[go: up one dir, main page]

HK1140201B - Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase - Google Patents

Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase Download PDF

Info

Publication number
HK1140201B
HK1140201B HK10106348.4A HK10106348A HK1140201B HK 1140201 B HK1140201 B HK 1140201B HK 10106348 A HK10106348 A HK 10106348A HK 1140201 B HK1140201 B HK 1140201B
Authority
HK
Hong Kong
Prior art keywords
alkyl
alkylene
group
halogen
aryl
Prior art date
Application number
HK10106348.4A
Other languages
Chinese (zh)
Other versions
HK1140201A1 (en
Inventor
Oliver Plettenburg
Armin Hofmeister
Joachim Brendel
Matthias LÖHN
Original Assignee
塞诺菲-安万特股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 塞诺菲-安万特股份有限公司 filed Critical 塞诺菲-安万特股份有限公司
Priority claimed from PCT/EP2007/011163 external-priority patent/WO2008077550A1/en
Publication of HK1140201A1 publication Critical patent/HK1140201A1/en
Publication of HK1140201B publication Critical patent/HK1140201B/en

Links

Description

Substituted isoquinoline and isoquinolinone derivatives as Rho-kinase inhibitors
The present invention relates to novel isoquinoline and isoquinolinone derivatives as claimed in the claims, their preparation and their use in the treatment and/or prevention of diseases associated with Rho-kinase inhibition and/or Rho-kinase mediated inhibition of myosin light chain phosphatase phosphorylation.
Small GTPase RhoA is activated by agonist stimulation, resulting in the conversion of RhoA from an inactive GDP-bound form to an active GTP-bound form, which subsequently binds to and activates Rho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known. Rho-kinase 2 is expressed in vascular smooth muscle cells and endothelial cells. Rho-kinase 2 activation by active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells by phosphorylation-mediated inhibition of myosin light chain phosphatase activity and upregulation of light chain activity regulated by myosin accordingly (Uehata et al, Nature 1997, 389, 990-994).
Rho-kinase is known to be involved in vasoconstriction, including the development of myogenic tension and smooth muscle over-contraction (Gokina et al, J.Appl.physiol.2005, 98, 1940-8), bronchial smooth muscle contraction (Yoshii et al, am.J.Resp.cell mol.biol.20, 1190-1200), asthma (Setoguchi et al, Br J Pharmacol.2001, 132, 111-8; Nakahara et al, Eur J2000, 389, 103) and chronic obstructive pulmonary disease (COPD, Maruoka, Nippon Rinsho, 1999, 57, 1982-7), hypertension, pulmonary hypertension (Fukukoto et al, Heart, 91, 391-2, 2005, Mukai et al, Nature, 389, 990-4) and ocular hypertension and intraocular pressure regulation (Hongjo et al, Scihot Ophal.42, Eur. 2002, Massach.144, Maskol.247, Maskoshii et al, Skoshikok et al, Skooho et al, Maskok et al, 2000, 103), and Maskoshikola officinalis et al, Skoshikok et al, Skooho et al, Kokooho, Kokohlo, Kokooho, Renal diseases include Hypertension-induced, non-Hypertension-induced and diabetic nephropathy, renal failure and Peripheral Arterial Occlusive Disease (PAOD) (Wakino et al, Drug News Perscope.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 Cell physiol.2006, 290, C661-8, Kishi et al, circle 2005, 111, 2741-2747), coronary heart disease, atherosclerosis, restenosis (Pacaud et al, Arch. major. Diabetes 2005, 98, 254, Rett 249, Reitt et al, Diabetes mellitus 2000, Diabetes mellitus 466, Diabetes mellitus syndrome, Diabetes mellitus 466, Diabetes mellitus, 49, 2178, Maeda et al, Cell metab.2005, 2, 119-29), sexual dysfunction, e.g. penile erectile dysfunction (Chitaley et al, Nature Medicine2001, 7, 119-122), retinopathy, inflammation, immune diseases, AIDS, osteoporosis, endocrine dysfunction, e.g. hyperaldosteronism, central nervous system disorders such as neuronal degeneration and spinal cord injury (Hara et al, Nature 1997, 389, 990; satoh et al, Life Sci.2001, 69, 1441-53; hitomi et al, Life Sci 2000, 67, 1929; yamamoto et al, J Cardiovasc Pharmacol.2000, 35, 203-11), cerebral vasospasm (Sato et al, Circ Res 2000, 87, 195; kim et al neurosurgey 2000, 46, 440), pain, e.g. neuropathic pain (Tatsumi et al Neuroscience 2005, 131, 491; inoue et al, Nature Medicine 2004, 10, 712), bacterial infections of the digestive tract (WO98/06433), carcinogenesis and progression, neoplasia in which Rho kinase inhibition has been shown to inhibit tumor cell growth and metastasis (Itoh 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 J2000, 348, 273), vascular smooth muscle cell proliferation and motility (Tammy et al, circ. res.1999, 84, 1186-1193; tangkijvanch et al, Atherosclerosis 2001, 155, 321-; yamashiro et al, j.cell biol.2000, 150, 797-; bauer et al, Blood 1999, 94, 1665-; retzer et al, CellSignal 2000, 12, 645) and leukocyte recruitment (Kawaguchi et al, Eur J pharmacol.2000, 403: 203-8; Sanchez-Madrid et al, J Immunol.2003, 171: 1023-34, Sanchez-Madrid et al, J Immunol.2002, 168: 400-10) and bone resorption (chelliaah et al, J Biol chem.2003, 278: 29086-97). Activation of the Na/H exchange transport system (Kawaguchi et al, Eur J Pharmacol.2000, 403: 203-8), Alzheimer's disease (Zhou et al, Science 2003, 302, 1215-.
Thus, compounds having inhibitory effects on Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase may be useful in the treatment and/or prevention of cardiovascular and non-cardiovascular diseases involving Rho-kinase as the primary or secondary cause, such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, peripheral circulation disorders, Peripheral Arterial Occlusive Disease (PAOD), coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic disease, ischemic organ failure (terminal organ damage), fibrotic lung, fibrotic liver, liver failure, kidney diseases including hypertension-induced, non-hypertension-induced and diabetic nephropathy, renal failure, fibrotic kidney, glomerulosclerosis, organ hypertrophy, asthma, Chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome, thrombotic disorders, diseases, Stroke, cerebral vasospasm, cerebral ischemia, pain such as neuropathic pain, neuronal degeneration, spinal cord injury, alzheimer's disease, premature labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone diseases such as osteoporosis, bacterial infections of the digestive tract, sepsis, cancer development and progression such as cancer of the breast, colon, prostate, ovary, brain and lung and metastases thereof.
WO 01/64238 describes optional coatings useful as neuroprotective agents
-(CH2)1-6-O-(CH2)0-6-、-(CH2)0-6-S-(CH2)0-6-or- (CH)2)0-6-a linked heterocyclyl substituted isoquinoline-5-sulfonamide derivative.
WO 2004/106325(Schering AG) describes prodrugs of the Rho-kinase inhibitor fasudil carrying an ether or ester group at position 1 of the isoquinoline ring.
WO 2001/039726 generally describes-O- (C) s useful for the treatment of microbial infections0-C10) Alkyl-heteroaryl substituted cyclohexyl derivatives.
JP 10087629a describes isoquinoline derivatives useful for the treatment of diseases caused by helicobacter pylori (Heliobacter pylori), such as gastritis cancer or ulcer. The isoquinoline derivative may be substituted at the 1-position by OH, preferably by X- [ (C)1-C6) Alkylene radical)]0-1-Y5-wherein X may be oxygen and Y may be aryl or heterocyclyl.
Hagihara et al (bioorg.Med.chem.1999, 7, 2647-2666) disclose 6-benzyloxy-isoquinoline for the treatment of infections caused by H.pylori.
US 5,480,883 discloses in general compounds of formula "Ar I-X-Ar II" useful as EGF and/or PDGF receptor inhibitors for inhibiting cell proliferation, wherein X may be (CHR)1)m-Z-(CHR1)nE.g. Z-CH2Wherein Z may be O, R1Is hydrogen or alkyl, ArI may especially be an optionally substituted isoquinolinone, Ar II may especially be an optionally substituted C3-7Monocyclic saturated heterocyclic ring systems.
WO 2005/030791(Merck &Co.) generally discloses isoquinolinone derivatives, optionally substituted at the 6-position by a group (CR), as potassium channel inhibitors, for the treatment of cardiac arrhythmias, stroke, congestive heart failure and the likeeRf)pOR43Substituted, where p may be zero, and R43Is, for example, optionally substituted by NR51R52Substituted (C)3-C10) Cycloalkyl, wherein R51And R52Can be hydrogen, (C)1-C6) Alkyl, etc.; or R43Is a group R81Defined as a 4-6 membered unsaturated or saturated monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms; and is substituted in the 4-position with a directly bonded optionally substituted aryl or heteroaryl group.
WO 2005/030130(Merck &Co.) discloses broadly as potassium channel inhibitors,Isoquinolinone derivatives, which may be substituted in position 1 with hydroxy and optionally in position 6 with a group (CR), for use in the treatment of cardiac arrhythmias, stroke, congestive heart failure, etceRf)pOR43Substituted, where p may be zero, and R43Is, for example, optionally substituted by NR51R52Substituted (C)3-C10) Cycloalkyl, wherein R51And R52Can be hydrogen, (C)1-C6) Alkyl, etc.; or R43Is a group R81Defined as a 4-6 membered unsaturated or saturated monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms; and is substituted in the 4-position with a directly bonded optionally substituted aryl or heteroaryl group.
WO 03/053330(Ube) describes in general isoquinolinone derivatives of the formula as Rho-kinase inhibitors.
WO 00/24718(Akzo) describes, inter alia, 1-amino-isoquinoline derivatives as serine protease inhibitors, which are substituted by a group-O- (CH)2)m-E-D-J is substituted at position 6, wherein m is 1 or 2 and E, D, J is as defined in the application.
EP-A-1541559(Asahi) describes in general isoquinoline and isoquinolinone derivatives as Rho-kinase inhibitors and substituted in the 5-position by ｃA group R3.
An embodiment of the present invention is a compound of formula (I), or a stereoisomeric form thereof and/or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof
Wherein
R1Is H, OH or NH2；
R2Is hydrogen, halogen or (C)1-C6) An alkyl group;
R3is that
H、
Halogen, halogen,
(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C1-C6) alkylene-R'),
OH、
O-R”、
NH2、
NHR”、
NR "R" or
NH-C(O)-R”；
R4Is that
H、
Halogen, halogen,
A hydroxyl group,
CN、
(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
R’、
(C1-C6) alkylene-R';
R5is that
H、
Halogen, halogen,
CN、
NO2、
(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C2-C6) An alkenyl group,
R’、
(C1-C6) Alkylene- (C)6-C10) Aryl, heteroaryl, and heteroaryl,
(C1-C6) Alkenylene radical- (C)6-C10) Aryl, heteroaryl, and heteroaryl,
(C1-C6) Alkylene- (C)5-C10) A heterocyclic group,
CH(OH)-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
NH2、
NH-R’、
NH-SO2H、
NH-SO2-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
NH-SO2-R’、
NH-C(O)-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
NH-C(O)-R’、
C(O)N[(C1-C6) Alkyl radical]2、
C (O) OH or
C(O)O-(C1-C6) An alkyl group;
R6is that
H、
R’、
(C1-C8) Alkyl, aryl, heteroaryl, and heteroaryl,
(C1-C6) alkylene-R'),
(C1-C6) alkylene-O- (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(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
(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、
(C1-C6) alkylene-C (O) N [ R']2；
(C1-C6) alkylene-C (O) O- (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
C(O)O-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
C(O)OR’、
C(O)(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
C(O)R’、
C(O)NH-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
C(O)NHR’、
C(O)N[(C1-C6) Alkyl radical]R’
C(O)N[(C1-C6) Alkyl radical]2、
C(O)-(C1-C6) alkylene-R' or
C(O)O(C1-C6) alkylene-R';
R7is that
H、
Halogen, halogen,
CN、
NO2、
(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
O-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C2-C6) An alkenyl group,
R’、
(C1-C6) Alkenylene radical- (C)6-C10) Aryl, heteroaryl, and heteroaryl,
(C1-C6) alkylene-R'),
CH(OH)-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
NH2、
NH-R’、
NH-SO2H、
NH-SO2-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
NH-SO2-R’、
SO2-NH2、
SO2-NHR’、
NH-C(O)-(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
NH-C(O)-R’、
C(O)N[(C1-C6) Alkyl radical]2、
C (O) OH or
C(O)O-(C1-C6) An alkyl group;
R8is H, halogen or (C)1-C6) An alkyl group;
n is 1, 2, 3 or 4;
m is 1, 2, 3, 4 or 5; and is
L is O or O- (C)1-C6) An alkylene group;
wherein
R' is
(C3-C8) A cycloalkyl group, a,
(C5-C10) A heterocyclic group,
(C6-C10) An aryl group;
r' is
(C3-C8) A cycloalkyl group, a,
(C5-C10) A heterocyclic group,
(C6-C10) Aryl, heteroaryl, and heteroaryl,
(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C1-C6) alkylene-R'),
(C1-C6) alkylene-O- (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C1-C6) alkylene-O-R' or
(C1-C6) alkylene-NRxRy; and is
Wherein Rx and Ry are independently of each other
(C1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C5-C10) A heterocyclic group,
(C6-C10) Aryl, heteroaryl, and heteroaryl,
(C1-C4) Alkylene- (C)5-C10) A heterocyclic group,
(C1-C4) Alkylene- (C)6-C10) Aryl, heteroaryl, and heteroaryl,
(C1-C4) alkylene-NH (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(C1-C4) alkylene-N [ (C)1-C6) Alkyl radical]2、
(C1-C4) alkylene-N [ (C)6-C10) Aryl radicals]2Or
(C1-C4) alkylene-N [ (C)5-C10) Heterocyclic radical]2；
