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(11) Patent Number: KE 540

(4S)Dateof,..ont' 23/03/2010
   
(12) PATENT
   
(Sl)Int.Cl.    (73)0wner:
C07D 217124 (2006.01)    SANOFI-AVENTIS DEUTSCHLAND GMBH of
A61P 9112 (2006.01)    lndustriepark Hochst, Building K80I, D-65929 Frankfurt
A61K3l/472(2006.01)    am Main, Germany
(21)Applicatioo Number:KE/P/2008/ 000697

(72) Inventors: KADEREIT, Dieter; PLETTENBURG, Oliver; HOFMEISTER. Armin; BRENDEL, Joachim and

(22) Filiog Date:    LOEHN, Matthias
20/07/2006   
   
(74) Agent/address for correspondence:
(30) Priority Data:    Kaplan & Stratton Advocates, P.O. Box 40111-00100,
05016153.826/07/2005 EP    Nairobi

(86)    PCT Data

PCf/EP06/007!40 20/07/2006 wo 2007/0I2422 01102/2007

(54)Titie:

CYCLOHEXYLAMJN JSOQUINOLONE DERIVATIVES AS RHO-KINASE INHIBITORS.

(57)    Abstract:

The invention relates to 6-cyclohexylamine-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.

CYCLOHEXYLAMIN  ISOQUINOLONE  DERIVATIVES  AS  RHO-KINASE  INHIBITORS

The present invention relates to novel lsoquinolone and isoquinoline derivatives as described in the claims, their preparation and their use in the treatment and/or prevention of diseases related to the inhibition of Rho-kinase and/or of Rho-kinase

mediated phosphorylation of myosin light chain phosphatase.

Activation of a small GTPase RhoA upon agonist stimulation results in conversion of

RhoA from the inactive GDP-bound form to the active GTP-bound fonm with a

10    subsequent binding to and activation of Rho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known. Rho-kinase 2 is e)(pressed in vascular smooth muscle cells and endothelial cells. Activation of Rho-kinase 2 by the active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells through phosphorylation-mediated inhibition of the myosin light chain phosphatase activity and thereby up-regulation of

15    the activity of myosin regulatory light chain (Uehata et al., Nature 1997, 389, 990-994).

It is known that Rho-kinase is involved in vasoconstriction, including the development of myoge~ic tone and smooth muscle hypercontractility (Gokina et al. J. Appl. Physiol. 2005, 98;1940-8), bronchial smooth muscle contraction (Yoshii et al. Am. J. Resp. Cell

W    Mol. Biolc20, 1190-1200), asthma (Setoguchi et al. Br J Pharmacal. 2001, 132,111-8; Nakahara, et al. Eur J 2000,389,1 03) and chronic obstructive 'pulmonarydisease (COPD, Maruoka, Nippon Rinsho, 1999 , 57, 1982-7). hypertension, pulmonary

hyperten,--on (Fukumoto et al. Heart, 91, 391-2, 2005, Mukai et al. Nature 1997,389, 990-4 ) a~d ocular hypertension and regulation of intraoccular pressure (Honjo et al.

25    Invest. Ophthalmol. Visual Sci. 2001, 42, 137-144), endothelial dysfunction (Steioff et al. Eur. J. Pharmacal. 2005, 512, 247-249), angina (Masumoto et al. Circ 2002, 105, 1545-47;'Shimokawaet al. JCP, 2002,40, 751-761), nephropathy, including hyperten§iol'l-induced,non-hypertension-induced, and diabetic nephropathies, renal
failure and  peripheral occlusive arterial disease (PAOD) (Wakino et ar: Drug News

30    Perspect. 2005, 18, 639-43), myocardial infarction (Demiryurek et al. Eur J Pharmacol. 2005,527, 129-40, Hattori et al. Circulation, 2004, 109,2234-9), cardiac hypertrophy and failure (Yamakawa, et al. Hypertension 2000, 35, 313-318, liao et al. Am J Physiol
 





2

Cell Physiol. 2006, 290, C661-8, Kishi et al. Circ 2005, 111, 2741-27,"':ronary~

heart disease, artherosclerosis, restenosis  (Pacaud et al. Arch. Mal. Coeur 2005, 98,

•249-254, Retzer, et al. FEBS Lett 2000,466,70, Negoro, et al. Biochem Biophys Res Commun 1999,262, 211 ), diabetes, 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, osteoporosis, endocrine dysfunctions, e.g. hyperaldosteronism, central nervous

system disorders such as neuronal degeneration and spinal cord injury (Hara, et al.

10    JNeurosurg 2000, 93, 94), cerebral ischemia (Uehata, et al. Nature 1997,38~;9.90: Satoh et al. Life Sci. 2001,69, 1441-53; Hitomi, etal. Life Sci 2000,67, 192~\• Yamamoto, et al. J Cardiovasc Pharmacal. 2000, 35, 203-11), cerebral vasb.spasrn'•,,

- (Sato, et al. Circ Res 2000,87, 195; Kim, et al. Neurosurgery 2000,46,440), pali,,,e.g.

<:neuropathic pain (Tatsumi, et al. Neuroscience  2005, 131,491, Inoue, et al. Naltjre.

15    •medicine2004, 10, 712), infection of digestive tracts with bacteria (WO 98/06433), cancer development and progression, neoplasia where inhibition of Rho kinase has been shown to inhibit tumor cell growth and metastasis (ltoh, 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 prol~eration 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.

Biophys. Res. Commun. 2000, 269, 633-640), stress fiber formation (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; Retzer, et al. Cell Signal 2000, 12,645) and leukocyte aggregation (Kawaguchi, et al. Eur J Pharmacol. 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 Pharmacol. 2000, 403:203-8), Alzheimer'sdisease (Zhou et al. Science 2003, 302, 1215-1217), adducin activation (Fukata et al. J. Bioi. Chern., 1998, 273, 5542-
 




3

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 inhibitory effect on Rho-kinase and/or on Rho-kinase mediated phosphorylation of myosin light chain phosphatase is useful for the treatment and/or prevention of 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 (COPO), 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 isoquino\ine-5-sulfonamide derivatives optionally substituted

25    by a -(CH2l1-6-0-(CH2)0-<;-. a -(CH2)o-6-S-(CH2)0-6- or a -(CH2)0-6-Iinked heterocyclic group useful as. neuroprotective agents.

WO 2004/106325 (Schering AG) describes prodrugs of the Rho-kinase inhibitor fasudil carrying an ether or ester group in the 1-position of the isoquinoline ring.

30

WO 20011039726 generically describes -0-(Co-C1o)alkyl-heteroaryl substituted cyclohexyl derivatives useful for the treatment of microbial infections.
 





4

JP 10087629 A describes isoquinoline derivatives useful for the tre~

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-C5)alkylene)Jo-1-Y wherein X may be oxygen andY may be

5    an aryl or a heterocyclic group.

Yoshida et al. (Bioorg. Med. Chern. 1999, 7, 2647-2666) disclose 6-benzyiOxy-

isoquinoline for the treatment of infections caused by Heliobacter pylori.

10    US 5,480,883 generically discloses as EGF and/or PDGF receptor inhibitors usefut'f<>J inhibiting cell proliferation compounds of the formula ~Ar 1- X- Ar W wherein X may be (CHR1)m-Z-(CHR1)n. e.g. Z-CH2, wherein Z may be 0, R1 is hydrogen or alkyl, Ar

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

•.P' others optionally substituted cyclohexyL

£
15

rf WO 2005/030791 (Merck & Co.) generically describes as potassium channel inhibitors

for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc.

isoquinolone derivatives which are optionally substituted in 6-position by a group

(CReiR~pOR43 wherein p may be zero, and R43 is e.g. a (C3-C1o)cycloalkyl residue

20    optionally substituted by NR51R52, wherein R51and R52 may be hydrogen,

(C 1-c6)alkyl etc.; or R43 is a group R81 defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with 1, 2, 3 or 4 heteroatoms; 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 inhibitors 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 (C3-C1o)cycloalkyl residue optionally substituted by NR51R52,

30    wherein R51and R52 may be hydrogen, (C1-C5)alkyl etc.; or R43 is a group R81
 






defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with

1, 2, 3 or 4 heteroatoms; and are substituted by a directly bound optionally subst~uted aryl or heteroaryl ring in the 4-position.

5 WO 03/053330 (Ube) describes isoquinolone derivatives of the formula ('lfl{aromaticring}- C(R)(R}(NH2)

HN~

0

as Rho-kinase inhibitors.

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





10    (I)

wherein

Rz isH, (C1-Cs)alkyl, [(C1-Cs)alkyleneJo-1-R', [(C1-Cs)alkyleneJo-1-0-(C1-C6)alkyl, [(C1-Cs)alkyleneJo-1-0-R',[(C1-Cs)alkylenelo-

15    1-NH2. [(C1-Cs)alkyleneJo-1-NH(C1-Cs)alkyl, [(C1-Cs)alkylene]o-1-N[(C1-Cs)alkyl]z, [(Ct-Cs)alkyleneJo-1-CH[R']2. [(C1-CsJalkyleneJo-1-C(O)-R',[(C1-Cs)alkyleneJo-1-C(O)NHz. [(C1-Cs)alkyleneJo-1-C(O)NH-R',or [(C1-Cs)alkyleneJo-1-C(O)N[R'l2;

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

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





6

R5 isH, halogen, CN, N02, (C1-C5)alkyl, (C2-C5)alkenyl, R', (C 1-C5)alkylene-(C6-C1 o)aryl, (C2-C6)alkenylene-(C5-C1 o)aryl,
(C 1-c6)alkylene-(C5-C1Q)heterocyclyl, NH2. NH-R',NH-S02H. NH-S02-(C1-C5)alkyl,

NH-S02-R',NH-C(O)-(C1-C6)alkyl, NH-C(O)-R',C(O)N[(C1-C6)alkyl]2, C(O)OH or

C(O)O-(C1-C6)alkyl;

R5 and R5'are independently of each other H, R',(C1-Cs)alkyl, (C1-C5)alkylene-R', (C1-C6)alkylene-O-(C1-C6)alkyl, (C1-C5)alkylene-O-R',(C1-C6)alkylene-CH[R'l2. (C1-C5)alkylene-C(O)-R',(C1-C5)alkylene-C(O)NH2, (C1-C5)alkylene-C(O)NH-R',or

10    (C1-C5)alkylene-C(O)N[R']2;

•R7 and Rs are independently of each other H, halogen, CN, N02. (C1-Ce)alkyl, O-(C1-Ce)alkyl, O-[(C1-C6)alkyleneJo-1-R',(C2-C5)alkenyl, R', (Cz-C6)alkenylene-(C6-C1o)aryl, (C1-C5)alkylene-R',NH2, NH-R',NH-S02H.
NH-S02-(C 1-C6)alkyl, NH-SOz-R',S02-NHz, SOz-NHR',NH-C(O)-(C1-C5)alkyl, NH-

15    C(O)-R',C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C1-C6)alkyl; Rg is halogen or (C1-Ce)alkyl;

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

20

Lis 0 or O-(C1-C5)alkylene;

wherein R'is (CJ-Cs)cycloalkyl,  (C5-C1Q)heterocyclyl or (Ce-C1Q)aryl; and

25    R" is (CJ-Cs)cycloalkyl, (C5-C1Q)heterocyci,., ,~0 ~ 1u'"ryl,(C1-Ce)alkyl, (C1-Ce)alkylene-R',(C1-Ce)alkylene-0-(C1-Ce)alkyl, (C1-Ce)alkylene-O-R',or (C1-Ce)alkylene-NRxRy; and
 





7

wherein Rx and Ry are independently of each other (C1-C6)alkyl,

(C5-C1 o)heterocyclyl, (C5-C 1o)aryl, (C 1-C4)alkylene-(Cs-C 1o)heterocyclyl, (C 1-C4)alkylene-(C5-C 1 o)aryl, (C1-C4)alkylene-NH( C1-C5)alkyl, (C1-C4)alkylene-N[(C1-C6)alkyl]2, (C1-C4)alkylene-N[(C6-C1o)aryl]2, or (C1-C4)alkylene-N[(Cs-C1o)heterocyclyl]2; and

wherein in residues~. Rs. R7 and Re 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

10    or more;

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

15    In another embodiment of a compound of fonnula (I) in residues ~. Rs, R7 and Re 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.

Stereoisomeric forms of the isoquinolone derivatives of the formula (I) include the

2.0    corresponding tautomeric 1-hydroxy-substituted isoquinoline derivatives of the fonnula

(I')





(I')

wherein R1 isH, (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl,

25    [(C1-C6)alkyleneJo-1-(C3-Ce)cycloalkyl, [(C1-C6)alkylene]o-1-(Cs-C1o)heterocyclyl, [(C1-C6)alkyleneJo-1-(C6-C 1o)aryl,
 







C(O)-(C1-Cs)alkyl, C(O)(C2-Cs)alkenyl, C(O)-(C2-Cs)alkynyl, C(O)-[(C1-Cs)alkylenelo-1-(C3-Cs)cycloalkyl, C(O)-[(C1-Cs)alkylenelo-1-(C5-C1o)heterocyclyl, or C(O)-[(C1-Cs)alkylenelo-1-(Cs-C 1o)aryl, and
5    wherein R3, R4, R5, Rs. Rs',R7, Rg, Rg, n and L are as defined above.

In a preferred embodiment, R2 in the compound of the fonrrula (I} is H, the compound is thus characterized by a compound ofthe fonrrula (II}




(II}.

10    In a further preferred embociment, R1 in the compound of the fonrrula (I')is H. the compound is thus characterized by a compound of the fonrrula (II')




(II').

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

15

For example the compound having the formula
H,ND,OV?
OH

is a tautom_e~ic form of the compound with the formula
 





100

Buffer: 25mM Tris pH7.5; 0.02% BSA; 5% Glycerol; 0.008% Triton X 1mM OTT; 1 mM MgCI2; 0.5~Ci/wel) y33P ATP

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

Final concentration of ATP in reaction mixture 401JM

5    Biotinylated substrate, diluted to 0.25~M with buffer described above (without ATP}

1.    10~1 Tris buffer(± Inhibitor}

2.    Add 30 ~L of enzyme solution

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

10    4. Incubate for 20 min at room temperature

5.    Stop reaction with 30~L of 50 mM EDTA

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

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

9. Radioactivity in the well was determined


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

20    form (salt or free base) obtained as in the examples described above and the following activities were measured.

Compound No.    piC50
   
10    +++++
   
11    +++++
   
12    +++++
   
13    +++++
   
14    +++++
   
20    +++++
   
29    +++++
   
37    +++++
   
 





101

Compound No.    piC5D   
       
41    +++++   
       
44    +++++   
       
45    +++++   
       
46    +++++   
48    +++++   
       
53    ++++   
56    +++++   
       
58    +++++   
       
65    +++++   
       
66    ++++   
       
67    +++++   
       
69    +++++   
       
70    +++++   
       
71    +++++   
       
77    +++++   
       
       
125    +++++   
       
137    +++++   
       
138    +++++   
       

The given activity is denoted as the negative decadallogarithm of the IC5o (piC 5o) as follows:
+:    piC 50    ,; 3.0
++:    3.o ->pic 50    < 4.0
+++    4.o--; plc 50 < 5.o
++++:    5.0--; piC5o  < 6.0

+++++:    6.0-> piC5o
 





102

Claims

1.    A compound of the fonmula (I)

R4    Rs    ~6   
R3WJ"': L~N,Rs'   
R2N    a    v   
o    R7    (Rg)n   
    R8    (I)   
           

or of the formula (I')





(I')

wherein

R1 isH, (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl,

1o    [(C1-Cs)alkyleneJo-1•(CJ-Cs)cycloalkyl, [(C1-Cs)alkyleneJo-1•(Cs-C1o)heterocyclyl, [(C1-Cs)alkyleneJo-1•(Cs-C1o)aryl,
C(O)-(C1-Cs)alkyl, C(O)(Cz-Cs)alkenyl, C(O)-(C2-Cs)alkynyl,

C (0 )-[(C 1-C s)alkyleneJo-1-(C J-Cs)cycloalkyl,

C(O)-[(C 1-Cs)alkyleneJo-1-(Cs-C 1o)heterocyclyl, or

15    C(O)-[(C 1-Cs)alkyleneJo-1-(Cs-C1 oJaryl,

R2 isH, (C1-Cs)alkyl, [(C1-Cs)alkylene]o-1-R',

[(C1-Cs)alkyleneJo-1-0-(C 1-Cs)alkyl, [(Cj•Cs)alkyleneJo-1-0-R',[(C1-Cs)alkyleneJo-

1•NHz, [(C1-Cs)alkyleneJo-1•NH(C1-Cs)alkyl, [(C1-Cs)alkyleneJo-1-N[(C1-Cs)alkyl]2.

