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NZ621599B2 - New dihydroquinoline-2-one derivatives - Google Patents
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NZ621599B2 - New dihydroquinoline-2-one derivatives - Google Patents

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NZ621599B2
NZ621599B2 NZ621599A NZ62159912A NZ621599B2 NZ 621599 B2 NZ621599 B2 NZ 621599B2 NZ 621599 A NZ621599 A NZ 621599A NZ 62159912 A NZ62159912 A NZ 62159912A NZ 621599 B2 NZ621599 B2 NZ 621599B2
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New Zealand
Prior art keywords
tetrahydro
methyl
quinolinyl
amide
methyloxo
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NZ621599A
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NZ621599A (en
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Johannes Aebi
Kurt Amrein
Benoit Hornsperger
Henner Knust
Bernd Kuhn
Yongfu Liu
Hans P Maerki
Alexander V Mayweg
Peter Mohr
Xuefei Tan
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F Hoffmann La Roche Ag
F Hoffmannla Roche Ag
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Priority claimed from PCT/EP2012/067744 external-priority patent/WO2013037779A1/en
Publication of NZ621599A publication Critical patent/NZ621599A/en
Publication of NZ621599B2 publication Critical patent/NZ621599B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Abstract

Provided are dihydroquinoline-2-one derivative compounds, of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include ethanesulfonic acid [5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yl]-amide and ethanesulfonic acid [5-(5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)pyridin-3-ylmethyl]-amide. The compounds are aldosterone synthase inhibitors. The compounds may be useful in the treatment chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome. 5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)pyridin-3-ylmethyl]-amide. The compounds are aldosterone synthase inhibitors. The compounds may be useful in the treatment chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome.

Description

New dihydroquinolineone derivatives The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to aldosterone synthase (CYP11B2 or CYP11B1) 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) wherein R is alkyl; R is H; R is H; R is H; R is H; R is R ; R is H; 8 9 10 11 12 13 14 15 16 R is -Om-(CR R )n-(CR R )p-(CR R )q-NR R ; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 11 12 or R and R together with the carbon atom to which they are attached form a cycloalkyl or a heterocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 14 or R and R together form -(CH2)t-; R is H, alkyl or alkoxyalkyl; 16 18 18 18 R is hydroxyalkyl, -S(O)2R , -C(O)R or -C(O)OR ; 16 or R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl; 11 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted 23 24 25 heterocycloalkyl is substituted with R , R and R ; 9 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted heterocycloalkyl is 23 24 25 substituted with R , R and R ; R is alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, wherein substituted aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, and halogen; 1 20 A is CR ; 2 21 A is CR ; 3 22 A is CR ; R is H or halogen; R is H, halogen or alkyl; R is H or halogen; 23 24 25 R , R and R are each independently selected from H, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxy, oxo, triazolylalkyl, and substituted aminoalkyl; whereinsubstituted aminoalkyl is substituted on the nitrogen atom with one to two substituents selected from alkyl; m is zero or 1, wherein in case m is 1, then the sum of n and p is 2, 3 or 4; n is zero, 1 or 2; p is zero, 1 or 2; q is zero, 1 or 2; t is zero, 1 or 2; or pharmaceutically acceptable salts or esters.
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 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 ICAM-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-1b 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, increased PAI-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 PAI-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 HPA axis and will differentiate different CYP11B2 inhibitors.
Described herein 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 -O-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, ethoxy and tert-butoxy.
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, ethoxymethoxy, 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, methoxymethyl, ethoxyethyl, methoxypropyl and ethoxypropyl. Particular alkoxyalkyl group include methoxymethyl and methoxyethyl. More particular alkoxyalkyl group is methoxymethyl.
The term “alkoxycarbonyl” denotes a group of the formula -C(O)-R’, wherein R’ is an alkoxy group. Examples of alkoxycarbonyl groups include groups of the formula -C(O)-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(O)-R’, wherein R’ is methoxy or tert-butoxy.
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 tert-butyl. Particular alkyl groups include methyl, isopropyl or ethyl. More particular alkyl group is methyl.
The term “alkylcarbonyl”of the formula -C(O)-R’, wherein R’ is an alkyl group.
Examples of alkylcarbonyl groups include groups of the formula -C(O)-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.
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 “alkylcarbonyloxyalkyl” denotes a hydroxyalkyl group wherein the hydrogen atom of the -OH group is replaced by an alkylcarbonyl group. Examples of alkylcarbonyloxyalkyl groups include alkylcarbonyloxymethyl and alkylcarbonyloxyethyl.
Particular alkylcarbonyloxyalkyl group is alkylcarbonyloxymethyl. More particular alkylcarbonyloxyalkyl group is methylcarbonyloxymethyl.
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 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. group.
The term “amino” denotes a -NH2 The term “aminoalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an amino group. Examples of aminoalkyl include aminomethyl, aminoethyl, aminopropyl, aminomethylpropyl and diaminopropyl.
The term “aminocarbonyl”of the formula -C(O)-NH2 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 “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, O and S.
The term “carbonyl” denotes a -C(O)- group.
The term “cyano” denotes a -C≡N group.
The term “cycloalkoxy” denotes a group of the formula -O-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 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 group 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, cyclobutylpropyl and cyclopentylbutyl.
The term “cycloalkylcarbonyl”of the formula -C(O)-R’, wherein R’ is a cycloalkyl group. Examples of cycloalkylcarbonyl groups include groups of the formula -C(O)-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 “cycloalkylcarbonylaminoalkyl” 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 “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 term “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 “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, trifluoromethoxyethyl, 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, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl groups are trifluoromethyl and trifluoroethyl.
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 “halohydroxyalkyl” 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 and at least one of the hydrogen atoms of the alkyl group has been replaced by hydroxy.
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 heteroatoms selected from N, O 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, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl. More particular heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl.
In particular in the definition of R , particular heteroaryl groups include imidazolyl, oxazolyl, furanyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl and isoxazolyl. More particularly oxazolyl, pyridinyl and pyrazolyl.
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, O 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, O 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-thiomorpholinyl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazinanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza- bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxaaza-bicyclo[3.2.1]octyl, 9-aza- bicyclo[3.3.1]nonyl, 3-oxaaza-bicyclo[3.3.1]nonyl, 3-thiaaza-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- thiomorpholinyl, 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. 9 15 In particular, the heterocycloalkyl formed by R and R together with the nitrogen and carbon atoms to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl or tetrahydro-pyridinyl. More particularly, pyrrolidinyl. 11 15 In particular, the heterocycloalkyl formed by R and R together with the nitrogen and carbon atoms to which they are attached is azetidinyl or pyrrolidinyl. 16 In particular, the heterocycloalkyl formed by R and R together with the nitrogen and carbon atoms to which they are attached is pyrrolidinyl, piperidinyl, thiomorpholinyl, thiazinanyl, isothiazolidinyl, 1,1-dioxo-thiomorpholinyl or 2,6-diaza-spiro[3.3]heptanyl.
More particularly, thiomorpholinyl or 1,1-dioxo-thiomorpholinyl. Further particularly, pyrrolidinyl or 1,1-dioxo-thiomorpholinyl. 11 12 In particular, the heterocycloalkyl formed by R and R together with the nitrogen and carbon atoms to which they are attached is oxetanyl.
The term “hydroxy” denotes a -OH group.
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, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. Particular example is hydroxymethyl.
The term “oxo” denotes a divalent oxygen atom =O.
The term “phenylalkyl” denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by a phenyl. Examples of phenylalkyl are benzyl and phenylethyl. Particular exampleof phenylalkyl is benzyl.
The term “tetrazolylalkyl” denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by a tetrazolyl. Examples of tetrazolylalkyl are tetrazolylmethyl and tetrazolylethyl. Particular exampleof tetrazolylalkyl is tetrazolylmethyl.
The term “triazolylalkyl” denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by a triazolyl. Examples of triazolylalkyl are triazolylmethyl and triazolylethyl. Particular exampleof triazolylalkyl is triazolylmethyl.
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 isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, 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. μAdditionally, any physiologically acceptable equivalents of the compounds of general 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 µM.
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 H (“D”), H 11 13 14 13 15 15 17 18 32 33 35 18 36 123 125 (“T”), C, C, C, N, N, O, O, O, P, P, S, F, Cl, I and I. Certain isotopically 3 14 labeled compounds of the present invention (e.g., those labeled with H or C) are useful in 3 14 compound and /or substrate tissue distribution assays. Tritiated ( H) and carbon-14 ( C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resuting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may 13 11 18 be preferred in some circumstances. Positron emitting isotopes such as O, N, C, and F are useful for 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 H 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.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is alkyl; R is H; R is H; R is H; R is H; R is R ; R is H; 8 9 10 11 12 13 14 15 16 R is -Om-(CR R )n-(CR R )p-(CR R )q-NR R ; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 11 12 or R and R together with the carbon atom to which they are attached form a cycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 14 or R and R together form -(CH2)t-; is H, alkyl, or alkoxyalkyl; 16 18 18 18 R is hydroxyalkyl, -S(O)2R , -C(O)R , or -C(O)OR ; 16 or R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl; 11 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted 23 24 25 heterocycloalkyl is substituted with R , R and R ; 9 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted heterocycloalkyl is 23 24 25 substituted with R , R and R ; R is alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, wherein substituted aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, and halogen; 1 20 A is CR ; 2 21 A is CR ; 3 22 A is CR ; R is H or halogen; R is H, halogen or alkyl; R is H or halogen; 23 24 25 R , R and R are each independently selected from H, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxy, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two substituents independently selected from alkyl; m is zero or 1, wherein in case m is 1, then the sum of n and p is 2, 3 or 4; n is zero, 1 or 2; p is zero, 1 or 2; q is zero, 1 or 2; t is zero, 1 or 2; or pharmaceutically acceptable salts or esters.
In a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is methyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R is H, alkyl or cycloalkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R is H or alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R is H.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H or alkyl.
The present invention also relates to compounds according to formula (I) as described herein, wherein R is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
Also an embodiment of the present invention are compounds according to formula 11 12 (I) as described herein, wherein R and R together with the carbon atom to which they are attached form a cycloalkyl.
A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
Also a particular embodiment of the present invention are compounds according to 14 formula (I) as described herein, wherein R and R together form -(CH2)t-.
Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H, alkyl or alkoxyalkyl.
Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H or alkyl.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
Also a particular embodiment of the present invention are compounds according to 9 15 formula (I) as described herein, wherein R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted 23 24 25 heterocycloalkyl is substituted with R , R and R .
Also an embodiment of the present invention are compounds according to formula 16 18 18 18 (I) as described herein, wherein R is hydroxyalkyl, -S(O)2R , -C(O)R or -C(O)OR .