Wherein at the residue R4、R5、R6、R7And R8The alkyl, alkylene or cycloalkyl group may optionally be substituted by OH, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONHCH3Or CON (CH)3)2One or more substitutions;
wherein at the residue R2To R8The alkyl or alkylene group may optionally be halogenated one or more times;
wherein at the residue R3To R8In (C)6-C10) Aryl and (C)5-C10) The heterocyclyl is unsubstituted or substituted one or more times by suitable groups independently selected from: halogen, OH, NO2、N3、CN、C(O)-(C1-C6) Alkyl, C (O) - (C)1-C6) Aryl, COOH, COO (C)1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2、(C3-C8) Cycloalkyl group, (C)1-C6) Alkyl, (C)1-C6) alkylene-OH, (C)1-C6) alkylene-NH2、(C1-C6) alkylene-NH (C)1-C6) Alkyl, (C)1-C6) alkylene-N [ (C)1-C6) Alkyl radical]2、(C2-C6) Alkenyl, (C)2-C6) Alkynyl, O- (C)1-C6) Alkyl, O-C (O) - (C)1-C6) Alkyl, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) Alkyl radical]2、S-(C1-C6) Alkyl, SO- (C)1-C6) Alkyl, SO2-(C1-C6) Alkyl, SO2-N＝CH-N[(C1-C6) Alkyl radical]2、C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) Alkyl radical]2、NH-C(O)-(C1-C6) Alkyl, NH-C (O) O- (C)1-C6) Alkyl, NH-SO2-(C1-C6) Alkyl, NH-SO2-(C6-C10) Aryl, NH-SO2-(C5-C10) Heterocyclic group, N (C)1-C6) alkyl-C (O) - (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) O- (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) -NH- (C)1-C6) Alkyl radical]、(C6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl, O- (C)6-C10) Aryl, O- (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)5-C10) Heterocyclic group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl, or O- (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group of which (C)6-C10) Aryl or (C)5-C10) The heterocyclic group may be substituted 1 to 3 times with a group independently selected from: halogen, OH, NO2、CN、O-(C1-C6) Alkyl, (C)1-C6) Alkyl, NH2、NH(C1-C6) Alkyl, N [ (C)1-C6) Alkyl radical]2、SO2CH3、COOH、C(O)O-(C1-C6) Alkyl, CONH2、(C1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O- (C)6-C10) Aryl or O- (C)1-C6) Alkylene- (C)6-C10) An aryl group;
or wherein (C)6-C10) Aryl is O- (C)1-C4) alkylene-O is substituted at the ortho position, thereby forming a 5-8 membered ring together with the carbon atom to which the oxygen atom is attached;
and wherein (C)6-C10) Aryl and (C)5-C10) The aryl or heterocyclyl substituent of the heterocyclyl may be further unsubstituted by an aryl or heterocyclyl containing group;
and wherein, if m is 3, R6Is not H, (C)5-C10) Heterocyclyl or (C)6-C10) An aryl group; and wherein, if m is 3 and R6Is a residue selected from:
(C1-C8) Alkyl, aryl, heteroaryl, and heteroaryl,
(C3-C8) A cycloalkyl group, a,
(C1-C6) alkylene-R'),
(C1-C6) alkylene-O- (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,
(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；
The alkyl, alkylene or cycloalkyl group in said residue is replaced by OH, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONHCH3Or CON (CH)3)2One or more, preferably 1 to 3, substitutions.
In a preferred embodiment of the invention R1Is H, which compound is thus characterized by the formula (II)
In another embodiment R1Is OH, which compound is thus characterized by the formula (III)
The compound of formula (III) has a tautomeric form of formula (III
This tautomeric form is also an embodiment of the invention.
In a further embodiment R1Is NH2And the compound has the following formula (IV)
R1Preferably H orOH。
R3Preferably H, halogen, (C)1-C4) alkylene-R', O-R ", or NHR". More preferably, R3Is H or NHR ". Most preferably, R3Is H, NH- (C)5-C6) Heterocyclyl or NH-phenyl, particularly preferably H, NH-containing one or more N atoms (C)5-C6) Heteroaryl or NH-phenyl.
Most particularly preferably, R3Is H.
R3Examples of substituents are
Preferably, R4Is H, halogen or (C)1-C6) An alkyl group. More preferably, R4Is H, halogen or (C)1-C4) An alkyl group. Most preferably, R4Is H.
Preferably, R5Is H, halogen, CN, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R', NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. More preferably, R5Is H, halogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R', NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. Most preferably, R5Is H, halogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)6-C10) Aryl, NH- (C)6-C10) Aryl group, (C)1-C2) Alkyl radical- (C)6-C10) Aryl or (C)5-C10) A heteroaryl group. Particularly preferably, R5Is H, halogen, phenyl, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)6-C10) Aryl or (C)5-C6) A heteroaryl group. Most especially preferred R5Is H, halogen, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl.
R5Examples of (a) are hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl, nitrile, nitro, (p-methoxy) -phenyl, N-aniline, benzyl, 2-propenyl, sec-butenyl, cyclopropyl, tetrazole, amino, 4-methoxy-aniline or N-acetyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl. More preferably, R5Is H, halogen, methyl or ethyl, most preferably R5Is H.
Preferably, R6Is H, (C)1-C6) Alkyl, R', (C)1-C4) Alkylene- (C)5-C10) Aryl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C4) alkylene-C (O) - (C)5-C10) Heterocyclic group, (C)1-C4) alkylene-C (O) - (C)6-C10) Aryl group, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) O- (C)1-C6) Alkyl, C (O) O- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) R', C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2Or C (O) (C)1-C6) alkylene-R'.
In a further preferred embodiment R6Is H, (C)1-C6) Alkyl, (C)5-C10) Heterocyclic group, (C)3-C8) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)6-C10) Aryl group, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) O- (C)1-C6) Alkyl, C (O) O- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) - (C)5-C10) Heterocyclic group, C (O) (C)3-C8) Cycloalkyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group.
In a still further preferred embodiment R6Is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)5-C10) Heterocyclic group, (C)5-C10) Aryl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)6-C10) Aryl group, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、C(O)O-(C1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O)-(C5-C10) Heterocyclyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group.
In a more preferred embodiment R6Is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)6-C10) Aryl group, (C)1-C4) alkylene-O- (C)1-C4) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) - (C)5-C10) Heterocyclic group, C (O) (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C4) Alkylene- (C)6-C10) And (4) an aryl group.
In a still more preferred embodiment R6Is that
H，
(C1-C6) An alkyl group, a carboxyl group,
(C3-C8) A cycloalkyl group;
(C1-C4) Alkylene- (C)3-C8) A cycloalkyl group;
(C1-C4) Alkylene- (C)5-C10) Heterocyclyl, wherein heterocyclyl is unsubstituted or substituted by (C)1-C4) Alkyl is substituted one or more times, preferably 1 or 2 times;
(C1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is unsubstituted or substituted by halogen, (C)1-C4) Alkyl, especially CH3Or CF3、O-(C1-C4) Alkyl, especially OCH3、SO2-(C1-C4) Alkyl, especially S (O)2CH3Or SO2CF3Or SO2-N＝CH-N[(C1-C6) Alkyl radical]2In particular SO2-N＝CH-N(CH3)2Once or more, preferably 1 to 3 times;
C(O)(C1-C6) Alkyl, preferably C (O) (C)1-C4) An alkyl group, a carboxyl group,
C(O)(C3-C6) A cycloalkyl group,
C(O)-(C5-C6) Heterocyclyl, wherein heterocyclyl is unsubstituted;
C(O)(C1-C4) Alkylene- (C)5-C10) Heterocyclyl, wherein heterocyclyl is unsubstituted; or
C(O)(C1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is unsubstituted or halogenated one or more times, preferably 1 to 3 times;
wherein:
(C1-C4) Alkyl or (C)1-C6) Alkyl is unsubstituted or independently selected from OH, halogen, NH2、NH(CH3) Or N (CH)3)2Is substituted 1 to 3 times, preferably 1 or 2 times,
(C1-C4) Alkylene being unsubstituted or substituted by amino or by N (CH)3)2Substituted once and (C)3-C8) Cycloalkyl unsubstituted or substituted by NH2Once substituted.
In another particularly preferred embodiment R6Is that
(C1-C6) alkylene-C (O) NH2，
(C1-C6) alkylene-C (O) NH- (C)1-C6) An alkyl group, a carboxyl group,
(C1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2，
C(O)(C1-C6) Alkyl, preferably C (O) (C)1-C4) An alkyl group, a carboxyl group,
C(O)(C3-C6) Cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by NH2The substitution is carried out once,
C(O)-(C5-C6) Heterocyclyl, wherein heterocyclyl is unsubstituted;
C(O)(C1-C4) Alkylene- (C)5-C10) Heterocyclyl, wherein heterocyclyl is unsubstituted;
C(O)(C1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is unsubstituted or halogenated one or more times, preferably 1 to 3 times;
wherein:
(C1-C4) Alkyl or (C)1-C6) Alkyl is unsubstituted or independently selected from OH, halogen, NH2、NH(CH3) Or N (CH)3)2Is substituted 1 to 3 times, preferably 1 or 2 times,
(C1-C4) Alkylene being unsubstituted or substituted by amino, NH (CH)3) Or N (CH)3)2Once substituted; or is
(C1-C6) Alkyl, wherein alkyl is substituted once by amino.
More preferably R6Is that
C(O)(C1-C6) Alkyl, preferably C (O) (C)1-C4) An alkyl group, a carboxyl group,
wherein alkyl is unsubstituted or preferably independently selected from OH, halogen, NH2、NH(CH3) Or N (CH)3)21-3 times, preferably 1 or 2 times, most preferably 1 time;
C(O)-(C5-C6) Heterocyclyl, wherein heterocyclyl is unsubstituted;
C(O)-(C3-C6) Cycloalkyl, wherein cycloalkyl is unsubstituted or substituted by amino, or
C(O)(C1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is phenyl, which is unsubstituted or halo-substituted one or more times, preferably 1-3 times, more preferably 1 time, and wherein alkylene is unsubstituted or preferably substituted by amino, NH (CH)3) Or N (CH)3)2Once substituted.
Especially preferred R6Is H, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group. In an even more particularly preferred embodiment R6Is H, preferably unsubstituted (C)1-C6) Alkyl or preferably unsubstituted (C)3-C8) A cycloalkyl group. Most preferred R6Is H.
In embodiments of the compounds of formula (I) R6Is not tert-butyloxycarbonyl.
As examples of these embodiments, R6Is hydrogen, methyl, ethyl, propyl, isopropyl, 3-methyl-butyl, 2-methyl-propyl, butyl, pentyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl or a substituent selected from:
other R6Examples are
The asterisk indicates that the bond is attached to the ring N atom.
Preferably, R7Is H, halogen, CN, (C)1-C6) Alkyl, O- (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R' or (C)1-C6) Alkylene- (C)3-C8) A cycloalkyl group. More preferably, R7Is H, halogen, CN, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, (C)1-C4) Alkenyl, phenyl, cyclopropyl or (C)5-C6) A heteroaryl group. Most preferably, R7Is H, fluoro, chloro, bromo, methyl, ethyl, methoxy, propyl, phenyl, nitrile, cyclopropyl, thienyl or vinyl, especially most preferably R7Is H, fluoro, chloro, bromo, methyl, propyl or methoxy. Most preferred R7Is H.
R8Preferably H, halogen or (C)1-C4) An alkyl group. More preferably, R8Is H, Cl, F, methyl or ethyl. Most preferred R8Is H.
Preferably, R2Is H, halogen or (C)1-C4) An alkyl group. Preferably, R2Is H or (C)1-C2) An alkyl group. More preferred R2Is H, methyl or ethyl. Most preferred R2Is H. R2May be bonded to any carbon atom of the ring, including the position to which the linking group L is bonded.
Preferably, n is 1, 2 or 3. More preferably, n is 1 or 2. Most preferably n is 1.
Preferably, m is 2, 3 or 4. More preferably m is 3. In another embodiment m is 1, 2, 4 or 5.
The linking group L may be bonded to the ring at any position via a ring carbon atom. In a preferred embodiment, m is 3 and L is attached to the 4-position of the piperidine ring
Or L is attached to the 3-position of the piperidine ring
In a particularly preferred embodiment, L is attached to the 4-position of the piperidine ring.
In a further preferred embodiment, L is O-methylene, O-ethylene or preferably O. In another preferred embodiment L is O-methylene or O. More preferably, m is 3 and L is O-methylene, O-ethylene or O, which is attached at the 4-position of the piperidine ring.
At residue R2To R8The alkyl or alkylene group may optionally be halogenated one or more times. Preferably alkyl or alkylene is substituted 1-3 times by a halogen selected from chlorine or bromine, but may be fluorinated one or more times, for example perfluorinated. Preferably the halogen is fluorine. More preferred alkyl or alkylene groups are not halogenated.
At residue R4、R5、R6、R7And R8The alkyl, alkylene or cycloalkyl group may optionally be independently selected from OH, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONHCH3Or CON (CH)3)2Substituted one or more times.
The number of substituents, if substituted, is preferably between 1, 2, 3 or 4, more preferably 1 or 2, still more preferably 1. Preferably, the alkylene or cycloalkyl group is unsubstituted. More preferably, the alkyl, alkylene or cycloalkyl group is unsubstituted. Preferably, at R4、R5、R7And R8Wherein alkyl, alkylene or cycloalkyl is unsubstituted. More preferably, at R4、R5、R6、R7And R8Wherein alkyl, alkylene or cycloalkyl is unsubstituted.