20    [(C1-Cs)alkylene]o-1-CH[R'J2.
 




103

[(C1-C(;)alkylene lo-1-C(O)-R',[(C1-C6)alkylenelo-1-C(O)NH2, [(C1-C6)alkylene!o-1-C(O)NH-R',or [(C1-C6)alkylene]o-1-C(O)N[R']2;

'R:JisH, halogen, CN, (C1-C5)alkyl, (C1-C5)alkylene-R',OH, 0-R", NH2, NHR",

NR"R" or NH-C(O)-R",

R4 is H. halogen, hydroxy, CN, (C1-C5)alkyl, (C3-Cs)cycloalkyl, (C1-C5)alkylene-R';

R5 isH, halogen, CN, N02, (C1-C5)alkyl, (C2-C5)alkenyl, R',

10    ( C1-C(;)alkylene-(C5-C1 o)aryl, (C2-C5)alkenylene-(C6-C1 o)aryl, (C1-C6)alkylene-(C5-C1Q)heterocyclyl, NH2, NH-R',NH-S02H, NH-S02-(C1-C6)alkyl, NH-S02-R',NH-C(O)-(C1-C6)alkyl, NH-C(O)-R',C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C1-C6)alkyl;

15    R5 and R5'are independently of each other H, R',(C1-Cs)alkyl, (C1-C5)alkylene-R', (C1-C6)alkylene-0-(C1-C6)alkyl, (C1-C6)alkylene-O-R',(C1-C6)alkylene-CH[R']2,(C1-C6)alkylene-C(O)-R',(C1-C6)alkylene-C(O)NH2. (C1-C6)alkylene-C(O)NH-R',or (C1-C6)alkylene-C(O)N[R']2;

20    R7 and Rs are independently of each other H, halogen, CN, N02, (C1-C5)alkyl, O-(C1-C5)alkyl, O-[(C1-C6)alkyleneJo-1-R',(C2-C5)alkenyl, R',(C2-C(;)alkenylene-(C6-C1o)aryl, (C1-C5)alkylene-R',NH2. NH-R',NH-S02H, NH-S02-(C1-C6)alkyl, NH-S02-R',S02-NH2, S02-NHR',NH-C(O)-(C1-C6)alkyl, NH-C(O)-R',C(O)N[(C1-

C6)alkyl]2, C(O)OH or C(O)O-(C1-C6)alkyl;

25

Rg is halogen or (C1-C5)alkyl;

n is 0, 1, 2, 3 or4; and
 





104

lis 0 or O-(C1-C5)alkylene;

wherein R'is (C3-Ca)cycloalkyl,  (Cs-C1o)heterocyclyl or (Cs-C10)aryl; a1111i.;.

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

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

10    (C5-C1 o)heterocyclyl, (Cs-C1 o)aryl, (C 1-C4)alkylene-(Cs-C1 o)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-C1oJaryl]2. or (C1-C4)alkylene-N[(C s-C 1o)heterocyclyl]2; and

15.::•  wherein in residues R4, Rs. R7 and Rs 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;

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

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

compound of the formula (II)

3.    A compound of the formula (I')according to claim 1 characterized by a

compound of the formula (II')       
R4    R 5    ~6
R3W"'"" L~N'Rs'
N  //    //    ~
    R7    (Rg)n
OH    R8    (II').

4.    A compound according to any of claims 1 to 3, wherein R5 and R5'are

independently of each other H, (C1-Cs)alkyf, R',(C1-C4)alkylene-(CJ-Cs)cycloalc., (C 1-C4)alkylene-(C5-C 1Q)heterocyclyl, (C 1-C4)alkylene-C(O)-(C s-C 1Q)heterocyclyl, (C1-C4)alkylene-C(O)-(Cs-C1 o)aryl or (C 1-Cs)alkylene-(Cs-C 1 o)aryl.

10    5. A compound according to any of claims 1 to 4, wherein R5 and R5'are independently of each other H, (C1-Cs)alkyl, (C5-C1 o)heterocyclyl, (CJ-Ca)cycloalkyl, (C1-C4)alkylene-(CJ-Ca)cycloalkyl, (C1-C4)alkylene-(Cs-C1olheterocyclyl or

(C 1-Cs)alkylene-(Cs-C 1o)aryl.

15    6. A compound according to any of claims 1 to 5, wherein Rs isH, (C1-Cs)alkyl, (CJ-Cs)cycloalkyl or (C1-C4)alkylene-(C3-Cs)cycloalkyl, and Rs'is H. (C1-Cs)alkyl, (C J-Ca)cycloalkyl, (C 1-C4)alkylene-(CJ-Ca)cycloalkyl, (Cs-C1 o)heterocyclyl,
(C 1-C4)alkylene-(Cs-C 1o)heterocyclyl or (C1-Cs)alkylene-(Cs-C 1o)aryl.

20 A compound according to any of claims 1 to 6, wherein Rs is H, (C1-Cs)alkyl and Rs'isH, (C1-Cs)alkyl, (C3-Cs)cycloalkyl, (C1-C4)alkylene-(CJ-Ca)cycloalkyl, (Cs -C 1o)heterocyclyl, (C 1-C4)alkylene-(Cs-C 1o)heterocyclyl or (C 1-Cs)alkylene-(Cs-C1o)aryl.
 







108


26.    A compound according to any of claims 1 to 25, whereinll'l!i:l~nd Ra'.rle"v~

independently of each other H, halogen, CN, (C1-C4)all<y\, 0-(G,_,._,_,,

(Cz-C4)alkenyl, phenyl, (C5-Cs)heteroaryl, (C3-Cs)cycloa\kyl or (C1-~

(CJ-Cs)cycloalkyl.

5

27 _   A compound according to any of claims 1 to 26, wherein Ry and Ra are

independently of each other H, halogen, (C1-C4)a\kyl, O-(C1-C4)a\l<y\ or

(CJ-Cs)cycloalkyl.


10    28. A compound according to any of claims 1 to 27, wherein Ry isH, halogen,

(C1-C4)alky\ or (CJ-Cs)cycloalkyl and Ra is H.


29. A compound according to any of claims 1 to 28, wherein Ry and Ra are H.

15    30. A compound according to any of claims 1- to 29, wherein Rg is halogen or (C 1-

C4)a\kyl.


31.    A compound according to any of claims 1 to 30, wherein Rg is Cl, F, methyl or

ethyl.

20

32.    A compound according to any of claims 1 to 31, wherein n is 0, 1, 2 or 3.


33.    A compound according to any of claims 1 to 32, wherein n is 0 or 1.


25    34. A compound according to any of claims 1 to 29, wherein n is 0.


35. A compound according to any of claims 1 to 34, wherein R3 is H, halogen, (C1-Cs)all<y\, (C1-C4)alkylene-R',0-R" or NHR".
 





109

36.    A compound i!Ccording to any of claims 1 to 35, wherein R3 isH, (C1-C6)alkyl orNHR".

37.    A compound according to any of claims 1 to 36, wherein R3 isH, (C1-C4)alkyl, NH-(Cs-C6)heterocyclyl or NH-phenyl.

36.    A compound according to any of claims 1 to 37, wherein R3 isH, (C1-C4)alkyl, NH-(Cs-C6)heteroaryl containing one or more N atoms or NH-phenyl.

1039.    A compound according to any of claims 1 to 38, wherein R3 is H.
40.    A compound according to any of claims 1 to 39, wherein L is attached to the 4.

position of the cyclohexyl ring




or

15

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

Rs,N/R5'

hD,.,,"

41.    A compound according to any of claims 1 to 40, wherein Lis attached to the 4-

20    position of the cyclohexyl ring.

42. A compound according to any of claims 1 to 41, wherein L is 0-methylene, a-ethylene or 0
 





110


43.    A compound according to any of clalms 1 to 42, wherein~~~thylene,

0-ethylene or 0 attached to the 4-position of the cyclohexyl ring.

44.    A compound according to any of claims 1 to 43, wherein L is 0.

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

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

10

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

Rs isH, halogen, CN, NOz, (C1-Ce)alkyl, (Cz-Ce)alkenyl, R', (C1-Ce)alkylene-(Ce-C1o)aryl, (Cz-C6)alkenylene-(C6-C1o)aryl,
15    (C 1-Ce)alkylene:(C5-C1o)heterocyclyl, NHz, NH-R',NH-SOzH, NH-S0z-(C1-Ce)alkyl, NH-SOz-R',NH-C(O)-(C1-C6)alkyl, NH-C(O)-R',C(O)N[(C1-C6)alkyl]z, C(O)OH or

C(O)O-(C1-C6)alkyl;

Re and Re'are independently of each other H, (C3-Cs)cycloalkyl, (C1-Cs)alkyl,

20    (C1-Ce)alkylene-R',(C1-Ce)alkylene-O-(C1-C6)alkyl, (C1-Ce)alkylene-O-R', (C1-Ce)alkylene-CH[R']z,(C1-Ce)alkylene-C(O)NHz, (C1-Ce)alkylene-C(O)NH-R',or (C1-Ce)alkylene-C(O)N[R']z;

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

25    (Cz-Ce)alkenyl, R',(Cz-Ce)alkenylene-(Ce-C1o)aryl, (C1-Ce)alkylene-R',NHz, NH-R', NH-S0z-(C 1-Ce)alkyl, NH-SOz-R',SOz-NHz, SOz-NHR',NH-C(O)-(C1-Ce)alkyl, NH-C(O)-R',C(O)N[(C1-C6)alkyl]z, C(O)OH or C(O)O-(C1-C6)alkyl;

Rg is halogen or (C1•Ce)alkyl;

30
 





111

n is 0, 1, 2; an<i

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

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

physiologically functional derivatives.

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

10    R3 is H. halogen, CN, (C1-C5)alkyl, (C1-C2)alkylime-R'or NHR";

R4 isH, halogen, CN, (C1-C5)alkyl, (CJ-Cs)cycloali<yl, (C1-C2)alkylene-R';

Rs isH, halogen, CN, N02. (C1-Ce)alkyl, (C2-C5)alkenyl, R',

15    (C 1-C5)alkylene-(C6-C 10)aryl, (C2-C6)alkenylene-(C5-C 10)aryi, (C1-C6)alkylene-(C5-C1o)heterocyclyl, NH2. NH-R',NH-C(O)-(C1-C6)alkyl, or
C(O)N[(C1-C6)alkyl]2;

R6 and Re'are independently of each other H. (CJ-Cs)cycloalkyl, (C1-Cs)alkyl, or (C t•CJ)alkylene-R';

20

Ry and Ra are independently of each other H, halogen, CN, N02, (C1-Ce)alkyl, (C2-C6)alkenyl, R',(C2-C3)alkenylene-(C6-C1o)aryl, (C1-C3)alkylene-R',NH-R',NH-S02-(Ct-C6)alkyl, or S02-NHz;

25    Rg is halogen or (C1-C5)alkyl; nis0or1;and
L is 0 or 0-methylene;
 




9

r'i"o'f'ln
H,NAJ    ~NH

0

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

(II) and (II'):

R3 is preferably H, halogen, (Ct-C6)alkyl, (Ct-C4)alkylene-R',0-R" or NHR". More preferred, R3 isH, (Ct-C6)alkyl or NHR". Most preferred, R3 isH, (Ct-C4)alkyl, NH-(C5-C6)heterocyclyl or NH-phenyl, especially preferred R3 isH, (Ct-C4)alkyl, NH-(C5-C5)heteroaryl containing one or more N atoms or NH-phenyl. Most especially

10    preferred, R3 is H.

Preferably, R4 isH, halogen, CN, (Ct-C6)alkyl, NH-(C6-Cto)aryl or (Ct-C6)alkylene-R'.More preferably, R4 isH, halogen, (Ct-C6)alkyl, NH-(C6-Cto)aryl or (Ct-C6)alkylene-R'. In a further preferred embodiment, R4 isH, halogen,
15    (Ct-C6)alkyl, NH-(C6-Cto)aryl or (Ct-C2)alkylene-(C6-Cto)aryl. Most preferred, R4 is H, halogen, or (Ct-C6)alkyl. Especially preferred, R4 isH, halogen or (Ct-C6)alkyl. More especially preferred, R4 isH or (Ct-C6)alkyl. Most especially preferred, R4 is H.

Preferably, R5 isH, halogen, CN, (Ct-C6)alkyl, R',NH-(C6-Cto)aryl or

20    (Ct-C6)alkylene-R'. More preferably, R5 isH, halogen, (Ct-C6)alkyl, R', NH-(C6-Cto)aryl or (Ct-C6)alkylene-R'.In a further preferred embodiment, Rs isH, halogen, (C6-Cto)aryl, NH-(C6-Cto)aryl, (Ct-C2)alkylene-(C6-Cto)aryl, (Ct-C6)alkyl or (C5-Cto)heteroaryl. Most preferred, R5 isH, halogen, phenyl, (Ct-C6)alkyl or

(C5-C5)heteroaryl. Especially preferred, R5 isH, halogen or (Ct-C6)alkyf. More

25    especially preferred, R5 isH or halogen. Most especially preferred, R5 is H.
 





10

Preferably, Rs and Rs'are independently of each other H, (C1-c~"\-):'', • (C 1-C4)alkylene-(C3-Ca)cycloalkyl, {C 1-C4)alkylene-(Cs-C1 o)hetero~

(C1-C4)alkylene-C{O)-{Cs-C1o)heterocyclyl, {C1-C4)alkylene-C(O)-(Cs-C1o)aryl or (C 1-Cs)alkylene-(Cs-C1o)aryL In a further preferred embodiment, Rs and Rs'are

5    independently of each other H, (C1-Cs)alkyl, (Cs-C1o)heterocyclyl, (C3-Ca)cycloalkyl,

(C1-C4)alkylene-(C3-Ca)cycloalkyl, (C1-C4)alkylene-(Cs-C1o)heterocyclyl or (C1-Cs)alkylene-(Cs-C1o)aryL In a more preferred embodiment, Rs isH, {C1-Cs)alkyl,

(C3-Cs)cycloalkyl or (C1-C4)alkylene-{C3-Cs)cycloalkyl, and Rs'isH, {C1-Cs)alkyl,

{C3-Ca)cycloalkyl, (C1-C4)alkylene-{C3-Ca)cycloalkyl, (Cs-C 1 o)heterocyclyl,

10    (C1-C4)alkylene-(C5-C1Q)heterocyclyl or (C1-Cs)alkylene-{Cs-C1o)aryL In a further more preferred embodiment, Rs is H. (C1-Cs)alkyl and Rs'isH, (C1-Cs)alkyl,

(C3-Ca)cycloalkyl, (C1-C4)alkylene-(C3-Ca)cycloa lkyl, (C 5-C 1o)heterocyclyl, (C1-C4)alkylene-(Cs-C1Q)heterocyclyl or (C1-Cs)alkylene-(Cs-C1o)aryL In a further even more preferred embodiment, Rs isH, (C1-Cs)alkyl and Rs'isH, {C1-Cs)alkyl,

15    (C3-Ca)cycloalkyl, (C1-C4)alkylene-(C3-Ca)cycloalkyl, (C1-C4)alkylene-{C5-C1Q)heterocyclyl in which heterocyclyl is unsubstituted or substituted by (C1-C4)alkyl or halogen, or is (C1-Cs)alkylene-{Cs-C1Q)aryl in which aryl is unsubstituted or substituted by halogen, (C1-C4)alkyl especially CH3 or CF3, O-(C1-C4)alkyl especially O-CH3, or S02-{C1-C4)alkyl especially S02-CH3 or S02-

20    CF3_  In a most preferred embodiment, Rs isH, (C1-Cs)alkyl and Rs'isH, (C1-

Cs)alkyl, (C3-Ca)cycloalkyl, In a further most preferred embodiment, Rs isH and Rs' isH, {C1-Cs)alkyl, (C3-Ca)cycloalkyL Especially preferred, Rs and Rs'are H.

