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(ll)Application Number:    KE/P/2008/ 000698   

(73) Owner:A 61K31/4725, A61P 9/12, C 07D SANOFI-AVENTIS  DEUTSCHLAND GMBH of401112 Industriepark Hochst, Building K801, D-65929 Frenkfurtam Main., Germany   

(72) Inventor:KADEREIT, Dieter of Sanofi-A ventis Deutschland

(22) Filing Date:        GmbH, 65926 Frenkfurt am Main, Germany;
20/0712006        PLETfENBURG, Oliver of Sanofi-Aventis Deutschland
        GmbH, 65926 Frankfurt am Main, Germany;
(30) Priority data:        HOFMEISTER, Armin of Sanofi-Aventis Deutschland
05016154.6  26/0712005    EP    GmbH, 65926 Frenkfurt am Main, Germany; BRENDEL,
        Joachim ofSanofi-Aventis Deutschland GmbH, 65926
(86)  PCT data        Frenkfurt am Main, Germany and LOEHN, Matthias of
PCTIEP06/007139   20/07/2006    Sanofi-Aventis Deutschland GmbH, 65926 Frankfurt am
WO 2007/012421 AI    0110212007    Main,  Germany.

(74)    AgenUaddress for correspondence: Kaplan & Stratton Advocates,  P.O. Box 40111-00100, Nairobi

(74) AgenUaddress for correspondence: Kaplan & Stratton Advocates,  P.O. Box 40111-00100, Nairobi

(54) Title: PIPERIDINYL-SUBSTITUTED ISOQUINOLONE DERIVATIVES AS RHO-KINASE INHffiiTORS.

(57) Abstract:  The invention relates to 6-piperidinyl-substituted isoquinolone derivatives of the formula (I) or 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.
 
Cell Physiol. 2006, 290, C661-a, Kishi et al. Circ 2005, 111, 2741-2747), coronary heart disease, artherosclerosis, restenosis (Pacaud et al. Arch. Mal. Coeur 2005, 98, 249-254, Relzer, et al. FEBS Lett 2000,466,70, Negoro, et al. Biochem Biophys Res Commun 1999,262, 211 ), diabeles, diabetic complications, glucose utilization and metabolic syndrome (Sandu, et ai.Diabetes 2000,49,2178, Maeda et al. Cell Metab. 2005,2, 119-29), sexual dysfunction, e.g., penile erectile dysfunction (Chitaley et al. Nature Medicine 2001,7, 119-122), retinopathy, inflammation, immune diseases, AIDS, osleoporosis, endocrine dysfunctions, e.g. hyperaldosteronism, central nervous syslem disorders such as neuronal degeneralion and spinal cord injury (Hara, et al.

10    JNeurosurg 2000, 93, 94), cerebral ischemia (Uehata, et al. Nature 1997,389,990; Salah et al. Life Sci. 2001, 69, 1441-53; Hitomi, et al. Life Sci 2000,67, 1929; Yamamoto, et al. J Cardiovasc Phannacol. 2000, 35, 203-11), cerebral vasospasm (Sate, et al. Circ Res 2000,87, 195; Kim, et al. Neurosurgery 2000,46,440), pain, e.g.

neuropathic pain (Tatsumi, et al. Neuroscience 2005, 131,491, Inoue, et al. Nature

15    medicine 2004, 10, 712), infeclion of digestive tracts with bacteria ~0 98/06433), cancer development and progression, neoplasia where inhibition of Rho kinase has been shown to inhibit tumor cell growth and metastasis (Itch, et al. Nature Medicine
1999,5,221; Somlyo, et al. Res Commun 2000,269,652), angiogenesis (Uchida, et al.

Biochem Biophys Res 2000, 269,633-40; Gingras, et al. Biochem J 2000, 348,273),

20    vascular smooth muscle cell proliferation and motility (Tammy et al. Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al. Atherosclerosis 2001, 155, 321-327), endothelial cell proliferation, endothelial cell retraction and motility (Oikawa et al. Biochem.
Blophys. Res. Commun. 2000, 269, 633-a40), stress fiber fonnation (Kimura et al.

Science 1997,275, 1308-1311; Yamashiro et al. J. Cell Bioi. 2000, 150, 797-806),

25    thrombotic disorders (Kikkawa, et al. FEBS Lett. 2000, 466, 70-74; Bauer et al. Blood 1999, 94, 1665-1672, Klages, et al. J Cell Biol1999,144, 745; Relzer, et al. Cell Signal 2000, 12,845) and leukocyte aggregation (Kawaguchi, et al. Eur J Phannacol. 2000,

403:203-8; Sanchez-Madrid, et al. J lmmunol. 2003, 171:1023-34, Sanchez-Madrid, et

al. J lmmunol. 2002, 168:400-10), and bone resorption (Chellaiah, et al.  J Bioi Chern.

30    2003, 278:29086-97). Na/H exchange transport system activation (Kawaguchi, et al. Eur J Phannacol. 2000, 403:203-8), Alzheimers disease (Zhou et al. Science 2003, 302, 1215-1217), adducin activation (Fukata et al. J. Bioi. Chern., 1998,273, 5542-

5548), and in SREB (Sterol response binding element) signalling and its effects on lipid metabolism (Lin et al. Circ. Res., 92, 1296-304, 2003).

Therefore, a compound having inhibHory 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 cardiovascular and non-cardiovascular diseases involving Rho-

kinase as the primary or secondary disease cause, like hypertension, pulmonary hypertension, ocular hypertension, retinopathy, and glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina

10    pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic
obstructive pulmonary disease (COPD), adult respiratory distress syndrome,

15    thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer'sdisease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood

vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS,

20    osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, cancer development and progression, e.g. cancers of the breast, colon, prostate, ovaries, brain and lung and their metastases.

WO 01/64238 describes isoquinoline-5-sulfonamide derivatives optionally substituted

25    by a -(CH2)1~-0-(CH2)o~-. a -(CH2)0-6•S-(CH2)~- or a -(CH2)0.e-linked heterocyclic group useful as neuroprotective agents.

WO 2004/106325 (Schering AG) describes prod rugs of the Rho-kinase inhibitor fasudil

carrying an ether or ester group in the 1-posHion of the isoquinoline ring.

30

WO 2001/039726 generically describes -O-(Co-C1o)alkyl-heteroaryl substHuted cyclohexyl derivatives useful for the treatment of microbial infections.
 
JP 10087629 A describes isoquinoline derivatives useful for the treatment of diseases caused by Heliobacter pylori such as for example gastritis cancer or ulcer. The isoquinoline derivatives may be substituted by OH in the 1-position and are preferably 5-substituted by X-{(C1-C6}alkylene}]o-1-Ywherein X may be oxygen andY may be an aryl or a heterocyclic group.

Yoshida et al. (Bioorg. Med. Chern. 1999, 7, 2647-2666} disclose 6-benzyloxy-isoquinoline for the treatment of infections caused by Heliobacter pylori.

10

US 5,480,883 generically discloses as EGF and/or PDGF receptor inhibnors useful for inhibiting cell proliferation compounds of the fonnula "Ar I -X- Ar II" wherein X may be (CHR1}m•Z-(CHR1}n. e.g. Z-CH2, wherein Z may be 0, R1 is hydrogen or alkyl, Ar

1 may be among others an optionally substituted isoquinolone and Ar II may be among

15    others an optionally substituted C3.7 monocyclic saturated heterocyclic system.

WO 2005/030791 (Merck & Co.} generically describes as potassium channel inhibttors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc. isoquinolone derivatives which are optionally substituted in 6-position by a group

20    (CReR~pOR43 wherein p may be zero, and R43 is e.g. a group R81 defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with 1, 2, 3 or 4 heteroatoms selected from N, 0 or S; and are substituted by a directly bound optionally substituted aryl or heteroaryl ring in the 4-position.

25    WO 2005/030130 (Merck & Co.} generically describes as potassium channel inhibttors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc. isoquinoline derivatives which may be substituted by hydroxyl in the 1-position and are optionally substituted in 6-position by a group (CReR~pOR43 wherein p may be zero,

and R43 is e.g. a group R81 defined as a 4-6 membered unsaturated or saturated

30    monocyclic heterocylic ring wnh 1, 2, 3 or 4 heteroatoms selected from N, 0 or S; and

are substituted by a directly bound optionally substijuted aryl or heteroaryl ring in the 4-position.

WO 03/053330 (Ube) describes isoquinolone derivatives of the formula

nY{heteroaryij- C(R)(R)(NH2)

HN~

0

as Rho-kinase inhibitors.

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

R4    Rs           
RaW,""' L-r~Rs   
R2N    o        ~   
    Ra    R7    (R9ln   
0            (I)   
wherein

R2 isH, (C1-Ce)alkyl, [(C1-Ce)alkyleneJo-1-R',

15    [(C1-Ce)alkylene]o-1-0-(C1-Ce)alkyl, [(C1-Ce)alkyleneJo-1-0-R',[(C1-Ce)alkyleneJo-1-NH2, [(C1-Ce)alkylene]o-1-NH(C1-Ce)alkyl, [(C1-Ce)alkyleneJo-1-N[(C1-Ce)alkyl]2. [(C1-Ce)alkyleneJo-1-CH[R']2.

[(C1-Ce)alkyleneJo-1-C(O)-R',[(C1-Ce)alkyleneJo-1-C(O)NH2,

[(C1-Ce)alkyleneJo-1-C(O)NH-R',or [(C1-Ce)alkyleneJo-1-C(O)N[R'J2;

20

R3 isH, halogen, CN, (C1-Ce)alkyl, (C1-Ce)alkylene-R',OH, 0-R", NH2, NHR", NR"R" or NH-C(O)-R",

R4 isH, halogen, hydroxy, CN, (C1-Ce)alkyl, (C3-Ca)cycloalkyl, (C1-Ce)alkylene-R';

R5 isH, halogen, CN, N02, (C1-Ce)alkyl, (C2-Cs)alkenyl, R', (C 1-Cs)alkylene-(C6-C 1o)aryl, (C2-Cs)alkenylene-(Cij-C1 o)aryl,

(C1-Cs)alkylene-(C5-C1Q)heterocyclyl, NH2, NH-R',NH-802H, NH-502•(C1-Cs)alkyl,

NH-802-R',NH-C(O}-(C1-Cs)alkyl, NH-C(O)-R',C(O)N[(C1-Cs)alkyl]2. C(O)OH or

C(O)O-(C1•Cs)alkyl;

Rs isH, R',(C1-Cs)alkyl,  (C1-Cs)alkylene-R',

(C1-Cs)alkylene-O-(C1-C6)alkyl, (C1-Cs)alkylene-O-R',(C1-Cs)alkylene-CH[R'J2.

10    (C1-Cs)alkylene-C(O)-R',(C1-Cs)alkylene-C(O)NH2. (C1-Cs)alkylene-C(O)NH-R',or (C1-Cs)alkylene-C(O)N[R']2;

R7 and Rs are independently of each other H, halogen, CN, N02. (C1-Ce)alkyl,

O-(C1-Cs)alkyl, O-[(C1-Cs)alkyleneJo-1-R',(C2-Cs)alkenyl, R',

15    (C2-Cs)alkenylene-(Cs-C10)aryl, (C1-Cs)alkylene-R',NH2, NH-R',NH-802H,

NH-502-(C1-Cs)alkyl, NH-802-R',802-NH2, 802-NHR',NH-C(O)-(C1-Cs)alkyl, NH-C(O)-R',C(O)N[(C1-Cs)alkyl]2. C(O)OH or C(O)O-(C1-Cs)alkyl;

Rg is halogen or (C1-Cs)alkyl;

20

n is 0, 1, 2, 3 or4; and

L is 0 or 0-(C 1-Cs)alkylene;

25    wherein R'is (CJ-Cs)cycloalkyl,  (C5-C1o)heterocyclyl or (Cs-C1o)aryl; and

R" is (CJ-Ca)cycloalkyl, (C5-C1o)heterocyclyl, (Cs-C1o)aryl, (C1-Cs)alkyl, (C1-Cs)alkylene-R',(C1-Cs)alkylene-O-(C1-C6)alkyl, (C1-Cs)alkylene-O-R',or (C1-Cs)alkylene-NRxRy; and


wherein Rx and Ry are independently of each other (C1-Ce)alkyl, (C5-C1o)heterocyclyl, (Cs-C1o)aryl, (C1-C4)alkylene-(C5-C1o)heterocyclyl, (C1-C4)alkylene-(Cs-C1o)aryl, (C1-C4)alkylene-NH(C1-Cs)alkyl, (C1-C4)alkylene-N[(C1-Cs)alkyl]2, (C1-C4)alkylene-N[(Cs-C1o)aryl]2, or (C1-C4)alkylene-N[(C5-C1o)heterocyclyl]2; and

wherein in residues R4, R5, R7 and Ra one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2,

10    CONH2, CONHCH3 or CON(CH3)2 or an alkyl or alkylene may be halogenated once or more;

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

physiologically functional derivatives.

15

In another embodiment of a compound of fonnula (I) in residues R4, R5, R7 and Ra 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.

20    Stereoisomeric fonns of the isoquinolone derivatives of the fonnula (I) include the corresponding tautomeric 1-hydroxy-substituted isoquinoline derivatives of the fonnula


wherein Rt isH, (Ct-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, [(Ct-Cs)alkylenelo-t-(CJ-Ce)cycloalkyl, [(Ct-Cs)alkylene]O-t-(Cs-Cto)heterocyclyl, [(Ct-Cs)alkylene]o-t-<Ce-Ct o)aryl,
C(O)-(Ct-Cs)alkyl, C(O)(C2-Cs)alkenyl, C(O)-(C2-Ca)alkynyl, C(O)-[(Ct-Cs)alkylene]o-t-(CJ-Ce)cycloalkyl, C(O)-[(Ct-Cs)alkyleneJo-t-(Cs-Cto)heterocyclyl, or C(O)-[(Ct-Ce)alkylenelo-t-(Cs-C 1o)aryl, and

wherein R3, R4, Rs. Rs, R7, Re, Rg, nand L are as defined above.

10    In a preferred embodiment, R2 in the compound of the formula (I) is H, the compound is thus characterized by a compound of the formula (II)




(II).

In a further preferred embodiment, Rt in the compound of the formula (I')is H, the

15    compound is thus characterized by a compound of the formula (II')

R4    Rs
R3w-..-;::,..;::: L-r~Ra
No    o    ~

R7    (Rgln   
OH   R8    (II').   
       

The compounds (II) and (II')are tautomeric forms of each other.

For example the compound of the formula

H0°'GQH

Example    Aldehyde or    Amine    Product            [M+Hl    RJ    Method   
    Ketone                            [min)       
                                       
                                       
    0                        417.2    1.30    B   
    oYH-6        0        9"    9"               
207        26    HN¢&    D~               
            0                           
                                       
            HN¢& ODJ)    360.2    0.78    B   
208    Hx    26                   
            0                           
                                       
    HYO        HN        N.... .....o    360.2    0.86    B   
                                   
                                   
209    OBoe    26                           
                                   
            ¢&:0"'               
            0                           
                                       
    \        ,¢6-0DJJ    370.2    1.17    B   
210    H0    26                   
                           
            0                           
    2                                   

Example    Aldehyde or    Amine        Product        [M+H1    RJ    Method   
            Ketone                            [min]       
                                               
                                               
            \            0        N,    371.1    1.01    B   
                                               
            ~                                   
                    HN¢&'DJ>               
211        H20    26                   
                                   
                    0                           
            0            0        407.2    1.15    B   
                                           
212            26    H¢& DJb               
            ~ 8                       
                    0                           
                                               
            "&"                                   
                                s    373.1    1.12    B   
                        0                       
213        H    0    26    HN¢&    Dfl               
            2        0                           
                                            I   
                                               
214        Hx    26    ~¢&UJJ    361.2    1.05    B   
                    0                        I   

Example    Aldehyde or    Amine        Product    [M+H1    RJ        Method       
                                       
    Ketone                            [min)               
                                               
    0            "W0    0D~    315.3        0.94        A   
215    ~H    31                                       
    0            "0u\    329.3        1.04        A   
216    ~H    31                                   
    0                329.3        1.07        A   
                ,woD~                       
217    YH    31                                   
                0                               

104

Product

,Q:YDJ'

0
Lu~
H~-yu     I

LoD~,

H~yu    rF

0
 
105

Example        Aldehyde or        Amine        Product        [M+H1        Rtf        Method       
                                                       
        Ketone                                [min]               
                                                       
                                                       
        0            ,QuoD~    369.2        1.05        A       
221        ci'H        31                               
                        0                               
                                                       
                                                       
222        cro        31    HNQ:ru0ND    355.3        1.15        A       
                                               
                                               
                                               
                                                       
        dH                        397.2        1.26        A       
223                31    HN    N    ""  I                           
        Cl                                               
                    Qcruff                           
                        0                               
                                                       


106
                                                [M+H1                Method       
    Example    Aldehyde or                Amine            Product                    RJ           
            Ketone                                                [min]           
                                                                       
                                                                       
                                                                       
        Cl'd                    0    ""'    397.2            1.28    A       
                                                           
                                                           
                                                           
                                                           
    224        I    H    31    HN'ON I A                           
            A                                               
                                ¢v~                           
                                    0                                   
                                                                       
                                                   
    225    C!H                31    HN¢voDJINA    397.2        1.28    A   
                                    0        Cl                           
                                                               
        0                    ¢vo'(l~    363.2        1.16    A   
    226    d'H    31                               
                                           
                                HN            N "" I                           

Example    Aldehyde or    Amine        Product        [M+H1    RJ    Method   
    Katona                                    [min]           
                                                   
                                                   
    dH        HN    NI . 6            377.3        1.26        A       
227        31                                           
            ~l)J)'                               
            0                                           
                                                       
                                431.3        431.3        A   
            0    "'>    F                               
228    F    31    HNwDff'•                               
    F~"                                       
    F        0                                           
                                                       
    dH        HN    NI .6            364.3        0.83        A   
229        31                                           
    N                                               
            W'DJ)                           


108

    Example    Aldehyde or        Amine        Product        [M+H1    RJ    Method   
        Ketone                                [min)       
                                               
                                               
        0                            364.3    1.06    A   
    c{H        31                               
    230                                           
                                               
        N            HN        N~ h               
                                           
                    QcruJJ               
                        0                       
                                               
                                    441.3    1.03    A   
                        0        ~0               
    231    "'I        31    Qu    ~'               
        0~,p                                   
        O's,            HN    0    D~                   
                                               
                                               
        a:i'Hh                            413.3    1.40    A   
232            31    HN        N "" "" I               
                                       
                                           
                    Quu~               
                        0                       


is a tautomer of the compound with the formula




The following preferred embodiments refer to the compounds of the formulae (1), (1'),

(II) and (II'):

R3 is preferably H, halogen, (C1-Cs)alkyl, (C1-C4)alkylene-R',0-R" or NHR". More preferred, R3 isH, (C1-Ce)alkyl or NHR". Most preferred, R3 isH, (C1-C4)alkyl, NH-(Cs-Cs)heterocyclyl or NH-phenyl, especially preferred R3 isH, (C1-C4)alkyl, NH-

10    (Cs-Cs)heteroaryl containing one or more N atoms or NH-phenyl. Most especially preferred, R3 is H.