Also an embodiment of the present invention are compounds according to formula 16 18 (I) as described herein, wherein R is hydroxyalkyl or -S(O)2R .
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is hydroxyalkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is hydroxyethyl or hydroxymethylbutyl.
Another embodiment of the present invention are compounds according to formula 16 18 (I) as described herein, wherein R is -S(O)2R .
Another embodiment of the present invention are compounds according to formula 16 18 (I) as described herein, wherein R is -C(O)R .
A further embodiment of the present invention are compounds according to formula 16 (I) as described herein, wherein R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl; A particular embodiment of the present invention are compounds according to 16 formula (I) as described herein, wherein R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl.
A further particular embodiment of the present invention are compounds according 16 to formula (I) as described herein, wherein R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from hydroxyalkyl and oxo.
A more particular embodiment of the present invention are compounds according to 16 formula (I) as described herein, wherein the heterocycloalkyl formed by R and R together with the nitrogen atom to which they are attached is selected from pyrrolydinyl, piperidinyl, thiomorpholinyl, thiazinanyl, isothiazolidinyl and 2,6-diaza- spiro[3.3]heptanyl.A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein the heterocycloalkyl formed by R and R together with the nitrogen atom to which they are attached is selected from pyrrolydinyl, piperidinyl, thiomorpholinyl, thiazinanyl and 2,6-diaza-spiro[3.3]heptanyl.
Another embodiment of the present invention are compounds according to formula 16 (I) as described herein, wherein R and R together with the nitrogen atom to which they are attached form 2- hydroxymethyl-pyrrolidinyl, 2- hydroxymethyloxo-pyrrolidin- 1-yl or isothiazolidinyl substituted on the sulfur atom by two oxo.
Another embodiment of the present invention are compounds according to formula 16 (I) as described herein, wherein R and R together with the nitrogen atom to which they are attached form 2- hydroxymethyl-pyrrolidinyl or 2- hydroxymethyloxo- pyrrolidinyl.
Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is alkyl, cycloalkyl, hydroxyalkyl, or alkylcarbonyloxyalkyl.
Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is alkyl, cycloalkyl, hydroxyalkyl, or alkylcarbonyloxyalkyl.
A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is alkyl or heteroaryl substituted with one to three substituents independently selected from alkyl and halogen.
A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is heteroaryl substituted with one to three substituents independently selected from alkyl and halogen.
A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is alkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is ethyl.
A embodiment of the present invention are compounds according to formula (I) as is H. described herein, wherein R A embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H or alkyl.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is H.
The present invention also relates to compounds according to formula (I) as described herein, wherein R is H.
Also an embodiment of the present invention are compounds according to formula 23 24 25 (I) as described herein, wherein R , R and R are each independently selected from hydrogen, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl.
A further embodiment of the present invention are compounds according to formula 23 24 25 (I) as described herein, wherein wherein R , R and R are each independently selected from hydrogen, hydroxyalkyl and oxo.
The present invention also relates to compounds according to formula (I) as 23 24 25 described herein, wherein at least one of R , R and R is different from hydrogen.
According to the present invention are compounds according to formula (I) as described herein, wherein m is zero or 1, wherein in case m is 1, then the sum of n, p and q is 2, 3, 4, 5 or 6.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein m is 1.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein m is zero.
Also a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein n is zero or 1.
A particular 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 p is zero or 1.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein q is zero or 1.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein q is zero.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein t is 2.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein t is zero.
Particular examples of compounds of formula (I) as described herein are selected from Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yl]-amide; Acetic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylcarbamoyl]-methyl ester; 2-Hydroxy-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]- acetamide; 6-[5-(2-Hydroxy-ethylamino)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 6-[5-((S)Hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((R)Hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((S)Hydroxymethyl-pyrrolidinylmethyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[5-((S)Hydroxymethyloxo-pyrrolidinylmethyl)-pyridinyl]methyl- 3,4-dihydro-1H-quinolinone; 6-[5-((S)Ethylaminomethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-((S)Methoxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 1-Methyl[5-((S)[1,2,4]triazolylmethyl-pyrrolidinyl)-pyridinyl]-3,4- dihydro-1H-quinolinone; 6-(5-Benzylamino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone; 6-[5-((S)Hydroxymethyloxo-pyrrolidinyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 1-Methyl[5-(2-oxo-pyrrolidinyl)-pyridinyl]-3,4-dihydro-1H-quinolinone; Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl[5-(2-oxo-pyrrolidinylmethyl)-pyridinyl]-3,4-dihydro-1H- quinolinone; 1-Methyl[5-(2-oxo-piperidinylmethyl)-pyridinyl]-3,4-dihydro-1H-quinolin- 2-one; 6-[5-(1,1-Dioxo-1λ -thiomorpholinylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-((S)Methoxymethyl-pyrrolidinylmethyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- pyrrolidinecarboxylic acid methyl ester; 1-Methyl{5-[(S)(2,2,2-trifluoro-ethoxymethyl)-pyrrolidinylmethyl]-pyridin- 3-yl}-3,4-dihydro-1H-quinolinone; 6-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-2,6-diaza- spiro[3.3]heptanecarboxylic acid tert-butyl ester ; 6-[5-((R)Hydroxymethylmethyl-propylamino)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[6-((R)Hydroxymethylmethyl-propylamino)-pyrazinyl]methyl-3,4- dihydro-1H-quinolinone; Ethanesulfonic acid [5-(5-methyloxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)- pyridinylmethyl]-amide; N-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- propionamide; Propanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; {2-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- carbamic acid tert-butyl ester; 3-Methoxy-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Cyclopropanecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 6-[5-(2-Amino-ethoxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride; N-{2-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- propionamide; 6-[5-(1,1-Dioxo-1λ -[1,2]thiazinanylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; and pharmaceutically acceptable salts thereof.
Also particular examples of compounds of formula (I) as described herein are selected from (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]- azetidinecarboxylic acid tert-butyl ester; (R)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-pyrrolidinecarboxylic acid tert-butyl ester; 3-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-azetidine- 1-carboxylic acid tert-butyl ester; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid tert-butyl ester; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- piperidinecarboxylic acid tert-butyl ester; 4-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- piperidinecarboxylic acid tert-butyl ester; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]- pyrrolidinecarboxylic acid tert-butyl ester; (S)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-pyrrolidinecarboxylic acid tert-butyl ester; (R)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid tert-butyl ester; (R)- 2-Methyl-propanesulfinic acid {3-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-oxetanyl}-amide; (R)Methyl-propanesulfinic acid {(S or R)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; (R) 2-Methyl-propanesulfinic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; {(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- cyclohexyl}-carbamic acid tert-butyl ester; 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 1-Methyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolin one hydrochloride; 1-Methyl[5-((S)-piperidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolin one; 1-Methyl[5-(piperidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolinone hydrochloride; 6-[5-((S)Azetidinylmethoxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((S or R)Amino-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one hydrochloride; 6-[5-((R or S)Amino-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one hydrochloride; 1-Methyl[5-((S)pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride; 7-Fluoromethyl[5-((R)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride; 1-Methyl[5-((R)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolin one hydrochloride; 6-[5-(3-Amino-oxetanyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride; 6-[5-(Azetidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride; 6-[5-((trans)Amino-cyclohexyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride; 6-[5-(1-Aminomethyl-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 6-(5-Aminomethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H-quinolinone ; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-[5-((S)Cyclopropanecarbonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 3-Methyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-butyramide; 3,3,3-Trifluoro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-propionamide; 2-Hydroxymethyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-propionamide; -Methyl-[1,3,4]oxadiazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-piperidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 2-Methoxy-pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide, 1-Methyl-1H-imidazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; -Trifluoromethyl-furancarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-(1-propionyl-piperidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; Pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 6-[5-((S)Cyclopropanecarbonyl-azetidinylmethoxy)-pyridinyl]methyl- 3,4-dihydro-1H-quinolinone; 3-Methyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 4-Fluoro-2,6-dimethyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-benzamide; 1-Methyl[5-((S)propionyl-azetidinylmethoxy)-pyridinyl]-3,4-dihydro- 1H-quinolinone; 3,6-Dichloro-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Cyclopropyl(2,2,2-trifluoro-ethyl)-1H-pyrazolecarboxylic acid [5-(1- methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]-amide; Pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1,3-Dimethyl-1H-pyrazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 6-Methoxy-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5-Methyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide; 6-Chloro-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloromethyl-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro- 1H-quinolinone; -Cyclopropyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 2-Methyltrifluoromethyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 2-Methyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; -Cyclopropyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 2,5-Dimethyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; -Methyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; 6-Chloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Methyl-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,6-Dichloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-Methyl-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Fluoro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; -Chloromethyl-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((R)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 7-Fluoromethyl[5-((S)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4- dihydro-1H-quinolinone; -Trifluoromethyl-pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 5-Methyl-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; -Chloro-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; -Trifluoromethyl-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((R)propionyl-pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro- 1H-quinolinone; 1-Methyl[5-(1-propionyl-azetidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; N-{3-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-oxetan yl}-propionamide; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3,6-Dichloro-pyridazinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 7-Fluoromethyl[5-((R)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4- dihydro-1H-quinolinone; -Chloromethoxy-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Methyltrifluoromethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-cyclopropyl}-amide; 3-Chloro-pyridinecarboxylic acid {1-methyl[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {1-methyl[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {1-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; 3-Methyl-pyridinecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-cyclopropyl}-amide; N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-cyclohexyl}-propionamide; -Trifluoromethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 7-Fluoromethyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; (R)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxymethyl]-pyrrolidinecarboxylic acid tert-butyl ester; 1-Methyl[5-((R)pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride; 6-(5-Aminomethyl-pyridinyl)-3,4-dihydro-1H-quinolinone; 6-[5-(1-Amino-cyclopropyl)-pyridinyl]fluoromethyl-3,4-dihydro-1H- quinolinone ; Ethanesulfonic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyloxy]-ethyl}-amide ; 3-Chloro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-benzenesulfonamide; 6-Methoxy-pyridinesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Cyclopropanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 3,4-Dichloro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-benzenesulfonamide; 