As examples for these embodiments, R6 or R6 • are, independently from each other,

hydrogen, methyl, ethyl, propyl, isopropyl, 3-methyl-butyl, 2-methyl-propyl, buiyl,

25    penlyl, 3,3,3-trifuoropropyl, 4,4,4-trifiuorobutyl or a substituent selected from the group consisting of


Preferably, R7 and Ra are independently of each other H, halogen, CN, (C1-C5)alkyo, O-(C1-Cs)alkyl, (C2-Cs)alkenyl, R'or (C1-Cs)alkylene-(C3-Ca)cycloalkyl. More

5    preferred, R7 and Ra are independently of each other H, halogen, CN, (C1-C4)alkyl, O-(C1-C4)alkyl, (C2-C4)alkenyl, phenyl, (C3-Cs)cycloalkyl, (C1-C4)alkylene-(C3-C6)cycloalkyl or (C5-C5)heteroaryl. Even more prefered, R7 and Ra are independently of each other H, halogen, (C1-C4)alkyl, O-(C1-C4)alkyl or

(C3-Cs)cycloalkyl. Most preferably, R7 is H, halogen, (C1-C4)alkyl or (C3-Cs)cycloalky

10    and Ra is H. Especially preferred, R7 and Ra are H.

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

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

15

The linker group L may be bound to the cyclohexyl ring in any position via a cyclohexyl

ring carbon atom and may thereby form the cis- or the trans-stereoisomer of a

compound according to the invention.

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

f6
~N,R5'
f--L   (Rg)n
or

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




13

Rs,N,Rs'

hD,..,"

in all their stereoisomeric forms.

In an especially preferred embodiment, L is attached to the 4-position of the cyclohexyl

ring.

Preferably, Lis 0-methylene, 0-ethylene or 0. More preferably, L is 0-methylene, 0-ethylene or most preferred 0 attached to the 4-position of the cyclohexyl ring.

10    Most preferably, Lis 0.

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 definitions of the groups

15    specified above or any one or some of the specific denotations which are comprised by the definitions of the groups and specified above, all combinations of preferred definitions, more preferred or most preferred and/or specific denotations being a subject of the present invention. Also with respect to all preferred embodiments the invention includes the compounds of the formulae (I) or (I')in all stereoisomeric forms

20    and mixtures of stereoisomeric forms in all ratios, and/or their physiologically acceptable salts.

A preferred embodiment of the present invention is a compound of the formulae (I), (1'),

(II) or (II')wherein

25

R3 isH, halogen, CN, (C1-C5)alkyl, (C1-C5)alkylene-R',OH, 0-R", NHz, or NHR";
 





14

R.j isH, halogen, hydroxy, CN, (C1-C5)alkyl, (C3-Ca)cycloalkyl,~s)alkylene-~

Rs isH, halogen, CN, N02, (C1-C5)alkyl, (C2-C5)alkenyl, R', (C 1-C6)alkylene-(C5-C 1o)aryl, (C2-C5)alke nylene-(C5-C 1o)aryl,

5    (C1-C6)alkylene-(Cs-C1Q)heterocyclyl, NH2, NH-R',NH-502H, NH-502-(C1-C5)alkyl, NH-502-R',NH-C(O)-(C1-C5)alkyl, NH-C(O)-R',C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C1-C5)alkyl;

Rs and Rs'are independently of each other H, (C3-Ca)cycloalkyl, (C1-Ca)alkyl,

10    (C1-C5)alkylene-R',(C1-C6)alkylene-O-(C1-C6)alkyl, (C1-C5)alkylene-O-R', (C1-C6)alkylene-CH[R']2,(C1-C6)alkylene-C(O)NH2. (C1-C5)alkylene-C(O)NH-R',or (C1-C6)alkylene-C(O)N[R']2;

R7 and Ra are independently of each other H, halogen, CN, N02, (C1-C5)alkyl,

15    '(c2-C5)alkenyl,R',(C2-C6)alkenylene-(C6-C1Q)aryl, (C1-C5)alkylene-R',NH2. NH-R', NH-502-(C1-C5)alkyl, NH-502-R',502-NH2. 50z-NHR',NH-C(O)-(C1-C5)alkyl, NH-C(O)-R',C(O)N[(C1-C6)alkyl]z, C(O)OH or C(O)O-(C1-C5)alkyl;

Rg is halogen or (C1-C5)alkyl;

20    n is 0, 1, 2; and

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

wherein R1. 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.

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

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




15

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

R4 isH, halogen, CN, (C1-C5)alkyl, (C3-Ca)cycloalkyl, (C1-C2)alkylene-R';

5    R5 is H. halogen, CN, N02, (CJ-Cs)alkyl, {C2-Cs)alkenyl, R',

{C 1-Cs)alkyfene-{Cs-C1 o)aryl, {C2-Cs)alkenylene-(Cs-C 1o)aryl, {C1•Cs)alkylene-(Cs-C1o)heterocyclyl, NH2. NH-R',NH-C{O)-{C 1-Cs)alkyl, or C{O)N[{C1-C6)alky1)2;

10    Rs and R5'are independently of each other H, {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-Ce)alkenyl, R',{C2-C3)alkenylene-(Cs-C1o)aryl, {CJ-C3)alkylene-R',NH-R',NH-

15    S02•(CJ-Cs)alkyl, or S02-NH2; Rg is halogen or (CJ-Ce)alkyl;
n is 0 or 1; and

20

L is 0 or 0-methylene;

wherein RJ, 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.

A most preferred embodiment of the present invention is a compound of the formulae

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

30
 





16

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

R4 isH, halogen, CN, (C1-C4)alkyl, (C3-Cs)cycloalkyl, (C1-C2)alkyl~

Rs isH, halogen, CN, N02, (C1-Cs)alkyl, (C2-Cs)alkenyl, R', (C1-Cs)alkylene-( Cs-C1 o)aryl, (C2-C5)a lkenylene-(Cs-C1 o)aryl, (C1-Cs)alkyfene-(Cs-C1o)heterocyclyl, NH-R';

Rs isH, (C3-Cs)cycloalkyl or (C1-C4)alkyl;

10

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

R7 and Rs 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',

15    NH-S02-(C1-C6)alkyl, or S02-NH2;

Rg is halogen or (C1-C4)alkyl;

n is 0; and

20    Lis 0;

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

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

25    physiologically functional derivatives.

In another most preferred embodiment of the present invention is a compound of the formulae (I), (1'),(II) or (II')wherein

30    R3 isH, halogen, (C1-Cs)alkyl;
 




17



Rs is H, halogen, (C1-C5)alkyl;

R5 isH, (C3-Ca)cycloalkyl, or (C1-Ca)alkyl;

R5'isH, (C3-Ca)cycloalkyl, (C1-Ca)alkyl, or(C1-C3)alkylene-R';

R7 and Ra are independently of each other H, halogen, CN, (C1-C5)alkyl or S02-NH2;

10

Rg is halogen or (C1-C4)alkyl;

n is 0; and

15    LisO;

wherein R 1, R2, and R'are as defined above;

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

20    physiologically functional derivatives.


As•in any embodiment of the invention, in the preceding embodiments which contain preferred, more preferred, most preferred or exemplary definitions of compounds

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

30    Physiologically acceptable salts of compounds of the fonnulae (I) and (I')mean both their organic and inorganic salts as described in Remington'sPharmaceutical Sciences
 




18

(17th edition, page 1418 (1985)). Because of the physical and chemical~~ the solubilrty, preference is given for acidic groups inter alia to sodium, potassiu;>": calcium and ammonium salts; preference is given for basic groups inter alia to salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid,

hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids,

for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates,_lactates, maleates, fumarates, malates, gluconates, and safts of amino acids, of natural bases or carboxylic acids. The preparation of physiologically acceptable salts from compounds of the formulae (I) and (I')which are

10    capable of salt formation, including their stereoiso~eric forms, takes place in a manner known per se. The compounds of the fonmula (I) fonm stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanotamine,

15    trometamol or else basic amino acids, for example lysine, ornithine or arginine. Where the compounds of the fonmulae (I) or (I')have basic groups, stable acid addition salts can also be prepared with strong acids. Suitable pharmaceutically acceptable acid addition salts of the comPounds of the invention are salts of inorganic acids such as

hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid,

20    and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, i~ethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.

Salts with a physiologically unacceptable anion such as, for example, trifluoroacetate

25    likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

The term ~physiologically functional derivative" used herein refers to any

30    physiologically tolerated derivative of a compound of the fonmulae (I) or (I')of the invention, for example an N-oxide, which on administration to a mammal such as, for
 




19

example, a human is able to form (directly or indirectly) a compound of the formula (I) or (I')or an activ~ metabolite thereof.

Physiologically functional derivatives include prod rugs of the compounds of the

invention, as described, for example, in H. Okada et al., Chern. Pharm. Bull. 1994, 42,

57-61. Such prodrugs can be metabolized in vivo to a compound of the invention.

These prodrugs may themselves be active or not.

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

10    race mates, racemic mixtures and pure enantiomers and to their diastereomers and mixtures thereof.

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

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

15    identical or different.

The compounds of the invention may also exist in various polymorphous forms, tor example as amorphous and crystalline polymorphous fonns. All polymorphous forms

of the compounds of the invention belong within the framework of the invention and are

20    a further aspect of the invention.

All references to "compound(s) of formula (I)" or to "cornpound(s) of formula (I')" hereinafter refer to compound(s) of the formulae (I) or (I')as described above, and their physiologically acceptable salts, solvates and physiologically functional

25    derivatives as described herein.

The term alkyl and the corresposponding alkylene substituents are understood as a hydrocarbon residue which can be linear, i.e. straight-chain, or branched and has 1, 2,
3, 4, 5 or 6 carbon atoms, respectively, where applicable. This also applies if an alkyl

30    group occurs as a substituent on another group, for example in an alkoxy group

(0-aikyl), 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-
 





20

isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl,~~

2,2-<Jimethylbulyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-b~r tert~,­ pentyl. Alkyl groups may- if not otherwise stated- be halogenated once or more, e.g. alkyl groups may be fiuorinated, e.g. perfluorinated. Examples of halogenated alkyl

5    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.

10    Alkynyl are, for example, ethynyl, 1-prbpynyl, 2-propynyl (= propargyl) or 2-butynyl.

~Halogen means fluoro, chloro, bromo or iodo.
,,

(C3-Cs)cycloalkyl groups are cydic alkyl groups containing 3, 4, 5, 6, 7 orB ring

15    carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1 or 2 double bonds (unsaturated cycloalkyl groups) like, for example, cyclopentenyl or cyclohexenyl can be bound via any carbon atom.

20    A (Cs-C 1Q)aryl group means an aromatic ring or a ring system which comprises two aromatic rings which are fused or otherwise linked, for example a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon-, indanyl- or indan-1-on-yl group. A preferred (C5-C 1Q)al)'lgroup is phenyl.

25    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 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, ?-position or 8-

30    position. (C5-C10)heterocyclyl groups may be (1) aromatic[= heteroal)'lgroups] or (2) saturated or (3) mixed aromatic/saturated.
 




22

Ce)alkyl, CONH2, CONH(C1-Ce)alkyl, CON[(C1-Ce)alkyiJ2. (C~~.~-~~oalkyl, . c

(C1-Ce)alkyl, (C1-Ce)alkylene-OH, (C1-Ce)alkylene-NH2. (C1-C5)~

Ce)alkyl, (C1-Ce)alkylene-N[(C1-Ce)alkyl]2. (C2-Ce)alkenyl, (C2-Ce)alkynyl{

O-(C1-Ce)alkyl, 0-C(O)-(C1-Ce)alkyl, O-C(O)-(Ce-C1 o)aryl,

O-C(O)-(Cs-C10)heterocyclyl, P03H2, S03H, S02-NH2, S02NH(C1-Ce)alky1,

S02N[(C1-Ce)alkyl]2, S-(C1-Ce)alkyl; S-(C1-Ce)alkylene-(Ce-C1 o)aryl,

S-(C 1-Ce)alkylene-(Cs-C 1o)heterocyclyl, SO-(C1-Ce)alkyl, SO-(C1-Ce)alkylene-(Ce-C1o)aryl, SO-(C1-Ce)alkylene-(Cs-C1o)heterocyclyl, S02-(C1-Ce)alkyl, S02-(C1-Ce)alkylene-(Ce-C 1o)aryl,

10    S02-(C1-Ce)alkylene-(Cs-C1o)heteracyclyl, S02-NH(C1-Ce)alkylene-(Ce-C1o)aryl, S02-NH(C1-Ce)alkylene-(Cs-C1o)heterocyclyl, S02-N[(C1-Ce)alkyi][(C1-Ce)alkylene-(Ce-C 1o)aryl], so2-N[(C1-Ce)alkyi][(C 1-Ce)alkylene-(C5-C 1o)heterocyclyl],

so2-N[(C1-Ce)alkylene-(Ce-C1oJaryl]2. S02-N[(C1-Ce)alkylene-(Cs-C1o)heterocyclyl]2.

15    C(NH)(NH2). NH2, NH-(C1-Ce)alkyl, N[(C1-Ce)alkyl]2. NH-C(O)-(C1-Ce)alkyl, NH-C(O)O-(C1-Ce)alkyl, NH-C(O)-(Ce-C 1o)aryl, NH-C(O)-(C5-C1 o)helerocyclyl, NH-C(O)O-(Ce-C1o)aryl, NH-C(O)O-(Cs-C1o)heterocyclyl, NH-C(O)-NH-(C1-Ce)alkyl, NH-C(O)-NH-(Ce-Cto)aryl, NH-C(O)-NH-(Cs-C1o)heterncyclyl, NH-S02-(C1-Ce)alkyl, NH-S02-(Ce-Cto)aryl, NH-S02-(Cs-Cto)heterocyclyl, N(Ct-Ce)alkyi-C(0)-

20    (Ct-Ce)alkyl, N(C1-Ce)alkyi-C(O)O-(Ct-Ce)alkyl, N(Ct-Ce)alkyi-C(O)-(Ce-C1o)aryl, N(Ct-Ce)alkyi-C(O)-heterocyclyl, N(Ct-Ce)alkyi-C(O)O-(Ce-Cto)aryl, N(Ct-Ce)alkyi-C(O)O-(Cs-Cto)heterncyclyl, N(C1-Ce)alkyi-C(O)-NH-(Ct-C6)alkyl], N(Ct-Ce)alkyi-C(O)-NH-(Ce-C1o)aryl, N(C1-Ce)alkyi-C(O)-NH-(C5-C1o)heterocyclyl,

N[(Ct-Ce)alkyi]-C(O)-N[(Ct-Ce)alky1]2,

25    N[(Ct-Ce)alkyi]-C(O)-N[(C1-C6)alkyi]-(Ce-Ct o)aryl, N[(C1-Ce)alkyi]-C(O)-N[(C1-C6)alkyHCs-Cto)heterocyclyl, N[(Ct-Ce)alkyi]-C(O)-N[(Ce-C1o)aryl]2, N[(Ct-Ce)alkyi]-C(O)-N[(C5-C1o)heteracyclyl]2. N[(Ce-C1o)aryi]-C(O)-(C1-Ce)alkyl,
 




23

I:JJ(Cs-Cto)heterocyclyi]-C{O)-(C1-C6)alkyl, Nf(Ce-C1o)aryi]-C(O)O-(C1-C6)alkyl, Nh&5:-S:Jg)heterocyclyi]-C{O)O-{C1-C6)alkyl, N{aryi)-C{O)-(Ce-C1o)aryl, Nf(Cs-C1o)-heterocyclyi]-C{O)-{Ce-Cto)aryl, Nf(Ce-C1o)aryi]-C(O)O-{Ce-Cto)aryl, N[(Cs-C 1o)heterocyclyi]-C{O)O-(Ce-C 1o)aryl, N[{Ce-Ct o)aryi]-C(O)-NH-{C 1-Ce)alkyl, N[(Cs-C1o)heterocyclyi]-C{O)-NH-{Ct-C6)alkyl, N(aryi)-C{O)-NH-{Ce-C1o)aryl, N[{Cs-C1o)heterocyclyi]-C{O)-NH-{Ce-Cto)aryl,

N[(Cs-C1 o)aryi]-C(O)-N[(C 1-Ce)alkyl]2, N[(Cs-C1o)heterocyclyi]-C{O)-N[{C1-C6)alkyl]2, N[(Ce-C1o)aryi]-C(O)-N[{Ct-Ce)alkyi]-(Ce-Ct o)aryl, N[{Cs-C 1o)heterocyclyl]-C{O)-N[{Cj-C6)alkyl]'{Ce-C 1o)aryl,

10    N[(Ce-C1Q)aryi]-C(O)-N[{Ce-C1o)ary1]2,

N[(Cs-C 1o)heterocyclyi]-C{O )-N[{Ce-C 1o)aryl]2, {Ce-C1 o)aryl, (Ct•Ce)alkylene-(Cs-C1o)aryl, O-(C1-Ce)alkylene-(Cs-C1o)aryl, (Cs-C1o)heterocyclyl, (C 1-Cs)alkylene-(Cs-C 1o)heterocyclyl, 0-(C 1-Cs)alkylene-(Cs-C 1o)heterocyclyl,
wherein the (Ce-C1 o)aryl or (Cs-C 1o)heterocyclyl may be substituted one to 3 times

15    by halogen, OH, N02, CN, O-(C1-Cs)alkyl, (C1-Cs)alkyl, NH2, NH(Ct-Cs)alkyl, N[(C1-Ce)alkyl]2, S02CH3, COOH, C(O)O-(C1-Ce)alkyl, CONH2, (C1-Ce)alkylene-0-(C1•Ce)alkyl, (C1•Ce)alkylene-O-{Ce-Cto)aryl, 0-(Ct-Ce)alkylene-(Ce-Cw)aryl; or wherein (Ce-C1o)aryl is vicinally substituted by a O-(Ct-C4)alkylene-O group whereby
a 5-8-membered ring is fonned together with the carbon atoms the oxygen atoms are

20    attached to. Aryl or heterocyclyl substituents of (Ce-C1o)aryl and {Cs-C1 o)heterocyclyl groups may not be further substituted by an aryl or heterocyclyl containing group.