In a preferred embodiment of the present invention, one or more or all of the groups comprised in the compounds of formula (I) may have, independently of each other, any of the above-mentioned preferred, more preferred or most preferred group definitions or any one or some of the specific representations covered by the group definitions and shown above, all combinations of preferred definitions, more preferred or most preferred and/or specific representations being the subject of the present invention. Furthermore, in respect of all preferred embodiments, the present invention includes all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios of the compounds of formula (I) and pharmaceutically acceptable salts thereof.
The term "onium" in the exemplary substituents described above indicates the position at which the substituent is attached, e.g., for R3Substituent group
And m is 3 and R1Is H, which represents a compound of the formula
A preferred embodiment are compounds of formula (I), or their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts, wherein:
R1is H or OH;
R2is hydrogen, halogen or (C)1-C6) An alkyl group;
R3is H, halogen, (C)1-C4) alkylene-R', O-R ", or NHR";
R4is H, halogen or (C)1-C6) An alkyl group;
R5is H, (C)1-C6) Alkyl, halogen, CN, (C)2-C6) Alkenyl, (C)6-C10) Aryl, NH- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)5-C10) Heterocyclyl or (C)1-C6) Alkylene- (C)5-C10) A heterocyclic group;
R6is H, R', (C)1-C8) Alkyl, (C)1-C6) alkylene-R', (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O-R', (C)1-C6) alkylene-CH [ R']2、(C1-C6) alkylene-C (O) NH2、(C1-C6) alkylene-C (O) NH-R', (C)1-C6) alkylene-C (O) N [ (C)1-C4) Alkyl radical]2、C(O)(C1-C4) Alkyl or (C)1-C6) alkylene-C (O) N [ R']2、
C(O)O-(C1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group.
R7Is H, halogen, CN, (C)1-C6) Alkyl, O- (C)1-C6) Alkyl, (C)2-C6) Alkenyl or R';
R8is H, halogen or (C)1-C6) An alkyl group;
m is 2, 3 or 4,
n is 1, 2 or 3, and
l is O, O-methylene or O-ethylene.
Further preferred embodiments are compounds of formula (I), or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, wherein:
R1is H or OH;
R2is H or (C)1-C4) An alkyl group;
R3is H, halogen or NHR ", wherein R" is as defined above;
R4is H, halogen or (C)1-C4) An alkyl group;
R5is H, (C)1-C6) Alkyl, halogen, (C)2-C4) Alkenyl, (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl or (C)5-C10) A heterocyclic group;
R6is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C3) alkylene-R', C (O) O- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) - (C)5-C10) Heterocyclyl, C (O) NH- (C1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C3) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C3) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C3) Alkylene- - (C)6-C10) An aryl group;
R7is H, halogen, CN, (C)1-C6) Alkyl, O (C)1-C6) Alkyl, (C)2-C6) Alkenyl or R';
R8is H, halogen or (C)1-C6) An alkyl group;
m is 2, 3 or 4;
n is 1, 2 or 3; and is
L is O.
A particularly preferred embodiment are compounds of formula (I), or their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts, wherein:
R1is H or OH;
R2is H, (C)1-C4) An alkyl group;
R3is H, NH- (C)5-C6) Heteroaryl or NH-phenyl;
R4is H, halogen or (C)1-C4) An alkyl group;
R5is H, (C)1-C4) Alkyl, halogen, (C)1-C4) Alkenyl, (C)6-C10) Aryl group, (C)1-C2) Alkyl radical- (C)6-C10) Aryl or (C)5-C6) A heteroaryl group;
R6is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C3) alkylene-R'；C(O)(C1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) - (C)5-C10) Heterocyclic group, C (O) (C)1-C3) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C3) Alkylene- (C)6-C10) And (4) an aryl group.
R7Is H, halogen, CN, (C)1-C4) Alkyl, O (C)1-C4) Alkyl, (C)1-C4) Alkenyl, phenyl, cyclopropyl, (C)5-C6) A heteroaryl group;
R8is H, halogen or (C)1-C4) An alkyl group;
m is 3;
n is 1; and is
L is O.
In one embodiment, the compound of formula (I) is not
(2S) -1-tert-Butoxycarbonyl-2- (2- (1-amino-isoquinolin-6-oxy) ethyl) -piperidine or
(2S) -1-tert-Butoxycarbonyl-2- (2- (1-amino-isoquinolin-6-oxy) ethyl) -pyrrolidine.
In another embodiment of the compounds of formula (I), wherein:
R1is NH2Or OH; r3And R8Is H; when R is1Is NH2When R is4Is H or when R1When is OH, R4Is H or bromine; r5Is H; r7Is H or methyl; m is 2, 3 or 4; l is O;
R6is not H, pyrrolyl, methyl, hydroxypropyl or phenylmethyl, wherein the phenyl group is unsubstituted or substituted by methanesulfonyl, methyl, fluoro or methoxy.
In another embodiment, the present invention relates to a compound of formula (I) selected from the group consisting of:
8.7-chloro-6- [1- (2-methylamino-acetyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
10.6- [1- (2-amino-3, 3-dimethyl-butyryl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
11.6- [1- (2-amino-propionyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
12.6- [1- (2-amino-2-methyl-propionyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
13.6- [ I- ((S) -2-amino-butyryl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
14.6- [1- ((S) -2-amino-4-methyl-pentanoyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
15.7-chloro-6- [1- ((S) -pyrrolidine-2-carbonyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
16.7-chloro-6- [1- (2-dimethylamino-acetyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
17.6- [1- ((S) -2-amino-propionyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
18.6- [1- ((S) -2-amino-2-phenyl-acetyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
19.6- [1- (1-amino-cyclopropanecarbonyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
20.6- [1- ((S) -2-amino-pentanoyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one,
22.6- {1- [ (S) -2-amino-3- (4-chloro-phenyl) -propionyl ] -piperidin-4-yloxy } -7-chloro-2H-isoquinolin-1-one,
23.6- {1- [ (S) -2-amino-3- (4-fluoro-phenyl) -propionyl ] -piperidin-4-yloxy } -7-chloro-2H-isoquinolin-1-one,
24.6- [1- (2-amino-acetyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
25.6- [1- ((R) -2-amino-pentanoyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
26.6- [1- ((S) -2-amino-4-methyl-pentanoyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
27.6- {1- [ (S) -2-amino-3- (4-chloro-phenyl) -propionyl ] -piperidin-4-yloxy } -2H-isoquinolin-1-one,
28.6- [1- (2-methylamino-acetyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
29.6- [1- ((S) -pyrrolidine-2-carbonyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
30.6- [1- ((S) -2-amino-3, 3-dimethyl-butyryl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
31.6- [1- ((S) -2-amino-butyryl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
32.6- [1- ((S) -2-amino-propionyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
34.6- [1- ((R) -2-amino-propionyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
35.6- [1- ((S) -2-amino-2-phenyl-acetyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
36.6- [1- ((S) -2-amino-hexanoyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
37.6- [1- ((S) -2-amino-4-methyl-pentanoyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one,
38.6- {1- [ (S) -2-amino-3- (4-fluoro-phenyl) -propionyl ] -piperidin-4-yloxy } -2H-isoquinolin-1-one,
39.6- [1- (2-amino-2-methyl-propionyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one, or
6- [1- (2-amino-acetyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one, or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to a compound of formula (I) selected from the group consisting of:
[4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -acetic acid ethyl ester,
[4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -acetic acid,
43.2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N, N-dimethyl-acetamide,
44.2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N-ethyl-acetamide,
45.2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N-methyl-acetamide, or
46.2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N-propyl-acetamide,
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention relates to a compound of formula (I) selected from the group consisting of:
52.6- (azepan-4-yloxy) -2H-isoquinolin-1-one,
53.6- ((R) - (pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
54.6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
55.6- (azepan-4-yloxy) -7-chloro-2H-isoquinolin-1-one,
56.6- ((R) -pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
57.6- ((S) -pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
58.6- (azetidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
59.6- (azepan-4-yloxy) -4, 7-dimethyl-2H-isoquinolin-1-one,
60.4, 7-dimethyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
61.4, 7-dimethyl-6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
62.4, 7-dimethyl-6- (1-methyl-pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
64.6- (1-methyl-pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
66.6- ((R) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
67.6- ((S) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
68.6- (azepan-4-yloxy) -7-methyl-2H-isoquinolin-1-one,
69.7-methyl-6- ((R) -1-pyrrolidin-3-ylmethoxy) -2H-isoquinolin-1-one,
70.7-methyl-6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one, or
71.7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
more preferably
55.6- (azepan-4-yloxy) -7-chloro-2H-isoquinolin-1-one,
56.6- ((R) -pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
57.6- ((S) -pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
58.6- (azetidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
59.6- (azepan-4-yloxy) -4, 7-dimethyl-2H-isoquinolin-1-one,
60.4, 7-dimethyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
61.4, 7-dimethyl-6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
62.4, 7-dimethyl-6- (1-methyl-pyrrolidin-3-yloxy) -2H-isoquinolin-1-one,
66.6- ((R) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
67.6- ((S) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one,
68.6- (azepan-4-yloxy) -7-methyl-2H-isoquinolin-1-one,
69.7-methyl-6- ((R) -1-pyrrolidin-3-ylmethoxy) -2H-isoquinolin-1-one,
70.7-methyl-6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one, or
7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one, or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
In another embodiment the invention relates to a compound of formula (I) selected from:
72.6- [1- ((S) -2-amino-propyl) -piperidin-3-yloxy ] -2H-isoquinolin-1-one,
73.6- [1- ((S) -2-amino-propyl) -piperidin-4-yloxy ] -5-fluoro-4-methyl-2H-isoquinolin-1-one,
74.6- [1- ((R) -2-amino-3-hydroxy-propyl) -piperidin-4-yloxy ] -2H-isoquinolin-1-one, or
75.6- [1- ((R) -2-amino-3-hydroxy-propyl) -piperidin-4-yloxy ] -5-fluoro-4-methyl-2H-isoquinolin-1-one,
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof. (numbering is in response to Compound/example number)
In the foregoing embodiments containing preferred, more preferred, most preferred or exemplary definitions of the compounds of the invention, as in any of the embodiments of the invention, one or more or all of the groups may have any of the above preferred, more preferred, most preferred definitions or any one or some of the specific indications encompassed by their definitions and shown above.
The isoquinoline substituent substitution pattern is numbered according to IUPAC rules:
all references below to "compounds of formula (I)" refer to the compounds of formulae (I), (II), (III') and (IV) as described above, as well as their pharmaceutically acceptable salts and/or their stereoisomeric forms, polymorphs and solvates. Also included are physiologically functional derivatives as described herein.
Pharmaceutically acceptable salts of the compounds of formula (I) are meant to be their organic and inorganic salts, as described in Remington's pharmaceutical Sciences (17 th edition, page 1418 (1985)). Sodium, potassium, calcium and ammonium salts are particularly preferred for the acidic groups due to physical and chemical stability and solubility; salts of maleic, fumaric, succinic, malic, tartaric, methanesulfonic, hydrochloric, sulfuric, phosphoric or carboxylic acids or sulfonic acids are particularly preferred for the basic groups, for example as the hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate, and salts of amino acids, natural bases or carboxylic acids. The preparation of pharmaceutically acceptable salts from compounds of formula (I), including their stereoisomeric forms, capable of salt formation is carried out in a manner known per se. The compounds of formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic agents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethylamine or triethylamine, ethanolamine, diethanolamine or triethanolamine, tromethamine, or other basic amino acids, for example lysine, ornithine or arginine. When the compounds of formula (I) have basic groups, stable acid addition salts can also be prepared with strong acids. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and of organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid.
Salts with non-pharmaceutically acceptable anions such as trifluoroacetate are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic applications, such as in vitro applications.