1-Methyl-1H-imidazolesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-Chloro-pyridinesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinylmethyl]-amide; 1-Methyl-1H-pyrazolesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-[5-((S)Ethanesulfonyl-piperidinyloxy)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-(1-Ethanesulfonyl-piperidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 2,2,2-Trifluoro-ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinylmethyl]-amide; C,C,C-Trifluoro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-methanesulfonamide; 6-[5-((S)Ethanesulfonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-((S)Ethanesulfonyl-azetidinylmethoxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; Ethanesulfonic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-cyclopropyl}-amide; 6-[5-((S)Ethanesulfonyl-pyrrolidinylmethoxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[5-((R)Ethanesulfonyl-pyrrolidinyloxy)-pyridinyl]fluoromethyl- 3,4-dihydro-1H-quinolinone; 6-[5-((R)Ethanesulfonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-(1-Ethanesulfonyl-azetidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; Ethanesulfonic acid {1-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-cyclopropyl}-amide; Ethanesulfonic acid {(trans)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-cyclohexyl}-amide; Ethanesulfonic acid {(R or S)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {(S or R)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; (rac)-Ethanesulfonic acid {2-methyl[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-propyl}-amide; (rac)-Ethanesulfonic acid {cyclopropyl-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-methyl}-amide; (rac)-Ethanesulfonic acid {1-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; 6-[5-(1,1-Dioxo-1λ6-isothiazolidinylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; (rac)-Ethanesulfonic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-propyl}-amide; Ethanesulfonic acid ethyl-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid methyl-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid {1-methyl[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid isopropyl-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid (2-ethoxy-ethyl)-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; (rac)-Ethanesulfonic acid methyl-{1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinyl]-ethyl}-amide; (rac)-Ethanesulfonic acid ethyl-{1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinyl]-ethyl}-amide; 3,5-Dimethyl-isoxazolecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 6-{5-[2-(1,1-Dioxo-1λ6-isothiazolidinyl)-ethoxy]-pyridinyl}methyl-3,4- dihydro-1H-quinolinone; Ethanesulfonic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {(S or R)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- 4-methyl-pyridinylmethyl]-amide; Ethanesulfonic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid [4-methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid methyl-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; N-Methyl-N-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-ethyl}-propionamide; 1-Methyl-1H-pyrazolecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Methyl-pyridinecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-methyl-amide; 3-Chloro-pyridinecarboxylic acid methyl-{1-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-methyl-amide; 6-{5-[(3-Ethyl-oxetanylamino)-methyl]-pyridinyl}methyl-3,4-dihydro-1H- quinolinone; Ethanesulfonic acid [5-(7-chloromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid [5-(5-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-methyl-amide; N-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-propionamide; (rac)-N-{1-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yl]-ethyl}-propionamide; (S)[5-(2-Oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-pyrrolidine carboxylic acid tert-butyl ester ; 3-Chloro-pyridinecarboxylic acid methyl-[5-(2-oxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinylmethyl]-amide ; (R)Methyl-propanesulfinic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide ; 6-(5-Aminomethylchloro-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride; 3,5-Dimethyl-isoxazolecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; (R)Methyl-propanesulfinic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide ; 6-(5-Aminomethylmethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride; 3,5-Dimethyl-isoxazolecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; (R)Methyl-propanesulfinic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide ; 6-(5-Aminomethylmethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H- quinolinone hydrochloride; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-methyl-amide; 3-Chloro-pyridinecarboxylic acid methyl-[4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 5'-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-5,6-dihydro-4H- [3,3']bipyridinylcarboxylic acid tert-butyl ester; {2-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- ethyl}-carbamic acid tert-butyl ester; 3-Chloro-pyridinecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide; 6-[5-(2-Amino-ethoxy)-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolin one hydrochloride; (R)Methyl-propanesulfinic acid {(R or S)[4-methyl(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 6-[5-((R or S)Amino-ethyl)methyl-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride; 3-Chloro-pyridinecarboxylic acid {(R or S)[4-methyl(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[4-methyl(1-methyl oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-cyclohexyl}-methanesulfonamide; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; -(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester; Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-methyl-amide; (R)Methyl-propanesulfinic acid {(R or S)[4-chloro(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 6-[5-((R or S)Amino-ethyl)chloro-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride; 3-Chloro-pyridinecarboxylic acid {(R or S)[4-chloro(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; (R)Methyl-propanesulfinic acid {(R or S)[5-(7-fluoromethyloxo- 1,2,3,4-tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide; 6-[5-((R or S)Amino-ethyl)methyl-pyridinyl]fluoromethyl-3,4- dihydro-1H-quinolinone hydrochloride; 6-[5-((S)Acetyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 1-Methyl{5-[(S)(1-methyl-1H-pyrazolecarbonyl)-pyrrolidinyloxy]- pyridinyl}-3,4-dihydro-1H-quinolinone; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid ethyl ester; 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[4-chloro(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {(R or S)[5-(7-fluoromethyloxo- 1,2,3,4-tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide; -Methyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; -(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',4',5',6'-tetrahydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester ; N-{(R or S)[4-Chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-ethyl}-propionamide ; 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-1H-quinolinone; N-{(R or S)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl) methyl-pyridinyl]-ethyl}-propionamide; N-[4-Chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-propionamide; N-{(R or S)[4-Methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-ethyl}-propionamide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; and pharmaceutically acceptable salts thereof.
Further particular examples of compounds of formula (I) as described herein are selected from 6-[5-(2-Hydroxy-ethylamino)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 6-[5-((S)Hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((S)Hydroxymethyl-pyrrolidinylmethyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[5-((S)Hydroxymethyloxo-pyrrolidinylmethyl)-pyridinyl]methyl- 3,4-dihydro-1H-quinolinone; Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl[5-(2-oxo-pyrrolidinylmethyl)-pyridinyl]-3,4-dihydro-1H- quinolinone; 6-[5-((R)Hydroxymethylmethyl-propylamino)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; and pharmaceutically acceptable salts thereof.
Also further particular examples of compounds of formula (I) as described herein are selected from 3,5-Dimethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; -Methyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 7-Fluoromethyl[5-((R)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4- dihydro-1H-quinolinone; 3-Chloro-pyridinecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-cyclopropyl}-amide; 3-Chloro-pyridinecarboxylic acid {1-methyl[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {1-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; Ethanesulfonic acid {(trans)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-cyclohexyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; Ethanesulfonic acid {1-methyl[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; 6-{5-[2-(1,1-Dioxo-1λ6-isothiazolidinyl)-ethoxy]-pyridinyl}methyl-3,4- dihydro-1H-quinolinone; Ethanesulfonic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {(S or R)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid methyl-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-amide; Ethanesulfonic acid [5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolinyl)- pyridinylmethyl]-amide; N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-cyclohexyl}-methanesulfonamide; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; -(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester; Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-methyl-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; 1-Methyl{5-[(S)(1-methyl-1H-pyrazolecarbonyl)-pyrrolidinyloxy]- pyridinyl}-3,4-dihydro-1H-quinolinone; and pharmaceutically acceptable salts thereof.
Processes for the manufacture of compounds of formula (I) as described herein are an aspect 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 diastereoisomers 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, CH2Cl2 = dichloromethane, DBU = 2,3,4,6,7,8,9,10-octahydro- pyrimido[1,2-a]azepine, DCE = 1,2-dichloroethane, DCM = dichloromethane, DIBALH = di-i-butylaluminium hydride, DCC = N,N’-dicyclohexylcarbodiimide, DMA = N,N- dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide, EDCI = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, EtOAc = ethylacetate, EtOH = ethanol, Et2O = diethylether, Et3N = triethylamine, eq = equivalents, HATU = O-(7-azabenzotriazolyl)-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, MeOH = methanol, NaBH3CN, sodium cyanoborohydride, NaBH4 = sodium borohydride, NaI = sodium iodide, Red-Al = sodium bis(2-methoxyethoxy) aluminium hydride, RT = room temperature, TBDMSCl = t-butyldimethylsilyl chloride, TFA = trifluoroacetic acid, THF = tetrahydrofuran, quant = quantitative.
Scheme 1a 4 5 101 R R R R R 3 R R R R 1 A B A X b A X a 2 7 R R 1 2 3 N 4 5 2 103 X A R 3 2 103 2 A R R X is Halogen or OSO CF 2 3 O 101 102 R and R e.g. together with the boron atom to which they are attached form R stands for substituents as e.g. shown in Schemes 2a and 2b, which allow further transformation into R at a later stage in the synthesis Lactam compounds 1 (Scheme 1a) are known or can be prepared by methods described herein or known to the man skilled in the art (see also Scheme 1b for alternative syntheses of compounds 5 and 7); compounds 1 can be alkylated at nitrogen using a base like sodium hydride or sodium or potassium tert-butoxide, followed by addition of an alkylating agent of formula R -X, wherein Y is halogen, tosylate or mesylate, in a solvent like DMF or THF preferably in a temperature range between 0 C and about 80 C giving N-alkylated lactams 2 (step a).
Reaction of lactams 2 with e.g. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-5 dioxaborolane) in solvents like dimethylsulfoxide or dioxane in the presence of potassium acetate and catalysts like (1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with dichloromethane) at temperatures up to about 100 °C gives boronic ester compounds 3 (step b). Condensation of boronic ester compounds 3 with suitable aryl halides 4 or 6 (for possible syntheses of aryl halides 4 or 6, see Schemes 2) can be performed using Suzuki conditions, e.g. in the presence of catalysts, such as tri-o- tolylphosphine/palladium(II)acetate, tetrakis-(triphenylphosphine)-palladium, bis(triphenylphosphine)palladium(II)chloride or dichloro[1,1'-bis(diphenylphosphino)- ferrocene]palladium(II) 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 N,N-dimethylformamide, and in an inert atmosphere such as argon or nitrogen, in a temperature range preferably between room temperature and about 130 °C leading to adducts 5 or 7 (steps c). Compounds 7 can be further transformed into compounds of the general formula 5 by methods described in the following Schemes, the examples or by methods well known to persons skilled in the art (step d).
Halo-nitro pryridine compounds 8 (Scheme 1b) with at least one hydrogen substituent R ortho to the nitro group react with 1-chloroR -methanesulfonylmethyl- benzene in solvents like THF and in the presence of a base like tert-BuOK in a temperature range between -78 C and room temperature to give regioisomeric sulfones 9 and 10 (step a). Treatment of sulfones 9 and 10 with a haloacetic acid ester compound in a solvent like N,N-dimethylformamide and in the presence of a weak base as e.g. sodium or potassium carbonate preferably in a temperature range between room temperature and about 80 C gives acetic acid ester adducts 11 and 16 (step b). Suzuki reactions of adducts 11 and 16 with suitable heteroaryl-boronic acid derivatives under conditions as described for step c (Scheme 1a) gives adducts 12 and 17 containing acrylic ester moieties by concomitant elimination of the 4-methyl-benzene-sulfonyl groups (step c). Catalytic hydrogentation e.g. using Pd/C and AcOH in methanol at elevated temperature and with H2 pressure of about 50-200 psi gives lactam compounds 13 and 18 (step d). Treatment of lactam compounds 13 and 18 with an alkylating agent like an alkyl or cycloalkyl halide, alkyl or cycloalkyl tosylate or an alkyl or cycloalkyl mesylate in a solvent like THF or N,N-dimethylformamide in the presence of a base like sodium or potassium hydride preferable around 0 C gives alkylated lactam compounds 14 and 19 (step e). Alkylated lactam compounds 14 and 19 can be further transformed into compounds of the general formula 15 or 20 by methods described in the following Schemes, the examples or by methods well known to persons skilled in the art (step f).