If substituted, preferred substituents for (Ce-C1o)aryl groups are (C 1-C4)alkyl, O-(Ct-

C4)alkyl, 0-phenyl, C(O)O-(Ct•Ce)alkyl, C(O)OH, C(O)-(Ct-C4)alkyl, halogen, N02,

25    S02NH2. CN, S02-(C1-C4)alkyl, NH-S02•(Ct-C4)alkyl, NH2, NH-C(O}-(Ct-C4)alkyl, {C3•Cs)cycloalkyl, (Cj-C4)alkyi-OH, C(O)N[(Ct-C4)alkyl]2, C(O)NH2, N[(C 1-C4)alkyl]2, (Ct-C4)alkenylene-(Ce-Cw)aryl, wherein the (Cs-C1Q)aryl may be further

substituted by (C1-C4)alkyl, (Ct-C4)alkylene-O-(C1-C6)alkyl, O-{C1-Ce)alkyi-(Ce-C1o)aryl, or may be vicinally substituted by a O-(C1-C4)alkylene-
 





24

0 group whereby a 5-8-membered ring is fonmed together with th~~bo~ atoms t~ oxygen atoms are attached to. More preferred substituents for (C1-C~

C10)aryl are halogen, (C1-C4)alkyl especially CH3 or CF3, O-(C1-C4)alkyl especially O-CH3, or S02-(C1-C4)alkyl especially S02-CH3 or S02-CF3.

In monosubstituted phenyl groups the substituent can be located in the 2-position, the 3-position or the 4-position, with the 3-position and the 4-position being preferred. If a phenyl group carries two substituents, they can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenyl groups carrying three

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

!,;--.
The above statements relating to phenyl groups correspondingly apply to divalent

.:;  groups derived from phenyl groups, i.e. phenylene which can be unsubstituted or

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

,    also correspondingly apply to the aryl subgroup in arylalkylene groups. Examples of arylalkylene groups which can also be unsubstituted or substituted in the aryl subgroup as well as in the alkylene subgroup, are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.
20

If substituted, preferred substituents for (Cs-C1o)heterocyclyl groups are (C1-C4)alkyl, O-(C1-C4ialkyl, (C1-C4)alkylene-phenyl, halogen, (C1-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,

25    (C1-C4)alkylene-O-(C1-C5)alkyl, O-(C1-C6)alkyi-(C6-C10)aryl, or may be vicinally substituted by a O-(C1-C4)alkylene-O group whereby a 5-8-membered ring is fonmed together with the carbon atoms the oxygen atoms are attached to. More preferred substituents for (Cs-C1o)heterocyclyl groups are (C1-C4)alkyl or halogen.
 





25

The general and preferred substituents of (C5-C1 oJaryl and (Cs-C 1o)heterocyclyl groups may be combined with the general and preferred definitions of Rj, R2, RJ, fl4,

Rs. Rs. Rs',R7, Rg, Rg, nand Las described above.

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

andfor 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 (I')and/or their physiologically acceptable salts and/or stereoisomeric forms for the

production of phannaceuticals for the treatment and/or preVention of diseases

10    associated with Rho-kinase and/or Rhe>-kinase mediated phosphorylation of myosin light chain phosphatase, i.e. for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, and 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, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive

25    tracts 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 preferred embodiment but

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

30    the compounds of the present invention.
 





26

The present invention furthennore relates to pharmaceutical prepa~Jor pharm.aceutical compositions) which contain an effective amount of at~

compound of the formula (I) or(!')and/or its physiologi_cally acceptable salts and/or

stereoisomeric forms and a pharmaceutically acceptable carrier, i. e. one or more

5    pharmaceutically acceptable carrier substances (or vehicles) and/or additives (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 fonn 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 (I')and/or its (their) physiologically acceptable

25    salts and/or its (their) stereisomeric forms as well as its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carrier substances for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc.

_30    Suitable carrier.-su.bstance~ for ~he production of solutions, for example injection

solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol,

polyo!s, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carrier substances
 





27

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 (I')and/or their physiologically

acceptable salts and/or their stereisomeric fonns. The amount of the active ingredient

of the formula (I) or (I'}and/or its physiologically acceptable sans and/or its

stereisomeric forms in the pharmaceutical preparations normally is from about 0.5 to

about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of the formula (J) or (1')andlor their physiologically

10    acceptable salts and/or stereisomeric forms and to carrier substances, the pharmaceutical preparations can contain one or more additives "such as, for example, fillers, disintegrants, binders, lubricants. wetting agents, stabilizers, emulsifiers,

preservatives, sweeteners, colorants, flavorings, aromatizers, thlckeners, diluents,

buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts 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 salts and/or their prodrugs. 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 phannacological profile of the pharmaceutical

20    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 such desired

25    compounds. Furthermore, in addition to at least one compound of the formula (I) or (I') and/or its physiologically acceptable salts and/or its stereisomeric forms, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active 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
 





28

compound employed, on the nature and severity of the-disease to~b~

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

5    daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 to about 1DO 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 seve.ral, 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 fonmulae (I) or (I')can be used as synthesis intermediates for the preparation of other compounds, in particular of other

15'    Jharmaceutical active ingredients, which are ob~ainable from the compounds of the formula I, for example by introduction of substituents or modification of functional lroups.

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) u, \'J l-oll uc pn::pon::d 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 prod rug of a compound of the
 




29

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, if desired, the product is then purified by customary

processes known to those skilled in the art. For example, a synthesized compound can be purified using well known methods such as crystallization, chromatography or
reverse phase-high performance liquid chromatography (RP-HPLC) or other methods

of separation based, for example, on the size, charge or hydrophobicity of the

compound. Similarly, well known methods such as amino acid .s~l!ence analysis,

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

lsaquinolinones can by synthesized via a variety of methods. The following general schemes illustrate some of the possible ways to access isoquino!ones, but do not limit

15    the present invention.


F~
~~
y

{iii)

----    FtQX"'--,    ---- I   
    I    o    --<N       
            FWX"'"'o-<N   
    y    Cl    y   
(iv)            OQ   
        (v)    !"l   
               





(vii)

Scheme 1:
 




30

A suitably substituted aldehyde, for example substituted by X or~­ from each other hydrogen, alkyl, alkoxy or halide attached in a suitable position, can
be reacted with a suitable compound such as for example an acta! of aminoacetaldehyde for example in a solvent like THF, chloroform or toluene under acid

5    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 titanium tetrachloride, ferrous halides, aluminium halides etc. at temperatures ranging from ambient to 100 oc 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 (iii) itself 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. The N-oxide (iv) can then be converted into the 1-chloro-isoquinoline derivative (v) by reacting it with a reagent like phosphorous oxychloride in or without 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 with a reagent like ammonium acetate.

---Fr"',""oIOH
"'"
y  ix
25

Scheme 2

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





31

with a reagent like triethyl phospho no 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

lithium 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 with sodium azide in a suitable solvent like ether, chlorofonn or acetone in or without 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

-    P,P,N~0i:Y""> -
h    4'
y
oa

(Xi)


P,P,N~Ow~">
A    NH
'    0

{lliii)

Scheme 3:

15    The above obtained 6-Fiuoro-isoquinolones, for example (vi), can be reacted with suitable P1 I Pz substituted amino alcohols wherein p, I Pz are independently from each other for example hydrogen, alkyl or a protecting group like for example Boc or

phthaJoyl in the presence of base such as DBU, cesium carbonate or sodium hydride

to give the corresponding alkoxy substituted derivatives (xi). Eventually, this

20    conversion can already by performed at earlier stages ofthe synthesis (e.g. by reacting a suitable intermediate). It is understood, that this may require in case of unprotected isoquino!ones protection on the nitrogen or oxygen of the isoquinolone moiety by suitable methods, like reaction with suitably substituted alkyl or benzyl halides in the presence of base.
 





32

The products like (xi) obtained via this method can then either ~~rated or, if a suitable amino functionality is present, be reacted with suitable a~des or keto~e_s.
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

5    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

10    performed 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 for example hydrochlorides, hydro bromides, phosphates, trifluoroacetates, sulfates or fumarates. The salts obtained can be converted into the corresponding free base by

15    either subjecting them to ion exchange chromatography or for example by alkaline aqueous treatment and subsequent extraction with suitable organic solvents like•for example methyl tert. butyl ether, chloroform. ethyl acetate or isopropanol/ dichloromethane mixtures and subsequent evaporation to dryness.

20    The general methods for the preparation of isoquinolone derivatives as described above can be readily adapted to the preparation of the compounds of the formula (I) or (I').In the following examples the preparation of the compounds of the present invention is outlined in more detail.
Accordingly, the following examples are part of and intended to illustrate but not to limit

25    the present invention. (2,2-Dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (1)
 




33

12.4 g of 4-fiuorobenzaldehyde were dissolved in 100 ml of toluene and reacted with 10.5 g of 2-aminoacetaldehyde dimethylacetal and 1.90 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 _dichloromethan~ and washed twice with water. The organic layer was extracted with brine, dried over

10    magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. R, = 0.86 min (Method B). Detected mass: 182.1 (M-OMel, 214.2 (M+H').

N-(2,2-Dimethoxy-<>lhyi)-N-(4-fluoro-benzyl)-4-methyl-benzene-sulfonamide (2)

0/
FQCt',,su
 

o    I

15
 

a
 

20 g of (2,2-dimethoxy-;,thyl)-(4-fiuoro-benzyl)-amine (1) were dissolved in 120 ml of dichloromethane. 20 ml of pyridine were added. At 0 oc a solution of 23.8 g p-

to\uenesulfonic acid chloride in dich!oromethane was added dropwise. The reaction

was allowed to warm to room temperature and stirring is continued until conversion

20    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 maw 336.1 (M-OMe).

25
 




34

6-Fiuoro-isoquinoline {3)



41.6 g of AICI3 were suspended in 400 ml of dichloromethane. At room temperature, a solution of 22.95 g of N-(2,2-0imethoxy-ethyi)-N-(4-fluoro-benzyl)-4-methyl-benzenesu~onamide (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 with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate.

10    The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (B.75g) is purified by silica gel chromatography to yield 2. 7 4 g of compound (23). R, = 0.30 min (Method C). Detected mass: 148.1 (M+H+) ..
'"'
7 -Chloro-6-fluoro-isoquinoline {4) Fm
;:/    I "'
Cl    ~   ...-::N
15

Starting from 3-chloro-4-fluoro-benzaldehyde, the title compound was prepared by the

sanie reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). R1 =

0.77 min {Method A). Detected mass: 162.1/184.1 (M+H").

20    7-Bromo-6-fluoro-isoquinoline {92)

F~
Br ~N
Starting from 3-bromo-4-fluoro-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").

25
 






7-Chloro-6-fluoro-isoquinoline 2-oxide (5)
FY0.
CI~N,o-

25 g (137.7 mmol) of 7-chloro-6-fluoro-isoquinoline (4) were in dissolved in 500 ml of dichloromethane. At room temperature 50.9 g (206.5 mmol) of m-<:hloro perbenzoic

acid (70 %) were added and the mixture was stirred at room temperature until

complete conversion is achieved. For worKup, the precipitate was filtered off and

washed with dichforomethane. The filtrate was washed twice with Sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried with magnesium sulfate and

10    evaporated. The so obtained solid material (18.4 g) was used without further purification. R, = 0.87 min (Method C). Detected mass: 198.1/200.1 (M+H').

1,7 -bichloro-6-fluoro-isoquinoline (6)

:X)Q
Cl

15    2.6 g (12.0 mmol) of 7-chloro-6-ftuoro-isoquinoline 2-oxide (5) were heated in 40 ml of

POCh at reflux tor 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 magnesium sulfate and evaporated t9
yield 2.91 g of the title compound, which was used without further purification. R, =

20    2.34 min (Method A). Detected mass: 216.01218.0 (M+H+). 5-Chloro-6-fluoro-isoquinoline (7)


7.0 g (38.1 mmol) of 6-fiuoroisoquinoline (3) were dissolved in 60 ml of concentrated

25    sulfuric acid. At 0 oc 10.18 g of N-chloro succinimide were added. After 1 h another 5.2 g of N-chloro succiminide were added and the solution was heated to 50 oc. Two more
 





36

portions of 5.2 g N-chloro succinimide were added successively an~

continued at 50 oc until the reaction was complete. The reaction mixture was cooled to

room temperature, was poured on ice and adjusted to pH 10 by addnion of sodium

hydroxide. The precipitate was filtered off, dissolved in dichloromethane and washed

with aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate,

evaporated and the crude product was purified by preparative HPLC to yield 4.04 g of 5-chloro-6-fluoro-isoquinoline (7) as trifluoroacetate. R, = 0.97 min (Method A). Detected mass: 182.0/184.0 (M+H').

10    5-Chloro~-fluoro-isoquinoline 2-oxide (8)
F+.

~~'a-

Starting from 5-chloro-6-fluoro-isoquinoline trifluoroacetate (7), the title compound was

obtained following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5).

R1 = 0.90 min (Method C). Detected mass: 198.1/200.1 (M+H•).

15

1,5•Dichloro-6-fluoro-isoquinoline (9)

'~

Cl

5-Chloro-6-fluoro-isoquinoline 2-oxide (8) was converted to the title compound

following the protocol described for the synthesis of 1,7-dichloro-6-fluoro-isoquinoline

20    (6). The crude product was purified by silica gel chromatography (heptane/ethyl acetate 4:1). R1 = 1.70min (Method C). Detected mass: 216.0/218.0 (M+H').

