CA2850700C - New bicyclic dihydroisoquinoline-1-one derivatives - Google Patents

New bicyclic dihydroisoquinoline-1-one derivatives Download PDF

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CA2850700C
CA2850700C CA2850700A CA2850700A CA2850700C CA 2850700 C CA2850700 C CA 2850700C CA 2850700 A CA2850700 A CA 2850700A CA 2850700 A CA2850700 A CA 2850700A CA 2850700 C CA2850700 C CA 2850700C
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dihydro
chloro
pharmaceutically acceptable
acceptable salt
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CA2850700A1 (en
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Johannes Aebi
Kurt Amrein
Wenming Chen
Benoit Hornsperger
Bernd Kuhn
Yongfu Liu
Hans P. Maerki
Alexander V. Mayweg
Peter Mohr
Xuefei Tan
Zhanguo Wang
Mingwei Zhou
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F Hoffmann La Roche AG
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4¸ R5, R6, A1, A2, A3, A4, A5 and n are as described herein,compositions including the compounds and methods of using the compounds as aldosterone synthase (CYP11B2 or CYP11B1) inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME1 ________________ DE 2 NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS/ PATENTS
THIS SECTION OF THE APPLICATION/ PATENT CONTAINS MORE
THAN ONE VOLUME.
NOTE: For additional volumes please contact the Canadian Patent Office.
The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to aldosterone synthase (CYP 1 1B2 or CYP 1 1B1) inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
The present invention provides novel compounds of formula (I) I IAl A5 A2 \IA3 R5 0 Ai\i) (I) wherein R1, R2, R3 and R4 are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocyclo alkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R12, R1'and R"; or R2 and R4 together form a double bond, wherein in case R2 and R4 together form a double bond, then R5 is H; or R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and 22, substituted heterocycloalkyl are substituted with R R2'and R24;
WO2013/079452 PCT/EP2012/073653 - 2 - or R3 and R4 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R29, le)and R31; or R1 and R3 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R44, R45and R46;
A1 is CR8 or N;
A2 is CR9 or N;
A3 is CR19 or N;
A4 is CRil or N;
A5 is CR6 or N; one of R5, R6, R7 and R8 is selected from halogen, cyano, alkoxy, hydroxyalkoxy, haloalkyl, haloalkoxy and hydroxy and the others are each independently selected from H, halogen, cyano, alkoxy, hydroxyalkoxy, haloalkoxy and hydroxy;
R9 is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, halo alkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl, wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted with R32, R"and R34;
R1 is -0m-(cR15R16)p_(cRt7Ri8)q_(cRi9R20)r_R21:
WO2013/079452 PCT/EP2012/073653 - 3 - or R9 and R1 together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl or a subtituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted with R15, eand R37;
R" is H;
R15, R17 and R19 are each independently selected from H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl;
R16, R'8 and R2 are each independently selected from H, hydroxy, halogen and alkyl; or R15 and R16 together with the carbon atom to which they are attached form a cycloalkyl; or R17 and R18 together with the carbon atom to which they are attached form a cycloalkyl; or R19 and R2 together with the carbon atom to which they are attached form a cycloalkyl; or R15 and R17 together form -(CH2),-; or R15 and R19 together form -(CH2)-; or R17 and R19 together form -(CH2)x-;
R21 is H, halogen, cyano, -0R25, -SR25, -S(0)R25, -S(0)2R25, -NR25R26, _NR26s02R25, _ NR26S02NR25R27, -NR26C(0)R25, -NR26C(0)NR25R27, -C(0)R28, -c(o)NR25R26, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl and substituted aryl are substituted with R38, eand R40;
R25 is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, halocycloalkoxyalkyl, alkylcycloalkoxyalkyl, alkoxyalkyl, halo alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkoxyalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted WO2013/079452 PCT/EP2012/073653 - 4 - heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R41, R42and R43;
R26 and R27 are each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl; or R15 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, eand R49; or R17 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; or R19 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49;
R28 is H, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R50, R51and R52;
R12, R13, R14, R22, R23, R24, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and K-52 are each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkylcarbonylamino, alkylsulfonyl, WO2013/079452 PCT/EP2012/073653 - 5 - alkylsulfonylamino, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, halo alkoxyalkoxyalkyl, chloropyridinylcarbonyl and heterocycloalkyl; n is zero or 1; m zero or 1; p, q and r are independently selected from zero and 1; v and x are independently selected from 1, 2, 3 or 4; w is zero, 1, 2 or 3; with the proviso that no more than two of A2, A3 and A4 are N; and pharmaceutically acceptable salts thereof Herein we describe inhibitors of aldosterone synthase that have the potential to protect from organ/ tissue damage caused by an absolute or relative excess of aldosterone.
Hypertension affects about 20% of the adult population in developed countries.
In persons 60 years and older, this percentage increases to above 60%. Hypertensive subjects display an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. The renin angiotensin aldosterone system is a pathway that has been linked to hypertension, volume and salt balance and more recently to contribute directly to end organ damage in advanced stages of heart failure or kidney disease. ACE inhibitors and angiotensin receptor blockers (ARBs) are successfully used to improve duration and quality of life of patients. These drugs are not yielding maximum protection.
In a relatively large number of patients ACE and ARB's lead to so-called aldosterone breakthrough, a phenomenon where aldosterone levels, after a first initial decline, return to pathological levels. It has been demonstrated that the deleterious consequences of inappropriately increased aldosterone levels (in relation to salt intake/levels) can be minimized by WO2013/079452 PCT/EP2012/073653 - 6 - aldosterone blockade with mineralocorticoid receptor antagonists. A direct inhibition of aldosterone synthesis is expected to provide even better protection as it will also reduce non-genomic effects of aldosterone as well.
The effects of aldosterone on Na/K transport lead to increased re-absorption of sodium and water and the secretion of potassium in the kidneys. Overall this results in increased blood volume and, therefore, increased blood pressure. Beyond its role in the regulation of renal sodium re-absorption aldosterone can exert deleterious effects on the kidney, the heart and the vascular system especially in a "high sodium" context. It has been shown that under such conditions aldosterone leads to increased oxidative stress which ultimately may contribute to organ damage. Infusion of aldosterone into renally compromised rats (either by high salt treatment or by unilaterally nephrectomy) induces a wide array of injuries to the kidney including glomerular expansion, podocyte injury, interstitial inflammation, mesangial cell proliferation and fibrosis reflected by proteinuria.
More specifically aldosterone was shown to increase the expression of the adhesion molecule ICA1vI-1 in the kidney. ICAM-1 is critically involved in glomerular inflammation. Similarly, aldosterone was shown to increase the expression of inflammatory cytokines, such as interleukin IL-lb and IL-6, MCP-1 and osteopontin. On a cellular level it was demonstrated that in vascular fibroblasts aldosterone increased the expression of type I collagen mRNA, a mediator of fibrosis. Aldosterone also stimulates type IV collagen accumulation in rat mesangial cells and induces plasminogen activator inhibitor-1 (PAI-1) expression in smooth muscle cells. In summary aldosterone has emerged as a key hormone involved in renal damage. Aldosterone plays an equally important role in mediating cardiovascular risk.
There is ample preclinical evidence that MR-antagonists (spironolactone and .. eplerenone) improve blood pressure, cardiac and renal function in various pre-clinical models.
More recently preclinical studies highlight the important contribution of CYP11B2 to cardiovascular and renal morbidity and mortality. The CYP11B2 inhibitor FAD286 and the MR antagonist spironolactone were evaluated in a rat model of chronic kidney disease (high angiotensin II exposure; high salt and uni-nephrectomy). Angiotensin II and high salt treatment caused albuminuria, azotemia, renovascular hypertrophy, glomerular injury, PCT/EP2012/073653 - 7 - increased PAT-1, and osteopontin mRNA expression, as well as tubulointerstitial fibrosis.
Both drugs prevented these renal effects and attenuated cardiac and aortic medial hypertrophy. Following 4 weeks of treatment with FAD286, plasma aldosterone was reduced, whereas spironolactone increased aldosterone at 4 and 8 weeks of treatment.
Similarly only spironolactone but not FAD286 enhanced angiotensin II and salt- stimulated PAT-1 mRNA expression in the aorta and the heart. In other studies the CYP11B2 inhibitor FAD286 improved blood pressure and cardiovascular function and structure in rats with experimental heart failure. In the same studies FAD286 was shown to improve kidney function and morphology.
Administration of an orally active CYP11B2 inhibitor, LCI699, to patients with primary aldosteronism, lead to the conclusion that it effectively inhibits CYP11B2 in patients with primary aldosteronism resulting in significantly lower circulating aldosterone levels and that it corrected the hypokalemia and mildly decreased blood pressure. The effects on the glucocorticoid axis were consistent with a poor selectivity of the compound and a latent inhibition of cortisol synthesis. Taken together these data support the concept that a CYP11B2 inhibitor can lower inappropriately high aldosterone levels.
Achieving good selectivity against CYP11B1 is important to be free of undesired side effects on the HPAaxis and will differentiate different CYP11B2 inhibitors.
Objects of the present invention are the compounds of formula (I) and their aforementioned salts and esters and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts or esters, the use of the said compounds, salts or esters for the treatment or prophylaxis of illnesses, especially in the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom and the use of the said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
The term "alkoxy" denotes a group of the formula -0-R', wherein R' is an alkyl group. Examples of alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy and tert-butoxy. Particular alkoxy group include methoxy.
The term "alkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group.
Examples of alkoxyalkoxy group include methoxymethoxy, ethoxyrnethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy. Particular alkoxyalkoxy groups .. include methoxymethoxy and methoxyethoxy.
The term "alkoxyalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group.
Examples of alkoxyalkoxyalkyl group include methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.
The term "alkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl and isopropoxymethyl. Particular alkoxyalkyl group include include methoxymethyl, methoxyethyl and isopropoxymethyl.
The term "alkoxycarbonyl" denotes a group of the formula -C(0)-R', wherein R' is an alkoxy group. Examples of alkoxycarbonyl groups include groups of the formula -C(0)-R', wherein R' is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxycarbonyl group is a group of the formula -C(0)-R', wherein R' is methoxy.
The term "alkoxycycloalkylalkyl" denotes a cycloalkylalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group is replaced by an alkoxy group. An example of alkoxycycloalkylalkyl group is cyclopropylmethoxymethyl.
The term "alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and.
Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl groups are methyl, isopropyl and ethyl.
The term "alkylcarbonyrof the formula -C(0)-R', wherein R' is an alkyl group.
Examples of alkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is methyl or ethyl.
The term "alkylcarbonylamino" denotes an amino group wherein one of the hydrogen atoms of the -NH2 group is replaced by an alkylcarbonyl group.
Examples of alkylcarbonylamino groups include groups wherein R' is methyl or ethyl.
Particular alkylcarbonylamino groups include groups wherein R' is ethyl.
The term "alkylcarbonylaminoalkyl" denotes an aminoalkyl group wherein one of the hydrogen atoms of the -NH2 group is replaced by an alkylcarbonyl group.
Examples of .. alkylcarbonylaminoalkyl groups include groups wherein R' is methyl or ethyl.
The term "alkylcycloalkoxy" denotes a cycloalkoxy group wherein at least one of the hydrogen atoms of the cycloalkoxy group is replaced by an alkyl group.
Examples of alkylcycloalkyl include methyl- cyclopropoxy, dimethyl- cyclopropoxy, methyl- cyclobutoxy, dimethyl-cyclobutoxy, methyl-cyclopentoxy, dimethyl-cyclopentoxy, .. methyl-cyclohexyloxy and dimethyl-cyclohexyloxy.
The term "alkylcycloalkoxyalkyr denotes a cycloalkoxyalkyl group wherein at least one of the hydrogen atoms of the cycloalkoxyalkylgroup is replaced by an alkyl group.
Examples of alkylcycloalkyl include methyl- cyclopropoxymethyl, dimethyl- cyclopropoxymethyl, methyl-cyclobutoxymethyl, dimethyl-cyclobutoxymethyl, methyl- cyclopentoxymethyl, dimethyl-cyclopentoxymethyl, methyl-cyclohexyloxymethyl and dimethyl-cyclohexyloxymethyl.
The term "alkylcycloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group is replaced by an alkyl group. Examples of alkylcycloalkyl include methyl-cyclopropyl, dimethyl-cyclopropyl, methyl- cyclobutyl, .. dimethyl-cyclobutyl, methyl-cyclopentyl, dimethyl-cyclopentyl, methyl- cyclohexyl and dimethyl-cyclohexyl. Particular alkylcycloalkyl groups include methyl- cyclopropyl and dimethyl-cyclopropyl.
The term "alkylcycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkylcycloalkyl group.
Examples of PCT/EP2012/073653 - 10 - alkylcycloalkylalkyl include methyl-cyclopropylmethyl, dimethyl- cyclopropylmethyl, methyl-cyclopropylethyl, dimethyl-cyclopropylethyl, methyl-cyclobutylmethyl, dimethyl- cyclobutylmethyl, methyl-cyclobutylethyl, dimethyl-cyclobutylethyl, methyl- cylopentylmethyl, dimethyl-cylopentylmethyl, methyl-cyclopentylethyl, dimethyl- cyclopentylethyl, methyl-cyclohexylmethyl, dimethyl-cyclohexylmethyl, methyl- cyclohexylethyl, dimethyl-cyclohexylethyl, methyl-cycloheptylmethyl, dimethyl- cycloheptylmethyl, methyl-cycloheptylethyl, dimethyl-cycloheptylethyl, methyl- cyclooctylmethyl, dimethyl-cyclooctylmethyl, methyl-cyclooctylethyl and dimethyl- cyclooctylethyl.
The term "alkylsulfonyl" denotes a group of the formula -S(0)2-R', wherein R' is an alkyl group. Examples of alkylsulfonyl groups include groups of the formula -S(0)2-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert- butyl.
The term "alkylsulfonylamino" denotes a group of the formula -NH2-S(0)2-R', wherein R' is an alkyl group. Examples of alkylsulfonyl groups include groups of the formula -NH2-S(0)2-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl and tert-butyl.
The term "amino" denotes a -NH2 group.
The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl group include phenyl and naphthyl. Particular aryl group is phenyl.
The term "arylalkyl" denotes denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced an aryl group. Particular arylalkyl group is phenylalkyl. More particular arylalkyl group is benzyl.
The term "arylhydroxyalkyl" denotes denotes an hydroxyalkyl group wherein at least one of the hydrogen atoms of the hydroxyalkyl group has been replaced an aryl group. Particular arylalkyl group is phenylhydroxymethyl.
The term "bicyclic ring system" denotes two rings which are fused to each other via a common single or double bond (annelated bicyclic ring system), via a sequence of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system). Bicyclic ring systems can be saturated, partially unsaturated, unsaturated or aromatic. Bicyclic ring systems can comprise heteroatoms selected from N, 0 and S.
The term "carbonyl" denotes a -C(0)- group.
The term "carboxyl" denotes a -C(0)0H group.
The term "carboxyalkyl" denotes an alkyl group wherein at least one of the hydrogen .. atoms of the alkyl group has been replaced by a carboxy group. Examples are carboxymethyl, carboxyethyl, carboxypropyl and 1-carboxy-2-methylpropyl.
Particular example is 1-carboxy-2-methylpropyl.
The term "cyano" denotes a -C-1\1 group.
The term "cycloalkoxy" denotes a group of the formula -0-R', wherein R' is a cycloalkyl group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.
The term "cycloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group.
Examples of cycloalkoxyalkyl group include cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.
The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments, cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having two carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples for monocyclic WO2013/079452 PCT/EP2012/073653 - 12 - cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.
Particular monocyclic cycloalkyl grous are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl. In particular, the .. cycloalkyl formed by R9 and Rm together with the carbon atoms to which they are attached is cyclohexyl and cyclopentyl. Further particular the cycloalkyl formed by R9 and Rl together with the carbon atoms to which they attached is cyclohexyl.
In particular the cycloalkyl formed by RI and R2 together with the carbon atoms to which they attached is cyclopropyl.
The term -cycloalkylalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.
The term "cycloalkylalkoxyalkyl" denotes an alkyl group wherein at least one of the .. hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group.
Examples of cycloalkylalkoxyalkyl include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.
The term "cycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl and cyclopentylbutyl. Particular examples of cycloalkylalkyl groups are cyclopropylmethyl, cyclopropylbutyl and 2- cyclopropylbutyl.
The term "cycloalkylcarbonyrof the formula -C(0)-R', wherein R' is a cycloalkyl group. Examples of cycloalkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is cyclopropyl.
The term "cycloalkylcarbonylamino" denotes an amino group wherein one of the hydrogen atoms of the -NH2 group is replaced by an cycloalkylcarbonyl group.
Examples of alkylcarbonylamino groups include groups wherein R' is cyclopropyl.
The term "cycloalkylcarbonylaminoalkyr denotes an aminoalkyl group wherein one of the hydrogen atoms of the -NH2 group is replaced by an cycloalkylcarbonyl group.
Examples of alkylcarbonylaminoalkyl groups include groups wherein R' is cyclopropyl.
The term "dialkoxyalkyl" denotes an alkyl group wherein two of the hydrogen atoms of the alkyl group have been replaced by two alkoxy group. Exemplary dialkoxyalkyl groups include dimethoxymethyl, diethoxymethyl, dimethoxyethyl, diethoxyethyl, dimethoxypropyl, diethoxypropyl and diisopropoxymethyl. Particular dialkoxyalkyl group is dimethoxymethyl.
The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by same or different halogen atoms. The tetra "perhaloalkoxy" denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.
Particular haloalkoxy groups are trifluoromethoxy and 2,2-difluoroethoxy.
The term "haloalkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a haloalkoxy group.
Examples of haloalkoxyalkyl include fluoromethoxymethoxy, difluoromethoxymethoxy, trifluoromethoxymethoxy, fluoroethoxymethoxy, difluoroethoxymethoxy, trifluoroethoxymethyoxy, fluoromethoxyethoxy, difluoromethoxyethoxy, trifluoromethoxyethoxy, fluoroethoxyethoxy, difluoroethoxyethoxy, trifluoroethoxyethoxy, fluoromethoxypropoxy, difluoromethoxypropoxy, trifluoromethoxypropoxy, fluoroethoxypropoxy, difluoroethoxypropoxy and trifluoroethoxypropoxy.
The term "haloalkoxyalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxyalkoxy group.
Examples of haloalkoxyalkyl include fluoromethoxymethoxymethyl, WO2013/079452 PCT/EP2012/073653 - 14 - difluoromethoxymethoxymethyl, trifluoromethoxymethoxymethyl, fluoroethoxymethoxymethyl, difluoroethoxymethoxymethyl, trifluoroethoxymethyoxymethyl, fluoromethoxyethoxymethyl, difluoromethoxyethoxymethyl, trifluoromethoxyethoxymethyl, fluoroethoxyethoxymethyl, difluoroethoxyethoxymethyl, trifluoroethoxyethoxymethyl, fluoromethoxypropoxymethyl, difluoromethoxypropoxymethyl, trifluoromethoxypropoxymethyl, fluoroethoxypropoxymethyl, difluoroethoxypropoxymethyl and trifluoroethoxypropoxymethyl.
The term "haloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group.
Examples of haloalkoxyalkyl include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, fluoroethoxymethyl, difluoroethoxymethyl, trifluoroethoxymethyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluorornethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, trifluoroethoxyethyl, fluoromethoxypropyl, difluoromethoxypropyl, trifluoromethoxypropyl, fluoroethoxypropyl, difluoroethoxypropyl and trifluoroethoxypropyl. Particular haloalkoxyalkyl is 2,2- difluoroethoxyethyl.
The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by same or different halogen atoms.
The term "perhaloalkyl" denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoro ethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl groups are trifluoromethyl. Also particular groups are difluoromethyl.
The term "halocycloalkoxy" denotes a cycloalkoxy group wherein at least one of the hydrogen atoms of the cycloalkoxy group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of halocycloalkoxy groups include fluorocyclopropoxy, difluorocyclopropoxy, fluorocyclobutoxy and difluorocyclobutoxy.
The term "halocycloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halocycloalkoxy group, WO2013/079452 PCT/EP2012/073653 - 15 - particularly fluoro atoms. Examples of halocycloalkoxyalkyl groups include fluorocyclopropoxymethyl, difluorocyclopropoxymethyl, fluorocyclobutoxymethyl and difluorocyclobutoxymethyl.
The term "halocycloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of halocycloalkyl groups include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl and difluorocyclobutyl.
The term "halocycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halocycloalkyl.
Examples of halocycloalkylalkyl groups include fluorocyclopropylmethyl, fluorocyclopropylethyl, difluorocyclopropylmethyl, difluorocyclopropylethyl, fluorocyclobutylmethyl, fluorocyclobutylethyl, difluorocyclobutylmethyl and difluorocyclobutylethyl.
The term "halogen" and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogens are chloro and fluoro.
The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatorns selected from N, 0 and S, the remaining ring atoms being carbon. Examples of heteroaryl group include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particular heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, benzoimidazolyl, indazolyl, indolyl, pyridinyl, isooxazoly1 and oxazolyl.
In particular, the heteroaryl groups formed by R9 and R1 together with the carbon atoms to which they are attached are pyrrolyl and pyrazolyl. In particular, in the case of R21, the term "heteroaryl" denotes the imidazolyl, pyrazolyl, triazolyl, benzoimidazolyl, indazolyl, indolyl, pyridinyl and izooxazolyl groups. More particularly the pyrazolyl group.
In particular, in the case of R25, the term "heteroaryl" denotes the pyridinyl, pyrazolyl and oxazolyl groups. In particular, in the case of R25, the term "heteroaryl" denotes the pyrazolyl and oxazolyl groups. Further particular heteroaryl in the case of R25 is pyrazolyl and pyridinyl. More particular is pyrazolyl.
The term "heteroarylalkyl" denotes denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a heteroaryl group.
Examples are pyrazolylalkyl and imidazolylalkyl. More particular examples are pyrazolylmethyl and imidazolylmethyl.
In particular, in the case of R25, the term "heteroarylalkyl" denotes the pyrazolylmethyl and imidazolylmethyl groups. In particular the pyrazolylmethyl group.
The term "heterocycloalkyl" denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, 0 and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, 0 and S, the remaining ring atoms being carbon. Examples for monocyclic saturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro- thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazinanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza- bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza- bicyclo [3 .3 . 1 ]nonyl, 3-oxa-9-aza-bicyclo [3.3 .1 ]nonyl, 3-thia-9-aza- bicyclo [3.3.1 ]nonyl and 2,6-diaza-spiro[3.3]heptanyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.
More particular examples of heterocycloalkyl group are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo- thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinanyl and .. 2,6-diaza-spiro[3.3]heptanyl. More particular examples of a heterocycloalkyl are pyrrolydinyl, piperidinyl, thiomorpholinyl, thiazinanyl and 2,6-diaza- spiro[3.3]heptanyl.
In particular, in the case of R21, the term "heterocycloalkyl" denotes the pyrrolidinyl, thiazinan-2-yl, isothiazolidin-2-yl, piperidinyl, morphonlinyl, thiomorphonlinyl, oxazolidinyl, imidazolidinyl, piperazinyl, 2-oxa-6-aza-spiro[3.4]heptanyl and 2-oxa-6-aza- spiro[3.4]octanyl groups. Further particularly the piperazinyl and 2-oxa-6-aza- spiro[3.4]octanyl groups More particularly the 2-oxa-6-aza-spiro[3.4]octanyl group. Also more particularly the piperazinyl group.
In particular, in the case of R25, the term "heterocycloalkyl" denotes the oxetanyl group.
In particular, in the case of R28, the term "heterocycloalkyl" denotes the morpholinyl, pyrrolidinyl and piperidinyl groups.
In particular the heterocycloalkyl formed by R15 and R26 together with the nitrogen atom and carbon atom to which they are attached are azetanyl, pyrrolidinyl and piperidinyl.
The term "heterocycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a heterocycloalkyl group.
Examples are tetrahydrofuranylalkyl, pyrrolidinylalkyl and piperazin-l-ylalkyl. More particularly, tetrahydrofuranylethyl, pyrrolidinylmethyl and piperazin-l-ylmethyl.
In particular, in the case of R9, the term "heterocycloalkylalkyl" denotes the piperazin-l-ylalkyl group. More particularly, the piperazin-l-ylalkyl group.
In particular, in the case of R25, the term "heterocycloalkylalkyl" denotes the tetrahydrofuranylalkyl and pyrrolidinylalkyl groups. More particularly, the tetrahydrofuranylethyl and pyrrolidinylmethyl groups.
The term "hydroxy" denotes a -OH group.
The term "hydroxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a hydroxy group.
Examples of hydroxyalkyl include hydroxyethethoxy, hydroxypropoxy and hydroxymethylpropoxy.
The term "hydroxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxy-l-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.
The term "oxo" denotes a divalent oxygen atom =0.
The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N- acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic .. amines and basic ion exchange resins, such as isopropylaminc, trimethylaminc, diethylamine, tricthylaminc, tripropylamine, ethanolaminc, lysine, argininc, N- ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts , methanesulfonic acid salts and citric acid salts. "Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. [Additionally, any physiologically acceptable equivalents of the compounds of general WO2013/079452 PCT/EP2012/073653 - 19 - formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
The term "protecting group" (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy- protecting groups or hydroxy-protecting groups. Particular protecting groups are the tert- butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protecting group is the tert- butoxycarbonyl (Boc).
The abbreviation uM means microMolar and is equivalent to the symbol iuM.
The compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom.
All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H ("D"), 3H 11C, 13C, 14c, 13-, 15N, 150, 170, 180, 32F, 33F, 35s, 18F, 36o, 1231 and 1251. Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3H or 14C) are useful in compound and /or substrate tissue distribution assays. Tritiated (3H) and carbon-14 ('4C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resuting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as iso, 13N, and 18F are useful for WO2013/079452 PCT/EP2012/073653 - 20 - positron emission tomography (PET) studies to examine substrate receptor occupancy.
Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting a non-isotopically labeled reagent with a isotopically labeled reagent. In particular, compounds of formula (I) wherein one or more H atom have been replaced by a 2H atom are also an embodiment of this invention.
The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
According to the Cahn-Ingold-Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration.
Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.
Also an embodiment of the present invention are compounds according to formula (I) as described herein wherein Ri, R2, K-3 and R4 are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R12, R13and R14; or R2 and R4 together form a double bond, wherein in case R2 and R4 together form a double bond, then R5 is H;
WO2013/079452 PCT/EP2012/073653 - 21 - or R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23and R24; or R3 and R4 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R29, eand R31; or R1 and R3 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R44, eand R46;
A1 iS CR8 or N;
A2 is CR9 or N;
A3 is CRi or N;
A4 is CRil or N;
A5 is CR6 or N; one of R5, R6, R7 and R8 is selected from halogen, cyano, alkoxy, hydroxyalkoxy, haloalkyl, haloalkoxy and hydroxy and the others are each independently selected from H, halogen, cyano, alkoxy, hydroxyalkoxy, haloalkoxy and hydroxy;
R9 is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, halo alkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl, wherein substituted arylalkyl, substituted arylhydroxyalkyl, WO2013/079452 PCT/EP2012/073653 - 22 - substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted with R32, R"and R"; ¨10 Kis -0ni-(CR15-16 )p-(CR17t('-µ18)q-(CR19R2o),-R21; or R9 and Ri together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl or a subtituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted with R35, R36and R37;
R" is H;
R15, 1117 and R19 are each independently selected from H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl;
R16; ¨18 Kand R2 are each independently selected from H, hydroxy, halogen and alkyl; or R15 and R16 together with the carbon atom to which they are attached form a cycloalkyl; or R17 and R18 together with the carbon atom to which they are attached form a cycloalkyl; or R19 and R2 together with the carbon atom to which they are attached form a cycloalkyl; or R15 and R17 together form -(CH2)v-; or R15 and R19 together form -(CH2)w-; or R17 and R19 together form -(CH2)x-;
R2' is H, halogen, cyano, -0R25, -SR25, -S(0)R25, -S(0)2R25, -NR25R 26, NR26S02R25, -NR26S02NR25R27, -NR26C(0)R25, -NR26C(0)NR25R27, -C(0)R28, -C(0)NR25R26, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl and substituted aryl are substituted with R38, R39and R40;
R25 is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, halocycloalkoxyalkyl, alkylcycloalkoxyalkyl, alkoxyalkyl, halo alkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkoxyalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R41, R42and R43;
R26 and R27 are each independently selected from H, alkyl, cycloalkyl, halo alkyl or halocycloalkyl; or R15 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; or R17 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R4 and R49; or R19 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49;
R28 is H, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted WO2013/079452 PCT/EP2012/073653 - 24 - heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R50, R51and R52;
R12, R115 R14, R22, RD, R24, R29, R305 R31, R32, R335 R345 R155 R16, R17, R385 R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and tc ¨52 are each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloall(yl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonylamino, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocyclo alkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, halo alkoxyalkoxyalkyl and heterocycloalkyl; n is zero or 1; m zero or 1; p, q and r are independently selected from zero and 1; v and x are independently selected from 1, 2, 3 or 4; w is zero, 1, 2 or 3; with the proviso that no more than two of A2, A3 and A4 are N; and pharmaceutically acceptable salts thereof Afurther embodiment of the present invention are compounds according to formula (I) as described herein, wherein Rl, R2, R3 and R4 are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl, wherein WO2013/079452 PCT/EP2012/073653 - 25 - substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R'2, 1 R 3and R14.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 and R4 together form a double bond, wherein in case R2 and R4 together form a double bond, then R5 is H.
In a further embodiment of the present invention are compounds according to formula (1) as described herein, wherein R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23and R24 Another further embodiment of the present invention are compounds according to formula (1) as described herein, wherein R3 and R4 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R29, R30and R31.
Another embodiment of the present invention are compounds according to formula (1) as described herein, wherein R1 and R3 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R44, R45and R46.
The present invention also relates to compounds according to formula (I) as described herein, wherein R1 is H, alkyl or arylalkyl substituted with R12, R13and R14.
Afurther particular embodiment of the present invention are compounds according to formula (1) as described herein, wherein R1 is H or alkyl.
Amore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein Rl is methyl or ethyl.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1, R2, R3 and R4 are independently selected from H, alkyl or arylalkyl substituted with R12, Ri'and R14.
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein is R1, R2, R3 and R4 are independently selected from H or alkyl.
Aparticular embodiment of the present invention are compounds according to formula (1) as described herein, wherein Rl is H, alkyl or arylalkyl substituted with R12, eand R14 and wherein R12, eand R14 are H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is H or alkyl.
The present invention also relates to compounds according to formula (I) as .. described herein, wherein R2 is H.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R2 is methyl.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23and R24.
The present invention also relates to compounds according to formula (1) as described herein, wherein 121 and R2 together with the carbon atom to which they are 22, attached form a cycloalkyl substituted with R R23and R24.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 and R2 together with the carbon atom to which they are attached form a cyclopropyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R3 is H or alkyl.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R3 is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R4 is H.
Aparticular embodiment of the present invention are compounds according to formula (1) as described herein, wherein A1 is CR8.
Afurther particular embodiment of the present invention are compounds according to formula (1) as described herein, wherein A1 is N.
Amore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A2 is CR9.
Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A2 is N.
Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A3 is CR1 .
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein A3 is N.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein A4 is CR11.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein A4 is N.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein A5 is CR6.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein A5 is N.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein one of R5, R6, R7 and R8 is selected from halogen, alkoxy and hydroxy and the others are each independently selected from H and halogen.
Afurther embodiment of the present invention are compounds according to formula (I) as described herein, wherein one of R5, R6 and R8 are H.
Also an embodiment of the present invention are compounds according to formula (1) as described herein, wherein one of R5, R6 and R8 are H and R7 is halogen or alkoxy.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein at least one of R5, R6, R7 and R8 is different from H.
Afurther embodiment of the present invention are compounds according to formula (I) as described herein, wherein R5 is H or halogen and wherein at least one of R5, R6, R7 and R8 is different from H.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R6 is H or halogen and wherein at least one of R5, R6, R7 and R8 is different from H.
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R7 is H, halogen, alkoxy or hydroxy and wherein at least one of R5, R6, R7 and RS is different from H.
Amore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R7 is halogen or alkoxy.
Another embodiment of the present invention are compounds according to formula (1) as described herein, wherein R7 is halogen.
Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R7 is chloro.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is H or halogen and wherein at least one of R5, R6, R7 and R8 is different from H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylallwxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocyclo alkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, halo alkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl, wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted with R12, eand Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 is H, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, substituted arylhydroxyalkyl or substituted heterocycloalkylalkyl, wherein substituted substituted arylhydroxyalkyl and substituted heterocycloalkylalkyl are substituted with R32, Rand R34.
The present invention also relates to compounds according to formula (I) as described herein, wherein R9 is H or halogen.
Afurther embodiment of the present invention are compounds according to formula .. (I) as described herein, wherein R9 is H.
Aembodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 and Rl together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl or WO2013/079452 PCT/EP2012/073653 - 30 - a subtituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted with R35, R36and R37.
Aembodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 and R1 together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted aryl or a subtituted heteroaryl, wherein substituted cycloalkyl, substituted aryl and substituted heteroaryl are substituted with R35, R36and Aembodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 and R1 together with the carbon atoms to which they are attached form a substituted cycloalkyl or a substituted aryl, wherein substituted cycloalkyl and substituted aryl are substituted with R35, R36and R37.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 and R1 together with the carbon atoms to which they are attached form a cycloalkyl substituted with R35, R36and R37.
The present invention also relates to compounds according to formula (I) as described herein, wherein R9 and R1 together with the carbon atoms to which they are attached form a cycloalkyl substituted with R'5, leand R37.
Aembodiment of the present invention are compounds according to formula (I) as described herein, wherein le, R17 and R19 are each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R15, R17 and R19 are each independently selected from H, alkyl, cycloalkyl and haloalkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R17 is H.
The present invention also relates to compounds according to formula (I) as described herein, wherein R19 is H, alkyl, cycloalkyl and haloalkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R19 is H or alkyl.
Afurther embodiment of the present invention are compounds according to formula (I) as described herein, wherein R19 is H.
The present invention also relates to compounds according to formula (I) as described herein, wherein le is alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R19 is methyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R16, R18 and R2 are each independently selected from H, hydroxy, halogen or alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R16, R18 and R2 are each independently selected from H, hydroxy and alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R18 is H.
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is H, hydroxy and alkyl.
Amore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R19 and R2 together with the carbon atom to which they are attached form a cycloalkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R19 and R2 together with the carbon atom to which they are attached form a cyclopropyl.
Another embodiment of the present invention are compounds according to foimula (I) as described herein, wherein R21 is H, halogen, cyano, -0R25, -SR25, -S(0)R25, -NR25R265 _NR26s02R25, _NR26c(0)R255 _N.-.K 26 C(0)NR25R275 _c(0)R285C(0)NR25R265 cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl and substituted aryl are substituted with R38, R39and R40.
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2' is H, halogen, -0R25, -NR25R26, NR26s02R25, _NR26cor 25, substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R38, R39and R40 .
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R21 is H, halogen, _0R255 _NR25=-K 26, substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R38, R39and R40.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2' is -0R255 _NR25R26, _NR26s 02R25 or _ NR26c(0)R25.
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2' is _NR25R26, _NR26 so2R25 or _ NR26c(o)R25.
An embodiment of the present invention are compounds according to formula (I) as described herein, wherein R21 is -0R25.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R25 is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted WO2013/079452 PCT/EP2012/073653 - 33 - heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R41, R42and R43.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R25 is H, alkyl, haloalkyl, cycloalkyl, substituted heteroaryl or substituted heteroarylalkyl, wherein substituted heteroaryl and substituted heteroarylalkyl are substituted with R41, R42and R43.
The present invention also relates to compounds according to formula (I) as described herein, wherein R21is -NR25R26 and R25 is substituted heteroaryl or substituted heteroarylalkyl.
Another embodiment of the present invention are compounds according to formula (1) as described herein, wherein R25 is H, alkyl, haloalkyl, cycloalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl or substituted heteroarylalkyl, wherein substituted heteroaryl and substituted heteroarylalkyl are substituted with R41, R42and R43.
The present invention also relates to compounds according to formula (I) as described herein, wherein R26 and R27 are each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R26 and R27 are each independently selected from H and alkyl.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R26 is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R12, R13, R14, R22, R23, R24, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and K-52 are each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, chloropyridinylcarbonyl and heterocycloalkyl.
Also an embodiment of the present invention are compounds according to formula (1) as described herein, wherein R12, R13, R14, R22, R23, R24, R29, R30, R31, R32, R33, R34, R35, R36, R17, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, K-49, R50, R51 and R52 are each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy and heterocycloalkyl.
Aparticular embodiment of the present invention are compounds according to formula (1) as described herein, wherein wherein R12, R13, R14, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R50, R51 and K-52 arc each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy and heterocycloalkyl.
Aparticular embodiment of the present invention are compounds according to Ri35 R14, R32, R33, R34, R35, R36, R37, R38, R39, formula (1) as described herein, wherein R12, R40, R41, R42, R43, R50, I( -51 and R52 are each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy and heterocycloalkyl.
Afurther particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R12, Ri3and R14 are H.
Amore particular embodiment of the present invention are compounds according to formula (1) as described herein, wherein R32 is alkyl or halogen, and R33 and R34 are H.
Also a particular embodiment of the present invention arc compounds according to formula (1) as described herein, wherein R35 is H, halogen, hydroxy, alkyl, haloalkyl or alkylcarbonylamino, and R36 and R37 are H.
Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R35 is H or alkyl, and R36 and R37 are H.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R38 is H, halogen, hydroxy, cyano, oxo, alkyl, PCT/EP2012/073653 - 35 - alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxycarbonyl or alkoxyalkyl, R39 is H, halogen, oxo, alkyl or hydroxyalkyl, and R4 is H.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R38 is H, halogen, hydroxy, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxycarbonyl or alkoxyalkyl, R39 is H, halogen, oxo, alkyl or hydroxyalkyl, and R4 is H.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R38 is H, alkyl alkylcarbonyl or alkylsulfonyl, and R39 and R4o is H.
Another embodiment of the present invention are compounds according to formula (1) as described herein, wherein R38 is H or alkyl, and R39 and R4 is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R41 is H, halogen, alkyl or haloalkyl, and R42 and R43 are H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R41 is alkyl, and R42 and R43 are H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R50, R5' and R52 are each independently selected from H, halogen, hydroxy or alkyl, R5' is H or halogen, and R52 is H.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R35, R36, R37, R38, R39, R40, R41, R42 and R.43 are each independently selected from H and alkyl.
Afurther particular embodiment of the present invention are compounds according to formula (1) as described herein, wherein p is zero.
Amore particular embodiment of the present invention are compounds according to formula (1) as described herein, wherein q is zero.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein r is zero or 1.
Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m is zero.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein n is zero.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein n is 1.
Aparticular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 and R4 together form a double bond, R5 is H, n is 1 and of formula (Ia).