Scheme 1b R NO 201 R NO X N X N R NO X N R 9 10 O S O 2 103 R 2 5 R O 22 22 + 22 N R R O R R 9 11 12 R R N 2 103 2 6 2 103 R A R A 22 22 22 R O N R O N 7 1 7 R R R 13 14 15 R N X R N X 7 2 103 O + N N R 20 O N R 16 17 N 5 20 20 20 R R R R e 2 6 103 R 2 2 103 1 R R 18 19 20 X is Halogen or OSO CF R stands for substituents as e.g. shown in Schemes 2a and 2b, which allow further transformation into R at a later stage in the synthesis R is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl Scheme 2a R 15 X 16 R 16 A Linker A Linker 101 102 103 Linker X A Linker 104 105 13 13 OAlkyl OAlkyl 11 11 2 c 2 Linker X A Linker X A A Linker 106 107 108 e f, g, h 16 OAlkyl N N R 11 11 2 c 2 c X A Linker A Linker X is Halogen or OSO CF Schemes 2a and 2b describe possible syntheses of aryl halide compounds 103, 105, 110, 114, 117 and 121 which correspond to aryl halides 4 and 6 in Scheme 1. The terms linker used in Scheme 2a are defined as follows: a 9 10 11 12 13 14 17 9 10 11 12 Linker = -O -(CR R ) -(CR R ) -(CR R ) -, -N R -(CR R ) -(CR R ) - m n p q m n p 13 14 9 10 11 12 13 14 (CR R ) - or -S (O) -(CR R ) -(CR R ) -(CR R ) -; q m r n p q b 9 10 11 12 17 9 10 11 12 Linker = -O -(CR R ) -(CR R ) -, -N R -(CR R ) -(CR R ) - or -S (O) - m n p m n p m r 9 10 11 12 (CR R ) -(CR R ) -; c 9 10 17 9 10 9 10 Linker = -O -(CR R ) -, -N R -(CR R ) - or -S (O) -(CR R ) -. m n m n m r n Compounds 101 (Scheme 2a) carrying an aliphatic Linker react with amino compounds 102 either 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 103 (step a). Compounds 101 in which Linker is absent react with amino compounds 102 (R is hydroxyalkyl,) either directly in the presence of a base like Hunig’s base in a solvent like butanol and elevated temperature or by using Pd(0)-catalyzed amination reactions (Buchwald-Hartwig coupling) under an inert atmosphere such as argon or nitrogen in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) or palladium(II) acetate (Pd(COOCH3)2), a phosphine ligand like triphenylphosphine, rac-2,2’- bis(diphenylphosphino)-1,1’-binaphthalene (rac-BINAP) or (R)-(-)[(S) (dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine and a base such as Cs2CO3 or KOtert-Bu in a solvent like toluene, ethanol or water or mixtures thereof at room temperature or elevated temperatures, whereby heating might be achieved conventionally or by microwave irradiation to give substituted adducts 103 in which Linker is absent (step a). a 16 Compounds 101 in which Linker is absent react with amino compounds 102 (R is 18 18 18 -S(O)2R , -C(O)R or -C(O)OR ) in solvents like 1,4-dioxane, in the presence of copper (I) iodide, potassium or cesium carbonate, and a chelating 1,2-diamino compound like N,N'-dimethylethylenediamine or trans-1,2-diamino-hexane, at elevated temperatures, preferable with the aide of microwave heating to give substituted adducts 103 in which Linker is absent (step a).
Suitable reductive amination procedures as e.g. treatment of aldehydes or ketones 104 and suitable amino-moieties with NaBH(OAc)3 in 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 NaBH4 preferably between 0 °C and room temperature converts aldehydes or ketones 104 into amino compounds 105; 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 R MgX, preferably between - 40 °C and 0 °C leading to amino compounds 105 carrying the specific R substituent (step Aldehydes and ketones 106 react in Horner-Emmons reactions using e.g. reagents like dimethyl(methoxycarbonyl)methlphosphonate, optionally carrying an additional R substituted at the methylene group, and a base like sodium hydride in a solvent like tetrahydrofuran preferable between about 0 C and the reflux temperature of the solvent to give unsaturated esters 107 (step c). Reduction of the double bond in unsaturated esters 107 can be performed e.g. by using a mixture of nickel chloride and sodiumborohydride as reducing agents in solvents like methanol preferably between about 0 C and room temperature leading to ester compounds 108 (step d). Alpha mono- or di-substituted esters 109 can be synthesized from esters 108, by treatment with a base like LDA or HMDS in solvents like tetrahydrofuran or 1,2-dimethoxyethane, followed by addition of one or sequentially two different alkyl halides, a reaction preferably performed between -78 °C and room temperature (step e). Esters 109 can be further transformed into amino compounds 110 suitable to function as compounds 4 or 6 in Scheme 1, e.g by amide formation with ammonia in methanol around room temperature, Hofmann rearrangement, treatment with sodium hydroxide, and bromine in a solvent like ethanol preferably between about 0 C and the reflux temperature of the solvent and subsequent introduction 16 of R and R substituents (steps f, g, h) by methods known to the man skilled in the art.
Amino compounds 110 can also be obtained by hydrolysis of esters 109 to the corresponding acids followed by treatment with diphenylphosphoryl azide, TEA in a solvent like toluene preferably at reflux and subsequent treatment with e.g. sodium trimethylsilanoate in a solvent like THF preferably around RT followed by subsequent 16 introduction of R and R substituents (steps f, g, h) by methods known to the man skilled in the art.
Di-halogen or di-triflate substituted heteroaromatic compounds 111 (Scheme 2b) react with unsaturated boronic acid derivatives 112 under Suzuki conditions as described in Scheme 1, step c, to adducts 113 (step i). Removal of the double bond in compounds 113 e.g. by catalytic hydrogenation, followed by additional standard synthetic modifications transforms compounds 113 into synthons 114 (step k).
Reaction of compounds 111 with amino compounds 115, performed under conditions as described for the transformation of compounds 101 in which Linker is absent into compounds 103, is giving compounds 116 or 117 (step l). Compounds 116 can be transformed by additional standard synthetic modifications into synthons 117 (step m).
Phenols or thiophenols 118 react with alcohols 119 under Mitsunobu conditions e.g. with triphenylphosphine and di-tert-butyl-, diisopropyl-, diethyl-azodicarboxylate or di-(4- chlorobenzyl)azodicarboxylate as reagents in solvents like toluene, dichloromethane or tetrahydrofuran preferably at ambient temperature to give adducts 120 or 121 (step n).
Compounds 120 can be transformed by additional modifications into synthons 121, such modifications include oxidation at sufur to the respective sulfoxide or sulfone e.g. by using m-chloroperbenzoic acid (step o).
Scheme 2b N R i + 102 13 14 15 16 -(CR R ) -NR - R or protecting group X A X q 111 112 X A 6 103 X A R or R 13 14 15 16 -(CR R ) -NR - R or protecting group 17 9 10 11 12 13 14 15 16 + HNR -(CR R ) -(CR R ) -(CR R ) -NR - R or protecting group n p q X A X 111 115 9 10 11 12 13 14 15 -(CR R ) -(CR R ) -(CR R ) -NR -protecting group or N n p q 2 A 6 103 X A R or R 2 116 6 103 X A R or R 9 10 11 12 13 14 15 16 + HO-(CR R ) -(CR R ) -(CR R ) -NR - R or protecting group n p q X A OH/SH 118 119 9 10 11 12 13 14 15 or 2 -(CR R ) -(CR R ) -(CR R ) -NR -protecting group O/S n p q 6 103 2 X A R or R 120 6 103 A R or R 120 121 X is Halogen or OSO CF 101 102 R and R e.g. together with the boron atom to which they are attached form R stands for substituents, which allow further transformation into R at a later stage in the synthesis 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); 101 2 6 4 5 4 5 R X A R R R R R (III) A B A 102 2 6 R A R O N O N 1 7 1 7 R R (II) R R 1 2 3 1 2 3 4 5 6 7 wherein A , A , A , R , R , R , R , R , R and R are as defined in claim1amd wherein X is 101 102 halogen or triflate, R and R are alkyl, cycloalkyl or together with the boron atom they are attached to form together a borolanyl.
In particular in the presence of catalysts, such as tri-o- tolylphosphine/palladium(II)acetate, tetrakis-(triphenylphosphine)-palladium, bis(triphenylphosphine)palladium(II)chloride or dichloro[1,1'-bis(diphenylphosphino)- ferrocene]palladium(II) 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 N,N-dimethylformamide, and in an inert atmosphere such as argon or nitrogen, in a temperature range particularly between room temperature and about 130 °, 1 2 3 1 2 3 4 5 6 7 wherein A , A , A , R , R , R , R , R , R and R are as defined in claim1amd wherein X is 103 104 halogen or triflate, R and R are alkyl, cycloalkyl or together with the boron atom they are attached to form together a borolanyl.
Also an embodiment of the present invention is a compound according to formula (I) as described herein for use as therapeutically active substance.
Likewise an embodiment of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.
Also described herein is 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.
Also described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease.
Also described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of congestive heart failure.
Also described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of hypertension.
Also described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of primary aldosteronism.
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, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
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.
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 (I) 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 (I) 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 described herein 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 described herein 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 described herein 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 described herein 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 described herein 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.
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.
G-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 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 (Cyp11B2) 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% FCS and 400 µg/ml 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: 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 µM Deoxycorticosterone and variable amounts of inhibitors; Cyp11B1 enzyme activity was tested in presence of 1 µM Deoxycortisol and variable amounts of inhibitors.
EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.170 3.70 0.076 0.41 1 11 2 0.430 >3 12 0.002 0.05 0.715 >3 0.319 17.89 3 13 4 0.011 0.35 14 0.308 1.57 0.019 1.08 15 0.019 1.20 6 0.098 3.34 16 0.011 0.86 0.056 0.57 4.649 >10 7 17 8 0.049 2.33 18 0.058 0.75 0.829 >10 0.023 0.80 9 19 0.020 0.17 20 0.003 0.02 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.021 0.26 0.010 0.12 21 39 22 0.025 0.10 40 0.015 0.75 0.032 0.39 0.067 5.56 23 41 24 0.007 0.22 42 0.028 0.16 0.005 0.11 43 0.040 1.56 26 0.018 0.57 44 0.005 0.568 0.007 0.27 0.087 0.863 27 45 28 0.121 0.78 46 0.005 0.298 0.260 5.56 0.003 0.061 29 47 0.170 10.22 48 0.049 0.392 31 0.172 >3 49 0.271 1.003 32 1.293 >10 50 0.003 0.024 1.256 >10 0.032 1.872 33 51 34 0.416 29.22 52 0.030 0.139 0.325 >10 0.008 0.453 53 36 0.071 2.57 54 n.d. 3.855 37 0.044 1.59 55 0.682 11.133 38 0.081 1.50 56 0.040 0.587 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.026 0.393 0.023 0.452 57 76 59 0.033 0.710 77 0.042 0.223 0.685 n.d. 0.121 1.145 60 78 61 0.508 20.108 79 0.035 0.302 62 0.177 8.543 80 0.043 0.493 63 0.731 15.994 81 0.172 4.635 0.423 12.328 0.008 0.020 64 82 65 0.315 13.084 83 0.009 0.046 0.710 n.d. 0.034 0.526 66 84 67 0.160 7.675 85 0.003 0.048 68 0.350 33.719 86 0.004 0.108 69 0.411 3.492 87 0.017 1.066 0.202 15.608 0.001 0.013 70 88 71 0.081 2.497 89 0.014 0.276 0.007 0.101 0.011 1.497 72 90 73 0.017 0.575 91 0.043 3.068 74 0.286 n.d. 92 0.016 0.632 75 0.008 0.509 93 0.023 0.613 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.023 1.336 0.006 0.151 94 112 95 0.017 1.781 113 0.075 1.575 0.022 1.676 0.008 0.142 96 114 97 0.006 0.111 115 0.001 0.014 98 0.011 0.360 116 0.003 0.081 99 0.035 1.117 117 0.008 0.121 0.007 0.140 0.004 0.682 100 118 101 0.002 0.179 119 0.006 0.075 0.014 1.441 0.000 0.008 102 120 103 0.015 2.927 121 0.019 1.371 104 0.010 0.094 122 0.009 0.535 105 0.086 2.581 123 0.062 2.917 0.020 2.683 0.005 0.138 106 124 107 0.002 0.044 125 0.003 0.154 0.032 1.110 0.007 0.642 108 126 109 0.078 0.712 127 0.012 0.400 110 0.006 0.187 128 0.119 2.286 111 0.004 0.081 129 0.030 0.613 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.162 10.483 0.375 11.100 130 153 131 0.003 0.440 154 0.114 1.427 0.029 4.800 0.047 0.589 132 155 133 0.010 0.837 156 0.155 1.374 134 0.003 0.094 157 0.463 3.256 135 0.006 0.163 158 0.239 6.429 0.047 2.433 0.180 7.933 136 159 137 0.006 0.872 160 0.113 0.716 0.003 0.267 0.001 0.008 138 161 139 0.018 0.455 162 0.062 2.853 140 0.114 6.646 163 0.061 2.387 141 0.856 19.889 164 0.009 0.207 0.003 0.380 0.013 0.494 142 165 143 0.009 0.051 166 0.022 1.206 0.004 0.460 0.018 0.898 144 167 145 0.175 3.779 168 0.014 0.273 151 0.005 0.090 169 0.035 0.850 152 0.154 4.752 170 0.015 0.699 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.009 0.420 0.002 0.093 171 189 172 0.001 0.069 190 0.007 0.442 0.031 0.800 0.010 0.777 173 191 174 0.033 1.225 192 0.029 1.981 175 0.007 0.688 193 0.022 1.009 176 0.128 n.d. 194 0.041 1.704 0.117 8.464 0.001 0.056 177 195 178 0.010 0.535 196 0.008 0.514 0.012 0.169 0.004 0.062 179 197 180 0.033 1.891 198 0.007 0.188 181 0.025 2.320 199 0.003 0.028 182 0.006 0.302 200 0.001 0.031 0.004 0.268 0.024 0.436 183 201 184 0.227 9.741 202 0.013 0.170 0.633 9.289 0.083 4.957 185 203 186 0.011 0.199 204 0.020 2.237 187 0.027 0.705 205 0.097 4.025 188 0.014 0.572 206 0.010 0.237 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.044 2.543 0.004 0.157 207 227 208 0.059 4.202 228 0.009 0.356 0.162 7.544 0.010 0.656 209 229 210 0.030 1.344 230 0.001 0.007 211 0.005 0.119 231 0.019 0.802 212 0.051 4.834 232 0.001 0.016 0.041 0.834 0.013 0.219 213 233 214 0.030 0.104 234 0.027 2.258 0.042 0.879 0.109 4.662 216 235 217 0.029 1.256 236 0.003 0.077 218 0.029 1.196 237 0.008 0.143 219 0.012 0.557 238 0.005 0.513 0.002 0.040 0.021 0.401 220 239 222 0.004 1.008 240 0.250 15.012 0.036 2.855 0.007 0.251 223 241 224 0.006 0.173 242 0.100 3.686 225 0.006 0.691 243 0.001 0.026 226 0.011 1.767 244 0.002 0.075 EC50 EC50 EC50 EC50 human human human human Example Example CYP11B2 CYP11B1 CYP11B2 CYP11B1 µM µM µM µM 0.001 0.072 0.022 0.679 245 257 246 0.013 4.723 258 0.013 0.291 0.005 0.069 0.001 0.154 247 259 248 0.000 0.007 260 0.000 0.001 249 0.014 0.261 261 0.062 1.222 250 0.035 1.247 262 0.084 1.817 0.001 0.006 3.101 n.d. 251 263 252 0.026 0.468 264 0.024 2.921 0.193 4.475 0.009 0.623 253 265 254 0.001 0.049 266 0.054 0.623 255 0.013 1.325 267 0.001 0.236 256 0.008 0.158 Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have EC (CYP11B2) values between 0.000001 uM and 1000 uM, particular compounds have EC (CYP11B2) values between 0.00005 uM and 500 uM, further particular compounds have EC (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, dragées, 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, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées 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 display also variable inhibition of CYP11B1. These compounds may be used for the inhibition of CYP11B1 in combination with variable inhibition of CYP11B2. 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), renal conditions, liver conditions, vascular conditions, inflammatory conditions, pain, retinopathy, neuropathy (such as peripheral neuropathy), insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction; fibrotic diseases, 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, heart failure, hypertrophic cardiomyopathy, impaired arterial compliance, impaired diastolic filling, ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrotic lesions, myocardial necrotic lesions cardiac arrhythmias, prevention of sudden cardiac death, restenosis, stroke, vascular damage.
Renal conditions include acute and chronic renal failure, end-stage renal disease, decreased creatinine clearance, decreased glomerular filtration rate, diabetic nephropathy, 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, nephropathy, proteinuria, reduced renal blood flow, renal arteriopathy, swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents).
Liver conditions include, but are not limited to, liver cirrhosis, liver ascites, hepatic congestion, nonalcoholic steatohepatitis and 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, splenic congestion, liver ascites, 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, 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 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 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 compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis Type II diabetes 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 I diabetes mellitus The invention is illustrated hereinafter by Examples, which have no limiting character.
In the following Examples, Examples 17, 24-28, 32-35, 74, 140, 141, 203-205, 208, 209, 216, 234-237 and 263 are reference examples.
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 1-Methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolin [A] 6-Bromomethyl-3,4-dihydro-1H-quinolinone To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0°C was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0 °C for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More MeI (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 °C until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2 x 200 mL). Combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (4.23 g, 80 %) as an off white solid. MS: 240.0, 242.1 (M+H ).
[B] 1-Methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolin A flask was charged with 6-bromomethyl-3,4-dihydro-1H-quinolinone (3 g, 12.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.81 g, 15.0 mmol), potassium acetate (3.68 g, 37.5 mmol) and dioxane (48 mL). The mixture was purged with Ar, then dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane complex (1:1) [PdCl (DPPF)-CH Cl adduct] (457 mg, 0.625 mmol) was added and the 2 2 2 resulting mixture was heated to 80 °C over night. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2 x 150 mL). The resulting filtrate was washed with brine, dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc- heptane gradient to give the title compound (2.63 g, 73 %) as an off white solid. MS: 288.0 (M+H ).
Intermediate A-2 6-(5-Amino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride [A] 2,2-Dimethyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]- propionamide A microwave vial was charged with N-(5-bromopyridinyl)pivalamide (0.2 g, 0.778 mmol), 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone (intermediate A-1) (0.246 g, 0.856 mmol) and DMF (4 mL). The reaction mixture was purged with Argon; then, bis(triphenylphosphine)palladium(II)chloride (0.055 g, 0.078 mmol), followed by 1N aqueous Na CO solution (2.33 mL, 2.33 mmol) were added and the reaction was heated in the microwave at 120 °C for 5 min. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2 x 20 mL). The resulting filtrate was washed with brine, dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.195 g, 74 %) as a white solid. MS: 338.2 (M+H ).
[B] 6-(5-Amino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride A suspension of 2,2-dimethyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-propionamide (0.195 g, 0.578 mmol) in 1N aqueous HCl (5.78 mL) was heated to 90 °C over night. The reaction mixture was evaporated to dryness and the resulting solid material was triturated in MeOH, filtered off and further dried in a the high vacuum to give the title compound (0. 115 g, 69 %) as an off white solid as the HCl salt.
MS: 254.1 (M+H ).
Intermediate A-3 6-{5-[(S)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]-pyridinyl} methyl-3,4-dihydro-1H-quinolinone [A] (S)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidine To a solution of (S)-pyrrolidinyl-methanol (0.69 g, 6.82 mmol) in DCM (3 mL) cooled to 0 °C was added TEA (1.38 g, 13.6 mmol) followed by TBDMS-Cl (1.03 g, 6.82 mmol) in DCM (3 mL). The reaction mixture was then stirred at room temperature over night and poured into NH Cl (20 mL). The aqueous layer was extracted with DCM (2 x 50 mL).
Combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness to give the title compound (1.11 g, 76%) as a yellow oil. MS: 216.2 (M+H ).