6-(cis-4-Amino-cyclohexyloxy)-7 -chloro-2H-isoquinolin-1-one (1 0)

•(yo~
H2N)._.J CI~NH

0
 





37

2.19 g (10.2 mmol) of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 20 ml of dimethyl actetamide. Under argon atmosphere, 814 mg (20.4 mmol) of sodium hydride (60%) were added and the mixture was stirred at room temperature. After 30 min, a solution of 2.0 g (9.26 mmol) of 1 ,7-<lichloro-6-ftuoro-

isoquinoline (6) in 5 ml of dimethyl acetamide was added and stirring was continued at

room temperature. After 1 h, 2.0 g (18.5 mmol) of benzyl alcohol and 740 mg (18.5 mmol) of sodium hydride (60 %) were added. The reaction was stirred for 2 hat room

temperature and 30 minutes at 80 oc to achieve complete conversion. The solvent was removed in vacuo and the residue was taken up in dichlorort:~ethane and washed twice

10    with water. After drying over magnesium sulfate, the organic layer was evaporated, to furnish 4.44 g of the crude intermediate cis-[4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester. The intermediate was dissolved in methanol and treated with 2 N HCI at room temperature. After stirring for 2 d, the reaction mixture was adjusted to alkaline pH by addition of sodium hydroxide. The

15    solvent was removed in vacuo and the residue was stirred in ethanol. Filtration and evaporation of the filtrate yielded a solid material, which was purified by preparative HPLC. The obtained trifluoroacetate was dissolved in 2 N HCI. Final lyophilization gave 433 rng of the title compound as hydrochloride. R, = 0.89 min (Method B). Detected mass: 293.2/295.2 (M+H•).
20

6-(cis-4-Amino-c yclohexyloxy)-5-chloro-2H-isoquinolin-1-one  (11)

(Yo~
H,N~ ~NH

0

Starting from cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 1,5-dichloro-6-fluoro-isoquinoline (9), the title compound was prepared as hydrochloride

25    following the route described for 6-(cis-4-amino-cyclohexyloxy)-7-chloro-isoquinolin-1-ol hydrochloride (10). R, = 1.04 min (Method B). Detected mass: 293.11295.1 (M+H.).
 




38

7 -Chloro-6-(cis-4-cyclopropylami no-cyclohexyloxy)-2H-isoqu~p-1-<>ne (12)

(yO"Y'In

~~AJCI~NH

0

and

7 -Chloro-6-(cis-4-dicyclopropylamino-<:yclohexyloxy)-2H-isoquinolin-1-<>.ne (13)

(yO"Y'In
~NAJCI~NH
t,    0

100 mg (0.3 mmol) of6-(cis-4-Amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-orie

. hydrochloride (10) were dissolved in 10 ml of methanoL 54.5 mg (0.54 mmol) oftriethyl

amine were added and the mixture was stirred at room temperature for 10 minutes.

10    Freshly dried molecular sieves, 159.3 mg (2.66 mmol) of acetic acid, 104.6 mg (0.6 mmol) of (1-ethoxy-cyclopropoxy) trimethyl silane and 56.5 mg (0.9 mmol) of sodium cyanoborohydride were added and the reaction mixture was refluxed for 3 h. 5 equivalents of (1-ethoxy-cyclopropoxy)-trimethyl-silane were added, followed by 2
equivalents of sodium cyanoborohydride. The mixture was allowed to stand at room

15    temperature overnight. The mixture was filtered and the filtrate was evaporated . .The residue was dissolved in dichloromethane. washed twice with 2 N NaOH and water and dried over magnesium sulfate. After evaporation of the solvent and purification by preparative HPlC 4.5 mg of?-chloro-6-(cis-4-cyclopropylamino-cyclohexyloxy)-isoquinolin-1-ol (12) as trifluoroacetate and 16 mg of 7-chloro-6-(cis-4-

20    dicyclopropylamino-cyclohexyloxy)-isoquinolin-1-ol (13) as trifiuoroacetate were obtained. R1 (12) =1.05J11in (Method A). Detected mass: 333.213352 (M<H').R1 (13) =

1.15    min (Method B). Detected mass: 373.11375.1 (M+W).
 




39

6-( trans-4-Ami no-cyclohexyl oxy)-7 -chloro-isoquinolin-1-ol ( 14)

(T•'OYY)H

H2NAJCI~'

0

Starting from trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 1,7-

dichloro..£-fluoro-isoquinoline (6) the title compound was prepared as hydrochloride

5    following the route described for 6-(cis-4-amino-cyclohexyloxy)-7-chloro-isoquinolin-1-ol hydrochloride (10). R1 = 1.08 min (Method B). Detected mass: 293.2/295.2 (M+H•).

trans-4-(lsoquinolin-6-yloxy)-cyclohexylamine (15)
_o••om
H2N    ~   h

10    6.1 g (53 mmol) of 4-amino-cyclohexanol were dissolved in 50 ml of dimethyl acetamide and 4.24 g (106 mmol) of sodium hydride (60%) were added at room temperature. After the reaction mixture was stirred for 30 minutes under argon, a
solution of 6.49 g (35.3 mmol) of 6-fluoro-isoquinoline hydrochloride was added and

the mixture was stirred at room temperature overnight. For workup, the solvent was

15    removed in vacuo and the residue was dissolved in dichloromethane and washed twice with water. The organic layer was separated, dried with magnesium sulfate and evaporated to yield 8.64 g of the crude product, which was used without further purification. R1 = 0.77 min (Method B). Detected mass: 243.1 (M+H•).

20    trans-N-[4-(Isoquinolin-6-yloxy)-cyclohexyl)-acetamide (16)

0    n••o~
A~ ~N
H

8.4 g (34.7 mmol) of 4-(isoquinolin-6-yloxy)-cyclohexylamine (15) were dissolved in 100 ml of dichloromethanelpyridine (4:1). At 0 'Ca solution of 3.27 g (41.6 mmol) of
acetyl chloride in 10 ml of dichloromethane was added and the reaction mixture was

25    stirred at room temperature. After 2 h, the solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. After washing twice with
 





40

2 N HCI, the product was transferred to the aqueous phase. T   i~f1-laye1~Wj(;e... '20J

9 adjusted to alkaline pH by addition of solid NaOH and extracte -~"."times with "

dichloromethane. Drying the organic layers with magnesium sulf . :t :~~ ;vaporatio/} pt the solvent gave 7.69 g of the crude product. After silica gel chromatog•.• • • .•.. :;:,;~
the title compound were isolated. R, = 0.87 min (Method A). Detected mass: 285.2 (M+H').

trans-N-[4-J2-0xy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (17)

o    ('r•o~
)lNA/    ~N:-
H    0

10    Starting from N-[4-(isoquinolin-6-yloxy)-cyclohexyl]-acetamide (16) the title compound•

was obtained following the method described for 7-chloro-6-fluoro-isoquino!ine 2-oxide

:s). R1 = 1.01 min (Method A). Detected mass: 301.2 (M+H').

!rans-N-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (18)
o  (1••ov;l""
)lNA/    ~  -4N
 

15




20
 
H
Cl

N-[4-(2-0xy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (17) was converted to the title

compound following the protocol described for 1 ,7-dichloro-6-fluoro-isoquinoline (6).

The crude product was purified by preparative HPLC. R1 = 1.49 min (Method B). Detected mass: 319.11321.1 (M+H+).

trans-N-[4-(1-Benzyloxy-isoquinolin-6-yloxy)-<:yclohexyl]-acetamide (19)
 




975 mg (3.06 mmol) of N-[4-(1-chloro-isoquinolirK>-yloxy)-cyclohexyl]-acetamide (18) were dissolved in 20 ml of dimethyl acetamide and 992 mg (9.17 mmol) of benzyl

25    alcohol were added. After addition of 367 mg (9.17 mmol) of sodium hydride (60 %),
 




41

the reaction mixture was stirred for 3 h at room temperature and for 1 h at 80 oc. Then, the solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with water. The organic layer was dried with magnesium sulfate

and evaporated. Final purification by preparative HPLC yielded 680 mg of the title compound. R1 = 1.75 min (Method B). Detected mass: 391.2 (M+H').

trans-6-(4-Amino-cyclohexyloxy)-2H-isoquinolin-1-one (20)
H,ND .. o~H

0

680 mg (1. 7 4 mmol) of N-[4-(1-benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide

10    (19) were heated in 2 N HCI in an autoclave at 120 oc until complete conversion is achieved. The solvent is removed in vacuo and the residue is purified by preparative
HPLC. The product fractions were evaporated and dissolved in 2 N HCI. After lyophilisation 182 mg of the title ccmpound could be obtained as hydrochloride. R1 = 0.97 min (Method B). Detected mass: 259.2 (M+H').

15

cis-4-(lsoquinolin-6-yloxy)-<:yclohexylamine (21)

(yo~
H,NAJ    ~N

Starting from 6-fluoro-isoquinoline hydrochloride and cis-4-amino-cyclohexanol the title

compound was prepared following the protoccl described for compound (15). R1 = 0.64

20    min (Method B). Detected mass: 243.2 (M+H'). cis-N-[4-(Isoquinolin-6-yloxy)-cyclohexyl]-acetamide (22)
5N.0a'O)

H

Starting from cis-4-(isoquinolin-6-yloxy)-cyclohexylamine (21) the title compound was

25    prepared following the protocol described for the compound (16). R1 = 0.90 min (Method B). Detected mass: 285.1 (M+H').
 





42

cis-N-[4-(2-0xy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (23)

o    (yo~
)lNA._/   ~N:-

H    0

Starting from cis-N-[4-(isoquinolin-S-y!oxy)-cyclohexylj-acetamide (22) the title

compound was obtained following the method described for 7-chloro-6-fluoro•

5    isoquinoline 2-oxide (5). R1 = 0.80 min (Method C). Detected mass: 301.2 (M+W).

cis- 4-(2-0xy-isoquinolin-6-yloxy)-cyclohexylamine (24)

(yo~
HNA._/   ~i(O_
2

2.43 g (8.1 mmol) of cis-N-[4-(2-oxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (2:1)

10    were refiuxed in 50 ml of 2 N HCI for 16 h. Evaporation of the solvent gave 2.46 g of the title compound (crude product) as HCI-salt. R1 = 0.59 min (Method C). Detected mass: 517.3; 259.2; 130.2 [(2M+H.), (M+H•), 1/2(M+W)].

cis-4-(1-Chtoro-isoquinolin-6-yloxy)-cyclohexylamine (25)

(yo~

    H2NA._/~N
15    Cl

2.46 g of cis- 4-(2-oxy-isoquinolin-6-yloxy)-cyclohexylamine (24, crude product) were heated to 100 oc in 20 ml POCJ,. After 1 h the mixture is cooled to room temperature

and poured on ice. The aqueous solution is brought to an alkaline pH by addition

ofsodium hydroxide and extracted three times with dichloromethane.  The combined

20    organic layers were dried with magnesium sulfate and the solvent was removed under reduced pressure to yield 1.14 g of the title compound as crude product, which was used without further purification. R, = 0.90 min (Method C). Detected mass: 277.11279.2 (M+W).
 





43

cis-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butylester (26)

'-I   0  fYOI'l/'l
~OJl~~ ~N

Cl

1.14 g of cis-4-(1-chloo-isoquinolin-6-yloxy)-cyclohexylamine (25, crude product) was dissolved in 20 ml of dichloromethane. At 0 oc a solution of 1.17 g (5.35 mmol) of di-

tert•butyl dicarbonate in 5 ml of dichloromethane was added and the solution was stirred at room temperature. After 1 h, the solution was washed with water, dried and

evaporated, to yield 1.65 g of the title compound, which was used without further purification. R, = 1.77 min (Method C). Detected mass: 377.11379.1 (M+H•).

10

cis-[4-(1-Benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (27)



Starting from cis- [4-(1-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl

15    ester (26, crude product) the title compound was prepared following the protocol described for trans-N-[4-(1-benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (19).

Final chromatography on a preparative HPLC gave a mixture of the desired product and the partially deprotected derivative having a free amino group. Rt = 2.01 min
(Method C). Detected mass: 449.2 (M+H•).

20

cis-6-(4-Amino-cyclohexyloxy)-2H-isoquinolin-1-<>ne (28)
fYOY"'n

H,N~ ~NH

0

The title compound was prepared by stirring cis-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (27) at room temperature in methanol/2 N
 





44

HCI (1:1). After complete conversion, the solvent was removed

pressure and the residue was purified by preparative HPLC. The    •.ioed

trifluoroacetate was converted to the corresponding hydrochloride by drsso_..,_...,.

compound in 2 N HCI and evaporation of the solvent. After dissolving the residue in

water and lyophilisation, the desired product (HCI-salt) was isolated as a coipt\ftess solid. R1 = 0.75 min (Method B). Detected mass: 259,2 (M+H').

General procedure A for the reductive amin_ation reaction:

0.243 mmol of the amine building block (hydrochloride), 0.243 mmol of the aldehyde

10    and 0.365 mmol of triethylamine were stirred in 3 ml of HC(OMe), for 1 hat room temperature. The mixture is cooled to -10 °C, 1.75 ml of a freshly prepared DMF solution containing 1.215 mmol of NaHB(OAc), and 1.215 mmol ofHOAc is added.
Stirring is continued at -10 oc for 30 min, the mixture is then allowed to warm to room l • temperature and left at room temperature over night. 0.5 ml of water was added and
15    the mixture was evaporated, dissolved in DMF and mono- and bis-akylated products, if obtained, were purified by preparative HPLC. The purified products were dissolved in 1 ml of HCI in isopropanol (5-<JM) and left over night at RT (cleaves BOC/IBu ester groups off some of the products)_ 2 ml of water were added and the solution is freeze-
dried to yield the hydrochlorides of the products.

20

According to this procedure the following products were obtained as hydrochlorides

from the mentioned amine and carbonyl component (Table 1)
 



45

Table 1:

                                                                       
Example    Amine                Aldehyde I                Product    [M+H']    R1/    Method   
                        Ketone                        [min]           
                                                                   
        HNr;ccuCl                                                   
29                    0                        HNQC(DCl ~/"'--.._    321.2    0.99    A       
            NH,    )lH                                   
    0                                            0                   
                                                                       
                                                                   
30        Q):oD    JH    HNQC(DCl~~    335.2    1.08    A       
                                   
        HN    C/    NH2                           
    0                                            0                   
                                                                       
                                                       
31        Q):aD            0            HNQCCDCl ~~    349.2    1.18    A       
                    ~H                       
        HN    C!    NH2                           
    0                                            0                   
                                                                   
32    HNQ):oDCl NH2    ro            IH~~~C(M~~    335.2    1.07    A       
                                       
    0                                                           
                                                i    0                   
 
 



47

JEx""'pleiAmine                j Aldehyde I        Product                            [M+H')    RJ    Method       
                        Ketone                                                [min)                   
                                                                                           
                                                                                       
38    HNQ):)JCl    _NH;!        (IH        HN            ......-::::            417.1    1.29        B   
                                    ~aD~                                   
    0                                0Cl    ~    I """                                   
                                                                                               
39    Cl        NH            0        HN                        377.2    1.26        A       
                                                                                       
    HNQ):)),        2        ~H            c;ccoD    N~                                   
                                        Cl                                               
                                                                                       
    0                            0                ~                                           
                                                                                           
                                                                                           
40    HNwonClNH            0        HN~:C(DCl                    405.2    1.40        A   
        2        YH            N~                                   
    0                            0        y                                        I   
                                                                                   
                                                                                   
41                        0                                                                   
    ~on                        HNQC(DClNV    401.2    1.28        AI   
        NH 2        ~H                                           
    HN//   Cl                                                I   
    0                                        ~                                    I   
                                0                                            I   
                                                                                       
                                                                        ---                       
 





Example 1Amine

42    I   Q):OD.
HN    Cl    NH2

0
43    HNWCI 0 D

NH2
o

44    ~0

H~yv DNH,

45    I   ~0
"1-(V D.,
 





Aldehyde I

Ketone

~
Cl    ! ~    H

.--_:;

~

H


JH



~

.. "
 



48

Product            T[M+H11Rtl    I Method   
            I    [min]       
~~    1541.1    11.84    lA   
HN    Cl'"''~vCIN-...:::           
0    Cl~    .&           
wou~    1321.2    11.01    lA   
HN        ~N ...............           
0            H           
                       
~        1335.2    11.06    IB   
HN~ U~~           
0                       
~0        1349.2    11.15    IB   
"j-(V    D,~ I    I . 1 .~   
 