Ri A5 A2 (la) Particular examples of compounds of formula (I) as described herein are selected from 6-Chloro-2-pyridin-3-y1-3,4-dihydro-2H-isoquinolin-1-one; 5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-nicotinonitrile; 6-Chloro-2-(5-hydroxymethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-(5-chloro-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-(5-fluoro-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-(4-chloro-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1 -one;
WO2013/079452 PCT/EP2012/073653 - 37 - 2-(5-Bro mo -pyrid in-3-y1)-6-chloro -3 ,4-d ihydro -2H-iso qu ino lin- 1 -one ; 6-Chloro-2-(5-methyl-pyridin-3-y1)-3 ,4-dihydro-2H-isoquino lin- 1 -o ne ; -(6-Chlo ro- 1 -o xo -3 ,4-dihydro- 1 H-iso quino lin-2-y1)-pyridine-3- carbaldehyde; 6-Chloro-2-(5-methoxy-pyridin-3-y1)-3 ,4-dihydro-2H-isoquino lin- 1 -one ; 5 6-Chloro-2-(5-isopropoxy-pyridin-3-y1)-3 ,4-dihydro-2H-iso quino lin- 1 - one ; 6-Chloro-2-[5 -(1-hydroxy- 1 -methyl-ethyl)-pyridin-3 -yll -3 ,4-dihydro -2H- iso quino lin- 1 -one; 6-Chloro-245-(1-hydroxy-ethyl)-pyridin-3-y1]-3 ,4-dihydro-2H-iso quino lin- 1 - one ; 6-Chloro-2-[5 -((R)- 1 -hydroxy-ethyl)-pyridin-3 -yl] -3 ,4-dihydro-2H- isoquino lin- 1- one; 6-Chloro-2-[5 -((S)- 1 -hydro xy- ethyl)-pyridin-3 -yl] -3,4-dihydro -2H-iso quino lin- 1 - one; 6-Chloro-245 -(1-metho xy-ethyl)-pyridin-3-yl] -3,4 -dihydro -2H-iso quino lin- 1 -one; 2-(5-Amino -pyridin-3-y1)-6-chloro -3,4-dihydro -2H-iso quino lin- 1 -one ; 6-Chloro-245 -(2,2,2-trifluoro - 1-hydro xy-ethyl)-pyridin-3 -yl] -3 ,4- dihydro -2H- iso quino lin- 1 -one; 6-Chloro-2-[5 -(2,2,2-trifluoro - 1 -methoxy-ethyl)-pyridin-3-y1]-3 ,4-dihydro- 2H- isoquino lin- 1 -one 6-Chlo ro-245 -(cyc lopropyl-hydro xy-methyl)-pyridin-3 -y1]-3 ,4-dihydro -2H- isoquino lin- 1 -o ne; 6-Chlo ro-245 -(cyc loprop yl-methoxy-methyl)-p yridin-3-yl] -3 ,4-dihydro-2H- iso q uino lin- 1 -one; 6-Chloro-2-(4-trifluoromethyl-pyridin-3 -y1)-3 ,4-dihydro-2H-isoquino lin- 1 - one;
WO2013/079452 PCT/EP2012/073653 - 38 - 6-Chloro-245 -(2-hydroxy-ethyl)-pyrid in-3 -y1]-3 ,4-dihydro-2H-iso qu ino lin- 1 -one; 6-Chloro-245 -(1-metho xy- 1 -methyl-ethyl)-p yridin-3-y1]-3 ,4-dihydro-2H- iso quino lin- 1 -one;
Ethanesulfonic acid [5 -(6-chloro- 1 -o xo-3,4-dihydro- 1H-iso quinolin-2-y1)- pyridin-3 - ylmethyl] -amide; 6-Chloro-2-[5 -(2-o xo-pyrrolidin- 1 -y1)-pyridin-3-yl] -3 ,4-dihydro-2H- isoquino lin- 1 - one; 6-Chloro-2-( 1 -methyl- 1H-pyrazo lo [3 ,4-c]pyridin-4-y1)-3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-8'-hydro xy-3 ,4,5 ',6',7', 8 '-hexahydro-[2,41biiso quino linyl- 1 - one;
N-(6-Chloro- 1 -oxo-3 ,4,5 ',6',7', 8'-hexahydro- 1H- [2,41biiso quino liny1- 8'-y1)- propionamide; 6-Chloro-2- t 5- [hydroxy-(1 -methyl- 1H-imidazol-2-y1)-methyl]-pyridin-3-yll - 3 ,4- dihydro-2H-isoquinolin- 1 -one; 6-Chloro-2- [(3 ,4-difluoro-phenyl)-hydroxy-methyl]-pyridin-3-y1 -3 ,4- dihydro- 2H-iso qu ino lin- 1 -one; 6-Chloro-2- {5- [(3 ,5-difluoro-phenyl)-hydroxy-methyl]-pyridin-3-y1} -3 ,4- dihydro- 2H-iso quino lin- 1 -one; 6-Chloro-2- 5- [(4-ethyl-phenyl)-hydro xy-methyl] -pyridin-3 -ylt -3 ,4- dihydro-2H- isoquino lin- 1 -one; 6-Chloro-2[5-(hydroxy-phenyl-methyl)-pyridin-3 -y11-3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-[5 -(1-hydroxy- 1 -phenyl-ethyl)-pyridin-3 -yl] -3 ,4-dihydro-2H- iso quino lin- 1 -one;
WO2013/079452 PCT/EP2012/073653 - 39 - 6-Chloro-2- {5-[ 1 -(3,4-d ifluo ro-pheny1)- 1 -hydroxy-ethyl] -pyridin-3 -y1} -3,4-d ihydro- 2H-iso quino lin- 1 -one ; 6-Chloro-2- {5- [ 1 -(3 ,5 -difluoro-phenyl)- 1 -hydroxy-ethyl] -p yridin-3 - y1} -3 ,4-dihydro- 2H-iso quino lin- 1 -one ; 6-Chloro-2-(6-methyl-pyrazin-2-y1)-3 ,4-dihydro-2H-iso quino lin- 1 -one ; 6-Chloro-2[5-(morpholine-4-carbonyl)-pyridin-3-y1]-3,4-dihydro-2H-isoquino lin- l- one; 6-Chloro-2-[5 -(3-hydroxy-pyrro 1idine- 1 -carbony1)-pyridin-3 -y1]-3 ,4- dihydro-2H- iso quino 1in- 1 -one; 5 -(6-Chloro- 1 -o xo-3,4-dihydro- 1H-iso quino lin-2-y1)-N,N-dimethyl- nicotinamide; 6-Chloro-245 -(pyrrolidine- 1 -carbony1)-pyridin-3 -yl] -3,4-dihydro-2H-iso quino lin- 1 - one; 5 -(6-Chloro- 1 -o xo-3,4-dihydro- 1H-iso quino lin-2-y1)-N-methyl- nicotinamide ; 5 -(6-Chloro- 1 -oxo-3,4-dihydro-1H-isoquinolin-2-y1)-N-cyclopropyl- nicotinamide; 5 -(6-Chloro- 1 -oxo-3,4-dihydro- 1 H-isoquino lin-2-y1)-N-(4-fluoro-pheny1)- nicotinamide; 5 -(6-Chloro- 1 -o xo-3,4-dihydro- 1H-iso qu ino lin-2-y1)-N-phenyl- nicotinamide; 6-Chlo ro-245 -(4,4-difluo ro-p ip eridine- 1 -carbony1)-pyridin-3 -yl] -3,4- dihydro-2H- iso quino lin- 1 -one; 6-Chloro-245 -((S)-2-methoxymethy1-p yrro lidin- 1 -ylmethyl)-p yridin-3 -y1]- 3 ,4- dihydro-2H-iso quino lin- 1 -one; 6-Chloro-245 -((S)-2-methoxymethyl-pyrro lidin- 1 -y1)-pyridin-3 -3 ,4- dihydro-2H- iso quino 1in- 1 -one;
WO2013/079452 PCT/EP2012/073653 - 40 - 6-Chloro-245 -((S)-2-hydro xyrnethyl-5-o xo-pyrrolidin- 1 -y1)-pyrid in-3-y1]- 3 ,4- dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-pyrimidin-5 -y1-3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-pyridazin-3 -y1-3 ,4-dihydro-2H-isoquino lin- 1 -one ; 6-Chloro-2-pyridin-3-y1-2H-isoquino lin- 1 -one; 6-Chloro-2-(5 -fluoro-pyridin-3-y1)-2H-isoquino lin- 1 -one; 6-Chloro-244-(1-hydroxy-ethyl)-pyridin-3 -y1]-3 ,4-dihydro-2H-iso quino lin- 1 -one ; 6-Chloro-2-(4-hydro xymethyl-pyridin-3 -y1)-3 ,4-dihydro-2H-iso quino lin- 1 - one; 2-[5-( 1 -Amino-eye lopropy1)-pyridin-3 -y1]-6-c hloro-3,4-dihydro-2H-iso quino lin- 1- one; 6-Chloro-2-[5 -(4-methy1-4H-[ 1 ,2,4]triazol-3 -y1)-pyridin-3-y1]-3 ,4-dihydro- 2H- iso quino lin- 1 -one; 6-Chloro-2-(5 -methylsulfanyl-pyridin-3 -y1)-3 ,4-dihydro-2H-iso quino lin- 1 - one; 6-Chloro-2-(5-difluoromethoxy-pyridin-3-y1)-3,4-dihydro-2H-isoquino lin- 1 - one; 6-Chloro-2-(4-dimetho xymethyl-pyridin-3 -y1)-3,4-dihydro-2H-iso quino lin- 1 - one; 6-Chloro-245 -fluoro-44 1 -hydro xy-ethyl)-pyridin-3 -yl] -3,4-dihydro-2H-iso quino lin-I-one; 6-Chloro-2- {4- [(4-fluoro-phenyl)-hydro xy-methyl] -pyrid in-3 -y1} -3 ,4-d ihydro-2H- iso quino lin- 1 -one; 6-Chloro-244-(1-metho xy-ethyl)-p yridin-3-yl] -3,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-( 1 -methyl- 1H-pyrro lo [3 ,2-c]pyridin-7-y1)-3 ,4-dihydro-2H- isoquino lin-1- one; 6-Chloro-2-(5 -cyclopropyl-pyridin-3 -y1)-3 ,4-dihydro-2H-iso quino lin- 1 - one;
WO2013/079452 PCT/EP2012/073653 - 41 - 6-Chlo ro-245 -(2-methy1-2H-[ 1 ,2,4]triazo 1-3 -y1)-pyridin-3-y1]-3 ,4-d ihydro-2H- iso quino 1in- 1-one; 6-Chloro-2-(5-cyclopropoxy-pyridin-3-y1)-3 ,4-dihydro-2H-isoquino lin- 1 -one; 6-Chloro-2-(4-methoxymethyl-pyridin-3-y1)-3 ,4-dihydro -2H-iso quino lin- 1 - one; 6-Chloro-245 -fluoro-4-( 1 -hydro xy- 1 -methyl-ethyl)-pyridin-3-y1]-3 ,4- dihydro-2H- iso quino 1in- 1-one; 6-Chloro-2-[5 -(5-methyl-pyrazo 1- 1 -ylmethyl)-pyridin-3-y1]-3 ,4-dihydro-2H- isoquino lin- 1-one; 6-Chloro-2-( 1 H-pyrro lo [3 ,2-c]pyridin-7-y1)-3 ,4-dihydro -2H-iso quino lin- 1-one; 6-Chloro-3 ,4-dihydro-[2,41bilsoquino linyl- 1 -one; 3 -(6-Chloro- 1 -o xo -3 ,4-dihydro- 1 H-iso quino lin-2-y1)- isonicotinonitrile; 6-Chloro-2-(5 -fluoro-4-metho xymethyl-pyridin-3 -y1)-3 ,4-dihydro-2H-isoquino lin- 1- one; 6-Chloro-245 -fluoro-4-( 1 -metho xy-ethyl)-pyridin-3-y1]-3 ,4-dihydro-2H- isoquinolin- 1 -one; 6-Chloro-2-(4-isopropoxymethyl-pyrid in-3-y1)-3 ,4-dihydro -2H-isoquino lin- 1 -one; 6-Chloro-2[4-(cyc lopropyl-methoxy-methyl)-pyri d in-3-yl] -3 ,4-dihydro-2H- iso quino 1in- 1-one; 6-Chlo ro-245 -(3,5 -dimethyl- 1H-p yrazo 1-4-y1)-p yridin-3 -y1]-3 ,4-dihydro- 2H- isoquino lin- 1-one; 6-Chloro-2-[5 -(3 ,5 -dimethy1-3 H-imidazol-4-y1)-pyridin-3 -yl] -3 ,4-dihydro -2H- iso quino 1in- 1-one; 6-Chloro-2-[5 -( 1, 1 -dioxo- 1 X6-[ 1,2]thiazinan-2-ylmethyl)-pyridin-3 -yl] - 3 ,4-dihydro - 2H-iso quino lin- 1 -one ;
WO2013/079452 PCT/EP2012/073653 - 42 - 6-Chlo ro-245 -(1,1 -dioxo- I X6-isothiazo lidin-2-ylmethyl)-pyrid in-3-yl] - 3,4-d ihydro- 2H-iso quino lin- 1 -one ; 6-Chloro-245 -((S)-2-hydro xymethy1-5-o xo-pyrrolidin- 1 -y lmethyl)-p yridin- 3-yl] - 3 ,4-dihydro-2H-iso quino tin- 1 -one; (S)- 1 - [5 -(6-Chloro- 1 -o xo-3,4-dihydro- 1 H-iso quino lin-2-y1)-pyridin-3 -ylmethyl] - pyrrolidine-2-carboxylic acid methyl ester; 6-Chloro-2-(5 -methoxy-pyridin-3-y1)-3 -methy1-3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-(5 -hydro xymethyl-pyridin-3 -y1)-3 -methy1-3,4-dihydro-2H-iso quino lin- 1 - one; 6-Chloro-245 -(2-isopropyl-imidazol- 1 -ylmethyl)-pyridin-3 -yl] -3-methy1-3 ,4- dihydro-2H-iso quino lin- 1-one; 6-Chloro-3 -methy1-2-pyridin-3-y1-3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-(5 -fluoro-pyridin-3-y1)-3 -methy1-3,4-dihydro-2H-iso quino lin- 1- one; 6-Chloro-3 -methy1-2-pyrimi din-5-y1-3 ,4-dihydro-2H-iso quino lin- 1 -one; (R)-6-Chloro-3 -methy1-2-pyridin-3 -y1-3 ,4-dihydro-2H-iso quino lin- 1 -one; (S)-6-Ch loro-3-methy1-2-pyri d in-3 -y1-3,4-dihydro-2H-iso qu ino lin- 1-one; 8-Chloro-3 -methy1-2-pyridin-3-y1-3 ,4-dihydro-2H-isoquino lin-1 -one; 6-Metho xy-2-pyridin-3 -y1-3 ,4-dihydro-2H-iso quino lin- 1 -one ; 5 ,6-Dichlo ro-2-pyridin-3 -y1-3 ,4-dihydro-2H-iso quino lin- 1 -one ; 2-Chlo ro-6-(5 -methoxy-p yridin-3-y1)-7, 8-dihydro-6H- [ 1,6]naphthyridin-5 - one; 2-Methoxy-6-(5-methoxy-pyridin-3-y1)-7,8-dihydro-6H-[ I ,6]naphthyridin-5-one; 2-Metho xy-6-p yridin-3 -y1-7, 8-dihydro-6H-[ 1,6]naphthyridin-5 -one; 6-Chloro-5 -fluoro-2-(5 -metho xy-pyridin-3 -y1)-3 ,4-dihydro-2H-iso quino lin- 1 -one;
WO2013/079452 PCT/EP2012/073653 - 43 - 6-Chloro-7-fluoro-2-(5-methoxy-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-7-fluoro-2-pyridin-3-y1-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-4,4-dimethy1-2-pyridin-3-y1-3,4-dihydro-2H-isoquinolin-l-one; 6-Chloro-2-(5-methoxy-pyridin-3-y1)-4,4-dimethy1-3,4-dihydro-2H-isoquinolin-1- one; 6-Chloro-2-(5-fluoro-pyridin-3-y1)-4,4-dimethy1-3,4-dihydro-2H-isoquinolin-1- one; 6-Chloro-4-methy1-2-pyridin-3-y1-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-(5-fluoro-pyridin-3-y1)-4-methyl-3,4-dihydro-2H-isoquinolin-l-one; 6-Chloro-2-(5-methoxy-pyridin-3-y1)-4-methyl-3,4-dihydro-2H-isoquinolin-1-one; 5-Chloro-2-pyridin-3-y1-2,3-dihydro-isoindol-1-one; 5-Chloro-245-(2-isopropyl-imidazol-1-ylmethyl)-pyridin-3-y1]-2,3-dihydro- isoindol-1-one; 5-Chloro-2-(5-[1,2,4]triazol-1-ylmethyl-pyridin-3-y1)-2,3-dihydro-isoindo1-1- one; 5-Chloro-245-(2-methyl-imidazol-1-ylmethyl)-pyridin-3-y1]-2,3-dihydro-isoindo1- 1- one; 5-Chloro-2-[5-(2-oxo-pyrrolidin-1-ylmethyl)-pyridin-3-y1]-2,3-dihydro-isoindo1- 1- one; 5-Chloro-2454(S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-y1]-2,3- dihydro-isoindol-1-one; 5-Chloro-2-[5-(2-oxo-piperidin-1-ylmethyl)-pyridin-3-y1]-2,3-dihydro-isoindo1- 1- one;
Ethanesulfonic acid [5-(5-chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyll-amide;
WO2013/079452 PCT/EP2012/073653 - 44 - -Chloro-2-( 1 -methyl- 1H-pyrazo lo [3 ,4-c]pyrid in-4-y1)-2,3 -dihydro-iso indol- 1 -one; 5 -Chloro-2-(8-hydro xy-5,6,7,84 etrahydro-isoquinolin-4-y1)-2,3 -dihydro-iso indol- 1 - one; 5 -Chloro-3 -methyl-2-pyridin-3-y1-2,3 -dihydro-iso indol- 1 -one; 5 6-Chloro-3 -methyl-2-pyridin-3-y1-2,3 -dihydro-iso indol- 1 -one; 5 -Chloro-2-(5 -methoxy-pyridin-3-y1)-3 -methyl-2,3 -dihydro-isoindol- 1 -one; 5 -Chloro-3 -methyl-2-(4-methyl-pyridin-3 -y1)-2,3 -dihydro-isoindol- 1 -one ; 5 -Chloro-245 -(1-hydroxy-ethyl)-pyridin-3 -y1]-3 -methy1-2,3-dihydro-iso indol- 1 -one; 5 -Chloro-2-(5 -fluoro-pyridin-3-y1)-3 -methyl-2,3 -dihydro-isoindol- 1 -one ; 3 -B enzy1-5 -chloro-2-pyridin-3 -y1-2,3 -dihydro-isoindol- 1 -one; 5 -Chloro-3 -ethyl-2-pyridin-3 -y1-2,3 -dihydro-isoindol- 1 -one; 5 -Chloro-3 -ethy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-iso indol- 1 -one ; 5 -Chloro-3 -ethy1-2-(5-metho xy-pyridin-3 -y1)-2,3-dihydro-isoindol- 1 -one ; 5 -Chloro-3 ,3-dimethy1-2-pyridin-3 -y1-2,3 -dihydro-isoindol- 1-one; 5 -Chloro-2-(5 -fluoro-pyridin-3-y1)-3 ,3 -dimethy1-2,3-dihydro-iso indol- 1 - one; 5 -Chloro-2-(5 -methoxy-pyridin-3-y1)-3 ,3-dimethy1-2,3-dihydro-iso indol- 1 - one; 5 -Chloro-2-(5 -difluorometho xy-pyridin-3 -y1)-3,3 -dimethy1-2,3 -dihydro- isoindol- 1 - one; 5 -Chloro-2-[5 -(1 -hydroxy-ethyl)-pyridin-3 -y1]-3 ,3 -dimethy1-2,3 -d ihydro- i so indol- 1- one; 5 -Chloro-2-(5 -hydro xymethyl-pyridin-3 -y1)-3 ,3 -dimethy1-2,3 -dihydro-iso indol- 1 - one;
WO2013/079452 PCT/EP2012/073653 - 45 - -Chlo ro-3 ,3-dimethy1-2- [5-(2-methyl-imid azol-1-ylmethyl)-pyrid in-3 -yl] - 2,3 - dihydro -iso indol-l-one ; 6-Chloro-245 -((S)-2-hydro xymethyl-p yrro lidin-l-y1)-p yridin-3-yl] -3 ,4- dihydro-2H- iso quino lin-l-one; 5 5 -Chloro-2-[5 -((S)-2-hydro xymethyl-pyrro lidin-l-y1)-pyridin-3-yl] - 2,3-dihydro- iso indol-l-one; 6-Chloro-245 4R)-3-hydroxy-pyrro lidin-l-y1)-pyridin-3-yl] -3,4-dihydro -2H- iso quino lin-l-one; 5 -Chloro-2-[5 -((R)-3-hydroxy-pyrro lidin-l-y1)-pyridin-3-yl] -2,3-dihydro - iso indo1-1- one; 2-Hydro xy-6-(5-metho xy-pyridin-3 -y1)-7,8-dihydro -6H-[1,6]naphthyridin-5- one ; 6-Chloro-2-(5 -imidazol-1 -ylmethyl-pyridin-3-y1)-3 ,4-dihydro-2H-iso quino lin-1 -one; 6-Chloro-245 -(2-isopropyl-imidazol-1-ylmethyl)-pyridin-3 -yl] -3,4-dihydro - 2H- iso quino lin- I -one; 6-Ch loro-2-[5 -(2-methyl-im i d azo 1-1-ylmethyl)-pyri d in-3 -yl] -3,4-d i hydro -2H- iso qu ino lin-l-one; 6-Chlo ro-245 -(2-ethy1-4-methyl- imidazol-1-ylmethyl)-pyridin-3 -y1]-3 ,4-d ihydro - 2H-iso quino lin-l-one ; 6-Chloro-2-[5 -(3-hydroxy-p ip eridin-l-ylmethyl)-pyridin-3 -yl] -3,4-dihydro - 2H- isoquino lin-l-one;
Propane-2-sulfonic acid [5 -(6-chloro-l-o xo -3,4-dihydro - 1H-iso quino lin-2- y1)- pyridin-3-ylmethyl] -amide 6-Chloro-2-[5-(3-hydroxy-pyrro lidin-l-ylmethyl)-pyridin-3 -yl] -3 ,4-dihydro - 2H- iso quino lin-l-one;
WO2013/079452 PCT/EP2012/073653 - 46 - 6-Chloro-2454(R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2454(S)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2454(S)-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-y11-3,4- dihydro-2H-isoquinolin-1-one; 6-Chloro-2-[5-((R)-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-y1]-3,4- dihydro-2H-isoquinolin-1-one; 6-Chloro-2-[5-(3,5-dimethyl-pyrazol-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquino1in-1-one;
N-[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-ylmethy1]- methanesulfonamide N-[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-ylmethyli- acetamide 6-Chloro-2-(5-morpholin-4-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1- one; 6-Chloro-245-(2-oxo-pyrrolidin-1-ylmethyp-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(1,1-dioxo-1k6-thiomorpholin-4-ylmethyl)-pyridin-3-y1]-3,4- dihydro- 2H-isoquinolin-1-one; 6-Chloro-245-(2-oxo-oxazolidin-3-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(3-methy1-2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-y1]-3,4- dihydro- 2H-isoquinolin-1-one;
WO2013/079452 PCT/EP2012/073653 - 47 - 6-Chloro-2-(5-pyrazo 1-1-ylmethyl-pyrid in-3 -y1)-3,4-dihydro-2H-iso qu ino lin-l-one; 6-Chloro-2-[5-(2-propyl-imidazol-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 145-(6-Chloro-1-o xo-3,4-dihydro-1H-iso quino lin-2-y1)-pyridin-3 -ylmethy1]- 1H- imidazole-2-carboxylic acid ethyl ester; 6-Chloro-2-[5-(2-hydroxymethyl-imidazol-1-ylmethyl)-pyridin-3-y11-3,4-dihydro- 2H-isoquinolin-1-one; 6-Chloro-245 -(o xetan-3-ylaminomethyl)-pyridin-3 -y1]-3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2- (5- [4-(2-hydroxy-ethyl)-pip erazin-l-ylmethyl] -pyridin-3 -y1} - 3,4- dihydro-2H-iso quino lin-l-one; 6-Chloro-245-(4-isopropyl-piperazin-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-[5 -(4-methyl-piperazin-l-ylmethyl)-pyridin-3-yl] -3 ,4-dihydro-2H- isoquino lin-l-one; 6-Chloro-245 -(4,4-difluoro-pip eridin-l-ylmethyl)-pyrid in-3-yl] -3,4-d ihydro-2H- iso quino lin-l-one; 6-Chloro-245 -(3,3 -difluoro-pyrro lidin-l-ylmethyl)-pyridin-3 -yl] -3,4- dihydro-2H- iso quino lin-l-one; 6-Chloro-2-[5 -(2-o xa-6-aza-spiro [3.4]oct-6-ylmethyl)-pyridin-3 -y1]-3 ,4- dihydro-2H- iso quino lin-l-one; 6-Chloro-2-[5 -(2-o xa-6-aza-spiro [3.3]hept-6-ylmethyl)-pyridin-3-y1]-3,4- dihydro- 2H-isoquinolin-1-one; 6-Chloro-245 -(3,3 -difluoro-pip eridin-l-ylmethyl)-pyridin-3-yl] -3,4-dihydro- 2H- isoquino lin-l-one;
WO2013/079452 PCT/EP2012/073653 - 48 - 6-Chloro-245-(2-oxo-piperidin-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-(5-[1,2,3]triazol-2-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H- isoquinolin-1- one; 6-Chloro-2-(5-[1,2,31triazol-1-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H- isoquinolin-1- one; 6-Chloro-2-[5-(2-chloro-imidazol-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(3-methyl-[1,2,4]triazol-4-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(5-methyl-[1,2,4]triazol-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-chloro-245-(3-methyl-[1,2,4]triazo1-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-(541,2,4]triazol-4-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H- isoquinolin-1- one; 6-Chloro-2-(5-[1,2,4]triazol-1-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H- isoquinolin-1- one; 6-Chloro-2-[5-(2-methyl-benzoimidazol-1-ylmethyl)-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-l-one; 6-Chloro-2-(5-indazol-1-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1- one; 6-Chloro-2-(5-indazol-2-ylmethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-l- one; 6-Chloro-2-[5-(6-fluoro-indo1-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one;
WO2013/079452 PCT/EP2012/073653 - 49 -6-Chlo ro-245 -(7-fluo ro-indo1-1-ylmethyl)-pyrid in-3 -yl] -3,4-d ihydro-2H- iso quino lin-l-one; 6-Chloro-245-(4-fluoro-indo1-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-[5-(4-methyl-pyrazo1-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245 -(2-cyc lopropyl-imidazo 1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245 -(2-trifluoromethyl-imidazol-1-ylmethyl)-pyridin-3-yl] -3,4- dihydro- 2H-isoquinolin-1-one; 6-Chloro-245-(3-methyl-pyrazo1-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(2-ethyl-imidazo1-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 2-(5-Amino methyl-pyrid in-3 -y1)-6-chloro-3,4-dihydro-2H-iso qu ino lin-l- one; 6-Chloro-2-(5-methoxymethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-l-one; 6-Chloro-2-(5-isopropoxymethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-l-one; 6-Chlo ro-2-[5 -(2,2,2-trifluoro-1-methyl-ethoxymethyl)-p yridin-3-yl] -3 ,4- dihydro- 2H-iso quino lin-l-one ; 6-Chloro-2- {5- [2-(1-methyl-pyrro lidin-2-y1)-etho xymethyl] -pyridin-3 -y1} - 3,4- dihydro-2H-iso quino lin-l-one; 6-Chloro-2-(5 -cyc lop entylo xymethyl-pyridin-3-y1)-3 ,4-dihydro-2H-iso quino tin-l- one;6-Chloro-2-(5 -cyc lopropylmetho xymethyl-pyridin-3 -y1)-3,4-dihydro-2H- isoquino lin-l-one;
WO2013/079452 PCT/EP2012/073653 - 50 - 6-Chloro-245 -(2-fluoro-pheno xymethyl)-pyridin-3 -yl] -3 ,4-d ihydro-2H-iso qu ino lin- 1-one; 6-Chloro-245 -(1-methyl-cyc loprop ylmetho xymethyl)-p yridin-3 -y1]-3 ,4- dihydro-2H- iso quino lin-l-one; 6-Chloro-245 -(tetrahydro-furan-2-ylmethoxymethyl)-pyridin-3-yl] -3 ,4-dihydro- 2H- iso quino lin-l-one; 6-Chloro-245-(2,2,2-trifluoro-ethoxymethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-(5 -cyclobuto xymethyl-pyridin-3 -y1)-3,4-dihydro-2H-iso quino lin- 1-one; 6-Chloro-245 -(3,5 -dimethyl-iso xazol-4-ylmethyl)-pyridin-3 -yl] -3,4-dihydro- 2H- iso quinolin-1-one; 6-Chloro-245-(4-methanesulfonyl-benzy1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(6-methyl-pyridin-3-ylmethyl)-pyri din-3-y1]-3 ,4-dihydro-2H- isoquino hin-l-one; 6-Chloro-245-(6-morpho lin-4-yl-pyrid in-3-ylmethyl)-pyrid in-3 -yl] -3,4- dihydro-2H- iso quino liri-l-one; 6-Chloro-245-(2-methy1-2H-pyrazol-3-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-[5-(1-methy1-1H-pyrazol-4-ylmethyl)-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-[5 -(2,3 -difluoro-benzy1)-pyridin-3 -yll -3 ,4-dihydro-2H-iso quino lin-l- one; 6-Chloro-245 -(3,5 -difluoro-benzy1)-pyridin-3 -yl] -3 ,4-dihydro-2H-iso quino lin-1- one;
WO2013/079452 PCT/EP2012/073653 -51 - 6-Chloro-245 -(2,5 -d ifluo ro-benzy1)-pyrid in-3 -y1]-3 ,4-dihydro-2H- isoquino lin- 1- one; 6-Chloro-2 -(2-trifluoromethy 1-b enzy1)-p yridin- 3 -y1]-3 ,4-dihydro-2H- isoquino lin- 1 -one; 6-Chloro-245 -(2,6-dichloro -benzy1)-pyridin-3 -y1]- 3 ,4-dihydro-2H-isoquino lin-l- one; 6-Chloro-245 -(2-chloro -6-fluoro-benzy1)-pyridin- 3 -yl] -3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-245 -(3 ,4-dich1oro -benzy1)-pyridin-3 -y1]- 3 ,4-dihydro-2H-isoquino lin- 1- one; 6-Chloro-245 -(2,5 -dich1oro -benzy1)-pyridin-3 -y1]- 3 ,4-dihydro-2H-isoquino lin-1- one;
Ethanesulfonic acid [5 -(6-chloro - 1 -o xo-3 ,4-dihydro - 1 H-iso quino - yl] -amide ;
N- [ 5 -(6-Chlo ro - 1 -o xo -3 ,4-dihydro- 1 H-iso quino lin-2-y1)-pyrid in-3 -y1]- benzenesulfonamide;
N- [5 -(6-Chloro - 1 -o xo -3 ,4-dihydro- 1 H-iso quino lin-2-y1)-pyridin-3 - y1]- methanesulfonamide;
Cyclopropanesulfonic acid [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)- pyridin-3-A-amide; 6-Chloro-245 -(4-fluoro-benzylamino)-pyridin-3 -yll -3 ,4-dihydro -2H-iso quino lin- 1 - one; 6-Chloro-245 -(2,2,2-trifluoro-ethylamino)-pyridin-3 -yl] -3 ,4-dihydro -2H- iso quino lin- 1-one; 6-Chloro-2-(5 -morph lin-4-yl-pyridin-3 -y1)-3 ,4-dihydro -2H-iso quino 1in- 1-one;
N- [5-(6-Chloro-l-oxo-3 ,4-dihydro-1H-isoquino lin-2-y1)-pyrid in-3 -yl] - propionamide; 6-Chloro-2- {5- [(2-methy1-2H-pyrazo1-3 -ylmethyl)-amino] -pyridin-3-y1} -3,4- dihydro-2H-iso quino lin-l-one; 245-(6-Chloro-l-oxo-3,4-dihydro-1H-iso quino lin-2-y1)-pyridin-3 -ylamino] -2- methyl-propionic acid; 6-Chloro-2- {5- [(1-methyl-1H-imidazol-4-ylmethyl)-amino] -pyridin-3 -y1} -3,4- dihydro-2H-iso quino lin-l-one; 6-Chloro-245 -(1H-pyrazol-4-y1)-pyridin-3 -y1]-3 ,4-dihydro-2H-iso quino lin-l- one; 6-Chloro-245 -(3,5 -dimethyl-iso xazol-4-y1)-pyridin-3-yl] -3,4-dihydro-2H- iso quino lin-l-one; 6-Chloro-245-(3-fluoro-pheny1)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-l-one; 6-Chloro-245 -(3,4-difluoro-pheny1)-pyridin-3 -y1]-3 ,4-dihydro-2H-iso quino lin-1- one; 6-Chloro-245-(3,5-difluoro-pheny1)-pyridin-3-y1]-3,4-dihydro-2H-isoquino lin-1- one; 6-Chloro-245-(3-chloro-pheny1)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-245 -(2,5 -difluoro-pheny1)-p yridin-3 -y1]-3,4-dihydro-2H-iso quino lin-1- one; 6-Chloro-245 -(3-trifluoromethyl-pheny1)-pyridin-3-yl] -3 ,4-dihydro-2H- isoquino lin- 1-one; 6-Chloro-245-(3-trifluoromethoxy-pheny1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245 -(2-methyl-2H-pyrazol-3-y1)-pyridin-3 -yl] -3,4-dihydro-2H- isoquinolin-l-one;
WO2013/079452 PCT/EP2012/073653 - 53 - 6-Chloro-245 -(1-methyl-1H-pyrazol-4-y1)-pyrid in-3 -yl] -3 ,4-d ihydro-2H- iso quinolin-l-one; 6-Chloro-245 -(4-chloro-3-fluoro-pheny1)-p yridin-3 -yl] -3,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-245 -(3,4-dichloro-pheny1)-pyridin-3-yl] -3,4-dihydro-2H-iso quino lin-1- one; 6-Chloro-245 -(2-trifluoromethyl-p heny1)-pyridin-3-yl] -3 ,4-dihydro-2H-iso quino lin- 1 -one; 6-Chloro-2-(5-isoxazol-4-y1-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-l-one; 6-Chloro-2-[5 -(1-methy1-1H-imidazol-2-y1)-pyridin-3 -y1]-3 ,4-dihydro-2H- iso quinolin-1-one; 6-Chloro-245 -(2,4-dimethy1-2H-pyrazo1-3 -y1)-pyridin-3 -y1]-3 ,4-dihydro-2H- iso quino lin-l-one; 5-[5-(6-Chloro-l-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-y1]-1-methy1-1 H- pyrazole-4-carbonitrile N- [5-(6-Chloro-l-o xo-3 ,4-dihydro-1H-iso quino lin-2-y1)-pyrid in-3 -yl] - isobutyramid e Cyclopropanecarboxylic acid [5-(6-chloro-1-oxo-3 ,4-dihydro-1H-iso quino lin-2- y1)- p yridin-3-yl] -amide N- [5-(6-Chloro-1-o xo-3 ,4-dihydro-1H-iso quino lin-2-y1)-pyridin-3 -yl] -4- fluoro- benz amide 1 -[5-(6-Chloro-1-o xo-3,4-dihydro-1H-iso quino lin-2-y1)-pyridin-3 -y1]-3 - cyc lo hexyl- urea 1 -[5-(6-Chloro-1-o xo-3,4-dihydro-1H-iso quino lin-2-y1)-pyridin-3 -y1]-3 -(3- trifluoromethyl-p heny1)-urea 6-Chloro-2-(5 -hydro xy-pyridin-3 -y1)-3,4-dihydro-2H-iso quino lin-1 -one;
WO2013/079452 PCT/EP2012/073653 - 54 - 245-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-yloxy]- acetamide; 2-[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-yloxy]-N- methyl- acetamide; [5 -(6-Chloro- 1 -oxo-3 ,4-dihydro-1H-isoquino lin-2-y1)-pyridin-3 -yloxy]- acetic acid methyl ester; 245-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-yloxyl-N,N- dimethyl-acetamide; 6-Chloro-2-(5 -phenylaminomethyl-pyridin-3-y1)-3,4-dihydro-2H-iso quino lin-1 - one; 6-Chloro-2- {5- [(4-fluoro-phenylamino)-methyl]-pyridin-3-y1} -3 ,4-dihydro-2H- 1 0 iso quino lin- 1-one; 6-Chloro-2- {5- [(3-fluoro-phenylamino)-methyl]-pyridin-3-y1} -3 ,4-dihydro-2H- iso quino lin- 1-one; 6-Chloro-2- {5- [(4-chloro-phenylamino)-methyl] -pyridin-3 -yll -3 ,4-dihydro- 2H- isoquino lin- 1 -one; 6-Chloro-2- {5-[(3-chloro-phenylamino)-methyl]-pyridin-3-y11-3 ,4-dihydro-2H- iso qu ino lin- 1-one; 6-Chloro-2- {5- [( 1H-pyrazol-3-ylarnino)-methyl] -pyridin-3 -y1} -3 ,4- dihydro-2H- iso quino lin- 1-one; 6-Chloro-245 -(2-morpho lin-4-y1-2-oxo-ethyl)-pyridin-3 -y1]-3 ,4-dihydro-2H- iso quino lin- 1-one; 2-[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-pyridin-3-y1]-N-(2- hydroxy- ethyl)-acetamide; 6-Chloro-245 -(1-methylamino-ethyl)-pyridin-3 -yl] -3 ,4-dihydro-2H-iso quino lin- 1 - one;
PCT/EP2012/073653 - 55 - 6-Chloro-245 -(1-d imethylamino-ethyl)-pyridin-3 -y1]-3 ,4-dihydro-2H-isoquino lin-l- one; 6-Chloro-2-[5-(1-methy1-1H-imidazole-2-carbony1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245 -(4-methy1-4H-[1,2,4]triazo1-3 -ylmethyl)-pyridin-3-yl] -3 ,4- dihydro- 2H-iso quino lin-l-one; 6-Chloro-2-[5 -(1- [1,2,3]triazo1-2-yl-ethyl)-pyridin-3-yl] -3 ,4-dihydro-2H- iso quino lin-l-one; 6-Chloro-2-[5 -(1-imidazol-1-yl-ethyl)-pyridin-3-yl] -3 ,4-dihydro-2H-isoquino lin-1- one; 6-Chloro-245-(1-pyrazol-1-yl-ethyl)-pyridin-3-yl] -3 ,4-dihydro-2H-iso quino lin-1- one; 6-Chloro-2- t5-[1-(oxazo 1-2-ylamino)-ethyl] -pyridin-3-ylt -3 ,4-dihydro-2H- isoquino lin-l-one; 6-Chloro-245 -(1- [1,2,4]triazo1-1-yl-ethyl)-pyrid in-3-yl] -3 ,4-dihydro-2H- iso quino lin-l-one; 6-Chloro-2- [1-(2-o xo- pyrrolidin-1-y1)-ethyl] -pyridin-3 -y1} -3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2- t5-[1-(2-oxo-oxazolidin-3-y1)-ethyl]-pyridin-3-yll -3 ,4-dihydro- 2H- isoquino lin-l-one;
N- 1- [5 -(6-Chloro-l-o xo-3,4-dihydro-1H-isoquino lin-2-y1)-pyridin-3-yll - ethyl} - methanesulfonamide; 6-Chloro-2- [5- [1-(3-fluoro-phenylamino)-ethyl] -pyridin-3-ylt -3 ,4-dihydro- 2H- iso quino lin-1-one; 6-Chloro-245 -(1-phenylamino-ethyl)-pyridin-3-yl] -3,4-dihydro-2H-iso quinolin- 1- one;
WO2013/079452 PCT/EP2012/073653 - 56 - 6-Chloro-2-(5-methanesulfinyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-[4-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; and pharmaceutically acceptable salts thereof.
