,13 mmol) 6-(Piperidine-4-yloxy)-isoquinorme hydrochloride (124) are dissolved in 10 mL of methanol. 202 mg of triethylamine, molecular sieves 4A, 600 mg of glacial acetic acid, 871 mg of (l-Ethoxy-cyclopropyloxy)-trimethyl-silane and 101 mg of sodium cyanoborohydrate are added successively and the reaction mixtuR6 is heated under reflux for 6 hours. The reaction mixtuR6 is cooled to room temperature, 6 mL of 2N sodium hydroxide are added and the reaction mixtuR6 is filtered. The filtrate is evaporated, the residue is taken up in dichloromethane, extracted with 2 N sodium hydroxide and brine, dried with sodium sulfate, evaporated to dryness and the crude material is purified by preparative HPLC. The product fractions are evaporated, the product is taken up in 2 N hydrochloric acid and lyophilized. Yield: 60 mg. Rt = 0.50 min (Method #1).Detected mass: 269.2 (M+H+). 3.97 g (12.1 mmoi) of 4-(lsoquinolin-6-yloxy)-piperidine-1-carboxylicacid tert-butyl ester (154) are dissolved in 100 ml of dichloromethane and 4.47 g (18.1 mmol) of 3-chloro-pertDenzoic acid (70 %) are added at room temperature. The reaction mixtuR6 is stirred for 1 h and then washed with saturated sodium bicarbonate-solution. The aqueous phase is separated and extracted with dichloromethane. The combined organic layers are dried over magnesium sulfate and evaporated, to yield 4.19 g of crude material, which can be used for further conversion without purification. Rt = 1.46 min (Method #1). Detected mass: 345.2 (M+H+). 1-Chlor0-6-(piperidin-4-yloxy)-isoquinoline-hydrochloride(161) 3.5 g (10.16 mmol) 4-(2-Oxy-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (160) were dissolved in 250 ml of HCI-saturated ethanol at 50 'C. The clear solution was concentrated i. vac. and the residue was refluxed in 50 ml POCI3, After 3 h the POCl3was removed i. vac. and the residue was taken up in H2O. The pH was adOPJusted to 11, by adding sodium hydroxide and the aqueous solution was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness. The residue was purified by preparative HPLC, by which the title compound was obtained as trifluoroacetate. This was converted to the corresponding HCI-salt by dissolving the product in 2 N HCI. followed by lyophilization. Yield: 950 mg. Rt = 1.03 min (Method #1). Detected mass: 263.1/265.1 (M+H+). 1.23 g (4.11 mmol) of 1-Chlor0-6-(piperidin-4-yloxy)-isoquinoline hydrochloride (161) were dissolved in 50 ml of dichloromethane and 0.85 ml (6.15 mmol) of triethylamine were added. At 0 °C a solution of 1.09 g (5.0 mmol) of tert-butyl-carbonate in 10 ml dichloromethane was added dropwise and the mixture was allowed to stand at room temperature overnight. For working up, the mixture was washed twice with H2O, dried over magnesium sulfate and evaporated, to yield 1.1 g of the desired product, which could be used without further purification. Rt = 1.86 min (Method # 4). Detected mass: 363.1/365.2 (M+H+). 