[B] 3-Bromo[(S)(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]-pyridine Br N To a solution of (S)((tert-butyldimethylsilyloxy)methyl)pyrrolidine (0.455 g, 2.11 mmol) in toluene (20 mL) were added tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (0.039 g, 0.042 mmol) and rac-2,2’-bis(diphenylphosphino)-1,1’- binaphthalene (rac-BINAP) (0.066 g, 0.106 mmol). The solution was purged with Argon and heated to 85 °C for 10 min. After cooling to room temperature, sodium tert-butoxide (0.406 g, 4.22 mmol) and 3,5-dibromopyridine (0.5 g, 2.11 mmol) were added and the reaction mixture was then heated to 85 °C over night. The mixture was poured into sat.
NH4Cl (20 mL) and the aqueous layer was extracted with DCM (2 x 25 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness.
The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH- DCM gradient to give the title compound (0.412 g, 53 %) as a yellow oil. MS: 371.0, 372.9 (M+H ).
[C] 6-{5-[(S)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]-pyridinyl} methyl-3,4-dihydro-1H-quinolinone A microwave vial was charged with 3-bromo[(S)(tert-butyl-dimethyl- silanyloxymethyl)-pyrrolidinyl]-pyridine (0.091 g, 0.245 mmol), 1-methyl(4,4,5,5- tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1, 0.077 g, 0.270 mmol) and DMF (1.5 mL). The reaction mixture was purged with Argon; then, bis(triphenylphosphine)palladium(II)chloride (0.017 g, 0.025 mmol), followed by a 1N Na CO aqueous solution (0.980 mL, 0.980 mmol) were added and the reaction mixture was heated in the microwave at 120 °C for 30 min. The reaction mixture was diluted with EtOAc, poured into aq. NaHCO (10 mL) and the aqueous layer was extracted with EtOAc (2 x 40 mL). Combined organics were washed with brine, dried over Na SO , filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.1 g, 90%) as a white solid. MS: 452.1 (M+H ).
Intermediate A-4 6-{5-[(R)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]-pyridinyl} methyl-3,4-dihydro-1H-quinolinone [A] (R)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidine In analogy to the procedure described for the preparation of intermediate A-3 [A], (R)- pyrrolidinyl-methanol was reacted with TBDMS-Cl in the presence of TEA to give the title compound as a yellow oil. MS: 216.3 (M+H ).
[B] 3-Bromo[(R)(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]-pyridine Br N In analogy to the procedure described for the preparation of intermediate A-3 [B], (R) (tert-butyl-dimethyl-silanyloxymethyl)-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: 371.0, 372.9 (M+H ).
[C] 6-{5-[(R)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]-pyridinyl} methyl-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of intermediate A-3 [C], 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to 3-bromo[(R)(tert-butyl-dimethyl- silanyloxymethyl)-pyrrolidinyl]-pyridine to give the title compound as a white solid.
MS: 452.1 (M+H ).
Intermediate A-5 3-Bromo((S)[1,2,4]triazolylmethyl-pyrrolidinyl)-pyridine Br N [A] [(S)(5-Bromo-pyridinyl)-pyrrolidinyl]-methanol Br N To a solution of 3-bromo[(S)(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidinyl]- pyridine (intermediate A-3 [B], 0.1 g, 0.269 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.202 mL, 0.808 mmol) and the reaction mixture was stirred at room temperature for 1h. The mixture was evaporated to dryness, the residue diluted with DCM, poured into aq. NaHCO (10 mL) and extracted with DCM (25 mL). The organic layer was dried over Na SO , filtered and evaporated to give the title compound (0.060 g, 87 %) as a yellow oil. MS: 257.0, 259.0 (M+H ).
[B] 3-Bromo((S)chloromethyl-pyrrolidinyl)-pyridine Br N To a solution of (S)-(1-(5-bromopyridinyl)pyrrolidinyl)methanol (0.060 g, 0.233 mmol) in DCM (1 mL) cooled to 0 °C was added thionyl chloride (0.112 g, 0.932 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min and then allowed to warm up to room temperature and stirring was continued over night. The mixture was diluted with DCM, poured into aq. NaHCO (10 mL) and the aqueous layer was extracted with DCM (2 x 20 mL). Combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness to give the title compound (0.055 g, 86 %) as an orange oil. MS: 275.0, 277.0 (M+H ).
[C] 3-Bromo((S)[1,2,4]triazolylmethyl-pyrrolidinyl)-pyridine To a solution of NaH (0.011 g, 0.272 mmol) in DMF (1 mL) was added 1H-1,2,4-triazole (0.016 g, 0.236 mmol) and the reaction mixture was stirred at room temperature for 30 min. Then, 3-bromo((S)chloromethyl-pyrrolidinyl)-pyridine (0.05 g, 0.181 mmol) in DMF (0.5 mL) was added to the reaction mixture which was heated to 80 °C over night.
The mixture was diluted with DCM, poured into aq. NaHCO3 (5 mL) and the aqueous layer was extracted with DCM (2 x 10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.04 g, 72 %) as a yellow oil. MS: 308.0, 310.0 (M+H ).
Intermediate A-6 3-Bromo((S)methoxymethyl-pyrrolidinyl)-pyridine In analogy to the procedure described for the preparation of intermediate A-3 [B], (S) methoxymethyl-pyrrolidine was reacted with 3,5-dibromopyridine in the presence of Pd (dba) , rac-BINAP and sodium tert-butoxide to give the title compound as a yellow oil.
MS: 271.1, 273.1 (M+H ).
Intermediate A-7 [2-(5-Bromo-pyridinyloxy)-ethyl]-carbamic acid tert-butyl ester To a solution of 5-bromopyridinol (0.5 g, 2.87 mmol) in THF (30 mL) cooled to 0 °C were added triphenylphosphine (0.829 g, 3.16 mmol) and tert-butyl 2- hydroxyethylcarbamate (0.51 g, 3.16 mmol) in THF (5 mL) followed by di-(4- chlorobenzyl)azodicarboxylate (1.16 g, 3.16 mmol), added portionwise, and the reaction mixture was then stirred at room temperature over night. The mixture was diluted with EtOAc, poured into aq. NaHCO3 (50 mL) and the aqueous layer was extracted with EtOAc (2 x 100 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was taken up in diethyl ether (50 mL) and left to stand in the fridge for 2h. After this time, the solid precipitate was filtered off and the resulting filtrate evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (0.57 g, 63%) as a white solid. MS: 317.0 and 319.0 (M+H ).
Intermediate A-8 Benzyl-(5-bromo-pyridinyl)-amine In analogy to the procedure described for the preparation of intermediate A-3 [B], benzylamine was reacted with 3,5-dibromopyridine in the presence of Pd (dba) , rac- BINAP and sodium tert-butoxide to give the title compound as a yellow solid. MS: 262.9, 264.9 (M+H ).
Intermediate A-9 (S)(5-Bromo-pyridinyl)hydroxymethyl-pyrrolidinone Br N In a sealed tube, 3,5-dibromopyridine (0.5 g, 2.11 mmol) was combined with (S) (hydroxymethyl)pyrrolidinone (0.243 g, 2.11 mmol), copper (I) iodide (0.040 g, 0.021 mmol), potassium carbonate (0.583 g, 4.22 mmol) and N,N’-dimethylethylenediamine (0.037g, 0.042 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated to 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 with a 0 to 10% MeOH-DCM gradient to give the title compound (0.140 g, 25 %) as a light yellow oil. MS: 271.1, 273.1 (M+H ).
Intermediate A-10 1-(5-Bromo-pyridinyl)-pyrrolidinone Br N In analogy to the procedure described for the preparation of intermediate A-9, 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 A-11 Ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide A flask 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 heated to 115 °C over night and then concentrated in vacuo. The residue was taken up in DCM (200 mL) and MeOH (200 mL) and NaBH4 (1.04 g, 27.4 mmol) was added portionwise 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 and washed with DCM (3 x 100 mL). The aqueous layer was separated and extracted with DCM (2 x 200 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% MeOH- DCM gradient to give the title compound (3.01 g, 79%) as an orange solid. MS: 279.0, 281.0 (M+H ).
Intermediate A-12 1-(5-Bromo-pyridinylmethyl)-pyrrolidinone [A] 3-Bromochloromethyl-pyridine To a solution of (5-bromopyridinyl)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 mL), basified with NaOH conc. (8 mL) and extracted with EtOAc (2 x 50 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-Heptane gradient to give the title compound (3.08 g, 93 %) as a white solid. MS: 206.0, 207.9 (M+H ).
[B] 1-(5-Bromo-pyridinylmethyl)-pyrrolidinone To a suspension of sodium hydride (60% in mineral oil, 0.044 g, 1.09 mmol) in DMF (2 mL) was added pyrrolidinone (0.081 g, 0.945 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 3-bromochloromethyl-pyridine (0.15 g, 0.727 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 EtOAc (2 x 10 mL).
Combined organics were dried over Na SO , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH- DCM gradient to give the title compound (0.217 g, 87 %) as a white solid. MS: 251.1, 257.1 (M+H ).
Intermediate A-13 1-(5-Bromo-pyridinylmethyl)-piperidinone In analogy to the procedure described for the preparation of intermediates A-12 [B], piperidinone was reacted with 3-bromochloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a colorless oil. MS: 269.2, 271.2 (M+H ).
Intermediate A-14 4-(5-Bromo-pyridinylmethyl)-thiomorpholine 1,1-dioxide In analogy to the procedure described for the preparation of intermediates A-12 [B], thiomorpholine 1,1-dioxide was reacted with 3-bromochloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a white solid. MS: 304.9, 307.0 (M+H ).
Intermediate A-15 3-Bromo((S)methoxymethyl-pyrrolidinylmethyl)-pyridine In analogy to the procedure described for the preparation of intermediates A-12 [B], (S) (methoxymethyl)pyrrolidine was reacted with 3-bromochloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow oil.
MS: 285.0, 286.9 (M+H ).
Intermediate A-16 6-{5-[(S)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinylmethyl]-pyridin yl}methyl-3,4-dihydro-1H-quinolinone [A] 3-Bromo[(S)(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidinylmethyl]- pyridine In analogy to the procedure described for the preparation of intermediates A-12 [B], (S) (tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine (intermediate A-3 [A]) was reacted with 3-bromochloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow solid. MS: 385.2, 387.2 (M+H ).
[B] 6-{5-[(S)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinylmethyl]-pyridin yl}methyl-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of intermediate A-3 [C], 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to 3-bromo[(S)(tert-butyl-dimethyl- silanyloxymethyl)-pyrrolidinylmethyl]-pyridine to give the title compound as an off white waxy solid. MS: 352.3 (M+H ).
Intermediate A-17 (S)(5-Bromo-pyridinylmethyl)-pyrrolidinecarboxylic acid methyl ester In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)- pyrrolidinecarboxylic acid methyl ester was reacted with 3-bromochloromethyl- pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a light yellow oil. MS: 299.2, 301.1 (M+H ).