Also particular examples of compounds of formula (I) as described herein are selected from 5 -Chloro -3,3 -dimethy1-245 -(1 -methyl- 1 H-pyrazol-4-ylmethyl)-pyridin-3 - yll -2,3 - dihydro-isoindol-l-one; 5-Chloro-2-(5-difluoromethoxy-pyridin-3-y1)-3-ethyl-2,3-dihydro-isoindol-l- one; 5 -Chloro -3-ethy1-2- [5 -(1 -hydroxy-ethyl)-pyridin-3-y1]-2,3 -dihydro-iso indo 1- 1-one; 5-Chloro-2-(4-chloro-pyridin-3-y1)-3-ethy1-2,3-dihydro-isoindo1-1-one; 5-Chloro-2-(4-chloro-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindo1-1-one; 6-Chloro-5'-nitro-3,4-dihydro-[2,4]biisoquinoliny1-1-one; 6-Chloro-8'-nitro-3,4-dihydro-[2,41biisoquinoliny1-1-one; 8'-Amino-6-chloro-3,4-dihydro42,41biisoquinoliny1-1-one;
Ethanesulfonic acid (6-chloro-1-oxo-3,4-dihydro-1H-[2,4']biisoquinolinyl-81- y1)- amide; 6'-Chloro-2'-(5-fluoropyridin-3-yOspiro[cyclopropane-1,1'-isoindo1]-3'(2'H)- one; 6'-Chloro-2'-[5-(difluoromethoxy)pyridin-3-yl]spiro[cyclopropane-1,1'- isoindo1]- 3'(2'H)-one; 2-Chloro-6-(5-fluoro-pyridin-3-y1)-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4- b]pyridin- 5-one;
WO2013/079452 PCT/EP2012/073653 - 57 - 2-Chloro-6-(5-difluoromethoxy-pyridin-3-y1)-7,7-dimethy1-6,7-dihydro- pyrrolo[3,4- b]pyridin-5-one; 6-(5-Fluoro-pyridin-3-y1)-2-methoxy-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one; 6-(5-Difluoromethoxy-pyridin-3-y1)-2-methoxy-7,7-dimethy1-6,7-dihydro- pyrrolo[3,4-b]pyridin-5-one; 6'-Chloro-2'-(pyridin-3-yl)spiro[cyclopropane-1,1'-isoindol]-3'(2'H)-one; 5-Chloro-3-cyclopropy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-isoindol-1-one; 2-Chloro-7,7-dimethy1-6-pyridin-3-y1-6,7-dihydro-pyrrolo[3,4-1Apyridin-5-one; 2-Ethoxy-6-(5-fluoro-pyridin-3-y1)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4- b]pyridin- 5-one; 2-Methoxy-7,7-dimethy1-6-pyridin-3-y1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one; 5-Chloro-3-cyclopropy1-2-pyridin-3-y1-2,3-dihydro-isoindo 1- 1 -one; 5-Chloro-3-cyclopropy1-2-(5-difluoromethoxy-pyridin-3-y1)-2,3-dihydro-isoindol- 1- 1 5 one; 6-(5-Difluoromethoxy-pyridin-3-y1)-2-ethoxy-7,7-dimethy1-6,7-dihydro- pyrrolo[3,4-b]pyridin-5-one; 5-Chloro-2-(5-isopropoxy-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindol-1- one; 6'-Chloro-T-(4-chloropyridin-3-Aspiro[cyclopropane-1,1'-isoindol]-3'(2'H)-one; 5-Chloro-2-(5-cyclopropoxy-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindol-1- one; (S or R)-6-Chloro-3-ethy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-isoindol-l- one; (R or S)-6-Chloro-3-ethy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-isoindol-1- one; (R or S)-5-Chloro-3-ethy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-isoindol-l- one;
WO2013/079452 PCT/EP2012/073653 - 58 - (S or R)-5-Chloro-3-ethy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-isoindol-l- one; 2-(8-Amino-5,6,7,8-tetrahydro-isoquinolin-4-y1)-5-chloro-2,3-dihydro-isoindol- 1- one;
N-[(R or S)-4-((R or S)-5-Chloro-1-ethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-propionamide;
N-[(R or S)-4-((S or R)-5-Chloro-1-ethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y11-propionamide;
N-[(R or S)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8-tetrahydro- isoquino1in-8-y1]-propionamide;
Ethanesulfonic acid [4-(5-chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8- tetrahydro-isoquinolin-8-y1]-amide;
Ethanesulfonic acid [(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y11-amide;
Ethanesulfonic acid [(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-arnide;
N-[(S or R)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-acetamide;
N-[(R or S)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y1]-acetamide;
N-((R or S)-6-Chloro-1-oxo-3,4,5',6',7',8'-hexahydro-1H42,41biisoquino1iny1-8'- y1)-acetamide;
N-((S or R)-6-Ch1oro-1-oxo-3,4,5',6',7',8'-hexahydro-1H42,41biisoquinoliny1-8'- y1)-acetamide;
N-[(S or R)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8-tetrahydro- isoquinolin-8-yll-acetamide;
N-[(R or S)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8-tetrahydro- isoquinolin-8-y1]-acetamide;
N-((S or R)-6-Ch1oro-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,41biisoquinolinyl- 8'- y1)-methanesulfonamide;
N-((R or S)-6-Chloro-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,41biisoquino1iny1- 8'- y1)-methanesulfonamide;
N-[(S or R)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8-tetrahydro- isoquinolin-8-y1]-methanesulfonamide;
N-[(R or S)-4-(5-Chloro-l-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8-tetrahydro- isoquinolin-8-y1]-methanesulfonamide;
N-((R or S)-6-Ch1oro-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,41biisoquinoliny1- 8'- y1)-propionamide;
N-((S or R)-6-Chloro-1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,41biisoquinoliny1- 8'- y1)-propionamide;
N-[(S or R)-4-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-methanesulfonamide;
N-[(R or S)-4-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-A-methanesulfonamide;
N-[(R or S)-4-(6-Chloro-l-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y1]-acetamide;
N-[(S or R)-4-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-acetamide;
N-[(R or S)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-methanesulfonamide;
N-[(S or R)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-methanesulfonamide;
Ethanesulfonic acid [(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-amide;
Ethanesulfonic acid [(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-amide;
N- [(S or R)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-propionamide;
N-[(R or S)-4-(5-Chloro-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7-dihydro-5H- [2]pyrindin-7-y11-propionamide; 5-Chloro-2-((S or R)-8-hydroxy-5,6,7,8-tetrahydro-isoquinolin-4-y1)-2,3- dihydro- isoindo1-1-one; 5-Chloro-2-((R or S)-8-hydroxy-5,6,7,8-tetrahydro-isoquinolin-4-y1)-2,3- dihydro- isoindol-1-one;
N- [(S or R)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-acetamide;
N-[(R or S)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-acetamide;
N-[(R or S)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-acetamide;
N- [(S or R)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-acetamide;
N-[4-(5-Ch1oro-3-ethyl-l-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8-tetrahydro- isoquinolin-8-y1]-methanesulfonamide;
N-[(R or S)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-methanesulfonamide;
N-[(S or R)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-methanesulfonamide;
N-[(S or R)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-methanesulfonamide;
N-[(R or S)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-methanesulfonamide;
N-[(S or R)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-propionamide;
N-[(S or R)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-propionamide;
N-[(R or S)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-propionamide;
N-[(R or S)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-propionamide;
N-[(S or R)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-acetamide;
N-[(S or R)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-acetamide;
N-[(R or S)-4-((S or R)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-acetamide;
N-[(R or S)-4-((R or S)-5-Chloro-3-ethy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8- tetrahydro-isoquinolin-8-y1]-acetamide;
N- [(R or S)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-34)- 5,6,7,8-tetrahydro-isoquinolin-8-A-propionamide;
N- [(S or R)-4-((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8-tetrahydro-isoquinolin-8-A-propionamide;
N- [(R or S)-4-((R or S)-5-Chloro-3-methy1-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5,6,7,8-tetrahydro-isoquinolin-8-A-propionamide;
N- [(S or R)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- ,6,7,8-tetrahydro-isoquino lin- 8-yl] -propionamide;
N- [(S or R)-4-((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5 ,6,7,8-tetrahydro-isoquino lin- 8-yl] -acetamide; 5 N- [(R or S)-4-((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2- y1)- 5 ,6,7,8-tetrahydro-isoquino lin- 8-yl] -acetamide;
N- [(S or R)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5 ,6,7,8 -tetrahydro -iso quino lin- 8-yl] -acetamide;
N- [(R or S)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 1 0 5 ,6,7,8 -tetrahydro -iso quino lin- 8-yl] -acetamide;
N- [(S or R)-4-((R or S)-5-Chloro-3 -ethyl- 1 -o xo - 1 ,3 -dihydro-iso indo 1- 2-y1)-6 ,7- dihydro-5H-[2]pyrindin-7-y1]-methanesulfonamide;
N- [(R or S)-4-((S or R)-5-Chloro-3 -ethyl- 1 -o xo - 1 ,3 -dihydro-iso indo 1- 2-y1)-6 ,7- d ihydro -5 H- [2]pyrindin-7-y1]-methanesulfonamid e;
N- [(R or S)-4-((R or S)- 5-Chloro-3 -ethyl- 1 -o xo - 1 ,3 -d ihydro-iso indo 1-2-y1)-6 ,7- dihydro -5 H- [2] pyrind in-7-y1]-methanesu lfo namide ;
N- [(S or R)-4-((S or R)-5-Chlo ro-3 -ethyl- 1 -o xo - 1 ,3 -dihydro-iso judo 1-2-y1)-6 ,7- dihydro-5H-[2]pyrindin-7-y1]-methanesulfonamide;
N- [(S or R)-4-((S or R)-5-Chloro-3-cyclopropyl- 1 -oxo- 1 ,3-dihydro -iso indo 1-2-y1)- 5 ,6,7,8 -tetrahydro -iso quino lin- 8-yl] -acetamide;
N- [(R or S)-4-((R or S)-5-Chloro-3-cyclopropyl- 1 -oxo- 1 ,3-dihydro -iso indo 1-2-y1)- 5 ,6,7,8-tetrahydro-isoquino lin- 8-yl] -acetamide;
N- [(S or R)-4-((R or S)-5-Chloro-3-cyclopropyl- 1 -oxo- 1 ,3-dihydro -iso indo 1-2-y1)- 5 ,6,7,8 -tetrahydro -iso quino lin- 8-yl] -acetamide;
N- [(R or S)-4-((S or R)-5-Chloro-3-cyclopropyl- 1 -oxo- 1 ,3-dihydro -iso indo 1-2-y1)- 5 ,6,7,8 -tetrahydro -iso quino lin- 8-yl] -acetamide;
N-[(R or S)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-propionamide;
N-[(R or S)-4-((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-propionamide;
N- [(S or R)-4-((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 6,7- dihydro-5H-[2]pyrindin-7-y11-propionamide;
N- [(S or R)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 6,7- dihydro-5H-[2]pyrindin-7-y1]-propionamide; 5 -Chloro -3,3 -dimethy1-2-(5 -pyrazo 1- 1 -ylmethyl-pyridin-3 -y1)-2,3 - dihydro -iso indo 1- 1-one; 2- [5-(3 -Amino -pyrazo1- 1 -ylmethyl)-pyridin-3 -yl] -5 -chloro -3 ,3 - dimethy1-2,3 - dihydro -iso indo 1- 1 -one ; 5 -Chloro -3,3 -dimethy1-2- {5-[( 1 H-pyrazol-3 -ylamino)-methyl] -pyridin-3 -2,3 - d ihydro -isoindo 1- 1 -one; 2- [543 -Amino -pyrazo1-1 -ylmethyl)-pyrid in-3 -yl] -6-chlo ro -3 ,4-dihydro- 2H- iso vino lin- 1-one; 2-Chloro-7,7-dimethy1-6- {5-[( 1 H-pyrazol-3 -ylamino)-methyl] -pyridin-3 - 6,7- dihydro -pyrro lo [3 ,4-b]pyridin-5 -one ; 2-Methoxy-7,7-dimethy1-6- {5-[( 1H-pyrazol-3 -ylamino)-methyl]Hpyridin-3-y4 - 6,7- dihydro-pyrrolo [3 ,4-b]pyridin-5 -one ; 2-Ethoxy-7,7-dimethy1-6- f 5 - [( 1 H-pyrazol-3-ylamino)-methyl]-pyridin-3 - y1) -6,7- dihydro -pyrro lo [3 ,4-b]pyridin-5 -one ; 6'-C hloro -2'- [5 -[(1H-pyrazol-3-ylamino)methyl]pyridin-3 -y1} Spiro [cyc loprop ane- 1 , 1 '-iso indo 1]-3 '(2'H)-one;
Ethane sulfonic acid [5 -(6-chloro- 1, 1 -dimethy1-3 -o xo - 1 ,3 -dihydro - iso indo 1-2-y1)- pyridin-3-ylmethy1]-amide;
Ethanesulfonic acid [5-(6-fluoro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)- pyridin-3-ylmethyl]-amide;
Ethanesulfonic acid [5-(6-cyano-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)- pyridin-3-ylmethyl]-amide;
Ethanesulfonic acid [5-((S or R)-5-chloro-3-ethyl-1-oxo-1,3-dihydro-isoindo1-2- y1)- pyridin-3-ylmethyll-amide;
N-[5-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- methanesulfonamide;
N-[5-(6-Ch1oro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y0-pyridin-3- ylmethyl]-N-methyl-methanesulfonamide;
N- [5 -(6'-Fluoro-3 '-o xo spiro [cyclopropane-1,1 '-isoindol] -2'(3 'H)- yOpyridin-3- yl] methyl} ethanesulfonamide;
N- [5 -(6'-Fluoro-3 '-o xo spiro [cyclopropane- 1 , 1 '-isoindol] -2'(3 'H)- yl)pyridin-3- yllmethylf-N-methylethanesulfonamide;
Ethanesulfonic acid [5-(6-chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)- pyridin-3-ylmethyl]-methyl-amide;
N- [5 -(6'-Chloro-3'-o xo sp iro [cyclopropane- 1,1 '-isoindol]-2'(3 'H)- yl)pyridin-3 - yllmethyllpropanamide;
N-[5-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- propionamide;
N-[5-(6-Fluoro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- propionamide;
N-[5-((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]-propionamide;
N-[5-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- acctamidc;
N- 115 -(5'-Fluoro-3 '-oxospiro [cyclopropane-1, 1 '-isoindol]-2'(3 'H)- yl)pyridin-3- yllmethyll methanesulfonamide;
N- [5 -(6-Cyano- 1,1 -dimethy1-3-o xo- 1,3 -dihydro-iso indo1-2-y1)-pyridin-3 - ylmethy1]- methane sulfonamide ;
N- [5 -(6-F luoro- 1,1 -dimethy1-3 -o xo- 1,3 -dihydro-isoindo 1-2-y1)-pyridin- 3 -ylmethy1]- methane sulfonamide ;
N- { [5 -(6'-Fluoro-3 '-o xo spiro [cyc lopropane- 1 , 1 '-iso indol] -2'(3 'H)-yOpyridin-3-Amethyl) methanesulfonamide;
N- [5 -((S or R)-5 -Chloro- 1 -ethy1-3 -o xo- 1,3 -dihydro-iso indo 1-2-y1)- pyridin-3 - ylmethyl] -methane sulfo namide ;
N- [5 -(5-F luoro- 1,1 -dimethy1-3 -o xo- 1,3 -dihydro-isoindo 1-2-y1)-pyridin- 3 -ylmethy1]- methane sulfonamide ;
N- [5 -((R or S)-5 -Chloro- 1 -ethy1-3 -o xo- 1,3 -dihydro-iso indo 1-2-y1)- pyridin-3 - ylmethyl] -methanesulfonamide;
N- [5 -(5-Ch1oro-1, 1 -dimethy1-3 -o xo-1 ,3-d ihydro-iso indo 1-2-y1)-pyridin- 3-ylmethyl] - methane sulfo namide ; 5 -Chloro-2-[5 -( 1, 1-dio xo- 126- iso thiazo lidin-2-ylmethyl)-p yridin-3- y1]-3 ,3- dimethy1-2,3 -dihydro-iso indo 1- 1 -one; 5 -Chloro-3,3 -dimethy1-245 -(2-o xo-pip eridin- 1 -ylmethyl)-pyridin-3 -y1]- 2,3 - dihydro-iso indol- 1 -one ; 5 -Chloro-3,3 -dimethy1-245 -(2-o xo-imidazo lidin- 1 -ylmethyl)-pyridin-3-yl] -2,3- dihydro-iso indol- 1 -one ; 5 -Chloro-3,3 -dimethy1-245 -(2-o xo-oxazo lidin-3 -ylmethyl)-pyridin-3 -yl] - 2,3 - dihydro-iso indol- 1 -one ; 5 -Chloro-3,3 -dimethy1-245 -(2-o xo-pyrrolidin-1 -ylmethyl)-pyridin-3-y1]-2,3- dihydro-iso indol- 1 -one ;
WO2013/079452 PCT/EP2012/073653 - 66 - 5-Chloro-3,3-dimethy1-245-(3-methyl-2-oxo-imidazolidin-1-ylmethyl)-pyridin-3- y1]-2,3-dihydro-isoindol-1-one; 5-Chloro-2-[5-(1,1-dioxo-126-[1,2]thiazinan-2-ylmethyl)-pyridin-3-y1]-3,3- dimethy1-2,3-dihydro-isoindo1-1-one; 5-Chloro-245-(3-isopropy1-2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-y11-3,3- dimethyl-2,3-dihydro-isoindo1-1-one; 6-Chloro-2-[5-(1,5-dimethy1-1H-imidazol-4-y1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 5-Chloro-3,3-dimethy1-245-(2-methy1-2H-pyrazol-3-y1)-pyridin-3-y11-2,3-dihydro- isoindol-1-one; 6-Chloro-245-(3-methy1-1H-pyrazo1-4-y1)-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(4-methy1-2H-pyrazo1-3-y1)-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-245-(4-chloro-2-methy1-2H-pyrazol-3-y1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-l-one; 6-Chloro-245-(2,5-dimethy1-2H-pyrazol-3-y1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one; 6-Chloro-2-[5-(1,5-dimethy1-1H-pyrazol-4-y1)-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-l-one; 6-Chloro-2-14-chloro-5-(2-methy1-2H-pyrazol-3-y1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-l-one; 2-Chloro-7,7-dimethy1-645-(2-methy1-2H-pyrazol-3-y1)-pyridin-3-y11-6,7-dihydro- pyrrolo[3,4-b]pyridin-5-one; 2-Methoxy-7,7-dimethy1-6-[5-(2-methyl-2H-pyrazol-3-y1)-pyridin-3-y1]-6,7- dihydro-pyrrolo[3,4-b]pyridin-5-one;
WO2013/079452 PCT/EP2012/073653 - 67 - 5-Chloro-245-(4-chloro-2-methy1-2H-pyrazol-3-y1)-pyridin-3-y1]-3,3-dimethy1- 2,3- dihydro-isoindo1-1-one; (R or S)-5-Chloro-3-ethy1-245-(2-methy1-2H-pyrazol-3-y1)-pyridin-3-y1]-2,3- dihydro-isoindol-1-one; (S or R)-5-Chloro-3-ethy1-245-(2-methy1-2H-pyrazol-3-y1)-pyridin-3-y1]-2,3- dihydro-isoindol-1-one; 3-Methyl-pyridine-2-carboxylic acid [5-(6-chloro-1,1-dimethy1-3-oxo-1,3- dihydro- isoindo1-2-y1)-pyridin-3-ylmethyl]-amide; 3-Chloro-pyridine-2-carboxylic acid [5-(6-chloro-1,1-dimethy1-3-oxo-1,3- dihydro- isoindo1-2-y1)-pyridin-3-ylmethy1]-amidc; 1-Methyl-1H-imidazolc-2-carboxylic acid [5-(6-chloro-1,1-dimethy1-3-oxo-1,3- dihydro-isoindo1-2-y1)-pyridin-3-ylmethyli-amide; 2-Chloro-N-[5-(6-chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin- 3- ylmethyl]-nicotinamide;
Pyridine-2-carboxylic acid [5-(6-chloro-1,1-dimethy1-3-oxo-1,3-dihydro- isoindo1-2- y1)-pyridin-3-ylmethyl]-amide; 3-Methy1-3H-imidazole-4-carboxylic acid [5-(6-chloro-1,1-dimethy1-3-oxo-1,3- dihydro-isoindo1-2-y1)-pyridin-3-ylmethyl]-amide;
N-[5-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- 6-methyl-nicotinamide; 3-Chloro-N-[5-(6-chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin- 3- ylmethyl]-isonicotinamide;
N-[5-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- nicotinamide;
N-[5-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- 2-methyl-nicotinamidc;
N-[5-(6-Ch1oro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-pyridin-3- ylmethyl]- 4-methyl-nicotinamide; 2-[5-(1-Acetyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-5-chloro-3,3-dimethy1-2,3- dihydro-isoindo1-1-one; 2-[5-((R)-1-Acetyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-5-ehloro-3,3-dimethy1-2,3- dihydro-isoindol-1-one; 2-[5-((S)-1-Acetyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-5-chloro-3,3-dimethy1-2,3- dihydro-isoindo1-1-one; 5-Chloro-3,3-dimethy1-2-[5-(1-propionyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-2,3- dihydro-isoindol-1-one; 5-Chloro-2-[5-(1-methanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-3,3- dimethy1- 2,3-dihydro-isoindol-1-one; 5-Chloro-2-[5-(1-ethanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-3,3-dimethy1- 2,3-dihydro-isoindo1-1-one; 5-Chloro-2-[5-((R)-1-ethanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-3,3- dimethy1-2,3-dihydro-isoindo1-1-one; 5-Chloro-2-[5-((S)-1-ethanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-y1]-3,3- dimethy1-2,3-dihydro-isoindo1-1-one; 2-[5-(1-Acetyl-piperidin-4-yloxy)-pyridin-3-y1]-5-chloro-3,3-dimethy1-2,3- dihydro- isoindol-l-one; 2-[5-(1-Acetyl-azetidin-3-yloxy)-pyridin-3-y11-5-chloro-3,3-dimethy1-2,3- dihydro- isoindol-l-one; 5-Chloro-3,3-dimethy1-2-[5-(1-propionyl-azetidin-3-yloxy)-pyridin-3-y1]-2,3- dihydro-isoindol-l-one; 5-Chloro-2-[5-(1-methanesulfonyl-azetidin-3-yloxy)-pyridin-3-y1]-3,3-dimethy1- 2,3-dihydro-isoindo1-1-one;
WO2013/079452 PCT/EP2012/073653 - 69 - -Chloro -2-[5 -( 1 -ethane su lfo nyl-azet id in-3-ylo xy)-pyrid in-3 -yl] -3 ,3 -dimethy1-2,3 - dihydro -iso indol- 1 -one ; 5 -Chloro -245 -((S)-3 -hydro xy-p yrro lidin- 1 -y1)-p yridin-3 -y1]-3 ,3 - dimethy1-2,3 - dihydro -iso indol- 1 -one ; 5 2- [5-(4-Acetyl-p iperazin- 1 -y1)-pyridin-3 -y1]-5 -chloro-3 ,3-dimethy1- 2,3 -dihydro- iso indol- 1 -one; 5 -Chloro -3,3 -dimethy1-245 -(4-propionyl-p ip erazin- 1 -y1)-pyridin-3-y1]- 2,3-dihydro- iso indol- 1 -one; 5 -Chloro -245 -(4-methanesulfo nyl-pip erazin- 1 -y1)-pyridin-3-yll -3,3- dimethy1-2,3- 1 0 dihydro -iso indol- 1 -one ; 5 -Chloro -245 -(4-ethane sulfo ny1-p iperazin- 1 -y1)-pyridin-3 -y1]-3 ,3 - dimethy1-2,3 - dihydro -iso indol- 1 -one ; 5 -Chloro -2- {5-[4-(3-chloro -pyridine-2-carbony1)-p ip erazin- 1 -yl] - pyridin-3 -yll -3 ,3 - d imethy1-2,3 -dihydro -isoindo 1-1-one; 2-[5-(1 -Acetyl-pyrro lid in-3 -y1)-pyrid in-3 -yl] -5-chloro -3 ,3-dimethy1- 2,3 -d ihydro - iso indol- 1 -o ne; 2-( l'-Acetyl- 1 ',2',3',4',5 ',6'-hexahydro - [3,41bip yridiny1-5-y1)-5 -ch10 ro -3 ,3-dimethyl- 2 ,3-dihydro-iso indol- 1 -one ; 2-[6-(1 -Acetyl-p iperidin-3-y1)-pyrazin-2-y1]-5 -chloro-3 ,3-dimethy1-2,3 - dihydro- iso indol- 1 -one; 5 -Chloro -3,3 -dimethy1-2-16-(1 -propionyl-pip eridin-3 -y1)-pyrazin-2-y1]- 2,3-dihydro- iso indol- 1 -one; 5 -Chloro -2-[6-( 1 -ethane sulfo nyl-p iperidin-3 -y1)-pyrazin-2-y1]-3 ,3 - dimethy1-2,3 - dihydro -iso indol- 1 -one ; 5 -Chloro -2-[6-( 1 -methanesulfo nyl-pip eridin-3 -y1)-pyrazin-2-yl] -3 ,3- dimethy1-2,3- dihydro -iso indol- 1 -one ;
N-[(S or R)-4-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8- tetrahydro-isoquinolin-8-y1]-acetamide;
N-[(R or S)-4-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8- tetrahydro-isoquinolin-8-y1]-acetamide;
N-[4-(6-Chloro-1,1-dimethy1-3-oxo-1,3-dihydro-isoindo1-2-y1)-5,6,7,8- tetrahydro- isoquinolin-8-y1]-propionamide; and pharmaceutically acceptable salts thereof.
Further particular examples of compounds of formula (I) as described herein are selected from 6-Chloro-2-pyridin-3-y1-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-(4-chloro-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 6-Chloro-2-(5-isopropoxy-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-onc; 6-Chloro-2-[5-((R)-1-hydroxy-ethyl)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- one; 6-Chloro-2-(5-cyclopropoxy-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one; 2-Methoxy-6-(5-methoxy-pyridin-3-y1)-7,8-dihydro-6H-[1,6]naphthyridin-5-one; 5-Chloro-3-ethy1-2-(5-fluoro-pyridin-3-y1)-2,3-dihydro-isoindol-l-one; 5-Chloro-2-(5-fluoro-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindol-1-one; 1- 205-Chloro-2-(5-difluoromethoxy-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro- isoindo1- one; 6-Chloro-245-(2-oxa-6-aza-spiro[3.4]oct-6-ylmethyl)-pyridin-3-y1]-3,4-dihydro- 2H- isoquinolin-l-one; 6-Chloro-2-(5-methoxymethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one;
WO2013/079452 PCT/EP2012/073653 - 71 - 6-Chlo ro-245 -( 1 -methyl- 1 H-pyrazol-4-ylmethyl)-pyrid in-3 -yl] -3 ,4- dihydro -2H- iso quino lin- 1-one; 6-Chloro-2- {5- [(2-methyl-2H-p yrazol-3 -ylmethyl)-amino] -p yridin-3-y1} -3 ,4- dihydro -2H-iso quino lin- 1-one; 6-Chloro-245 -(2-methyl-2H-pyrazo 1-3 -y1)-pyridin-3 -yll -3 ,4-dihydro -2H- iso quino lin- 1-one; 6-Chloro-2- { 5 - [( 1 H-pyrazol-3 -ylamino)-methyl] -pyridin-3 -y1} -3 ,4- dihydro-2H- iso quino lin- 1-one; and pharmaceutically acceptable salts thereof.
Also further particular examples of compounds of formula (I) as described herein are selected from (R or S)-5 -Chloro-3 -ethy1-2-(5 -fluoro-pyridin-3 -y1)-2,3 -dihydro -iso indo 1- 1 -one ; (S or R)-5 -Chloro-3 -ethy1-2-(5 -fluoro-pyridin-3 -y1)-2,3 -dihydro -iso indo 1- 1 -one ;
N- [(R or S)-4-((R or S)-5-Ch loro-3 -ethyl- 1 -oxo- 1 ,3 -dihydro-i so in do 1-2-y1)-5 ,6,7,8 - tetrahydro-isoquino lin- 8-yl] -acetami d e ;
N-[(R or S)-4-((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 5 ,6,7,8-tetrahydro-isoquino lin- 8-yl] -prop ionamide ;
N-[(R or S)-4-((S or R)-5-Chloro-3-methyl-l-oxo-1,3-dihydro-isoindo1-2-y1)- 5 ,6,7,8 -tetrahydro -iso quino lin- 8-yl] -acetamide;
N- [(R or S)-4-((S or R)-5-Chloro-3 -ethyl- 1 -oxo- 1 ,3 -dihydro-iso indo 1-2- y1)-6 ,7- dihydro-5H-[21pyrindin-7-y1]-methanesulfonamide;
N- [(R or S)-4-((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindo1-2-y1)- 6,7- dihydro-5H-[2]pyrindin-7-y1]-propionamide;
N-[(S or R)-4-((R or S)-5-Chloro-3-methyl-l-oxo-1,3-dihydro-isoindo1-2-y1)-6,7- dihydro-5H-[2]pyrindin-7-y1]-propionamide;
WO2013/079452 PCT/EP2012/073653 - 72 - -Chloro-3,3 -d imethy1-2- { 5-[(1H-pyrazol-3 -ylamino)-methyl] -pyrid in-3 - y1} -2,3- dihydro-iso indol- 1 -one ; 6'-Chloro-2'- {5 - [( 1H-pyrazol-3-ylamino)methyl]p yridin-3 -y1{ Spiro [cycloprop ane- 1 , 1'-isoindol]-3'(2'H)-one; 5 N- [5 -(6-Chloro- 1 , 1 -dimethy1-3 -o xo- 1 ,3-dihydro-iso indo1-2-y1)- pyridin-3-ylmethyl] - methanesulfonamide ; 3 -Methyl-pyridine-2-carboxylic acid [5 -(6-chloro- 1, 1 -dimethy1-3-o xo- 1,3- dihydro- iso indo1-2-y1)-pyridin-3 -ylmethyl] -amide; 2-[5-((R)- 1 -Acetyl-pyrrolidin-3 -ylo xy)-pyridin-3 -y1]-5 -chloro-3 ,3- dimethy1-2,3 - 1 0 dihydro-iso indol- 1 -one ; 2-[5-((S)- 1-Acetyl-pyrro lidin-3-ylo xy)-pyridin-3 -yl] -5-chloro-3,3- dimethy1-2,3 - dihydro-iso indol- 1 -one ; 5 -Chloro-2-[5 -( 1 -methanesulfonyl-pyrro lidin-3 -ylo xy)-pyridin-3 -yl] - dimethyl- 2,3-dihydro-isoindol- 1 -one; 5 -Chloro-2-[5 -((R)- 1-ethanesu lfo nyl-pyrro lid in-3 -ylo xy)-pyridin-3-y1]- 3 ,3 - dimethy1-2,3 -dihydro- iso indol- 1 -one; 5 -Chloro-2-[5 -((S)- 1 -ethanesulfonyl-p yrro lidin-3-y lo xy)-p yridin-3 - yl] -3 ,3 - dimethy1-2,3 -dihydro-iso indol- 1 -one; 2-[5-(1 -Acetyl-p iperidin-4-ylo xy)-pyridin-3 -y1]-5 -chloro-3 ,3 -dimethy1- 2,3 -dihydro- iso indol- 1 -one; 5 -Chloro-2-[5 -( 1 -ethanesulfonyl-azetidin-3-ylo xy)-pyridin-3 -yl] -3,3 - dimethy1-2,3 - dihydro-iso indol- 1 -one ; 2- [5-(4-Acetyl-p iperazin- 1 -y1)-pyridin-3 -y1]-5 -chloro-3 ,3-dimethy1-2,3 - dihydro- iso indol- 1 -one; 5 -Chloro-245 -(4-methanesulfonyl-pip erazin- 1 -y1)-pyridin-3-yl] -3 ,3- dimethy1-2,3- dihydro-iso indol- 1 -one ;
WO2013/079452 PCT/EP2012/073653 - 73 - 5-Chloro-245-(4-ethanesulfonyl-piperazin-1-y1)-pyridin-3-y1]-3,3-dimethy1-2,3- dihydro-isoindol-1-one; 2-(P-Acetyl- 1 ',2',3',4',5',6'-hexahydro-[3,41bipyridiny1-5-y1)-5-chloro-3,3- dimethyl- 2,3-dihydro-isoindol-1-one; and pharmaceutically acceptable salts thereof.
Processes for the manufacture of compounds of formula (I) as described herein are an object of the invention.
The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereo isomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to the man skilled in the art such as e.g. chiral chromatography or crystallization. The substituents and indices used in the following description of the processes have the significance given herein.
The following abbreviations are used in the present text:
AcOH = acetic acid, BOC = t-butyloxycarbonyl, BuLi = butyllithium, CDI= 1,1- carbonyldiimidazole, DCM = dichloromethane, DBU = 2,3,4,6,7,8,9,10-octahydro- pyrimido[1,2-a]azepine, DCE = 1,2-dichloroethane, DIBALH = di-i-butylaluminium hydride, DCC = N,N'-dicyclohexylcarbodiimide, DMA = NA-dimethylacetamide, DMAP 4-dimethylaminopyridine, DMF = /V,N-dimethylformamide, EDCI = N-(3- dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride, Et0Ac = ethylacctate, Et0H = ethanol, Et20 = diethylether, Et3N = triethylamine, eq = equivalents, HATU = azabenzotriazol-1-y1)-1,1,3,3-tetramethyluronium hexafluorophosphate, HPLC = high performance liquid chromatography, HOBT = 1-hydroxybenzo-triazole, Huenig's base = iPr2NEt = N-ethyl diisopropylamine, IPC= in process control, LAH = lithium aluminium hydride, LDA = lithium diisopropylamide, LiBH4 = lithium borohydride, Me0H = methanol, NaBH3CN, sodium cyanoborohydride, NaBH4 = sodium borohydride, NaI =
WO2013/079452 PCT/EP2012/073653 - 74 - sodium iodide, Red-Al = sodium bis(2-methoxyethoxy) aluminium hydride, RT = room temperature, TBDMSC1= t-butyldimethylsilyl chloride, TFA = trifluoroacetic acid, THF = tetrahydrofuran, quant = quantitative.
Halogen or triflate substituted heterocyclic compounds 2 react with aryl lactams 1 in solvents like 1,4-dioxane, in the presence of copper (I) iodide, potassium or cesium carbonate, a chelating 1,2-diamino compound like NN'-dimethylethylenediamine or trans- 1,2-diamino-hexane, at elevated temperatures, preferable with the aid of microwave heating to form lactam substituted heterocyclic compounds 3 (step a) as described in Scheme 1.
Scheme 1 Ri 2 Ri 2 3 3 2 R4 Ta T1 2 Xis halogen or OSO2CF3 Treatment of heteroaryl linked alcohol compounds 51 (Scheme 2b) with a base like sodium hydride in a solvent like THF or DMF and subsequently with a suitable alkylating agent such as a halide, mesylate or tosylate preferably between RT and the reflux temperature of the solvent gives compounds 52 (step a). Alternatively (Scheme 2a), heteroaryl linked alcohol compounds 51 can e.g. be converted into the corresponding chlorides by treatment with thionyl chloride in a solvent like dichloromethane preferably between 0 C and room temperature (step b). Said heteroaryl linked chlorides, compounds 53, react with nucleophilic amino-moieties 54a or aryl, heteroaryl or heterocycloalkyl compounds 54b per se or after anion formation e.g. with sodium hydride in solvents like N,N'-dimethylformamide in a temperature range between 0 C and about 100 C to form adducts 55a or 55b (step c).
Scheme 2a Fe 2 3 1 R
R7....r,õ 4 n A,,-- On,-(CR15R16)p-(CR17R18)q-CR19R20-OH
R5 0 A- 51 b R4 -Y"-- n 2 NyA=, ,,,,,,,,,Orn-(CR
A5 ,../ 15R16)p_(CR17R18)q-CR19R2O_CI
R5 0 P,-,,J1 H¨ clo 53 c 54b R1o4 , H¨N
Ri ¨2 Y `R26 3 54a IR7A1 n R4 A5 NyA-Om-(CR15R164-(CR17R18)q_CR19R2O_NR104R26 R5 0 55a R4 =Ny,A0m-(CR15R16)p-(cRi7Rie)cicRi9R2o_ Fe 0 R104 is R25, -S(0)2R25, 55b -C(0)R25 or -C(0)NR25R27 H¨NO is heteroaryl or heterocyclyi substituted by R38, R39, R40, SUBSTITUTE SHEET(RULE 26) Scheme 2b Ri 2 3 n R4 N..............õ"Orn-(CR15R16)p_(CR17R18)q-CR19R20_0H
R5 0 51 a R4 ji 2 N....i......."q,,,...õOrri_(CR15R16)p_(CR17R18)q_CR19R20_0R25 Alternatively (Scheme 2c), heteroaryl linked chloride compounds 53 react with boronic acids or esters 56 i) by using Suzuki conditions, e.g. in the presence of catalysts, such as tri-o-tolylphosphine/palladium(H)acetate, tetrakis- (triphenylphosphine)-palladium, his(triphenylphosphine)palladium(H)chloride or dichloro[1,1'- bis(diphenylphosphino)- ferrocene]palladium(H) optionally in the form of a dichloromethane complex (1:1), and in the presence of a base, such as aqueous or non aqueous potassium phosphate, sodium or potassium carbonate, in a solvent, such as dimethylsulfoxide, toluene, ethanol, dioxane, tetrahydrofuran or /V,N-dimethylformamide, and in an inert atmosphere such as argon or nitrogen, in a temperature range preferably between room temperature and about 130 C or ii) by using a nickel (0) catalyst, e.g. bis(1,5-cyclooctadiene)nickel (0) in the presence potassium phosphate, bis(1-methy1-1H-imidazol-2-yOmethane in /V,N-dimethyl acetamide at temperatures around 100 C giving adducts 57 (steps d).
Scheme 2c RyAl R4 io A A2 53 _________________________________________________________ R ?R101 R21,- \ 0 R 1 02 57 56 R101 and R102 are H or alkyl, or R101 and R102 together with the boron atom to which they are attached form BH
R21 is substituted aryl or substituted heteroaryl Aldehydes or ketones 58 (Scheme 2d) can be treated with suitable amino- moieties 59 the presence of NaBH(OAc)3in a one step procedure in a solvent like methanol preferably around room temperature or in a two step procedure by first treatment with titanium (IV) isopropoxide in solvents like methanol or toluene preferably at temperatures between room temperature and the reflux temperature of the solvents followed by reaction with NaBF14 preferably between 0 C and room temperature which converts aldehydes or ketones 58 into amino compounds 60; alternatively imines obtained after treatment with titanium (IV) isopropoxide can be evaporated, then be re-dissolved in a solvent like THF and being treated with a Grignard reagent R20MgX, preferably between -40 C and 0 C leading to amino compounds 60 carrying the specific R2 substituent (step e).
SUBSTITUTE SHEET(RULE 26) Scheme 2d Ri 2 3 A NyA
H¨N \ R26 59 A5 õ/ NyA...,70m_(cR15R16)p_(cR17R18)q_cR19R2O_NR104R26 R104 is R25, _s(0)2R25, _c(0)R25 or -C(0)NR25R27 Heteroaryl halides 101 (Scheme 2e) react with boronic acids or esters 102 using Suzuki conditions as described above to give adducts 103 (step a). Phenols 104 react with alcohols 105 under Mitsunobu conditions e.g. with triphenylphosphine and di- tert-butyl-, 5 diisopropyl-, diethyl-azodicarboxylate or di-(4- chlorobenzyl)azodicarboxylate as reagents in solvents like toluene, dichloromethane or tetrahydrofuran preferably at ambient temperature to give adducts 106 (step b). Compounds 106 can be transformed by additional standard modifications into synthons 107 (step c).