4-(1*Methylamino-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (163) 154 mg (0.42 mmol) of 4-(1-ChlorO"isoquinolin-6-yloxy)-piperidine-1-carboyclic acid tert-butyl ester (162) were heated in 15 ml of an aqueous methylamine-solution (41 %) at 110 **C in a sealed tube. After 7h the reaction mixture was evaporated and the residue was taken up in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and the solvent was removed i. vac. The residue was purified by silica gel chromatography (ethyl acetate/methanol 5:1). Yield: 45 mg. Rt = 1.14 min (Method # 4). Detected mass: 358.3 (M+H+). 4-(1-Methylamino-isoquinolin-6-yloxy)-piperJdine-1"Carboxylic acid tert-butyi ester (163) was converted to the deprotected title compound by the general procedure, described in AAV2, by which 34 mg of the corresponding HCI-salt could be obtained. Rt = 0.69 min (Method #1). Detected mass: 258.3 (M+H^). Following the synthetic route, described for compound 164, the following compounds were prepared starting from 4-(1-Chloro-isoquinolin-6-yloxy)-piperidine-1-carboyclic acid tert-butyi ester (162) and the corresponding amines: 5.0 g (22,8 mmol) of 2-Chloro-5-formyl-benzenesulfonamide were dissolved in 50 ml of dichioromethane. 4.08 g (34.3 mmol) of dimethylformamide dimethylacetal were added and the mixture was refluxed for 2 h. After cooling to room temperature, the solution was washed twice with H2O. dried over magnesium sulfate and evaporated. 5.16 g of the crude product were obtained and used in the next step without further purification. Rt = 1.14 min (Method #1). Detected mass: 275.1/277.1 (M+H+). 200 mg (0.88 mmol) of 6-(piperidine-4-yloxy)-isoquinoline hydrochloride (124) were dissolved in 20 ml of methanol and 158 mg (1.56 mmol) of triethylamine were added. After stirring for 15 minutes at room temperature 467 mg (7.78 mmol) of glacial acetic acid, 482 mg (1.76 mmol) of 2-Chloro-N-dimethylaminomethylene-5-formyl-benzenesulfonamide (168), 166 mg (2.64 mmol) of sodium cyanoborohydride and freshly dried molecular sieves were added and the mixture was refluxed for 3 h. After stirring overnight at room temperature, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichioromethane and washed twice with saturated sodium bicarbonate solution and brine. After drying over magnesium sulfate and evaporation of the solvent, the crude product was purified by preparative HPLC, by which 133 mg of the desired product could be isolated as trifluoroacetate. Rt = 0.87 min (Method #2). Detected mass; 487.2/489.2 (M+H+). 2-Chloro-5-[4-(isoquinolin-6-yloxy)-piperidin-1-ylmethyl]-benzenesulfonamide (170) 133 mg (0.27 mmol) of 2-Chloro-N-dimethylaminomethylene-5-[4-(isoquinolin-6-yloxy)-piperidin-l-ylmethylj-benzenesulfonamide (169) were dissolved in ethanol. After adding 50 ml of 2N NaOH. the solution was heated to 60 °C for 6 h. After cooling to room temperature, the mixture was neutralized by addition of aqueous HCI and the solvent was removed i. vac. The residue was stirred with ethanol. the inorganic salts were filtered off and the filtrate was evaporated. Rt = 0.78 min (Method #2), Detected mass: 432.1 (M+H+). 90 mg (0.47 mmol) 6-Fluoro-5-nitroHsoquinoline (152) were treated with 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester following the method described for the preparation of compound 154. 18.5 mg (0.05 mmol) 4-(5-Nitro-isoquinoiin-6"yloxy)-piperidine-1-carboxylic acid tert-butyl ester (171) were deprotected following the procedure, described in AAV2, by which 12.5 mg of the title compound could be isolated as HCI-salt. Rt = 0.57 min (Method #1). Detected mass: 274.2 (M+H+). 