Intermediate A-18 6-{5-[(S)(tert-Butyl-dimethyl-silanyloxymethyl)oxo-pyrrolidinylmethyl]- pyridinyl}methyl-3,4-dihydro-1H-quinolinone [A] (S)(tert-Butyl-dimethyl-silanyloxymethyl)-pyrrolidinone In analogy to the procedure described for the preparation of intermediate A-3 [A], (S) hydroxymethyl-pyrrolidinone was reacted with TBDMS-Cl in the presence of TEA to give the title compound as a colorless liquid. MS: 230.3 (M+H ).
[B] (S)(5-Bromo-pyridinylmethyl)(tert-butyl-dimethyl-silanyloxymethyl)- pyrrolidinone In analogy to the procedure described for the preparation of intermediates A-12 [B], (S) (tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidinone was reacted with 3-bromo chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a colorless oil. MS: 399.2, 401.2 (M+H ).
[C] 6-{5-[(S)(tert-Butyl-dimethyl-silanyloxymethyl)oxo-pyrrolidinylmethyl]- pyridinyl}methyl-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of intermediate A-3 [C], 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to (S)(5-bromo-pyridinylmethyl)(tert-butyl- dimethyl-silanyloxymethyl)-pyrrolidinone to give the title compound as a brown foam.
MS: 480.3 (M+H ).
Intermediate A-19 3-Bromo[(S)(2,2,2-trifluoro-ethoxymethyl)-pyrrolidinylmethyl]-pyridine [A] (S)Benzyl(2,2,2-trifluoro-ethoxymethyl)-pyrrolidine To a suspension of sodium hydride (60% in mineral oil, 0.314 g, 7.84 mmol) in THF (20 mL) was added (S)-(1-benzyl-pyrrolidinyl)-methanol (1.0 g, 5.23 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 2,2,2-trifluoroethyl methanesulfonate (1.4 g, 7.84 mmol) was added and stirring was continued at room temperature over night. The reaction mixture was quenched with H O (10 mL) and extracted with EtOAc (2 x 50 mL). Combined organics were dried over Na SO filtered 2 4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5 % MeOH(1% NH OH)-DCM gradient to give the title compound (0.706 g, 37 %) as a light yellow liquid. MS: 274.3 (M+H ).
[B] (S)(2,2,2-Trifluoro-ethoxymethyl)-pyrrolidine To a solution of (S)benzyl(2,2,2-trifluoroethoxymethyl)-pyrrolidine (0.5 g, 1.83 mmol) in MeOH (20 mL) was added Hunig's base (1.18 g, 9.15 mmol). The flask was purged three times with Ar and 10 % Pd/C (0.487 g, 0.457 mmol) was added to the mixture. The flask was purged three times with hydrogen and the reaction mixture was stirred at room temperature for 1h. The mixture was filtered through a pad of Celite, washed with MeOH (20 mL) and the resulting solution was concentrated in vacuo to give the title compound (0.250 g, 75%) as a colorless semi-solid. MS: 184.1 (M+H ).
[C] 3-Bromo[(S)(2,2,2-trifluoro-ethoxymethyl)-pyrrolidinylmethyl]-pyridine In analogy to the procedure described for the preparation of intermediates A-12 [B], (S) (2,2,2-trifluoro-ethoxymethyl)-pyrrolidine was reacted with 3-bromochloromethyl- pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow oil. MS: 353.1, 355.1 (M+H ).
Intermediate A-20 2-(6-Chloro-pyrazinylamino)-ethanol Cl N N In a sealed tube, 2,6-dichloropyrazine (1 g, 6.71 mmol) was mixed with 2-aminoethanol (0.492 g, 8.05 mmol), Hunig's base (1.13 g, 8.73 mmol) in BuOH (7 mL) and the reaction mixture was heated to 80 °C over night. The mixture was concentrated in vacuo and the residue partitioned between NaHCO (20 mL) and EtOAc (100 mL). The organic phase was separated, washed with brine, dried over Na SO , filtered and evaporated to dryness to give the title compound (0.583 g, 50%) as a light yellow foam. MS: 174.1 (M+H ).
Intermediate A-21 Benzyl-(6-chloro-pyrazinyl)-amine Cl N N In analogy to the procedure described for the preparation of intermediates A-20, benzyl- amine was reacted with 2,6-dichloropyrazine in presence of Hunig’s base to give the title compound as a light yellow foam. MS: 220.1 (M+H ).
Intermediate A-22 7-Fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone F N O [A] 6-Bromofluoromethyl-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of intermediates A-1 [A], 6- bromofluoro-3,4-dihydro-1H-quinolinone was reacted with methyl iodide in presence of potassium tert-butoxide to give the title compound as a white foam. MS: 258.0, 259.9 (M+H ).
[B] 7-Fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone F N O In analogy to the procedure described for the preparation of intermediates A-1 [B], 6- bromofluoromethyl-3,4-dihydro-1H-quinolinone was reacted with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in presence of potassium acetate and PdCl (DPPF)-CH Cl to give the title compound as a white solid. MS: 306.1 (M+H ). 2 2 2 Intermediate A-23 1,4,4-Trimethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone In analogy to the procedure described for the preparation of intermediates A-1 [B], 6- bromo-1,4,4-trimethyl-3,4-dihydro-1H-quinolinone was reacted with 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) in presence of potassium acetate and PdCl (DPPF)-CH Cl to give the title compound as an off-white solid. MS: 316.1 2 2 2 (M+H ).
Intermediate A-24 6-(6-Chloro-pyrazinyl)-2,6-diaza-spiro[3.3]heptanecarboxylic acid tert-butyl ester Cl N N In analogy to the procedure described for the preparation of intermediate A-20, 2,6-diaza- spiro[3.3]heptanecarboxylic acid tert-butyl ester was reacted with 2,6-dichloropyrazine in presence of Hunig’s base to give the title compound as a white solid.
Intermediate A-25 6-(5-Bromo-pyridinyl)-2,6-diaza-spiro[3.3]heptanecarboxylic acid tert-butyl ester Br N In analogy to the procedure described for the preparation of intermediate A-3 [B], 2,6- diaza-spiro[3.3]heptanecarboxylic acid tert-butyl ester 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 white solid.
Intermediate A-26 (S)(5-Bromo-pyridinyloxymethyl)-azetidinecarboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (S)hydroxymethyl-azetidinecarboxylic acid tert- butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as an amorphous colorless solid. MS: 343.1 and 345.1 (M+H ).
Intermediate A-27 (R)(5-Bromo-pyridinyloxy)-pyrrolidinecarboxylic acid tert-butyl ester Br O In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (S)hydroxy-pyrrolidinecarboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a white solid. MS: 343.1 and 345.1 (M+H ).
Intermediate A-28 3-(5-Bromopyridinyloxy)-azetidinecarboxylic acid tert-butyl ester Br O To a solution of 5-bromopyridinol (0.285 g, 1.64 mmol) in DMF (2.5 mL) was added K CO (0.453 g, 3.28 mmol), followed by 3-bromo-azetidinecarboxylic acid tert-butyl ester (0.425 g, 1.8 mmol) in DMF (0.5 mL) and the reaction mixture was heated to 60 °C and stirred over night. The reaction mixture was diluted with EtOAc, poured into sat.
NaHCO3 solution (10 mL) and the aqueous layer was extracted EtOAc (2 x 20 mL).
Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (0.539 g, 100%) as a colorless crystalline solid. MS: 329.1 (M+H ).
Intermediate A-29 (S)(5-Bromo-pyridinyloxy)-pyrrolidinecarboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (R)hydroxy-pyrrolidinecarboxylic acid tert- butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless oil. MS: 343.1 and 345.1 (M+H ).
Intermediate A-30 (S)- 3-(5-Bromopyridinyloxy)-piperidinecarboxylic acid tert-butyl ester Br O In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (R)hydroxy-piperidinecarboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a light yellow oil. MS: 357.1 and 359.1 (M+H ).
Intermediate A-31 4-(5-Bromopyridinyloxy)-piperidinecarboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with 4-hydroxy-piperidinecarboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a light yellow amorphous solid. MS: 357.0 and 359.0 (M+H ).
Intermediate A-32 (S)((5-Bromopyridinyloxy)methyl)pyrrolidinecarboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (S)(hydroxymethyl)pyrrolidinecarboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless oil. MS: 357.0 and 359.0 (M+H ).
Intermediate A-33 (R)-N-(3-(5-Bromopyridinyl)oxetanyl)methylpropanesulfinamide [A] (R)Methyl-N-(oxetanylidene)-propanesulfinamide To a solution of Ti(OEt) (2.02 g, 7.53 mmol) in THF (20 mL) was added (R) methylpropanesulfinamide (0.854 g, 7.05 mmol) followed by oxetanone (0.493 g, 6.84 mmol) in THF (5 mL) and the reaction mixture was heated to 50 °C over night. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and a saturated solution of brine (20 mL) was slowly added under stirring. After 15 min, the mixture was filtered through a plug of Dicalite and washed with EtOAc. The organic phase was separated, dried over Na SO and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40 % EtOAc-heptane gradient to give the title compound (0.242 g, 20 %) as a light yellow oil. MS: 176.2 (M+H ).
[B] (R)-N-(3-(5-Bromopyridinyl)oxetanyl)methylpropanesulfinamide Br S To a solution of 3-bromoiodopyridine (0.14 g, 0.493 mmol) in THF (2 mL) cooled at - 78 °C was added nBuLi (462 µl, 0.74 mmol) dropwise over 5 min. The reaction mixture was stirred at -78 °C for 15 min, then (R)methyl-N-(oxetanylidene)-propane sulfinamide (0.1 g, 0.567 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 10 min then allowed to warm up to RT. The mixture was quenched with water (2 mL) and extracted with EtOAc (2 x 10 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 100 % EtOAc-heptane gradient to give the title compound (0.096 g, 58 %) as a light yellow oil. MS: 333.0 and 335.1 (M+H ).
Intermediate A-34 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)-3,4-dihydroquinolin-2(1H)-one In analogy to the procedure described for the preparation of intermediates A-1 [B], 6-bromo-3,4-dihydroquinolin-2(1H)-one was reacted with 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(1,3,2-dioxaborolane) in presence of potassium acetate and PdCl (DPPF)-CH Cl to 2 2 2 give the title compound as a colorless solid. MS: 274.4 (M+H ).