Scheme 2e 3 R1 2 R7 A1 R1 2 3 .,,A2 R4 a _________________________________ , FtAl I In R4 21 A5 r101 A .....õ...- A2 N R
R5 0 3\02 5 I
I
R21 0 7- 0 103 -rNI 101 102 R1 2 3 17&,,._,,,A,1 R4 IIn N A2 OH y + HO-(CR15R16)p-(CR17R18)q-(CR19R20)r-R109 0 Pk-.,, - 105 R1 2 b 3 ' F:Z7A1 R4 41 n -----f-''(-- A2 0 -(CR15R16) p- (CR17 R18) cc(CR1gR20) (R109 R5 0 otk I k-, Ri R2 3 R7 A1 , R4 -, c il 2 106 --..- A NyA0-(CR15R16)p_(CR17R18)q_(cRi9R20)(R21 R5 0 A.k...
R101 and R102 are H or alkyl, or R101 and R102 together with the boron atom to which they are attached form o iT6BH
R21 is substituted aryl or substituted heteroaryl Xis halogen or OSO2CF3 R109 represents substituents as defined in R21 or substituents which can easily be transformed into R21 (step c).
SUBSTITUTE SHEET(RULE 26) Carbamates 201 (Scheme 3) react with polyphosphoric acid at elevated temperature (e.g. 100-180 C) to form 3,4-dihydro-2H-isoquinolin-1-one derivatives 202 (step a).
Trifluroacetamides 203 can be cylized to 1-(3,4-dihydro-1H-isoquinolin-2-y1)- 2,2,2- trifluoro-ethanone compounds 204 by treatment with paraformaldehyde in a mixture of concentrated sulfuric acid and acetic acid preferably around room temperature (step b).
Removal of the trifluoroacteyl group by treatment with e.g. potassium hydroxide in a solvent like ethanol at temperatures around room temperature gives tetrahydro- isoquinoline compounds 205 (step c). Oxidation of tetrahydro-isoquinoline compounds 205 e.g. with iodoso benzene and potassium bromide preferably in water gives 3,4- dihydro-2H-isoquinolin-1-one compounds 202 (step d). Reaction of isoindole-1,3- dione compounds 206 with a Grignard reagent RiMgX in a solvent like THF preferably around 0 Cgives adducts 207 (step e). Subsequent treatment with triethylsilane and trifluoroboron etherate in a solvent like dichloromethane and in a temperature range preferably between - 25 C and RT gives isoindolone compounds 208 (step f). Introduction a methoxybenzyl protecting group into isoindolone compounds 209 (e.g. by treatment with sodium bis(trimethylsily1) amide and 1-bromomethy1-4-methoxy-benzene in THF between 0 C and RT) gives protected compounds 210 (step g); similarly, a methoxybenzyl protecting group can be introducted into compounds 208. Treatment of compounds 208 carrying an additional methoxybenzyl protecting group or compounds 210 with a base like sodium hydride in a solvent like THF and then with an alkyl halide, mesylate or tosylatc preferably between RT and the reflux temperature of the solvent gives compounds 211 with structurally different or structurally identical R1 and R2 groups (step h).
Alternatively, treatment of compounds 208 carrying an additional methoxybenzyl protecting group or compounds 210 with a base like NaH, LDA or LiHMDS in solvents like DMF, tetrahydrofuran or 1,2-dimethoxyethane and then with one or sequentially with two different alkyl halides, mesylates or tosylates preferably between -78 C and the reflux temperature of the solvent gives compounds 211 with structurally different or structurally identical Rl and R2 groups (step h). Removal of the protecting group, e.g. by treatment with trifluoroacetic acid at elevated temperature gives isoindolone compounds 212 (step i).
Treatment of compounds 210 with a base like sodium hydride in a solvent like THFand then with an alpha, omega di-haloalkane or di-haloheteroalkane like e.g. 1,2- dibromoethane, preferably between RT and the reflux temperature of the solvent gives Spiro compounds 213 (step k) and after subsequent removal of the protecting group, Spiro compounds 214 (step!).
Scheme 3 Ri 2 R1 -2 3 .3 7 R n I
An R4 a I I I R4 ______________________________________________ , A5 NH
R4 p n R1 R2 3 F C
R5 0 g NH
Ib 205 R1 -2 .3 F
A5 ./ HNyi<F
SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 81a - 1 H 7 1 R1 H 1=27 7 R.i.< R P
II H
TIf e A / ...r,-- H
A5 / A / ..,----R5 0 R5 0 207 206 208 1 g, h Ri 2 g Ri 2 I
A5 ,.V. I IR71 ---11. I I H
R5 0 A5 ,/ 211 R5 0 1 / 212 / h 0 0 D 7 1 k II A5 ,-Ig IR7, ,A1 RA'Ti H (..õ........õ,,s( A5 /
A/
Dis a substituted cycloalkyl or a substituted heterocycloalkyl formed by R1 and R2 together with the carbon atom to which they are attached , wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23 and R24 SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 81b - 5-Halo-nicotinic acid or pyridazine carboxylic acid compounds 301 or 305 (Scheme 4a) react with acrylic acid ester compounds 302 after deprotonation with base like LDA or LiHMDS in solvents like THF preferably around -78 C giving cyclic beta keto ester SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 82 - compounds 303 and 306 (step a). Ester compounds 303 or 306 with Ri = H can be treated with a base like NaH, LDA or LiHMDS in solvents like DMF, tetrahydrofuran or 1,2-dimethoxyethane, followed by addition of an alkyl or cycloalkyl halide, mesylate or tosylate, or e.g. a N-halobenzensulfonamide, a reaction preferably performed between -78 Cand room temperature, to give ester compounds 303 or 306 carrying a substituent different from H. Treatment of beta keto-ester compounds 303 or 306 with aqueous acid preferably at reflux induces ester hydrolysis and subsequent decarboxylation providing ketones 304 and 307 (step b). Ketones 304 and 307 with R111 = H and R113 = H can be treated with a base like NaH, LDA or LiHMDS in solvents like DMF, tetrahydrofuran or 1,2-dimethoxyethane, followed by addition of one or subsequently two different alkyl or cycloalkyl halides, mesylates or tosylates, or e.g. N-halobenzensulfonamides, a reaction preferably performed between -78 C and room temperature, to give ketones 304 and 307 carrying at least one of the substituents Rill or RH3 different from H.
Optionally, ketones 304 and 307 can be converted into the corresponding imines (e.g. with N- butylamine by using a catalyst like toluene sulfonic acid or pyridinum p-toluenesulfonate in a solvent like ethanol preferably at reflux); such imines with Rill = H can be reacted with e.g. N- fluorobenzenesulfonimide using K2C01 or triethyamine as base in solvents like DMFor acetonitrile or mixtures thereof, in the presence of molecular sieves preferably at room temperature to give imines carrying fluoro subsitutents and after imine hydrolysis (e.g. with hydrochloric acid in acetonitrile) ketones 304 and 307 with Ri = F.
Ketones 304 and 307, can function as compounds 2 (scheme 1) or can be converted into different compounds 2 (Scheme 1) by further structural modification using methods well known in the art as e.g. reduction of the keto function to a secondary hydroxy group with a reagent like sodium borohydride in methanol or reduction of the keto group to a primary or secondary amino function by reductive amination e.g. by reacting with an amine and NaBH(OAc); in methanol.
Scheme 4a 0 R110 0 a xo 0 Fe"
R110 .,112 Rill 0 a IR112y Rilo 0 X .='9(` 0 Rill 305 302 306 Ib R112 R11, R1" 0 Xis halogen or OSO2CF3 A
I
Three of R110, R111, R112 and R113 are R35 or R36 or R37 and the 307 other one is H.
SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 83a -Dihalopyridine or pyridazine compounds 351 (Scheme 4b) react with bromo- tetramethyl-azadisilolidine reagents 352 after deprotonation with lithium diisopropyl amide in solvents like tetrahydrofuran between -78 C and 0 C to give aminoalkyl substituted pyridines or pyridazine 353 (step a). After attachment of a protecting group onto compounds 353 (e.g. by introducing a BOC- or a SES-protecting group by reaction with BOC20 or 2- trimethylsilanyl-ethanesulfonyl chloride, triethylamine, DMF around 0 C), treatment of amino protected pyridine or pyridazine compounds 354 with a base like potassium carbonate, in a solvent like toluene, and in the presence of a catalyst like ietrakis- (triphenylphosphine)- palladium at temperatures around 100 C gives bicyclic compounds 355, still carrying a protecting group (step b, c). Standard BOC removal or use of tetrabutylammonium fluoride hydrate, acetonitrile preferably between room temperature and the reflux temperature of acetonitrile then gives bicyclic compounds 356 (step d). Amino compounds 356 can function as compounds 2 (Scheme 1) either as such or after further structural modification by methods well known in the art.
SUBSTITUTE SHEET(RULE 26) Scheme 4b H R110 H .,N,,, H a + R1,2 H Rii, X X NH2 i*-,,, .
Br n H 1 Het) Rilo H b R11i H
H H
H Rili Riii R112 H H
X NH X N X
Id I prot.
C/ 1 1 prot.
A,1...., N N
N 356 355 354 prot. = protecting group X is halogen or OSO2CF3 R110 is R35, R36 or R37.
R111 is R35, R36 or R37.
R112 is R35, Roo or R37. 5-Halo-nicotinic acid compounds 305 (Scheme 4c) react with alkene compounds 400 after deprotonation with a base like LDA or LiHMDS in solvents like THF preferably around -78 C giving alkenes 401 (step a). Diester compounds 402 can be synthesized by methods known to persons skilled in the art such as e.g by ozonolysis of alkenes 401 in the presence of methanolic NaOH to give compounds 402 which can be cyclized using Dieckmann condensation conditions to give beta keto-ester compounds 403 (step b, c).
Treatment of beta keto-ester compounds 403 with aqueous acid preferably at reflux temperature induces ester SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 84a - hydrolysis and subsequent decarboxylation providing ketones 404 (step e).
Ester compounds 403 (Rill is H) can be treated with a base like NaH, LDA or LiHMDS in solvents like DMF, tetrahydrofuran or 1,2-dimethoxyethane, followed by addition of an alkyl or cycloalkyl halide, mesylate or tosylate, or e.g. a N-halobenzensulfonamide, a reaction preferably performed between -78 C and room temperature, to give ester compounds 403 carrying a substituent I different from H
SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 85 - (step d). Hydrolyses and decarboxylation as described above gives ketones 404 (step e).
Ketone compounds 404 can function as compounds 2 (Scheme 1) either as such or after further structural modification by methods described herein or by methods well known in the art.
Scheme 4c Ri10 R11 o Rill R113 R111 ,112 R113 a N 0 X
Ri 10 A4 I 305 400 401 b 0 0 R1" R110 R113 Rilo Rua R"1 R"1 Ril2 e x C, d 0 0 Xis halogen or OSO2CF3 X1 is Halogen, Mesylate or Tosylate R110 is H, R35, R36 or R37.
R111 is H, R35, R36 or R37.
R112 is H, R35, R36 or R37.
R113 is H, R35, R36 or R37.
Also an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);
SUBSTITUTE SHEET(RULE 26) R
R4 On) TI
A5 NyAi R5 R5 0 A4....k1\1) (II) (I) wherein R1, R2, R3, R4, R5, R6, A1, A2, A3, A4, A5 and n are as defined above and wherein, Xis halogen or triflate.
In particular, in the presence of copper (I) iodide, potassium or cesium carbonate, a chelating 1,2-diamino compound like NN'-dimethylethylenediamine or trans-1,2- diamino- hexane, at elevated temperatures, preferable with the aid of microwave heating and in solvents like 1,4-dioxane..
Also an object of the present invention is a compound according to formula (I) as described herein for use as therapeutically active substance.
Likewise an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of diabetic nephropathy.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of kidney or heart fibrosis.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of congestive heart failure.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of hypertension.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of primary aldosteronism.
Aparticular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
Also a particular embodiment of the present invention is a compound according to formula (1) as described herein for the treatment or prophylaxis of diabetic nephropathy.
Another particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of kidney or heart fibrosis.
Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease.
Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of congestive heart failure.
Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of hypertension.
Also a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of primary aldosteronism.
The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of diabetic nephropathy.
The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of kidney or heart fibrosis.
Also an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of chronic kidney disease.
Also an embodiment of the present invention is the use of a compound according to formula (1) as described herein for the preparation of a medicament for the treatment or prophylaxis of congestive heart failure.
Also an embodiment of the present invention is the use of a compound according to formula (1) as described herein for the preparation of a medicament for the treatment or prophylaxis of hypertension.
Also an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of primary aldosteronism.
Also an object of the invention is a method for the treatment or prophylaxis of .. chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
Also an object of the invention is a method for the treatment or prophylaxis of diabetic nephropathy, which method comprises administering an effective amount of a compound according to formula (1) as described herein.
Also an object of the invention is a method for the treatment or prophylaxis of kidney or heart fibrosis, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
Also an embodiment of the present invention is a method for the treatment or prophylaxis of chronic kidney disease, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
Also an embodiment of the present invention is a method for the treatment or prophylaxis of congestive heart failure, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
Also an embodiment of the present invention is a method for the treatment or prophylaxis of hypertension, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
Also an embodiment of the present invention is a method for the treatment or prophylaxis of primary aldosteronism, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
Also an embodiment of the present invention is a compound of formula (I) as described herein, when manufactured according to any one of the described processes.
Assay procedures Herein we identified the use of the G-402 cell line as a host cell to ectopically express (transiently or stably) enzymes of the CYP11 family. Specifically we developed stable G-402 cells expressing ectopically human CYP11B1, human CYP11B2, human CYP11A1, cynmolgus CYP11B1 or cynomolgus CYP11B2 enzyme activity. Importantly the identified cell line G-402 expresses co-factors (adrenodoxin and adrenodoxin reductase) important for the activity of the CYP11 family and no relevant enzyme activity of the CYP11 family (in comparison to H295R cells) was detected in these cells. Therefore the G-402 cell line is uniquely suited as a host cell for the ectopic expression of enzymes from the CYP11 family. 0-402 cells can be obtained from ATCC (CRL-1440) and were originally derived from a renal leiomyoblastoma.
The expression plasmids contains the ORF for either human / cyno CYP11B1 or CYP11B2 under the control of a suitable promoter (CMV-promoter) and a suitable WO2013/079452 PCT/EP2012/073653 - 90 - resistance marker (neomycin). Using standard techniques the expression plasmid is transfected into G-402 cells and these cells are then selected for expressing the given resistance markers. Individual cell-clones are then selected and assessed for displaying the desired enzymatic activity using 11-Deoxycorticosterone (Cypl 1B2) or 11-Deoxycortisol (Cyp11B1) as a substrate.
G-402 cells expressing CYP11 constructs were established as described above and maintained in McCoy's 5a Medium Modified, ATCC Catalog No. 30-2007 containing 10%
FCSand 400 1.1g/m1 G418 (Geneticin) at 37 C under an atmosphere of 5%
CO2/95% air.
Cellular enzyme assays were performed in DMEM/F12 medium containing 2.5 % charcoal treated FCS and appropriate concentration of substrate (0.3-10 uM 11-Deoxycorticosterone, 11-Deoxycortisol or Corticosterone). For assaying enzymatic activity, cells were plated onto 96 well plates and incubated for 16h. An aliquot of the supernatant is then transferred and analyzed for the concentration of the expected product (Aldosterone for CYP11B2; Cortisol for CYP11B1). The concentrations of these steroids can be determined using HTRF assays from CisBio analyzing either Aldosterone or Cortisol.
Inhibition of the release of produced steroids can be used as a measure of the respective enzyme inhibition by test compounds added during the cellular enzyme assay.
The dose dependent inhibition of enzymatic activity by a compound is calculated by means of plotting added inhibitor concentrations (x-axes) vs. measured steroid/product level (y-axes). The inhibition is then calculated by fitting the following 4- parameter sigmoidal function (Morgan-Mercer-Flodin (MMF) model) to the raw data points using the least squares method:
AB+ CxD
Y= B + xp wherein, A is the maximum y value, B is the EC50 factor determined using XLFit, C is the minimum y value and D is the slope value.
The maximum value A corresponds to the amount of steroid produced in the absence of an inhibitor, the value C corresponds to the amount of steroid detected when the enzyme is fully inhibited.
EC50 values for compounds claimed herein were tested with the G402-based assay system described. Cyp11B2 enzyme activity was tested in presence of 1 ILLM
Deoxycorticosterone and variable amounts of inhibitors; Cypl1B1 enzyme activity was tested in presence of 1 iuM Deoxycortisol and variable amounts of inhibitors.
EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example IIIM IIIM IIIM IIM 1 0.0860 4.6072 8 0.0449 0.8072 2 0.4421 7.3919 9 0.1170 4.7416 3 0.0965 3.7211 10 0.0260 0.8220 4 0.0671 1.2377 11 0.0127 0.2566 5 0.0925 4.2705 12 0.0357 0.1177 6 0.0300 1.2079 13 0.0543 0.8652 7 0.0779 0.7042 14 0.0550 1.0961 !
EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 15 0.0682 0.9130 24 0.0056 0.0214 16 0.0193 0.1262 25 0.4010 17 0.5967 14.0208 26 0.3214 8.1518 18 0.0586 0.5071 27 0.0753 0.7309 19 0.0603 0.1984 28 0.1035 0.7566 20 0.0859 1.0495 29 0.3184 12.9186 21 0.0415 0.2632 30 0.7512 2.0686 22 0.0557 0.5168 31 0.0502 0.3283 23 0.0640 0.5714 32 0.0468 0.5139 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 33 0.2100 0.4847 42 0.3269 7.8639 34 0.0316 0.2873 43 0.3724 35 0.0188 0.1462 44 5.9322 16.9135 36 0.0140 0.1881 45 0.2953 37 0.0092 0.1494 46 0.6978 13.8752 38 1.0661 8.3906 47 1.0252 23.2395 39 1.0940 10.0398 48 0.1413 1.1052 40 1.6796 10.4624 49 0.0496 0.1880 41 3.7521 6.0795 50 1.5035 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example IIIM IIIM IIIM ILIM 51 2.6789 60 0.0707 0.7938 52 0.3822 2.4620 61 2.8309 53 0.1204 10.7585 62 0.9355 54 0.2121 63 0.4479 4.4257 55 0.3429 9.8504 64 0.1268 6.3126 56 0.2968 13.7841 65 0.0973 2.3468 57 1.2847 7.9991 66 0.0069 0.0697 58 2.0592 67 0.1021 1.2006 59 0.0081 0.1354 68 0.0067 0.1566 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 69 0.1537 7.5432 78 0.7612 1.4503 70 0.4595 0.3919 79 0.0051 0.0340 71 0.0902 1.5795 80 0.0047 0.0581 72 0.5883 16.4938 81 0.1781 2.3633 73 0.0135 0.2514 82 0.0789 0.5968 74 0.4490 83 0.5896 15.7133 75 0.1657 2.7583 84 0.2251 4.8264 76 0.4921 13.8461 85 0.0596 2.8554 77 0.6653 12.7918 86 0.3767 7.7744 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example IIIM IIIM IIIM ILIM 87 0.2507 9.3698 96 0.0458 0.5326 88 0.7614 97 0.0169 0.2202 89 0.2715 16.8487 98 0.2274 6.8266 90 1.2312 99 0.9008 7.2722 91 0.3949 100 0.0172 0.4853 92 0.2682 11.3701 101 0.1042 3.5415 93 0.7752 14.0060 102 1.5376 94 2.0631 103 0.5639 10.9865 95 0.3272 10.2668 104 2.3394 59.7842 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 105 0.3817 4.4881 114 0.4240 12.7810 106 0.5158 8.5638 115 0.6825 13.5418 107 0.0635 0.7696 116 0.1322 5.1321 108 0.1626 9.7819 117 0.1267 0.8941 109 0.2288 1.3489 118 0.1229 1.2484 110 0.1845 1.2775 119 0.7219 111 0.0642 0.9228 120 0.0247 0.2073 112 0.6742 11.9975 121 0.0071 0.0390 113 0.3419 1.3593 122 0.0423 0.1802 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 123 0.1220 7.7317 132 0.0378 0.5266 124 1.0695 0.2249 133 0.0986 1.3716 125 0.1213 3.3410 134 0.0186 0.4243 126 0.0379 3.5625 135 0.0931 0.5232 127 0.0545 0.2657 136 0.1022 2.6575 128 0.1077 4.2761 137 0.0101 0.1082 129 0.0636 3.1638 138 0.0162 0.1928 130 0.0155 0.2398 139 0.9532 11.1720 131 0.0119 0.2635 140 0.0118 0.0704 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 141 0.0405 1.3088 150 0.2266 5.3241 142 0.0802 0.9809 151 0.1005 3.9244 143 0.2579 4.4495 152 0.2946 11.5673 144 0.0237 0.1400 153 0.3021 14.9952 145 1.4972 1.8956 154 0.0747 0.1929 146 0.0398 0.1142 155 0.1315 4.0942 147 0.0367 0.2470 156 0.0439 0.3369 148 0.0451 0.1391 157 0.3520 11.1514 149 0.1262 1.9169 158 0.1823 6.0298 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 159 0.2090 4.4617 168 0.0034 0.0475 160 0.0361 0.4182 169 0.0052 0.0381 161 0.1014 0.3410 170 0.0035 0.0146 162 0.1866 2.0029 171 0.0172 0.0889 163 0.2155 3.3596 172 0.0223 0.1441 164 0.1409 0.8618 173 0.3340 12.2938 165 0.0035 0.0604 174 0.0258 0.2112 166 0.0141 0.0963 175 0.1051 0.6564 167 0.0479 0.1681 176 0.0098 0.0578 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 177 0.4116 6.3108 186 0.0232 0.2107 178 0.0542 0.4797 187 0.1368 2.2324 179 0.6196 7.7205 188 0.2275 4.1486 180 0.1233 0.8017 189 0.0553 0.7099 181 0.2168 1.9663 190 0.3279 7.3219 182 0.0275 0.3060 191 0.3944 8.5507 183 0.0299 0.3853 192 2.2023 10.3297 184 0.0177 0.2712 193 0.0201 0.2168 185 0.0660 0.6732 194 0.0203 0.2243 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 195 0.0373 0.4865 204 0.0408 0.9002 196 0.1775 1.0297 205 0.0005 0.0006 197 0.0468 0.5554 206 0.0017 0.0068 198 2.4539 0.9902 207 0.0028 0.0182 199 0.1037 0.2818 208 0.0021 0.0189 200 0.0325 0.3146 209 0.0009 0.0147 201 0.0304 0.2932 210 0.0186 0.1298 202 0.0653 0.4734 211 0.0044 0.0532 203 0.0224 0.2123 212 0.0084 0.0816 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 213 0.0391 0.2781 222 0.0803 0.3426 214 0.0636 0.3003 223 0.1155 1.4171 215 0.0296 0.1368 224 0.0372 0.2932 216 0.0381 0.3639 225 2.5506 217 0.0920 0.8026 226 0.0534 3.4026 218 1.5500 14.2551 227 4.2089 219 2.2159 17.5743 228 0.2634 12.3727 220 1.0754 229 0.2038 0.7447 221 2.1615 10.1235 230 0.0070 0.1495 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 231 0.0233 0.4686 240 0.1148 3.2729 232 0.0266 1.3509 241 0.5820 233 0.2705 21.5699 242 0.0256 0.2062 234 0.0445 1.5779 243 0.2678 3.3424 235 0.0227 0.2211 244 1.8627 4.6905 236 0.1334 4.3865 245 0.0011 0.0257 237 0.2044 3.6068 246 0.1023 0.5463 238 0.1044 5.9872 247 4.5758 7.4708 239 0.0105 0.0900 248 2.6463 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 249 3.2181 7.6048 257 0.0113 0.0954 250 4.4379 12.3402 258 0.0037 0.0418 251 5.8839 15.8337 259 0.0122 0.0738 260 0.4711 0.3450 252 9.7643 0.2721 261 0.0267 0.1052 253 0.5808 10.0383 262 0.0141 0.3002 254 2.1317 32.5224 263 0.4910 4.9268 255 2.8003 7.6090 264 0.8428 4.1868 256 0.7744 265 0.4373 5.0201 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example IIIM IIIM IIIM IIM 266 0.0444 0.2756 275 0.7311 7.8164 267 1.6052 11.2653 276 0.2837 2.0297 268 1.6485 14.1758 277 0.0641 0.1634 269 0.0462 0.4253 278 0.0061 0.0344 270 0.0063 0.0279 279 0.6004 11.1051 271 0.0248 0.2512 280 1.7985 272 0.0604 0.2099 273 0.0640 0.4487 281 0.0004 0.003 274 0.1275 1.0511 282 0.0429 0.4748 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 283 0.0667 0.6328 292 0.5152 36.2254 284 0.0205 0.2494 293 0.0164 0.2848 285 0.0076 0.3556 294 0.2042 9.8508 286 0.2655 3.0382 295 0.0488 0.8488 287 0.5546 6.4082 296 0.1316 4.4957 288 0.539 8.8668 297 0.2072 12.784 289 0.0706 0.1856 298 0.1747 13.7042 290 0.1012 3.91 299 0.7869 48.5358 291 0.0032 0.1218 300 0.2161 14.2793 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 301 0.1606 32.5099 310 0.0165 3.9684 302 0.0932 5.1857 311 0.8134 6.4778 303 0.0936 12.5809 312 0.0482 4.008 304 0.0024 0.0781 313 0.1184 3.5436 305 0.0054 0.8598 314 0.0282 5.2254 306 0.0058 0.1138 315 1.0508 31.0217 307 0.3892 15.4452 316 0.0402 1.831 308 0.3805 26.3474 317 0.1088 2.6377 309 0.016 2.4468 318 >30 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 319 0.1089 5.1301 328 0.1731 18.44 320 8.0313 329 6.0154 11.9661 321 0.0556 3.995 330 >30 322 5.1407 39.6231 331 4.3466 35.0631 323 0.0442 2.3486 332 14.7777 324 2.8107 333 0.0958 5.2386 325 0.0592 4.4874 334 0.3831 34.5562 326 1.8693 6.6127 335 13.8179 327 1.3648 10.6987 336 0.9489 29.9696 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 337 24.2997 346 0.0263 2.571 338 >30 347 0.162 22.9422 339 0.0545 7.9851 348 2.8265 36.9471 340 0.0883 14.1639 349 0.9822 15.1179 341 0.0321 1.6765 350 0.0594 3.6822 342 0.0151 0.0947 351 3.6617 343 0.1338 4.688 352 0.0965 39.4185 344 0.0312 1.5032 353 0.3963 16.1819 345 0.0494 2.003 354 0.0122 0.3454 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 355 0.0153 8.1702 364 0.1303 5.5675 356 2.0005 0.7368 365 0.3368 15.9004 357 0.0982 3.224 366 0.0044 0.082 358 0.005 0.4326 367 0.0621 5.2403 359 0.006 0.4113 368 0.0121 0.7227 360 0.8527 16.1218 369 0.0403 12.4126 361 0.0656 9.4139 370 0.1955 362 0.0532 6.0869 371 4.2585 363 0.1707 2.3291 372 0.1 22.847 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 IIIM IIIM11M 11M 373 >30 382 0.0339 1.5202 374 0.3541 383 0.021 0.7714 375 5.6207 384 0.024 3.1595 376 0.026 7.9592 385 0.8927 377 0.0034 0.4478 386 0.006 0.4181 378 0.2125 14.6493 387 0.0922 2.8398 379 0.0258 0.3698 388 0.2717 3.9689 380 0.0366 2.4244 389 0.1154 2.9541 381 0.0034 0.1379 390 0.3159 5.4731 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 391 0.0297 1.452 400 0.0589 2.7442 392 0.0092 0.3266 401 0.3602 9.105 393 0.2654 8.4296 402 0.0342 2.2146 394 0.0456 2.924 403 0.0317 1.9302 395 0.008 0.679 404 0.2977 5.4805 396 0.2065 5.251 405 0.5464 35.1743 397 0.2819 7.9485 406 0.1651 3.1455 398 0.2809 2.3021 407 0.9865 20.6904 399 0.3133 11.2522 408 0.9228 14.2627 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example IIIM IIIM IIIM11M 409 0.0069 0.4291 418 0.004 0.062 410 0.0165 1.7304 419 0.0091 0.122 411 0.0196 0.772 420 0.0274 0.281 412 0.0466 1.6678 421 0.0007 0.0324 413 0.0207 0.8128 422 0.1544 11.0996 414 0.0302 2.0382 423 0.0637 1.0188 415 0.0055 0.4838 424 0.0062 0.1405 416 0.006 0.7234 425 0.0562 1.2703 417 0.2243 9.0943 426 0.0121 0.5715 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 427 0.0024 0.0472 436 0.0058 0.1582 428 0.02 0.1054 437 0.0776 1.6426 429 0.0043 0.0577 438 0.0038 0.202 430 0.0069 0.7375 439 0.1189 6.9015 431 0.0444 0.9117 440 0.0176 1.2703 432 0.0222 1.4548 441 0.0166 0.9878 433 0.0143 1.313 442 0.0056 0.4274 434 0.0066 0.2277 443 0.009 1.175 435 0.0088 0.256 444 0.0084 0.5143 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 04 04 04 04 445 0.0074 0.9144 454 0.0066 0.062 446 0.1852 0.2628 455 0.0086 0.7169 447 0.0019 0.2332 456 0.0012 0.1056 448 0.0212 1.9778 457 0.0018 0.2975 449 0.0028 0.2347 458 0.0017 0.3511 450 0.1219 20.1047 459 0.0056 0.5941 451 0.0389 5.3319 460 0.0123 0.5161 452 0.0268 1.7391 461 0.004 0.3608 453 0.0051 0.8761 462 0.0326 0.7196 EC50 EC50 EC50 EC50 human human human human Example CYP11B2 CYP11B1 Example CYP11B2 CYP11B1 11M 11M 463 0.0471 0.9322 466 0.4666 21.2595 464 0.0028 1.6504 467 0.0288 2.1821 465 0.0669 2.2689 468 0.0528 2.6647 Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have EC50 (CYP11B2) values between 0.000001 uM and 1000 uM, particular compounds have EC50 (CYP11B2) values between 0.00005 uM and 500 uM, further particular compounds have EC50 (CYP11B2) values between 0.0005 uM and 50 uM, more particular compounds have EC50 (CYP11B2) values between 0.0005 uM and 5 uM. These results have been obtained by using the described enzymatic assay.
The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or WO2013/079452 PCT/EP2012/073653 - 118 - derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.
In accordance with the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of aldosterone mediated diseases.
The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein are inhibitiors of CYP11B2. The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein display also variable inhibition of CYP11B1. These compounds may be used for the inhibition of CYP11B2 in combination PCT/EP2012/073653 - 119 - with variable inhibition of CYP11B1. Such compounds may be used for treatment or prophylaxis of conditions displaying excessive cortisol production/levels or both excessive cortisol and aldosterone levels (for ex. Cushing syndrome, burn trauma patients, depression, post-traumatic stress disorders, chronic stress, corticotrophic adenomas, Morbus Cushing).
In accordance with the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of cardiovascular conditions (including hypertension and heart failure), vascular conditions, endothelial dysfunction, baroreceptor dysfunction, renal conditions, liver conditions, fibrotic diseases, inflammatory conditions, retinopathy, neuropathy (such as peripheral neuropathy), pain, insulinopathy, edema, edematous conditions, depression and the like.
Cardiovascular conditions include congestive heart failure, coronary heart disease, arrhythmia, arterial fibrillation, cardiac lesions, decreased ejection fraction, diastolic and systolic heart dysfunction, fibrinoid necrosis of coronary arteries, cardiac fibrosis, hypertrophic cardiomyopathy, impaired arterial compliance, impaired diastolic filling, ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrotic lesions, cardiac arrhythmias, prevention of sudden cardiac death, restenosis, stroke, vascular damage.
Renal conditions include acute and chronic renal failure, nephropathy, end- stage renal disease, diabetic nephropathy, decreased creatinine clearance, decreased glomerular filtration rate, expansion of reticulated mesangial matrix with or without significant hypercellularity, focal thrombosis of glomerular capillaries, global fibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, microalbuminuria, proteinuria, reduced renal blood flow, renal arteriopathy, swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents).
Renal conditions also include glomerulonephritis (such as diffuse proliferative, focal proliferative, mesangial proliferative, membranoproliferative, minimal change membranous glomerulonephritis), lupus nephritis, non-immune basement membrane WO2013/079452 PCT/EP2012/073653 - 120 - abnormalities (such as Alport syndrome), renal fibrosis and glomerulosclerosis (such as nodular or global and focal segmental glomerulosclerosis).
Liver conditions include, but are not limited to, liver steatosis, nonalcoholic steatohepatitis, liver cirrhosis, liver ascites, hepatic congestionand the like.
Vascular conditions include, but are not limited to, thrombotic vascular disease (such as mural fibrinoid necrosis, extravasation and fragmentation of red blood cells, and luminal and/or mural thrombosis), proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction, and the like.
Inflammatory conditions include, but are not limited to, arthritis (for example, osteoarthritis), inflammatory airways diseases (for example, chronic obstructive pulmonary disease (COPD)), and the like.
Pain includes, but is not limited to, acute pain, chronic pain (for example, arthralgia), and the like.
Edema includes, but is not limited to, peripheral tissue edema, hepatic congestion, liver ascites, splenic congestion, respiratory or lung congestion, and the like.
Insulinopathies include, but are not limited to, insulin resistance, Type I diabetes mellitus, Type II diabetes mellitus, glucose sensitivity, pre-diabetic state, pre-diabetes, syndrome X, and the like.
Fibrotic diseases include, but are not limited to myocardial and intrarenal fibrosis, renal interstitial fibrosis and liver fibrosis.
Furthermore, the compounds of formula (I) or their pharmaceutically acceptable salts and esters as described herein can also be used for the treatment or prophylaxis of cardiovascular condition selected from the group consisting of hypertension, heart failure (particularly heart failure post myocardial infarction), left ventricular hypertrophy, and stroke.
In another embodiment, the cardiovascular condition is hypertension.
In particular embodiment, the cardiovascular condition is treatment-resistant hypertension.
In another embodiment, the cardiovascular condition is heart failure.
In another embodiment, the cardiovascular condition is left ventricular hypertrophy.
In another embodiment, the cardiovascular condition is congestive heart failure, more particularly in patients with preserved left ventricular ejection fraction.
In another embodiment, the cardiovascular condition is stroke.
In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis renal condition.
In another embodiment, the renal condition is nephropathy.
In another embodiment, the renal condition is auto-immune glomerulonephritis.
In another embodiment, the chronic kidney disease is diabetic nephropathy.
In another embodiment, the fibrotic disease is kidney or heart fibrosis.
In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis Type IIdiabetes mellitus.
In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis Type Idiabetes mellitus.
In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of diabetic retinopathy.
The invention is illustrated hereinafter by Examples, which have no limiting character.
In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g. chiral chromatography or crystallization.
Examples All examples and intermediates were prepared under argon atmosphere if not specified otherwise.
Intermediate A-1 6-Chloro-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one dL,CI
NH 0 {A] (3-Chloro-2-fluoro-phenyl)-methanol CI
OH
To a solution of 2-fluoro-3-chloro-benzaldehyde (4.74 g, 30 mmol) in THF (20 mL) was added NaBH4 (1.48 g, 40 mmol). The resulting mixture was stirred at room temperature for 30 min before diluting with DCM. The organic layer was washed with water and brine.
The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give desired product without further purification (4.8g, 100%). MS: 161.0 (M+H)+. [B] 1-Bromomethy1-3-chloro-2-fluoro-benzene CIisBr To a solution of (3-chloro-2-fluoro-phenyl)-methanol (3.2 g, 20 mmol) in DCM (20 mL) was added dropwise PBr3(1 mL) at 0 C. The reaction mixture was stirred at room temperature for another 1 hour before quenching with satd. aq. NaHCO3 solution. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the desired product without further purification (4.1 g, 92%).
MS: 223.2 (M+H)'. [C] (3-Chloro-2-fluoro-phenyl)-acetonitrile CI s's N
To a solution of 1-chloro-3-bromomethy1-2-fluoro-benzene (2.22 g, 10 mmol) in CH3CN (30 mL) was added trimethylsilyl cyanide (1.5 mL) and TBAF (1M in THF, 12 mmol, 12 mL). The resulting reaction mixture was heated at reflux temperature for 30 min. After cooling to room temperature, the volatiles were evaporated under reduced pressure. The residue was partitioned between Et0Ac and water. The organic layer was then washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to give the title compound (1.48 g, 88%).
MS: 170.1 (M+H)+. [D] 2-(3-Chloro-2-fluoro-phenyl)-ethylamine To a solution of (3-chloro-2-fluoro-pheny1)-acetonitrile (1.48 g, 8.8 mmol) in anhydrous THF(20 mL) was added a solution of borane (20 mL, 1M in THF) dropwise. The resulting reaction mixture was heated at reflux temperature for 2 hours. After cooling to room temperature, Me0H was added and the mixture was stirred at room temperature for additional 30 min. After removal of volatiles under reduced pressure, desired title product (1.30 g, 90%) was obtained as oil. MS: 174.0 (M+H)'.
WO2013/079452 PCT/EP2012/073653 - 125 - [E] [ 2-(3-Chloro-2-fluoro-pheny1)-ethylamine]-carbamic methyl ester To a solution of 2-(3-ehloro-2-fluoro-phenyl)-ethylamine (1.30 g, 7.9 mmol) in CH2C12 (25 rriL) was added dropwise methyl chloroformate (1.04 g, 11 mmol) and Et3N at 5 C with vigorous stirring. The solution was then stirred at room temperature for lh. The reaction was poured into ice-water (50 mL) and extracted with CH2C12 (2x 25 mL). The organic phase was washed with H20 (2x 25 mL), dried over Na2SO4, filtered and evaporated to afford the final product without purification (1.78 g, 98%). MS: 232.1 (M+H)'. [F] 6-Chloro-5-fluoro-3,4-dihydro-2H-isoquino line-1-one CI
N H 0 [2-(3-Chloro-2-fluoro-phenyl)-ethylamine]-carbamic methyl ester (890 mg, 3.85 mmol) and polyphosphoric acid (15 mL) were added to a 1-L, round bottom flask equipped with a magnetic stirring bar and reflux condenser. The reaction mixture was heated in an oil bath at 140-160 C for 2 hours while keeping vigorous stirring. The reaction mixture was then allowed to cool to room temperature and poured into H20 (100 mL). After extraction with Et0Ac, the organic layer was washed with brine, dried over anhy. MgSO4, filtered and concentrated to give a yellowish oil which was crystallized from Et20 to give title compound as a white solid (30 mg, 4%). MS: 200.1 (M+H)' .
Intermediate A-2 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one CI
NH 0 [A] [2-(3-Chloro-phenyl)-ethyl]-carbamic acid methyl ester 0y0,, CI NH
At 0 , methyl chloroformate (4.6 g, 48 mmol) was added dropwise to a solution of 2-(3- chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et3N (6.4 g, 64 mmol) in DCM (100 mL).
After the addition, the mixture was stirred at room temperature for 0.5 hour.
The organic layer was washed with water (3 x 30 mL), 1N HC1 (20 mL) and brine (30 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo. After vacuum drying, the title compound was obtained (6.49 g, 95%) as a white solid. MS: 214.1 (M+F1'). [B] 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one CI
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-ethyl]carbamic acid methyl ester (5.0 g, 23.4 mmol) and PPA (polyphosphoric acid) (20 g) in a 250 mL round- bottom flask was vigorously stirred at 120 C for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. Then, the mixture was then extracted with Et0Ac, and the organic layer was washed with brine, dried over anhy. Na2SO4 and filtered. After removal of solvent under reduced pressure, the crude product obtained was further washed with ethyl ether to give title compound (1.66 g, 39%) as a white solid. MS: 182.0 (M+H+).