7-Chlor0-6-(piperidin-4-yloxy)-isoquinoline"hydrochloride (173) starting from 7-Chlor0-6-fluoro-isoquinoline (150). the title compound was prepared by the same synthetic route as for compound 124. Rt = 0.66 min (Method #1), detected mass: 263.1/265.1 (M+H""). Step 1: 188 g of 5-Fluro-indanone-1 (174) were dissolved in 1.81 of diethyl ether, 50ml of EtOH saturated with HCI are added at 0°C and 1.1 I of a 15% ethyl nitrite solution in ether is added over 1 hour. The solution is allowed to stir for an additional 3 hours to reach room temperature, then the solvent is removed partially and the precipitated product is collected by filtration. Step 2 129 g of the product from Step 1 was added to a mixture of 170g of PCI5 in 21 of POCI3. Then gaseous HCI was added at 0°C until saturation of the solution was reached. The remaining mixture was heated to 60°C for 6h, the solvent partially removed in vacuo and the residue was hydrolyzed on a crushed ice/water mixture. The precipitated product is isolated by filtration. Steps 155g of product from Step 2 were added to a nnixture of 740nil HOAc and 330 ml HI (57%) containing 53g of red phosphorous. After heating to reflux for 4 hours, the solution was treated with concentrated NaOH (until pH = 8) and the precipitated product is isolated by filtration. Step 4: 16.5 g of N-BoC-4-hydroxypiperidine were dissolved in 210ml of diglyme and treated with 4.1g 50% NaH under nitrogen. The resulting mixture was stirred for 1h at room temperature, then 14.8 g of the product from Step 4 was added. The mixture was allowed to stir for 1 day at room temperature, then 100 ml of toluene were added and the resulting mixture was washed with water 3 times. The organic phases were collected and the solvent was removed in vacuo. 100 mg of compound 178 and 1.1 equivalents of the corresponding aniline are dissolved in 5 ml of dioxane, 350 mg of CS2CO3, 20mg of Pd(0Ac)2 and 60 mg of XANTHPHOS are added and the resulting mixtuR6 is heated to reflux under nitrogen until the starting material is consumed, (reaction is monitored by LCMS) The solvent is removed in vacuo and the residue is subOPJected to chromatography on a HPLC system. Step 6: The products of Step 5 are dissolved in 5 ml of ethanol saturated with gaseous HCI. After stirring for 5h the desired product is isolated by removal of the solvent in vacuo. All 3,5,6-trisubstituted derivatives were synthesized according to the procedure illustrated.by the synthesis of compound 184. For synthesis of compound 185, acetamide was used as amine component in the Pd coupling step. 200 mg of 4-(3-Chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (178) were dissolved in 5 ml of CH3CN and heated to 85°C. Then a mixture of 148 mg of N-bromosuccinimide and 9 mg of AIBN was added as solid and the resulting mixture was heated to reflux for 1 h. The solvent was removed in vacuo and the residue subOPJected to flash column chromatography. The yield of the isolated product was 41% LCMS : detected mass :441.03. Rt= 2.41 min (Method #1) Synthesis of of 4-[3-Chloro-5-(4-fluoro-phenyl)-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert- butyl ester (182) 150 mg of 4-(5-Bromo-3-chloroisoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert- butyl ester (181) were dissolved in a mixture of 9 ml of dioxane and 3ml of water. 