The term "physiologically functional derivative" as used herein refers to any physiologically tolerated derivative of a compound of formula (I) according to the invention, for example an N-oxide, which on administration to a mammal, for example a human, is capable of forming (directly or indirectly) a compound of formula (I) or an active metabolite thereof.
Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H.Okada et al, chem.pharm.Bull.1994, 42, 57-61. These prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may themselves be active or inactive.
The present invention relates to stereoisomeric forms of compounds of formula (I), (II), (III) or (III') including racemates, racemic mixtures, pure enantiomers and diastereomers and mixtures thereof.
The compounds of the present invention may also exist in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the present invention and are a further aspect of the invention.
If a group or substituent can occur once or more than once in a compound of the formula (I), they can all have the meanings indicated and can be identical or different, independently of one another.
Term (C)1-C2) Alkyl, (C)1-C4) Alkyl, (C)1-C6) Alkyl, (C)1-C8) Alkyl and corresponding alkylene substituents are understood to be hydrocarbon radicals which may each be linear, i.e. straight-chain or branched, and have 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. This also applies when alkyl is a substituent for another group, for example in alkoxy (O-alkyl), S-alkyl or-O (C)1-C6) alkylene-O-, alkoxycarbonyl, or arylalkyl. Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl or hexyl, the n-isomers of all these radicals, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. If not otherwise stated, the alkyl or alkylene group may be halogenated one or more times, for example the alkyl group may be fluorinated, for example perfluorinated. Examples of haloalkyl are CF3And CH2CF3、OCF3、SCF3or-O- (CF)2)2-O-。
Alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl (═ allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1, 3-pentadienyl.
Alkynyl is, for example, ethynyl, 1-propynyl, 2-propynyl (═ propargyl) or 2-butynyl.
Halogen means fluorine, chlorine, bromine or iodine.
(C3-C8) Cycloalkyl is a cyclic alkyl radical having 3, 4, 5, 6, 7 or 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which may also be substituted and/or have 1 or 2 double bonds (unsaturated cycloalkyl), e.g. cyclopenteneThe radical or cyclohexenyl radical may be bonded via any carbon atom.
(C6-C10) Aryl means an aromatic ring or a ring system comprising two fused or otherwise connected aromatic rings, for example phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha-or beta-tetralone-, indanyl-or indan-1-one groups. Preferably (C)6-C10) Aryl is phenyl.
(C5-C10) Heterocyclyl means a mono-or bicyclic ring system in which one or more carbon atoms may be replaced by one or more heteroatoms (e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulphur atoms or a combination of different heteroatoms). The heterocyclyl group may be bonded at any position, for example, the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. (C)5-C10) The heterocyclic group may be (1) aromatic [ ═ heteroaryl]Or (2) saturated or (3) mixed aromatic/saturated heterocyclic groups.
Is suitably (C)5-C10) Heterocyclic groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomorpholinyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, furyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, benzopyranyl, benzopyran-2-onyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] amino]Tetrahydrofuran, furyl, furazanyl, homomorpholinyl, homopiperazinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuryl, isobenzodihydropyranyl, isoindolyl, isoquinolyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazalyl, and the likeOxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, prolyl (prolinyl), pteridinyl, purynyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2, 5-thiadiazinyl, thiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thienyl, triazolyl, thiadiazolyl, and the like, Tetrazolyl and xanthenyl. Pyridyl represents 2-, 3-and 4-pyridyl. Thienyl represents 2-and 3-thienyl. Furyl represents 2-and 3-furyl. Also included are the corresponding N-oxides of these compounds, such as 1-oxy-2-, 3-, or 4-pyridyl.
(C5-C10) The substitution of the heterocyclic group may occur at a free carbon atom or at a nitrogen atom.
(C5-C10) Preferred examples of heterocyclyl groups are pyrazinyl, pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, benzofuranyl, quinolinyl, tetrazolyl and triazolyl.
(C6-C10) Aryl and (C)5-C10) The heterocyclyl is unsubstituted or, if not indicated otherwise, substituted one or more times, preferably 1 to 3 times, with a suitable group independently selected from: halogen, OH, NO2、N3、CN、C(O)-(C1-C6) Alkyl, C (O) - (C)1-C6) Aryl, COOH, COO (C)1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2、(C3-C8) Cycloalkyl group, (C)1-C6) Alkyl, (C)1-C6) alkylene-OH, (C)1-C6) Alkylene oxideradical-NH2、(C1-C6) alkylene-NH (C)1-C6) Alkyl, (C)1-C6) alkylene-N [ (C)1-C6) Alkyl radical]2、(C2-C6) Alkenyl, (C)2-C6) Alkynyl, O- (C)1-C6) Alkyl, O-C (O) - (C)1-C6) Alkyl, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) Alkyl radical]2、S-(C1-C6) An alkyl group; SO- (C)1-C6) Alkyl, SO2-(C1-C6) Alkyl, SO2-N＝CH-N[(C1-C6) Alkyl radical]2、C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) Alkyl radical]2、NH-C(O)-(C1-C6) Alkyl, NH-C (O) O- (C)1-C6) Alkyl, NH-SO2-(C1-C6) Alkyl, NH-SO2-(C6-C10) Aryl, NH-SO2-(C5-C10) Heterocyclic group, N (C)1-C6) alkyl-C (O) - (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) O- (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) -NH- (C)1-C6) Alkyl radical]、(C6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl, O- (C)6-C10) Aryl, O- (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)5-C10) Heterocyclic group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group, O- (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group of which (C)6-C10) Aryl or (C)5-C10) The heterocyclyl group may be substituted 1 to 3 times with groups independently selected from: halogen, OH, NO2、CN、O-(C1-C6) Alkyl, (C)1-C6) Alkyl, NH2、NH(C1-C6) Alkyl, N [ (C)1-C6) Alkyl radical]2、SO2CH3、COOH、C(O)O-(C1-C6) Alkyl, CONH2、(C1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O- (C)6-C10) Aryl, O- (C)1-C6) Alkylene- (C)6-C10) An aryl group; or wherein (C)6-C10) Aryl is O- (C)1-C4) alkylene-O is substituted at the ortho position, thereby forming a 5-8 membered ring together with the carbon atom to which the oxygen atom is attached. (C)6-C10) Aryl and (C)5-C10) The aryl or heterocyclyl substituents of the heterocyclyl group may be further unsubstituted by an aryl or heterocyclyl containing group.
(C6-C10) Preferred substituents for aryl are (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, O-phenyl, C (O) O- (C)1-C6) Alkyl, C (O) OH, C (O) - (C)1-C4) Alkyl, halogen, NO2、SO2NH2、CN、SO2-(C1-C4) Alkyl, SO2-N＝CH-N[(C1-C6) Alkyl radical]2、NH-SO2-(C1-C4) Alkyl, NH2、NH-C(O)-(C1-C4) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C4) alkyl-OH, C (O) N [ (C)1-C4) Alkyl radical]2、CONH(C1-C6) Alkyl, C (O) NH2、N[(C1-C4) Alkyl radical]2、(C1-C4) Alkylene- (C)6-C10) Aryl group of which (C)6-C10) The aryl group may be further substituted by (C)1-C4) Alkyl, (C)1-C4) alkylene-O- (C)1-C6) Alkyl, (C)6-C10) Aryl radical O- (C)1-C6) Alkyl-(C6-C10) Aryl is substituted 1-3 times (preferably 1 time), or may be substituted by O- (C)1-C4) alkylene-O is substituted at the ortho position, thereby forming a 5-8-membered ring together with the carbon atom to which the oxygen atom is attached. (C)6-C10) More preferred substituents for aryl are halogen, CN, phenyl, O-phenyl, NH-C (O) - (C)1-C4) Alkyl, especially NH-C (O) -CH3、C(O)-(C1-C4) Alkyl, especially C (O) -CH3、(C1-C4) Alkyl, especially CH3Or CF3、O-(C1-C4) Alkyl, especially O-CH3、SO2-NH2、SO2-(C1-C4) Alkyl, especially SO2-CH3Or SO2-CF3Or SO2-N＝CH-N[(C1-C4) Alkyl radical]2Especially SO2-N＝CH-N[(CH3)2。
In monosubstituted phenyl the substituent may be in the 2-, 3-or 4-position, with the 3-and 4-positions being preferred. If the phenyl group has two substituents, they may be in the 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-positions. The substituents may be located at the 2, 3, 4-position, 2, 3, 5-position, 2, 3, 6-position, 2, 4, 5-position, 2, 4, 6-position or 3, 4, 5-position in the phenyl group having three substituents.
The above description relating to phenyl applies correspondingly to divalent radicals derived from phenyl, i.e. phenylene which may be unsubstituted or substituted 1, 2-phenylene, 1, 3-phenylene or 1, 4-phenylene. The above description also applies correspondingly to arylidene groups in arylalkylene. Examples of arylalkylene which may also be unsubstituted or substituted in the arylene and alkylenearylene groups are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.
(C5-C10) Preferred substituents of the heterocyclic group are (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, (C)1-C4) Alkylene-phenyl, halogen, (C)1-C4) alkylene-O- (C)1-C4) Alkyl, (C)5-C10) Heterocyclic group, (C)1-C4) alkylene-N [ (C)1-C4) Alkyl radical]2Or (C)6-C10) Aryl group of which (C)6-C10) The aryl group may be further substituted by (C)1-C4) Alkyl, O- (C)1-C6) Alkyl, halogen, (C)1-C4) alkylene-O- (C)1-C6) Alkyl, O- (C)1-C6) Alkyl radical- (C)6-C10) Aryl substituted or may be O- (C)1-C4) alkylene-O is substituted at the ortho position, thereby forming a 5-8 membered ring together with the carbon atom to which the oxygen atom is attached. (C)5-C10) A more preferred substituent for the heterocyclic group is (C)1-C4) Alkyl, halogen or phenyl, wherein phenyl may be further substituted by halogen, (C)1-C4) Alkyl or O- (C)1-C4) Alkyl is substituted 1 to 3 times, preferably 1 time.
(C6-C10) Aryl and (C)5-C10) General and preferred substituents for heterocyclyl groups may be as defined above for R1、R2、R3、R4、R5、R6、R7、R8N, m and L in combination with the general and preferred definitions.
The invention therefore also relates to the use of a compound of formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs, a compound of formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs for the manufacture of a medicament for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, i.e. for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulation disorders, Peripheral Arterial Occlusive Disease (PAOD), coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic disease, ischemic organ failure (terminal organ damage), fibrotic lung, fibrotic liver, liver failure, renal disease, including hypertension induced diseases, Non-hypertension induced and diabetic nephropathy, renal failure, fibrotic kidney, glomerulosclerosis, organ hypertrophy, asthma, Chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, alzheimer's disease, preterm labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone diseases such as osteoporosis, bacterial infections of the digestive tract, sepsis, cancer occurrence and progression, cancer of e.g. the breast, colon, prostate, ovary, brain and lung, and metastases thereof.
The invention also relates to a pharmaceutical preparation (or pharmaceutical composition) comprising an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances (or media) and/or additives (or excipients).
The medicaments can be administered orally, for example in the form of pills, tablets, spray-coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the application can also be carried out as follows: rectally, e.g. in the form of suppositories, or parenterally, e.g. intravenously, intramuscularly or subcutaneously, in the form of injection or infusion solutions, microcapsules, implants or implant sticks, or transdermally or topically, e.g. in the form of ointments, solutions or tinctures, or by other routes, e.g. in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to the person skilled in the art, using pharmaceutically inert inorganic and/or organic carrier substances and/or additives in addition to the compounds of the formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs. For the preparation of pills, tablets, coated tablets and hard gelatine capsules it is possible to use, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like. Carrier materials for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils and the like. Suitable carrier substances for the preparation of solutions, e.g. injection solutions or emulsions or syrups, are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils and the like. Suitable carrier materials for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. Pharmaceutical formulations typically contain from about 0.5 to about 90% by weight of a compound of formula (I) and/or a pharmaceutically acceptable salt and/or prodrug thereof. The amount of active ingredient of formula (I) and/or a pharmaceutically acceptable salt and/or prodrug thereof in the pharmaceutical formulation is generally from about 0.5 to about 1000mg, preferably from about 1 to about 500 mg.