Intermediate A-3-1 6-Chloro-3-methy1-3,4-dihydro-2H-isoquino1in-1-one CI
Intermediate A-3-2 8-Chloro-3-methyl-3,4-dihydro-2H-isoquinolin-l-one NH
CI0 [A] 2-(3-Chloro-pheny1)-1-methyl-ethylamine CI NH, To a solution of 3-chlorobenzylmagnesium chloride (0.1 mol) in anhydrous ether (100 mL) (prepared from 3-chlorobenzyl chloride (16.1 g, 0.1 mol) and magnesium turnings (2.4 g, 0.1 mol) in anhydrous ether (100 mL)) was added anhydrous acetonitrile (4.1 g, 0.1 mol) dropwise at room temperature. When the reaction mixture was stirred at 60 Cfor 3 hours, it was cooled to 0 C followed by addition of THF (50 mL). Lithium aluminum hydride (4.2 g, 0.1 mol) was then added cautiously into the above reaction mixture and it was heated to reflux temperature for 3 hours. Ice-water was added to quench the reaction.
After partitioning between ether and H20, the separated organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. Flash column chromatography separation (silica gel, 180 g, 5% methanol in DCM) then yielded the title compound as yellowish oil (1.9 g, 11%). MS: 170.1 (M+H+). 113] 12-(3-Chloro-phenyl)-1-methyl-ethy1]-carbamic acid methyl ester 0 0 Y
CI NH
At 0 C, methyl chloroformate (0.67 g, 7.1 mmol) was added dropwise to a mixture of 2- (3-chloro-pheny1)-1-methyl-ethylamine (1.0 g, 5.9 mmol) and potassium carbonate (1.63 g, 11.8 mmol) in THF (20 mL). After the addition, the mixture was stirred at room temperature over night. After filtration and evaporation of the volatiles, the crude product was purified by flash column chromatography (silica gel, 12 g, 50% hexane in dichloromethane) to give the title compound as a white solid (1.2 g, 90%). MS: 228.1 (M+H'). [C] 6-Chloro-3-methyl-3,4-dihydro-2H-isoquinolin-1-one and 8-chloro-3-methy1- 3,4- dihydro-2H-isoquinolin-1-one CI
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-1-methyl-ethyl]carbamic acid methyl ester (1.2 g, 5.3 mmol) and PPA (polyphosphoric acid) (10 g) in a 100 mL round bottom flask was stirred at 120 C for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the .. pH to 8. The mixture was then extracted with ethyl acetate and the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product obtained was further washed with ether to give 6-chloro-3-methy1-3,4- dihydro- 2H-isoquinolin-1-one (0.27 g, 26%) (intermediate A-3-1) as a white solid. MS: 196.1 (M+H+). The ether filtrate was concentrated under reduced pressure and purified by flash chromatography to afford 8-chloro-3-methy1-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-3-2) (54 mg, 5.2%) as a white solid. MS: 196.1 (M+H').
Intermediate A-3-la (R)-6-Chloro-3-methyl-3,4-dihydro-2H-isoquinolin-l-one CI
Intermediate A-3-lb (S)-6-Chloro-3-methy1-3,4-dihydro-2H-isoquinolin-1-one CI ys Chiral HPLC separation of 6-chloro-3-methyl-3,4-dihydro-211-isoquinolin-1 -one (0.4 g, 2.05 mmol, intermediate A-3-1) afforded both (R)-6-chloro-3-methy1-3,4-dihydro- 2H- isoquinolin-1-one (0.15 g, 37.5%) and (S)-6-chloro-3-methy1-3,4-dihydro-2H- isoquinolin- 1-one (0.12 g, 30%) as white solids. MS: 196.1 (M+H+).
Intermediate A-4 6-Chloro-4-methy1-3,4-dihydro-21/-isoquinolin-1-one CI yJ
NH 0 [A] 2-(3-Chloro-phenyl)-propionitrile CI
To a solution of 3-chlorobenzylnitrile (15.2 g, 0.1 mol) in THF (300 mL) was added dropwise lithium bis(trimethylsily0amide (100 mL, 1M in THF, 0.1 mol) at -78 C. After stirring at -78 C for 1 hour, iodomethane (14.2 g, 0.1 mol) was added dropwise. After additional stirring at -78 C for 1 hour and subsequent warming up to room temperature for 2 hours, the reaction was quenched with water and extracted with ether. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo. Flash column chromatography separation (silica gel, 180 g, 1% to 4% ether in hexane) then gave the title compound as an oil (7.3 g, 44%).
WO2013/079452 PCT/EP2012/073653 - 130 - [13] 2-(3-Chloro-phenyl)-propylamine hydrochloride CI NH, .HCI
To a solution of 2-(3-chloro-phenyl)-propionitrile (5.0 g, 30.2 mmol) in THF (80 mL) was added borane-tetrahydrofuran complex solution (45 mL, 45.3 mmol). The reaction mixture was stirred at room temperature overnight. Ethanol (10 mL) was then added to the reaction mixture; after stirring at room temperature for 20 min, a solution of HCl in ether (2 M, 12.5 mL) was added. After stirring for another 1 hour, water was added to induce the precipitation of the product. The white solid was collected by filtration and dried in vacuo to give the title compound (3.6 g, 70%). MS (for free amine): 170.1 (MAI). [] [2-(3-Chloro-phenyl)-propyl]-carbamic acid methyl ester oYo CI= NH
To a solution of 2-(3-chloro-phenyl)-ethylamine hydrochloride (6.22 g, 30.2 mmol) and Et3N (6.1 g, 60.4 mmol) in DCM (20 mL) was added methyl chloroformate (4.28 g, 45 mmol) dropwise at 0 C, and the resulting mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then washed with water (3 x 10 mL), 1N HC1 (10 mL) and brine (10mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue formed was dried in vacuo to give the title compound (5.5 g, 80%) as yellow oil. MS: 228.1 (M+H).
ID] [6-Chloro-4-methy1-3,4-dihydro-2H-isoquinolin-1-one CI
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-propyl]-carbamic acid methyl ester (3.0 g, 13.2 mmol) and PPA (polyphosphoric acid) (10 g) in a 100 mL flask was stirred at 120 C for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. The mixture was extracted with Et0Ac, and the organic layer was washed with brine, dried over anhy.
Na2SO4, filtered and concentrated in vacuo. The crude product formed was further washed with ether to give the title compound (0.52 g, 20%) as a white solid. MS: 196.1 (M+H-).
Intermediate A-5 6-Chloro-4,4-dimethy1-3,4-dihydro-2H-isoquinolin-1-one CI yçJ
NH 0 [A] 2-(3-Chloro-phenyl)-2-methyl-propionitrile CI
To a solution of 3-chlorobenzylnitrile (15.2 g, 0.1 mol) in DMF (100 mL) at 0 Cwas added sodium hydride (6.0 g, 0.15 mol) portionwise. After stirring at 0 C for 0.5 hours, iodomethane (14.2 g, 0.1 mol) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for additional 2 hours before quenching with water. The mixture was extracted ether and H20, the organic layer was dried over anhy.
Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 180 g, I% to 4% ether in hexane) to yield the title compound as oil (6.4 g, 36%). [13] 2-(3-Chloro-phenyl)-2-methyl-propylamine To a solution of 2-(3-chloro-pheny1)-2-methyl-propionitrile (6.4 g, 35.7 mmol) in THF (80 mL) was added borane-tetrahydrofuran complex solution (71.3 mL, 71.3 mmol), and the resulting mixture was heated to reflux for 5 hours. After cooling to0 C, aq.
HC1 (2 M, 10 mL) was added dropwise to quench the reaction. The mixture was then concentrated in vacuo to afford a solid residue, which was treated with aq. ammonia solution (6M in H20).
After extraction with ethyl acetate, the organic layer was dried over anhy.
Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 180 g, 5% methanol in dichloromethane) to yield the title compound as oil (2.8 g, 43%). MS: 184.1 (M+H'). [C] [2-(3-Chloro-phenyl)-2-methyl-propyl]-carbamic acid methyl ester 0 0 Y ci NH
To a solution of 2-(3-chloro-phenyl)-2-methyl-propylamine (1.4 g, 7.63 mmol) and Et3N (1.54 g, 15.26 mmol) in DCM (20 mL) was added dropwise methyl chloroformate (1.08 g, 11.4 mmol) at 0 C. After the addition, the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then washed with water (3x 10 mL), 1N HC1 (10 mL) and brine (10 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue formed was dried in vacuo give the title compound (1.84 g, 100%) as yellow oil. MS: 242.1 (M+H'). fDi 6-Chloro-4,4-dimethy1-3,4-dihydro-2H-isoquinolin-1-one CI
Under N2 protection, a mixture of [2-(3-chloro-pheny1)-2-methyl-propy1]- carbamic acid methyl ester (1.84 g, 7.63 mmol) and PPA (polyphosphoric acid) (8 g) in a 100 mL round bottom flask was stirred at 120 C for 2 hours. After cooling to room temperature, the mixture was treated with ice-water and aq. ammonia solution to adjust the pH to 8. After extraction with ethyl acetate, the organic layer was washed with brine, dried over anhy.
Na2SO4, filtered and concentrated in vacuo. The crude product formed was further washed with ether to give the title compound (0.32 g, 20%) as a white solid. MS: 210.1 (M+H-).
Intermediate A-6 6-Chloro-2H-isoquinolin-1-one CI
Amixture of 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (181.5 mg, 1 mmol, intermediate A-2) and DDQ (227 mg, 1 mmol) in dioxane (3 mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was treated with satd. aq. NaHCO3 solution, and then extracted with ethyl acetate (2 x 10 mL). The organic layers were dried over anhy.
Na2SO4, filtered, and concentrated in vacuo to afford a crude product which was then purified by silica gel flash chromatography to give title compound (108 mg, 60%) as a white solid. MS: 180.0 (M+H+).
Intermediate A-7 6-Chloro-7-fluoro-3,4-dihydro-2H-isoquinolin-1-one CI
NH 0 [A] 4-Bromomethy1-2-chloro-1-fluoro-benzene CI
Br To a solution of (3-chloro-4-fluoro-pheny1)-methanol (4.3 g, 26.8 mmol) in DCM (20 rnL) was added PBr3 (1 mL) at 0 C. The resulting mixture was stirred at room temperature for 1 hour before it was quenched with satd. aq. NaHCO3 solution. The organic solution was .. washed with water, brine, dried over anhy. Na2SO4 and concentrated in vacuo to give the desired product (3.7 g, 61.9%). It was used directly in the next step, without further purification. [B] (3-Chloro-4-fluoro-phenyl)-acetonitrile CI
N
To a solution of 4-bromomethy1-2-chloro-1-fluoro-benzene (3.7 g, 16.5 mmol) in CH3CN (30 mL) was added trimethylsilyl cyanide (2.1 mL) and TBAF (4.8 g, 18.4 mmol).
The resulting mixture was heated at reflux for 30 min. After cooling of the mixture to room temperature, it was extracted with Et0Ac. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel flash column chromatography to give the title compound (1.7 g, 60.7%) as an oil. [C] 2-(3-Chloro-4-fluoro-phenyl)-ethylamine CI NH, To a solution of (3-chloro-4-fluoro-pheny1)-acetonitrile (1 g, 5.9 mmol) in THF(30 mL) was slowly added BH3-THF (8.26 m1). After the addition, the reaction mixture was heated to reflux for 3 hours. Me0H was added to quench the reaction and volatiles were removed under reduced pressure. The crude product was first dissolved in aq. HCl solution (30 mL) and impurities were removed by exaction with Et0Ac (2x 30 mL). The pH of the aqueous WO2013/079452 PCT/EP2012/073653 - 135 - solution was adjusted to 8 using K2CO3 and the mixture was then extracted with DCM(3 x 30 mL). The combined organic layers were then washed with brine, dried with anhy.
Na2SO4, filtered and concentrated in vacuo to give the title compound (570 mg, 55.8%) as an oil.
ID] N-[2-(3-Chlor o -4 -fluor o-pheny1)- ethy11-2 ,2 ,2-tr ifluor o - acetamide To a solution of 2-(3-chloro-4-fluoro-phenyl)-ethylamine (570 mg, 3.3 mmol) and Et3N (1 mL) in CH2C12 (25 mL) was added trifluoroacetic anhydride (761 mg, 3.6 mmol) at 5 C dropwise and with vigorous stirring. Then, the solution was allowed to stir at room temperature for 3 hours before it was poured into ice-water (50 mL) and extracted with DCM(2x 25 mL). The organic layer was washed with H20 (2x 25 mL), dried over anhy.
Na2SO4, filtered and concentrated in vacuo to give the title compound (700 mg, 78.6%) as a white solid. It was used directly in the next step without further purification.
IE] 1-(6-Chloro-7-fluoro-3,4-dihydro-1H-isoquinolin-2-y1)-2,2,2-trifluoro- ethanone CI j(F 0 N42-(3-Chloro-4-fluoro-pheny1)-ethy1]-2,2,2-trifluoro-acetamide (400 mg, 1.48 mmol) and paraformaldehyde (89 mg, 2.96 mmol) were added sequentially at 0 C to a solution of acetic acid (3 mL) in sulfuric acid (2 mL). After stirring of the reaction mixture at room temperature for 16 hours, the clear colorless solution was poured into ice- water (20 mL).
The mixture was extracted with Et0Ac (2x 30 mL) and the organic layer was washed with satd. aq. NaHCO3 (20 mL), H20 (2x 25 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude title product together with a regioisomer (400 mg) as white solid.
WO2013/079452 PCT/EP2012/073653 - 136 - [F] 6-Chloro-7-fluoro-1,2,3,4-tetrahydro-isoquinoline CI
NH
To a solution of 1-(6-chloro-7-fluoro-3,4-dihydro-1H-isoquinolin-2-y1)-2,2,2- trifluoroethanone (400 mg) in Me0H (15 mL) was added K2CO3 (572 mg, 4 mmol) in H20 (10 mL). The resulting reaction mixture was stirred at room temperature for 2 hours before it was acidified with HC1 (1N) to pH 8. It was then extracted with Et0Ac and the organic layer was washed with H20 (2 x 25 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo to tive the crude title product together with a regioisomer (170 mg).
Prep-TLC separation (30% Et0Ac in petroleum ether) then gave the desired title compound (130 mg) as a white solid. [G] 6-Chloro-7-fluoro-3,4-dihydro-2H-isoquinoline-1-one CI
Amixture of 6-chloro-7-fluoro-1,2,3,4-tetrahydro-isoquinoline (130 mg, 0.7 mmol), potassium bromide (83.5 mg, 0.7 mmol) and iodoso benzene (0.46 g, 2.1 mmol) in water .. (4 mL) was stirred at room temperature overnight. The mixture was then extracted with Et0Ac and the organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 12 g, 30% Et0Ac in hexane) then afforded the tile compound (58 mg, 41 %) as a white solid.
Intermediate A-8 2-Chloro-7,8-dihydro-6H-[1,6]naphthyridin-5-one CI
NH 0 [A] 2-Chloro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester To a solution of 2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridinc hydrochloride (1.54 g, 7.5 mmol) in DCM (25 mL) was added Et3N (3.1 mL, 22 mmol). After the addition and stirring at room temperature for 5 min, the solution was cooled to 0 C, followed by the addition of methylchloroformate (0.85 mL, 11 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then washed with satd. aq.
NaHCO3 solution and brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 40 g, 30% Et0Ac in hexane) then afforded the tile compound (1.53 g, 90 %) as a white solid. MS: 227.3 (M+H-). [B] 2-Chloro-5-oxo-7,8-dihydro-5H41,6]naphthyridine-6-carboxylic acid methyl ester 0 y 0 0 2-Chloro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester (226.7 mg, 1 mmol) was dissolved in CC14 (3.57 mL) and MeCN (0.357 mL) at room temperature before adding NaI04 (0.643 g) in 1 mL of H20, followed by RuC13.hydrate (62.2 mg). The reaction mixture was stirred vigorously at room temperature for 2 hours. After dilution with DCM, it was filtered through Celite and the filter cake was washed three times with DCM. The combined organic solution was concentrated in vacuo to give a crude product.
Flash column chromatography separation (silica gel, 12 g, 20% Et0Ac in hexane) then afforded the tile compound (143 mg, 60 %) as a white solid. MS: 241.1 (M+H+). 2-Chloro-7,8-dihydro-6H-[1,6]naphthyridin-5-one CI N
NH 0 .. A mixture of 2-chloro-5-oxo-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.25 mmol) and sodium methoxide (40 mg, 0.75 mmol) in 2 ml. of 1,4- dioxane was subject to microwave reaction at 110 C for 30 min. After removal of 1,4- dioxane, the residue was dissolved in DCM and the DCM solution was washed with water and brine. The organic layer was then dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product. Prep-TLC separation (30% Et0Ac in hexane) then afforded the tile compound (28 mg, 63 %) as a white solid. MS: 183.1 (M+H+).
Intermediate A-9 2-Methoxy-7,8-dihydro-6H-11,6]naphthyridin-5-one 0 [A] 2-Chloro-7,8-dihydro-5H-[1,61naphthyridine-6-carboxylic acid tert-butyl ester 0 To a solution of 2-chloro-5,6,7,8-tetrahydro-[1,61naphthyridine hydrochloride (1.54 g, 7.5 mmol) in DCM (25 ml.) was added Et3N (2 ml., 15 mmol). After the addition and stirring WO2013/079452 PCT/EP2012/073653 - 139 - at room temperature for 5 min, the solution was cooled to 0 C, followed by the addition of (Boc)20 (1.88 g, 8.63 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then washed with H20 and brine. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (1.87 g, 93%) as a white solid. MS: 269.1 (M+H+). It was used directly in the next step without further purification. [B] 2-Chloro-5-oxo-7,8-dihydro-5H-[1,6-Inaphthyridine-6-carboxylic acid tert- butyl ester 0 0 In analogy to the procedure described for the preparation of intermediates A-8 [B], 2- chloro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester was used to yield the title compound as a white solid. MS: 283.1 (M+H+). [C] 2-Methoxy-7,8-dihydro-6H-[1,6]naphthyridin-5-one In analogy to the procedure described for the preparation of intermediates A-8 [C], 2- chloro-5-oxo-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester was used to yield the title compound as a white solid. MS: 179.2 (M+H+).
Intermediate A-10 5-Chloro-3-methyl-2,3-dihydro-isoindo1-1-one CI
Intermediate A-11 6-Chloro-3-methy1-2,3-dihydro-isoindo1-1-one 0 CI
NH {A] 5-Chloro-3-hydroxy-3-methy1-2,3-dihydro-isoindo1-1-one and 6-chloro-3- hydroxy-3- methy1-2,3-dihydro-isoindo1-1-one CI CI
To a solution of 5-chloro-isoindole-1,3-dione (3.63 g, 20 mmol) in DCM (150 mL) was added methylmagnesium chloride (3 M in THF, 20 mL) dropwise at 0 C. After the addition, the mixture was stirred at 0 C for 3 hours before it was quenched with satd. aq.
NH4C1 solution. After extraction with DCM, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product containing a mixture of two regioisomers (3.95 g, 100%). MS: 198.1 (M+H'). [B] 5-Chloro-3-methy1-2,3-dihydro-isoindo1-1-one and 6-chloro-3-methy1-2,3- dihydro- isoindol-l-one 0 CI CI
Under N2 protection, triethylsilane (23 g, 200 mmol) and trifluoroboron etherate (8.51 g, 60 mmol) were added successively at -15 C to a mixture of 5-chloro-3-hydroxy- 3-methyl- 2,3-dihydro-isoindol-1-one and 6-chloro-3-hydroxy-3-methy1-2,3-dihydro- isoindo1-1-one (3.95 g, 20 mmol) in dry DCM (100 mL). Afterwards, the reaction mixture was stirred at room temperature for 2 hours and a saturated aqueous solution of NaHCO3 (30 mL) was added. The mixture was then extracted with DCM and the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude mixture of products. The two regioisomers were separated by prep-HPLC to give the title compounds, 5-chloro-3-methy1-2,3-dihydro-isoindo1-1-one (0.4 g, 11%) and 6- chloro-3- methyl-2,3-dihydro-isoindo1-1-one (0.35 g, 9.6%) as white solids. MS: 182.0 (M+H').
Intermediate A-12 5-Chloro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one CI
IA] 5-Chloro-2-(4-methoxy-benzy1)-2,3-dihydro-isoindo1-1-one Sodium bis(trimethylsily1) amide (2 mL, 2 M in THF, 2 mmol) was added dropwise at 0 Cto a solution of 5-chloro-2,3-dihydro-isoindol-1-one (0.34 g, 2 mmol) in THF (10 mL).
After stirring for 10 min, 1-bromomethy1-4-methoxy-benzene (0.52 g, 2.6 mmol) was added dropwise. The resulting reaction mixture was allowed to stir at room temperature for 48 hours before quenching with saturated aqueous ammonium chloride solution.
After extraction with Et0Ac, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude product (0.6 g, 100%) as a yellow oil.
MS: 288.0 (M+H+). It was used directly in the next step, without further purification.
WO2013/079452 PCT/EP2012/073653 - 142 - [3] 5-Chloro-2-(4-methoxy-benzy1)-33-dimethyl-2,3-dihydro-isoindol-1-one To a solution of 5-chloro-2-(4-methoxy-benzy1)-2,3-dihydro-isoindol-1-one (0.6 g, 2.0 mmol) in THF (10 mL) was added sodium hydride (60% in mineral oil, 0.17 g, 4.2 mmol) .. at room temperature. The resulting reaction mixture was stirred for 30 min before iodomethane (0.60 g, 4.2 mmol) was added. After stirring at room temperature overnight, the mixture was quenched with brine and extracted with Et0Ac. The organic layer was then washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude product which was then purified by flash column chromatography (silica .. gel 14 g, 5% to 20% ethyl acetate in DCM). The title compound was obtained (0.38 g, 57%) as a white solid. MS: 316.2 (M+H+). [C] 5-Chloro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one CI
Asolution of 5-chloro-2-(4-methoxy-benzy1)-3,3-dimethy1-2,3-dihydro-isoindol- 1-one .. (0.38 g, 1.2 mmol) in trifluoro acetic acid (5 mL) was heated to reflux for 20 hours. After removal of trifluoro acetic acid under reduced pressure, the crude product was purified by flash column chromatography (silica gel 14 g, 5% to 50% ethyl acetate in DCM) to give the title compound (0.20 g, 85%) as a white solid. MS: 196.1 (M+H').
Intermediate A-12-1 5-Chloro-2-(5-chloromethyl-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindo1-1- one CI
CI
O [A] (5-Bromo-pyridin-3-y1)-methanol OH
Sodium borohydride (2.2 g, 59.1 mmol) was added to a suspension of 5-bromo- pyridine-3- carbaldehyde (10.0 g, 53.7 mmol) in Me0H (100 mL) at 0 C. The mixture was stirred at 0 Cfor 1 hour before it was quenched by the addition of water (5.0 mL).
Evaporation of solvents afforded a light yellowish oil which was re-dissolved in Et0Ac and washed with water. The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (9.6 g, 95%) as colorless oil. MS: 188.0 & 190.0 (M+H+). [B] 5-Chloro-2-(5-hydroxymethyl-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro- isoindol-1-one CI
In a 25-mL sealed tube, (5-bromo-pyridin-3-y1)-methanol(900 mg, 4.8 mmol), 5- chloro- 3,3-dimethy1-2,3-dihydro-isoindo1-1-one (intermediate A-12 [C], 858 mg, 4.4 mmol), Cul (200 mg, 1.1 mmol), Cs2CO3(3.0 g, 9.2 mmol) and (+)-(S,S)-1,2- diaminocyclohexanc (0.4 mL, 3.2 mmol) were dissolved in dioxane (8.0 mL). The resulting reaction mixture was heated at 150 C for 3 hours before it was poured into H20 (50 mL) and extracted with Et0Ac (2 x 125 mL). The organic layer was washed with brine, dried over anhy.
Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel WO2013/079452 PCT/EP2012/073653 - 144 - flash chromatography (30-100% Et0Ac-hexane gradient) to yield the title compound (1.2 g, 90%) as a light yellow solid. MS: 303.2 (M+H+). [C] 5-Chloro-2-(5-chloromethyl-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindol- l-one Thionyl chloride (1.4 mL, 19.0 mmol) was added slowly at 0 C to a solution of 5-ehloro- 2-(5-hydroxymethyl-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindo1-1-one (1.14 g, 3.8 mmol) in DCM (50 mL). After the addition, the reaction mixture was stirred at 2-5 C for 2 hours before it was poured into satd. aq. NaHCO3solution (50 mL) and extracted with Et0Ac (2 x 150 mL). The organic layer was washed with brine, dried over anhy.
Na2SO4, filtered and concentrated in vacuo to give a crude product (1.42 g, 92%) as a light yellowish solid. MS: 322.1 (M+H1).
Intermediate A-13 5-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one CI
NH 0 [A] 5-Chloro-3-ethy1-3-hydroxy-2,3-dihydro-isoindo1-1-one and 6-chloro-3-ethy1- 3- hydroxy-2,3-dihydro-isoindo1-1-one CI CI
To a solution of 5-chloro-isoindole-1,3-dione (5.0 g, 27.5 mmol) in DCM (200 mL) was added ethylmagnesium chloride (2 M in THF, 41.3 mL) dropwise at 0 C. After the addition, the mixture was allowed to stir at 0 C for 3 hours before it was quenched with satd. aq. NH4C1 solution. After extraction with DCM, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product containing a mixture of two regioisomers (5.82 g, 100%). MS: 212.0 (M+H'). [B] 5-Chloro-3-ethy1-2,3-dihydro-isoindo1- 1-one CI
Under N2 protection, triethylsilane (19.3 g, 166 mmol) and TFA (20 mL) were added successively to a mixture of 5-chloro-3-ethy1-3-hydroxy-2,3-dihydro-isoindo1-1- one and 6- chloro-3-ethy1-3-hydroxy-2,3-dihydro-isoindo1-1-one (3.52 g, 16.6 mmo 1).
After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with a satd. aq. solution of NaHCO3 (30 friL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude mixture of products. The desired regioisomer, 5-chloro-3-ethy1-2,3-dihydro-isoindo1-1-one was obtained by prep-HPLC separation as a white solid (0.65 g, 200/0). MS: 196.1 (M+H').
Intermediate A-13-1 5-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one CI
Intermediate A-13-2 6-Chloro-3-ethyl-2,3-dihydro-isoindo1-1-one CI 0 fAl 5-Chloro-3-ethy1-3-hydroxy-2,3-dihydro-isoindo1-1-one and 6-chloro-3-ethy1- 3- hydroxy-2,3-dihydro-isoindo1-1-one CI CI
To a solution of 5-chloro-isoindole-1,3-dione (5.0 g, 27.5 mmol) in DCM (200 mL) was added ethylmagnesium chloride (2 M in THF, 41.3 mL) dropwise at 0 C. After the addition, the mixture was allowed to stir at 0 C for 3 hours before it was quenched with satd. aq. NH4C1 solution. After extraction with DCM, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product .. containing a mixture of two regioisomers (5.82 g, 100%). MS: 212.0 (M+H+). [B] 5-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one and 6-Chloro-3-ethy1-2,3- dihydro- isoindo1-1-one Ci NH NH
CI 0 0 and Under N2 protection, triethylsilane (19.3 g, 166 mmol) and TFA (20 mL) were added successively to a mixture of 5-chloro-3-ethy1-3-hydroxy-2,3-dihydro-isoindo1-1- one and 6- chloro-3-ethy1-3-hydroxy-2,3-dihydro-isoindo1-1-one (3.52 g, 16.6 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with a satd. aq. solution of NaHCO1 (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude mixture of products. Both 5-chloro-3-ethyl-2,3-dihydro-isoindo1-1-one (0.65 g, 20%) MS: 196.1 T/EP2012/073653 - 147 - (M+H+) and 6-chloro-3-ethyl-2,3-dihydro-isoindo1-1-one (0.62 g, 19%) MS: 196.1 (M+H+) were obtained by prep-HPLC separation as white solids.
Intermediate A-13-la (R or S)-5-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one CI
Intermediate A-13-lb (S or R)-5-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one CI
Intermediate A-13-2a (R or S)-6-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one Intermediate A-13-2b (S or R)-6-Chloro-3-ethy1-2,3-dihydro-isoindo1-1-one The mixture of 5-chloro-3-ethyl-2,3-dihydro-isoindo1-1-one and 6-chloro-3- ethy1-2,3- dihydro-isoindol-1-one was subject to SFC separation (IC 250 mm x 50 mm, 5 urn, mobile phase A: supercritical CO2, B: IPA (0.05% NH3H20), A: B = 60: 40 at 140 mIlmin) to give (R or S)-5-chloro-3-ethyl-2,3-dihydro-isoindo1-1-one (intermediate A-13- 1a) and (S or R)-5-chloro-3-ethyl-2,3-dihydro-isoindo1-1-one as one pair of enantiomers and (R or 5)- 6-chloro-3-ahy1-2,3-dihydro-isoindo1-1-one and (S or R)-6-chloro-3-ethy1-2,3- dihydro- isoindol-1-one as another pair of enantiomers.
Intermediate A-13-3 (S or R)-5-Chloro-2-(5-chloromethyl-pyridin-3-y1)-3-ethy1-2,3-dihydro-isoindo1- 1-one CI
N
In analogy to the procedure described for the preparation of intermediate A-12- 1, (S or R)- 5-chloro-3-ethy1-2,3-dihydro-isoindo1-1-one was used to afford the title compound as yellowish oil. MS: 322.1 (M+H+).
Intermediate A-13-4 (R or S)-5-Chloro-2-(5-chloromethyl-pyridin-3-y1)-3-ethyl-2,3-dihydro-isoindol- 1-one CI
In analogy to the procedure described for the preparation of intermediate A-12- 1, (R or S)- 5-chloro-3-ethy1-2,3-dihydro-isoindo1-1-one was used to afford the title compound as yellowish oil. MS: 322.1 (M+H+).
Intermediate A-14 3-Benzy1-5-chloro-2,3-dihydro-isoindo1-1-one CI
NH 0 [A] 3-Benzy1-5-chloro-3-hydroxy-2,3-dihydro-isoindo1-1-one and 3-benzy1-6- chloro-3- hydroxy-2,3-dihydro-isoindol-1-one CI CI
To a solution of 5-chloro-isoindole-1,3-dione (3.63 g, 20 mmol) in DCM (150 mL) was added benzylmagnesium chloride (2 M in THF, 30 mL) dropwise at 0 C. After the addition, the reaction mixture was allowed to stir at 0 C for 3 hours before it was quenched with satd. aq. NH4C1 solution. After extraction with DCM, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product containing a mixture of two regioisomers (5.47 g, 100%). MS: 274.1 (M+H+).
WO2013/079452 PCT/EP2012/073653 - 150 - [B] 3-Benzy1-5-chloro-2,3-dihydro-isoindo1-1-one CI
Under N2 protection, triethylsilane (23 g, 200 mmol) and TFA (10 mL) were added successively to a mixture of 3-benzy1-5-chloro-3-hydroxy-2,3-dihydro-isoindo1- 1-one and 3-benzy1-6-chloro-3-hydroxy-2,3-dihydro-isoindo1-1-one (5.47 g, 20 mmol).
After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with a satd. aq. NaHCO3 solution (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude mixture of products. The desired regio isomer, 3-benzy1-5-chloro-2,3-dihydro-isoindol-1-one was obtained by prep-HPLCseparation as a white solid (1.03 g, 20%). MS: 258.1 (M+H+).
Intermediate A-15 5-Chloro-3-cyclopropy1-2,3-dihydro-isoindo1-1-one CI
IA] (2-bromo-5-chlorophenyl)(cyclopropyOmethanamine V
Br To a solutionof2-bromo-5-chlorobenzonitrile (20 g, 93 mmol) in THF (200 mL) was added cyclopropylmagnesiumbromide (558 mL, 279 mmol) at 0 C. The resulting reaction WO2013/079452 PCT/EP2012/073653 - 151 - mixture was stirred at 0-5 C for 5 hours before Me0H (100 mL) was added and stirring continued at room temperature for 15 min. NaBH4 (7.1 g, 186 mmol) was added subsequently and the reaction mixture was stirred at room temperature overnight. Water was added and reaction mixture was exacted with AcOEt (300 mL x 3). The combined organic layers were concentrated in vacuo to give a crude product which was then purified by chromatography to give (2-bromo-5-chlorophenyl)(cyclopropyOmethanamine (8.2 g, yield 34%). [B] 5-Chloro-3-cyclopropy1-2,3-dihydro-isoindo1-1-one CI
Amixture of (2-bromo-5-chlorophenyl)(cyclopropyOmethanamine (2 g, 7.7 mmol), Pd(dppf)C12 (0.2 g), DIPEA (3 g, 23.1 mmol) in 20 mL of DMF was heated in an autoclave at 130 C under 2 MPa of CO (g) for 16 hours. After the reaction, the mixture was diluted with AcOEt (150 mL) and washed with brine (30 mL x 3). The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by chromatography to give title compound (1.1 g, yield 68.7%) as a yellow solid. MS: 207.9 (M+H+, 1C1).
Intermediate A-16 2-Chloro-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one CIN [A] 3-(Methoxyearbony1)-2-methylpyridine 1-oxide WO2013/079452 PCT/EP2012/073653 - 152 - 0 1, 0 To a stirred solution of methyl-2-methylnicotinate (95 g, 629 mmol) in DCM (1.5 L) was added m-CPBA (119 g, 692 mmol) at 0 C. After the reaction mixture was stirred at room temperature for 16 hours, it was washed with a mixture of satd. aq. Na2S03 and NaHCO3 solition. The organic layer was then dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (60 g, yield 57%), which was used in the next step reaction without further purification. [B] Methyl 2-(chloromethyl)nicotinate 0 The crude 3-(methoxycarbony1)-2-methylpyridine- 1-oxide (35 g, 210 mmol) was added in small portion to POC13 (300 g) at room temperature. After the addition, the reaction mixture was refluxed for 3 hours before it was concentrated in vacuo. The residue was poured into ice-water, neutralized with aq. NaHCO3 solution and extracted with AcOEt (125 mL x 3). The combined organic layers were washed with brine, dried over anhy.
Na2SO4, filtered, and concentrated in vacuo to afford a crude product which was then purified by column chromatography to give title compound (12 g, yield 30%). [C] 2-(Chloromethyl)-3-(methoxycarbonyl)pyridine 1-oxide 0 ClaY' CI _ 0 To a stirred solution of methyl-2-(chloromethypnicotinate (20 g, 108 mmol) in DCM(300 mL) was added m-CPBA (20.5 g, 119 mmol) at 0 C. After it was stirred at room temperature for 16 hours, the reaction mixture was washed with a mixture of satd. aq.
Na2S03 and NaHCO3 solution. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give the crude title product (20 g, yield 92%), which was used in the next step reaction without further purificaition. [D] Methyl 6-chloro-2-(chloromethyl)nicotinate 0 0"-CI
CI1\1 The crude of 2-(chloromethyl)-3-(methoxycarbonyl)pyridine-1-oxide (20 g, 99.5 mmol) was added in small portion to POC13 (200 g) at room temperature. The mixture was refluxed for 3 hours before it was concentrated in vacuo. The residue was poured into ice- water, neutralized with NaHCO3 solution, and extracted with AcOEt (125 mL x 3). The combined organic layers were concentrated to give the crude title product (17 g, yield 78%), which was used in the next step reaction without further purification. [E] 2-Chloro-6-(4-methoxybenzy1)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one CI N___________ 0 To a stirred solution of crude methyl 6-chloro-2-(chloromethypnicotinate (10 g, 45.4 mmol) in THF (150 mL) was added PMBNH2 (15.5 g, 113.5 mmol) at 0 C. The resulting reaction mixture was stirred at room temperature for 16 hours before it was concentrated under reduced pressure to give a crude product. After washing with MTBE (100 mL x 3), the tilte compound was obtained (8.8 g, yield 67%) as a white solid. MS: 288.8 (M+14', 1C1). [F] 2-Chloro-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one CI N= 0 To a solution of 2-chloro-6-(4-methoxy-benzy1)-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one (5.8 g, 20.0 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 1.7 g, 42.0 mmol) at room temperature. The resulting reaction mixture was stirred for 30 min before iodomethane (6.0 g, 42.0 mmol) was added. After stirring at room temperature over night, the mixture was quenched with water and extracted with Et0Ac. The organic layer was then washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude product which was then purified by flash column chromatography (silica gel 20 g, 5% to 20% ethyl acetate in DCM). The title compound was obtained (3.8 g, 57%) as a white solid. MS: 316.2 (M+H'). [G] 2-Chloro-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one CI
To solution of 2-chloro-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro- pyrrolo[3,4- b]pyridin-5-one (1.58 g, 5.0 mmol) in CH3CN (20 mt.) was added ceric ammonium nitrate (8.2 g, 15.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and Et0Ac was added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give title compound (617 mg, 63%) as a solid. MS: 197.2 (M+H).
Intermediate A-16-1 [3,4- bj CIN CI
N 0 [A] 2-Chloro-6-(5-hydroxymethyl-pyridin-3-y1)-7,7-dimethyl-6,7-dihydro- pyrrolo[3,4- b]pyridin-5-one CI ¨N
OH 0 I 2-Chloro-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (intermediate A- 16 [G], 39.2 mg, 0.2 mmol), (5-bromo-pyridin-3-y1)-methanol (example 3 [A], 74.8 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (IS, 2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 nit). The reaction mixture was subjected to microwave reaction at 140 'V for 1 hours before it was poured into H20 (50 nit) and extracted with Et0Ac (2x 25 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (55.7 mg, 92%) as solid. MS: 304.1 (M+H+). [B] 2-Chloro-6-(5-chloro-methyl-pyridin-3-y1)-7,7-dimethy1-6,7-dihydro- pyrrolo[3,4- blpyridin-5-one CI \ /
CI 0 ' Thionyl chloride (0.14 mL, 1.9 mmol) was added slowly at 0 C to a solution of 2-chloro- 6-(5-hydroxymethyl-pyridin-3-y1)-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one (55.7 mg, 0.18 mmol) in DCM (10 mL). After the addition, the reaction mixture was stirred at 2-5 C for 0.5 hours before it was poured into satd. aq. NaHCO3 solution (10 mL) and extracted with DCM (2 x 15 mL). The organic layer was washed with brine, dried over PCT/EP2012/073653 - 156 - anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (58 mg 100%) as light yellowish solid. MS: 322.1 (M+H+).
Intermediate A-17 2-Methoxy-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one 0 N 0 [A] 2-Methoxy-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4- b]pyridin-5- one 0 0 41' 0 To solution of 2-chloro-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro- pyrrolo[3,4- b]pyridin-5-one (intermediate A-16 [F], 3.15 g, 10 mmol) in DMF (30 mL) was added sodium methanolate (0.813 g, 15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours before it was quenched with water and extracted with Et0Ac. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title compound (2.8 g, 90%) as a solid. MS: 313.1 (M+H+). [13] 2-Methoxy-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one ON
To solution of 2-methoxy-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro- pyrrolo[3,4- b]pyridin-5-one (0.31 g, 1.0 mmol) in CH3CN (5 mL) was added ceric ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and Et0Ac were added into the mixture.
The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.12 g, 63%) as a solid. MS: 193.1 (M+H').
Intermediate A-17-1 6-(5-Chloromethyl-pyridin-3-y1)-2-methoxy-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4- lApyridin-5-one 0 In analogy to the procedure described for the preparation of intermediate A-12- 1, the title compound was obtained as yellowish oil. MS: 318.3 (M+H+).