47mg of 4-fluoro-benzene-boronic acid, 47mg of NaaCOa and 40mg of Pd(PPh3)4 were added and the resulting mixture was heated to 100^*0 for 6h. The solvent was. removed in vacuo and the residue subOPJected to chromatography on a HPLC system. Yield: 44% LCMS : detected mass :457.22, Rt = 2.45 min (Method #1) 70 mg of 4-[3"Chloro-5-(4-fluoro-phenyl)-isoquinolin-6-yloxy]-piperidine-1 -carboxylic acid tert- butyl ester(182) were dissolved in 7ml of toluene, 20mg of Pd(OAc)2, 60 mg of XANTHPHOS. 400mg of CS2CO3 and 30 mg of 3.4,5 trimethoxyanlline were added and the resulting mixture was heated to 100°C for 6h. Then the solvent was removed in vacuo and the residue subOPJected to chromatography on a HPLC system. The yield of isolated product was 24% LCMS : detected mass :604.17. RT = 1.81 min (Method #1) 20 mg of 4-[5-(4-Fluoro-phenyl)-'3-(3,4,5"trimethoxy-phenylamino)-isoquinolin-6-y!oxy]-piperidine-1- carboxylic acid tert-butyl ester (183) were dissolved in 5 ml of ethanol saturated with HCI (gaseous). The resulting mixture was stirred for 1h. then the solvent was evaporated and the product collected. Yield: 85% LCMS : detected mass :503.22, Rt = 1.22 min (Method #1) The compound 266 was synthesized in a similar fashion as described for compound 90, using ethyl iodide. LCMS Method # 1. retention time 0.98 min. detected mass 257.31 [M+H]+ Also using the same reaction sequence as for the synthesis of 6-Fluoro-isoquinoline (23), the following two compounds were obtained; 8-Chlor0-6-fluoro-isoquinoline (267) Rt = 0.83 min (Method #1). Detected mass: 182.12 (M+H+). Rt = 0.70 min (Method #TOP). Detected mass: 162.3 (M+H+). 8-Chloro-6"(Piperidin-4-yloxy)- isoquinoline hydrochloride (269) was obtained in a similar fashion as described above for the synthesis of (124), starting from 267 Rt = 0.63 min (Method #1). Detected mass: 263.14 (M+H+). 6-(Piperidin-4-yloxy)-7-methyl isoquinoline hydrochloride (270) was obtained in a similar fashion as described above for the synthesis of (124), starting from 268 Rt = 0.64 min (Method #1). Detected mass: 243.18 (M+H+). I The following set of compounds was obtained the same way. following the reductive amination procedure used to obtain examples 93-123 using 269,129 or 270, respectively and the corresponding aldehydes as starting material. All LCMS in the following tables were obtained using LCMS method #2. 5,6,7-Trifluoro-isoquinoline (373) is obtained by the same reaction sequence, used for the synthesis of 6-Fluoro-isoquinoline (23), starting from 3,4,5-TrifluorobenzaIdehyde. Final purification by preparative HPLC gave the desired isoquinoline as trifluoroacetat. Rt = 1.15 min (Method #2). Detected mass: 183.0. The title compound was synthesized following the protocol described for 4-(lsoquinolin-6-yloxy)-piperidine-1-carbocyclic acid-tert-butylester (154), Rt = 1.27 min (Method #TOP). Detected mass: 365.2 (M+H+). 