Example~mine
I
4G    I ~

H~yV ODNH,

0

., ,.y&u.,

0
?'A
 





Aldehyde I
Ketonero


o
'~'"
 



49

Product

?'
H~l)_~J___

0
~ulfl
.yo

0
 





I[M+H11Rm,'.on  I Method

[    I

!335.2    11.06   IB



/349.2    /1.15   IB
 
46    I
"0 ODNH,
0

49    1  ~

H~JO ODNH,

0
 

J vd H

h

Cl
 
~0    /347.2   11.05   I B

"~~ D-~v

0
~-'c"'-0--~-- 1541.1   11.83   lA
H  H~ DN-u

0    ~  """Cl

Cl
 



50

ExampleAmine                Aldehyde I        Product                    R,/        I Method   
                                Ketone                            [min]           
50                                                                        lA   
                                0            H~UNUCI        1.88           
    ""    ""    0            \CI~H                           
                "'                                           
    10HNI- DNH,                                   
    0                            0    Cl~  -"'                   
                                                        I""                   
51                                0                            1349.1    11.10        lA   
    10""I""o                        0                       
            )lH        HNy& DN~                   
            HN    --"        DNH,                                       
    0                                                   
                                0            )                   
                                                                       
                                                                           
52                                0            Cl                1377.2    11.27        lA   
    ""    ""    0    DNH,        ~H                                       
    10HNI--"                    H¢UN~                   
    0                                                l~~   
                                        0            ~  I    I           
53                                0            J~houN~    J405.2    J1.47    ff11<1   
    ""    "'    0            ~H                           
    10    DNH,                                   
            HN    I""                                           
    0                            0            ~                   
                                                            I    .~\l'e..l,   
                                                                       
 





Example    Amine
54    I  y&

""    "'  OYI
~NH,HNIh

o

55    I   ~0

H~~ UNH,

0

56    I H(YYo ()_

~~CI NH, o

57    IHNN)0•0

~gc1    NH2
 





Aldehyde I

Ketone

0
"'--- )l
T  H


0
~H

)lo

H

J

H
 



51

Product        R,J    I Method   
q}OY"'l    [min]       
    1.45    I A   
HN    ~N~       
0    i(    I       
H~~~ 0 D.N~ 1401.2    11.31    /A
0    ~  v

~o•••("'j    \349.2    11.10   1 s
HN    ~ l/' .....
0    Cl

H~O.,Q    1335.2    11.12   lA

I >JI('VAc1    ~~

0
 



52

                                                                                       
Example  IAmine                Aldehyde I    Product                    [M+H1    R,/    Method           
                                                               
                            Ketone                                [min]                   
                                                                                       
58            H~C(0Cl            0            QCCO,Q        349.2    1.24    B           
                        ~H                                       
                NH            HN    Cl    ~~~                               
        °            2                                                       
        0                ro        0                                               
                                                                               
        HQCC0Cl0                                                               
59            NH 2            HN    ,            ~    335.2    1.11    B           
        0                            ~;x::c••0Cl    ~                               
                                        0                                               
                                                                                       
60            HNQCC00            0                                349.2    1.22    B           
                NH2                HN                                               
        0    Cl        YH    wo•UCl N~                               
                            0        H                                   
                                                                                       
61            QCC0'0    0        ycco•o_                    541.1    1.86    A           
                                                                       
                ffH    HN                                               
            HN 0    Cl    NH2            Cl    N~            .                   
                            Cl--"    o    ~        "'c,                               
                                            Cl                        ~    ''"~        ..   
                                                                                   
 




53

Example  IAmine                                                                       
                    Aldehyde I        Product            [M+H']    Rtf        Method   
                    Ketone                                [min]               
                                                                       
                                                                   
62    HQ:):0Cl    0 NH2    Cltr'    w:~o    541.1    1.89        A   
                            .,       
    0                        I ~    H                           
                                        0    ""        "'                       
                                            I"'                           
                                            Cl                               
                                           
63    Q:):o0    0        Hyo:0•,0~    377.2    1.28        A   
        __JlH                           
    HN    Cl        NH2                            ~                       
    0                                    O    Cl                               
                                                                           
                                                                       
                                                                           
64    Q:):o0    0        r~o.C)_        405.2    1.50        A   
                                               
    HN    Cl        NH2    ~H        HN        I "" Cl    N~                       
    0                                    0        ~                       
                                                                       
                                                   
65    HQ:):Cl0    0 NH2    0        ~o,Q    N~    405.2    1.40        A   
            YH                                   
    0                            HN        I ""'cl    y                           
                                        0                               
                                            -                               
                                                                           
 




















...
"'
 




55

General procedure B for the reductive ami nation reaction:

15o•mg (0.46 mmol) of 6-cis-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one hydrochloride (10) were dissolved in 10 ml of methanol. After addition of molecular sieves 4 A, 92.3 mg (0.57 mmol) of triethylamine, 273.8 mg (4.56 mmol) of acetic acid and 0.57 mmol of the corresponding aldehyde, a solution of 86.0 mg (1.37 mmol) of sodium cyanoboro hydride is added dropwise and the mixture is stirred at room temperature until comprete conversion is achieved. tn some cases it was necessary to heat the mixture to 70 "C to achieve complete conversion. For the isolation of the products the solution was filtered and the solvent was removed under reduced

tO pressure. The residue was dissolved in dichloromethane, washed with 1 N NaOH and sat. sodium chloride solution, dried with magnesium suJ:fate and evaporated. The mono- or bis alkylated products, if obtained, were purified by preparative HPLC or precipitated from methanolic HCI

The obtained tritluoroacetates were stirred in 2 N HCI/Methanol, evaporated, dissolved

15    jn water and freeze dried to yield the desired products as hydrochlorides. Soc-protected products were de protected during the evaporation of the HPLC-product fractions, which contained 0.1% TFA, or during the subsequent stirring in 2 N HCI/Methanol.

20

According to this procedure the following productS were obtained as hydrochlorides

from amine (10) and the mentioned aldehyde (Table 2)
 



56

Table 2:       
Example   Aldehyde    Product    [M+H']  RJ[min]    Method

                                                   
    2                z        z    z    z       
    0..        ~J:        ~J:            ~I'    ~J:       
                        I        I               
    .,        ob    b    I    I       
                               
        ,".,                    )=o    =<0            0~~    ob       
                                                       
        .c,        0                           
        "'        )\        -i               
        ;;:                                           
        ..                                                   
                                                           
        0.                                                   
        E        ,._                .,                       
        )(..                                    .,    ~       
        UJ        .,                .,                       
                                                "'    "'       
                                                           
 




62

7 -Bromo-6-fluoro-isoquinoline 2-oxide (93)

0 _.NCCCBrF

Starting from (92} the title compound was prepared following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5}. R, = 0.93 min (Method C). Detected mass: 242.2/244.2 (M+W}.





Starting from 7-bromo-6-fluoro-isoquinoline 2-oxide (93) the desired product was

10    synthesized according to the protocol described for 1,7-dichloro-6-fluoro-isoquinoline

(6}. R1 = 1.70 min (Method C). Detected mass: 260.0/262.0 (M+W}.





15    12.9 g (49.5 mmol} 7-bromo-1-chloro-6-fiuoro-isoquinoline (94) were dissolved in 250 ml of acetic acid. After addition of 38.7 g (0.5 mol} of ammonium acetate, the solution is stirred at 100 "C. After 3 h, the solvent was removed under reduced pressure and the residue was poured into water. The precipitate is filtered and dried to yield 9.91 g (63%} of the title compound. R, = 1.15 min (Method C). Detected mass: 242.2/244.1

20    (M+H•}.

7 -Bromo-6-fluoro-2-(4-methoxy-benzyi)-2H-isoq uinolin-1-one (96)
/o~QCX"' F
~N  [//
Br

0
 





63

9.66 g (39.9 mmol) of 7-Bbromo-6-ftuoro-2H-isoquinolin-1-one (95) 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 of 7.50 g (48.0 mmol) of 4-methoxy benzylchloride in 25 ml of dimethyl acetamide was added. The mixture was stirred at

room temperature untif complete conversion was achieved. The solvent was removed under reduced pressure, the residue was taken up in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layers were dried
with magnesium sulfate and evaporated to yield 16.8 g of a dark oil as crude product,

which was stirred in methanol. Fiffration of the precipitate gave 6.56 g of .the title

10    compound as a yellow solid. The mother liquor was evaporated and the residue purified by preparalive HPLC to yield additional2.62 g of the desired product. R1 = 1.71 min (Method C). Detected mass: 362.3/364.3 (M+H').

6-cis-(4-Amino-cyclohexyloxy)-7-bromo-2-(4-methoxy-benzyi)-2H-isoquinolin-1-15 one (97)
--'0'[7)   ('(YOY'l
~~~Br~NH2

0

135 mg (0.625 mmol) of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 2.5 ml of dimethyl acetamide and 30 mg (0.75 mmol} of sodium hydride (60%} were added. After stirring for 15 minutes at room temperature 181 mg (0.5

20    mmol} of 7-bromo-6-ftuoro-2-(4-methoxy-benzyl}-2H-isoquinolin-1-one (96} were added and stirring was continued. To achieve complete conversion, additional 30 mg
of sodium hydride (60%} were added after 3 h. After stirring overnight 2 ml of acetic acid followed by 2 ml of 2 N HCI were added and the mixture was stirred at 50 oc until the deprotection of the Boc-group was complete. The solvent was removed under

25    reduced pressure, the residue dissolved in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layers were dried with magnesium sulfate and evaporated. Final purification by preparative HPLC gave 83 mg of the product as triftuoroacetate. R1 = 1.31 min (Method B). Detected mass: 457.2/459.2 (M+H'}.

30
 





64

6-cis-(4-Amino-cyclohexyloxy)-7 -bromo-2H-isoquinolin-1-one (9(:.,.

H~:MNH,

0

62 mg (0.11 mmol) of6-(4-amino-cyclohexyloxy)-7-bromo-2-(4-methoxy-benzyi)-2H-

isoquinolin-1-one trifluoroacetate (97) were dissolved in 2 ml ofTFA and heated in a

5    microwave oven at 140 oc for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 2 N HCI and washed twice with dichloromethane. The combined organic layers were extracted with 2 N HCI and the combined aqueous solutions were evaporated. The residues were dissolved in water and freeze dried.
Final purification by preparative HPLC gave 8 mg of the desired product as

10    trifluoroacetate. Rt = 0.86 min (Method B). Detected mass: 337.1/339.1 (M+H').

-;;• 6-trans-(4-Amino-cyclohexyloxy)-7-bromo-2-(4-methoxy-benzyi)-2H-iso-quinolin• 1-one (99)
/o'Q{Y)o'"(),
"~sr    NH2

0

15    Starting with trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 7 -bromo-6-fluoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-one (96) the title compound was synthesized following the protocol described for 6-cis-(4-amino-cyclohexyloxy)-7• bromo•2•(4•methoxy-benzyi)•2H-isoquinolin-1-one(97). Rt = 1.34 min (Method B). Detected mass: 457.2/459.2 (M+W).

20

6-trans-(4-Amino-cyclohexyloxy)-7-bromo•2H-isoquinolin-1-one (100)
H(Y)0 '0
""~sr    NH2

0

Starting from 6-trans-(4-amino-cyclohexyloxy)-7-bromo-2-(4-methoxy-benzyi)-2H-iso-quinolin-1-one (99) the desired product was prepared by the methode described for 6-
 




65

cis-(4-amino-cyclohexyloxy)-7-bromo-2H-isoquinolin-1-one (98). The compound was isolated as trifluoroacetate. R, = 0.88 min (Method B). Detected mass: 337.1/339.1

(M+H').

5    7.Chloro-6-Huoro-2H-isoquinolin-1-one (101)

F

HN
Cl

0

Starting from 1 ,7-<lichloro-6-fiuoro-isoquinoline (6) the title compound was prepared following the protocol described for 7-bromo-6-fluoro-2H-isoquinolin-1-one (95). R, =

1.11 min (Method C). Detected mass: 198.2 (M+H').

10

7 .Chloro-6-fi uoro-2-(4-melhoxy-benzyi)-2H-isoquinolin-1-one (1 02)

I
OY)    r1("'~(F
~N~'c1

0

Starting from 7-chloro-6-fluoro-2H-isoquinolin-1-one (101) the title compound was prepared following the protocol described for 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-
15    2H-isoquinolin-1-one (96). R, = 1.66 min (Method C). Detected mass: 318.3 (M+H').








14.74 g (74.6 mmol) of7-chloro-6-fiuoro-2H-isoquinolin-1-one (101) were dissolved in

20    150 ml of toluene. After addition of 30.86 g (111.9 mmol) of silver carbonate and 15.31 g (89.5 mmol) of benzyl bromide, the mixture was stirred at 80 "C for 3 h. After cooling
 




66

down to room temperature, the reaction mixture was filtered and the fi   j:•;Jas•
evaporated. The residue was dissolved in dichloromethane and w E•:.....h water\.. , dried with magnesium sulfate and evaporated. Final purification b , parati~C

gave 11.63 g ofthe title compound. R1 ; 2.51 min (Method B). Del . , ass: 288.11290.1 (M+W).

General Procedure for the reaction of the arylchlorides 7 -chloro-6-fluoro-2-{4-

methoxy-benzyi)-2H-isoquinolin-1-one (102) and 1-benzyloxy-7-chloro-6-fluoro-

isoquinoline (103) with grignard reagents under Fe(acac)3 catalysis.

10    2 mmol of the respective arylchloride and 35.3 mg (0.1 mmol) ofiron(lll) acelylacetonate were dissolved in 24 ml of THF and 2 ml of NMP were added. At 0 'C

2.4    mmol of the grignard reagent were added via syringe under argon and the reaction !W.was stirred at 0 oc for 10 minutes. To achieve complete conversion, in some cases

another 0.6 mmol of the grignard reagent were added and stirring was continued for 10

15    minutes.

tn the case of the N-PMB-protected compounds, the reaction was quenched by pouring into 1M HCI. The 0-Benzyl protected analogs were quenched by pouring into saturated NH4CI-solution.
The mixture was evaporated and the residue was dissolved in dichloromethane and

20    washed with water. The organic layer was dried with Na2S04 and the solvent was removed under reduced pressure. Final pu~ification by prepara~ive HPLC gave the desired 7-alkylated derivatives.

According to this procedure the following products were obtained from the mentioned

25    arylchloride and Grignard reagent (Table 3)
 
 





68

6-cis-(4-Amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-propylj{(:;,;.oquinolin-1- {II one (109)





58 mg (0.38 mmol) of cis 4-aminocyclohexanol hydrochloride were dissolved in 10 ml

5    of dimethyl acetamide. Under argon, 38 mg (0.96 mmol) of sodium hydride (60%) were added and the reaction was stirred for 30 minutes at room temperature. After addition of a solution of 100 mg (0.31 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-propyi-2H-isoquinolin-1-one (105) the solution was stirred at 80 "C. To obtain complete

conversion. the same amounts of the 4-aminocyclhexanol hydrochloride and sodium

10    hydride were added twice and the temperature was increased to 110 °C. After complete conversion, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and evaporated. After purification by preparative HPLC the

desired product was isolated as trifluoroacetate. R, = 1.14 min (Method C). Detected 15 mass: 421.6 (M+H').

The following compounds were prepared as trifluoroacetates by the protocol described

for 6-cis-(4-Amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-propyi-2H-isoq uinolin-1-one

(109)(Table 4):

20
 



69

    Table 4                                                   
                                                                   
    Example        Arylfluoride    Product    [M+H']    Rtf[min)    Method   I   
                                                                   
                                                                   
    110                106            I    435.6    1.18    c       
                                                   
                                    'Q~'"•            I   
                                                       
                                                               
    111            107            I    421.6    1.13    c       
                                    OQ~DNH,            I   
                                    0                       
                                                               
    112            108                ~D NH,    389.5    1.22    c       
                                                           
                                                           
                                    oc0            I   
                                                                   
 






Oeprotection of the N-PMB-protected isoquinolinones 109, 1

The protected starting compounds were heated in TFA in a micr

until complete conversion was observed. Evaporation of the solven    ~J

preparative HPLC gave the desired deprotected products as trifluoroaceta e  .

5    were dissolved in 2 N HCI and evaporated. After dissolving the residue in water and lyophilization, the compounds were isolated as HCI-salts.

Deprotection of the 0-benzyl protected lsoquinolinone 112

4-(1-Benzyloxy-7-cyclopropyl-isoquinolin-ll-ylory)-cyctohexylamine (112) was stirred in

10    2 N HCI at room temperature until conversion is complete. After evaporation of the solvent under reduced pressure, the crude product was purified by preparative HPLC, which gave the desired product as trifluoroacetate. The product was dissolved in 2 N HCI and the solvent was removed under reduced pressure. After dissolving the residue in water and lyophilization, the product was isolated as HCI-salt.

15

After deprotecUon of the compounds 109 to 112, the following compounds were

isolated as HCI salts (Table 5):
 



                                            71                                                                               
    Tabla 5                                                                                                                           
                                                                                                                               
    Example    Starting    Product                        [M+H'j    R,l[min]        Method   
            compound                                                                                                                       
                                                                                                                   
                HN9=\'D0                                                                                               
    113        109                301.4                            0.89                        c   
                        NH2                                                                                           
                                                                                                                   
                HN9C\? NH,                                                                               
    114        110        315.4                            0.93                        c           
    I                                                                                                       
                                                                                                           
    115        111                                301.4                            0.86                        c           
                HN    I ~                                                                                                       
                M-DNH 2                                                                                           
                    0                                                                                                               
                                                                                                           
116        112                                299.4                            0.82                        c       
                HN                NH,                                                                                           
                ~D                                                                                               
                                                                                                                       
0
----    ---  - ••• --  --    -----    -    ------    -   ---    -    -    - - - - -   - - - - - .  - - -  - - -    - - - - - - -   ---
 





General procedure C for the reductive amination reaction:

62 mg (0.25 mmol) of6-frans-(4-amino-cyclohexyloxy)-7-chlor   "'E-~~ui;o~n..ite"tJ;i9
 

hydrochloride (14) were dissolved in 3 ml oftrimethoxy methan

corresponding aldehyde or ketone were added {dissolved in 0.2
.    .
 
\tl. 5 mmolof the   c•.w.

~ -~for as '?1.      ~ .,.

{~~--~.,.• .   -- ~t-ul-'"'
 
solid) followed by 46 mg (0.375 mmol) oftnethylamme. After 1 hat roilljj;iiill!dilifa~~ the solution was cooled to-10 oc and a solution of265 mg (1.25 mmol) of sodium triacetoxy borohydride in 1.5 ml DMF was added, followed by 73.5 mg (1.225 mmol) of

acetic acid. After 30 min at 0 "C, the solution was left at room temperature overnight. For workup, 0.5 ml of water were added and the solvent was removed under reduced

10    pressure. The residue was purified by-preparative HPLC. The obtained trifluoroacetates were dissolved in 1.0 ml of a 5-6 M HCI solution in isopropanol and left at room temperature overnight. After addition of 2.0 ml of water, the solutions were lyophilized yielding the desired products as HCI-salts.

15    The compounds listed in table 6 below were synthesized according to this method and obtained as HCI salt:
 

6-(cis-4-(Cyclopropylmethyl-amino )-cyclohexyloxy]-2H-isoquinolin-1-o ne (125)

N'yoYI
"'~ ~~

125 was obtained as hydrochloride using the previously described general method employing cyclopropane carbaldehyde and cis-6-(4-amino-cyclohexyloxy)-2H-isoquinolin-1-one (28) as starting materials. R1 = 1.04 miil (Method B). Detected mass: 313.2 (M+H').


7-Benzylsulfanyl-6-fluoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-one (126)
/0~  (l(YF
~N~s~
0    v

10    500 mg (1.38 mmol) of 7 -bromo-6-fluoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-one (96), 627.3 mg (1.52 mmol) oftributyltin benzylthiolate, 96.2 mg (1.66 mmol) of freshly dried potassium fluoride and 24.0 mg (0.041 mmol) of XANTPHOS were dissolved in 5 ml ofNMP and stirred for 15 min at room temperature. After addition of 19.0 mg (0.021 mmol) of Pd.,dba3, the reaction mixture was stirred at 100 °C. To achieve complete

15    conveision, another 0.01 mmol of Pd 2dba3 were added and stirring was continued at

100 •c. After 5 h the solution was cealed to room temperature, diluted with ethyl acetate (10 ml) and treated with 5% KF-solution. The mixture was stirred vigorously for
15 minutes and filtered. The filtrate was separated and the organic phase was washed twice with water and once with saturated sodium chloride solution. After drying with

20    magnesium sulfate, the organic layer was evaporated and the crude product was purified by preparative HPLC. R1 = 1.83 min (Method C). Detected mass: 406.5 (M+H').


25
 





76

6-{4-Amino-cis-cyclohexyloxy)-7-benzylsulfanyl-2-{4-methoxy-b~-2H-isO­

quinolin-1-one (127)
/oY')    (I(Yo'f'l
~~~S~NH
0    l~ 2
v