Preferably, R4 isH, halogen, CN, (C1-Cs)alkyl, NH-(Cs-C1o)aryl or (C1-Cs)alkylene-

R'.More preferably, R4 isH, halogen, (C1-Cs)alkyl, NH-(Cs-C1o)aryl or

15    (C1-Cs)alkylene-R'. In a further preferred embodiment, R4 isH, halogen, (C1-Cs)alkyl, NH-(Cs-C1o)aryl or (C1-C2)alkylene-(Ce-C1o)aryl. Most preferred, R4 is H, halogen, or (C1-Cs)alkyl. Especially preferred, R4 isH, halogen or (C1-Cs)alkyl. Most especially preferred, R4 is H.

20    Preferably, R5 isH, halogen, CN, (C1-Cs)alkyl, R',NH-(Cs-C1o)aryl or (C1-Cs)alkylene-R'. More preferably, R5 isH, halogen, (C1-Cs)alkyl, R', NH-(Ce-C1o)aryl or (C1-Cs)alkylene-R'. In a further preferred embodiment, R5 isH, halogen, (Cs-C1o)aryl, NH-(Cs-C1o)aryl, (C1-C2)alkylene-(Cs-C1o)aryl, (C1-Cs)alkyl

or (Cs-C1o)heteroaryl. Most preferred, R5 isH, halogen, phenyl, (C1-Cs)alkyl or

25    (Cs-Cs)heteroaryl. Especially preferred, R5 isH, halogen or (C1-Cs)alkyl. More especially preferred R5 is H or halogen. Most especially preferred, R5 is H.
09

Example        Aldehyde or    Amine        Product    (M+H1    RJ    Method           
                                           
                Ketone                                    [min]               
                                                                       
                                                                       
            \            ,QuoDJ)    366.3        1.19    A           
                                                       
233            H20    31                                       
                                                           
                            0                                       
                                                                       
234                31        ,QuoD~    403.3        1.11    A           
                                                   
                ~ u            0                                       
                "2?J"                                                   
                                                                       
                H20                ,QuoD~'    369.2        1.12    A           
235                31                                       
                            0                                       
                                                                   
                _ L _ ... _                                               
 





,                       
                       
0                       
    i    <(    "'    "'   
                   
:!!                       
            'E'~    "'C!    "'~   
    ii'!_~           
                   
    r    N    N    ...:   
    :J:    .,;    ..;       
+                       
            ;;;    "'    "'   
    I'!            ;:!;   
                    "'       
                )    ~        ~   
                               
        'll        0    0        0   
,"        0            0   
        e            0           
...        0            0   
                        0       
                z    z        ~Iz   
                ~:J:               
                    ~I           
        c        0    0        0   
"                       
        .,    .,        .,   
        e                   
<(                       
                               
~    ..c        :J:        :J:   
0        I               
,..            0=)           
        ~...    ~s    0=\            0<   
                               
        :a:                       
        ..            ,        .,   
                               
        i5.        CD               
        E        .,               
                N    ..N        N   
        w                    "'   
        =                       
 



111
 

Example  I    Aldehyde or    .        Product       
    Ketone    Am me               
"'        " ,Q&oD~   
    '~"       
                    0       
    F  F    0        I w       
240    F~H    30        OD       
                HN    N~F   
                0        F  F   
        0        wo    Cl   
241I    Cl'd    30           
    I    H            y"] J)I"""   
        0        HN    ~N    A   


387.1




415.2
 


'

I 1.20   I    B



I 1.24   I    B
 




112
 

Example  I    Aldehyde or        .        Product       
        Ketone        Am me               
u,        y,        ~    ,Q&o'()~   
                    0        Cl   
    Cl    O  H        wo    ~   
243    I  VCl        30    HN 0    D    : I Cl   
        o            w       
244    ff    H    30        °Y'"l    0f'   
                HN    ~N~   
                    0           
 


'


1449.2111.49 I A 451.2




I  395.2  I  1.32  I    B
 





Example  I    Aldehyde or    .
Am me
Ketone

245    ~H0          30
l)

0
~H
246    ~~     30

u•  1 cd'"l •
 



113

Product

~ O'(l(~        B   
~        ~~~           
    0        I 382.5  11.23    I  D   
~    0'(1  t:j~           
7    ""<::               
HN    I ~    ~~~           
l,~oD~ I~'' I'~ I '

0
 




114

Example    Aldehyde or    Amine        Product        [M+H1        RJ        Method   
                                           
    Ketone                            [min]           
                                           
    0                        387.3        1.42        A   
248    crH        30        ,Q&'D~                           
                    0                           
    0                                           
    )lH                                           
249            32        HNFN--.._../        319.2        0.94        A   
                                               
                    c5o:'D                           
                    0                           
    0                ,Q=x:u~                           
250    ~H        32                333.1        0,98        A   
                                               
                    0                           
                                               
                                               
                                               
 



115

'Example    Aldehyde or            Amine        Product        [M+H1        RJ        Method   
                                                   
                                                   
                                                   
        Ketone                                    [min]               
                                                           
t--                                                               
                                                               
                                                               
251        ~H            32        ,¢:x:DJ        347.2        1.14            A       
                                                               
                                                               
                            0                                   
        0                    ,.Qccoy                                   
252        A            32                333.2        0.97            A   
                                                           
                                                           
                            0                                   
        0                    ,w:u~                                   
253        YH        32                347.1        1.05            A   
                            0                                   
                                                               
                                                               
                                                               
 




116

[    Example    Aldehyde or        Product                [M+H1        RJ            Method'   
                                                       
        Ketone    Amine                            [min]                       
                                                               
        0                                                           
254    ~H    32    "~:D0    -P    345.2        1.04            A   
                                                   
255    UH    32    ,~:u'~            361.16    1.23            A   
                0                                                   
        F0        ,~:D'-'1<:                                           
256    :~H    32        367.1    1.06            A   
                0    F                            I   
                                                               
                                                                   
 



117
    Example        Aldehyde or        Amine            Product            [M+H1        RJ        Method   
                                                               
            Ketone                                            [min]               
                                                                       
            0                ,Q:;c:u__c                           
    257        c{H        32            387.2        1.38        A   
            cro                0                                           
                                                                       
    258                32        Q:toD        373.15        1.24        A   
                            HN    0F    ND                           
            0                                                           
    259        dH        32        HN                I    415.1/        1.31        A   
                                    N    "'-        417.1                   
                                                                       
            Cl                Q:xuffF                           

118

    Example    Aldehyde or                Amine    Product        [M+Hl    Rtf    Method   
        Ketone                                    [min]       
                                                   
                                               
        0                                       
        CI~H                0    """    415.11           
                                           
    260    lh                    32    FIC:1    h    417.1    1.29    A   
                                                   
                                HNQo:J)I               
                                0                   
                                                   
    261        H                32    HNQo:oD~FNIh    415.2/    1.20    B   
        .,.,:;                            417.2           
                                               
        C!                                       
                                0    Cl               
                                           
    321            H    32    HNf,o:UJ!aFNIh    449.1/    1.35    B   
                                    451.1           
        Cl                                       
        u                        0    Cl               
                                                   

Preferably, Ra isH, (C1-Cs)alkyl, R',(C1-C4)alkylene-(C3-Ca)cycloalkyl, (C1-C4)alkylene-(Cs-C1o)helerocycllyl, (C1-C4)alkylene-C(O)-(Cs-C1o)heterocyclyl, (C1-C4)alkylene-C(O)-(Ca-C10)aryl or (C1-Ca)alkylene-(Cs-C1Q)aryl. In a further preferred embodiment, Rs isH, (C1-Ca)alkyl, (Cs-C1o)heterocyclyl, (C3-Ca)cycloalkyl, (C 1-C4)alkylene-(C3-Ca)cycloalkyl, (C 1-C4)alkylene-(Cs-C1 o)heterocyclyl or (C1-Ca)alkylene-(Cs-C1o)aryl. More preferred, Rs isH, (C1-Cs)alkyl, (C3-Ca)cycloalkyl, (C1-C4)alkylene-(C3-Ca)cycloalkyl, (C1-C4)alkylene-{Cs-C1o)helerocyclyl or (C1-Cs)alkylene-(Cs-C1o)aryl.

In a more preferred embodiment, Ra isH, (C1-Cs)alkyl, (C3-Ca)cycloalkyl,

10    (C1-C4)alkylene-(C3-Ca)cycloalkyl, (C1-C4)alkylene-{Cs-C1o)heterocyclyl, in which the helerocyclyl is unsubstituled or subsmuted by (C1-C4)alkyl, or is (C1- C4)alkylene-(Cs-C1o)aryl, in which lhe aryl is unsubstituted or subst~uled, preferably one to three times, by halogen, (C1-C4)alkyl especially methyl, ethyl, isopropyl or 3,3,3-trifluoromethyl, O-(C1-C4)alkyl especially methoxy, 802-(C1-C4)alkyl especially 502-

15    CH3 or 802-CF3, or by N[(C1-C4)alkyl]2 especially N(CH3)2, In a more especially preferred embodiment Ra isH, (C1-Ca)alkyl, (C3-Ca)cycloalkyl, (C1-C4)alkylene-(C3-Ca)cycloalkyl, (C1-C2)alkylene-thienyl, (C1-C2)alkylene-pyridyl, (C1-C2)alkylene-piperidinyl, (C 1-C2)alkylene-pyrrolidinyl, (C1-C2)alkylene-1-methyl-pyrrolyl,

(C 1-C2)alkylene-1-melhy~pyrazolyl, (C 1-C2)alkylene-furanyl, (C 1-C2)alkylene-

20    tetrahydrofuranyl or (C1-C2)alkylene-1H-indazolyl, (C1-C2)alkylene-naphtyl or (C1-C2)alkylene-phenyl wherein phenyl is unsubst~uted or subst~uted by halogen, methyl, ethyl, isopropyl, 3,3,3-trifluoromethyl, melhoxy, 802-CH3, 802-CF3 or N(CH3l2; preferably the (C1-C2)alkylene is methylene. In a more especially preferred

embodiment, Rs isH, (C1-Cs)alkyl, (C3-Cs)cycloalkyl or

25    (C1-C4)alkylene-(C3-Cs)cycloalkyl. In a further more especially preferred embodiment, Rs isH, (C1-Cs)alkyl. In a most preferred embodiment, Ra is H. Examples of Rs groups are hydrogen, melhyl, ethyl, propyl, isopropyl, cyclopropyl, 3-methyl-butyl, butyl, s-butyl, 3,3,3-trifluoropropyl or a substituent selected from lhe group consisting of
 
121

Example    Aldehyde or        Amine    Product    [M+H1    Rtl    Method   
    Ketone                    [min]       
                               
                               
    H0            Ht?XD~NH            I   
                               
270            16        342.2    0.86    B   
    <SBoc            0               
                               
    c            HQC(D ~               
271    \;{-""        16        399.2    1.28    B   
        H        0               
                               
272    cdH    16    HNQC(D~N"'"'I    399.2    1.26    B   
            0               
    -""                           
                               
    0~::::... ,p            F               
273            16    "'    481.2    1.26    B   
    QS'CF3        HN(;C(D~~;NI-~               
            0               
                               
L _    -        L ___                   
                               
 




122
    Example        Aldehyde or        Amine        Product            [M+H1        RJ        Method       
                                                               
            Ketone                                        [min)               
                                                                   
            I                H~D~s,o                           
            O=S-0                                           
                                                       
274        HPF        16            445.2        1.05        B       
                                                   
                            0        0''                           
                                                                   
            0                                                       
            H                        0                               
            0~~ /?                QC(D~'s/                           
275                16        HN    N    "'"" I    •c.    427.2        1.07        B       
            d's,                0                                       
                                                                   
                                                                   
            cfHN                        N    -..,                           
276                16        HN    N    I    -""'    350.2        1.01               
                                                        B       
                        \XXDJ)                           
                                                       
                            0                                       
        dH                HN~~C(DNJ)                           
277                16            350.2        0.87        B       
            N                0                                       
                                                                   
                                                                   
                                                                   
                                                                   
 



123

        Example        Aldehyde or        Amine        Product        [M+H1        RJ        Method       
                                                               
                Ketone                                            [min]               
                                                                           
                                                                           
                Nd'H                            "N                               
    278                16    HN            NI ""'        350.2        0.79        B       
                            QC(D~                               
                            0                F                               
                            QCC            '-"'  F                       
    279    ~"    16        D    ffFI.6    417.2        1.25        B       
                HN a                                               
                : F                                                           
    280        dH        16    H~Dff 363.2        1.18        B       
                            0                                               
            0~~:    H16                    Cl                           
    281            H~D~Cl    417.1/        1.28        B       
                                           
                    419.2                       
                            0                                               
                Cl                                                           
                                                                           
                                                                           
 




124

Example    Aldehyde or        Amine            Product            [M+H1        RJ    Method   
    Ketone                                                    [min]       
                                                               
                                                               
282    d'H        16    HN            N    ,. 1        349.19        1.09    B   
                QXD~                   
                                       
                    0                                       
                                               
283    ClB    H 16    HN~UJ;rc1NI""""'    417.13        1.25    B   
                        0            Cl                       
                                                               
284        H16    HN            N    """"'        383.21        1.14    B   
                                                   
    C!        Q):ouJ?I    385.2               
                        0            Cl                       
                                                           
                                                           
285    Cl'dIH     16                    Cl        383.2/        1.18    B   
                        I """"'                   
        HN            N        385.2               
    """"'                QXD~                       
                        0                                       
                                                               
 



125

Example    Aldehyde or    Product    [M+H1    R~    Method   
    Ketone    Amine        [min]       
                       
        dH        QCXD~c1 383.21       
286            18    HN    N""-  I    385.2    1.18    B   
    Cl    cro        0                   
287            18    HN~D0ND    341.2    1.15    B   
                                   
        0        HQXD~               
288    cYH    16        355.5    1.40    D   
                           
                0                   
                                   
        F0        HNyC(DN~F355.5           
289    :~H    18        1.18    D   
                0    F  F               
 




126

Example    Aldehyde or    Amine    Product        [M+H1    RJ    Method   
        Ketone                        [min]       
                                       
                                   
290        ~H    16    HN\XXDN~    313.1    0.95    B   
                0                       
                                   
291        D  H    16    HN\XXDN~    315.5        1.23    D   
                                   
                0                       
                                       
                                       
        0                               
292        A    18    HN  0    NY    301.5        1.09    D   
                ~D                   
        0        ~D                   
                                   
293        ~H    16        315.2    1.00    B   
                               
                "'0    \                   
L . __                -----                       
                                       


General procedure B for the reductive amlnation reaction:

100 mg (0.25 mmol) 7-Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one trifluoro-acetate (54, trifluoroacetate) were dissolved in 5 mL Methanol. After adding molecular sieves 4 A, 51.5 mg (0.51 mmol) triethylamine, 152.9 mg (2.55 mmol) acetic acid and 0.32 mmol of the conresponding aldehyde, a solution of 48.0 mg (0.76 mmol) sodium

cyanoboron hydride is added dropwise and the mixture is stirred at room temperature until complete conversion is achieved. In some cases rt was necessary to heat the

mixture at 60 •c to achieve complete conversion. For the isolation of the products, the

solution was filtered and the solvent was removed i. vac. The residue was dissolved in

dichloromethane, washed with 1 N NaOH and sat. NaCI-solution, dried with MgS04 and evaporated. The crude products were purified by preparative HPLC. The obtained trifluoroacetates were stirred in 2 N HCI/Methanol, evaporated, dissolved in water and freeze dried to yield the desired products as hydrochlorides.