4-(5,7-Difluoro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (374) is deprotected in Methanol/2 N HCI by the general procedure described in AAV2 to yield the title compound as HCI-salt. Rt = 0.43 min (Method #TOP). Detected mass: 265.1 (M+H+). 5.0 g (27.5 mmol) 7-Chlor0-6-fluoro-isoquinoline (150) were dissolved in 90 ml of cone, sulphuric acid. At room temperature 7.35 g (55.0 mmol) N-Chloro-succinimid were added and the mixture was stirred at 50 °C. After standing overnight at room temperature another 3 eq. N-Chloro-succinimid were added and at the following again 5 eq. N-Chloro-succinimid were added and the temperature was increased to 80 "^C. After no further conversion could be detected, the mixture was cooled to room temperature and poured on ice. The aqueous solution was brought to basic pH by adding solid NaOH. The precipitate was filtered off and washed three times with dichloromethane. After drying the organic filtrates with MgS04 and evaporation of the solvent 1.09 g of the desired isoquinoline could be isolated. Rt = 1.26 min (Method #TOP). Detected mass: 216.0/218.0 (M+H+). The title compound was synthesized following the protocol described for 4-(lsoquinolin-6-yloxy)-piperidine-1-carbocyclic acid-tert-butylester (154). After final purification by preparative HPLC and evaporation of the product fractions, the Boc-group is already partially cleaved. Rt = 1.71 min (Method #2). Detected mass: 397.2/399.2 (M+H+). 150 mg 4-(5.7-Dichloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (377, already partially deprotected) were dissolved in 10 ml of dichloromethane and 1 ml of trifluoroacetic acid is added at 0°C. The solution is stirred for 2 h at room temperature. For working up, 50 ml Dichloromethane were added and the solution was washed with saturated NaHC03-solution. The layers were separated and the aqueous phase was extracted once with Dichloromethane. The combined organic layers were again washed with saturated NaHCOS-solution , dried with MgS04 and evaporated. The residue was purified by preparative HPLC. The product fractions were evaporated and the residue dissolved In 2 N HCI. After evaporation, the title compound was isolated as HCI-sait Rt= 0.90 min (Method #2). Detected mass: 297.1/299.1 (M+H""). Determination of Rho kinase inhibition To measure Rho-kinase inhibition, IC50 values were determined according to the following protocol: Buffer: 25mM Tris pH7,5; 0.02% BSA; 5% Glycerol; 0,008% Triton XI00; 2% DMSO, ImM DTT; 1mM MgCb; 0,5MCi/welJ y33P ATP Enzyme: ROCKII or ROKa) (Upstate, Catalog # 14-451 Lot# 24880U) 0.1 ng/pl Final concentration of ATP in reaction mixture 40µM Biotinylated substrate, diluted to 0.25µM with buffer described above (without ATP) 1. lOµI Tris buffer (± Inhibitor) 2. Add 30 µL of enzyme solution 3. Start the reaction with 30µL of mix substrate/ATP/ATP33 4. Incubate for 20 min at room temperature 5. Stop reaction with 30µL of 50 mM EDTA 6. Transfer 50 µL of stopped solution to Streptavidin Flash Plate plus, Perkin Elmer, SMP 103A 7. Incubate for 30 min at RT 8. Wash 4 times with 300 µl of PBS/0.1% Tween 20 9. Radioactivity in the well was determined The given activity is denoted as the negative logarithm of the IC50 (PIC50) as follows: Claims 1. A compound of the formula (I) wherein R 1 is H. (C1-C6)alkyl, R', NH-(C1-C6)alkyl, NHR', or