In addition to the active ingredient of the formula (I) and/or its pharmaceutically acceptable salts and 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, flavorants, aromatics, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of formula (I) and/or pharmaceutically acceptable salts thereof. Where a pharmaceutical formulation contains two or more compounds of formula (I), the selection of each compound may depend on the particular overall pharmacological properties of the pharmaceutical formulation. For example, highly potent compounds with shorter duration of action may be combined with long acting compounds with lower efficacy. The flexibility allowed with respect to the choice of substituents in the compounds of formula (I) allows for a great deal of control over the biological and physicochemical properties of the compounds, thereby enabling the selection of such desired compounds. Furthermore, the pharmaceutical preparations may contain, in addition to at least one compound of the formula (I) and/or a pharmaceutically acceptable salt thereof, one or more further therapeutically or prophylactically active ingredients.
When using the compounds of the formula (I), the dosage can vary within wide limits and, as is customary and known to the skilled worker, the dosage should be adapted to the individual case in each case. Depending on, for example, the particular compound employed, the nature and severity of the disease being treated, the mode and regimen of administration, or whether an acute or chronic condition is being treated or prevented. Suitable dosages may be established using clinical methods known in the medical arts. In general, the daily dose to achieve the desired result in an adult human weighing about 75kg is from about 0.01 to about 100mg/kg, preferably from about 0.1 to about 50mg/kg, in particular from about 0.1 to about 10mg/kg (in each case in mg/kg body weight). Especially in the case of administration of larger amounts, the daily dose may be divided into several portions, for example 2, 3 or 4 portions. It may be necessary to deviate upwards or downwards from the indicated daily dose, usually depending on the individual behaviour.
Furthermore, the compounds of formula (I) can be used as synthesis intermediates for the preparation of further compounds, in particular further pharmaceutically active ingredients which can be obtained from the compounds of formula I, for example by introducing substituents or modifying functional groups.
In general, protecting groups which may still be present in the product obtained in the coupling reaction are subsequently removed by standard methods. For example, a tert-butyl protecting group, particularly tert-butoxycarbonyl group, as an amino-protected form may be deprotected, i.e., converted to an amino group, by treatment with trifluoroacetic acid. As already explained, it is also possible to generate functional groups from suitable precursor groups after the coupling reaction. Furthermore, the conversion to a pharmaceutically acceptable salt or prodrug of a compound of formula (I) may be subsequently carried out by known methods.
In general, the reaction mixture containing the final product of formula (I) or intermediates is worked up and, if desired, the product is purified by conventional methods known to those skilled in the art. For example, the synthesized compounds can be purified using well known methods such as crystallization, chromatography, or reverse phase high performance liquid chromatography (RP-HPLC) or other separation methods based on, for example, compound size, charge, or hydrophobicity. Similarly, well-known methods such as amino acid sequence analysis, NMR, IR and Mass Spectrometry (MS) can be used to characterize the compounds of the invention.
Isoquinolines and isoquinolinones can be synthesized by a variety of methods. The following general scheme illustrates some of the possible methods for obtaining isoquinolinones, but does not limit the invention.
Scheme 1:
an appropriately substituted aldehyde, for example an X-or Y-substituted aldehyde attached in suitable positions, independently of one another as hydrogen, alkyl, alkoxy or halide, can be reacted with an acetal of a suitable compound, for example aminoacetaldehyde, for example in a solvent such as THF, chloroform or toluene, under toluene sulfonic acid or another suitable acid catalysis to give an imine (ii) in which Q' can be, for example, methyl or ethyl, which can then be cyclized to isoquinoline (iii) by different methods. This may be done, for example, by Lewis acid catalysis with a suitable Lewis acid such as titanium tetrachloride, iron halides, aluminum halides, etc., at temperatures from ambient to 100 ℃, or by reduction of the imine to the corresponding amine by the action of a suitable reducing agent such as sodium borohydride, conversion of the amine to an amide or sulfonamide by reaction with a suitable acid chloride, followed by cyclization to isoquinoline by the action of a suitable Lewis acid. The isoquinoline itself (iii) can then be converted to the corresponding N-oxide (iv) by the action of a suitable oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, and the like, at room or elevated temperature. The N-oxide (iv) may then be converted to the 1-chloro-isoquinoline derivative (v) by reaction with a reagent such as phosphorus oxychloride in the presence or absence of phosphorus pentachloride. This derivative (v) can then be converted into a suitable 1-alkoxy-derivative by reaction with various alcohols Q-OH such as methanol, ethanol or benzyl alcohol in the presence of a suitable base such as sodium hydride in a suitable solvent such as dimethylformamide, dimethylacetamide and the like. Alternatively, (v) can be converted directly to isoquinolinone derivatives (vii) by reaction with a reagent such as ammonium acetate.
Scheme 2:
alternatively, the isoquinoline may be obtained as follows: reaction of a suitable 3-formylated or acetylated fluorobenzene (viii) where Z is for example H or an alkyl group such as methyl or ethyl with a reagent such as triethyl phosphonate acetate in the presence of a suitable base such as sodium hydride gives the corresponding cinnamate ester which is subsequently cleaved in a suitable solvent by the action of a suitable base such as potassium hydroxide, sodium hydroxide or lithium hydroxide to give the acid (ix). (ix) The corresponding acid chloride can then be converted by known methods, which can be converted to the acyl azide by reaction with sodium azide in a suitable solvent such as ether, chloroform or acetone, with or without the presence of water. The corresponding azide can then be converted to isoquinolinone (x) by reaction in a suitable solvent such as diphenylmethane or diphenyl ether at a suitable temperature.
Scheme 3:
the 6-fluoro-isoquinolinones obtained above, e.g. (vi), can be reacted with suitable P-substituted aminoalcohols wherein P is e.g. hydrogen, alkyl or a protecting group such as Boc, in the presence of a base such as DBU, cesium carbonate or sodium hydride to give the corresponding alkoxy-substituted derivatives (xi). Finally, the conversion may have been carried out at an early stage of the synthesis (e.g. by a suitable intermediate reaction). It should be understood that: in the case of unprotected isoquinolinones, this may require protection at the nitrogen or oxygen of the isoquinolinone moiety by suitable methods such as reaction with an appropriately substituted alkyl or benzyl halide in the presence of a base. By using fluoroisoquinolines such as (iii) in the reactions described for the conversion of (vi) to (xi), isoquinoline derivatives can be obtained, in this particular case, OQ is equal to H. The amino group of such derivatives can be modified according to the methods described below.
The product obtained via the process, e.g. (xi), can then be liberated or, if a suitable amino function is present, reacted with a suitable aldehyde or ketone in the presence of a reducing agent, e.g. sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, in a suitable solvent, in the presence of a water absorbing agent, e.g. molecular sieves or a suitable orthoester. The amino group may have to be released in an initial step, e.g. removal of the Boc-group under acidic conditions. Furthermore, the amino group can be acylated by reaction with a suitable acid chloride in the presence of a base such as triethylamine or Hunig base or by reaction with a suitable carboxylic acid in the presence of a base such as triethylamine or Hunig base and a coupling reagent such as EDC, PyBOP or TOTU.
In the case of protected isoquinolinones, it is necessary to cleave the protecting group used to release the desired isoquinolinone (xii). However, this release can be carried out before or after the reductive amination step, depending on the nature of the aldehyde/ketone used and the protecting group used.
Isoquinolinone derivatives such as (xii) can be obtained as free bases or as various salts, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate or fumarate salts. The resulting salt can be converted to the corresponding free base by subjecting it to ion exchange chromatography or, for example, by treatment with aqueous base, followed by extraction with a suitable organic solvent such as methyl tert-butyl ether, chloroform, ethyl acetate or an isopropanol/dichloromethane mixture, followed by evaporation to dryness.
The general procedures for the preparation of isoquinolinone derivatives as described above can be readily adapted to prepare compounds of formula (I). In the following examples, the preparation of the compounds of the invention is illustrated in more detail.
The following examples are, therefore, part of the present invention and are intended to illustrate, but not to limit the invention.
It should be understood that: variations that do not materially affect the activity of the various embodiments of the invention are included within the scope of the invention disclosed herein.
LC/MS-method:
the method A comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2
Gradient: ACN + 0.05% TFA: H2O+0.05％TFA
5: 95(0 min.) to 95: 5(3.4 min.) to 95: 5(4.4 min.)
Flow rate 1 mL/min
The method B comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2
Gradient: ACN + 0.05% TFA: H2O+0.05％TFA
5: 95(0 min.) to 95: 5(2.5 min.) to 95: 5(3.0 min.)
Flow rate 1 mL/min
The method C comprises the following steps:
stationary phase: col YMC Jsphere ODS H8020 x 2
Gradient: ACN H2O+0.05％TFA
4: 96(0 min.) to 95: 5(2.0 min.) to 95: 5(2.4 min.)
Flow rate 1 mL/min
The method D comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2.1
Gradient: grad ACN + 0.08% FA: H2O + 0.1% FA (formic acid)
5: 95(0 min.) to 95: 5(2.5 min.) to 95: 5(3 min.)
Flow rate 1.3 mL/min
The method E comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2
Gradient: ACN + 0.05% TFA: H2O+0.05％TFA
5: 95(0 min.) to 95: 5(2.5 min.) to 95: 5(3.2 min.)
Flow rate 1.3 mL/min
Method F:
stationary phase: col YMC-Pack Pro C18 RS 33 x 2.1
Gradient: grad ACN + 0.1% FA: H2O + 0.1% FA (formic acid)
5: 95(0 min.) to 95: 5(2.5 min.) to 95: 5(3 min.)
Flow rate 1.3 mL/min
(3-chloro-4-fluoro-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1)
100g (0.63mol) of 3-chloro-4-fluoro-benzaldehyde are dissolved in 300ml of toluene at room temperature and 66.3g (0.63mol) of 2-aminoacetaldehyde dimethyl acetal are added. After addition of 12.0g (0.06mol) of p-toluenesulfonic acid monohydrate, the reaction is heated for 3 hours in a dean Stark apparatus. The solution was then cooled to room temperature and saturated NaHCO was used3The solution and water were washed twice. The aqueous solution was extracted with toluene. Over MgSO4The combined organic layers were dried and evaporated. The imine intermediate obtained is directly dissolved in 300mL of ethanol and 11.93g (0.32mol) of sodium borohydride are added in small portions each time. After stirring overnight, 10mL of acetic acid were added and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and washed twice with water. Over MgSO4After drying, the solvent was evaporated to give 147.0g of crude product as a yellow oil, which was used without further purification. RtAfter 0.81 min (method C). Actually measured quality: 248.2(M + H)+)。
N- (3-chloro-4-fluoro-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methylbenzenesulfonamide (2)
147.0g of (3-chloro-4-fluoro-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1, crude product) are dissolved in 540ml of dichloromethane/pyridine (8: 1). A solution of 145.8g (1.04mol) of p-toluenesulfonyl chloride in 200ml of dichloromethane was added at 0 ℃. After 5 hours at room temperature, a further 20ml of pyridine, 29.16g (0.15mol) of p-toluenesulfonyl chloride and a catalytic amount of DMAP were added. The solution was stirred at room temperature for 7 hours and then refluxed for 4 hours. 29.16g (0.15mol) of p-toluenesulfonyl chloride and a catalytic amount of DMAP were again added and the mixture was stirred overnight. For working up, the solution is washed twice with 2N HCl and saturated NaHCO3The solution was washed twice. Over MgSO4The organic layer was dried and evaporated. Chromatography on silica gel (heptane/ethyl acetate 4: 1) gave 155g of the title compound as a yellow oil. Rt1.80 minutes (method B). Actually measured quality: 370.2 (M-OMe)-)。