The following compounds in Table 3 were synthesized and obtained as hydrochlorides by this procedure using compound 54.
 
132

7 -Fiuoro-6-(1-isopropyl-piperidin-4-yloxy)-4-methyi-2H-isoquinolin-1-one (308)

~OY'l

HN~F ~N~

0

By alkylation of 50 mg of 7 -fluoro-4-methyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one

(22) with isopropylbromide in the presence of triethylamine in DMF atso•c 31 mg of 7-

Fiuoro-6-(1-isopropyl-piperidin-4-yloxy)-4-methyi-2H-isoquinolin-1-<>ne were obtained.

R1 ~ 0.93 min (Method B). Detected mass: 319.2 (M+H/.

5.Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (309)

~OY'I
HNyv    ~NH

0

10    60 mg (0.21 mmol} 6-(piperidin-4-yloxy)-2H-isoquinolin-1-<>ne-hydrochloride (12) were dissolved in 5 ml of concentrated sulphuric acid. At 0 •c 28.6 mg (0.21 mmol) of N-

chloro succinimide were added and the mixture was stimed at 50 •c. After 2 h the solution was poured on ice and the pH was brought to about12 by adding solid NaOH.
The aqueous solution was extracted twice w~h dichloromethane. The organic layers

15    were dried wilh MgS04 and evaporated. The crude product was purified by preparative HPLC. The obtained trifluoroacetate was dissolved in 2 N HCI and the solvent was removed i. vac. Dissolving the residue in water, followed by lyophilization gave the desired product as HCI-salt. Rt ~ 0.86 min (Method A). Detected mass:

279.11281.1 (M+H/.

20

7-Sromo-6-fluoro-isoquinollne 2-oxlde (310)


Starting from 7-bromo-6-fluoro-isoquinoline (15), the title compound was prepared following the method described for 7-<:hloro-6-fluoro-isoquinoline 2-oxide (5). R1 = 0.93 min (Method C). Detected mass: 242.2 /244.2 (M+H•).

7-Bromo-1-<:hloro-6-fluoro-lsoquinoline (311)
rYYF

~~Br

Cl

Starting from 7-bromo-6-fluoro-isoquinoline 2-oxide (310) the desired product was

synthesized according to the protocol described for 1,7-di-chloro-6-fluoro-isoquinoline

(6). R1 = 1.70 min (Method C). Detected mass: 260.01262.0 (M+W).

10

7-Bromo-6-fluoro-2H-isoquinolin-1-one (312)

F

HN
Br

0

12.9 g (49.5 mmol) 7-bromo-1-chloro-6-fluoro-isoquinoline (311) were dissolved in 250 ml of acetic acid. After adding 38.7 g (0.5 mol) ammonium acetate, the solution was
15    stirred at 100 •c. After3 h, the solvent was removed i. vac. and the residue was

poured on water. The precipitate was fi~ered and dried to yield 9.91 g (83%) of the title compound. R1 = 1.15 min (Method C). Detected mass: 242.21244.1 (M+H•).

7-Bromo-6-lluoro-2-{4-melhoxy-benzyi)-2H-isoquinolin-1-one (313)
/oQiyC(r

20    0   
       

9.66 g (39.9 mmol) of7-bromo-6-fluoro-2H-isoquinolin-1-one (312) were dissolved in 180 mL of dimethyl acetamide and 1.92 g (48.0 mmol) of sodium hydride (60%) were added. After 1 hat room temperature a solution of7.50 g (48.0 mmol) of 4-methoxy benzylchloride in 25 ml of dimethyl acetamide was added. The mixture was stirred at

room temperature until complete conversion is achieved. For the isolation procedure,

the solvent is removed i. vac., the residue was taken up in saturated sodium

bicarbonate solution and extracted three times w~h dichloromethane. The organic layers are dried with MgS04 and evaporated to yield 16.8 g of a dark oil as crude product, which was stirred in methanol. Filtration of the precipitate gave 6.56 g of the title compound as a yellow solid. The mother liquor was evaporated and the residue purified by preparative HPLC, which gave additional 2.62 g of the desired product. R1 =

1. 71 min (Method C). Detected mass: 362.3/364.3 (M+H+).

10    4-[7-Bromo-2-{4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-piperidlne-1-carboxyllc acid tert-butyl ester (314)
/ORyct::ct!oY:

126 mg (0.625 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester were

dissolved in 2.5 ml of dimethylacteamide and 30 mg (0.75 mmol) of NaH (60% purity)

15    were added at room temperature. After 15 minutes 181 mg (0.5 mmol) of 7-bromo-6-fluoro-2-{4-methoxy-benzyi)-2H-isoquinolin-1-one (313) were added and stirring was continued at room temperature. After 5.5 h the solvent was removed i. vac. After adding saturated sodium bicarbonatesodium bicarbonate solution, the mixture was
extracted twice with dichloromethane. The organic layers were dried with MgS04 and

20 evaporated. After final purification by preparative HPLC, 182 mg of the product could be isolated. R1 = 1.93 min (Method C). Detected mass: 543.5/545.5 (M+H+).

7-Bromo-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (17) HNQCCODBrNH
0

25    182 mg 4-[7-bromo-2-(4-methoxy-benzyl)-1-oxo-1 ,2-dihydro-isoquinolin~-yloxy]­ piperidine-1-carboxylic acid tert-butyl ester (314) were dissolved in 5 ml of trifluoroacetic acid. After 2 hat room temperature, the mixture was heated at 140 'Cin


a microwave for 2 h. The solvent was removed i. vac. and the residue was dissolved 2

N HCI. The aqueous solution was washed twice wijh dichloromethane and the organic layers were extracted wijh 2 N HCI. The combined aqueous solutions were evaporated i. vac. and the residue was dissolved in water. After lyophilization the title compound was isolated as HCI-satt. R1 = 0.80 min (Method B). Detected mass: 323.1/325.1 (M+W).

6-Ftuoro-2-(4-methoxy-benzyl)-7-phenyi-2H-isoquinolin-1-one (315)
....-oQycco"'F
""-I   N      I.-<'
"'
o    I.-<'

10    453 mg (1.25 mmol) 7-bromo-6-fluoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-one (313), 432 mg (3.125 mmol) K2C03 and 190.5 mg (1.56 mmol) phenylboronic acid

were dissolved in 12.5 ml toluene. Under Argon, 72 mg (0.062 mmol) Pd(Ph3)4 were added and the solution was stirred at 100 •c. After complete conversion, the solvent is removed i. vac. and saturated sodium bicarbonate solution is added. The aqueous

15    solution is extracted three times with dichloromethane and the organic layers are dried wnh MgS04. After evaporation, the crude product is purified by preparative HPLC. R1 = 1.80 min (Method C). Detected mass: 360.4 (M+H).

4-{2-(4-Methoxy-benzyl)-1-oxo-7-phenyl-1,2-dihydro-isoquinolin~-yloxy]-

20    piperidine-1-earboxylic acid tert-butyl ester (316)


168 mg (0.83 mmol) 4-hydroxy-piperidine-1-<:arboxylic acid lert-butyl ester were dissolved in 5 ml of dimethylacetamide and 20 mg (0.83 mmol) of sodium hydride (60

%) were added. The mixture was stirred at room temperature. After 30 minutes a solution of 240 mg {0.67 mmol) 6-fluoro-2-{4-methoxy-benzyl)-7-phenyi-2H-iso-quinolin-1-<>ne {315) in 5 ml of dimethylacetamide was added and stirring was continued at room temperature. After standing overnight, 20 mg {0.83 mmol) of sodium hydride {60 %) were added and the solution was stirred at 100 •c. After 1 h, the

solvent was removed i. vac. and saturated sodium bicarbonate solution was added.

The aqueous phase was extracted three times with dichloromethane. The organic

lay""'were dried with MgS04 and evaporated. The crude product was purified by

preparative HPLC. R1 = 1.98 min {Method C). Detected mass: 541.7 {M+H).

10

7-Phenyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one  (317)
¢
0

HN

h

4-[2-{4-Methoxy-benzyl)-1-oxo-7 -phenyl-1,2-<lihydro-isoquinolin~yloxy]-piperidine-1-

carboxylic acid tert-butyl ester {316) was deprotected following the method described

15    for 7-bromo-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one {H). Similar work up delivers the title compound as HCI.,;a~. R1 = 1.05 min (Method B). Detected mass: 321.1 {M+W).

7-Ethyl-6-fluoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-<>ne (318)

/0-y:")    ('(YF
    ~N~   
20    0   
       
    The title compound was synthesized following the method described for 6-fluoro-2-{4-   
    methoxy-benzyl)-7-phenyi-2H-isoquinolin-1-one {315) starting from 7-bromo-6-fluoro-2-   
    (4-methoxy-benzyi)-2H-isoquinolin-1-one (313) and ethylboronic acid. R1 = 1.69 min   
    {Method C). Detected mass: 312.4 {M+H•).   


4-[7-Ethyl-2-(4-methoxy-benzyl}-1-oxo-1,2-dihydro-isoquinolln-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (319}



The t~le compound was synthesized following the method described for 4-[2-(4-methoxy-benzyl)-1-oxo-7 -phenyl-1 ,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (316), starting from 7 -ethyi-S-fluoro-2-(4-melhoxy-benzyi)-2H-isoquinolin-1-one (318) and 4-hydroxy-piperidine-1-carboxylic acid tell-butyl ester. R1 = 1.91 min (Method C). Detected mass: 493.6 (M+H•).

10

7 -Ethyl~-(piperidin-4-yloxy)-2H-isoquinolin-1-one (320)
()JOY'!
HN!('I~NH

4-[7-Ethyl-2-(4-methoxy-benzyl)-1-oxo-1 ,2-<lihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (319) is deprotected following the melhod described for
15    7-bromo-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (17). Final purification by preparative HPLC delivers the t~le compound as trifluoroacetate. R1 = 0.92 min (Method A). Detected mass: 273.2 (M+H}.
 

Method A:

10    Stationary phase: Gradient:

Flow

15    Method B: Stationary phase: Gradient:
 


Col YMC Jsphere 33 x 2 ACN+0.05% TFA: H,O + 0.05% TFA

5:95(0 min) to 95:5(3.4 min) to 95:5(4.4 min)

1 mUmin


Col YMC Jsphere 33 x 2 ACN+0.05% TFA: H20 + 0.05% TFA


Flow

Method C:

Stationary phase:

Gradient:

Flow

10    Method D:

Stationary phase: Gradient:

Flow

15
 





138

5:95(0 min) to 95:5(2.5 min) to 95:5(3.0 min)

1 mUmin


Col YMC Jsphere ODS H80 20 x 2 ACN : H20 + 0.05% TFA
4:96(0 min) to 95:5(2.0 min) to 95:5(2.4 min)

1 mUmin


Col YMC Jsphere 33 x 2.1

Grad ACN+0.08% FA:H20+0.1 %FA (Formic acid) 5:95 (Om in) to 95:5 (2.5min) to 95:5 (3m in) 1.3mUmin
 

Determination of Rho kinase inhibition

To measure Rho-kinase inhib~ion, ICso values were determined according to the

20    following protocol:

Buffer: 25mM Tris pH7.5; 0.02% BSA; 5% Glycerol; 0.008% Triton X100; 2% DMSO, 1mM OTT; 1mM MgCI2; O.S~Ci/wel) y33P ATP

Enzyme: ROCKII or ROKa) (Upstate, Catalog# 14-451 Lot# 24880U) 0.1 ng/~1

Final concentration of ATP in reaction mixture 40~M

25    Biotinylated substrate, diluted to 0.25~M with buffer described above (w~hout ATP)

1.    10~1 Tris buffer(± lnhib~or)

2.    Add 30 ~L of enzyme solution

3.    Start the reaction w~h 30~L of mix substrate/ATP/ATP33

4.    Incubate for 20 min at room temperature

30    5. Stop reaction w~h 30~L of 50 mM EDTA
 


The asterisk (•) denotes where the bond is connected to the N-atom of the piperidine.

Preferably, R7 and Ra are independently of each other H, halogen, CN, (C1-Ce)alkyl, O-(C1-Ce)alkyl, (Cz-Ce)alkenyl, R'or (C1-Ce)alkylene-(C3-Ca)cycloalkyl. More preferred, R7 and Ra are independently of each other H, halogen, CN, (C1-C4)alkyl, O-(C1-C4)alkyl, (Cz-C4)alkenyl, phenyl, (C3-Ce)cycloalkyl, (C1-C4)alkylene-

IO (C3-Ce)cycloalkyl or (Cs-Ca)heteroaryl. Even more prefered, R7 and Ra are independently of each other H, halogen, (C1-C4)alkyl, O-(C1-C4)alkyl or (C3-Ce)cycloalkyl. Most preferably, R7 isH, halogen, (C1-C4)alkyl or O-(C1-C4)alkyl and Ra is H. In another even more prefered embodiment R7 and Ra are independently of each other H, halogen, (C1-C4)alkyl, O-(C1-C4)alkyl or phenyl. Especially preferred,

15    R7 and Ra are H.

Rg is preferably halogen or (C1-C4)alkyl. More preferred, Rg is Cl, F, methyl or ethyl. More preferably Rg is methyl.

20    Preferably, n is 0, 1, 2 or 3.  More preferred, n is 0 or 1. Most preferred, n is 0.

The linker group L may be bound to the piperidinyl ring in any position via a piperidinyl ring carbon atom and may thereby form the (R)- or the ($)-stereoisomer of a compound according to the invention.
25

In a preferred embodiment, L is attached to the 4-position of the piperidinyl ring

6.    Transfer 50 ~L of stopped solution to Streptavidin Flash Plate plus, Per1dn Elmer, SMP 103A
7.    Incubate for 30 min at RT

8.    Wash 4 times with 300 ~I of PBS/0.1% Tween 20

9.    Radioactivity in the well was detenmined

The following products/compounds were tested in said assay by using the respective

fonm (salt or free base) obtained as in the examples described above and the following

activities were measured.

10

No.    ptC5o
   
12    +++++
17    +++++
21    +++++
23    +++++
25    ++++
28    +++++
31    +++++
32    ++++
40    +++++
45    +++++
49    ++++
52    +++++
54    +++++
55    +++++
58    +++++
101    +++++
265    +++++
266    +++++
275    +++++
276    +++++
309    +++++
 





140


The given activi1y is denoted as the negative decadallogarithm of the IC5o (piC5ol as

follows:

+:    piC    50    ,; 3.0
++:    3.0 ,; p1c    50    < 4.0

+++    4.0 ,; piC 50 < 5.o

++++:    5.o,; plc50  < s.o

+++++:    s.o,;piC5o


Claims

1.    A compound of the formula (I)


or of the formula (I')

(I')

wherein

LO    R1 isH, (C1-Ca)alkyl, (C2-Ca)alkenyl, (C2-Ca)alkynyl, [(C1-Ca)alkylenelo-1-(C3-Cs)cycloalkyl, [(C1-Ca)alkyleneJo-1•(Cs-C1o)heterocyclyl, [(C1-Ca)alkylene]{}-1•(Ca-C1o)aryl,
C(O)-(C1-Ca)alkyl, C(O)(C2-Ca)alkenyl, C(O)-(C2-Ca)alkynyl,

C(O)-](C1-Ca)alkyleneJo-1-(C3-Cs)cycloalkyl,

15    C(O)-[(C1-Ca)alkylene]{}-1•(Cs-C1o)heterocyclyl, or C(O)-[(C1-Ca)alkylene]{}-1-{Ca-C1 o)aryl,

R2 isH, (C1-Ca)alkyl, [(C1-Ca)alky1ene]{}-1•R', [(C1-Ca)alkyleneJo-1-0-(C1-Ca)alkyl, [(C1-Ca)alkyleneJo-1-0-R',[(C1-Ca)alkylenelo-

20    1-NH2, [(C1-Ca)alkylene]o-1-NH(C1-Ca)alkyl, [(C1-Ca)alkyleneJo-1-N[(C1-Ca)alkyl]2, [(C1-Ca)alkylenelo-1-CH[R']2,

[{C1-Ce)alkylenelo-1-C{O)-R',[{C1-Ce)alkyleneJo-1-C{O)NH2. [{C1-Ce)alkylenelo-1-C{O)NH-R',or [{C 1-Ce)alkylene]a-1-C{O)N[R']2;

R3 isH, halogen, CN, {C1-Ce)alkyl, {C1-Ce)alkylene-R',OH, 0-R", NH2. NHR", NR"R" or NH-C{O)-R",

R4 isH, halogen, hydroxy, CN, {C1-Ce)alkyl, {C3-Ca)cycloalkyl, {C1-Ce)alkylene-R';