N[(C1-C6)alkyl]2: R2 is hydrogen, halogen or (C1-C6)alkyl; . R3 is H, halogen, (C1-C6)alkyl, (C1-C6)alkylene-R', OH, 0-R", NH2, NHR". NR"R" or NH-C(0)-R", R4 is H. halogen, hydroxy, CN, (C1-C6)alkyl, R'. (C1-C6)alkylene-R'; R5 is H, halogen, CN, NO2. (C1-C6)alkyl. (C2-C6)alkenyl, R', (C1 -C6)alky lene-(C6-C 10)aryl, (C1 -C6)alkenylene-(C6-C 1 o)aryl. (C1 -C6)alkylene-(C5-C 1 o)heteroGyclyl, CH(0HH(C1-C6)alkyl, NH2, NH-R'. NH-SO2H. NH-S02-(C1-C6)alkyl. NH-SO2-R', NH-C(0)-(C1-C6)alkyl, NH-C(0)-R', C(0)N[(C1-C6)alkyI]2. C(0)OH, or C(0)0-(C1-C6)alky!; R6 is H, R". (C1-C8)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylene-0-(C1-C6)alkyl, (C1-C6)alkylene-0-R', (C1-C6)alkylene-CH[R']2, (C1-C6)alkylene-C(0)-R', (C1-C6)alkylene-C(0)NH2. (C1-C6)alkylene-C(0)NH-R', or (C1-C6)alkylene-C(0)N[R']2; R7 is H, halogen, CN. NO2. (C1-C6)alkyl, (C2-C6)alkenyl, R'. (C1-C6)alkenylene-(C6-C10)aryl, (C1-C6)alkylene-R'. CH(OH)-(C1-C6)alkyl, NH2. NH-R", NH-SO2H, NH-S02-(C1-C6)alkyl, NH-SO2-R'. SO2-NH2, SO2-NHR', NH-C(0)-(C1-C6)aIkyl, NH-C(0)-R', C(0)N[(C1-C6)alkyl]2, C(0)OH, or C(0)0-(C1-C6)alkyl; Rs is H, halogen or (C1-C6)alkyl; n is 1, 2, 3 or 4; and L is O or 0-(C1-C6)alkylene; wherein R'is (C3-C8)cycloaikyl, (C5-C1 o)heterocyclyl, (C6-C10)aryl; and R" is (C3-C8)cycloalkyl, (C5-C1 o)heterocycly!, (C6-C10)aryl, (C1-C6)alkyl, (C1-C6)alkylene-R', (C1 -C6)alkylene-0-(C 1 -C6)alkyl, (C1-C6)alkylene-0-R*, or (C1-C6)alkylene-NRxRy; and wherein Ry and Ry are independently of each other (C1-C6)all (C5-C1 o)heterocyclyl, (C6-C10)aryl, (C1 -C4)allcylene-(C5-C-| o)heterocyclyl, (C1 -C4)alkylene-(C6-C 1 o)aryl, (C1-C4)alkylene-NH(C1-C6)alkyl, (C1 -C4)aIkylene-N[(C 1 -C6)alkyl]2, (C1 -C4)alkylene-N[(C6-C 1 o)aryl]2, or (C1-C4)alkylene-N[(C5-C10)heterocyclyl]2; and wherein in residues R4, R5, R7 and RQ one alky! or alkylene hydrogen atom can optionally be substituted by OH. F, OCH3, COOH, COOCH3. NH2. NHCH3, N(CH3)2. CONH2. CONHCH3 or CON(CH3)2; and their phamnaceuticaily acceptable salts and/or physiologically functional derivatives. 2. A compound according to claim 1, wherein R1 is H, (C1-C5)alkyl, (C6-C10)aryl, NH-(C1-C6)alkyl, NH-(C6-C10)aryl or N[(C1-C6)alkyl]2. 3. A compound according to one of claims 1 or 2, wherein R-i is H, (C1-C4)alkyl, NH-(C1-C4)alkyl, N[(C1-C4)alkyl]2 or NH-phenyl. 4. A compound according to one of claims 1 to 3, wherein R1 is H, (C1-C2)aikyl or NH-(C1-C2)alkyl. 5. A compound according to one of claims 1 to 4, wherein R1 is H. 6. A compound according to one of claims 1 to 5. wherein R3 is H, halogen, (C-|-C4)alkylene"R' O-R" or NHR", and wherein R' and R" are defined as in claim 1. 7. A compound according to one of claims 1 to 6, wherein R3 is H or NHR". 8. A compound according to one of claims 1 to 7. wherein R3 is H; NH-(C5-C6)heterocyclyl. preferably NH-(C5-C6)heteroaryl containing one or more N atoms; or NH-phenyl. 9. A compound according to one of claims 1 to 8, wherein Rg is H. halogen or (C-|-C4)alkyl. 10. A compound according to one of claims 1 to 9, wherein Rg is H, CI, F. methyl or ethyl. 11. A compound according to one of claims 1 to 10. wherein R4 is H, halogen or (C1-C6)alkyL 12. A compound according to one of claims 1 to 11, wherein R4 is H, halogen or {Ci-C4)alkyl. 