90 mg (0.59 mmol) of cis 4-amino-cyclohexanol hydrochloride were dissolved in 10 ml dimethyl acetamide and 59.3 mg (1.48 mmol) of sodium hydride (60%) were added.

After stirring 30 minutes at room temperature, a solution of 200 mg (0.49 mmol} of 7-

benzylsulfanyl-6-fluoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-one (126) in 20 ml of dimethyl acetamide was added and the mixture was stirred at 80 oc for 1h, then at 130

"C for 3 h. Another 1.2 equivalents of cis 4-amino-cyclohexanol hydrochloride and 2.5 10 equivalents of sodium hydride were added and the temperature was increased to 160
~r oc. After 8h the solution is cooled down to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water and dried with magnesium sulfate. After evaporation of the solvent and purification by preparative HPLC, the title compound was isolated as

15    trifluoroacetate, R, = 1.18 min (Method C). Detected mass: 501.6 (M+H)

N-{4-[7 -Benzylsulfanyl-2-(4-methoxy-benzyl)-1-oxo-1,2-<lihydro-isoquino lin-6-yloxy]-cis-cyclohexyl}-acetamide (128)





20    45 mg (0.073 mmol) of 6-(4-amino-cis-<:yclohexyloxy)-7-benzylsulfany~2-(4-methoxy­

benzyi)-2H-iso-quinolin-1-one (127) were dissolved in 5 ml of dichloromethane and 14.8 mg (0.146 mmol) of triethylamine were added. At 0 oc, 6.9 mg (0.088 mmol) of

acetylchloride were added and the solution was stirred at room temperature. After 2h, dichloromethane was added and the solution was washed with 2 N HCI and saturated
 




77

sodium bicarbonate solution. After drying with magnesium sulfate and evaporation of the solvent, the title compound was isolated as crude product, which was used without
further purification. R1 = 1.53 min (Method C). Detected mass: 543.6 (M+H•).

5    6-{4-Acetylamino-cis-<:yclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-7-sulfonyl chloride (129)
/oQr\;:U~
~~f .... cl      ~
0    0

37 mg of N-{4-[7 -benzylsulfanyl-2-(4-methoxy-benzyl)-1-oxo-1 ,2-dihydro-isoquinolin-6-yloxy]-<:yclohexyl}-acetamide (128, crude product) were dissolved in 5 ml of

10    dichloroinethane. At 0 oc, 16.4 mg (0.273 mmol) of acetic add, 4.9 mg (0.273 mmol) of water and 273 ~I (0.273 mmol) of sulfuryl chloride (1 Min dichloromethane) were added. After 30 minutes, ethyl acetate was added and the solution was washed with

sodium bicarbonate solution (2%), water and saturated sodium chloride solution. The organic layer was dried with Na2S04 and evaporated. The so obtained crude product
15    was used without further purification. Rt = 1.55 min (Method C). Detected mass: 553.5 (M+H•).

N-{4-(4-Chloro-2-{4-methoxy-benzyl)-1-oxo-7-sulfamoyl-1,2-dihydro-isoquinolin-6-ylo><y]-cis-cyclohexyl}-acetam ide (130)
/OQr\;:UJt
~~p'NH ~
 

20
 
0    0    2
 

To a solution of 29 mg of 6-(4-acetylamino-cis-<:yclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1 ,2-dihydro-isoquinoline-7-sulfonyl chloride (129, crude product) in 2 ml

of THF 2 ml of 33% aqueous ammonia solution were added. After 1h at room temperature the solvent was removed under reduced pressure and the crude product
 





78

was used without further purification. R1 = 1.22 min (Method C). ~fua;;s: 534.5

(M+H•).

6-(4-Amino-cis-cyclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1,2::Uillf&ib-

isoquinoline-7 -sulfonic acid amide (131)

/oQ?Y;:nNH~~t'NH2

0    0    ,

32 mg of N-{4-[4-chloro-2-(4-methoxy-benzyl)-1-oxo-7-sulfamoyl-1 ,2-dihydro-isoquinolin-6-yloxy]-cis-cyclohexyl}-acetamide (130, crude product) were dissolved in 5 ml of ethanol and 15 ml of 2 N HCI and heated for 2 hat 90 oc. The solvent was

:;. removed under reduced pressure and the residue was dissolved in 6 N HCI and

10 l'heating at 90 oc was continued for 20h. After cooling down to room temperature, the aqueous solution was evaporated and the title compound was isolated as HCI-salt
ll (crude product). R1 = 1.00 min (Method C). Detected mass: 492.5 (M+H+).

6-{4-Amino-cis-cyclohexyloxy)-4-chloro-1-oxo-1 ,2-dihydro-isoqu inoline-7-.. 15 sulfonic acid amide (132)




Crude131 was dissolved in 15 ml of trifluoroacetic acid and heated for 3 h at 140 oc

under microwave conditions. After evaporation of the solvent, the crude product was

purified by preparative HPLC, which delivers the title compound as trifluoroacetate  R1

20    = 0.90 min (Method B). Detected mass: 372.3 (M+H•).
 





79

1-Benzyloxy-7-chloro-{;-(1 ,4-<lioxa-spiro[4.5]dec-B-yloxy)-isoquinoline (133)






1.26 g ( 8.34 mmol) of dioxa-spiro[4.5]decan-8-ol were dissolved in 50 ml of dimethyl acetamide and 695.2 mg (17.4 mmol) of sodium hydride (60%) were added. After stirring 30 minutes at room temperature a solution of 2.0 g (6.95 mmol) of 1-benzyloxy-7-chloro-6-fluoro-isoquinoline (103) in 50 ml of dimethyl acetamide was added and

stirring was continued at room temperature. After 1 h the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sutfate and evaporated, which

1o gave 3.30 g of the crude product, which was used without further purification. R, ; 2.05 min (Method C). Detected mass: 426.5 (M+W).
7-Chloro-{;-{4-oxo-cyclohexyloxy)-2H-isoquinolin0-1-one (134)
HrTIY D
•~CI    0

0

15    3.30 g of 1-benzyloxy-7 -chloro-6-(1 ,4-dioxa-spiro[4.5]dec-B-yloxy)-isoquinoline (133, crude product) were stirred in 30 ml of 6 N HCUacetone (1 :2) at room temperature.
After 3 h the reaction mixture was poured on saturated sodium bicarbonate solution

and extracted with dichloromethane. The organic layer was dried with magnesium

sulfate and evaporated. The crude product was purified by preparative HPLC. R, ;

20    1.34 min (Method B). Detected mass: 2g2.0 (M+W).

Starting from 7-chloro-6-(4-oxo-cyclohexyloxy)-2H-isoquinolin-1-one (134), the following compounds were synthesized as hydrochlorides in analogy to the general procedure B for the reductive amination reactions (Table 7):
 



80

Table 7

Example        Amine        Product                        Remark    [M+H']    R,l[min]    Me tho       
                                                                               
135        I        ~oD                    cis~ and trans isomers    321.1        0.99    B       
            HN--...            ••w"'"    separated by prep. HPLC;                           
                            HN  o    Cl                                   
                                            I    cis-isomer obtained in                           
                                                        approx. 80% purity.                           
                                                                               
                                                                                   
136        I        HN~oDCl                cis- and trans isomers    321.1        0.92    B       
            HN--...            N/    separated by prep. HPLC;                           
                                o            I    cis-isomer obtained in                           
                                                        approx. 85% purity.    ----                   
                                                                               
                                                                               
 





6-{trans-4-Amino-cyclohexyloxy)-7 -methyi-2H-isoquinolin-1-one (137)
H(Yt)'o .. Q
'~    NH2

0

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

5

To a solution of 10.0 g (55.5 mmol) of3-ftuoro-4-methyl-cinnamic acid in 80 ml of acetone were subsequently added at 0 'C6 .74 g (66.6 mmol) of triethylamine in 10 ml of acetone followed by 7.83 g (72.2 mmol) of ethyl chloroform ate. After stirring for 2 h at 0 to 5 'Ca solution of4.0 g (61.1 mmol) of sodium azide in 9.5 ml of water was

10    added. After stirring for 1 additional h the reaction mixture was poured onto 200 rnl of ice water and extraced twice with chloroform. The organic phase was dried over magnesium sulfate, 40 ml diphenylether were added and the chloroform was

cautiousfy 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

15    stirred further for 1 h at 230- 250 'C.After cooling down to 150'Cthe reaction mixture was poured into 270 m1 of heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 4.1 g 6-ftuoro-7 -methyi-2H-isoquinolin-
1-one were obtained.

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

To a solution of 9.17 g (51.8 mmol) of 6-ftuoro-7-methyi-2H-isoquinolin-1-one in 80 ml of OMF were added 20.2 g (62.1 mmol) of cesium carbonate and then 8.92 g (56.9 rnmol) of 4-methoxybenzylchloride. After stirring at room temperature for 90 minutes

25    the reaction mixture was poured into 600 ml of water, stirred for 1 h, and then the precipitated product was isolated by suction. From the mother liquor additional pruducted was isolated by chromatography with heptane I ethyl acetate (80:20). The combined products were recrystallized from ethyl acetate and 8.39 g 6-ftuoro-2-(4-methoxy-benz:y!)-7 -methyi-2H-isoquinolln-1 ~one were received.
 




82

/./'
c) 6-(trans-4-Amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-metW~:~iSbquinolin-1-one

To a solution of 1.48 g (9.75 mmol) oftrans-4-aminocyclohexanol hy~i!f:l!j ml of dimethylacetamide where added 1.95 g (48.77 mmol) of sodium hydride (60% and the mixture was stirred for 15 minutes. Subsequently 2.90 g (9.75 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyi-2H-isoquinolin-1-one in 30 ml of
dimethylacetamide were added and the reaction mixture was heated to BO"C for 2 days. After cooling the mixture was poured into 300 ml of ice water and the
10    precipitated crude product was purified by chromatography, First the remaining starting material was eluted whfth ethyl acetate I heptane (2:1) und finally the desired product was eluted by pure methanol giving 1.98 g 6-(trans-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7 -methyi-2H-isoquinolin-1-one.