Rs isH, halogen, CN, N02, {C1-Ce)alkyl, {C2-Ce)alkenyl, R',

10    {C1-Ce)alkylene-{Ce-C1 o)aryl, {C:z-Ce)alkenylene-{Ce-C1 o)aryl, {C1-Ce)alkylene-{Cs-C1o)heterocyclyl, NH2, NH-R',NH-S02H, NH-S02-{C1-Ce)alkyl, NH-S02-R',NH-C(O)-{C1-Ce)alkyl, NH-C{O)-R',C{O)N[{C1-Ce)alkyl]2. C{O)OH or C{O)O-{C1-C6)alkyl;

15    ReisH, R',{C1-Ca)alkyl, {C1-Ce)alkylene-R',{C1-Ce)alkylene-0-{C1-Ce)alkyl, {C1-Ce)alkylene-O-R',{C1-Ce)alkylene-CH[R']2.{C1-Ce)alkylene-C{O)-R', {C1-Ce)alkylene-C{O)NH2, {C1-Ce)alkylene-C{O)NH-R',or {C1-Ce)alkylene-C{O)N[R']2;

20 R7 andRe are independently of each other H, halogen, CN, N02, {C1-Ce)alkyl, O-(C1-Ce)alkyl, O-[{C1-Ce)alkyleneJo-1-R',{C2-Cs)alkenyl, R',{C2-Ce)alkenylene-{Ce-C1o)aryl, {C1-Ce)alkylene-R',NH2, NH-R',NH-S02H. NH-S02-{C1-Ce)alkyl, NH-S02-R',S02-NH2. S02-NHR',NH-C{O)-{C1-Ce)alkyl, NH-C{O)-R',C{O)N[{C1-Ca)alkyl]2, C{O)OH or C{O)O-{C1-Ce)alkyl;
25

Rg is halogen or {C1-Ce)alkyl;

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

Lis 0 or O-(C1-Ce)alkylene;

wherein R'is (C3-Ca)cycloalkyl,  (Cs-C1o)heterocyclyl or (Ce-C1o)aryl; and

R" is (C3-Ca)cycloalkyl, (Cs-C1o)heterocyclyl, (Ce-C1o)aryl, (C1-Ce)alkyl, (C1-Ce)alkylene-R',(C1-Ce)alkylene-O-(C1-Ce)alkyl, (C1-Ce)alkylene-O-R',or (C1-Ce)alkylene-NRxRy: and

wherein Rx and Ry are independently of each other (C1-Ce)alkyl,

(C5-C1 o)heterocyclyl, (Ce-C1 o)aryl, (C 1-C4)alkylene-(Cs-C 1o)heterocyclyl, (C1-C4)alkylene-(Ce-C1o)aryl, (C1-C4)alkylene-NH(C1-Ce)alkyl, (C1-C4)alkylene-N[(C1-Ce)alkyl]2. (C1-C4)alkylene-N[(Ce-C1o)aryl]2, or (C1-C4)alkylene-N[(Cs-C1 o)heterocyclyl]2; and

wherein in residues R4, Rs, R7 and Ra one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2 or an alkyl or alkylene may be halogenated once

or more;

!0    or their phannaceutically acceptable salts and/or stereoisomeric forms and/or

physiologically functional derivatives.

2. A compound of the fonnula (I) according to claim 1 characterized by a compound of the fonnula (II)

R:ML - oRs
IN~R7  (Rg)n

!5    0    Ra    (II).



4. A compound according to any of claims t to 3, wherein R5 isH, (Ct-C6)alkyl, R',(Ct-C4)alkylene-(C3-CB)cycloalkyl, (Ct-C4)alkylene-(C5-Cto)heterocyclyl, (Ct-C4)alkylene-C(O)-(C5-C t o)heterocyclyl, (C t-C4)alkylene-C(O)-(C6-C t o)aryl or (Ct-C6)alkylene-(C6-Cto)aryl.

10    5. A compound according lo any of claims t to 4, wherein R5 is H, (Ct-C6)alkyl, (C5-Cto)heterocyclyl, (C3-CB)cycloalkyl, (Ct-C4)alkylene-(C3-CB)cycloalkyl, (Ct-C4)alkylene-(C5-Cto)heterocyclyl or (Ct-Cs)alkylene-(C6-Cto)aryl.

6.    A compound according to any of claims t to 5, wherein Rs isH, (Ct-C6)alkyl,

15    (C3-CB)cycloalkyl, (Ct-C4)alkylene-(C3-CB)cycloalkyl, (Ct-C4)alkylene-(C5-Cto)heterocyclyl in which heterocyclyl is unsubstituted or substituted by (Ct-C4)alkyl, or is (Ct- C4)alkylene-(C5-Cto)aryl in which aryl is unsubstituted or substituted by halogen, (Ct-C4)alkyl, O-(Ct-C4)alkyl, S02-(Ct-

C4)alkyl, or N[(Ct-C4)alkyll2•

20

7. A compound according to any of claims t to 6, wherein Rs isH, (Ct-C6)alkyl, (C3-C6)cycloalkyl or (Ct-C4)alkylene-(C3-C6)cycloalkyl.

B.    A compound according to any of claims t to 7, wherein R5 isH or (Ct-Cs)alkyl.

25

9.    A compound according to any of claims t to B, wherein R5 is H.

10.    A compound according to any of claims 1 to 9, wherein R5 isH, halogen, CN, (C1-C5)alkyl, R',NH-(C5-C1o)aryl or (C1-C5)alkylene-R'.

11.    A compound according to any of claims 1 to 10, wherein R5 isH, halogen, (C1-C5)alkyl, R',NH-{C5-C1o)aryl or (C1-C5)alkylene-R'.

12.    A compound according to any of claims 1 to 11, wherein R5 isH, halogen, (C1-C5)alkyl, (C5-C1o)aryl, (C5-C1olheteroaryl, NH-(C5-C1o)aryl or
10    (C1-C2)alkylene-(C5-C1o)aryl.

13. A compound according to any of claims 1 to 12, wherein R5 isH, halogen, (C1-C5)alkyl, phenyl or (C5-C5)heteroaryl.

15    14. A compound according to any of claims 1 to 13, wherein R5 isH, halogen or (C1-C5)alkyl.

15.    A compound according to any of claims 1 to 14, wherein Rs isH or halogen ..

10    16.    A compound according to any of claims 1 to 15, wherein R5 is H.

17. A compound according to any of claims 1 to 16, wherein~ isH, halogen, CN, (C1-C5)alkyl, NH-(C5-C1o)aryl or (C1-C5)alkylene-R'.

25    18. A compound according to any of claims 1 to 17, wherein~ is H. halogen, (C1-C5)alkyl, NH-(C5-C1o)aryl or (C1-C5)alkylene-R'.

19.    A compound according to any of claims 1 to 18, wherein~ isH, halogen,

(C1-C5)alkyl, NH-{C5-C1o)aryl or (C1-C2)alkylene-(C5-C1o)aryl.

30

20.    A compound according to any of claims 1to 19, wherein R4 isH, halogen, or {C1-Cs}alkyl.

21.    A compound according to any of claims 1 to 20, wherein R4 is H.

22.    A compound according to any of claims 1to 21, wherein R7 and Ra are independently of each other H, halogen, CN, {C1-Cs}alkyl, O-{C1-Ca}alkyl, (C2-Cs)alkenyl, R'or {C1•Ca}alkylene-{C3-Ca}cycloalkyl.

10    23. A compound according to any of claims 1 to 22, wherein R7 and Ra ar" independently of each other H, halogen, CN, {C1-C4}alkyl, O-{C1-C4}alkyl, {C2-C4}alkenyl, phenyl, {C5-Cs}heteroaryl, {C3-Cs}cycloalkyl or {C1-C4}alkylene-{C3-Cs}cycloalkyl.

15    24. A compound according to any of claims 1to 23, wherein R7 and Ra are independently of each other H, halogen, {C1-C4}alkyl, O-{C1-C4)alkyl or phenyl.

25.    A compound according to any of claims 1 to 24, wherein R7 and Ra are H.

20    26. A compound according to any of claims 1to 25, wherein R9 is halogen or {C1• C4}alkyl.

27.    A compound according to any of claims 1 to 26, wherein Rg is Cl, F, methyl or

ethyl.

25

28.    A compound according to any of claims 1 to 27, wherein R9 is methyl.

29.    A compound according to any of claims 1 to 28, wherein n is 0, 1, 2 or 3.

30    30.    A compound according to any of claims 1 to 29, wherein n is 0 or 1.


31.    A compound according to any of claims 1to 25, wherein n is 0.

32.    A compound according to any of claims 1 to 31, wherein R3 isH, halogen, (C1-C5)alkyl, (C1-C4)alkylene-R',0-R" or NHR".

33.    A compound according to any of claims 1to 32, wherein R3 isH, (C1-C5)alkyl orNHR".

34.    A compound according to any of claims 1to 33, wherein R3 isH, (C1-C4)alkyl, NH-(Cs-C6)heterocyclyl or NH-phenyl.

35.    A compound according to any of claims 1 to 34, wherein R3 is H, (C1-C4)alkyl, NH-(C5-C5)heteroaryl containing one or more N atoms or NH-phenyl.

36.    A compound according to any of claims 1 to 35, wherein R3 is H.

37.    A compound according to any of claims 1 to 36, wherein Lis attached to the 4-

position of the cyclohexyl ring



!0

L is attached to the 3-position of the cyclohexyl ring

Rs
N

i--L .f)(Rg)n


38.    A compound according to any of claims 1 to 37, wherein lis attached to the 4-

posijion of the cyclohexyl ring.

39.    A compound according to any of claims 1 to 38, wherein lis 0-methylene, 0-ethylene or 0.

40.    A compound according to any of claims 1 to 39, wherein l is 0-methylene, 0-ethylene or 0 attached to the 4-position of the cyclohexyl ring.

10    41.    A compound according to any of claims 1 to 40, wherein lis 0.

42.    A compound according to any of claims 1 to 3, wherein

R3 isH, halogen, CN, (C1-Ca)alkyl, (C1-Ca)alkylene-R',OH, 0-R", NH2, or NHR";

15

R4 isH, halogen, hydroxy, CN, (C1-Ca)alkyl, (CJ-Ca)cycloalkyl, (C1-Ce)alkylene-R';

Rs isH, halogen, CN, N02. (C1-Ca)alkyl, (C2-Ca)alkenyl, R', (C1-Ca)alkylene-(Ca-C1o)aryl, (C2-Ca)alkenylene-(Ca-C1o)aryl,

20    (C1-Ca)alkylene-(Cs-C1o)heterocyclyl, NH2. NH-R',NH-S02H. NH-S02-(C1-Ca)alkyl, NH-S02-R',NH-C(O)-(C1-Ca)alkyl, NH-C(O)-R',C(O)N[(C1-Ca)alkyl]2. C(O)OH or
C( 0)0-( C1-Ca)alkyl;

Rs isH, (C3-Cs)cycloalkyl, (C1-Cs)alkyl,  (C1-Ce)alkylene-R',(C1-Ca)alkylene-0-(C1-

25    Ca)alkyl, (C1-Ca)alkylene-O-R',(C1-Ca)alkylene-CH[R'J2.(C1-Ca)alkylene-C(O)NH2, (C1-Ca)alkylene-C(O)NH-R',or (C1-Ca)alkylene-C(O)N[R']2;

R7 and Rs are independently of each other H, halogen, CN, N02, (C1-Ca)alkyl, (C2-Ca)alkenyl, R',(C2-Ca)alkenylene-(Ca-C1o)aryl, (C1-Ca)alkylene-R',NH2, NH-R',

f~Rs
t-L~(R)
9  nor

Lis attached to the 3;Josition of the piperidinyl ring

Rs
N

t-LJ:)(Rg)n

in all their stereochemical forms.

In an especially prefened embodiment, L is attached to the 4-position of the piperidinyl

ring.

10    Preferably, Lis 0-methylene, 0-ethylene or 0. More preferably, Lis 0-methylene, 0-ethylene or most prefened 0 attached to the 4-position of the piperidinyl ring.

Most preferably, L is 0.

15    In preferred embodiments of the present invention one or more or all of the groups contained in the compounds of formulae (I) or (I')can independently of each other have any of the preferred, more preferred or most preferred defin~ions of the groups specified above or any one or some of the specific denotations which are comprised by the defin~ions of the groups and specified above, all combinations of preferred

20    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 inverrtion includes the compounds of the formulae (I) or (I')in all stereoisomeric forms

and mixtures of stereoisomeric forms in all ratios, and/or their physiologically

acceptable salts.

NH-502-(Ct-Cs)alkyl, NH-802-R',802-NH2, 802-NHR',NH-C(O)-(Ct-Cs)alkyl, NH-

C(O)-R',C(O)N[(Ct-Cs)alkyl]2, C(O)OH or C(O)O-(Ct-Cs)alkyl;

Rg is halogen or (Ct-Ca)alkyl;

nis0,1,2;and

L is 0 or 0-(C 1-C3)alkylene;

or their phannaceutically acceptable salts and/or stereoisomeric fonns and/or physiologically functional derivatives.

43.    A compound according to any of claims 1 to 3, wherein

!5    R3 isH, halogen, CN, (Ct-Cs)alkyl, (Ct-C2)alkylene-R'or NHR";

R4 isH, halogen, CN, (Ct-Cs)alkyl, (C3-Cs)cycloalkyl, (Ct-C2)alkylene-R';

Rs is H, halogen, CN, N02, (Ct-Cs)alkyl, (C2-Cs)alkeny1, R', to (Ct-Cs)alkylene-(Cs-Ct o)aryl, (C2-Cs)alkenylene-(Cs-Ct o)aryl,

(Ct-Ca)alkylene-(Cs-Cto)heterocyclyl, NH2, NH-R',NH-C(O)-(Ct-Ca)alkyl, or C(O)N[(Ct-Ca)alkyl]2;

Rs isH, (C3-Cs)cycloalkyl, (Ct-Cs)alkyl, or (Ct-C3)alkylene-R';

!5

R7 and Ra are independently of each other H, halogen, CN, N02, (Ct-Cs)alkyl, (C2-Cs)alkeny1, R',(C2-C3)alkenylene-(Ca-Cto)aryf, (Ct-C3)alkylene-R',NH-R',NH-502-(Ct-Cs)alkyl, or 802-NH2;

lO    Rg is halogen or (Ct-Cs)alkyl;

C(O)-R',C(O)N[(Ct•Cs)alkyl]2, C(O)OH or C(O)O-(Ct•Cs)alkyl;

Rg is halogen or (C1-Cs)alkyl;

n is 0, 1, 2; and

Lis 0  or O-(C1-C3)alkylene;

or their phannaceutically acceptable salts and/or stereoisomeric forms.:_ •---------______ .... ~J..-- :':a:ca~~~nctional
'-'''"'""-"""'"""-'----

43.    A compound according to any of claims 1 to 3, wherein

R3 isH, halogen, CN, (C1-C5)alkyl, (C1-C2)alkylene-R'or NHR";

R4 isH, halogen, CN, (Ct-Cs)alkyl, (C3-Cs)cycloalkyl, (Ct-C2)alkylene-R';

Rs isH, halogen, CN, N02, (Ct-Cs)alkyl, (C2-Cs)alkenyl, R', (Ct-Cs)alkylene-(Cs-C 1o)aryl, (C2-Cs)alkenylene-(Cs-Ct o)aryl, (Ct-Cs)alkylene-(Cs-Cto)heterocyclyl, NH2, NH-R',NH-C(O)-(Ct•Cs)alkyl, or C(O)N[(Ct-Cs)alkyl]2;

Rs isH, (C3-Cs)cycloalkyl, (Ct-Cs)alkyl, or (Ct-C3)alkylene-R';

R7 andRe are independently of each other H, halogen, CN, NOz, (C1-Cs)alkyl,

(C2-Cs)alkenyl, R',{C2-C3)alkenylene-(Cs-C1o)aryl, (C1-C3)alkylene-R',NH-R',NH-

S02-{Ct-Cs)alkyl, or S02-NH2;

Rg is halogen or (C1-Cs)alkyl;

nis0or1;and

L is 0 or O~methylene;

or their pharmaceutically acceptable salts and/or stereoisomeric forms., __

44.    A compound according to any of claims 1 to 3, wherein

R3 isH, halogen, CN, (C1-Ce)alkyl, (C1-C2)alkylene-R'or NHR";

10

R4 isH, halogen, CN, (C1-C4)alkyl, (C3-Cs)cycloalkyl, (C1-Cz)alkylene-R';

Rs isH, halogen, CN, N02, (C1-Ce)alkyl, (C2-Ce)alkenyl, R', (C1-Cs)alkylene-{Cs-C1o)aryl, (Cz-Cs)alkenylene-(Cs-C1o)aryl,

15    (C1-Ce}alkylene-(Cs-C1o)heterocyclyl, NH-R'; Rs isH, (C3-Cs)cycloalkyl or (C1-C4)alkyl;
R7 and Ra are independently of each other H, halogen, CN, N02, (C1-Ce)alkyl,

20    (Cz-Cs)alkenyl, R',(Cz-C3)alkenylene-(Cs-C1o)aryl, (C1-C3)alkylene-R', NH-SOz-(C1-Cs)alkyl, or SOz-NHz;

n is 0 and Rg is not present or

n is 1 and Rg  is halogen or (C1-C4)alkyl; and

25

L isO;

I or their pharmaceutically acceptable salts and/or stereoisomeric forms.: ...