13. A compound according to one of claims 1 to 12, wherein R4 is H. 14. A compound according to one of claims 1 to 13, wherein R5 is H, halogen, CN, (C1-C6)alkyl, R'. NH-(C6-C10)aryl or (C1-C6)alkylene-R 15. A compound according to one of claims 1 to 14, wherein R5 is H, halogen. (C1-C6)alkyl, R\ NH-(C6-C10)aryl or (C1-C6)alkylene-R'. 16. A compound according to one of claims 1 to 15, wherein R5 is H, halogen, (C1-C6)alkyl. (C6-C10)aryl, NH-(C6-C10)aryl. (C1-C2)alkyKC6-C10)ary»or (C5-C10)heteroaryL 17. A compound according to one of claims 1 to 16, wherein R7 is H, halogen, CN, (C1-C6)alkyl, (C2-C6)alkenyl, R' or (C1-C6)alkylene-(C3-C8)cycloalkyl. 18. A compound according to one of claims 1 to 17. wherein R7 is H. halogen, CN. (C-i-C4)alkyl. (C1-C4)alkenyl, phenyl, cyclopropyl or (C5-C6)heteroaryl. 19. A compound according to one of claims 1 to 18, wherein R7 is H, fluoro, chloro. bromo, methyl, ethyl, phenyl, nitrile, cyclopropyl, thienyl or vinyl. 20. A compound according to one of claims 1 to 19, wherein n is 1, 2 or 3. 21. A compound according to one of claims 1 to 20, wherein n is 1. 22. A compound according to one of claims 1 to 21, wherein R2 is H, halogen or (C1-C4)alkyl. 23. A compound according to one of claims 1 to 22, wherein R2 is H or (C1-C4)alkyl. 24. A compound according to one of claims 1 to 23, wherein R2 is H, (C-j-C2)alkyl. 25. A compound according to one of claims 1 to 24. wherein R6 is H, (C'|-C6)aikyl, R', (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-C(OHC5-C10)heterocydyl, (C1-C4)alkylene-C(O)-(C6-C10)arylor (C1 -C6)alkylene-(C6-C10)aryl. 26. A compound according to one of claims 1 to 25. wherein Rs is H. (C1-C6)alkyl, (C5-C10)heterocyclyl, (C1-C4)alkylene-(C5-C-10)heterocyclyl or (C1-C6)alkylene-(C6-C10)aryL 27. A compound according to one of claims 1 to 26, wherein L is attached to the 3-position or to the 4-position of the piperidine ring. 28. A compound according to one of claims 1 to 27, wherein L is attached to the 4-position of the piperidine ring. 29. A compound according to one of claims 1 to 28, wherein L is 0-methylene, O-ethylene or preferably O. 30. A compound according to claim 1, wherein R1 isH, (C1-C6)alkyl, (C6-C10)aryl, NH-(C1-C6)alkyl, NH-(C6-C10)aryl. or N[(C1-C6)alkyl]2; R2 is hydrogen, halogen, or (C1-C6)alkyl; R3 is H, halogen, (C1-C4)alkylene-R', 0-R" or NHR", wherein R' and R" are defined as in claim 1; R4 is H, halogen or (C1-C6)alkyl; R5 is H, (C1-C6)alkyl, halogen. CN, (C6-C10)aryl. NH-(C6-C10)aryl. (C1-C6)alkylene-(C6-C10)aryl, (C5-C-io)heterocydyl or (C1 -C6)alkylene-(C5-C10)heterocycly I; R6 is H. (C1-C6)alkyl, R\ (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C6)alkylene-C(OHC6-C10)aryl. (C1-C4)alkylene-C(OHC5-C10)hetero^^ (C1-C6)alkylene-(C6-C10)aryl; R7 is H, halogen, CN, (C1-C6)alkyl, (C2-C6)alkenyl or R'; R8 is H, halogen or (C'|-C6)alkyl; n is 1. 2 or 3, and L is O, O-methylene or 0-ethylene. 