7-chloro-6-fluoro-isoquinoline (3)
343.6g (2.54mol) of AlCl3Suspended in 1.1l of dichloromethane and stirred with a mechanical stirrer for 30 minutes. To this suspension, 204g (0.51mol) of a solution of (N- (3-chloro-4-fluoro-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methylbenzenesulfonamide (2) were added and the mixture was stirred at room temperature for 5 hours, after standing overnight, the reaction suspension was poured onto ice, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane, 1N NaOH and saturated NaHCO3The combined organic layers were washed twice with solution over MgSO4Dried and evaporated. The crude product obtained is purified by chromatography on silica gel (heptane/ethyl acetate 1: 1) to yield 61.3g of the title compound. RtAfter 0.73 minutes (method B). Actually measured quality: 182.1(M + H)+)。
7-chloro-6-fluoro-isoquinoline 2-oxide (4)
25g (137.7mmol) of 7-chloro-6-fluoro-isoquinoline (3) are dissolved in 500ml of dichloromethane. 50.9g (206.5mmol) of 3-chloro-perbenzoic acid (70%) are added at room temperature and the mixture is stirred at room temperature until complete conversion. For working up, the precipitate is filtered off and washed with dichloromethane. With NaHCO3The filtrate was washed twice with water. The layers were separated and the aqueous phase was washed twice with dichloromethane. Over MgSO4The organic phase was dried and evaporated. The solid thus obtained (18.4g) was used without further purification. Rt0.87 min (method C). Actually measured quality: 198.1/200.1(M + H)+)。
1, 7-di-chloro-6-fluoro-isoquinoline (5)
2.6g (12.0mmol) of 7-chloro-6-fluoro-isoquinoline 2-oxide (4) are placed in 40mL of POCl3Heated at medium reflux for 4 hours. After the mixture had cooled to room temperature, it was poured onto ice. The aqueous solution was extracted three times with dichloromethane. Over MgSO4The combined organic layers were dried and evaporated to give 2.91g of the title compound, which was used without further purification. Rt2.34 minutes (method a). Actually measured quality: 216.0/218.0(M + H)+)。
4- (1-benzyloxy-7-chloro-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (6)
289.8mg (1.44mmol) of 4-hydroxy-piperidineTert-butyl-1-carboxylate was dissolved in 10ml of dimethylacetamide and 57.6mg (1.44mmol) of sodium hydride (60%) were added. The reaction mixture was stirred at room temperature. After 30 minutes a solution of 310mg (1.44mmol) of 1, 7-dichloro-6-fluoro-isoquinoline (5) in 3ml of dimethylacetamide is added and the mixture is stirred at room temperature for 1 hour until complete conversion. 155.7mg (1.44mmol) of benzyl alcohol are then added, followed by 57.6mg (1.44mmol) of sodium hydride (60%) and stirring is continued at room temperature. To achieve complete conversion, after two hours and standing overnight, 0.5 equivalents of benzyl alcohol and sodium hydride are added twice. For working up, the solvent is evaporated, the residue is dissolved in dichloromethane and washed twice with water and over MgSO4Dried and evaporated. Final purification was done by preparative HPLC.
7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one-hydrochloride (7)
254mg (0.52mmol) of tert-butyl 4- (1-benzyloxy-7-chloro-isoquinolin-6-yloxy) -piperidine-1-carboxylate (6) are stirred in methanol/2N HCl (1: 1) at room temperature overnight. The solvent was removed under vacuum and the residue was purified by preparative HPLC. The product fractions were evaporated and dissolved in 2N HCl. Freeze drying afforded 57mg of the desired compound. Rt0.95 min (method B). Actually measured quality: 279.1(M + H)+)。
General procedure for acylation of 7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (7)
0.74mmol of the carboxylic acid derivative was dissolved in 10ml of DMF. After addition of 0.74mmol of triethylamine, 0.74mmol of TOTU was added at 0 ℃ and the solution was stirred at room temperature for 30 minutes. This solution was then added to a solution of 0.74mmol of 7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (7, free base) in 10ml of DMF at 0 ℃. Stirring was continued at room temperature until complete conversion. For separation, the solvent was removed under vacuum and the residue was dissolved in dichloromethane. Washing the solution with water and passing throughMgSO4And (5) drying. The crude product obtained was purified by preparative HPLC. The product fractions were evaporated and the residue was dissolved in 2N HCl. In the case of the Boc-protected product, the 2N HCl solution was stirred at room temperature until complete cleavage of the Boc-group. After evaporation of the aqueous solution, the compound was dissolved in water and lyophilized to give the desired compound as HCl-salt.
The compounds described in table 1 below were obtained using this general procedure.
6- [1- (2-amino-acetyl) -piperidin-4-yloxy ] -7-chloro-2H-isoquinolin-1-one (40)
140mg (0.35mmol) of 2- {2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl]-2-oxo-ethyl } -isoindole-1, 3-dione (9) is dissolved in 5mL of ethanol and 30.1mg (0.60mmol) of hydrazine hydrate are added. After 2 hours at room temperature, 30.1mg (0.60mmol) hydrazine hydrate are added and the reaction mixture is heated to 80 ℃. After 16 h, the solvent was removed in vacuo and the crude product was purified by preparative HPLC. Evaporation of the product fractions gave the desired compound as the trifluoroacetate salt, which was dissolved in 2N HCl. The solvent was removed under vacuum and the residue was dissolved in water. After lyophilization, the title compound was isolated as the HCl-salt. Rt0.91 min (method B). Actually measured quality: 336.1(M + H)+)。
[4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -acetic acid ethyl ester (41)
1.5g (5.38mmol) of 7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (7, free base) are dissolved in 100mL of methanol. At room temperature, 1.09g (10.8mmol) of triethylamine, 3.23g (53.8mmol) of acetic acid, 7.63g (33.6mmol) of ethyl glyoxylate and molecular sieve (4A) were added, followed by 253.6mg (4.04mmol) of sodium cyanoborohydride. After stirring at room temperature for 2 hours, the reaction mixture was filtered and the filtrate was evaporated under vacuum. The residue was dissolved in dichloromethane and washed with 1N NaOH and saturated NaCl solution. Over MgSO4Drying the organic layer and evaporatingAnd (4) sending. The crude product obtained was used without further purification.
[4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -acetic acid (42)
1.56g (4.27mmol) of [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl]Ethyl acetate (41) was dissolved in 20mL of methanol and 20mL of 2N NaOH was added. After stirring at room temperature for 1 hour, the solvent was removed under vacuum and the residue was dissolved in water. The aqueous solution was neutralized by adding 2n hcl. The precipitate was filtered and dried to yield 856mg of the title compound. Rt0.82 min (method B). Actually measured quality: 337.1(M + H)+)。
2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N, N-dimethyl-acetamide (43)
2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -piperidine using 40% aqueous dimethylamine solution]The title compound was synthesized by the method described for acetamide (42). After final purification by preparative HPLC, the trifluoroacetate salt was obtained and dissolved in 2N HCl. The solvent was evaporated and the aqueous solution of the residue was freeze-dried to give the title compound as HCl-salt. Rt0.80 min (method B). Actually measured quality: 364.1(M + H)+)。
2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N-ethyl-acetamide (44)
Using 70% aqueous ethylamine solution according to the method for preparing 2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl]The title compound was synthesized by the method described for acetamide (43). After final purification by preparative HPLC, the trifluoroacetate salt was obtained and dissolved in 2N HCl. The solvent was evaporated and the aqueous solution of the residue was freeze-dried to give the title compound as HCl-salt. Rt0.80 min (method C). Actually measured quality: 364.2(M + H)+)。
2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N-methyl-acetamide (45)
Using 40% methylamine in water, according to the ratio of 2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl]The title compound was synthesized by the method described for acetamide (43). After final purification by preparative HPLC, the trifluoroacetate salt was obtained and dissolved in 2N HCl. The solvent was evaporated and the aqueous solution of the residue was freeze-dried to give the title compound as HCl-salt. Rt0.77 min (method C). Actually measured quality: 350.2(M + H)+)。
2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl ] -N-propyl-acetamide (46)
Using propylamine, according to the formula of p-2- [4- (7-chloro-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy) -piperidin-1-yl]The title compound was synthesized by the method described for acetamide (43). RtAfter 0.98 min (method B).
Actually measured quality: 378.2(M + H)+)。
6-fluoro-isoquinolinone (47)
4.8mL (90.3mmol, 1.5 equivalents) of thionyl chloride are added portionwise to a solution of 10g (60.2mmol) of 3-fluorocinnamic acid in 44mL of chloroform and 1mL of DMF. The reaction was heated at reflux for 2.5 hours. The solvent was then distilled to give 11.4g of crude acid chloride, which was used without any further purification.
The acid chloride was dissolved in 45mL of acetone. 8.03g of NaN are added in portions at 0 DEG.C3(123.5mmol, 2 equiv.). 41mL of water was then added while maintaining the temperature below 5 ℃. The reaction was stirred for an additional 1.5 h. Then 55mL of chloroform was added. The mixture was extracted first with 80mL of water followed by 40mL of brine. Through Na2SO4After drying and filtration, 14mL of diphenyl ether was added and most of the chloroform was removed under vacuum (without heating). Complete removal of chloroform should be avoided.
The solution containing azide, diphenyl ether and remaining chloroform was added dropwise over 15 minutes at 260 ℃ to a solution of 10mL tributylamine in 97mL diphenyl ether. A vigorous reaction was observed during the addition. The reaction was stirred at 260 ℃ for an additional 20 minutes. After cooling to room temperature, 270mL of n-heptane were added. The precipitated product was filtered off and washed with ether to yield 5.65g of the title compound. Ms (dci) measured mass: 164.0(M + H)+)。
6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (48)
169 uL of p-methoxybenzyl chloride (1.24mmol, 1.1 equiv.) is added to 200mg of 6-fluoro-isoquinolinone (13) (1.13mmol) and 368mg of Cs2CO3(1.36mmol, 1.2 equiv.) in 3mL of DMF. Mixing the mixtureStir for 2 hours and then pour onto ice. The precipitate was filtered, washed with water and dried to yield 300mg of the title compound. LCMS method B, retention time 1.76 min, measured mass: 284.14[ M + H]+
4, 7-dimethyl-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (49)
Starting from 3- (3-fluoro-4-methylphenyl) -but-2-enoic acid in an analogous manner to that described for (48), 4, 7-dimethyl-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (49) is obtained. Rt1.96 minutes (method B). Actually measured quality: 312.1(M + H)+)。
5, 6-difluoro-2- (4-methoxy-benzyl) -4-methyl-2H-isoquinolin-1-one (50)
Starting from 3- (2, 3-difluorophenyl) -but-2-enoic acid in an analogous manner as described for (48), 5, 6-difluoro-2- (4-methoxy-benzyl) -4-methyl-2H-isoquinolin-1-one (50) is obtained. Rt1.94 minutes (method B). Actually measured quality: 316.1(M + H)+)。
6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (51)
117mg (0.58mmol) of tert-butyl 4-hydroxy-piperidine-1-carboxylate are dissolved in 2mL of N, N-dimethylacetamide. Under an argon atmosphere, 63.6mg (2.7mmol) of sodium hydride were added, and the mixture was stirred at room temperature. After 30 minutes, 150mg (0.53mmol) of 6-fluoro-2- (4-methoxybenzyl) -2H-iso-isomer are addedQuinolin-1-one (14), and the solution is heated to 80 ℃ for 1 hour. The mixture was poured into water and extracted with chloroform. The organic layers were combined and washed with Na2SO4Drying, filtering and evaporating. The crude intermediate was purified by preparative HPLC. The protected intermediate was dissolved in 2mL TFA and the reaction was heated to 150 ℃ in a microwave reactor for 2 hours to remove the protecting group. The reaction mixture was quenched with methanol and evaporated to dryness. The remaining residue was dissolved in dichloromethane, extracted three times with 1N HCl, the aqueous layers combined and extracted once with dichloromethane. The combined aqueous layers were freeze dried and the residue was dissolved twice with water and freeze dried again to give the product as HCl salt. The purity of the product obtained is sufficient, but the impurities which ultimately occur can be removed by chromatography on silica gel or HPLC. Rt0.75 min (method B). Actually measured quality: 245.1(M + H)+)。