30  I 45.    A compound according to claim 1 selected from the group consisting of

or their phannaceutically acceptable salts and/or stereoisomeric forms.

;4~.  I,J~~- of at]~st <?~~-~~~P~l!n9 ~q~_e.fo~u!a (I) ClUD~_~~-~he_i! p_hy~_i~l~gi~~!!Y_

acceptable salts and/or stereoisomeric fonns as claimed in one of claims 1 to 4.§._fg_r:

producing a medicament.

47. Use of at least one compound of the fonnutae (I) or (I'),or their physiologically acceptable salts and/or stereoisomeric forms as claimed in one of claims 1 to 4.§. ~r the production of a pharmaceutical for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase.

• Gel6scht:4S .AOJII1poundofthE fonnulae{!)or{l'),orthelr physiologica!!yacc:aptablesaltsanc stereoisomeric forms as c~imed in ordaims1to44 roruseasa
medica11ent,1

.  Gel6scht:4
 

48.    Use of at least one compound of the formula (I) or (1'),or their physiologically
.• -{Gei11Kht:4
acceptable salts and/or stereoisomeric fonns as claimed in one of claims 1 to 4.§.fl?!. producing a medicament for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease {COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, Alzheimer'sdisease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes


ana compucallons m maoeles, meraoonc synarume, mooo vessel resrenus1s, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy, infection of digestive tracts with bacteria, sepsis or cancer development and progression.

49.    A medicament comprising an effective amount of at least one compound of the

fonnula (I) or (I'),or their phannacologically acceptable salts and/or stereoisomeric

fonns as claimed in any of claims 1 to 4.§._p_~y-~[9.1_9gj~~I_IY.J9.1.~.@~~~-~?;~_iP.i~!.1.1~.~~~ ......  -J .. •{c:Ge='""'=":.:"---

carriers and, where appropriate, further additives and/or other active ingredients.

A preferred embodiment of the present invention is a compound of the fonnula (1), (1'), (II) or (II')wherein

R3 isH, halogen, CN, (C1-Cs)alkyl, (C1-Cs)alkylene-R',OH, 0-R", NHz, or NHR";

R4 isH, halogen, hydroxy, CN, (C1-Ca)alkyl, (C3-Cs)cycloalkyl, (C1-Cs)alkylene-R';

Rs isH, halogen, CN, NOz, (C1-Cs)alkyl, (Cz-Cs)alkenyl, R', (C 1-Cs)alkylene-(Cs-C 1o)aryl, (Cz-Cs)alkenylene-(Cs-C 1o)aryl,

10    (C1-Cs)alkylene-(Cs-C1o)heterocyclyl, NHz, NH-R',NH-SOzH, NH-SOz-(C1-Cs)alkyl, NH-SOz-R',NH-C(O)-(C1-Cs)alkyl, NH-C(O)-R',C(O)N[(C1-Cs)alkyl]z, C(O)OH or C(O)O-(C1-Cs)alkyl;

Rs isH, (C3-Cs)cycloalkyl, (C1-Cs)alkyl,  (C1-Cs)alkylene-R',(C1-Ca)alkylene-O-(C1-

15    Cs)alkyl, (C1-Ca)alkylene-O-R',(C1-Cs)alkylene-CH[R'l2.(C1-Cs)alkylene-C(O)NHz, (C1-Cs)alkylene-C(O)NH-R',or (C1-Cs)alkylene-C(O)N[R']z;

R7 and Rs are independently of each other H, halogen, CN, N02, (C1-Cs)alkyl,

(Cz-Cs)alkenyl, R',(C2-Cs)alkenylene-(Cs-C1Q)aryl, (C1-Cs)alkylene-R',NH2. NH-R',

20    NH-SOz-(C1-Cs)alkyl, NH-SOz-R',SOz-NHz, S02-NHR',NH-C(O)-(C1-Cs)alkyl, NH-C(O)-R',C(O)N[(C1-Cs)alkyl]2. C(O)OH or C(O)O-(C1-Cs)alkyl;

Rg is halogen or (C1-Ca)alkyl;

25    nisO, 1,2;and

Lis 0 or O-(C1-C3)alkylene;

wherein R1, R2. R',R", Rx and Ry are as defined above;

30

or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.

A further preferred embodiment of the present invention is a compound of the formula

(1), (I'),(II) or (II')wherein

R3 isH, halogen, CN, (C1-Cs)alkyl, (C1-C2)alkylene-R'or NHR";

R4 isH, halogen, CN, (C1-Cs)alkyl, (C3-Ca)cycloalkyl, (C1-C2)alkylene-R';

10

Rs isH, halogen, CN, N02, (C1-Cs)alkyl, (C2-Cs)alkenyl, R', (C1-Cs)alkylene-(Cs-C1o)aryl, (C2-Cs)alkenylene-(Cs-C1o)aryl, (C1-Ca)alkylene-(Cs-C1o)heterocyclyl, NH2. NH-R',NH-C(O)-(C1-Cs)alkyl, or C(O)N[(C1-Cs)alkyl]2;

15

Rs isH, (C3-Ca)cycloalkyl, (C1-Ca)alkyl, or (C1-C3)alkylene-R';

R7 and Ra are independently of each other H, halogen, CN, N02. (C1-Cs)alkyl, (C2-Cs)alkenyl, R',(C2-C3)alkenylene-(Cs-C1o)aryl, (C1-C3)alkylene-R',NH-R',NH-

20    S02-(C1-Cs)alkyl, or S02-NH2; Rg is halogen or (C1-Cs)alkyl;
n is 0 or 1; and

25

L is 0 or 0-methylene;

wherein R1, R2. R',R", Rx and Ry are as defined above;

30    or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.

R3 isH, halogen, CN, (C1-Cs)alkyl, (C1-Cs)alkylene-R',OH, 0-R", NH2, or NHR";

R4 isH, halogen, hydroxy, CN, (C1-Cs)alkyl, (C3-Ca)cycloalkyl, (C1-Cs)alkylene-R';

Rs isH, halogen, CN, N02, (C1-Cs)alkyl, (C2-Cs)alkenyl, R', (C1-Cs)alkylene-(Cs-C1o)aryl, (C2-Cs)alkenylene-(Cs-C1o)aryl, (C1-Cs)alkylene-(Cs-C1o)heterocyclyl, NH2, NH-R',NH-S02H, NH-802-(C1-Cs)alkyl, NH-802-R',NH-C(O)-(C1-Cs)alkyl, NH-C(O)-R',C(O)N[(C1-Cs)alkyl]2. C(O)OH or C(O)O-(C1-Ca)alkyl;

10

Ra isH, (C3-Ca)cycloalkyl, (C1-Ca)alkyl, (C1-Cs)alkylene-R',(C1-Cs)alkylene-O-(C1-c6)alkyl, (C1-Ca)alkylene-O-R',(C1-Ca)alkylene-CH[R'J2.(C1-Cs)alkylene-C(O)NH2, (C1-Ca)alkylene-C(O)NH-R',or (C1-Cs)alkylene-C(O)N[R']2;

IS R7 and Ra are independently of each other H, halogen, CN, N02. (C1-Ca)alkyl, O-(C1-Cs)alkyl, (C2-Cs)alkenyl, R',(C2-Cs)alkenylene-(Cs-C10)aryl, (C1-c6)alkylene-R',NH2, NH-R',NH-802-(C1-Cs)alkyl, NH-802-R',802-NH2, 802-NHR',NH-C(O)-(C1-Cs)alkyl, NH-C(O)-R',C(O)N[(C1-Cs)alkyl]2. C(O)OH or C(O)O-(C1-Ca)alkyl;

20

Rg is halogen or (C1-Ca)alkyl;

n is 0, 1, 2; and

25    lis 0 or O-(C1-C4)alkylene;

wherein R1, R2, R',R", Rx and Ry are as defined above;

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

30    physiologically functional derivatives.
 

A most preferred embodiment of the present invention is a compound of the formula (I), (1'),(II) or (II')wherein

R3 isH, halogen, CN, (C1-Cs)alkyl, (Ct-C2)alkylene-R'or NHR";

R4 isH, halogen, CN, (Ct-C4)alkyl, (CJ-Cs)cycloalkyl, (C1-C2)alkylene-R';

Rs isH, halogen, CN•, N02, (C1-Cs)alkyl, (C2-Cs)alkenyl, R',

10    (Ct-Cs)alkylene-(Cs-Cto)aryl, (C2-Cs)alkenylene-(Cs-C1o)aryl, (Ct-Cs)alkylene-(Cs-C1o)heterocyclyl, NH-R';

Rs is H, (CJ-Cs)cycloalkyl or (C1-C4)alkyl;

15    R7 and Rs are independently of each other H, halogen, CN, N02, (Ct-Cs)alkyl, (C2-Cs)alkenyl, R',(C2-CJ)alkenylene-(Cs-C1o)aryl, (Ct-CJ)alkylene-R', NH-502-(Ct-Cs)alkyl, or S02-NH2;

n is 0 and Rg is not present or

20    n is 1 and Rg is halogen or (C1-C4)alkyl; and LisO;
wherein Rt. R2. R',R", Rx and Ry are as defined above;

25

or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.

In another preferred embodiment of the present invention is a compound of the formula 30 (1), (1'),(II) or (II')wherein

A further preferred embodiment of the present invention is a compound of the formula

(1), (1'), (II) or (II')wherein

R3 isH, halogen, CN, (Ct-Cs)alkyl, or (Ct-C2)alkylene-R';

R.j isH, halogen, CN, (Ct-Cs)alkyl, or (Ct-C2)alkylene-R';

Rs isH, halogen, CN, N02, (Ct-Cs)alkyl,

10 Rs isH, (CJ-Ca)cycloalkyl, (Ct-Ca)alkyl, (Ct-CJ)alkylene-(CJ-Cs)cycloalkyl, (Ct-CJ)alkylene-(Cs-Cto)aryl or (Ct-CJ)alkylene-(Cs-Cto)heterocyclyl;

R7 and Ra are independently of each other H, halogen, CN, N02. (Ct-Cs)alkyl, 0-(Ct-Ce)alkyl, (CJ-Cs)cycloalkyl or phenyl;
15

Rg is halogen or (Ct-Cs)alkyl;

n is 0 or 1; and

20    L is 0 or 0-melhylene;

wherein Rt. R2. R',are as defined above;

or their pharmaceutically acceptable salts and/or stereoisomertc forms and/or 25 physiologically functional derivatives.

A most prefenred embodiment of the present invention is a compound of the formula (I), (1'),(II) or (II')wherein

30    R3 isH;

R.j isH, halogen, or (C1-C4)alkyl;

Rs isH, halogen or (Ct-Cs}alkyl;

Rs isH, (C3-Cs}cycloalkyl, (Ct-C4}alkyl, (Ct-C2}alkylene-{C3-Ce}cycloalkyl, (Ct-C4}alkylene-(Cs-Cto}heterocyclyl, in which heterocyclyl is unsubstijuted or substijuted by (Ct-C4}alkyl, or is (Ct-C4}alkylene-(Cs-Cto}aryl, in which aryl is unsubstijuted or substituted by halogen, (Ct-C4}alkyl, 0-(Ct-C4}alkyl, S02-(Ct-C4}alkyl or N[(Ct-C4}alkyl]2;

10    R7 and Ra are independently of each other H, halogen, (Ct-C4}alkyl, O-(Ct-C4)alkyl or phenyl;


15    nis0or1 ;and LisO;

wherein Rt. R2 are as defined above, preferabyl Rt isH and R2 isH;

20

or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.

As in any embodiment of the invention, in the preceding embodiments which contain

25    preferred, more preferred, most preferred or exemplary definijions of compounds according to the invention, one or more or all of the groups can have any of its preferred, more preferred, most preferred definitions specified above or any one or some of the specific denotations which are comprised by its definijions and are specified above.

30

Physiologically acceptable saHs of compounds of the formulae (I} and (I'}mean both
 





20

their organic and inorganic salts as described in Remington'sPharmaceutical Sciences

(17th ed~ion, 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,
hydrochlortc 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

10    physiologically acceptable saHs from compounds of the formulae (I) and (I')which are capable of salt formation, including their stereoisomeric forms, takes place in a manner known per se. The compounds of the formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts ~h basic reagents such as

hydroxides, carbonates, bicarbonates, alcohotates and ammonia or organic bases, for •

IS    example trimethyl- or methylamine, ethanolamine, diethanolamine or trtethanolamine,

trometamol or else basic amino acids, for example lysine, ornithine or arginine. Where

the compounds of the formulae (I) or (I')have basic groups, stable acid add~ion salts

can also be prepared w~ strong acids. Suitable pharmaceutically acceptable acid

addition salts of the compounds of the invention are salts of inorganic acids such as

20    hydmchlortc acid, hydrobromic, phosphortc, metaphosphortc, nitric and su~uric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.

25    Salts with a phylliologically unacceptable anion such as, for example, trifluoroacetate likewise belong ~in the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable saHs and/or for use in nontherapeutic, for example in vitro, applications.

30    The term "physiologically functional dertvative" used herein refers to any physiologically tolerated derivative of a compound of the formulae (I) or (I')of the invention, for example an N-oxide, which on administration to a mammal such as, for
 





21

example, a human is able to fonn (directly or indirectly) a compound of the fonnula (I) or (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., Chern. Phann. Bull. 1994, 42, 57.01. Such prodrugs can be metabolized in vivo to a compound of the invention. These prod rugs may themselves be active or not.

The invention relates to a compound of the formula (I) or (I')in the fonn of their

racemates, racemic mixtures and pure enantiomers and to their diastereomers and

I 0    mixtures thereof.

If radicals or substituents may occur more than once in the compounds of the fonnulae

(I) or (1'),they may all, independently of one another, have the stated meaning and be

identical or different.

15

The compounds of the invention may also exist in various polymorphous forms and/or

solvates, for example as amorphous and crystalline polymorphous fonns. All polymorphous fonns of the compounds of the invention belong within the framework of
the invention and are a further aspect of the invention.

20

All references to "compound(s) of formula (I)" or to "compound(s) of fonnula (I')" hereinafter refer to compound(s) of the fonnulae (I) or (I')as described above, and their physiologically acceptable salts, solvates and physiologically functional
derivatives as described herein.

25

The tenn alkyl and the corresposponding alkylene substituents are understood as a hydrocarbon residue which can be linear, i.e. straight-<:hain, or branched and has 1, 2, 3, 4, 5 or 6 carbon atoms, respectively, where applicable. This also applies ~an alkyl group occurs as a substituent on another group, for example in an alkoxy group

30    (0-alkyl), S-alkyl or a -O(C1-Ce)alkylene-O-, an alkoxycarbonyl group or an arylalkyl 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,
 





22

2,2-<limethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. Alkyl groups may- ff not otherwise stated- be halogenated once or more, e.g. alkyl groups may be fluorinated, e.g. perfluorinated. Examples of halogenated alkyl groups are CF3 and CH2CF3. OCF3. SCF3. or -O-(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.

10    Halogen means fluoro, chloro, bromo or iodo.

(C3-Cs)cycloalkyl groups are cyclic alkyl groups containing 3, 4, 5, 6, 7 or 8 ring

carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooclyl, which

can also be substituted and/or contain 1 or 2 double bounds (unsaturated cycloalkyl

15    groups) like, for example, cyclopentenyl or cyclohexenyl can be bonded via any carbon atom.

A (C6-C1o)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,

20    biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon-, indanyl- or indan-1-<:>n-yl group. A preferred (C6-C1o)aryl group is phenyl.

A (C5-C1o)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

25    nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or combinations of different

hetero atoms. The heterocyclyl residues can be bound at any positions, for example on the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-pos~ion or a-position. (C5-C1o)heterocyclyl groups may be (1) aromatic[= heteroaryl groups] or (2)

saturated or (3) mixed aromatic/saturated.

30    Suitable (C5-C1o)heterocyclyl group include acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzomorpholinyl, benzothienyl, benzothiophenyl, benzoxazolyl,
 





23

benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, !uranyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, chromen-2-onyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1 ,5,2-<lithiazinyl, 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,

10    oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, prolinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl,

pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,

15    tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1 ,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 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-lhienyl. 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.

20

Substitutions in (C5-C1o)heterocyclyl residues can occur on free carbon atoms or on

nitrogen atoms.

Preferred examples of (C5-C1o)heterocyclyl residues are pyrazinyl, pyridyl,

25    pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, benzofuryl, quinolinyl, tetrazolyl and triazolyl.