15    d) 6-(trans-4-Amino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-one hydrochloride

2.64 g (6.7 mmol) of 6-(trans-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7 -methyi-2H-isoquinolin-1-one and 15,3 g (134,5 mmol) of trtfluoroacetic acid were heated for 2

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

20    in vacuo and the residue was diluted with 130 ml of 1 M hydrochlorid acid. The aqueous phase was washed with methylene chloride 3 times and then it was freeze dried t6 give a hydrochloride, which was recrystallized from isopropanol. This furnished

1 _1 g 6-(trans-4-amino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-one (137) as hydrochloride. R1 ; 0.92 min (Method B). Detected mass: 27322 (M+W),

25




CIH

a) cis-4-Aminocyclohexanol hydrochloride
 




83

To a solution of 30.0 9 (0.265 mol) of cyclohexanone oxime in 300 ml of methylene chloride and 38 ml of ethanol was slowly added at 0 'C34.5 g (0.318 mol) oftert-buty\-hypochlorite. The resulting dark blue solution was cooled to -20'Cand then 31.9 g (0.398 mol) of 1,3-cyclohexadiene were added and the mixture was stored in a

5    freezer at S'Cfor 2 days until the blue color had disappeared. The reaction mixture was concentrated to 50% of its volume and then 600 ml of diethyl ether were slowly added. After stirring overnight the resulting precipitate was isolated by suction to yield

29,0 g of 2-ma-3-aza-bicyclo[2.2.2]oct-5-<:ne hydrochloride. 5.0 g (0.045 mol) of this •

material were hydrogenated with 3.0 g (0.013 mol) platinum oxide at 2 bar hydrogen

10    pressure. After 7 h the catalyst was filtered off and a solution of 20 ml 4 M hydrochloric acid in dioxane was added. After evaporation the residue was recrystallized from 30 ml isopropanol giving 3.1 9 of cis-4-aminocyc\ohexanof hydrochloride.

b) 6-( cis-4-Aminocyclohexyloxy)-7 -methyf-2H-isoquinolin-1-one hydrochloride

15

From 2.55 g (16.8 mmol) of cis-4-aminocyclohexanol hydrochloride and 5.0 g (16.8 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methy\-2H-isoquinolin-1-one (137, step b) were prepared 0.98 g of 6-(cis-4-amino-cyclohexy\oxy)-7-methyl-2H-isoquinolin-1-<me hydrochloride as described in example 137 steps c and d.

20    R1 ~ 0.99 min (Method B). Detected mass: 273.18 (M+H•).

6-(cis-4-Ethylamino-cyc\ohexy\oxy)-7 -methyl-2H-isoquinolin-1-one (139)
HNW OM /'...
CH3    H    CH3

0

25    0.2 g (0.65 mmol) of 6-(cis-4-amino-cyclohexyloxy)-7-methy\-2H-isoquinolin-1-one hydrochloride (138), 69 mg (0.68 mmol) of triethylamine and 35 mg (0. 78 mmol) of acetaldehyde were stirred in 13 ml of dry methanol for 4 h at S'C.After addition of 37 mg (0.97 mol) of sodium borohydride the mixture was stirred overnight at room temperature. Since incomplete conversion of the starting amine was observed the
 





B4

same amounts of actetaldehyde and sodium borohydride were ad

sequentially within 2 h. After further stirring for 2 hours the reaction

acidified with concentrated hydrochloric acid and the methanol was ev

aqueous residue was washed with ethyl acetate and then saturated with potassium

carbonate and extracted whith methylene chloride to give 145 mg of 6-(cis-4-ethylamino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-one (139). R, = 0.89 min (Method A). Detected mass: 301.20 (M+H}.

6-(cis-4-lsobutylamino-cyclohexyloxy),7-methyi-2H-isoquinolin-1-one (140)



10

From 0.2 (0.65 mmol) of 6-(cis-4-amino-cyclohexyfoxy)-7-methyi-2H-isoquinolin-1-one hydrochloride (138) and isobutyraldehyde were obtained analogous to example 139
'i 51 mg of 6-(4-isobutylamino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-one. R, = 1.10

15    min (Method A). Detected mass: 329.20 (M•H•).

Analogous to examples 139 and 140 the following compounds were prepared from the respective amines and aldehyde (Table 8).
 


6-(cis-4-Diethylamino-cy~(;"~H-isoquinolin-1-one (146)

HN~~N~
0    l__

A reaction mixture consisting of 150 mg (0.49 mmol) 6-(cis-4-amino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-one hydrochloride (example 138), 38 mg (0.63 mmol) of acetic acid, 43 mg (0.97 mmol) of acetaldehyde, molecular sieves and 515 mg (2.4 mmol) of sodium triacetoxy borohydride in 5 ml of methylene chloride was stirred overnight. The reaction mixture was added to 10 ml of 1 M sodium hydroxide solution and extracted twice with a mixture of methylene chloride and isopropanol. After drying and evaporation 122 mg of 6-(cis-4-diethylamino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-

10    one (146) were obtained. R, = 0.99 min (Method B). Detected mass: 329.17 (M+W).

6-(cis-4-lsopropylamino-~~~-2H-isoquinolin-1-one (147)

HN~ ~~~

0

Analogous to example 146 121 mg of 6-(cis-4-isopropylamino-cyclohexyloxy)-7-

15    methyi-2H-isoquinolin-1-one (147) were obtained from 150 mg (0.49 mmol) of 6-(cis-4-amino-cyclohexyloxy)-7-methyi-2H-isoquinolin-1-one hydrochloride (138) by reaction with acetone. R, = 1.07 min (Method B). Detected mass: 315.13 (M+W).

2,2,2-Trilluoro-N-(trans-4-hydroxy-cyclchexyl)-acetamide (148)
 



20
 
HOD ... ~ykFO
 

25 g of trans-4-aminocyclohexanol hydrochloride were suspended in 250 ml of dry dioxane and 30 mL of sodium methylate solution (30% in methanol, 1 equivalent) were added. 39.3 ml of ethyltrifluoroacetate were added and the reaction mixture was
allowed to stir until the reaction was complete. The reaction mixture was evaporated,
 





88

taken up in 50 ml of 0.1 N HCI and extracted several times

dichloromethane:isopropanol3:1. The combined organic layer

0.1 N HCI and brine, dried over sodium sulfate and evaporated to dryness o y1e g of 148. R, = 0.69 min (Method C). Detected mass: 212.2 (M+W}.

5

2,2,2-Trifluoro-N-(4-hydroxy-cyclohexyi}-N-methyl-acetamide (149)
'-. 1
6 /F
I'

OH

5 g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyl}-acetamide (148} were dissolved in 25 ml of dimethyl acetamide, 625 mg of 95% sodium hydride were added and the
10    reaction mixture was cooled to 0°C. 1.64 ml of iodomethane were added slowly and the reaction mixture was allowed to warm to room temperature. Upon completion, the reaction mixture was poured into water, extracted three times with methyl tert. butyl ether and the combined organic layer was extracted once with brine, dried over sodium
sulfate and evaporated to dryness. The residue was taken up in water and lyophilized

15    to remove remainders of dimethyl acetamide to yield 4.0 g of product. R, = 0.95 min (Method C). Detected mass: 226.2 (M+W}.

trans-4-Methylamino-.:yclohexanol (150)

I
NH

,..()   CIH
HO'

20    2g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyi}-N-methyl-acetamide (149} were suspended in 10 ml of 1N HCI and heated in a microwave at 150° until conversion was complete. The resulting solution was lyophilized and the residue was taken up in
 





89

water and lyophilized again, twice to yield 1.45 g of 4-methylamino-cyclohexanol (150).

R, ;0.13 min (Method C). Detected mass: 130.3 (M+H•).

2•(trans-4-Methoxy-benzyl)•6-(4•methylamino-cyclohexyloxy)-2H-isoquinolin•1• 5 one (151)






630 mg of sodium hydride (95%) were suspended in 40 ml of dimethyl acetamide.. 1 .45 g of 4-methylamino-cyclohexanol (150), dissolved in 40 ml of dimethyl acetamide, were added dropwise and 15 min. later 2.48 g of 6-fluoro-2-(4-methoxy-

10    benzyi)-2H-isoquinolin-1-one (177), dissolved in another 40 ml of dimethyl acetamide, were added. The reaction mixture was stirred at 80 oc until the reaction was complete.

The mixture was poured into an lee-water mixture, extracted three times with methy!-tert.-butyl ether and the combined organic layer was dried over sodium sulfate and

evaporated. Water was added and the crude product was subjected to lyophilization to

15    remove r.emainders of dimethyl acetamide.

The obtained product is sufficiently pure for further conversion. R, = 1.24 min (Method B), detected mass: 393.2 (M+W).

6•(trans-4-Methylamino-cyclohexyloxy)-2H•isoquinolin•1-one(152)
HrnJO.,,,Cl

~~    NH
 

20
 
o    I
 

2.46    g of 2-(4-methoxy-benzy1)•6•(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one

(151)    were dissolved in 15 ml ofTFA and heated in a microwave oven at 150 'Cfor 2

h. Methanol was added and the reaction mixture was evaporated. The solution was 25 taken up in 1N HCI and extracted three times with dichloromethane. The combined
 




90

dichloromethane layers were extracted with 1N HCI twice and were lyophilized, the residue was taken up in water and !yo
g of 6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (1

= 0.81 min (Method B). Detected mass: 273.2 (M+H').

5

The following two products were obtained as hydrochlorides by the same reaction sequence described for the synthesis of 152, using appropriate alkyl halides tor the alkylation of 148.

10    6-(trans-4-Ethylamino-cyclohexyloxy)-2H-isoquinolin-1-one (153)




A1 = 0.85 min (Method B). Detected mass: 287.1 (M+H').

6-(trans-4-lsopropylamino-cyclohexyloxy)-2H-isoquinolin-1-one  (154)
H(Y}o.... Q
•~  LY

15

A1 = 1.16 min (Method B). Detected mass: 315.2 (M+H').
 






General procedure D tor the reductive ami nation reaction:

250 mg of 153 (or of another monosubstituted isoquinolonone-amine) are dissolved in

8 mL of dichloromethane and 6 mL of DMF. 3 eq. of aldehyde, 1.3 eq. of acetic acid,

5    300 mg of molecular sieves and 3 eq. of sodium triacetoxy borohydride are added. The reaction mixture is stirred for 16 h at 55 oc. The mixture is poured into 5 mL of 1N

NaOH and 25 mL of dichloromethane and 10 mL of isopropanol are added. The

organic layer is separated and the aqueous layer is extracted three times with

isopropanol:dichloromethane 1 :3. The combined organic layer is evaporated to 1o dryness and the residue is pulified by HPLC and eventually converted into the

corresponding HCI salts by addition of 2N HCI and subsequent lyophilizaiion.

The following compounds were prepared according to this procedure and obtained as

free base or hydrochlorides (Table 9)

15
 



92

Table 9

Example    lsoquinolinone    Aldehyde    Product                    [M+H']    R1/[min]        Method   
155        152        dH    r?CJo .. Q            363.2        1.14        A           
                    HN    0    ~    HCI    ~    ~                                   
                                        I ~                                   
                                                                           
156    152        0        HN~0.(~ N~    315.2        1.02        D           
                JH                                       
                            0        HCI        I                                   
                                                                               
                                                                               
157        152        0        HWO.. '()_N    329.2            1.05        D       
                YH                                       
                        0        HCI        ,I                                   
                                                           
158        152        0        Hyuo•..o.NV    327.2        1.00        D   
                                                           
                ~H        o            I                        ~           
                                                                       
                                                                       
 



93

Example    lsoquinolinone        Aldehyde    Product                        [M+Hj  '•    R1/[min]    Method   
159    154    0            HWo.. ClN=n        405.1    1.25        A   
                ~H    0    yl //                                   
160    154            dH        HycrO (),N:o        439.3    1.51        A   
                                               
            Cl    0    y~ Cl                                   
                                                                   
                                                                               
161    154    0            ,W'0,:c                                       
                                406. 2    1.08        A   
                                                           
                                                                       
                N~H                y    _.eN                                       
                    0                                               
162    154    0                    HQUO"Q            357.2    1.10        B   
                JH                                                       
                            0    9                                           
 
















I
I
 



94

    Example    lsoquinolinone    Aldehyde        Product                [M+H']    R1/[min]    Method       
                                                                   
    163    154    0            HNy::to_ N~        371.2            1.15    B       
                                                       
                                                       
                YH                                       
                                                       
                        0    y                               
                                                           
                                                           
    164    154    dH    HWOO.N:o        406.3            0.94    A   
                                        I   
                                        I   
                                               
                N        0    y~                               
                                                           
                                                           
                                                               
                                                       
165    154    CF~HJ0        HQ)'o'Q        425,2            1.26    B       
                            0    ~CF,                               
                                                                   
                                                               
166    152    dH        HNlpo.. Q N~        397.1            1.21    E       
                                            I   
                                               
            Cl--"        ~, .. ,    I   I ""  Cl            /;            '       
                                                       
                                                               
                            ''.  '"":~~ : ~~~:,.                                       
                                                                   
                                                        •'           
 



95

Example   lsoquinolinone   Aldehyde    Product    [M+H']    R,t[min]   Method

167    152    0            H~O••o_NV 364.2    0.77        E   
            ~H    0        I    I ""'                           
                                                       
                N                                                               
                                                                                   
    168    154    0            H~O•,o.N    369.1        1.10            B   
            ~H                                                       
                        0        Yv                           
                                                           
    169    152    0                        343.2        1.20        B   
            ~H HN~o.,Q N~                           
                                       
                        0    HCI    I                                           
    170    152    0            Hycro.QN~    397.2    1.16        B   
            cCH    0        I    I ""'                           
                                                       
                    Cl                                                               
                                                           
                                Hycro••n                                           
171    152    0                383.1        1.09        B   
                                           
            CF~H            o        N~CF                           
            '                        I    '                                   
            -        --    -                                               
                                                                           
 



96

Example   lsoquinolinone   Aldehyde    Product    [M+H']    RJ[mln]   Method

172    152                        H~o.O.NU 364.1    0.73            B   
            c!H        0        I   I    ..<N                       
            N                                           
                                                       
                                                       
173    152    0        H~O••o.    369.2    1.21            B   
            ci'H    0    HCI    7~                       
                                                               
                                                                   
174    153    0                        357.2    1.18            B   
            ~H HNwo... Q N~                       
                                   
                                   
                                0        l__                           
                                HNwo .. Q                               
175    153        CF~H30            ~    397.1    1.14            B   
                                0    ,    ~    CF3            ~       
                                                    ~           
                                                               
                                                    "       
 




97

6-Ffuoro-isoquinolinone (176)

FUQH

0

4.8 ml (90.3 mmol, 1.5 eq.) ofthionyl chloride was added portionwise to a solution of 10 g (60.2 mmol) of 3-ftuoro cinnamic acid in 44 ml of chloroform 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 raw acid chloride, which was used Without any further purifcation.

The acid chloride was dissolved in 45 ml of acetone. At 0 oc 8.03 9 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 oc. The reaction was stirred for another 1.5 h. Then 55 ml of chloroform were added. The mixture was extracted with 80 mL of water followed by 40 mL of brine. After drying over Na2S04 and filtration 14 mL of diphenyl ether were added and most of the chloroform was removed in vacuo (without heating). A total removal of the chloroform should be avoided.

15

The solution containing the azide, diphenyl ether and the remaining chloroform was

added dropwise at 260 oc within 15 minutes to a solution of 10 mL of tributyl 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 oc. 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 9 of the title compound. MS (DCI) Detected mass:
164.0    (M+H").

6-Fiuoro-2-(4-methoxy-benzyi)-2H-isoquinolin-1-one (177)

I
OY'!J    f"'](yF

~N~

25    0   
       
 




98

169 ~L of p-methoxybenzylchloride (1.24 mmol, 1.1 eq) were -----~r••-r--c

200 mg of 6-fluoro-isoquinolinone (176) (1.13 mmol) and 368 mg of mmol, 1.2 eq) in 3 ml of DMF. The mixture was stirred for 2 h and The precipitate was filtered, washed with water and dried to yield 300

5    compound. LCMS Method 8, retention time 1.76 min, detected mass 284.14 [M+Hr

4-Ethyl-6,7-difluoro-2H-isoquinolin-1-one (178)

F~

FAJly~H

0

4-iithyl-6, 7-difiuoro-2H-isoquinolin-1-one (178) was obtained by the same method 10 .•describedfor the synthesis of 176, using (3,4-difluoro-phenyl)-pent-2-

enoic acid as a starting material. Rt = 1.46 min (Method B). Detected mass: 210.1 ;(fii+H').The used acrylic acid was synthesized from the corresponding aldehyde in similar fashion as described in the literature (see for instance: J. Med. Chern. 2005, 48, 71-90).

15

6-{trans-4-Amino-<:yclohexyloxy)-4-<>lhyl-7 -fluoro-2H-isoquinolin-1-one ( 179)






6-( 4-Amino-cyclohexyloxy)-4-ethyl-7 -fluoro-2H-isoquinolin-1-one (179) was

synthesized as hydrochloride by a similar reaction sequence as described for the

20    conversion 137 (steps b, c and d), using 178 as the starting material. R1 = 0.97 min (Method B). Detected mass: 305.2 (M+H').
 


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