Intermediate A-18 2-Ethoxy-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-13]pyridin-5-one I N 0 [Ai 2-Ethoxy-6-(4-methoxy-benzy1)-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4- b]pyridin-5- one WO2013/079452 PCT/EP2012/073653 - 158 _ 0 N =0 0 To solution of 2-chloro-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro-pyrrolo [3,4- b]pyridin-5-one (intermediate A-16 [F], 3.15 g, 10 mmol) in DMF (30 mL) was added sodium ethoxide (1.02 g, 15 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours before it was quenched by water and extracted with Et0Ac. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give title product (2.9g, 89%) as a solid. MS: 327.2 (M+H-). [B] 2-Ethoxy-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one 0 N 0 .. To solution of 2-methoxy-6-(4-methoxy-benzy1)-7,7-dimethyl-6,7-dihydro- pyrro lo [3,4- b]pyridin-5-one (0.33 g, 1.0 mmol) in CH1CN (5 mL) was added ceric ammonium nitrate (1.64 g, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and Et0Ac were added into the mixture.
The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give the title compound (0.15 g, 72%) as a solid. MS: 207.1 (M+H+).
Intermediate A-18-1 6-(5-Chloromethyl-pyridin-3-y1)-2-ethoxy-7,7-dimethy1-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one WO2013/079452 PC T/EP2012/073653 - 159 _ ON________________________________ i2 N
In analogy to the procedure described for the preparation of intermediate A-12- 1, the title compound was obtained as yellowish oil. MS: 332.1 (M+H').
Intermediate A-19 5-Fluoro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one N H 0 [A] 4-Fluoro-2-methyl-benzoic acid methyl ester Lyo To a stirred solution of 4-fluoro-2-methyl-benzoic acid (13 g, 84 mmol) in Me0H (500 mL) was added SOC12 (20 g, 168 mmol) dropwise at 0 C.After the addition, the reaction mixture was stirred at room temperature for 16 hours. When TLC indicated that no starting material was left, the mixture was concentrated under reduced pressure to give a crude product (12.7 g, yield 90.7%), which was used in the next step reaction without further purification. [B] 2-Bromomethy1-4-fluoro-benzoic acid methyl ester F
Br 0 0 Amixture of 4-fluoro-2-methyl-benzoic acid methyl ester (12.7 g, 75.5 mmol), NBS(13.4 g, 75.5 mmol), and di-benzoyl peroxide (BPO) (0.85 g, 3.5 mmol) in CC14 (200 mL) was heated to reflux for 3 hours until all starting material was consumed. After vacuum filration, the filtrate concentrated in vacuo to give a crude product (17 g, yield 91%), which was used in the next step reaction without further purification. [C] 5-Fluoro-2-(4-methoxy-benzy1)-2,3-dihydro-isoindo1-1-one 0 010 0 To a stirred solution of 2-bromomethy1-4-fluoro-benzoic acid methyl ester (17 g, 68.8 mmol) in THF (200 mL) was added PMBNH2 (23.6 g, 172 mmol) at 0 C. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo to give a crude product which was then purified by column chromaography to give the title compound (13 g, yield 69%) as a solid.
ID] 5-Fluoro-2-(4-methoxy-benzy1)-3,3-dimethyl-2,3-dihydro-isoindol-1-one 0 0 To a solution of 5-fluoro-2-(4-methoxy-benzy1)-2,3-dihydro-isoindol-1-one (6 g, 22 mmol) in THF (30 mL) was added NaH (4.42 g, 110 mmol) slowly at 0 C. After stirred at 0 C for 30 min, Mel (18.8 g, 132 mmol) was added dropwise and the resulting reaction mixture was heated to 70 C for 5 hours. After cooling to room temperature, the reaction mixture WO2013/079452 PCT/EP2012/073653 - 161 - was poured into aq. NH4C1 solution and exacted with Et0Ac. The organic layer was dried over anhy. Na2SO4, filtered, and then concentrated to give a crude product which was then purified by column chromatography to give tile product (4.8 g, yield 72.5%) as a solid. [E] 5-Fluoro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one To a stirred solution of 5-fluoro-2-(4-methoxy-benzy1)-3,3-dimethyl-2,3- dihydro-isoindo1- 1-one (3.8 g, 12.7 mmol) in MeCN (80 ml) and H20 (40 mL) was added CAN (20.9 g, 38.1 mmol) at 0 C. After stirring for 2 hours at 0 C, the reaction mixture was diluted with Et0Ac and washed with brine. The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to provide a crude product, which was purified by column chromatography to give tile product (1.03 g, yield 45%) as a solid.
Intermediate A-19-1 2-(5-Chloromethyl-pyridin-3-y1)-5-fluoro-3,3-dimethy1-2,3-dihydro-isoindo1-1- one In analogy to the procedure described for the preparation of intermediate A-12- 1, the title compound was obtained as yellowish oil. MS: 305.1 (M+H').
Intermediate A-20 6-Fluoro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one F
NH 0 [A] 1-(2-Bromo-4-fluoro-pheny1)-1-methyl-ethylamine Br To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25 mmol) in ether (100 mL) was added MeMgBr (25 mL, 75 mmol) at room temperature. The solution was stirred at room temperature for 0.5 hour before Ti(Oi-Pr)4 (41 mL, 25 mmol) was added and the resulting mixture was heated to reflux for 6 hours. Aqueous NaOH (10%, 200 mL) solution was then slowly added to the reaction mixture at 0 C and the reaction mixture was stirred at room temperature for additional 30 minutes. After dilution with aq. Na2CO3 (5%, 400 mL) solution, it was extracted with t-BuOMe (100 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue obtained was diluted with aq. HC1 solution (5%) and the aqueous layer was washed with t-BuOMe (50 mL x 2) and basified with 20% aq. NaOH to pH¨ 10. The resulting aqueous layer was further extracted with t-BuOMe (100 mL x 3). The combined organic layers were then dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by column chromatography to give the title product (3.0 g, yield 51.7%) as yellowish oil. MS: 231.7 (M+H', 1Br) B6-Fluoro-3 3-dimeth 1-2 3-dih dro-isoindol-l-one FX
Amixture of 1-(2-bromo-4-fluoro-pheny1)-1-methyl-ethylamine (1.5 g, 6.52 mmol), Pd(dppf)C12 (0.15 g), DIPEA (2.52 g, 19.6 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130 C for 16 hours. After it was cooled to room temperature, the reaction mixture was diluted with Et0Ac (300 mL). The organic layer was washed with brine, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to give the title compound (100 mg, yield 8.6%) as a brown solid.
Intermediate A-20-1 2-(5-Chloromethyl-pyridin-3-y1)-6-fluoro-3,3-dimethyl-2,3-dihydro-isoindol-l- one N C I [A] 6-Fluoro-2-(5-hyroxymethyl-pyridin-3-y1)-3,3-dimethyl-2,3-dihydro-isoindol- 1-one Amixture of 6-fluoro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one (intermediate A- 20 [13], 35.8 mg, 0.2 mmol), (5-bromo-pyridin-3-y1)-methanol (74.8 mg, 0.4 mmol), Cul (3.8 mg, 0.02 mmol), (1S, 2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 140 C for 1 hour before it was poured into H20 (50 mL) and extracted with Et0Ac (2x 25 mL). The organic layer was washed with brine, dried over anhy. Na2504, filtered and concentrated in vacuo to give a crude product (52 mg, 92%) as a solid. MS: 287.1 (M+H). [B] 2-(5-Chloromethyl-pyridin-3-y1)-6-fluoro-3,3-dimethy1-2,3-dihydro-isoindo1- 1-one To a solution of 6-fluoro-2-(5-hyroxymethyl-pyridin-3-y1)-3,3-dimethyl-2,3- dihydro- isoindol-1-one (52 mg) in DCM (10 mL) was added thionyl chloride (0.14 mL, 1.9 mmol) slowly at 0 C. After the addition, the reaction mixture was stirred at 2-5 C for 0.5 hour before it was poured into satd. aq. NaHCO3 solution (10 mL) and extracted with DCM(2 x mL). The combined organic layers were washed with brine, dried over anhy.
Na2SO4, filtered and concentrated in vacuo to give a crude product (58 mg 100%) as light yellowish solid. MS: 322.1 (M+H+).
Intermediate A-21 10 3,3-Dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile NC
N H 0 [A] 4-Bromo-2-methyl-benzoic acid methyl ester Br 0 To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14mol) in 115 mL of methanol 15 was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stirred at 70 C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6%) as a solid.
WO2013/079452 PCT/EP2012/073653 - 165 - [B] 4-Cyano-2-methyl-benzoic acid methyl ester Amixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g,140.7 mmol) was heated at 180 C for 5 hours before it was poured into .. ice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g, 63%) as a solid. [C] 2-Bromomethy1-4-cyano-benzoic acid methyl ester N C
Br 0 A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g,71.35 mmol), NBS (12.7 g,71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g,3.28 mmol) in Cal (200 mL) was heated to reflux temperature for 3 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification. [D] 2-(4-Methoxy-benzy1)-1-oxo -23-dihydro-1H-isoindo le-5-carbonitri le N C0 ==,.. 0 To a solution of 2-bromomethy1-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate WO2013/079452 PCT/EP2012/073653 - 166 - was concentrated in vacuo. The residue obtained was re-dissolved in Et0Ac and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography (11.69 g, 56.0%) as a soild. 1E] 2-(4-Methoxy-benzy1)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5- carbonitrile To a solution of 2-(4-methoxy-benzy1)-1-oxo-2,3-dihydro-1H-isoindole-5- carbonitrile (11.6 g,41.7 mmol) in THF (300 mL) was added NaH (8.34 g, 208.4 mmol, 60% in mineral oil) and the reaction mixture was stirred at room temperature for 1 hour before iodomethane (35.5 g,250.1 mmol) was added. After the addition, the reaction mixture was stirred at 70 C for 2 hours until all the starting material was comsumed.
After it was cooled to room temperature, satd. aq. NH4C1 solution was added and the mixture was extracted with Et0Ac (200 m1Lx3). The combined organic layers were dried over anhy.
MgSO4, filtered, and concentrated under redured pressure to give a crude product which was purified by column chromatography to afford the title compound (7.22 g, 56.5%) as a solid. [F] 3,3 -Dimethyl-l-oxo-2,3-dihydro-1H-isoindo le-5-carbonitrile NC
To a solution of 2-(4-methoxy-benzy1)-3,3-dimethyl-1-oxo-2,3-dihydro-1H- isoindole-5- carbonitrile (3.5 g, 11.42 mmol) in MeCN (70 mL) was added CAN (18.79 g, 34.27 mmol) in 30 nth of water at 0 C. The resulting reaction mixture was stirred at 0 C for 1 hour until all the starting material was comsumcd. The reaction mixture was extracted between WO2013/079452 PCT/EP2012/073653 - 167 - water and Et0Ac and the combined organic layers were dried over anhy. MgSO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography to afford the title compound (1.06 g, 49.8%) as a solid.
Intermediate A-21-1 2-(5-Chloromethyl-pyridin-3-y1)-3,3-dimethyl-l-oxo-2,3-dihydro-1H-isoindole-5- carbonitrile NC
In analogy to the procedure described for the preparation of intermediate A-12- 1, the title compound was obtained as yellowish oil. MS: 312.1 (M+H').
Intermediate A-22 6'-Chlorospiro[eyelopropane-1,1'-isoindolin]-3'-one CI
NH 0 fAl 1-(2-Bromo-5-chlorophenyl)cyclopropanamine CI
Br To a stirred solution of 2-bromo-5-chlorobenzonitrile (10 g, 46 mmol) and Ti(Oi-Pr)4 (16.64 mL, 55 mmol) in THF (200 mL) at -78 C was added EtMgBr (138 mL, 138 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred WO2013/079452 PCT/EP2012/073653 - 168 - for 2 hours. BF3-Et20 (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HC1 solution and washed with Et0Ac. The aqueous phase was adjusted to pH ¨ 10 with aq. NaOH solution, and exacted with Et0Ac (3 x).
The combined organic layers were concentrated to give a crude product which was purified by chromatography to afford title compound (2 g, yield 17.6%). MS: 246.7 (M+FL, 1C1) as oil. [B] 6'-Chlorospiro[cyclopropane-1,1'-isoindolin]-3'-one CI
Amixture of 1-(2-bromo-5-chlorophenyl)cyclopropanamine (2 g, 8.1 mmol), Pd(dppf)C12 (0.2 g), DIPEA (3.1 g, 24.3 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130 C for 16 hours. The reaction mixture was diluted with Et0Ac (300 mL), and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (700 mg, yield 44.6%) as a yellow solid. MS: 193.8 (M+H', 1C1).
Intermediate A-22-1 6'-Chloro-2'-(5-(chloromethyl)pyridin-3-yl)spiro[cyc1opropane-1,1'-isoindolini- 3'-one CI
At"
In analogy to the procedure described for the preparation of intermediate A-12- 1, title compound was obtained as yellowish oil. MS: 320.1 (M+H}).
Intermediate A-23 6'-Fluorospiro[cyclopropane-1,1'-isoindolin]-3'-one N H 0 [A] 1-(2-Bromo-5-fluoro-pheny1)-cyclopropylamine Br To a stirred solution of 2-bromo-5-fluoro-benzonitrile (1 g, 5 mmol) and Ti(Oi-Pr)4 (1.81 mL, 5.5 mmol) in ether (20 mL) was added EtMgBr (3.67 mL, 11 mmol) at -78 C.
After stirring at -78 C for 10 min, the solution was warmed up to room temperature and stirred for 1 hour. BF3-Et20 (1.25 mL) was added before it was stirred for another 1 hour. After addition of 1 N aq. HC1 (15 mL) and ether (30 mL), aq. NaOH (10%, 45 mL) solution was added to give two clear phases. The mixture was exacted with Et0Ac (30 mL x 5). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by column chromatography (PE:EA = 5:1) to afford the title compound (800 mg, 70%) as oil. {B] 6'-Fluorospiro[cyclopropane-1,1'-isoindolin]-3'-one Asolution of 1-(2-bromo-5-fluoro-phenyl)-cyclopropylamine (4.2 g, 18.3 mmol), Pd(dpp0C12 (0.42 g), DIPEA (7 g, 54.8 mmol) in 40 mL of DMF was heated at 130 C
WO2013/079452 PCT/EP2012/073653 - 170 - under 2 MPa of CO for 12 hours. After it was cooled to room temperature, Et0Ac was added it was washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give title compound (0.3 g, yield 65.2%) as a solid, meanwhile, 3.3 g of starting material was recovered.
Intermediate A-23-1 2'-(5-(Chloromethyl)pyridin-3-y1)-6'-fluorospiro[cyclopropane-1,1'-isoindolin]- 3'-one In analogy to the procedure described for the preparation of intermediate A-12- 1, the title compound was obtained as yellowish oil. MS: 303.1 (M+H').
Intermediate A-24 5'-Fluorospiro[cyclopropane-1,1'-isoindolin]-3'-one JAI1-(2-Bromo-4-fluorophenyl)cyclopropanamine Br To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25 mmol) and Ti(Oi-Pr)4 (9.05 mL, 27.5 mmol) in ether (100 mL) at -78 C was added EtMgBr (18.3 mL,55 mmol) dropwise. The solution was allowed to warm to room temperature and stirred for 1 hour before BF3-Et20 (6.25 mL) was added and stirring continued at room temperature for another 1 hour. The reaction solution was quenched with 1 N HC1 solution, and washed with Et0Ac. The aqueous layer was adjusted to pH 10 with aq. NaOH (2 N) solution and then exacted with Et0Ac (3 x). The combined organic layers were dried over anhy.
Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to give title compound (3.0 g, yield 52.2%) as yellowish oil. [B] 5'-Fluorospiro[cyclopropane-1,1'-isoindolin]-3'-one Amixture of 1-(2-bromo-4-fluorophenyl)cyclopropanamine (3.0 g, 17.4 mmol), Pd(dppf)C12 (0.4 g), DIPEA (5.05 g, 39.1 mmol) in DMF (40 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130 C for 16 hours. After it was cooled down to room temperature, the reaction mixture was diluted with Et0At (300 mL) and washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to afford title compound (600 mg, yield 26%) as a brown solid.
Intermediate A-24-1 2'-(5-(Chloromethyl)pyridin-3-y1)-6'-fluorospiro[cyclopropane-1,1'-isoindolin]- 3'-one In analogy to the procedure described for the preparation of intermedaite A-12- 1, the title compound was obtained as yellowish oil. MS: 303.1 (M+H+).
Intermediate A-25 6-Chloro-3,3-dimethy1-2,3-dihydro-isoindo1-1-one NH
In analogy to the procedure described for the preparation of intermediate A- 20, 2-bromo- 4-chloro-benzonitrile (step A) and 1-(2-bromo-4-chloro-pheny1)-1-methyl- ethylamine (step B) were used to yield the title compound as a solid (yield 40%). MS: 196.1 (M+H+).
Intermediate A-25-1 6-Chloro-2-(5-chloromethyl-pyridin-3-y1)-3,3-dimethy1-2,3-dihydro-isoindo1-1- one In analogy to the procedure described for the preparation of intermedaite A-12- 1, the title compound was obtained as yellowish oil. MS: 322.1 (M+H+).
Intermediate B-1 3-Bromo-5-(2-isopropyl-imidazol-1-ylmethyl)-pyridine Br [A] 3-Bromo-5-chloromethyl-pyridine CI
To a solution of (5-bromopyridin-3-yl)methanol (3 g, 16.0 mmol) in DCM (15 mL) cooled to 0 C was added thionylchloride (7.59 g, 63.8 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was poured onto ice/water (20 nit), basified with NaOH conc. (8 mL) and extracted with Et0Ac (2 x 50 mL).
Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% Et0Ac- heptane gradient to give the title compound (3.08 g, 93 %) as a white solid. MS: 206.0, 207.9 (M+H'). fE31 3-Bromo-5-(2-isopropyl-imidazol-1-ylmethyl)-pyridine Br To a suspension of sodium hydride (60% in mineral oil, 0.073 g, 1.82 mmol) in DMF(3 mL) was added 2-isopropyl-1H-imidazole (0.173 g, 1.57 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 3-bromo-5-chloromethyl- pyridine (0.25 g, 1.21 mmol) was added and the resulting suspension was heated at 60 C over night. The mixture was quenched with water (2 mL) and extracted with Et0Ac (2x 10 mL).
Combined organics were dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by silica gel flash chromatography eluting with a 0 to 5%
Me0H-DCMgradient to give the title compound (0.275 g, 81 %) as a light yellow oil.
MS: 280.0, 282.0 (M+H+).
Intermediate B-2 3-Bromo-5-(2-methyl-imidazol-1-ylmethyl)-pyridine Br N
In analogy to the procedure described for the preparation of intermediates B-1 [B] , 2- methyl-imidazol has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a light brown solid. MS: 251.9, 254.0 (M+H+).
Intermediate B-3 3-Bromo-541,2,41triazol-1-ylmethyl-pyridine N
In analogy to the procedure described for the preparation of intermediates B-1 [B], 1H- 1,2,4-triazole has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a white solid. MS: 238.9, 241.3 (M+H+).
Intermediate B-4 1-(5-Bromo-pyridin-3-ylmethyl)-pyrrolidin-2-one 0 In analogy to the procedure described for the preparation of intermediates B-1 [B], pyrrolidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a white solid. MS: 251.1, 257.1 (M+H+).
Intermediate B-5 1-(5-Bromo-pyridin-3-ylmethyl)-piperidin-2-one Br In analogy to the procedure described for the preparation of intermediates B-1 [B], piperidin-2-one has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a colorless oil. MS: 269.2, 271.2 (M+H1).
Intermediate B-6 3-Bromo-54(S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-pyridine 0 In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-2- (methoxymethyl)pyrrolidine has been coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as a yellow oil. MS: 285.0, 286.9 (M+H').
Intermediate B-7 Ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide WO2013/079452 PCT/EP2012/073653 - 176 - 0 , 0 Aflask was charged with 5-bromonicotinaldehyde (2.55 g, 13.7 mmol), ethanesulfonamide (2.99 g, 27.4 mmol) and toluene (250 mL), then titanium isopropoxide (5.84 g, 20.6 mmol) was added dropwise. The reaction mixture was stirred at 115 C over night and then concentrated in vacuo. The residue was taken up in DCM (200 mL) and Me0H (200 mL) and NaBH4 (1.04 g, 27.4 mmol) was added partionwise at 0 C. The reaction mixture was stirred at 0 C for 30 min and then poured into water (100 mL) and the resulting suspension was filtered through a pad of dicalite. The dicalite layer was washed with DCM (3x 100 mL). The resulting aqueous layer was separated and extracted with DCM (500 mL). Combined organics were dried over Na2SO4, filtered and preadsorbed on silica gel. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% Me0H-DCM gradient to give the title compound (3.01 g, 79%) as an orange solid. MS: 279.0, 281.0 (M+H').
Intermediate B-8 (S)-1-(5-Bromo-pyridin-3-y1)-5-hydroxymethyl-pyrrolidin-2-one Br OH
In a sealed tube, 3,5-dibromopyridine (0.5 g, 2.11 mmol) was combined with (S)- 5- (hydroxymethyl)pyrrolidin-2-one (0.243 g, 2.11 mmol), copper (I) iodide (0.040 g, 0.021 mmol), potassium carbonate (0.583 g, 4.22 mmol) and /V,N'- dimethylethylenediamine (0.037g, 0.042 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated at 110 C over night. The mixture was cooled to room temperature, filtered through dicalite and washed with DCM. The residue was purified by silica gel flash chromatography eluting WO2013/079452 PCT/EP2012/073653 - 177 - with a 0 to 10% Me0H-DCM gradient to give the title compound (0.140 g, 25 %) as a light yellow oil. MS: 271.1, 273.1 (M+H+).
Intermediate B-9 1-(5-Bromo-pyridin-3-y1)-pyrrolidin-2-one 0 In analogy to the procedure described for the preparation of intermediate B-8, pyrrolidin- 2-one has been coupled to 3,5-dibromopyridine to yield the title compound as a light yellow solid. MS: 241.0, 243.0 (M+H').
Intermediate B-10 3-Bromo-54(8)-2-methoxymethyl-pyrrolidin-1-y1)-pyridine BrR
In analogy to the procedure described for the preparation of example 135 [B], (S)-2- methoxymethyl-pyrrolidine was reacted with 3,5-dibromopyridine in the presence of Pd2(dba)3, rac-BINAP and sodium tert-butoxide to give the title compound as a yellow oil.
MS: 271.1, 273.1 (M+H').
Intermediate B-11 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-ol Br.,&OH
IA] Ethyl 5-bromo-4-methylnicotinate 0 0 To a stirred light brown suspension of 5-bromo-4-methylnicotinic acid (10.00 g, 46.3 mmol) and ethanol (2.97 mL) in DCM (231 mL) at 0 C under argon was added EDCI (10.9 g, 55.5 mmol) and DMAP (566 mg, 4.63 mmol); stirring was continued over night and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was then poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3x). The organic phases were washed once with aq. 10% KH2PO4, with sat.
NaHCO3 and with aq. sat. Nan solution. The combined organic phases were dried (Na2SO4), filtered and evaporated to afford the title compound (9.49 g, 84%) as brown solid. MS: 244.0 (M+H', 1Br). [B] Methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinolinc-7-carboxylatc 0 0 Br 0 Ethyl 5-bromo-4-methylnicotinate (7.04 g, 28.8 mmol) in THF (28.8 mL) was added over a period of 20 min to a solution of LDA (31.7 mmol) [generated from /V, N- diisopropylamine (4.52 ml, 31.7 mmol) and n-butyllithium (19.8 mL, 31.7 mmol, 1.6M in hexane) in 144 mL THF] at -78 C. The resulting dark red solution was stirred for 20 min, WO2013/079452 PCT/EP2012/073653 - 179 - then methyl acrylate (6.21 g, 72.1 mmol) in THF (28.8 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH was added (resulting pH = 4- 5) and the reaction was allowed to warm to room temperature. After evaporation, the residue was poured on aq. sat. NaHCO3 and extracted with Et0Ac (3x). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (7.80 g, 95% in 70% purity with 30% starting material) as brown solid. MS: 284.0 (M+H', 1Br). [C] 4-Bromo-6,7-dihydroisoquinolin-8(5H)-one Br 0 The crude methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (7.79 g, 27.4 mmol) was dissolved (small amount of not dissolved material) in aq. 6M HO (84.1 ml, 505 mmol) and heated at reflux for 2.5 h. The acidic solution was concentrated in vacuo, suspended in water (ca. 25 mL), cooled in ice and basified with 6.0 M
KOH. The aqueous solution was extracted with ether (2x) and CH2C12 (3x), the combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound (4.30 g, 69%) as a brown solid. MS: 226.0 (M+H', 1Br). [D] 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-ol Bk,611_, OH 4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (2.135 g, 9.44 mmol) was suspended in Me0H (18.9 mL), cooled to 0 C and treated with NaBH4 (357 mg, 9.44 mmol) in 5 portions over 30 min; then, the reaction was stirred for 3/4 h at 0 C (TLC after 30 min showed no more starting material). AcOH was then added dropwise until pH ¨ 5-6 and the reaction mixture was evaporated. The residue was diluted with water and poured on aq.
WO2013/079452 PCT/EP2012/073653 - 180 - sat. NaHCO3-sol. followed by extraction with Et0Ac (3x). The organic layers were washed once with aq. sat. NaHCO3-sol. and aq. 10% NaCl-sol., dried over Na2SO4 and concentrated in vacuo. The residue was re-dissolved in CH2C12, evaporated with n-pentane (3x) to around 20 ml each time, while the product precipitates; then, the solvent was decanted and the residue washed with n-pentane and dried in high vacuum to afford the title compound (1.98 g, 92%) as dark brown viscous oil. MS: 227 (M-', 1Br).
Intermediate B-12 N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide 0 Br EJ [A] 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine Br NH 4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate B-11 [C]) (4.81g, 21.3 mmol), titanium (IV) isopropoxide (12.1 g, 42.6 mmol) and ammonia, 2.0 M solution in Me0H (53.2 mL, 106 mmol) were stirred at room temperature for 5 h. The reaction was cooled to 0 C and NaBH4 (1.21 g, 31.9 mmol) was added portionwise over 10 min; the resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by pouring it into aq. ammonium hydroxide 25%, the precipitate was filtered and washed with Et0Ac (3x, each time suspended in AcOEt and stirred for 5 min). The organic layer was separated and the remaining aqueous layer was extracted with Et0Ac. The combined organic extracts were extracted with 1 M HC1. The acidic aqueous extracts were washed with ethyl acetate (1x), then treated with aqueous sodium hydroxide (2 M) to give pH 10- 12 and extracted with Et0Ac (3x). The combined organic extracts were washed with brine, WO2013/079452 PCT/EP2012/073653 - 181 - dried (Na2SO4), and concentrated in vacuo to afford the title compound (4.11 g, 85%) as brown solid. MS: 225 (Mt, 1Br). [B] N-(4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide 0 To a stirred brown solution of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (318 mg, 1.4 mmol) and propionic acid (114 mg, 1.54 mmol) in CH2C12 (7.0 mL) at 0 C under argon was added EDCI (63.3 mg, 0.330 mop. Stirring was continued over night and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured onto aq. 10% KH2PO4 solution followed by extraction with AcOEt (3x).
The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaC1 solution; the combined organic phases were dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2C12, evaporated with n-pentane (3x) to ca. 10 ml each time, while the product precipitated; then, the solvent was decanted and the residue washed twice with n-pentane to afford the title compound (0.365 g, 92%) as light brown solid. MS: 283.0 (M+H', 1Br).
Intermediate B-13 2-(5-Bromo-pyridin-3-ylmethy1)41,21thiazinane 1,1-dioxide Brw, In analogy to the procedure described for the preparation of intermediates B-1 [B], [1,2]thiazinane 1,1-dioxide has been coupled to 3-bromo-5-chloromethyl- pyridine (intermediate B-1 [A]) to yield the title compound as off-white solid. MS: 305.1, 307.1 (M+H').
Intermediate B-14 3-Bromo-5-(1,1-dioxo-1 6-isothiazolidin-2-ylmethyl)-pyridine In analogy to the procedure described for the preparation of intermediates B-1 [B], isothiazolidine 1,1-dioxide has been coupled to 3-bromo-5-chloromethyl- pyridine (intermediate B-1 [A]) to yield the title compound as a light yellow oil. MS: 290.9, 292.8 (M+H+).
Intermediate B-15 (S)-1-(5-Bromo-pyridin-3-ylmethyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)- 1 0 pyrrolidin-2-one In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)-5- (tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one has been coupled to 3- bromo-5- chloromethyl-pyridine (intermediate B-1 [A]) to yield the title compound as colorless oil.
MS: 399.2, 401.2 (M+H').
Intermediate B-16 (S)-1-(5-Bromo-pyridin-3-ylmethyl)-pyrrolidine-2-carboxylic acid methyl ester In analogy to the procedure described for the preparation of intermediates B-1 [B], (S)- pyrrolidine-2-carboxylic acid methyl ester has been coupled to 3-bromo-5- chloromethyl- pyridine (intermediate B-1 [A]) to yield the title compound as light yellow oil. MS: 299.2, 301.1 (M+1-1+).
Intermediate B-17 N-(4-Bromo-5,6,7,8-tetrahydro-isoquinolin-8-y1)-acetamide 0 Br To a stirred solution of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-12 [A], 318 mg, 1.4 mmol) and Et1-1\1 (3.0 mL) in DCM (10 mL) was added acetyl chloride (0.106 mL, 1.4 mmol) at 0 C and stirring was continued at 0 C for 1 hour.
The resulting mixture was extracted with Et0Ac (2 x 100 mL). The combined organics were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product which was purified by silica gel flash chromatography eluting with a 0 to 50 %
Et0Ac-heptane gradient to give the title compound (346 mg, 92 %) as light yellow solid.
MS: 269.1 & 271.1 (M+H+).
Intermediate B-18 N-(4-Bromo-6,7-dihydro-5H-Pipyrindin-7-y1)-propionamide Br fA] Ethyl 3-(3,5-dibromopyridin-4-yl)propanoate co Br.U,Br Asolution of 3,5-dibromo-4-methylpyridine (20 g, 0.08 mol) in THF (50 mL) was added over a period of 1 hour to a solution of LDA (0.088 mol) [generated from N,N- diisopropylamine (8.9 g, 0.088 mol) and n-butyllithium (35 mL, 0.088 mol, 2.5 Min hexane) in 400 mL THF] at -78 C. The resulting dark red solution was stirred at -78 C for 30 min before ethylbromoacetate (33.4 g, 0.2 mol) in THF (50 mL) was added over a period of 30 min. The reaction mixture was stirred for an additional 2.5 hour at -78 C before 10% AcOH was added (resulting in a pH = 4-5). The reaction mixture was then allowed to warm up to room temperature. After evaporation of the solvents, the residue was poured into satd. aq. NaHCO3 solution and extracted with Et0Ac (100 mL x 3). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound (9 g, 33.5 %) as a yellow solid. MS: 337.7(M+H, 2Br). fB1 4-Bromo-5H-cyclopenta[c]pyridin-7(6H)-one Br CO
To a solution of ethyl 3-(3,5-dibromopyridin-4-yl)propanoate (4 g, 11.9 mmol) in THF (60 mL) was slowly added n-BuLi (9.52 mL, 23.8 mmol, 2.5 M in hexane) while keeping the WO2013/079452 PCT/EP2012/073653 - 185 - inner temperature below -70 C. After the addition, the reaction mixture was stirred below -65 C for additional 2 hours. The reaction was quenched with water and then extracted with Et0Ac (100 ml. x 3). The combined organic layers were dried over anhy.
Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by column .. chromatography to afford the title compound (1.2 g, 47.6%) as a solid. MS:
MS: 213.7 (M+H', 1Br). [C] 4-Bromo-6,7-dihydro-5H-[2]pyrindin-7-ylamine CH1COONH4 (4.8 g, 62 mmol), NaCNBH3(315 mg, 5 mmol) and 4-bromo-5H- cyclopenta[c]pyridin-7(6H)-one (1.0 g, 4.15 mmol) in Et0H (10 mL) was added to a sealed microwave vial. The mixture was subject to microwave radiation at 130 Cfor 4 min. After the majority of Et0H was evaporated under reduced pressure, it was treated with aq. 2 N NaOH until pH >10 and extracted with Et0Ac (50 mL x2). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude title product (800 mg) which was used in the next step reaction without further purification. MS: 212.9 (M+H+, 1Br).
ID] N-(4-Bromo-6,7-dihydro-5H-cyclopentarclpyridin-7-y1)propionamide 0 BrN) To a solution of 4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (650 mg, 3.05 mmol, 65% purity) and Et3N (400 mg, 3.97 mmol) in THF (20 mL) was added propionyl chloride (219 mg, 2.38 mmol) at 0 C and stirring continued for 2 hours. Water (10 mL) and Et0Ac (10 mL) were added and the aqueous layer was extracted with Et0Ac (10 mL x3). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated WO2013/079452 PCT/EP2012/073653 - 186 - in vacuo to give a crude product which was purified by column chromatography to afford the title compound (200 mg, 37.6%) as a white solid. MS: 270.9 (M+H+, 1Br).
Intermediate B-19 N-(4-Bromo-6,7-dihydro-5H421pyrindin-7-y1)-acetamide 0 Br IrYLN) In analogy to the procedure describe for the preparation of intermediate B-18 (step D), the title compound was obtained as a white solid using acetyl chloride as starting material.
MS: 256.9 (M+FL, 1Br).
Example 1 6-Chloro-2-pyridin-3-y1-3,4-dihydro-211-isoquinolin-1-one In a sealed tube, 3-bromopyridine (0.1 g, 0.633 mmol) was combined with 6- chloro-3,4- dihydroisoquinolin-1(2H)-one (intermediate A-2) (0.115 g, 633 mmol), copper (I) iodide (0.012 g, 0.063 mmol), potassium carbonate (0.175 g, 1.27 mmol) and /V,N'- dimethylethylenediamine (0.013g, 0.127 mmol) in 1,4-dioxane (2 mL). The reaction mixture was heated at 110 C over night. The mixture was cooled to room temperature, filtered through dicalitc and washed with DCM. The residue was purified by silica gel flash chromatography eluting with a 5 to 100% Et0Ac-heptane gradient to give the title compound (0.107 g, 65 %) as a white solid. MS: 259.1 (M+H+).
Example 2 5-(6-Chloro-l-oxo-3,4-dihydro-1H-isoquinolin-2-y1)-nicotinonitrile CI
N 0 6-Chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36 mg, 0.2 mmol), 5- bromo-nicotinonitrile (73 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S, 25)- cyclohexane- 1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 150 'V for 2.5 hours before it was poured into H20 (50 mL) and extracted with Et0Ac (2x 25 mL).
The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (15 mg, 26%) as a white solid. MS: 284.1 (M+H+).
Example 3 6-Chloro-2-(5-hydroxymethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-l-one CI
OH 0 [A] (5-Bromo-pyridin-3-y1)-methanol OH
Sodium borohydride (2.2 g, 59.1 mmol) was added at 0 C to a suspension of 5- bromo- pyridine-3-carbaldehyde (10.0 g, 53.7 mmol) in Me0H (100 mL). The mixture was stirred at 0 C for 1 hour before it was quenched by addition of water (5.0 mL).
Evaporation of WO2013/079452 PCT/EP2012/073653 - 188 - solvents afforded a light yellowish oil which was re-dissolved in Et0Ac and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (9.6 g, 95%) as colorless oil. MS: 188.0 & 190.0 (M+H+). {B] 6-Chloro-2-(5-hydroxymethyl-pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1-one CI
In a 25 niL sealed tube, (5-bromo-pyridin-3-y1)-methanol (900 mg, 4.8 mmol), 6- chloro- 3,4-dihydro-2H-isoquinolin-1 -one (intermediate A-2) (800 mg, 4.4 mmol), Cut (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (8.0 mL). The resulting reaction mixture was heated at 150 C for 3 hours before it was poured into H20 (50 naL) and extracted with Et0Ac (2 x 125 naL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% Et0Ac-hexane gradient) to yield the title compound (1.1 g, 90%) as a light yellow solid. MS: 289.2 (M+H+).
The following compounds listed in Table 1 were prepared in analogy to the procedures described for the preparation of examples 1, 2 or 3[B] using appropriate starting materials.
Table 1 Prepared MS
Compound Compound Starting by Ex Name Structure Materials analogy to (M+H)+ example Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(5-chloro-pyridin-3 -y1)-3 ,4- dihydro-2H-i soquino lin-1-one 6-Chloro-3,4-CI dihydro-2H- isoquinolin-l-one 2 (intermediate A-2) and 1-bromo-3- 0 chloro-benzene 293.1 6-Chloro-2-(5 -fluoro-pyri din-3 -y1)-3,4- dihydro-2H-isoquino lin-1-one 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one 3 [B] (intermediate A-2) and_3 -bromo-5 - 0 =N fluoro-pyridine 277.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(4-chloro-pyridin-3-y1)-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- a dihydro-2H-CI isoquinolin-l-one 2 .ouN (intermediate A-2) and 3-bromo-4- 0 chloro-pyridine 293.1 2-(5-Bromo-pyridin-3-y1)-6-chloro-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one 2 (intermediate A-2) and 3-bromo-5- 0 iodo-pyridine 337.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(5-methyl-pyridin-3-y1)-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3,4-CI dihydro-2H- isoquinolin-l-one 3[B]
NW(intermediate A-2) and 3-bromo-5- methyl-pyridine 273.1 5-(6-Chloro-1-oxo-3,4-dihydro-1H- isoquino1in-2-y1)-pyridinc-3-carbaldehyde 6-Chloro-3,4- dihydro-2H-CI isoquinolin-1-one (intermediate A-2) 2 0,1 0 and 5-bromo-N pyridine-3- carbaldehyde 287.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+II)+ to example 6-Chloro-2-(5-methoxy-pyridin-3-y1)-3,4- dihydro-2H-isoquinolin-l-one CI40 6-Chloro-3,4- dihydro-2H- 0 isoquinolin-l-one 1 (intermediate A-2) and 3-bromo-5- methoxy-pyridine 6-Chloro-2-(5-isopropoxy-pyridin-3-y1)-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one 2 (intermediate A-2) and 3-bromo-5- 0 isopropoxy-pyridine 317.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(1-hydroxy-1-methyl-ethyl)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- 6-Chloro-3,4- one dihydro-2H-CIisoquinolin-l-one (intermediate A-2) 2 OHand 2-(5-bromo- pyridin-3-y1)- 0 propan-2-ol 317.2 6-Chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3- y1]-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CIisoquinolin-l-one (intermediate A-2) 2 :211 OHand 1-(5-bromo- 0 ethanol 303.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-((R)-1-hydroxy-ethyp-pyridin- 3-y1]-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-1 -one (intermediate A-2) 2 741 OHand (R)-1-1-(5- bromo-pyridin-3- =N y1)-ethanol 303.1 6-Chloro-2-[54(S)-1-hydroxy-ethyl)-pyridin- 3-y1]-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-1 -one F. (intermediate A-2) 2 OHand (S)-1-1-(5- 0 bromo-pyridin-3- y1)-ethanol 303.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(1-methoxy-ethyl)-pyridin-3- y1]-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-l-one (intermediate A-2) 2 and 3-bromo-5-(1- 0 methoxy-ethyl)- pyridine 317.2 2-(5-Aminopyridin-3-y1)-6-chloro-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one 2 N H2 (intermediate A-2) and 5-bromo- 0 pyridin-3-ylamine 274.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(2,2,2-trifluoro-1-hydroxy- ethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CIisoquinolin-l-one (intermediate A-2) 2 and 1-(5-bromo-OH pyridin-3-y1)-2,2,2- 0 trifluoro-ethanol 357.2 6-Chloro-215-(2,2,2-trifluoro-1-methoxy- ethyl)-pyridin-3-y1]-3,4-dihydro-2H- 6-Chloro-3,4- isoquinolin-1-one dihydro-2H- isoquinolin-1-one CI F F(intermediate A-2) 2 and 3-bromo-5-N 0 (2,2,2-trifluoro-1- 0 methoxy-ethyl)- pyridine 371.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example 6-Chloro-245-(cyclopropyl-hydroxy-methyp- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- 6-Chloro-3,4- one dihydro-2H- isoquinolin-l-one CI (intermediate A-2) 2 IIIIand (5-bromo-N.N.c,N)3,,.