(Cs-C1 o)aryl and (C5-C1o)heterocyclyl groups are unsubsliluted or, unless otherwise

stated, substituted one or more times by suitable groups independently selected from

30    halogen, CF3, N02, N3, CN, C(O)-(C1-Ca)alkyl, C(O)-(C1-Ca)aryl, COOH, COO(C1-Cs)alkyl, CONH2, CONH(C1-Cs)alkyl, CON[(C1-Cs)alkyl]2, (C3-Ca)cycloalkyl,
 





24

(Ct-Ca)alkyl, (Ct-Ca)alkylene-OH, (Ct-Ca)alkylene-NH2, (Ct-Ca)alkylene-NH(Ct-Cs)alkyl, (Ct-Cs)alkylene-N[(Ct-Ca)alky~2. (C2-Ca)alkenyl, (C2-Ca)alkynyl, 0-(Ct-Ca)alkyl, 0-C(O)-(Ct-Ca)alkyl, 0-C(O)-(Ca-Cto)aryl, 0-C(O)-(Cs-Cto)heterocyclyl, P03H2, 803H, 802-NH2, 502NH(Ct-Ca)alkyl, 502N[(Ct-Cs)alkyl)2, 5-(Ct-Ca)alkyl; S-(Ct-Ca)alkylene-{Cs-Cto)aryl,

5-(C t-Ca)alkylene-(Cs-C 1o)heterocyclyl, 50-(Ct-Cs)alkyl, 50-(Ct-Ca)alkylene-(Cs-Cto)aryl, 50-(Ct-Ca)alkylene-(Cs-Cto)heterocyclyl, 502-(Ct-Ca)alkyl, 502-(Ct-Cs)alkylene-(Cs-Cto)aryl, 502-(Ct-Ca)alkylene-(Cs-Cto)heterocyclyl, 502-NH(Ct-Ca)alkylene-(Ca-Cto)aryl,

10    502-NH(Ct-Ca)alkylene-(Cs-Cto)heterocyclyl, 502-N[(Ct-Ca)alkyi)[(Ct-Ca)alkylene-(Cs-Cto)aryl], 502-N[(Ct-Ca)alkyi][(Ct-Ca)alkylene-(Cs-Cto)heterocyclyl], 502-N[(Ct-Cs)alkylene-(Ca-Cto)aryl]2,
502-N[(Ct-Ca)alkylene-(Cs-Ct o)heterocyclyl]2,

C(NH)(NH2). NH2. NH-(Ct-Ca)alkyl, N[(Ct-Ca)alkyl)2. NH-C(O)-(Ct-Ca)alkyl,

15    NH-C(O)O-(Ct-Ca)alkyl, NH-C(O)-(Cs-Cto)aryl, NH-C(O)-(Cs-Cto)heterocyclyl, NH-C(O)O-(Ca-Cto)aryl, NH-C(O)O-(Cs-Cto)heterocyclyl, NH-C(O)-NH-(Ct-Ca)alkyl, NH-C(O)-NH-(Ca-Cto)aryl, NH-C(O)-NH-(Cs-Cto)heterocyclyl, NH-S02-(Ct-Ca)alkyl, NH-502-(Ca-Cto)aryl, NH-S02-(Cs-Cto)heterocyclyl, N(Ct-Ca)alkyi-C(O)-

(Ct-Ca)alkyl, N(Ct-Ca)alkyi-C(O)O-(Ct-Ca)alkyl, N(Ct-Ca)alkyi-C(O)-(Ca-Cto)aryl,

20    N(C1-c6)alkyi-C(O)-heterocyclyl, N(Ct-Ca)alkyi-C(O)O-(Ca-Cto)aryl, N(Ct-Ca)alkyi-C(O)O-(Cs-Cto)heterocyclyl, N(Ct-Ca)alkyi-C(O)-NH-(Ct-Ca)alkyl], N(Ct-Ca)alkyi-

C(O)-NH-(Ca-Cto)aryl, N(Ct-Ca)alkyi-C(O)-NH-(Cs-Cto)heterocyclyl,

N[(Ct-Ca)alkyi]-C(O)-N[(Ct-Ca)alkyl]2,

N((Ct-Ca)alkyi]-C(O)-N[(Ct-Ca)alkyi]-(Cs-Cto)aryl,

25    N[(Ct-Ca)alkyi)-C(O)-N[(Ct-Ca)alky~-(Cs-Cto)heterocyclyl,

N[(Ct-Ca)alkyi)-C(O)-N[(Ca-Cto)aryl)2.

N((Ct-Ca)alkyi]-C(O)-N((Cs-Cto)heterocycly~2. N[(Cs-Cto)aryi)-C(O)-(Ct-Ca)alkyl,

N[(Cs-Cto)heterocyclyi]-C(O)-(Ct-Ca)alkyl, N[(Ca-Cto)aryi]-C(O)O-(Ct-Ca)alkyl,

N[(Cs-C1Q)heterocyclyi]-C(O)Q..(C1-C6)alkyl, N(aryi)-C(O)-(Cs-C1o)aryl,

N[(Cs-C 1o)heterocyclyi]-C(O)-(Cs-C1 o)aryl, N[(Cs-C1 o)aryi]-C(O)O-(Cs-C 1o)aryl, N[(Cs-C1o)heterocyclyi]-C(O)O-(Cs-C1o)aryl, N[(Ce-C1o)aryi]-C(O)-NH-(C1•Cs)alkyl, N[(C5-C1o)heterocyclyi]-C(O)-NH-(C1-Cs)alkyl, N(aryi)-C(O)-NH-(Cs-C1o)aryl, N[(C5-C1o)heterocyclyi]-C(O)-NH-(Cs-C1o)aryl, N[(Cs-C1o)aryi]-C(O)-N[(C1-Cs)alkyl]z,

N[(C5-C1 o)heterocyclyi]-C(O)-N[(C 1-Cs)alkyijz, N[(Cs-C1 o)aryi]-C(O)-N[(C1-Cs)alkyi]-(Cs-C1 o)aryl, N[(C5-C 1o)heterocyclyi]-C(O)-N[(C 1-Cs)alkyi]-(Ca-C 1o)aryl, N[(Ce-C1o)aryi]-C(O)-N[(Ce-C1o)aryl]z,
10    N[(C5-C1o)heterocyclyi]-C(O)-N[(Ce-C1o)aryl]z, <Cs-C1o)aryl,

(C 1-Cs)alkylene-(Ce-C 1o)aryl, 0-(C 1-Ce)alkylene-(Ce-C1 o)aryl, (C5-C1 o)heterocyclyl, (C 1-Cs)alkylene-(C5-C1 o)heterocyclyl, 0-(C 1-Ce)alkylene-(C5-C 1o)heterocyclyl, wherein the (Cs-C1o)aryl or (C5-C1o)heterocyclyl may be substituted one to 3 times

by halogen, OH, NOz, CN, O-(C1-Cs)alkyl, (C1-Cs)alkyl, NHz, NH(C1-Cs)alkyl,

15    N[(C1•Cs)alkyl]z, SOzCHJ, COOH, C(O)O-(C1-Ca)alkyl, CONHz, (C1-Ca)alkylene-0-(C1-Cs)alkyl, (C1-Ce)alkylene-O-(Cs-C1o)aryl, O-(C1-Ce)alkylene-(Ce-C1Q)aryl; or wherein (Ce-C1o)aryl is vicinally subst~uted by a O-(C1-C4)alkylene-O group whereby

a 5-8-membered ring is fonned together w~ the carbon atoms the oxygen atoms are

attached to. Aryl or heterocyclyl substnuents of (Ce-C1 o)aryl and (C5-C1 o)heterocyclyl

20    groups may not be further substituted by an aryl or heterocyclyl containing group.

If substituted, preferred substituents for (Ce-C1o)aryl groups are (C1-C4)alkyl, O-(C1-C4)alkyl, 0-phenyl, C(O)O-(C1-Ca)alkyl, C(O)OH, C(O)-(C1-C4)alkyl, halogen, NOz,

SOzNH2, CN, S02-(C1-C4)alkyl, NH-S02-(C1-C4)alkyl, NHz, NH-C(O)-(C1-C4)alkyl,

25    (CJ-Ca)cycloalkyl, (C1-C4)alkyi-OH, C(O)N[(C1-C4)alkyl]z, C(O)NH2, N[(C1-C4)alkyl]2, (C1-C4)alkenylene-(Ce-C1o)aryl, wherein the (Ce-C1o)aryl may be further substnuted by (C1-C4)alkyl, (C1-C4)alkylene-O-(C1-Ce)alkyl, O-(C1-Ce)alky~(Ce-C1o)aryl, or may be vicinally substituted by a O-(C1-C4)alkylene-O group whereby a 5-8-membered ring is fonned together wnh the carbon atoms the

oxygen atoms are attached to. More preferably, substiluents for (C5•C10)aryl are halogen, (C1..C4)alkyl especially methyl, ethyl, isopropyl or 3,3,3-trifluoromelhyl, O-(C1-C4)alkyl especially methoxy, S02•!C1-C4)alkylespecially S02•CH3or S02• CF3, or N[(C1..C4)alkyl]2 especially N[(CH3)2.

In monosubstituted phenyl groups the substituent can be located in the 2-posHion, the

.3-position or the 4-posHion, wnh 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-posHion, 3,4-position or 3,5-position. In phenyl groups carrying three

10    substituents the substHuents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-posHion, 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 unsubsiliuted or

substituted 1,2-phenylene, 1 ,3-phenylene or 1,4-phenylene. The above statements

15    also correspondingly apply to the aryl subgroup in arylalkylene groups. Examples of arylalkylene groups which can also be unsubsiliuted or substituted in the aryl subgroup as well as in the alkylene subgroup, are benzyl, 1-phenylethylene, 2-phenylelhylene, 3-phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.

20    If substituted, preferred substituents for (Cs•C1o)heterocyclyl groups are (C1..C4)alkyl, 0-(C 1..C4)alkyl, (C1..C4)alkylene-phenyl, halogen, (C 1•C4)alkylene..O-(C1..C4)alkyl, (Cs-C1o)heterocyclyl, (C1-C4)alkylene-N[(C1-C4)alkyl]2. or (C5-C1o)aryl, wherein the (C5.C1o)aryl may be further substituted by (C1-C4)alkyl, (C1-C4)alkylene-O-(C1..C6)alkyl, O.(C1-C6)alkyi-(C6..C1o)aryl, or may be vicinally

25    subsiliuted by a 0-(Ct•C4)alkylene-Ogroup whereby a 5-8-membered ring is formed together wHh the carbon atoms the oxygen atoms are attached to. More preferred substHuents for (Cs-C1o)heterocyclyl are (C1..C4)alkyl.

The general and preferred subsmuents of (Cs-C1o)aryl and (Cs-C1o)heterocyclyl groups may be combined with the general and prefemed definHions of R1, R2. R3, ~.

Rs. Re. R7, Ra, Rg, n and L as described above.

The present invenlion therefore also relates to the compounds of the formulae (I) or

(1'), or their physiologically acceptable salts and/or stereoisomeric forms for use as pharmaceuticals (or medicaments), to the use of the compounds of the formulae (I) or

(1'),or their physiologically acceptable salts and/or stereoisomeric forms for the production of pharmaceuticals for the treatment and/or prevention of diseases

10    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, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart

disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic

15    organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory

distress syndrome,  thrombotic disorders, stroke, cerebral vasospasm, cerebral

20    ischemia, pain, e.g. neuropathic pain; neuronal degeneration, spinal cord injury, Alzheimer'sdisease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabeles and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osleoporosis, infection of digestive

25    lracts with bacteria, sepsis, cancer development and progression, e.g. cancers of the breast, colon, prostate, ovaries, brain and lung and their metastases.

The treatment and/or prevention of diseases in humans is a prefemed embodiment but

also warm blooded animals such as cats, dogs, rats, horses etc. may be treated with

30    the compounds of the present invention.

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) or (1'),or its physiologically acceptable salts and/or
stereoisomeric forms and a pharmaceutically acceptable carrier, i. e. one or more

pharmaceutically acceptable carrier substances (or vehicles) and/or addijives (or excipients).

Optionally the physiologically functional derivatives, including the prod rugs, of a compound of the formula (I) or (I')may be utilized in the above mentioned uses and

10    pharmaceutical preparations.

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,
15    however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection 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.

20

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 formulae (I) or (1'),or its (their) physiologically acceptable salts

25    and/or ijs (their) stereoisomeric forms as well as their prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, com stanch or derivatives thereof, talc, stearic acid or ijs 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

30    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. Suijable 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 a compound of the formula (I) or (1'),or their physiologically acceptable salts and/or their stereoisomeric forms. The amount of the active ingredient of the formula (I) or (I') and/or its physiologically acceptable salts and/or its stereoisomeric forms in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.

In addnion to the active ingredients of the formula (I) or (I')and/or their physiologically

10    acceptable salts and/or stereoisomeric forms and to carrier substances, the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubrtcants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents,
buffer substances, solvents, solubilizers, agents for achieving a depot effect, sa~s for

15    altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formulae (I) and/or (I')and/or their physiologically acceptable satts and/or their stereoisomeric forms. In case a pharmaceutical preparation contains two or more compounds of the formulae (I) and/or (1'),the selection of the individual compounds can aim at a specific overall pharmacological
20    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 formulae (I) or (I')allows a great deal of control over the biological

and physico-chemical properties of the compounds and thus allows the selection of

25    such desired compounds. Furthermore, in addnion to at least one compound of the formula (I) or (I')and/or its physiologically acceptable salts and/or its stereoisomeric fonns, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically actiive ingredients.

30    When using the compounds of the formulae (I) or (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 mglkg, preferably from about 0.1 to about 50 mglkg, in particular from about 0.1 to about 10 mglkg, (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

10    usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated.

Furthermore, the compounds of the formulae (I) or (I')can be used as synthesis

intermediates for the preparation of other compounds, in particular of other

15    pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups.

It is understood that modifications that do not substantially affect the activity of the

20    various embodiments of this invention are included within the invention disclosed herein.

The compounds of the formulae (I) or (I')can be prepared according to the following exemplified compounds without limiting the scope of the claims.

25

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 protection form of an amino group, can be deprotected, i. e. converted into the amino group, by

30    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

formulae (I) or (I')can then be carried out by known processes.

In general, a reaction mixture containing a final compound of the formula (I) or (I')or an intermediate is worked up and, ff 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 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. Similar1y, well known methods such as amino acid sequence analysis,

10    NMR, IR and mass spectrometry (MS) can be used for characterizing a i:ompound of the invention.

lsoquinolinones can by synthesized via a variety of methods. The following general

schemes illustrate some of the possible ways to access isoquinolones, but do not limit

15    the present invention.

Q'O    OQ'
'(N

--- I"'X~H
F    -<'

y  (ii)    (iii)   
       
•~-

~~,0-


A suitably substttuted aldehyde, for example substituted by X or Y being independently from each other hydrogen, alkyl, alkoxy or halogen attached in a suitable posttion, can be reacted with a suitable compound such as for example an acetal of aminoacetaldehyde in a solvent like THF, chloroform or toluene under acid catalysis by toluene sulfonic acid or another appropriate acid to give imine (ii) wherein Q'can be for instance methyl or ethyl, which in turn can be cyclized by different methods to the isoquinoline (iii). For example this can be done by lewis acid catalysis by suitable lewis acids like tttanium tetrachloride, ferrous halides, aluminium halides etc. at temperatures ranging from ambient to 100 •c or by reducing the imine to the

10    corresponding amine by action of a suitable reducing agent like sodium borohydride, converting the amine into an amide or sulphonamide by reaction with a suitable acid chloride and subsequent cyclization to the isoquinoline by action of an appropriate

lewis acid. The isoquinoline (Ill) ttse~ can then be converted to the corresponding N-

oxide (iv) by action of a suitable oxidative agent like hydrogen peroxide, m-chloro

15    perbenzoic acid or others at room temperature or elevated temperature. TheN-oxide

(iv) can then be converted into the 1-chloro-isoquinoline derivative (v) by reacting it with a reagent like phosphorous oxy chloride in or wtthout presence of phosphorous

pentachloride. The derivative (v) can then be turned into suitable 1-alkoxy-derivatives

by reacting it with various alcohols Q-OH like methanol, ethanol or benzyl alcohol in

20    the presence of a suitable base like sodium hydride and in a suitable solvent like dimethyl formamide, dimethyl acetamide or others. Alternatively (v) can be directly converted into the isoquinolinone derivative (vii) by reacting it wtth a reagent like ammonium acetate.

---F~OHz0                     FM
~NH
y    IX    0   
25    X       

Scheme2.

Alternatively isoquinolines can be obtained by reacting suitable 3-formylated or acylated fluorobenzenes (viii), wherein z is for example H or alkyl like methyl or ethyl,


with a reagent like triethyl phosphene acetate in the presence of a suitable base like sodium hydride to give the corresponding cinnamic acid ester, which subsequently is cleaved by action of a suitable base like potassium hydroxide, sodium hydroxide or ltlhium hydroxide in a suitable solvent to deliver acid (ix). (ix) can then be converted in the corresponding acid chloride by well known methods, which can be transferred into the acid azide by reaction wtlh sodium azide in a suitable solvent like ether, chloroform

or acetone in or wfthout the presence of water. The corresponding azide then can be

converted into isoquinolinone (x) by reacting it in a suitable solvent like

diphenylmethane or dipenylether at suitable temperature.

10
'txtyOQ__. ()nco'P?
y    OQ

(vi)    (xl)


.()-noM
~NH y 0

(xiii)
Scheme 3.