The following compounds, obtained as their HCl salts, were prepared in a similar manner using the indicated starting materials.
6- ((R) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one (66)
104mg of 60 are suspended in 2mL of dry dichloromethane. 71 μ L of triethylamine and 105 μ L of benzene were addedFormaldehyde, 26 μ L acetic acid and 150mg powdered molecular sieve. The solution was stirred for 2 hours and 220mg of sodium triacetoxyborohydride was added. The solution was stirred for 3 hours. The reaction mixture was poured into 1N NaOH, the aqueous layer was extracted with dichloromethane: isopropanol (3: 1), and the organic layer was dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography. Rt1.14 min (method B). Actually measured quality: 355.1(M + H)+)。
6- ((S) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one (67)
6- ((S) -1-benzyl-pyrrolidin-3-yloxy) -7-chloro-2H-isoquinolin-1-one (67) was obtained in a similar manner as described for (66). Rt1.11 minutes (method B). Actually measured quality: 355.1(M + H)+)。
6- (azepan-4-yloxy) -7-methyl-2H-isoquinolin-1-one (68)
a) 6-fluoro-7-methyl-2H-isoquinolin-1-one
To a solution of 10.0g (55.5mmol) of 3-fluoro-4-methyl-cinnamic acid in 80mL of acetone at 0 ℃ were successively added a solution of 6.74g (66.6mmol) triethylamine in 10mL of acetone and 7.83g (72.2mmol) ethyl chloroformate. After stirring for 2 hours at 0 to 5 deg.C, a solution of 4.0g (61.1mmol) of sodium azide in 9.5mL of water was added. After stirring for another 1 hour, the reaction mixture was poured onto 200mL of ice-water and extracted twice with chloroform. The organic phase is dried over magnesium sulfate, 40mL of diphenyl ether are added and the chloroform is carefully removed in vacuo. The residue was then added dropwise to 50mL of diphenyl ether which had been preheated to 245 ℃. After complete addition, it was stirred for an additional 1 hour at 230 ℃ and 250 ℃. After cooling to 150 ℃ the reaction mixture is poured into 270mL heptane, after further cooling in an ice bath, the precipitated product is filtered off with suction to give 4.1g 6-fluoro-7-methyl-2H-isoquinolin-1-one.
b) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one
To a solution of 9.17g (51.8mmol) 6-fluoro-7-methyl-2H-isoquinolin-1-one in 80mL DMF was added 20.2g (62.1mmol) cesium carbonate followed by 8.92g (56.9mmol) 4-methoxybenzyl chloride. After stirring at room temperature for 90 minutes, the reaction mixture was poured into 600mL of water, stirred for 1 hour, and the precipitated product was filtered off with suction. Additional product was isolated from the mother liquor by chromatography (heptane/ethyl acetate (80: 20)). The combined product was recrystallized from ethyl acetate to yield 8.39g 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one.
c)6- (azepan-4-yloxy) -2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one
A solution of 58mg (0.51mmol) of azepan-4-ol in 5ml of dimethylacetamide is stirred with 45mg (1.52mmol) of 80% sodium hydride for 45 minutes at room temperature. 150mg (0.51mmol) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one in dimethylacetamide is then added. The reaction mixture was heated to 80 ℃ for 3 days, during which additional amounts of azepan-4-ol and sodium hydride were added until complete conversion to 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one. The reaction mixture was slowly added to 10ml of water, the product was isolated by filtration after 1 hour of stirring, and dried in vacuo overnight. 82mg of 6- (azepan-4-yloxy) -2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one are obtained.
d)6- (azepan-4-yloxy) -7-methyl-2H-isoquinolin-1-one hydrochloride
81mg of 6- (azepan-4-yloxy) -2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one were dissolved in 0.47 trifluoroacetic acid and heated in a microwave oven for 2 hours at 150 ℃. The excess trifluoroacetic acid is then distilled off in vacuo and the residue is diluted with 10ml of 1M hydrochloric acidA compound (I) is provided. The aqueous phase was washed twice with dichloromethane and then freeze dried. The residue is stirred in isopropanol and filtered to yield 15mg of 6- (azepan-4-yloxy) -7-methyl-2H-isoquinolin-1-one as the hydrochloride salt. Rt0.77 min (method C). Actually measured quality: 273.2(M + H)+)。
7-methyl-6- ((R) -1-pyrrolidin-3-ylmethoxy) -2H-isoquinolin-1-one (69)
a) (R) -3- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester
A solution of 271mg (1.35mmol) of (R) -3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 12ml of dimethylacetamide is stirred with 121mg (4.0mmol) of 80% sodium hydride for 30 minutes at room temperature. A solution of 0.5g (1.68mmol) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one (68, step b) in 20ml dimethylacetamide is then added. The reaction mixture was stirred at room temperature overnight, after which the same amounts of (R) -3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and sodium hydride were added to complete the reaction. After stirring for a further 3 hours, the reaction mixture is slowly added to 15ml of water, after 1 hour the product is isolated by filtration and dried in vacuo overnight. This gives 0.53g of (R) -3- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester.
b) 7-methyl-6- ((R) -1-pyrrolidin-3-ylmethoxy) -2H-isoquinolin-1-one hydrochloride
0.53g (1.1mmol) of (R) -3- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxymethyl]Tert-butyl-pyrrolidine-1-carboxylate was dissolved in 2.5g (22mmol) of trifluoroacetic acid. After 1 hour at room temperature, the mixture was heated in a microwave oven at 150 ℃ for 2 hours. The excess trifluoroacetic acid is then distilled off in vacuo and the reaction mixture is washed with 10ml of 1M hydrochloric acid dilutes the residue. The aqueous phase was washed twice with dichloromethane and then lyophilized to give 7-methyl-6- ((R) -1-pyrrolidin-3-ylmethoxy) -2H-isoquinolin-1-one as the hydrochloride salt. Rt0.82 min (method B). Actually measured quality: 259.1(M + H)+)。
7-methyl-6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one (70)
a) (S) -3- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy ] -pyrrolidine-1-carboxylic acid tert-butyl ester
A solution of 252mg (1.35mmol) of tert-butyl (S) -3-hydroxy-pyrrolidine-1-carboxylate in 12ml of dimethylacetamide is stirred with 81mg (2.7mmol) of 80% sodium hydride for 30 minutes at room temperature. A solution of 0.4g (1.3mmol) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one (68, step b) in 15ml dimethylacetamide is then added. The reaction mixture was heated to 80 ℃ for 2 hours, during which time a clear solution was obtained. The reaction mixture was slowly added to 10ml of water, stirred for 30 minutes, filtered to isolate the product, and dried in vacuo overnight. This gives 0.54g of (S) -3- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy ] -pyrrolidine-1-carboxylic acid tert-butyl ester.
b) 7-methyl-6- ((S) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one hydrochloride
0.54g (1.2mmol) of (S) -3- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy]Tert-butyl-pyrrolidine-1-carboxylate was dissolved in 2.7g (23mmol) of trifluoroacetic acid. After 1 hour at room temperature, the mixture was heated in a microwave oven at 150 ℃ for 2 hours. The excess trifluoroacetic acid is then distilled off in vacuo and the residue is diluted with 10ml of 1M hydrochloric acid. The aqueous phase was washed twice with dichloromethane and then lyophilized to give 0.256g of 7-methyl-6- ((S) -pyrrolidin-3-yloxy)Yl) -2H-isoquinolin-1-one as the hydrochloride salt. Rt0.90 min (method B). Actually measured quality: 245.2(M + H)+)。
7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one (71)
a)2- (4-methoxy-benzyl) -7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one hydrochloride
A solution of 125mg (1.0mmol) of (R) -3-pyrrolidinol hydrochloride in 9ml of dimethylacetamide is stirred with 61mg (2.0mmol) of 80% sodium hydride for 30 minutes at room temperature. A solution of 0.3g (1.0mmol) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one (68, step b) in 10ml dimethylacetamide is then added. The reaction mixture was stirred at 80 ℃ for 12 hours, after which the same amounts of (R) -3-pyrrolidinol hydrochloride and sodium hydride were added to complete the reaction. After heating at 80 ℃ for two more days, the reaction mixture was slowly added to 8ml of water and extracted with dichloromethane. After evaporation the residue was dissolved in 20ml of 1M hydrochloric acid and washed with ethyl acetate. The aqueous phase was freeze-dried to yield 247mg of 2- (4-methoxy-benzyl) -7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one hydrochloride.
b) 7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one hydrochloride
245g of 2- (4-methoxy-benzyl) -7-methyl-6- ((R) -pyrrolidin-3-yloxy) -2H-isoquinolin-1-one hydrochloride are dissolved in 1.4g of trifluoroacetic acid and the mixture is heated in a microwave oven for 2 hours at 150 ℃. The excess trifluoroacetic acid is then distilled off in vacuo and the residue is diluted with 10ml of 1M hydrochloric acid. The aqueous phase was washed twice with dichloromethane and then lyophilized to give 134mg of 7-methyl-6- ((R) -1-pyrrolidin-3-ylmethoxy) -2H-isoquinolin-1-one hydrochloride. Rt0.92 min (method B). Actually measured quality: 245.1(M + H)+)。
General procedure for reductive amination reaction:
0.243mmol of 6- (piperidin-4-yloxy) -2H-isoquinolin-1-one-hydrochloride (51) or other suitable amine, 0.243mmol of aldehyde and 0.365mmol of triethylamine in 3mLHC (OMe) at room temperature3And stirred for 1 hour. The mixture was cooled to-10 ℃ and 1.75mL of freshly prepared solution containing 1.215mmol of NaHB (OAc) was added3And 1.215mmol of HOAc in DMF. Stirring was continued for 30 minutes at-10 ℃ and then the mixture was allowed to warm to room temperature and left at room temperature overnight. 0.5mL of water was added and the mixture was evaporated, dissolved in DMF and purified by preparative HPLC. The purified product was dissolved in 1mL of isopropanol (5-6M) containing HCl and stirred until Boc or isopropylidene was completely removed. 2mL of water was added and the solution was freeze dried to give the product hydrochloride.
The following compounds shown in the table below were synthesized in a manner similar to that described in the general procedure to give the hydrochloride salts (table 4).
Assay for Rho kinase inhibition
To determine Rho-kinase inhibition, IC was determined according to the following protocol50The value:
active human recombinant ROCK II (N-terminal His 6-tagged recombinant human ROCK-II residues 11-552) was purchased from Upstate ltd, dunde, UK. The Peptide substrate fluorescein-AKRRRLSSLRA-COOH was purchased from JPT Peptide Technologies, Berlin, Germany. Adenosine-5' -triphosphate (ATP), Bovine Serum Albumin (BSA), dimethyl sulfoxide (DMSO), 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid (Hepes), Brij-35, and Dithiothreitol (DTT) were purchased from Sigma-Aldrich, Munich, Germany. Tris (hydroxymethyl) -aminomethane (Tris), magnesium chloride, NaOH, 1M HCl and EDTA were purchased from Merck Biosciences, Darmstadt, germany. "complete" protease inhibitors are from Roche Diagnostics, Mannheim, Germany.
In buffer 1(25mM Tris-HCl pH 7.4, 5mM MgCl)22mM DTT, 0.02% (w/v) BSA and 3% DMSO) to the appropriate concentration. In buffer 2(25mM Tris-HCl pH 7.4, 5mM MgCl)2ROCK II enzyme was diluted to 100ng/ml in 2mM DTT and 0.02% (w/v) BSA). Peptide substrate and ATP were diluted to 3. mu.M and 120. mu.M, respectively, in buffer 2. Mu.l of the compound solution was mixed with 2. mu.l of the diluted enzyme in 384-well small volume microplates (Greiner, Bio-one, Frickenhausen, Germany) and the kinase reaction was initiated by adding 2. mu.l of the solution containing the peptide substrate and ATP. After incubation at 32 ℃ for 60 minutes, the reaction was stopped by adding 20. mu.l of a solution containing 100mM Hepes-NaOH pH 7.4, 0.015% (v/v) Brij-35, 45mM EDTA and 0.227% chip coating reagent 1(Caliper Life science Inc, Hopkinton, Mass.). Phosphorylation of the substrate peptide was then determined on the Caliper 3000 instrument essentially as described by Pommereau et al (j.biomol. screening 9(5), 409-416, 2004). The separation conditions were as follows: pressure-1.3 psi, upstream voltage-1562V, downstream voltage-500V, sample time 200 ms. Positive control (buffer 1 instead of compound) and negative control (buffer 1 instead of compound and buffer 2 instead of ROCK II) were run in parallel on each plate.
In said test, the following products/compounds were determined and the following activities were determined using the respective forms (salts or free bases) as obtained in the above examples:
example numbering pIC50
15 +++++
11 +++++
16 +++++
19 ++++
22 +++++
24 +++++
55 +++++
46 +++++
58 +++++
66 +++++
67 ++++
68 +++++
69 +++++
70 +++++
75 ++++
The activities given are expressed as IC50Base 10 negative logarithm (pIC)50)：
+：pIC50≤3.0
++：3.0≤pIC50＜4.0
+++：4.0≤pIC50＜5.0
++++：5.0≤pIC50＜6.0
+++++：6.0≤pIC50