OHpyridin-3-y1)-Ocyclopropyl- methanol 329.2 6-Chloro-245-(cyclopropyl-methoxy-methyl)- pyridin-3-y11-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H-CI Visoquinolin-l-one (intermediate A-2) ;11 o--/- and 3-bromo-5- 0 2 (cyclopropyl- methoxy-methyl)- pyridine 343.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(4-trifluoromethyl-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one CI10 6-Chloro-3,4- dihydro-2H-Nisoquinolin-l-one (intermediate A-2) 3[13] iI and 3-bromo-4- 0 Ntrifluoromethyl- pyridine 327.1 6-Chloro-245-(2-hydroxy-ethyl)-pyridin-3- y11-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one OH(intermediate A-2) 2 `Al 0 and 2-(5-bromo-V pyridin-3-y1)- 303.1 ethanol SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(1-methoxy-1-methyl-ethyl)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-1-one (intermediate A-2) 2 0 and 3-bromo-5-(1- methoxy-1-methyl- ethyl)-pyridine 331.2 Ethanesulfonic acid [5-(6-chloro-1-oxo-3,4- dihydro-1H-isoquinolin-2-y1)-pyridin-3- 6-Chloro-3,4- ylmethy1}-amide dihydroisoquinolin- 1(21/)-one CI(intermediate A-2) and ethanesulfonic Racid (5-bromo- pyridin-3- ylmethyp-amide (intermediate B-7) 380.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example 6-Chloro-2-[5-(2-oxo-pyrrolidin-l-y1)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- 6-Chloro-3,4- one dihydroisoquinolin- 1(211)-one CI (intermediate A-2) 1 Iand 1-(5-bromo-N-111R 0 ridin-3- 1 PY-Y) 0 pyrrolidin-2-one (intermediate B-9) 342.0 6-Chloro-2-(1-methyl-1H-pyrazolo[3,4- cipyridin-4-y1)-3,4-dihydro-2H-isoquinolin-l- one 6-Chloro-3,4- dihydroisoquinolin-C I Iso 1(2H)-one (intermediate A-2) 0 1 and 4-bromo-l-NI
NNmethyl-1H- pyrazolo[3,4- c]pyridine 313.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-8'-hydroxy-3,4,5',6',7',8'-hexahydro- 6-Chloro-3,4- [2,41biisoquinoliny1-1-one dihydroisoquinolin- 1(2H)-one CI (intermediate A-2) and 4-bromo- 1 0 OH5,6,7,8- tetrahydroisoquinoli n-8-ol (intermediate B-11) 329.1 6-Chloro-3,4-N-(6-Chloro-1-oxo-3,4,5',6',7',8'-hexahydro- dihydroisoquinolin- 1H-[2,4"ibiisoquinoliny1-8'-y1)-propionamide 1(211)-one (intermediate A-2) CI 0 and N-(4-bromo- iriiiIii1 cl NTcliFli/L/ 5,6,7,8- tetrahydroisoquinoli 0 ...- n-8- yl)propionamide 384.1 (intermediate B-12) SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2- {5- [hydroxy-(1-methyl- 1 H- imidazol-2-y1)-methyl]-pyridin-3-y1}-3,4- 6-Chloro-3,4- dihydro-2H-isoquinolin-1-one dihydro-2H- isoquinolin-l-one CI
OH (intermediate A-2) / and (5-bromo- 3[13]
I I1 pyridin-3-y1)-(1-N 0 methyl-1 H- imidazol-2-y1)- 369.1 methanol 6-Chloro-2-{5-[(3,4-difluoro-pheny1)- hydroxy-methyl]-pyridin-3-y1}-3,4-dihydro- 6-Chloro-3,4- 2H-isoquinolin-1-one dihydro-2H- isoquinolin-l-one CI (intermediate A-2) 3[13]
Fand (5-bromo- -., ZcI pyridin-3-y1)-(3,4- 0 Fdifluoro-pheny1)- methanol 401.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-{5-[(3,5-difluoro-pheny1)- hydroxy-methy1]-pyridin-3-y1}-3,4-dihydro- 6-Chloro-3,4- 2H-isoquinolin-1-one dihydro-2H- isoquinolin-1-one CI (intermediate A-2) 3[B] ru Fand (5-bromo- ,,,. pyridin-3-y1)-(3,5- 0 difluoro-pheny1)- methanol 401.1 6-Chloro-2-15-[(4-ethyl-pheny1)-hydroxy- methy1]-pyridin-3-341-3,4-dihydro-2H- 6-Chloro-3,4- isoquinolin-1-one dihydro-2H- isoquinolin-l-one CI (intermediate A-2) 3[B] and (5-bromo- =,,, pyridin-3-y1)-(4- 0 ethyl-phenyl)- methanol 393.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-245-(hydroxy-phenyl-methyl)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- 6-Chloro-3,4- one dihydro-2H- isoquinolin-l-one CI
OH(intermediate A-2) 3[B] and (5-bromo- pyridin-3-y1)- 0 phenyl-methanol 365.1 6-Chloro-2-[5-(1-hydroxy-1-phenyl-ethyl)- pyridin-3 -yl] -3 ,4-dihydro-2H-i soquinol in-1- 6-Chloro-3,4- one dihydro-2H- isoquinolin-l-one CI (intermediate A-2) 3[B] and 1-(5-bromo- ,, pyridin-3 -y1)-1- 0 phenyl-ethanol 379.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2- { 5-[1 -(3,4-difluoro-pheny1)- 1- hydroxy-ethyl] -pyridin-3 -y11-3 ,4-dihydro-2H- 6-Chloro-3,4- isoquinolin-1-one dihydro-2H- isoquinolin-1-one Cl (intermediate A-2) OH3[B] and 1-(5-bromo-N pyridin-3-y1)-1- 0 F(3,4-difluoro- pheny1)-ethanol 415.1 6-Chloro-2- {5 41-(3,5-difluoro-pheny1)-1- hydroxy-ethy1]-pyridin-3 -y11-3,4-dihydro-2H- , A 11-1,-,111%-l1el- isoquinolin- 1-one di hydro-2H- isoquinolin-l-one CI
OH(intermediate A-2) 3 [B] et-d and 1-(5-bromo- pyridin-3 -y1)-1- 0 (3 ,5-difluoro- pheny1)-ethanol 415.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stueture Starting Materials analogy Ex MS (M-I-H) to example 6-Chloro-2-(6-methyl-pyrazin-2-y1)-3,4- dihydro-2H-isoquinolin-1-one 01 6-Chloro-3,4- dihydro-2/1-N Nisoquinolin-l-one 3[B] (intermediate A-2) 0 and 2-bromo-6-N methyl-pyrazine 274.1 6-Chloro-245-(morpholine-4-carbony1)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- 6-Chloro-3,4- one dihydro-2H-CIisoquinolin-l-one 0 (intermediate A-2) rs1 2 and (5-bromo- 0 morpholin-4-yl- 372.1 methanone SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(3-hydroxy-pyrrolidine-1- carbony1)-pyridin-3-y1]-3,4-dihydro-2H- 6-Chloro-3,4- isoquinolin-1-one dihydro-2H-CIisoquinolin-l-one 0 (intermediate A-2) Na_a_ and (5-bromo- 2 0 pyridin-3-y1)-(3- hydroxy-pyrrolidin- 372.1 1-y1)-methanone 5-(6-Chloro-1-oxo-3,4-dihydro-1H- isoquinolin-2-y1)-N,N-dimethyl-nicotinamide 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one NN====='N¨,-)IN"N---".. (intermediate A-2) .. 2 and 5-bromo-N, N- 0 dimethyl- nicotinamide 330.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(pyrrolidine-1-carbony1)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H-CIisoquinolin-l-one 0 (intermediate A-2) 2 Nand (5-bromo- 0 pyridin-3-y1)- pyrrolidin-1-yl- methanone 356.2 5-(6-Chloro-l-oxo-3,4-dihydro-1 H- isoquinolin-2-y1)-N-methyl-nicotinamide 6-Chloro-3,4-CIdihydro-2H- 0 isoquinolin-l-one (intermediate A-2) 2 '41 and 5-bromo-N- 0 methyl- nicotinamide 316.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 5-(6-Chloro-1-oxo-3,4-dihydro-1H- isoquinolin-2-y1)-N-cyclopropyl-nicotinamide 6-Chloro-3,4-CIdihydro-2 H-O isoquinolin-l-one (intermediate A-2) 2 and 5-bromo-N-Ne cyclopropyl- 342.2 nicotinamide 5-(6-Chloro-1-oxo-3,4-dihydro-1H- isoquinolin-2-y1)-N-(4-fluoro-pheny1)- 6-Chloro-3,4- nicotinamide dihydro-2H- isoquinolin-l-one CI 0 (intermediate A-2) '41 and 5-bromo-N-(4- 2 H 0 fluoro-pheny1)- nicotin 396.0 amide SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 5-(6-Chloro-1-oxo-3,4-dihydro-1H- isoquinolin-2-y1)-N-phenyl-nicotinamide 6-Chloro-3,4-CIdihydro-2H- 0 isoquinolin-l-one (intermediate A-2) 2 0 and 5-bromo-N- phenyl- 378.2 nicotinamide 6-Chloro-245-(4,4-difluoro-piperidine-1- carbony1)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CIisoquinolin-l-one 0 I1 III II:IN (intermediate A-2) 2 NI and (3-bromo- 0 pheny1)-(4,4- difluoro-piperidin- l-y1)-methanone 406.2 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-((S)-2-methoxymethyl- 6-Chloro-3,4- pyrrolidin-1-ylmethyl)-pyridin-3-y1]-3,4- dihydro-2H- dihydro-2H-isoquinolin-1-one isoquinolin-1-one (intermediate A-2) CI and 3-bromo-5-((S)- 1 `41 0 2-methoxymethyl-N pyrrolidin-l-Nw ylmethyl)-pyridine (intermediate B-6) 386.3 6-Chloro-2-[5-((S)-2-methoxymethyl- 6-Chloro-3,4- pyrrolidin-1-y1)-pyridin-3-y1]-3,4-dihydro-2H- dihydro-2H- isoquinolin-1-one isoquinolin-1-one (intermediate A-2) CI and 3-bromo-5-((S)- 1 2-methoxymethyl- pyrrolidin-1 -y1)- 0 0 pyridine (intermediate B-10) 372.0 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[54(S)-2-hydroxymethy1-5-oxo- 6-Chloro-3,4- pyrrolidin-1-y1)-pyridin-3-y1]-3,4-dihydro-2H- dihydro-2H- isoquinolin-1-one isoquinolin-l-one CI0 (intermediate A-2) OHand (S)-1-(5-bromo- 1 pyridin-3-y1)-5- hydroxymethyl- pyrrolidin-2-one (intermediate B-8) 372.0 6-Chloro-2-pyrimidin-5-y1-3,4-dihydro-2H- isoquinolin-l-one 0i 40 6-Chloro-3,4- dihydro-2H-Nisoquinol in-1-one 3[B] hi I (intermediate A-2) 0 õ,..= and 5-bromo-Npyrimidine 260.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-pyridazin-3-y1-3,4-dihydro-2H- isoquinolin-1-one CI6-Chloro-3,4- dihydro-2H- isoquinolin-1-one 2 trAl "==,. (intermediate A-2) and 3-bromo- pyridazine 260.1 6-Chloro-2-p-yridin-3-y1-2H-isoquinolin-l-one CI6-Chloro-2H- isoquinolin-1-one (intermediate A-6) 3[B] fi21 and 3-bromo- pyridine 257.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example 6-Chloro-2-(5-fluoro-pyridin-3-y1)-2H- isoquinolin-1-one CI6-Chloro-2H- isoquinolin-1-one al (intermediate A-6) 3[B] and 3-bromo-5- 0 fluoro-pyridine 275.1 6-Chloro-2-[4-(1-hydroxy-ethyl)-pyridin-3- y1]-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4-CI10 OH dihydro-2H- isoquinolin-1-one (intermediate A-2) 2 and 1-(3-bromo- pyridin-4-y1)- 0 ethanol 303.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(4-hydroxymethyl-pyridin-3-y1)- 3,4-dihydro-211-isoquinolin-1-one; compound with trifluoro-acetic acid 6-Chloro-3,4-OH dihydro-2H-CI isoquinolin-1-one 0 N(intermediate A-2) 2 and (3-bromo-4-Fpyridin-4-y1)- methanol 0 289.1 2-[5-(1-Amino-cyclopropy1)-pyridin-3-y11-6- chloro-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2 H-CI isoquinolin-l-one (intermediate A-2) 2 and 1-(5-bromo-N H2 0 pyridin-3-y1)- cyclopropylamine 314.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M-FH)+ to example 6-Chloro-2-[5-(4-methy1-4H11,2,4]triazol-3- y1)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin- 6-Chloro-3,4- 1-one dihydro-2H- isoquinolin-l-one CI
N---N (intermediate A-2) 2 491 N and 3-bromo-5-(4-I\ methy1-4H- 0 [1,2,4]triazol-3-y1)- pyridine 339.2 6-Chloro-2-(5-methylsulfanyl-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-l-one (intermediate A-2) 2 ml and 3-bromo-5- 0 methylsulfanyl- pyridine 305.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(5-difluoromethoxy-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-l-one Si (intermediate A-2) 2 and 3-bromo-5-Fdifluoromethoxy- pyridine 325.1 6-Chloro-2-(4-dimethoxymethyl-pyridin-3- y1)-3,4-dihydro-2H-isoquinolin-1-one 1 0 0 dihydro-2H- 6-Chloro-3,4-CIle ./' isoquinolin-l-one (intermediate A-2) 2 and 3-bromo-4- 1 dimethoxymethyl- 0 Npyridine 333.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (IVI+H)+ to example 6-Chloro-2-[5-fluoro-4-(1-hydroxy-ethyl)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H-CIisoquinolin-l-one ru (intermediate A-2) 2 Fand 1-(3-bromo-5- fluoro-pyridin-4- 0 y1)-ethanol 321.1 6-Chloro-2-{4-[(4-fluoro-pheny1)-hydroxy- methy1]-pyridin-3-y11-3,4-dihydro-2H- isoquinolin-1-one 6-Chloro-3,4- dihydro-2H- isoquinolin-1-one CI HO(intermediate A-2) 2 :21 and (3-bromo-Npyridin-4-y1)-(4- fluoro-pheny1)- 0 methanol 383.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stueture Starting Materials analogy Ex MS (M-i-H)+ to example 6-Chloro-2-[4-(1-methoxy-ethyp-pyridin-3- y1]-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoqumolin-l-one (intermediate A-2) 2 and 3-bromo-4-(1- methoxy-ethyl)- 0 pyridine 317.1 6-Chloro-2-(1-methyl-1H-pyrrolo[3,2- c]pyridin-7-y1)-3,4-dihydro-2H-isoquinolin-1- one 6-Ch1oro-3,4- dihydro-2H- isoquinolin-1-one CIop \ N (intermediate A-2) :21 Nand 7-bromo-1- 2 methyl-1H- pyrrolo[3,2-c]- =N pyridine 312.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(5-cyclopropyl-pyridin-3-y1)-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2 H-CI isoquinolin-l-one (intermediate A-2) 2 and 3-bromo-5- cyclopropyl- pyridine 299.1 6-Chloro-245-(2-methy1-21-141,2,41triazol-3- y1)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin- 6-Chloro-3,4- 1-one dihydro-2H- isoquinolin-l-one CI(intermediate A-2) 3[B]
N I2\1 and 3-bromo-5- (2- \ N methy1-2H-I\ 0 [1,2,4]triazol-3- y1)- pyridine 340.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(5-cyclopropoxy-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-l-one I(intermediate A-2) 2 and 3-bromo-5- 0 cyclopropoxy- pyridine 315.1 6-Chloro-2-(4-methoxymethyl-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2 H-CIis 0 isoquinolin-l-one (intermediate A-2) 2 S I
N= and 3-bromo-4- methoxymethyl- 0 pyridine N 303.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound NameiStucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-fluoro-4-(1-hydroxy-1-methyl- ethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one 6-Chloro-3,4- dihydro-2H- 01 isoquinolin-l-one (intermediate A-2) 2 PI
N\ F and 2-(3-bromo-5- 0 Ifluoro-pyridin-4- y1)-propan-2-ol 335.1 6-Chloro-2-[5-(5-methyl-pyrazol-1-ylmethyp- pyridin-3-y11-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H- isoquinolin-l-one CI (intermediate A-2) 3[B] '7-1 NI and 3-bromo-5-(5- methyl-pyrazol-1- 0 ylmethyl)-pyridine 353.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(1H-pyrrolo[3,2-e]pyridin-7-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-l-one (intermediate A-2) 2 Pi] and 7-bromo-1H- pyrrolo[3,2- 0 c]pyridine 298.1 6-Chloro-3,4-dihydro-[2,4']biisoquinoliny1-1- one 6-Chloro-3,4-CIdihydro-2H- isoquinolin-1-one 3[B]
PI(intermediate A-2) and 4-bromo- isoquinoline 309.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example 3-(6-Chloro-l-oxo-3,4-dihydro-1H- i soquinolin-2-y1)-isonicotinonitrile 6-Chloro-3,4-Ci I I dihydro-2 H- isoquinolin-1-one T-11 N (intermediate A-2) 2 0 and 3-bromo- ,,. 7 isonicotinonitrile 284.1 6-Chloro-2-(5-fluoro-4-methoxymethyl- pyridin-3-y1)-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H- isoquinolin-1-one 01 0 (intermediate A-2) and 3-bromo-5- 2 N Ffluoro-4- methoxymethyl- 0 N pyridine 321.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-fluoro-4-(1-methoxy-ethyl)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4- dihydro-2H-CIisoquinolin-l-one (intermediate A-2) 2 NI
N Fand 3-bromo-5- fluoro-4-(1- 0 methoxy-ethyl)-Npyridine 335.1 6-Chloro-2-(4-isopropoxymethyl-pyridin-3- y1)-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-CI isoquinolin-1-one NI N(intermediate A-2) 2 and 3-bromo-4- 0 isopropoxymethyl-N pyridine 333.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example 6-Chloro-244-(cyclopropyl-methoxy-methyl)- pyridin-3-y1]-3,4-dihydro-2H-isoquinolin-1- one 6-Chloro-3,4-Pdihydro-2H- iso uinolin-l-one CIle 0 \ (intermediate A-2) 2 and 3-bromo-4-N(cyclopropyl- methoxy-methyl)- 0 pyridine 343.1 6-Chloro-2-[5-(3,5-dimethy1-1H-pyrazol-4- y1)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin- 6-Chloro-3,4- 1-one dihydro-2H- isoquinolin-l-one CI
NH(intermediate A-2) 3[B] and 3-bromo-5- (3,5-dimethy1-1 H-Opyrazol-4-y1)- pyridine 353.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(3,5-dimethy1-3H-imidazol-4- y1)-pyridin-3-y1]-3,4-dihydro-2H-isoquinolin- 6-Chloro-3,4- 1-one dihydro-2H- isoquinolin-l-one CI
Noci (intermediate A-2) 3[B]
N Iand 3-bromo-5-N\ (3,5-dimethy1-3 H-I 0 imidazol-4-y1)- pyridine 353.1 6-Chloro-245-(1,1-dioxo-1X6-[1,2]thiazinan- 2-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- 6-Chloro-3,4- isoquinolin-1-one dihydro-2H- isoquinolin-l-one CI Hoo (intermediate A-2) 0 and 2-(5-bromo- 1 COI Npyridin-3- 0 ylmethyl)- [1,2]thiazinane 1,1- dioxide (intermediate B-13) 406.3 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-[5-(1,1-dioxo-116-isothiazolidin- 2-ylmethyl)-pyridin-3-y1]-3,4-dihydro-2H- isoquinolin-1-one 6-Chloro-3,4- dihydro-2H-C I401 isoquinolin-l-one (intermediate A-2) --- 0 0 S and 3-bromo-5- 1 0 isothiazolidin-2- ylmethyl)-pyridine (intermediate B-14) 392.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-3,4- dihydro-2H- isoquinolin-1-one (intermediate A-2) and (S)-1-(5-bromo- pyridin-3- ylmethyl)-5-(tert- butyl-dimethyl- 6-Chloro-2-[5-((S)-2-hydroxymethy1-5-0x0- silanyloxymethyl)- pyrrolidin-l-ylmethyl)-pyridin-3-y1]-3,4- pyrrolidin-2-one dihydro-2H-isoquinolin-1-one (intermediate B-15) to 2- {5-[(S)-2-(tert-C I Iso butyl-dimethyl- )õ...40/H silanyloxymethyl)- 0 1 5-oxo-pyrrolidin-l- ylmethy1]-pyridin-Nw 3-yll -6-chloro -3,4- dihydro-2H- isoquinolin-l-one 386.0 (light brown amorphous solid, MS: 500.3, 502.3 (M+H+)) and subsequent removal of the protecting group (4M HC1 in dioxane, Me0H 2h, RT). ________________ SUBSTITUTE SHEET (RULE 26) _______________________ Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example (S)-1-[5-(6-Chloro-l-oxo-3,4-dihydro-1H- i soquinolin-2-y1)-pyridin-3-ylmethyl]- 6-Chloro-3,4- pyrrolidine-2-carboxylic acid methyl ester dihydro-2H- isoquinolin-1-one CI (intermediate A-2) 0 and (S)-1-(5-bromo- p 1 0 ylmethyl)- yridin-3- pyrrolidine-2-N carboxylic acid methyl ester 400.0 (intermediate B-16) 6-Chloro-2-(5-methoxy-pyridin-3-y1)-3- methyl-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3-methyl-CI3,4-dihydro-2H- xxi isoquinolin-1-one Ord (intermediate A-3- 3[B] 1) and 3-bromo-5- 0 methoxy-pyridine 303.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-2-(5-hydroxymethyl-pyridin-3-y1)- 3-methy1-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3-methyl-CI3,4-dihydro-2H- isoquinolin-1-one N.õ..,/"..2=k.,=,,/*"..01.i (intermediate A-3- 3[B] a 1) and (5-bromo- 0 pyridin-3-y1)- methanol 303. 1 6-Chloro-2-[5-(2-isopropyl-imidazol-1- ylmethyl)-pyridin-3-y1]-3-methy1-3,4-dihydro- 6-Chloro-3-methy1- 2H-isoquinolin-1-one 3,4-dihydro-2H- isoquinolin-1-one CI (intermediate A-3- 1) and 3-bromo-5- 3[B]
NI (2-isopropyl- 0 imidazol-1- ylmethyl)-pyridine 395.3 (intermediate B-1) SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-3-methy1-2-pyridin-3-y1-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3-methyl-C1 40 3,4-dihydro-2H- isoquinolin-1-one rel (intermediate A-3- 3[B] 1) and N 3-bromo- pyridine = 273.1 6-Chloro-2-(5-fluoro-pyridin-3-y1)-3-methyl- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-3-methyl-C1 10 3,4-dihydro-2H- isoquinolin-1-one at'D' N F (intermediate A- 3- 3[B] 1) and 3-bromo-5- 0 fluoro-pyridine 291.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Chloro-3-methy1-2-pyrimidin-5-y1-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-3-methyl-CIop 3,4-dihydro-2H- isoquinolin-1-one (intermediate A-3- 3[B]
I1) and 5-bromo- pyrimidine 274.1 (R)-6-Chloro-3-methy1-2-pyridin-3-y1-3,4- dihydro-2H-isoquinolin-1-one (R)-6-Chloro-3-CI10 methy1-3,4-dihydro- 2H-isoquinolin-1- gl one (intermediate 3[B]
A-3-1a) and 3- 0 bromo-pyridine 273.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example (S)-6-Chloro-3-methy1-2-pyridin-3-y1-3,4- dihydro-2H-isoquinolin-1-one (S)-6-Chloro-3-Cmethy1-3,4-dihydro- 2H-isoquinolin-1- one (intermediate 3[B]
A-3-1b) and 3- bromo-pyridine 273.1 8-Chloro-3-methy1-2-pyridin-3-y1-3,4- dihydro-2H-isoquinolin-1-one 8-Chloro-3-methyl- 3,4-dihydro-2H- isoquinolin-1-one 1110 N (intermediate A-3- 3 [B] 2) and 3-bromo-C I0 pyridine 273.1 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H)+ to example 6-Methoxy-2-pyridin-3-y1-3,4-dihydro-2H- isoquinolin-1-one 0 0 6-Methoxy-3,4- dihydroisoquinolin- 1(2H)-one and 3- 1 bromopyridine 255.2 5,6-Dichloro-2-pyridin-3-y1-3,4-dihydro-2H- isoquinolin-1-one CI 5,6-Dichloro-3,4-CIis dihydroisoquinolin- 1 CC,1 1(21-1)-one and 3- iodopyridine 0 293.0 SUBSTITUTE SHEET(RULE 26) Prepare d by Compound Name/Stucture Starting Materials analogy Ex MS (M+H) to example 2-Chloro-6-(5-methoxy-pyridin-3-y1)-7,8- dihydro-6H-[1,6]naphthyridin-5-one 2-Chloro-7,8- dihydro-6H-CI [1,6]naphthyridin-5- one (intermediate 2 egl .
A S) and 3-bromo- 5-methoxy-pyridine 0 290.2 2-Methoxy-6-(5-methoxy-pyridin-3-y1)-7,8- dihydro-61-141,6inaphthyridin-5-one 2-Methoxy-7,8- dihydro-6H- [1,6]naphthyridin-5- one (intermediate 2 A-9) and 3-bromo- 5-methoxy-pyridine 286.2 SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 236a -Prepare d by Ex Compound Name/Stucture Starting Materials analogy to example 2-Methoxy-6-pyridin-3-y1-7,8-dihydro-6H- [1,6]naphthyridin-5-one 2-Methoxy-7,8- dihydro-6H- [1,6]naphthyridin-5- one (intermediate A- 3[8] 9) and 3-bromo- pyridine 0 256.1 1 I
SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 236b - 6-Chloro-5-fluoro-2-(5-methoxy-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-5-fluoro- 3,4-dihydro-2H-CI isoquinolin-1-one (intermediate A-1) 2 '&1 and 3-bromo-5- methoxy-pyridine 0 307.1 6-Chloro-7-fluoro-2-(5-methoxy-pyridin-3-y1)- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-7-fluoro-CI3,4-dihydro-2H- isoquinolin-1-one 2 '81 N 0 (intermediate A-7) F and 3-bromo-5- 0 methoxy-pyridine 307.1 SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 236c - 6-Chloro-7-fluoro-2-pyridin-3-y1-3,4-dihydro- 2H-isoquinolin-l-one 6-Chloro-7-fluoro-CI3,4-dihydro-2H- isoquinolin-l-one N(intermediate A-7) 2 and 3-bromo- pyridine N 277.1 6-Chloro-4,4-dimethy1-2-pyridin-3-y1-3,4- dihydro-2H-isoquinolin-1-one 6-Chloro-4,4-CL_A dihydro-2H-Nisoquinolin-1-one 3[B] (intermediate A-5) 0 and 3-bromo-Npyridine 287.2 SUBSTITUTE SHEET(RULE 26) WO2013/079452 PCT/EP2012/073653 - 236d - 6-Chloro-2-(5-methoxy-pyridin-3-y1)-4,4- dimethy1-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-4,4-CIdimethy1-3,4- dihydro-2H- isoquinolin-1-one 3[13] (intermediate A-5) 0 and 3-bromo-5- methoxy-pyridine 317.2 6-Chloro-2-(5-fluoro-pyridin-3-y1)-4,4- dimethy1-3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-4,4-CIdimethy1-3,4- dihydro-2H- isoquinolin-l-one 3[13] (intermediate A-5) 0 and 3-bromo-5-Nfluoro-pyridine 305.2 SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 236e - 6-Chloro-4-methy1-2-pyridin-3-y1-3,4- dihydro-2H-isoquinolin-1-one C1 6-Chloro-4-methyl- 3,4-dihydro-2H- isoquinolin-1-one 3[B] (intermediate A-4) and 3-bromopyridine 0 273.1 6-Chloro-2-(5-fluoro-pyridin-3-y1)-4-methyl- 3,4-dihydro-2H-isoquinolin-1-one 6-Chloro-4-methyl- 3,4-dihydro-2H-CI isoquinolin-l-one (intermediate A-4) 3[B] and 3-bromo-5- 0 fluoro-pyridine 291.1 SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 236f - 6-Chloro-2-(5-methoxy-pyridin-3-y1)-4- methy1-3,4-dihydro-2H-isoquinolin-l-one 6-Chloro-4-methyl-CIel 3,4-dihydro-2H- isoquinolin-1-one (intermediate A-4) 3[13] and 3-bromo-5- 0 methoxy-pyridine 303.2 5-Chloro-2-pyridin-3-y1-2,3-dihydro-isoindol- 1-one CI 5-Chloro-2,3- dihydro-isoindol-1- 1 El 11 one and 3-Niodopyridine 0 N 245.1 SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 236g - 5-Chloro-2-[5-(2-isopropyl-imidazol-1- ylmethyl)-pyridin-3-y1]-2,3-dihydro-isoindol- 1-one 5-Chloro-2,3-CI dihydro-isoindo1-1- one and 3-bromo-5- 0 (2-isopropyl- 1 imidazol-1-N ylmethyp-pyridine ,N (intermediate B-1) 367.0 5-Chloro-2-(5-[1,2,4]triazol-1-ylmethyl- pyridin-3-y1)-2,3-dihydro-isoindol-l-one CI5-Chloro-2,3-I
None and 3-bromo-5- 0 [1,2,4]triazol-1- 1 ylmethyl-pyridine (intermediate B-3) 326.2 SUBSTITUTE SHEET(RULE 26) PCT/EP2012/073653 - 236h - 5-Chloro-2-[5-(2-methyl-imidazol-1- ylmethyl)-pyridin-3-y1]-2,3-dihydro-isoindol- 1-one 5-Chloro-2,3-CI dihydro-isoindo1-1- one and 3-bromo-5- 0 1 (2-methyl-imidazol-Nw 1-ylmethyl)-pyridine (intermediate B-2) 339.1 5-Chloro-2-[5-(2-oxo-pyrrolidin-1-ylmethyl)- pyridin-3-y1]-2,3-dihydro-isoindol-1-one Cl 5-Chloro-2,3- 0 dihydro-isoindo1-1-N one and 1-(5-bromo- pyridin-3-ylmethyl)- 1 N, pyrrolidin-2-one (intermediate B-4) 342.1 SUBSTITUTE SHEET(RULE 26) DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
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Claims (496)

- 401 - CLAIMS
1. Compounds of formula (1) <IMG> wherein R1, R2, R3 and R4 are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R12, R13and R14; or R2 and R4 together form a double bond, wherein in case R2 and R4 together form a double bond, then R5 is H; or R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23and R24; or R3 and R4 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R29, R30and R31; - 402 - or R1 and R3 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R44, R45and R46; A1 is CR8 or N; A2 is CR9 or N; A3 is CR10 or N; A4 is CR11 or N; A5 is CR6 or N; one of R5, R6, R7 and R8 is selected from halogen, cyano, alkoxy, hydroxyalkoxy, haloalkyl, haloalkoxy and hydroxy and the others are each independently selected from H. halogen, cyano, alkoxy, hydroxyalkoxy, haloalkoxy and hydroxy; R9 is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl, wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted with R32, R33and R34; R10 is -O m-(CR15R16)p-(CR17R18)q-(CR19R20)r-R21; or R9 and R10 together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl or a subtituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted with R35, R36and R37; -403- R11 is H; R15, R17 and R19 are each independently selected from H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl; R16, R18 and R20 are each independently selected from H, hydroxy, halogen and alkyl; or R15 and R16 together with the carbon atom to which they are attached form a cycloalkyl; or R17 and R18 together with the carbon atom to which they are attached form a cycloalkyl; or R19 and R20 together with the carbon atom to which they are attached form a cycloalkyl; or R15 and R17 together form -(CH2)v-; or R15 and R19 together form -(CH2)w-; or R17 and R19 together form -(CH2)x-; R21 is H, halogen, cyano, -OR25, -SR25, -S(O)R25, -S(O)2R25, -NR25R26, NR26SO2R25, -NR26SO2NR25R27, -NR26C(O)R25, -NR26C(O)NR25R27, -C(O)R28, -C(O)NR25R26, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl and substituted aryl are substituted with R38, R39and R40; R25 is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, halocycloalkoxyalkyl, alkylcycloalkoxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkoxyalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted -404- heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R41, R42and R43; R26 and R27 are each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl; or R15 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; or R17 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; or R19 and R26 together with the nitrogen atom and carbon atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R47, R48and R49; R28 is H, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R50, R51and R52; R12, R13, R14, R22, R23, R24, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and R52 are each independently - 405 - selected from H. halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonylamino, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, chloropyridinylcarbonyl and heterocycloalkyl; n is zero or 1; m zero or 1; p, q and r are independently selected from zero and 1; v and x are independently selected from 1, 2, 3 or 4; w is zero, 1, 2 or 3; with the proviso that no more than two of A2, A3 and A4 are N; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R1, R2, R3 and 124 are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R12, R13and R14.
3. A compound according to any one of claims 1 and 2, wherein R1 is H, alkyl or arylalkyl substituted with R12, R13and R14.
4. A compound according to any one of claims 1 to 3, wherein R2 is H or alkyl. - 406 -
5. A compound according to claim 1, wherein R1 and R2 together with the carbon atom to which they are attached form a substituted cycloalkyl or a substituted heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R22, R23and R24.
6. A compound according to claim 1. wherein R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl substituted with R22, R23and R24.
7. A compound according to any one of claims 1 to 6, wherein R3 is H or alkyl.
8. A compound according to any one of claims 1 to 7, wherein R4 is H.
9. A compound according to any one of claims 1 to 8, wherein A1 is CR8.
10. A compound according to any one of claims 1 to 9, wherein A2 is CR9.
11. A compound according to any one of claims 1 to 10, wherein A3 is CR10.
12. A compound according to any one of claims 1 to 11, wherein A4 is CR11.
13. A compound according to any one of claims 1 to 12, wherein A5 is CR6.
14. A compound according to any one of claims 1 to 13, wherein one of R5, R6, R7 and R8 is selected from halogen, alkoxy and hydroxy and the others are each independently selected from H and halogen.
15. A compound according to any one of claims 1 to 14, wherein R9 is H, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, substituted arylhydroxyalkyl or substituted heterocycloalkylalkyl, wherein substituted substituted arylhydroxyalkyl and substituted heterocycloalkylalkyl are substituted with R32, R33and R34.
16. A compound according to any one of claims 1 to 15, wherein R9 and R10 together with the carbon atoms to which they are attached form a substituted cycloalkyl, a substituted aryl or a subtituted heteroaryl, wherein substituted cycloalkyl, substituted aryl and substituted heteroaryl are substituted with R35, R36and R37. - 407 -
17. A compound according to any one of claims 1 to 16, wherein R15, R17 and R19 are each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl.
18. A compound according to any one of claims 1 to 17, wherein R16, R18 and R20 are each independently selected from H, hydroxy, halogen or alkyl.
19. A compound according to any one of claims 1 to 18, wherein R21 is H, halogen, cyano, -SR25, -S(O)R25, -NR25R26, -NR26SO2R25, -NR26C(O)R25, -NR26C(O)NR25R27, -C(O)R28, -C(O)NR25R26, cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl and substituted aryl are substituted with R38, R39 and R40.
20. A compound according to any one of claims 1 to 19, wherein R25 is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R41, R42 and R43.
21. A compound according to any one of claims 1 to 20, wherein R26 and R27 are each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl.
22. A compound according to any one of claims 1 to 21, wherein R12, R13, R14, R22, R23, R24, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and R52 are each independently selected from H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, chloropyridinylcarbonyl and heterocycloalkyl.
23. A compound according to claim 1, wherein said compound is 6-Chloro-2- pyridin-3- yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. -408-
24. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-nicotinonitrile, or a pharmaceutically acceptable salt thereof.
25. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- hydroxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- chloro- pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
27. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- fluoro- pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
28. A compound according to claim 1, wherein said compound is 6-Chloro-2-(4- chloro- pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
29. A compound according to claim 1, wherein said compound is 2-(5-Bromo- pyridin-3- yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
30. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methyl- pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
31. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-3-carbaldehyde, or a pharmaceutically acceptable salt thereof.
32. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 409 -
33. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- isopropoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
34. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
35. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
36. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((R)-1- hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
37. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-1- hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
38. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methoxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
39. A compound according to claim 1, wherein said compound is 2-(5-Amino- pyridin-3- yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
40. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,2,2- trifluoro-1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
41. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,2,2- trifluoro-1-methoxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 410 -
42. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (cyclopropyl-hydroxy-methyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-l-one, or a pharmaceutically acceptable salt thereof.
43. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (cyclopropyl-methoxy-methyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-l-one, or a pharmaceutically acceptable salt thereof.
44. A compound according to claim 1, wherein said compound is 6-Chloro-2-(4- trifluoromethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
45. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
46. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methoxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
47. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylmethyl]-amide, or a pharmaceutically acceptable salt thereof.
48. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxo- pyrrolidin-1-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
49. A compound according to claim 1, wherein said compound is 6-Chloro-2-(1- methyl- 1H-pyrazolo[3,4-c]pyridin-4-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
50. A compound according to claim 1, wherein said compound is 6-Chloro-8'- hydroxy- 3,4,5',6',7',8'-hexahydro-[2,4']biisoquinolinyl-1-one, or a pharmaceutically acceptable salt thereof. - 411 -
51. A compound according to claim 1, wherein said compound is N-(6-Chloro-1- oxo- 3,4,5',6',7',8'-hexahydro-1H42,41biisoquinolinyl-8'-yl)-propionamide, or a pharmaceutically acceptable salt thereof.
52. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [hydroxy-(1-methyl-1H-imidazol-2-yl)-methyl]-pyridin-3-yl}-3,4-dihydro-2H- isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
53. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(3,4- difluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
54. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(3,5- difluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
55. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(4- ethyl-phenyl)-hydroxy-methyl]-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
56. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (hydroxy-phenyl-methyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
57. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- hydroxy-1-phenyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
58. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [1-(3,4- difluoro-phenyl)-1-hydroxy-ethyl]-pyridin-3-yl1-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
59. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- [1-(3,5- difluoro-phenyl)-1-hydroxy-ethyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof. - 412 -
60. A compound according to claim 1, wherein said compound is 6-Chloro-2-(6- methyl- pyrazin-2-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
61. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (morpholine-4-carbonyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
62. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- hydroxy-pyrrolidine-1-carbonyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
63. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-N,N-dimethyl-nicotinamide, or a pharmaceutically acceptable salt thereof.
64. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (pyrrolidine-1-carbonyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
65. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-N-methyl-nicotinamide, or a pharmaceutically acceptable salt thereof.
66. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-N-cyclopropyl-nicotinamide, or a pharmaceutically acceptable salt thereof.
67. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-fluoro-phenyl)-nicotinamide, or a pharmaceutically acceptable salt thereof.