The above obtained 6-Fiuoro-isoquinolones, for example (vi), can be reacted with

15    suitable P-substituted amino alcohols wherein Pis for example hydrogen, alkyl or a protecting group like for example Boc in the presence of base such as DBU, cesium carbonate or sodium hydride to give the corresponding alkoxy substituted derivatives (xi). Eventually, this conversion can already by performed at earlier stages of the
synthesis (e.g. by reacting a suitable intermediate). tt is understood, that this may

20    require in case of unprotected isoquinolones protection on the nitrogen or oxygen of the isoquinolone moiety by suitable methods, like reaction wtlh suitably subs!tluted alkyl or benzyl halides in the presence of base.
The products like (xi) obtained via this method can then, if a suitable amino functionaltly is present, be reacted wtlh sutlable aldehydes or ketones in the presence

of a reducing agent like sodium triacetoxy borohydride, sodium borohydride or sodium cyanoborohydride in a suitable solvent and in the presence of a water withdrawing agent like molecular sieves or a suitable ortho ester. This amino group may have to be liberated in an initial step like for example acidic removal of Bee-groups.
In case of use of protected isoquinolones, cleavage of the used protection groups is required to liberate the desired isoquinolone (xii). This liberation, however, can be perlonned before or after the reductive amination step, depending on the nature of the used aldehyde I ketone and the protection group used.

lsoquinolone derivatives like (xii) can be obtained as free bases or as various salts like

10    for example hydrochlorides, hydrobromides, phosphates, sulfates or fumarates. The salts obtained can be converted into the corresponding free base by either subjecting them to ion exchange chromatography or for example by alkaline aqueous treatment and subsequent extraction wtth suitable organic solvents like for example methyl tert.
butyl ether, chlorofonn, ethyl acetate or isopropanol/ dichloromethane mixtures and

15    subsequent evaporalon to dryness.

The general methods for the preparation of substituted isoquinolone derivatives as described above can be readily adapted to the preparation of the compounds of the
fonnula (I) or fonnula (1').In the following examples the preparation of the compounds

20    of the present invention is outlined in more detail. Accordingly, the following examples are part of and intended to illustrate but not to limit the present invention.

(2,2-Dimethoxy-ethyl)-(4-fluoro-benzyl).,amine (1)




25    12.4 g of 4-fluorobenzaldehyde were dissolved in 100 ml of toluene and reacted wtth 10.5 g of 2-aminoacetaldehyde dimethylacetal and 1.90 g (10 mmol) of

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 wnh water. The organic layer was extracted wnh brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions wnhout purification. R1 =

0.86 min (Method B). Detected mass: 162.1 (M-OMe), 214.2 (M+H').

N-{2,2-Dimethoxy•thyi)-N-(4-Duoro-banzyl)-4-mathyl-benzena-sulfonamide (2)

20 g of (2,2-<fimethoxy-ethyl)-(4-fluoro-benzyl)-amine (1) were dissolved in 120 ml of dichloromethane. 20 ml of pyridine were 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

15    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 22.95 g of compound 2 as an orange oil. R, = 1. 71 min (Method C). Detected mass: 336.1 (M-OMe").

20

6-Fiuoro-isoquinoline (3)

F~
~N

41.6 g of AICI, were suspended in 400 ml of dichloromethane. At room temperature, a solution of 22.95 g of N-{2,2-<fimethoxy-ethyi)-N-(4-fluoro-benzyl)-4-methyl-

25    benzenesulfonamide (2) 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 w~h dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75 g) is purified by silica gel chromatography to yield 2.74 g of compound (3). R1 = 0.30 min (Method C). Detected mass: 148.1 (M+H).
7 .Chloro-6-fluoro-lsoquinoline (4) Fro">
Cl    ~  I ..-:. N
Starting from 3-chloro-4-fluoro-benzaldehyde, the title compound was prepared by the

10    same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt =

0.77 min (Method A). Detected mass: 182.1/184.1 (M+H).
7 .Chloro-6-fluoro-isoquinoline 2Fro">-oxide(5)
I    •
Cl    ""-    --'N,O.

15    25 g (137.7 mmol) of 7-chloro-S-fluoro-isoquinoline (4) were in dissolved in 500 mL of dichloromethane. At room temperature 50.9 g (206.5 mmol) of m-chloro perbenzoic acid (70 %) were added and the mixture was stirred at room temperature until complete conversion iwas achieved. For workup, the precipitate was filtered off and

washed with dichloromethane. The filtrate was washed twice with sodium bicarbonate-

20    solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried with MgS04 and evaporated. The so obtained solid material (18.4 g) was used w~hout further purification. R1 = 0.87 min (Method C). Detected mass: 198.1/200.1 (M+H).

25    1,7-Di-chloro-6-fluoro-isoquinoline (6)
FY'rll

a~N

2.6 g (12.0 mmol) of 7-chloro~-fluoro-isoquinoline 2-oxide (5) were heated in 40 mL of POCI, at reflux for 4 h. After the mixture has cooled down to room temperature, it was poured on ice. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried with Mgso. and evaporated to yield 2.91 g of the title compound, which was used without further purification. R1 = 2.34 min (Method A). Detected mass: 216.01218.0 (M+H').

4-(lsoquinolin-6-yloxy)-piperidine-1-carboxylic acid-tert-butylester (7)

(yo~
::yoyN~ ~N

0

10    7.49 g of 4-hydroxy-piperidine-1-carboxylic acid-tert-butylester were dissolved in 20 mL of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) were added. Then a
solution of 3.65 g of 6-fluoroisoquinoline (3) in dimethyl acetamide was added dropwise. The solution was heated at 80 •c for 2 hours, then the solvent was removed and the residue was taken up in dichloromethane. The organic layer was extracted

15    twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to yield 6.22 g of
4-(isoquinolin~-yloxy)-piperidine-1-carboxylic acid-tert-butylester (7). R1 = 1.32 min

(Method B). Detected mass: 329.1 (M+H').

20    4-(2-0xy-isoquinolin-6-yloxy)-piperidine-1-carboxyllc acid tert-butyl ester (8)

(yo~
::yoyN~ ~N:0_

0

3.97 g (12.1 mmol) of 4-(isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (7) were dissolved in 100 mL of dichloromethane and 4.47 g (18.1 mmol) of m-chloro perbenzoic acid (70 %) were added at room temperature. The reaction mixture
25    was stirred for 1 h and then washed with saturated sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to yield 4.19 g of
 

crude material, which can be used for further conversion without purification. R1 = 1.46 min (Method B). Detected mass: 345.2 (M+H•).

1-Chloro~-{piperidin-4-yloxy)-isoquinoline-hydrochloride (9)

(yo~
HN~ ~N

HCI    Cl

3.5 g (10.16 mmol) of 4-(2-oxy-isoquinolin~-yloxy)-piperidine-1-<:arboxylic acid tart-butyl ester (8) were dissolved in 250 ml of HCI-saturated ethanol at 50 oc. The clear solution was concentrated i. vac. and the residue was refluxed in 50 ml of POCI,. After 3 h the POCI3 was removed i. vac. and the residue was taken up in water. The pH was

10    adjusted 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. IS Yield: 950 mg. R1 = 1,03 min (Method B). Detected mass: 263.11265.1 (M+W).

411-Chloro-isoquinolin~-yloxy)-piperidine-1-<:arboxylic acid tert-butyl ester (10)

(yo~
)(I(N~ ~N

0    Cl

1.23    g (4.11 mmol) of 1-<:hlor~-(piperidin-4-yloxy)-isoquinoline hydrochloride (9) were

20 dissolved in 50 ml of dichloromethane and 0.85 ml (6.15 mmol) of triethylamine were added. AJ 0 oc a solution of 1.09 g (5.0 mmol) of di-tert-butyl~~carbonate in 10 ml of

dichloromethane was added dropwise and the mixture was allowed to stand at room temperature overnight. For workup, the mixture was washed twice with water, dried over magnesium suffate and evaporated, to yield 1.1 g of the desired product, which

25    could be used without further purification. Rt = 1.86 min (Method C). Detected mass: 363.11365.2 (M+H•).

4-(1-Benzyloxy-isoquinolin~-yloxy)-piparldine-1-<:arboxylic acid tart-butyl ester

0.70 g (6.49 mmol) of benzyl alcohol were dissolved in 10 ml of dimethyl acetamide. 260 mg (6.49 mmol) of sodium hydride (60 %) were added and the solution was stirred at room temperature. Aller 30 min a solution of 1.57 g (4.33 mmol) of4-(1-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (10) in 10 ml of
10    dimethyl acetamide was added and the resuning mixture was heated at 90 oc (bath

temperature). After 8 h and standing at room temperature overnight 1.0 addijional equivalents of benzyl alcohol and sodium hydride were added and heating at 90 oc was continued for 8 h. For workup, the solvent was removed i. vac. and the residue

was dissolved in dichloromethane. The organic solution was washed twice with water,

15    dried with MgSO. and evaporated. The resuning crude product was purified by preparative HPLC. R, = 2.13 min (Method C). Detected mass: 435.2 (M+H').

6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one (12)

H0°'CQH

0

20    Coumpound (11) was dissolved in ethanol/2 N HCI (1:1) and slimed at room temperature until complete conversion was achieved. The solvent was removed i. vac. and the residue was purified by preparative HPLC. The resuning lrifluoroacetate was dissolved in 2 N HCI and lyophilized. After another lyophilization from water, 850 mg of

the title compound could be obtained as HCI salt. R1 = 0.75 min (Method B). Detected

25    mass: 245.1 (M+H'). Anemative synthetic approach:
 

6-Fiuoro-isoquinolinone (13)
 

40

F'OQH

0
 

4.8 mL (90.3 mmol, 1.5 eq.) of thionyl chloride was added portionwise to a solution of 10 g (60.2 mmol) of 3-fluoro cinnamic acid in 44 mL of chlorofonn and 1 mL of DMF. The reaction was heated to reflux for 2.5 h. Then the solvents were distilled to to yield 11.4 g of the crude acid chloride, which was used without any further purifcation.

The acid chloride was dissolved in 45 mL of acetone. At 0 'C8 .03 g of NaN3 (123.5 mmol, 2 eq.) were added portionwise. Then 41 mL of water were added while the

10    temperature was kept below 5 'C.The reaction was stirred for another 1.5 h. Then 55 mL of chlorofonn were added. The mixture was extracted with 80 mL of water followed by 40 mL of brine. After drying over Na,SO, and filtration 14 mL of diphenyl ether were added and most of the chlorofonn was removed in vacuo (without heating). A total removal of the chlorofonn should be avoided.

15

The solution containing the azide, diphenyl ether and the remaining chlorofonn was added dropwise at260 'Cwithin 15 minutes to a solution of 10 mL oftributyt amine in 97 mL of diphenyl ether. A vigorous reaction can be observed during the addition. The reaction was stirred for another 20 minutes at 260 'C.After cooling to room

20    temperature 270 mL of n-heptane were added. The precipitated product was filtered off and washed with ether to yield 5.65 g of the title compound. MS (DC I) Detected mass: 164.0 (M+H').

6-Fiuoro-2-(4-methoxy-benzyi)-ZH-isoquinolin-1-one (14)
I
0~  r"'TTYF
~N~

25    0   


169 ~L of p-methoxybenzylchloride (1.24 mmol, 1.1 eq) were added to a suspension of 200 mg of6-fluoro-isoquinolinone (13) (1.13 mmol) and 368 mg ofCs2C03 (1.36 mmol, 1.2 eq) in 3 mL of DMF. The mixture was stirred for 2 h and then poured on ice. The precipitate was filtered, washed with water and dried to yield 300 mg of the title compound. LCMS Method B, retention time 1.76 min, detected mass 284.14 [M+Ht

6-(Piperidin-4-yloxy)-2H-isoquinolin-1-one (12)

H0°'CQH

0

117 mg (0.58 mmol) of 4-hydroxy-piperidine-1-carboxylic acid-tert-butylester were

10    dissolved in 2 mL of N,N-dimethyl acetamide. Under an argon atmosphere, 63.6 mg (2.7 mmol) of sodium hydride were added and the mixture was stirred at room

temperature. After 30 minutes, 150 mg (0.53 mmol) of 6-fluoro-2-(4-methoxybenzyi)-2H-isoquinolin-1-one (14) were added and the solution was heated to 80 •c for 1 h.

The mixture was poured in water and extracted with chloroform. The combined organic

IS    laye!l'were dried over Na2SO,, fiHered and evaporated. The crude intermediate was purified by preparative HPLC. The protecting groups were removed by dissolving the protected intermediate in 2 mL of TFA and heating the reaction to 150 •c for 2 h in a
microwave reactor. The reaction mixture was quenched with methanol and evaporated

to dryness. The remaining residue was taken up in dichloromethane, extracted three

20    times with 1N HCI and the combined aqueous layer was extracted once with dichloromethane. The combined aqueous layer was lyophilized, the remainder was taken up in water twice and lyophilized again to give the product as HCI salt. The purity of the obtained product is sufficient, but eventually occurring impurtties could be
removed by silica gel chromatography or HPLC.

25

7-Bromo-6-lluoro-isoquinoline (15)
BXX)""'I-"'"N

Starting from 3-bromo-4-fluom-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). R1 =

0.91 min (Method B). Detected mass: 226.0 /228.0 (M+H').

7-Methyl~-(piperidin-4-yloxy)-2H-isoquinolin-1-<>ne (16)
fiiYOYl

HN~ ~NH

0

a) 6-Fiuoro-7 -methyi-2H-isoquinolin-1-<>ne

10    To a solution of 10.0 g (55.5 mmol) of 3-fluoro-4-methyl-cinnamic acid in 80 mL of acetone were subsequently added at ooc 6.74 g (66.6 mmol) oftriethylamine in 10 mL

of acetone followed by 7.83 g (72.2 mmol) of ethyl chloroformate. After stirring for 2 h at 0 to soc a solution of 4.0 g (61.1 mmol) of sodium azide in 9.5 mL of water was

added. After stirring for one additional hour the reaction mixture was poured onto 200

15    mL of ice water and extraced twice with chloroform. The organic phase was dried over magnesium sulfate, 40 mL of diphenylether were added and the chloroform was cautiously removed in vacuo. The residue was then added dropwise into 50 mL of

diphenylether, which had been preheated to 245°C. After complete addition it was

stirred for one further hour at 230- 250°C. After cooling down to 150°C the reaction

20    mixture was poured into 270 mL of heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 4.1 g 6-fluoro-7-methyi-2H-isoquinolin-1-<>ne were obtained.

b) 6-Fiuoro-2-(4-methoxy-benzyl)-7-methyi-2H-isoquinolin-1-one

25

To a solution of 9.17 g (51.8 mmol) of 6-fluoro-7 -methyi-2H-isoquinolin-1-one in 80 mL of DMF were added 20.2 g (62.1 mmol) cesium carbonate and then 8.92 g (56.9 mmol) 4-methoxybenzylchloride. After stirring at room temperature for 90 minutes the reaction mixture was poured into 600 mL of water, stirred for 1 h, and then the precipitated

product was filtrated by suction. From the mother liquor additional producted was isolated by chromatography wijh heptane I ethyl acetate (80:20). The combined products were recrystallized from ethyl acetate and 8.39 g 6-fluoro-2-(4-methoxy-benzyl)-7-methyi-2H-isoquinolin-1-one were received.

c) 4-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1 ,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-<:arboxylic acid tert-butyl ester

A solution of 3.2 g (15.9 mmol) Hert-butoxycarbonyl-4-hydroxypiperidine in 110 ml

10    dimethylacetamide was stirred wijh 1.36 g (45.4 mmol) of 80-% sodium hydride for 1 h at room temperature. Then a suspension of 4.5 g (15.1 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyi-2H-isoquinolin-1-<me in dimethylacetamide was added. The

reaction mixture was heated to sooc for 2h during which time a clear solution was

obtained. The reaction mixture was slowly added to 160 ml water and afler 1 h of

15    stilling the product was isolated by filtration and dried over night in vacuum. 6.4 g of 4-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1 ,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester were obtained.

d) 7-Methyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-<Jne hydrochloride

20

6.4 g (13.4 mmol) 4-[2-(4-methoxy-benzyl)-7-methyl-1-oxe>-1 ,2-dihydre>-isoquinolin-6-yloxy]-piperidine-1-<:arboxylic acid tert-butyl ester were dissolved in 30.5 g (267.4 mmol) trifluoroacetic acid. After 1 h at room temperature the mixture was heated for 2

h in a microwave oven at 150°C. Then the excess trifluoroacetic acid was distilled off in

25    vacuo and the residue was diluted with 130 ml of 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride 3 times and then ij was freeze dried to give a hydrochloride, which was crystallized from isopropanol. This furnished 3.2 g 7-methyl-6-(piperidin-4-yloxy)-2H-isoquinolin-1-<Jne (16) as hydrochloride.

R1 = 1.24 min (Method B). Detected mass: 259.1 (M+H•).