Claims (28)

1. Compounds of formula (I), or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof
Wherein:
R1is H, OH or NH2；
R2Is H, halogen or (C)1-C6) An alkyl group;
R3is H;
R4is H or (C)1-C6) An alkyl group;
R5is H or halogen;
R6is (C)1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C6) Alkyl, C (O) R', C (O) - (C)1-C6) alkylene-R';
R7is H, halogen or (C)1-C6) An alkyl group;
R8is H, halogen or (C)1-C6) An alkyl group;
n is 1;
m is 3;
l is O and L is attached to the 4-position of the piperidine ring;
wherein:
r' is (C)3-C8) Cycloalkyl group, (C)5-C10) Heterocyclyl or (C)6-C10) An aryl group;
wherein at the residue R4、R6And R7In which alkyl, alkylene or cycloalkyl is optionally substituted by OH, OCH3、NH2、NHCH3Or N (CH)3)2One or more substitutions;
wherein at the residue R6In (C)6-C10) Aryl is unsubstituted or substituted one or more times by halogen.
2. A compound of formula (I) according to claim 1, wherein R1Is H and is characterized by the formula (II)
3. A compound of formula (I) according to claim 1, wherein R1Is OHAnd is characterized by the formula (III)
4. A compound of formula (I) according to claim 1 or 3, wherein R1Is OH and is characterized by the formula (III
5. The compound according to claim 1, wherein R1Is NH2。
6. The compound according to claim 1, wherein R8Is H, halogen or (C)1-C4) An alkyl group.
7. The compound according to claim 1, wherein R8Is H, C1, F, methyl or ethyl.
8. The compound according to claim 1, wherein R8Is H.
9. The compound according to claim 1, wherein R4Is H or (C)1-C4) An alkyl group.
10. The compound according to claim 1, wherein R4Is H.
11. The compound according to claim 1, wherein R5Is H.
12. According to claim 1A compound of formula (I) wherein R7Is H, halogen or (C)1-C4) An alkyl group.
13. The compound according to claim 1, wherein R7Is H, fluorine, chlorine, bromine, methyl, propyl or ethyl.
14. The compound according to claim 1, wherein R7Is H, fluorine, chlorine, bromine, methyl or propyl.
15. The compound according to claim 1, wherein R7Is H.
16. The compound according to claim 1, wherein R2Is H, halogen or (C)1-C4) An alkyl group.
17. The compound according to claim 1, wherein R2Is H or (C)1-C2) An alkyl group.
18. The compound according to claim 1, wherein R2Is H, methyl or ethyl.
19. The compound according to claim 1, wherein R6Is (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)5-C10) Heterocyclic group, C (O) (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group.
20. The compound according to claim 1, wherein
R6Is C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) - (C)5-C10) Heterocyclic group, C (O) (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C4) Alkylene- (C)6-C10) And (4) an aryl group.
21. A compound according to claim 1, wherein:
R6is that
C(O)(C1-C6) An alkyl group;
C(O)(C3-C6) A cycloalkyl group;
C(O)-(C5-C6) Heterocyclyl, wherein heterocyclyl is unsubstituted;
C(O)(C1-C4) Alkylene- (C)5-C10) Heterocyclyl, wherein heterocyclyl is unsubstituted; or
C(O)(C1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is unsubstituted or substituted one or more times by halogen;
and wherein:
(C1-C6) The alkyl is unsubstituted or independently selected from OH, NH2、NH(CH3) Or N (CH)3)2Is substituted 1 to 3 times by the group (A),
(C1-C4) Alkylene being unsubstituted or substituted by amino or N (CH)3)2Substituted once, and (C)3-C6) Cycloalkyl unsubstituted or substituted by NH2Once substituted.
22. A compound according to claim 1, wherein:
R1is H, OH, NH2；
R2Is hydrogen, halogen or (C)1-C6) An alkyl group;
R3is H;
R4is H or (C)1-C6) An alkyl group;
R5is H or halogen;
R6is (C)1-C6) alkylene-C (O) N [ (C)1-C4) Alkyl radical]2、C(O)(C1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) An aryl group;
R7is H, halogen or (C)1-C6) An alkyl group;
R8is H, halogen or (C)1-C6) An alkyl group;
n is 1.
23. A compound according to claim 1, wherein:
R1is H or OH;
R2is H or (C)1-C4) An alkyl group;
R3is H;
R4is H or (C)1-C4) An alkyl group;
R5is H or halogen;
R6is C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) - (C)5-C10) Heterocyclic group, C (O) (C)1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) An aryl group;
R7is H, halogen or (C)1-C6) An alkyl group;
R8is H, halogen or (C)1-C6) An alkyl group;
n is 1.
24. A compound according to claim 1, wherein:
R1is H or OH;
R2is H or (C)1-C4) An alkyl group;
R3is H;
R4is H or (C)1-C4) An alkyl group;
R5is H or halogen;
R6is C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) - (C)5-C10) Heterocyclic group, C (O) (C)1-C3) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C3) Alkylene- (C)6-C10) An aryl group;
R7is H, halogen or (C)1-C4) An alkyl group;
R8is H, halogen or (C)1-C4) An alkyl group;
n is 1.
25. Use of at least one compound of formula (I) according to any one of claims 1 to 24 and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulation disorders, peripheral arterial occlusive disease, coronary heart disease, heart failure, ischemic disease, fibrotic lung, fibrotic liver, liver failure, renal disease, organ hypertrophy, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, pain, neuronal degeneration, spinal cord injury, alzheimer's disease, premature labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, inflammation, autoimmune disease, AIDS, inflammatory bowel disease, inflammatory bowel syndrome, inflammatory bowel disease, Bone disease, bacterial infection of the digestive tract, sepsis or cancer development and progression.
26. The use of claim 25, wherein the organ hypertrophy is cardiac hypertrophy or prostatic hypertrophy and the arteriosclerosis is atherosclerosis.
27. Use of at least one compound of formula (I) according to any one of claims 1 to 24 and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of angina pectoris, ischemic organ failure and end organ damage caused by ischemic organ failure, cerebral ischemia, renal failure, fibrotic kidneys, glomerulosclerosis.
28. A medicament comprising an effective amount of at least one compound according to any one of claims 1 to 24 or/and pharmaceutically acceptable salts thereof, physiologically tolerated excipients and carriers and, where appropriate, further additives and/or further active ingredients.
HK10106348.4A 2006-12-27 2007-12-19 Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase HK1140201B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06026898.4 2006-12-27
EP06026898 2006-12-27
PCT/EP2007/011163 WO2008077550A1 (en) 2006-12-27 2007-12-19 Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase

Publications (2)

Publication Number Publication Date
HK1140201A1 HK1140201A1 (en) 2010-10-08
HK1140201B true HK1140201B (en) 2014-01-30

Family

ID=

Similar Documents

Publication Publication Date Title
CN101616909B (en) Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase
CN101228149B (en) Piperidinyl-substituted isoquinolinone derivatives as Rho-kinase inhibitors
JP5405315B2 (en) Substituted isoquinoline and isoquinolinone derivatives
JP5318778B2 (en) Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives
JP5313919B2 (en) Novel substituted isoquinoline and isoquinolinone derivatives
JP5405314B2 (en) Cycloalkylamine substituted isoquinolone derivatives
JP5049970B2 (en) Cyclohexylamine isoquinolone derivatives as RHO-kinase inhibitors
HK1140201B (en) Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase
HK1123035B (en) Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors
HK1138583B (en) Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives
HK1138582A (en) Substituted isoquinoline and isoquinolinone derivatives