31. A compound according to claim 1, wherein Rl is H, (C1-C6)alkyl. (C6-C10)aryl, NH-(C1-C6)alkyl. NH-(C6.C10)aryl, or N[(C1-C6)alkyl]2; R2isH or(C1-C4)alkyl; R3 is H, halogen or NHR", wherein R" is defined as above; R4 is H, halogen or (C'i-C4)alkyl; R5 is H, (C1-C6)alkyl, halogen. (C6-C10)aryl, NH-(C6-C10)aryl, (C1-C6)alkylene-(C6-C-10)aryl or (C5-C10)heterocyclyl; R6 is H. (C1-C6)alkyl, R', (C1-C4)alkylene-{C5-C10)heterocyclyl or (C1-C6)alkylene-(C6-C 10)aryl; R7 is H, halogen, CN, (C1-C6)alkyl, (C2-C6)alkenyl or R'; Rg is H, halogen or (C1-C6)alkyl; n is 1, 2 or 3; and LisO. 32. A compound according to claim 1, wherein R-l is H. (C1-C4)alkyl. NH-(C1-C4)alkyl, N[(C1-C4)alkyl]2 or NH-phenyl; R2 is H. (C1-C4)alkyl; R3 is H, NH-(C5-C6)heteroaryl or NH-phenyl; R4 is H, halogen or (C1-C4)alkyl; R5 is H. (C1-C4)alkyl, halogen. (C6-C10)aryl. NH-(C6-C10)aryl. (C1-C2)alkyl-(C6-C10)aryl or {C5-C10)heteroaryl; Re is H, (C1-C6)alkyl, (C5-C10)heterocyclyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C6-C10)aryl or (C1-C6)alkylene-(C6-C10)aryl; R7 is H, halogen, CN, (C1-C4)alkyl, (C1-C4)alkenyl, phenyl, cyclopropyl, (C5-C6)heteroaryl; R8 is H, halogen or (C1-C4)alkyl; n is 1; and L is O. 33. Use of at least one compounds of the formula (I) and/or their physiologically acceptable salt as claimed in one of claims 1 to 32 for producing a medicament. 34. Use of at least one compounds of the formula (I) and/or their physiologically acceptable salt as claimed in one of claims 1 to 32 for producing a medicament for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, peripheral circulatory disorder, angina pectoris, cerebral vasospasm, asthma, premature birth, hyperaggregability of platelets, Peripheral Occlusive Arterial Disease (PAOD), Chronic Obstructive Pulmonary Disease (COPD). cancer development, erectile dysfunction, arteriosclerosis, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, fibroid kidney, renal glomerulosclerosis, kidney failure, organ hypertrophy, prostatic hypertrophy, complications of diabetes, blood vessel restenosis, atherosclerosis, cancer, cardiac hypertrophy, heart failure ischemic diseases; inflammation; autoimmune diseases; AIDS, osteopathy such as osteoporosis, brain functional disorder, infection of digestive tracts with bacteria, sepsis, adult respiratory distress syndrome, retinopathy, glaucoma or Alzheimer's disease. 35. A medicament comprising an effective amount of at least one compound as claimed in any of claims 1 to 32 and/or a pharmacologically acceptable salt thereof, physiologically tolerated excipients and carriers and, where appropriate, further additives and/or other active ingredients.

Documents:

6027 CHENP 2007 Fresh Form 3.pdf

6027 CHENP 2007 Petition for Form 3.pdf

6027 CHENP 2007 Petition for POR.pdf

6027-CHENP-2007 AMENDED PAGES OF SPECIFICATION 22-12-2014.pdf

6027-CHENP-2007 AMENDED CLAIMS 22-12-2014.pdf

6027-CHENP-2007 CORRESPONDENCE OTHERS 20-03-2014.pdf

6027-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 22-12-2014.pdf

6027-CHENP-2007 FORM-1 22-12-2014.pdf

6027-CHENP-2007 FORM-3 26-06-2008.pdf

6027-chenp-2007 correspondence others-26-06-2009.pdf

6027-chenp-2007 form-18-26-06-2009.pdf

6027-chenp-2007-abstract.pdf

6027-chenp-2007-claims.pdf

6027-chenp-2007-correspondnece-others.pdf

6027-chenp-2007-description(complete).pdf

6027-chenp-2007-form 1.pdf

6027-chenp-2007-form 26.pdf

6027-chenp-2007-form 3.pdf

6027-chenp-2007-form 5.pdf

6027-chenp-2007-pct.pdf