30

7-Bromo-6~piperidin-4-yloxy)-2H-isoquinolin-1-one (17)

(l(YOY'l
N~Br~N

0

a) 3-(4-Brom<>-3-fluoro-phenyl)-acrylic acid ethyl ester

To a solution of 13.4 g (60 mmol) triethyl phosphonoacetate in 80 ml of toluene was added 1.8 g (60 mmol) 80percent sodium hydride at o•c.After 30 minutes 11.0 g (54 mmol) 4-brom<>-3-fluorobenzaldehyde in 40 ml of toluene were added and the resuHing thick mixture was stirred with a mechanical stirrer overnight. After dilution with 500 ml of ethyl acetate and 200 ml of water the organic phase was separated and washed w~h sodium bicarbonate solution and brine. After drying over magnesium suffate followed by evaporation and purification by flash chromatography 10.6 g of 3-
10    (4-bromo-3-fluore>-phenyl)-acrylic acid ethyl ester were obtained.

b) 3-(4-Brom<>-3-fluor<>-phenyl)-acrylic acid

10.5 g (38.6 mmol) of 3-(4-bromo-3-fluor<>-phenyl)-acrylic acid ethyl ester were

dissolved in 100 ml of methanol and stirred overnight ~h 97 ml of aqueous 1 M IS sodium hydroxide solution. After removal of the methanol in vacuo the residue was
acidified w~h concentrated hydrochloric acid. The precipitate was isolated by suction and dried in vacuo at 5o•c furnishing 8.0 g of 3-(4-brom<>-3-fluoro-phenyl)-acrylic acid.

c) 7-Brom<>-6-fluor<>-2H-isoquinolin-1-one

20    To a solution of 4.0 g (16.3 mmol) of 3-(4-bromo-3-fluoro-phenyl)-acrylic acid in 60 ml acetone were subsequently added at 0- 5•c 2.0 g (19.6 mmol) triethylamine in 10 ml of acetone followed by 2.3 g (21.2 mmol) of ethyl chloroformate in 10 ml of acetone.
After stirring for 1 h at 0- 5•c a solution of 1.6 g (24.5 mmol) of sodium azide in 9 ml

of water was added. After stirring for 1 additional h the reaction mixture was poured

25    onto 200 ml ice water and extraced with chloroform twice. The organic phase was dried over magnesium sulfate, 24 ml of diphenylether were added and the chloroform was cautiously removed in vacuo. The residue was then added dropwise into 60 mL of diphenylether, which had been preheated to 25o•c. After complete add~ion the reaction mixture was stirred for additional 30 minutes at 230- 250•c. After cooling
 
down to 100"C the reaction mixture was poured into 100 ml of heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 2.4 g of crude 7-bromo-Q-fluoro-2H-isoquinolin-1-one were obtained.

d) 7 -Bromo~-fluoro-2-( 4-methoxy-benzyi}-2H-isoquinolin-1-one

From 2.4 g of crude 7-bromo~-fluoro-2H-isoquinolin-1-one, 3.9 g (11.9 mmol} of cesium carbonate and 1. 7 g (1 0.9 mmol} of 4-methoxybenzylchloride were obtained 0.93 g of 7-bromo-Q-fluoro-2-(4-methoxy-benzyi}-2H-isoquinolin-1-one analogous to the procedure described in step b of example 16.

10

e) 7 -Bromo~-(piperidin-4-yloxy}-2H-isoquinolin-1-one-hydrochloride

From 0.93 g (2.6 mmol} of 7-bromo-6-fluoro-2-(4-methoxy-benzyi}-2H-isoquinolin-1-one and 0.54 g (2.7 mmol} of 1-tert-butoxycartlonyl-4-hydroxypiperidine were obtained 0.35 g of 7-bromo-Q-(piperidin-4-yloxy}-2H-isoquinolin-1-one as hydrochloride

15    analogous to the procedures described in steps c and d of example 16. R1 = 0.80 min (Method A}. Detected mass: 323.1 /325.1 (M+H').

Cis and trans N-Boc-2-methyl-piperidin-4-ol (18 and 19}


HO-({Boc    HO--QBoc

20    racemic - cis    racemic- trans   
           
    18    19   

213 mg (5.6 mmol} of NaBH, were added portionwise at o•c to a solution of 1.0 g (4. 7 mmol} 1-boc-2-methyl-piperidin-4-on in 10 ml of ethanol. The mixture was stirred at room temperature for 2 h. The solvent was removed by distillation and the remainder

25    was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over Na,so,. After filtration the solvent was removed by distillation and the crude product was purified by column chromatography (n-heptanelethyl acetate 1/1} to yield 367 mg (36%} of the cis-isomer

18 and 205 mg (20%) of the trans-isomer 19 in addition to 97 mg (10%) mixture of both

isomers.

Cis-Isomer (18):

1H-NMR (CDCI3): S= 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-Isomer (19):

1H-NMR (CDCI3):S =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 =

10    7.1 Hz).

1-Cyclopropyl-piperidin-4-ol (20)

5g of 4-hydroxypiperidine were dissolved in methanol. 23.8 ml of 1[(1-

15    ethoxycyclopropyl)oxy]lrimethylsilane and 5.8 g of sodium cyano borohydride were added and the mixture was reacted at 60°C for 12h. The same amounts of the two reagents were added again and stirring was continued at 60°C for another 12h.
The mixture was diluted with methanol, fittered over celite and evaporated to dryness.

The residue was taken up in ethyl acetate, extracted twice with 2N sodium hydroxide

20    and once with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography to yield 2g of product 20, MS:141 (M)

The following compounds were obtained as their HCI satt in a similar fashion as

described in the syntheses of 12, 16 or 17, starting from the acids and amines listed in

25    the subsequen!Table 1.

The used acrylic acids were either commercially available or synthesized from the corresponding aldehydes in similar fashion as described in the literature (see for instance: J. Med. Chern. 2005, 48, 71-90). One example is described in the synthesis of 17, step a.

Table 1

Example    Acid    Amine    Product                    [M+Hl/    R,/    Method   
                                                [min]               
                                                                   
21        3-(3-Fiuoro-phenyl)•    HOD    HNW'DNH                        B   
                                           
        but-2-enoic acid    NBoc            259.3    0.85       
                                                   
                                                       
                    0                                               
                                                                   
                HOD                                                   
            3-(3,4-Difluoro-        HN        NH                               
22        phenyl)-but-2-enoic            F        277.2    0.80    B   
                                                       
            acid    NBoc    Q:x'D                               
                    0                                               
                                                                   
23        3,3-Difluoro cinnamic    HOD        F                263.1    0.77    B   
                                               
                                               
                ~oD               
            acid    NBoc    HN        NH                               
                    0                                               
                                                                   
            3-Fiuoro-4-    HOD    ~oD                               
            trifluoromethyl                    0.92    B   
24                    313.3           
                NBoc    HN    CF3    NH                               
            cinnamic acid        0                                               
                                                                   

                        Product            [M+H1/        R'        Method   
    Example    Acid    Amine                                       
                                            [min]           
                                                       
    25        3-Fiuoro-4-methoxy    HOD    HN~:CCDo,NH    275.4        0.32        D   
                                           
                                           
            cinnamic acid        NBoc                           
                        0                               
                                                       
                                                       
            3-(2, 3-Difluoro-    HOD        0    ~H                       
26        phenyl)-but-2-enoic        HN            277.46        1.00        D   
                    NBoc                                   
            acid            ¢&                               
                        0                               
                                                       
                                                       

Example    Acid        Amine        Product        [M+H1/        R'        Method   
                                               
                                    [min]           
                                               
    3-(3-Fiuoro-4-        HOD                                   
27    trifluoromethyl phenyl)-                HN    NH    327.2        0.97        B   
            NBoc                                   
                                               
    but-2-enoic acid                ¢ceoCF3                       
                    0                           
                                               
    3-(3-Fiuoro-4-methyl        HOD        HN¢o:"CNH                       
                                        B   
28    phenyl)-but-2-enoic                    273.0        0.89           
            NBoc                               
    acid                                       
                                           
                    0                           
                                           
29    3-Fiuoro cinnamic acid        DBoc        QUo~"    259.3        0.89        B   
                    HN                           
                    0                           
                                               
    -        -    _ L    _                           


Example    Acid        Amine        Product        [M+H1/        Rtl        Method   
                                               
                                    [min]           
                                               
                                               
    3-(2,3-Difluoro-        HOD        ,¢&"-0                           
30    phenyl)-pent-2-                        291.0        1.06        B   
    enoic acid        NBoc                                   
                                               
                    0                           
                                               
    3-(3-Fiuoro-phenyl)-        HOD        ~'0~                           
31    pent-2-                        273.1        1.33        D   
    enoic acid        NBoc                                   
                    0                           
                                               
32    3-(3,4 -Difluoro-        HOD        ,Q:co,                        A   
                                               
    phenyl)-pent-2-                        291.1        0.68           
    enoic acid        NBoc                                   
                    0                           


ExampleAcid    Amine    Product    [M+H']/ Rtf    Method
            [min]   

    19    .(X   
333-Fiuoro cinnamic acid    HN~0    259.20.78B   
           
    0       

34    3-Fiuoro cinnamic acid    18    OJ):    259.2    0.75    B   
            HN~0               
                           
        HOD/    D/               
35    3-Fiuor-4-Methoxy        (00    289.5    0.62    D   
    cinnamic acid                       
            HN  0O/               
' ----    --

    Example    Acid    Amine    Product            [M+H1/        R~    Method   
                        D/                [min]       
        3-(2,3 -Difluoro-    D/    F                           
                                           
    36    phenyl}-but-2-                291.2        1.00    B   
                                       
        enoic acid    HO    HN                           
                    ¢&'                       
                    0    D/                       
                                               
                                               
        3-(3-Fiuoro-4-methyl        D/                               
                                               
                                               
    37    phenyl}-but-2-enoic                    287.2        0.95    B   
                                           
        acid        HO    HN                           
                    ¢u                       
                    0    D/                       
        3-(2,3 -Difluoro-        D/    F                           
                                               
    38    phenyl)-pent-2-            HN~0        305.2        0.97    B   
        enoic acid        HO                               


ExampleAcid    Amine    Product    [M+H1/    RJ    Method       
                D/    [min]           
    3-(3 -Fiuoro-phenyl)-    D/    HN~00                   
39    pent-2-            287.2    0.87    B       
    enoic acid    HO        D/               
40    3-Fiuoro cinnamic acid    D/    (00            c       
                259.3    0.72           
        HO    HN  0                   
41    3-Fiuoro cinnamic acid        DA               
        20    265.2    0.77    A   
                           
        HN~0                   
        0                   


Example    Acid        Amine    Product    [M+H1/    RJ    Method   
                                D/        [min]       
                                               
            3-(3-Fiuoro-4-            D/                   
42        trifluoromethyl phenyl)-                HN¢o:o    341.2    0.91    c   
            but-2-enoic acid        HO                   
                                CF3               
                                0               
                                       
43            3-Fiuoro-4-methyl        HOD    HNQC(D~    259.2    0.82    B   
            cinnamic acid                NBoc                   
                                0               
                                               
                                               
44            3-Fiuoro-4-methyl            D/    HNQCCDN...._    273.2    0.83    B   
            cinnamic acid                               

    Example        Acid    Amine    Product                [M+H1/    RJ    Method       
                                            [min]           
                                                       
                HOD                H               
    45        3-Fiuoro cinnamic acid        HN~0    D    245.2    0.75    8       
                                           
                NBoc                                   
                    0        H                       
                                                   
                                                       
                H                                       
                                                       
    (R)-45        3-Fiuoro cinnamic acid        HN~0    D    245.2    0.78    8       
                                           
                                           
                HOD                                   
                        56                           
                                                   
Example        Acid    Amine        Product                [M+H1/    Rtl    Method   
                                            [min]       
                                                   
                                H                   
46            4-Chloro-3-fluoro        H    QJ:o    J)        279.1    0.86    B   
                                               
            cinnamic acid    HOf)                           
                        HN    Cl                   
                        0        H                   
                                                   
            3-(3-Fiuoro-4-methyl        H            J)                   
                                                   
    47    phenyl)-but-2•<moic                        273.2    0.81    A   
                    HN                       
            acid    HOf)                               
                        ¢x                       
                        0                           
                                               
                            f"".QH                   
46            3-Fluoro cinnamic acid    ( .. Oboe    HNwo        259.2    0.85    B   
                OH   CJH                           
                                           

Example    Acid        Amine        Product    [M+H1/    RJ    Method   
                            [min)       
                                   
                    PH               
49    3~Fiuoro cinnamic acid        Pboc        259.1    0.95    B   
            OH        HN               
                                   
                CIH    ~X~(               
                    0               
                                   
                               
so    3-F/uoro cinnamic acid        C'Osoc    HNr,pro"    273    0.92    A   
                    0               
                                   
51    3-Fiuoro cinnamic acid    •    NBoc    HNQY~NH    301.5    1.25    D   
        ~    0               
4-Bromo-6~piperidin-4-yloxy)-2H-isoquinolin-1-one (52)


0

200 mg of (12) were suspended in 25 mL of chloroform. 100~L of triethylamine was added and stirring was continued tor 2h. The solution was evaporated and the residue was purified by silica gel chromatography (dichloromethane: methanol: triethylamine 10:1:0.1). Another purification by HPLC and changing the anion to HBr yielded 73 mg of product as hydrobromide. R, = 1.35 min (Method A). Detected mass: 407.1/409.1 (M+H•).

10    4-(1-Benzyloxy-7-<:hloro-isoquinolin-6-ytoxy)-piperidine-1-<:arboxylic acid tart-butyl-ester (53)



289.8 mg (1.44 mmol) of 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl-ester were dissolved in 10 mL of dimethyl acetamide and 57.6 mg (1.44 mmol) of sodium hydride
15    (60%) were added. The reaction mixture was stirred at r0omtemperature. After 30 minutes a solution of 310 mg (1.44 mmol) of 1,7-di-chloro-6-fluoro-isoquinoline (6) in 3 mL of dimethyl acetamide was added and the mixture was stirred at room temperature for 1 h to complete conveiSion. Then 155.7 mg (1.44 mmol) of benzyl alcohol followed

by 57.6 mg (1.44 mmol) of sodium hydride (60%) were added and stirring was

20    continued at room temperature. To reach complete conveiSion, 0.5 equivalents of benzyl alcohol and sodium hydride were added twice, after 2 h and standing overnight.
For working up, the solvent was evaporated, the residue was taken up in dichloromethane, washed twice with water, dried with MgSO, and evaporated. Final purification was accomplished by preparative HPLC.
25


7-Chloro-6-(piperidln-4-yloxy)-2H-isoqulnolin-1-one (54)

Q~X)Q

0

254 mg (0.52 mmol) of 4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-piperidine-1-csrboxylic acid tert-butyl-ester (53) were stirred in methanol/2 N HCI (1:1) at room

temperature overnight. The solvent was removed i. vac. and the residue was purified

by preparative HPLC. The product fractions were evaporated and dissolved in 2 N HCI. Lyophilization results in 57 mg of the desired compound as hydrochloride. R1 = 0.95 min (Method B). Detected mass: 279.1 (M+H•).

10    7-Chloro-6-(1-isopropyl-piperidin-4-yloxy)-2H-isoquinolin-1-one (55)

(yo~
IN--/CI~N

0

64 mg (0.23 mmol) of7-chloro-6-(piperidin+yloxy)-2H-isoquinolin-1-one-hydro-chloride (54) were dissolved in 5 ml of methanol. 41.4 mg (0.41 mmol) oftriethyl
amine were added and the mixture stirred at room temperature for 10 minutes. After

15    adding freshly dried molecular sieves, 122.4 mg (2.04 mmol) acetic acid, 26.7 mg (0.46 mmol) of acetone and 43.3 mg (0.69 mmol) of sodium cyanoborohydride, the reaction mixture was refluxed for 8 h. After the addition of 2 equivalents acetone and 2 equivalents of sodium cyanoborohydride at room temperature, the reaction was refluxed for another 2 h to complete conversion. For working up, the mixture was

20    filtered and the fi~rate was evaporated. The residue was dissolved in dichloromethane, washed twice with 2 N NaOH and water and dried over Mgso• . After evaporation of the solvent and purificstion by preparative HPLC, 13 mg of the title compound were obtained as trifiuoroacetate. Rt = 0.98 min (Method B). Detected mass: 321.1/323.2 (M+H+).

!5


General procedure A for the reductive amination reaction:

0.243 mmol of6-(piperidin-4-yloxy)-2H-isoquinolin-1-one-hydrochloride (12) or of another suitable amine, 0.243 mmol of the aldehyde and 0.365 mmol triethylamine are stirred in 3 ml HC(OMe), for 1 hat room temperature. The mixture is cooled to -10 oc,

1.75 ml of a freshly prepared DMF solution containing 1.215 mmol NaHB(OAc), and 1.215 mmol HOAc is added. Stirring is continued at-10 oc for 30 min, the mixture is then allowed to warm to room temperature and left at room temperature over night. 0.5 ml of water is added and the mixture is evaporated, dissolved in DMF and purified by preparative HPLC. The purified products are dissolved in 1 ml HCI in isopropanol (5-

10    6M) and left over night at room temperature (cleaves BOC/IBu ester groups of some of the products). 2 ml water is added and the solution is freeze-dried to yield the hydrochlorides of the products.

15    The following compounds shown in the subsequent Table 2 were synthesized in a similar fashion as described in this general procedure and obtained as hydrochloride salts:
 

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