68. A compound according to claim 1, wherein said compound is 5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-N-phenyl-nicotinamide, or a pharmaceutically acceptable salt thereof. -413-
69. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4,4- difluoro-piperidine-1-carbonyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
70. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-2- methoxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
71. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-2- methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
72. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-2- hydroxymethyl-5-oxo-pyrrolidin-1-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
73. A compound according to claim 1, wherein said compound is 6-Chloro-2- pyrimidin- 5-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
74. A compound according to claim 1, wherein said compound is 6-Chloro-2- pyridazin- 3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
75. A compound according to claim 1. wherein said compound is 6-Chloro-2- pyridin-3- yl-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
76. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- fluoro- pyridin-3-yl)-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
77. A compound according to claim 1, wherein said compound is 6-Chloro-2-[4- (1- hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. -414-
78. A compound according to claim 1, wherein said compound is 6-Chloro-2-(4- hydroxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
79. A compound according to claim 1, wherein said compound is 2-[5-(1-Amino- cyclopropyl)-pyridin-3-yl]-6-chloro-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
80. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
81. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methylsulfanyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
82. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- difluoromethoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
83. A compound according to claim 1, wherein said compound is 6-Chloro-2-(4- dimethoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
84. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- fluoro- 4-(1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
85. A compound according to claim 1, wherein said compound is 6-Chloro-2-{4- [(4- fluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
86. A compound according to claim 1, wherein said compound is 6-Chloro-2-[4- (1- methoxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. -415-
87. A compound according to claim 1, wherein said compound is 6-Chloro-2-(1- methyl- 1H-pyrrolo[3,2-c]pyridin-7-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
88. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- cyclopropyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
89. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- methyl-2H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
90. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- cyclopropoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
91. A compound according to claim 1, wherein said compound is 6-Chloro-2-(4- methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
92. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- fluoro- 4-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
93. A compound according to claim 1. wherein said compound is 6-Chloro-2-[5- (5- methyl-pyrazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
94. A compound according to claim 1, wherein said compound is 6-Chloro-2- (1H- pyrrolo[3,2-c]pyridin-7-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
95. A compound according to claim 1, wherein said compound is 6-Chloro-3,4- dihydro- [2,4']biisoquinolinyl-1-one, or a pharmaceutically acceptable salt thereof. -416-
96. A compound according to claim 1, wherein said compound is 3-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-isonicotinonitrile, or a pharmaceutically acceptable salt thereof.
97. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- fluoro- 4-methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
98. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- fluoro- 4-(1-methoxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
99. A compound according to claim 1, wherein said compound is 6-Chloro-2-(4- isopropoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
100. A compound according to claim 1, wherein said compound is 6-Chloro-2-[4- (cyclopropyl-methoxy-methyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
101. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- dimethyl-1H-pyrazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
102. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- dimethyl-3H-imidazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
103. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1,1- dioxo-1.lambda.6-[1,2]thiazinan-2-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H- isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
104. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1,1- dioxo-1.lambda.6-isothiazolidin-2-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H- isoquinolin-1- one, or a pharmaceutically acceptable salt thereof. - 417 -
105. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-2- hydroxymethyl-5-oxo-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H- isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
106. A compound according to claim 1, wherein said compound is (S)-1-[5-(6- Chloro-1- oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylmethyl]-pyrrolidine-2- carboxylic acid methyl ester, or a pharmaceutically acceptable salt thereof.
107. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methoxy-pyridin-3-yl)-3-methyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
108. A compound according to claim 1. wherein said compound is 6-Chloro-2-(5- hydroxymethyl-pyridin-3-yl)-3-methyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
109. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- isopropyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3-methyl-3,4-dihydro-2H- isoquinolin- 1-one, or a pharmaceutically acceptable salt thereof.
110. A compound according to claim 1, wherein said compound is 6-Chloro-3- methyl-2- pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
111. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- fluoro- pyridin-3-yl)-3-methyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
112. A compound according to claim 1, wherein said compound is 6-Chloro-3- methyl-2- pyrimidin-5-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
113. A compound according to claim 1, wherein said compound is (R)-6-Chloro-3- methyl-2-pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 418 -
114. A compound according to claim 1, wherein said compound is (S)-6-Chloro-3- methyl-2-pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
115. A compound according to claim 1, wherein said compound is 8-Chloro-3- methyl-2- pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
116. A compound according to claim 1, wherein said compound is 6-Methoxy-2- pyridin- 3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
117. A compound according to claim 1, wherein said compound is 5,6-Dichloro-2- pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
118. A compound according to claim 1, wherein said compound is 2-Chloro-6-(5- methoxy-pyridin-3-yl)-7,8-dihydro-6H-[1,6]naphthyridin-5-one. or a pharmaceutically acceptable salt thereof.
119. A compound according to claim 1, wherein said compound is 2-Methoxy-6-(5- methoxy-pyridin-3-yl)-7,8-dihydro-6H-[1,6]naphthyridin-5-one, or a pharmaceutically acceptable salt thereof.
120. A compound according to claim 1, wherein said compound is 2-Methoxy-6- pyridin- 3-yl-7,8-dihydro-6H-[1,6]naphthyridin-5-one, or a pharmaceutically acceptable salt thereof.
121. A compound according to claim 1, wherein said compound is 6-Chloro-5- fluoro-2- (5-methoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
122. A compound according to claim 1, wherein said compound is 6-Chloro-7- fluoro-2- (5-methoxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 419 -
123. A compound according to claim 1, wherein said compound is 6-Chloro-7- fluoro-2- pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
124. A compound according to claim 1, wherein said compound is 6-Chloro-4,4- dimethyl-2-pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
125. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methoxy-pyridin-3-yl)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
126. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- fluoro- pyridin-3-yl)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
127. A compound according to claim 1, wherein said compound is 6-Chloro-4- methyl-2- pyridin-3-yl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
128. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- fluoro- pyridin-3-yl)-4-methyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
129. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methoxy-pyridin-3-yl)-4-methyl-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
130. A compound according to claim 1, wherein said compound is 5-Chloro-2- pyridin-3- yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
131. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (2- isopropyl-imidazol-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 420 -
132. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- [1,2,4]triazol-1-ylmethyl-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
133. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (2- methyl-imidazol-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
134. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (2-oxo- pyrrolidin-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
135. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- ((S)-2- methoxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
136. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (2-oxo- piperidin-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
137. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-amide, or a pharmaceutically acceptable salt thereof.
138. A compound according to claim 1, wherein said compound is 5-Chloro-2-(1- methyl- 1H-pyrazolo[3,4-c]pyridin-4-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
139. A compound according to claim 1, wherein said compound is 5-Chloro-2-(8- hydroxy-5,6,7,8-tetrahydro-isoquinolin-4-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
140. A compound according to claim 1, wherein said compound is 5-Chloro-3- methyl-2- pyridin-3-yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 421 -
141. A compound according to claim 1, wherein said compound is 6-Chloro-3- methyl-2- pyridin-3-yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
142. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- methoxy-pyridin-3-yl)-3-methyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
143. A compound according to claim 1, wherein said compound is 5-Chloro-3- methyl-2- (4-methyl-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
144. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1- hydroxy-ethyl)-pyridin-3-yl]-3-methyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
145. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- fluoro- pyridin-3-yl)-3-methyl-2.3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
146. A compound according to claim 1, wherein said compound is 3-Benzyl-5- chloro-2- pyridin-3-yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
147. A compound according to claim 1, wherein said compound is 5-Chloro-3- ethyl-2- pyridin-3-yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
148. A compound according to claim 1, wherein said compound is 5-Chloro-3- ethyl-2-(5- fluoro-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
149. A compound according to claim 1, wherein said compound is 5-Chloro-3- ethyl-2-(5- methoxy-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 422 -
150. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-pyridin-3-yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
151. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- fluoro- pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
152. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- methoxy-pyridin-3-yl)-3,3-dimethyl-23-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
153. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- difluoromethoxy-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
154. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1- hydroxy-ethyl)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
155. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- hydroxymethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
156. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(2-methyl-imidazol-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro- isoindol-1- one, or a pharmaceutically acceptable salt thereof.
157. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-2- hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
158. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- ((S)-2- hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 423 -
159. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((R)-3- hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
160. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- ((R)-3- hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
161. A compound according to claim 1, wherein said compound is 2-Hydroxy-6-(5- methoxy-pyridin-3-yl)-7,8-dihydro-6H-[1,6]naphthyridin-5-one, or a pharmaceutically acceptable salt thereof.
162. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- imidazol-1-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
163. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- isopropyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
164. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- methyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
165. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- ethyl-4-methyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
166. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- hydroxy-piperidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
167. A compound according to claim 1, wherein said compound is Propane-2- sulfonic acid [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylmethyl]- amide, or a pharmaceutically acceptable salt thereof. - 424 -
168. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- hydroxy-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
169. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((R)-3- hydroxy-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
170. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-3- hydroxy-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
171. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((S)-2- hydroxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
172. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- ((R)-2- hydroxymethyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
173. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- dimethyl-pyrazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
174. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
175. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylmethyl]-acetamide, or a pharmaceutically acceptable salt thereof.
176. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- morpholin-4-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 425 -
177. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxo- pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
178. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1,1- dioxo-1X,6-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
179. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxo- oxazolidin-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
180. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxo- imidazolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
181. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- methyl-2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
182. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- pyrazol- 1-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
183. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- propyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
184. A compound according to claim 1, wherein said compound is 1-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylmethyl]-1H-imidazole-2-carboxylic acid ethyl ester, or a pharmaceutically acceptable salt thereof.
185. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- hydroxymethyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof. - 426 -
186. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (oxetan- 3-ylaminomethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof:
187. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [4-(2- hydroxy-ethyl)-piperazin-1-ylmethyl}-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
188. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- isopropyl-piperazin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
189. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharinaceutically acceptable salt thereof.
190. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4,4- difluoro-piperidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
191. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,3- difluoro-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
192. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxa- 6-aza-spiro[3.4]oct-6-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
193. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxa- 6-aza-spiro[3.3]hept-6-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
194. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,3- difluoro-piperidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 427 -
195. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2-oxo- piperidin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1 -one, or a pharmaceutically acceptable salt thereof.
196. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- [1,2,3]triazol-2-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
197. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- [1,2,3]triazol-1-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
198. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- chloro-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
199. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- methyl11,2,4]triazol-4-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
200. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (5- methyl-[1,2,4]triazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
201. A compound according to claim 1, wherein said compound is 6-chloro-2-[5- (3- methyl-[1,2,4]triazol-1-yl methyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
202. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- [1,2,4]triazol-4-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
203. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- [1,2,4]triazol-1-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 428 -
204. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- methyl-benzoimidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
205. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- indazol- 1-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
206. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- indazol- 2-ylmethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
207. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (6- fluoro-indol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
208. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (7- fluoro-indol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
209. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- fluoro-indol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
210. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- methyl-pyrazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
211. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- cyclopropyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
212. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- trifluoromethyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof. - 429 -
213. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- methyl-pyrazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
214. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- ethyl-imidazol-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
215. A compound according to claim 1, wherein said compound is 2-(5- Aminomethyl- pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
216. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
217. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- isopropoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
218. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,2,2- trifluoro-1-methyl-ethoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
219. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [2-(1- methyl-pyrrolidin-2-yl)-ethoxymethyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
220. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- cyclopentyloxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
221. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- cyclopropylmethoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 430 -
222. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- fluoro-phenoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
223. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methyl-cyclopropylmethoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
224. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (tetrahydro-furan-2-ylmethoxymethyl)-pyridin-3-3,1]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
225. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,2,2- trifluoro-ethoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
226. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- cyclobutoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof
227. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- dimethyl-isoxazol-4-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
228. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- methanesulfonyl-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
229. A compound according to claim l, wherein said compound is 6-Chloro-2-[5- (6- methyl-pyridin-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
230. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (6- morpholin-4-yl-pyridin-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof. - 431 -
231. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- methyl-2H-pyrazol-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
232. A compound according to claim I, wherein said compound is 6-Chloro-2-[5- (1- methyl-1H-pyrazol-4-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
233. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,3- difluoro-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
234. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- difluoro-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
235. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,5- difluoro-benzyl)-pyridin-3-yl]-3.4-dihydro-2H-isoquinolin-1 -one, or a pharmaceutically acceptable salt thereof.
236. A compound according to claim I, wherein said compound is 6-Chloro-2-[5- (2- trifluoromethyl-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
237. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,6- dichloro-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinoli11-1-one, or a pharmaceutically acceptable salt thereof.
238. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- chloro-6-fluoro-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
239. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,4- dichloro-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. -432-
240. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,5- dichloro-benzyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
241. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-amide, or a pharmaceutically acceptable salt thereof.
242. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
243. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
244. A compound according to claim 1, wherein said compound is Cyclopropanesulfonic acid [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-amide, or a pharmaceutically acceptable salt thereof.
245. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- fluoro-benzylamino)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
246. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,2,2- trifluoro-ethylamino)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
247. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- morpholin-4-yl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
248. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-propionamide, or a pharmaceutically acceptable salt thereof. -433-
249. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(2- methyl-2H-pyrazol-3-ylmethyl)-amino]-pyridin-3-yl}-3,4-dihydro-2H-isoquinoIin- 1- one, or a pharmaceutically acceptable salt thereof.
250. A compound according to claim 1, wherein said compound is 2-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-ylamino]-2-methyl-propionic acid, or a pharmaceutically acceptable salt thereof.
251. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(1- methyl-1H-imidazol-4-ylmethyl)-amino]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin- 1-one, or a pharmaceutically acceptable salt thereof.
252. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1H- pyrazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
253. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- dimethyl-isoxazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
254. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- fluoro-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
255. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,4- difluoro-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
256. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,5- difluoro-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
257. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- chloro-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 434 -
258. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,5- difluoro-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1 -one, or a pharmaceutically acceptable salt thereof.
259. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- trifluoromethyl-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1 -one, or a pharmaceutically acceptable salt thereof.
260. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- trifluoromethoxy-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
261. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
262. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
263. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- chloro-3-fluoro-phenyl)-pyridin-3-yl1-3,4-dihydro-2-[4-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
264. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3,4- dichloro-phenyl)-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one. or a pharmaceutically acceptable salt thereof.
265. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- trifluoromethyl-phenyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
266. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- isoxazol-4-yl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 435 -
267. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methyl-1H-imidazol-2-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
268. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,4- dimethyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
269. A compound according to claim 1, wherein said compound is 5-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-1-methyl-1H-pyrazole-4- carbonitrile, or a pharmaceutically acceptable salt thereof.
270. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-isobutyramide, or a pharmaceutically acceptable salt thereof.
271. A compound according to claim 1, wherein said compound is Cyclopropanecarboxylic acid [5-(6-chloro-1 -oxo-3,4-dihydro-1H-isoquinolin-2- yl)- pyridin-3-yl]-amide, or a pharmaceutically acceptable salt thereof.
272. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- l-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-4-fluoro-benzamide, or a pharmaceutically acceptable salt thereof.
273. A compound according to claim 1, wherein said compound is 1-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-3-cyclohexyl-urea, or a pharmaceutically acceptable salt thereof.
274. A compound according to claim 1, wherein said compound is 1-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-3-(3-trifluoromethyl-phenyl)- urea, or a pharmaceutically acceptable salt thereof.
275. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- hydroxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 436 -
276. A compound according to claim 1, wherein said compound is 2-[5-(6-Chloro- 1 -oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yloxy]-acetamide, or a pharmaceutically acceptable salt thereof.
277. A compound according to claim 1, wherein said compound is 2-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yloxy]-N-methyl-acetamide, or a pharmaceutically acceptable salt thereof.
278. A compound according to claim 1, wherein said compound is [5-(6-Chloro-1- oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yloxy]-acetic acid methyl ester, or a pharmaceutically acceptable salt thereof.
279. A compound according to claim 1, wherein said compound is 2-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yloxy]-N,N-dimethyl-acetamide, or a pharmaceutically acceptable salt thereof.
280. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- phenylaminomethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
281. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(4- fluoro-phenylamino)-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
282. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(3- fluoro-phenylamino)-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
283. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(4- chloro-phenylamino)-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof
284. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(3- chloro-phenylamino)-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 437 -
285. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [(1H- pyrazol-3-ylamino)-methyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
286. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2- morpholin-4-yl-2-oxo-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
287. A compound according to claim 1, wherein said compound is 2-[5-(6-Chloro- 1-oxo- 3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-N-(2-hydroxy-ethyl)-acetamide, or a pharmaceutically acceptable salt thereof.
288. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methylamino-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
289. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- dimethylamino-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
290. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- methyl-1H-imidazole-2-carbonyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
291. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- methyl-4H-[1,2,4]triazol-3-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin- 1- one, or a pharmaceutically acceptable salt thereof.
292. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- [1,2,3]triazol-2-yl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
293. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- imidazol-1-yl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 438 -
294. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- pyrazol-1-yl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
295. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [1- (oxazol-2-ylamino)-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
296. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- [1,2,4]triazol-1-yl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
297. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [1-(2- oxo-pyrrolidin-1-yl)-ethyl]-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
298. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [1-(2- oxo-oxazolidin-3-yl)-ethyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
299. A compound according to claim 1, wherein said compound is N-{1-[5-(6- Chloro-1- oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-ethyl}-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
300. A compound according to claim 1, wherein said compound is 6-Chloro-2-{5- [1-(3- fluoro-phenylamino)-ethyl]-pyridin-3-yl}-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
301. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1- phenylamino-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
302. A compound according to claim 1, wherein said compound is 6-Chloro-2-(5- methanesulfinyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 439 -
303. A compound according to claim 1, wherein said compound is 6-Chloro-2[4-(4- methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
304. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(1-methyl-1H-pyrazol-4-ylmethyl)-pyridin-3-yl]-2,3-dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof.
305. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- difluoromethoxy-pyridin-3-yl)-3-ethyl-2,3-dihydro-isoindol-l-one, or a pharmaceutically acceptable salt thereof.
306. A compound according to claim 1, wherein said compound is 5-Chloro-3- ethyl-2-[5- (1-hydroxy-ethyl)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
307. A compound according to claim 1, wherein said compound is 5-Chloro-2-(4- chloro- pyridin-3-yl)-3-ethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
308. A compound according to claim 1, wherein said compound is 5-Chloro-2-(4- chloro- pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
309. A compound according to claim 1, wherein said compound is 6-Chloro-5'- nitro-3,4- dihydro-[2,4']biisoquinolinyl-1-one, or a pharmaceutically acceptable salt thereof.
310. A compound according to claim 1, wherein said compound is 6-Chloro-8'- nitro-3,4- dihydro-[2,4']biisoquinolinyl-1-one, or a pharmaceutically acceptable salt thereof.
311. A compound according to claim 1, wherein said compound is 8'-Amino-6- chloro- 3,4-dihydro-[2,4']biisoquinolinyl-1-one, or a pharmaceutically acceptable salt thereof. - 440 -
312. A compound according to claim 1, wherein said compound is Ethanesulfonic acid (6-chloro-1-oxo-3,4-dihydro-1H-[2,4']blisoquinolinyl-8'-yl)-amide, or a pharmaceutically acceptable salt thereof.
313. A compound according to claim 1, wherein said compound is 6'-Chloro-2'-(5- fluoropyridin-3-yl)spiro[cyclopropane-1,1'-isoindol]-3'(2'H)-one, or a pharmaceutically acceptable salt thereof.
314. A compound according to claim 1, wherein said compound is 6'-Chloro-2'-[5- (difluoromethoxy)pyridin-3-yl]spiro[cyclopropane-1,1'-isoindol]-3'(2'H)-one, or a pharmaceutically acceptable salt thereof.
315. A compound according to claim 1, wherein said compound is 2-Chloro-6-(5- fluoro- pyridin-3-yl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
316. A compound according to claim 1, wherein said compound is 2-Chloro-6-(5- difluoromethoxy-pyridin-3-yl)-7,7-d imethyl-6,7-d ihyd ro-pyrrolo[3,4- b]pyridin-5- one, or a pharmaceutically acceptable salt thereof.
317. A compound according to claim 1, wherein said compound is 6-(5-Fluoro- pyridin-3- yl)-2-methoxy-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
318. A compound according to claim 1, wherein said compound is 6-(5- Difluoromethoxy- pyridin-3-yl)-2-methoxy-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
319. A compound according to claim 1, wherein said compound is 6-Chloro-2'- (pyridin- 3-yl)spiro[cyclopropane-1,1'-isoindol]-3'(2'H)-one, or a pharmaceutically acceptable salt thereof.
320. A compound according to claim 1, wherein said compound is 5-Chloro-3- cyclopropyl-2-(5-fluoro-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 441 -
321. A compound according to claim 1, wherein said compound is 2-Chloro-7,7- dimethyl-6-pyridin-3-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
322. A compound according to claim 1, wherein said compound is 2-Ethoxy-6-(5- fluoro- pyridin-3-yl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
323. A compound according to claim 1, wherein said compound is 2-Methoxy-7,7- dimethyl-6-pyridin-3-yl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
324. A compound according to claim 1, wherein said compound is 5-Chloro-3- cyclopropyl-2-pyridin-3-yl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
325. A compound according to claim 1, wherein said compound is 5-Chloro-3- cyclopropyl-2-(5-difluoromethoxy-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
326. A compound according to claim 1, wherein said compound is 6-(5- Difluoromethoxy- pyridin-3-yl)-2-ethoxy-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
327. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- isopropoxy-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
328. A compound according to claim 1, wherein said compound is 6'-Chloro-2'-(4- chloropyridin-3-yl)spiro[cyclopropane-1,1'-isoindol]-3'(2'H)-one, or a pharmaceutically acceptable salt thereof.
329. A compound according to claim 1, wherein said compound is 5-Chloro-2-(5- cyclopropoxy-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 442 -
330. A compound according to claim 1, wherein said compound is (S or R)-6- Chloro-3- ethyl-2-(5-fluoro-pyridin-3-yl)-2,3-dihydro-isoindol-1 -one, or a pharmaceutically acceptable salt thereof.
331. A compound according to claim 1, wherein said compound is (R or S)-6- Chloro-3- ethyl-2-(5-fluoro-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
332. A compound according to claim 1, wherein said compound is (R or S)-5- Chloro-3- ethyl-2-(5-fluoro-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
333. A compound according to claim 1, wherein said compound is (S or R)-5- Chloro-3- ethyl-2-(5-fluoro-pyridin-3-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
334. A compound according to claim 1, wherein said compound is 2-(8-Amino- 5,6,7,8- tetrahydro-isoquinolin-4-yl)-5-chloro-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
335. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-1-ethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
336. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-1-ethyl-3-oxo-1.3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-ya-propionamide, or a pharmaceutically acceptable salt thereof.
337. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (5- Chloro-1-oxo-1.3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- propionamide, or a pharmaceutically acceptable salt thereof.
338. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [4-(5-chloro-1 -oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin- 8-yl]- amide, or a pharmaceutically acceptable salt thereof. - 443 -
339. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-amide, or a pharmaceutically acceptable salt thereof.
340. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-amide, or a pharmaceutically acceptable salt thereof.
341. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- acetamide, or a pharmaceutically acceptable salt thereof.
342. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6.7-dihydro-5H-[2]pyrindin-7-yl]- acetamide, or a pharmaceutically acceptable salt thereof.
343. A compound according to claim 1, wherein said compound is N-((R or S)-6- Chloro- 1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,4']biisoquinolinyl-8'-yl)-acetamide, or a pharmaceutically acceptable salt thereof.
344. A compound according to claim 1, wherein said compound is N-((S or R)-6- Chloro- 1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,4]biisoquinolinyl-8'-yl)-acetamide, or a pharmaceutically acceptable salt thereof.
345. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- acetamide, or a pharmaceutically acceptable salt thereof.
346. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- acetamide, or a pharmaceutically acceptable salt thereof.
347. A compound according to claim 1, wherein said compound is N-((S or R)-6- Chloro- 1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,4']biisoquinolinyl-8'-yl)- methanesulfonamide, or a pharmaceutically acceptable salt thereof. - 444 -
348. A compound according to claim 1, wherein said compound is N-((R or S)-6- Chloro- 1-oxo-3,4,5',6',7,8'-hexahydro-1H-[2,4']biisoquinolinyl-8'-yl)- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
349. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
350. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
351. A compound according to claim 1, wherein said compound is N-((R or S)-6- Chloro- 1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,4']biisoquinolinyl-8'-yl)-propionamide, or a pharmaceutically acceptable salt thereof.
352. A compound according to claim 1, wherein said compound is N-((S or R)-6- Chloro- 1-oxo-3,4,5',6',7',8'-hexahydro-1H-[2,4']biisoquinolinyl-8'-yl)-propionamide, or a pharmaceutically acceptable salt thereof.
353. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (6- Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
354. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (6- Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
355. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (6- Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- acetamide, or a pharmaceutically acceptable salt thereof.
356. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (6- Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dihydro-5 H-[2]pyrindin-7- yl]- acetamide, or a pharmaceutically acceptable salt thereof. - 445 -
357. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
358. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
359. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-amide, or a pharmaceutically acceptable salt thereof.
360. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-amide, or a pharmaceutically acceptable salt thereof.
361. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- propionamide, or a pharmaceutically acceptable salt thereof.
362. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (5- Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]- propionamide, or a pharmaceutically acceptable salt thereof.
363. A compound according to claim 1, wherein said compound is 5-Chloro-2-((S or R)- 8-hydroxy-5,6,7,8-tetrahydro-isoquinolin-4-yl)-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
364. A compound according to claim 1, wherein said compound is 5-Chloro-2-((R or S)- 8-hydroxy-5,6,7,8-tetrahydro-isoquinolin-4-yl)-2,3-dihydro-isoindol-l-one, or a pharmaceutically acceptable salt thereof.
365. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-acetamide, or a pharmaceutically acceptable salt thereof. - 446 -
366. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
367. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
368. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
369. A compound according to claim 1, wherein said compound is N-[4-(5-Chloro- 3- ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
370. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-methanesulfonamide. or a pharmaceutically acceptable salt thereof.
371. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
372. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7.8-tetrahydro- isoquinolin-8-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
373. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
374. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof. - 447 -
375. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
376. A compound according to claim I, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
377. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
378. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
379. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
380. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl1-acetamide, or a pharmaceutically acceptable salt thereof.
381. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
382. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
383. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof. - 448 -
384. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6.7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
385. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
386. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
387. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
388. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]acetamide, or a pharmaceutically acceptable salt thereof.
389. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
390. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
391. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
392. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof. - 449 -
393. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-methanesulfonamide, or a pharmaceutically acceptable salt thereof.
394. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-cyclopropyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
395. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-cyclopropyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-A-acetamide, or a pharmaceutically acceptable salt thereof.
396. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-cyclopropyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5.6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
397. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-cyclopropyl-1-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]acetamide, or a pharmaceutically acceptable salt thereof.
398. A compound according to claim I, wherein said compound is N-[(R or S)-4- ((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin-7-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
399. A compound according to claim 1, wherein said compound is N-[(R or S)-4- ((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
400. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((R or S)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin- 7-yl]-propionamide, or a pharmaceutically acceptable salt thereof.
401. A compound according to claim 1, wherein said compound is N-[(S or R)-4- ((S or R)-5-Chloro-3-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H- [2]pyrindin-7-yl]-propionamide, or a pharmaceutically acceptable salt thereof. - 450 -
402. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-(5-pyrazol-1-ylmethyl-pyridin-3-yl)-2.3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt thereof.
403. A compound according to claim 1, wherein said compound is -2-[5-(3-Amino- pyrazol-1-ylmethyl)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
404. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-{5-[(1H-pyrazol-3-ylamino)-methyl]-pyridin-3-yl}-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
405. A compound according to claim 1, wherein said compound is 2-[5-(3-Amino- pyrazol-1-ylmethyl)-pyridin-3-yl]-6-chloro-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
406. A compound according to claim 1, wherein said compound is 2-Chloro-7,7- dimethyl-6-{5-[(1H-pyrazol-3-ylamino)-methyl]-pyridin-3-yl}-6,7-dihydro- pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
407. A compound according to claim 1, wherein said compound is 2-Methoxy-7,7- dimethyl-6-{5-[(1H-pyrazol-3-ylamino)-methyl]-pyridin-3-yl}-6,7-dihydro- pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
408. A compound according to claim 1, wherein said compound is 2-Ethoxy-7,7- dimethyl-6-{5-[(1H-pyrazol-3-ylamino)-methyl]-pyridin-3-yl}-6,7-dihydro- pyrrolo[3,4-b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
409. A compound according to claim 1, wherein said compound is 6'-Chloro-2'-{5- [(1H- pyrazol-3-ylamino)methyl]pyridin-3-yl}spiro[cyclopropane-1,1'-isoindol]- 3'(2'H)- one, or a pharmaceutically acceptable salt thereof.
410. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- amide, or a pharmaceutically acceptable salt thereof. -451-
411. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(6-fluoro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- amide, or a pharmaceutically acceptable salt thereof.
412. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(6-cyano-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- amide, or a pharmaceutically acceptable salt thereof.
413. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-((S or R)-5-chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3- ylmethyl]- amide, or a pharmaceutically acceptable salt thereof.
414. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
415. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-N-methyl- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
416. A compound according to claim 1, wherein said compound is N-{[5-(6'- Fluoro-3'- oxospiro[cyclopropane-1,1'-isoindol]-2'(3'H)-yl)pyridin-3- yl]methyl}ethanesulfonamide. or a pharmaceutically acceptable salt thereof.
417. A compound according to claim 1, wherein said compound is N-{[5-(6'- Fluoro-3'- oxospiro[cyclopropane-1,1'-isoindol]-2'(3'H)-yl)pyridin-3-yl]methyl}-N- methylethanesulfonamide, or a pharmaceutically acceptable salt thereof.
418. A compound according to claim 1, wherein said compound is Ethanesulfonic acid [5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methyl-amide, or a pharmaceutically acceptable salt thereof.
419. A compound according to claim 1, wherein said compound is N-{[5-(6'- Chloro-3'- oxospiro[cyclopropane-1,1'-isoindol]-2'(3'H)-yl)pyridin-3- yl]methyl}propanamide, or a pharmaceutically acceptable salt thereof. -452-
420. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-propionamide, or a pharmaceutically acceptable salt thereof.
421. A compound according to claim 1, wherein said compound is N-[5-(6-Fluoro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-propionamide, or a pharmaceutically acceptable salt thereof.
422. A compound according to claim 1, wherein said compound is N-[5-((S or R)- 5- Chloro-3-ethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- propionamide, or a pharmaceutically acceptable salt thereof.
423. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-acetamide, or a pharmaceutically acceptable salt thereof.
424. A compound according to claim 1, wherein said compound is N-{[5-(5'- Fluoro-3'- oxospiro[cyclopropane-1,1'-isoindol]-2'(3'H)-yl)pyridin-3- yl]methyl}methanesulfonamide, or a pharmaceutically acceptable salt thereof.
425. A compound according to claim 1, wherein said compound is N-[5-(6-Cyano- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
426. A compound according to claim 1, wherein said compound is N-[5-(6-Fluoro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
427. A compound according to claim 1, wherein said compound is N-{[5-(6'- Fluoro-3'- oxospiro[cyclopropane-1,1'-isoindol]-2'(3'H)-yl)pyridin-3- yl]methyl}methanesulfonamide, or a pharmaceutically acceptable salt thereof.
428. A compound according to claim 1, wherein said compound is N-[5-((S or R)- 5- Chloro-1-ethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof. -453-
429. A compound according to claim 1, wherein said compound is N-[5-(5-Fluoro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
430. A compound according to claim 1, wherein said compound is N-[5-((R or S)- 5- Chloro-1-ethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
431. A compound according to claim 1, wherein said compound is N-[5-(5-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- methanesulfonamide, or a pharmaceutically acceptable salt thereof.
432. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1,1- dioxo-1.lambda.6-isothiazolidin-2-ylmethyl)-pyridin-3-yl]-3,3-dimethyl-2,3- dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof.
433. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(2-oxo-piperidin-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
434. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
435. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(2-oxo-oxazolidin-3-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
436. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(2-oxo-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
437. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(3-methyl-2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-yl]-2,3- dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof. -454-
438. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1,1- dioxo-1.lambda.6-[1,2]thiazinan-2-ylmethyl)-pyridin-3-yl]-3,3-dimethyl-2,3- dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof.
439. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (3- isopropyl-2-oxo-imidazolidin-1-ylmethyl)-pyridin-3-yl]-3,3-dimethyl-2,3- dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof.
440. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1,5- dimethyl-1H-imidazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
441. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
442. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (3- methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
443. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
444. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (4- chloro-2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1- one, or a pharmaceutically acceptable salt thereof.
445. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (2,5- dimethyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
446. A compound according to claim 1, wherein said compound is 6-Chloro-2-[5- (1,5- dimethyl-1H-pyrazol-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof. - 455 -
447. A compound according to claim 1, wherein said compound is 6-Chloro-2-[4- chloro- 5-(2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, or a pharmaceutically acceptable salt thereof.
448. A compound according to claim 1, wherein said compound is 2-Chloro-7,7- dimethyl-6-[5-(2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
449. A compound according to claim 1, wherein said compound is 2-Methoxy-7.7- dimethyl-6-[5-(2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-6,7-dihydro-pyrrolo[3,4- b]pyridin-5-one, or a pharmaceutically acceptable salt thereof.
450. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (4- chloro-2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
451. A compound according to claim 1, wherein said compound is (R or S)-5- Chloro-3- ethyl-2-[5-(2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
452. A compound according to claim 1, wherein said compound is (S or R)-5- Chloro-3- ethyl-2-[5-(2-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
453. A compound according to claim 1, wherein said compound is 3-Methyl- pyridine-2- carboxylic acid [5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)- pyridin- 3-ylmethyl]-amide, or a pharmaceutically acceptable salt thereof.
454. A compound according to claim 1, wherein said compound is 3-Chloro- pyridine-2- carboxylic acid [5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)- pyridin- 3-ylmethyl]-amide, or a pharmaceutically acceptable salt thereof.
455. A compound according to claim 1, wherein said compound is 1-Methyl-1H- imidazole-2-carboxylic acid [5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro- isoindol- 2-yl)-pyridin-3-ylmethyl]-amide. or a pharmaceutically acceptable salt thereof. - 456 -
456. A compound according to claim 1, wherein said compound is 2-Chloro-N45-(6- chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- nicotinamide, or a pharmaceutically acceptable salt thereof.
457. A compound according to claim 1, wherein said compound is Pyridine-2- carboxylic acid [5-(6-chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3- ylmethyl]-amide, or a pharmaceutically acceptable salt thereof.
458. A compound according to claim 1, wherein said compound is 3-Methyl-3H- imidazole-4-carboxylic acid [5-(6-chloro-1.1-dimethyl-3-oxo-1,3-dihydro- isoindol- 2-yl)-pyridin-3-ylmethyl]-amide, or a pharmaceutically acceptable salt thereof.
459. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-6-methyl- nicotinamide, or a pharmaceutically acceptable salt thereof.
460. A compound according to claim 1, wherein said compound is 3-Chloro-N45-(6- chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]- isonicotinamide, or a pharmaceutically acceptable salt thereof.
461. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-nicotinamide, or a pharmaceutically acceptable salt thereof.
462. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-2-methyl- nicotinamide, or a pharmaceutically acceptable salt thereof.
463. A compound according to claim 1, wherein said compound is N-[5-(6-Chloro- 1, l- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-4-methyl- nicotinamide, or a pharmaceutically acceptable salt thereof.
464. A compound according to claim 1, wherein said compound is 2-[5-(1-Acetyl- pyrrolidin-3-yloxy)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof. - 457 -
465. A compound according to claim 1, wherein said compound is 2-[5-((R)-1- Acetyl- pyrrolidin-3-yloxy)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
466. A compound according to claim 1, wherein said compound is 2-[5-(N-1- Acetyl- pyrrolidin-3-yloxy)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
467. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(1-propionyl-pyrrolidin-3-yloxy)-pyridin-3-yl]-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
468. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1- methanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol-1-one. or a pharmaceutically acceptable salt thereof.
469. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1- ethanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof:
470. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- ((R)-1- ethanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
471. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- ((S)-1- ethanesulfonyl-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
472. A compound according to claim 1, wherein said compound is 2-[5-(1-Acetyl- piperidin-4-yloxy)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2.3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
473. A compound according to claim 1, wherein said compound is 2-[5-(1-Acetyl- azetidin-3-yloxy)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof. - 458 -
474. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(1-propionyl-azetidin-3-yloxy)-pyridin-3-yl]-2,3-dihydro- isoindol-1- one, or a pharmaceutically acceptable salt thereof.
475. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1- methanesulfonyl-azetidin-3-yloxy)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol- 1-one, or a pharmaceutically acceptable salt thereof.
476. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (1- ethanesulfonyl-azetidin-3-yloxy)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol-1- one, or a pharmaceutically acceptable salt thereof.
477. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- ((S)-3- hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
478. A compound according to claim 1, wherein said compound is 2-[5-(4-Acetyl- piperazin-1-yl)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
479. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[5-(4-propionyl-piperazin-1-yl)-pyridin-3-yl]-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
480. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (4- methanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro- isoindol- I - one, or a pharmaceutically acceptable salt thereof.
481. A compound according to claim 1, wherein said compound is 5-Chloro-2-[5- (4- ethanesulfonyl-piperazin-1-yl)-pyridin-3-yl]-3,3-dimethyl-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
482. A compound according to claim 1, wherein said compound is 5-Chloro-2-{5- [4-(3- chloro-pyridine-2-carbonyl)-piperazin-1-A-pyridin-3-yl}-3,3-dimethyl-2,3- dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof. - 459 -
483. A compound according to claim 1, wherein said compound is 2-[5-(1-Acetyl- pyrrolidin-3-yl)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
484. A compound according to claim 1, wherein said compound is 2-(1'-Acetyl- 1',2',3',4',5',6'-hexahydro-[3,4]bipyridinyl-5-yl)-5-chloro-3,3-dimethyl-2,3- dihydro- isoindol-1-one, or a pharmaceutically acceptable salt thereof.
485. A compound according to claim 1, wherein said compound is 2-[6-(1-Acetyl- piperidin-3-yl)-pyrazin-2-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1- one, or a pharmaceutically acceptable salt thereof.
486. A compound according to claim 1, wherein said compound is 5-Chloro-3,3- dimethyl-2-[6-(1-propionyl-piperidin-3-yl)-pyrazin-2-yl]-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
487. A compound according to claim 1, wherein said compound is 5-Chloro-2-[6- (1- ethanesulfonyl-piperidin-3-yl)-pyrazin-2-yl]-3,3-dimethyl-2,3-dihydro-isoindol- 1- one, or a pharmaceutically acceptable salt thereof.
488. A compound according to claim 1, wherein said compound is 5-Chloro-2-[6- (1- methanesulfonyl-piperidin-3-yl)-pyrazin-2-yl]-3,3-dimethyl-2,3-dihydro- isoindol-1- one, or a pharmaceutically acceptable salt thereof.
489. A compound according to claim 1, wherein said compound is N-[(S or R)-4- (6- Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
490. A compound according to claim 1, wherein said compound is N-[(R or S)-4- (6- Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro- isoquinolin-8-yl]-acetamide, or a pharmaceutically acceptable salt thereof.
491. A compound according to claim 1, wherein said compound is N14-(6-Chloro- 1,1- dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-isoquinolin-8-yl]- propionamide, or a pharmaceutically acceptable salt thereof. - 460 -
492. A compound according to any one of claims 1 to 491 for use in the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.
493. A pharmaceutical composition comprising a compound according to any one of claims 1 to 491 and a therapeutically inert carrier.
494. The use of a compound according to any one of claims 1 to 491 for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.
495. A compound according to any one of claims 1 to 491 for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.
496. The use of a compound according to any one of claims 1 to 491 for the preparation of a medicament for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.
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