Intermediate A-35 (R)Methyl-propanesulfinic acid [(S and R)(5-bromo-pyridinyl)-ethyl]- amide [A] (R, E)-N-(1-(5-Bromopyridinyl)ethylidene)methylpropanesulfinamide To a solution of 1-(5-bromopyridinyl)ethanone (1.01 g, 5.04 mmol) in DCM (20 mL) was added (R)methylpropanesulfinamide (0.555 g, 4.58 mmol) followed by Ti(OEt)4 (1.23 g, 4.58 mmol) dropwise and the reaction mixture was heated to 40 °C over night.
After cooling, the solvent was removed under vacuum and the residue taken up in EtOAc (80 mL). This solution was vigorously stirred while a saturated solution of brine (20 mL) was slowly added. After 15 min, the mixture was filtered through a plug of Dicalite and washed with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 50 % EtOAc-heptane gradient to give the title compound (0.964 g, 69 %) as a yellow oil.
MS: 303.1 and 305.0 (M+H ).
[B] (R)Methyl-propanesulfinic acid [(S and R)(5-bromo-pyridinyl)-ethyl]- amide Br S (R and S) (S and R) To a solution of (R, E)-N-(1-(5-bromopyridinyl)ethylidene)methylpropane sulfinamide (0.3 g, 0.989 mmol) in MeOH (20 mL) cooled at 0 °C with an ice bath was added NaBH (0.075 g, 1.98 mmol) portionwise and the reaction mixture was stirred at this temperature for 30 min and then at room temperature for another 30 min. The mixture was quenched with sat. ammonium chloride solution (10 mL), the organic solvent was evaporated and the resulting aqueous solution was extracted with EtOAc (2 x 25 mL).
Combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness to give the title compound (0.293 g, 97 %) as a colorless solid as a 2:1 mixture of both diastereoisomers. MS: 305.0 and 307.1 (M+H ).
Intermediate A-36 6-(6-(2,6-Diazaspiro[3.3]heptanyl)pyrazinyl)methyl-3,4-dihydroquinolin- 2(1H)-one 2,2,2-trifluoroacetate To a solution of 6-[6-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyrazinyl]-2,6- diaza-spiro[3.3]heptanecarboxylic acid tert-butyl ester (example 28, 0.231 g, 0.53 mmol) in DCM (3 mL) was added TFA (0.605 g, 5.3 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was evaporated several times with toluene and then the residue was purified by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH-H2O (0.05 % TEA) gradient to give the title compound (0.203 g, 99 %) as a yellow solid (TFA salt). MS: 336.3 (M+H ).
Intermediate A-37 (rac)-N-(1-(5-Bromopyridinyl)ethyl)ethanesulfonamide Br S In analogy to the procedure described for the preparation of intermediate A-11, 1-(5- bromo-pyridinyl)-ethanone was reacted with ethanesulfonamide in presence of titanium tetra-isopropoxide and then NaBH to give the title compound as a light yellow oil. MS: 293.1 and 295.3 (M+H ).
Intermediate A-38 (rac)-N-(1-(5-Bromopyridinyl)propyl)ethanesulfonamide Br S A flask was charged with 5-bromonicotinaldehyde (0.5 g, 2.69 mmol), ethanesulfonamide (0.367 g, 3.36 mmol) and toluene (25 mL), then titanium tetra-isopropoxide (1.53 g, 5.38 mmol) was added dropwise. The reaction mixture was heated to 110 °C over night and then concentrated in vacuo. The residue was dissolved in THF (25 mL) and cooled down to -40 °C. A 3 M solution of ethylmagnesium bromide in ether (2.24 mL, 6.72 mmol) was added dropwise at this temperature and the resulting mixture was slowly warmed up to -20 °C and stirred for 2.5 h. The mixture was poured into a saturated NH Cl solution (15 mL), the resulting suspension was filtered and the filtrate was extracted with DCM (2 x 50 mL).
Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH- DCM gradient to give the title compound (0.5 g, 56%) as light yellow oil. MS: 307.1 and 308.9.
Intermediate A-39 (rac)-N-((5-Bromopyridinyl)(cyclopropyl)methyl)ethanesulfonamide In analogy to the procedure described for the preparation of intermediate A-38, 5- bromonicotinaldehyde was reacted with ethanesulfonamide in presence of titanium tetra- isopropoxide and then cyclopropylmagnesium bromide (0.5 M in THF) to give the title compound as a yellow oil. MS: 319.0 and 320.9 (M+H ).
Intermediate A-40 (rac)-N-(1-(5-Bromopyridinyl)methylpropyl)ethanesulfonamide Br S In analogy to the procedure described for the preparation of intermediate A-38, 5- bromonicotinaldehyde was reacted with ethanesulfonamide in presence of titanium tetra- isopropoxide and then isopropylmagnesium chloride (2 M in THF) to give the title compound as a red oil. MS: 321.0 and 323.0 (M+H ).
Intermediate A-41 N-((5-Bromopyridinyl)methyl)-N-methylethanesulfonamide Br S To a solution of ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A- 11, 0.21 g, 0.752 mmol) in DMF (6 mL) cooled at 0 °C with an ice bath was added 60 % NaH in mineral oil (0.039 g, 0.98 mmol) and the mixture was stirred for 15 min. Then, MeI (0.136 g, 0.96 mmol) was added and the reaction was stirred at 0 °C for another 15 min before being quenched with aq. ammonia (2 mL). The mixture was further diluted with brine and then extracted with EtOAc (2 x 15 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness to give the title compound (0.209 g, 85 %) as a yellow oil which was used with no further purification. MS: 293.1 and 295.1 (M+H ).
Intermediate A-42 N-((5-Bromopyridinyl)methyl)-N-ethylethanesulfonamide To a solution of ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A- 11, 0.051 g, 0.182 mmol) in DMF (3 mL) cooled at 0 °C with an ice bath was added 60 % NaH in mineral oil (0.011 g, 0.274 mmol) and the mixture was stirred at room temperature for 20 min. Then, iodoethane (0.045 g, 0.292 mmol) was added and the reaction mixture was stirred for 3 h before being quenched with water (5 mL). The aqueous solution was extracted with EtOAc (2 x 15 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness to give the title compound (0.051 g, 82 %) as orange oil which was used with no further purification. MS: 307.1 and 309.2 (M+H ).
Intermediate A-43 N-((5-Bromopyridinyl)methyl)-N-isopropylethanesulfonamide Br S In analogy to the procedure described for the preparation of intermediate A-42, ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11) was reacted with 2-iodopropane in presence of NaH (60 % in mineral oil) to give the title compound as white solid after purification by reverse phase HPLC on a Gemini-NX column. MS: 323.1 (M+H ).
Intermediate A-44 N-((5-Bromopyridinyl)methyl)-Nethoxy-ethylethanesulfonamide In analogy to the procedure described for the preparation of intermediate A-42, ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11) was reacted with 2-bromoethyl ethyl ether in presence of NaH (60 % in mineral oil) to give the title compound as yellow oil after purification by reverse phase HPLC on a Gemini-NX column. MS: 351.0 and 353.1 (M+H ).
Intermediate A-45 (rac)-N-(1-(5-Bromopyridinyl)ethyl)-N-methylethanesulfonamide Br S In analogy to the procedure described for the preparation of intermediate A-41, N-(1-(5- bromopyridinyl)ethyl)ethanesulfonamide (intermediate A-37) was reacted with MeI in presence of NaH (60 % in mineral oil) to give the title compound as a light yellow solid.
MS: 307.1 and 309.2 (M+H ).
Intermediate A-46 (rac)-N-(1-(5-Bromopyridinyl)ethyl)-N-ethylethanesulfonamide Br S In analogy to the procedure described for the preparation of intermediate A-42, N-(1-(5- bromopyridinyl)ethyl)ethanesulfonamide (intermediate A-37) was reacted with iodoethane in presence of NaH (60 % in mineral oil) to give the title compound as a yellow oil. MS: 321.0 and 323.1 (M+H ).
Intermediate A-47 1-Methyl-1H-pyrazolecarboxylic acid (5-bromo-pyridinylmethyl)-amide In analogy to the procedure described for the preparation of example 75, coupling of (5- bromopyridinyl)methanamine with 1-methyl-1H-pyrazolecarboxylic gave the title compound as a colorless solid. MS: 297.1 and 295.0 (M+H ).
Intermediate A-48 2-(5-Bromo-pyridinylmethyl)-isothiazolidine 1,1-dioxide In analogy to the procedure described for the preparation of intermediate A-12 [B], isothiazolidine 1,1-dioxide was reacted with 3-bromochloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a light yellow oil. MS: 292.8 and 290.9 (M+H ).
Intermediate A-49 N-(2-(5-Bromopyridinyl)propanyl)ethanesulfonamide A flask was charged with 1-(5-bromopyridinyl)ethanone (0.5 g, 2.5 mmol), ethanesulfonamide (0.341 g, 3.12 mmol) and toluene (25 mL), then titanium tetra- isopropoxide (1.42 g, 5 mmol) was added dropwise. The reaction mixture was heated to 110 °C over night and then concentrated in vacuo to give the imine intermediate (0.73 g) as a light brown oil. A part of this the imine intermediate (0.4 g) was dissolved in THF (10 mL) and the mixture was cooled down to -78 °C. A 3 M solution of methylmagnesium bromide in ether (1.14 mL, 3.43 mmol) was added dropwise at this temperature and the resulting mixture was stirred at -70 °C for 3 h. It was then allowed to warm up to 0 °C before being quenched with a saturated NH Cl solution (10 mL). The resulting suspension was filtered and the filtrate was extracted with DCM (2 x 30 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.1 g, 17 %) as a yellow oil which was used with no further purification.
MS: 307.1 and 309.1 (M+H ).
Intermediate A-50 N-((5-Bromopyridinyl)methyl)-N,3,5-trimethylisoxazolecarboxamide In analogy to the procedure described for the preparation of intermediate A-41, 3,5- dimethyl-isoxazolecarboxylic acid (5-bromo-pyridinylmethyl)-methyl-amide (prepared as described for the preparation of intermediate A-47) was reacted with MeI in presence of NaH (60 % in mineral oil) to give the title compound as a yellow solid. MS: 326.3 and 324.2 (M+H ).
Intermediate A-51 3-Bromo[2-(1,1-dioxo-1λ -isothiazolidinyl)-ethoxy]-pyridine Br O [A] 2-(2-Chloro-ethyl)-isothiazolidine-1,1-dioxide To a solution of 2-(1,1-dioxo-1λ -isothiazolidinyl)-ethanol (0.14 g, 0.847 mmol) in DCM (4 mL) was added SOCl (0.151 g, 1.27 mmol) and the reaction mixture was heated to 40 °C for 2 h. The mixture was cooled to room temperature, diluted with DCM, poured into a sat. NaHCO solution (10 mL) and the aqueous layer was extracted with DCM (2 x mL). Combined organics were dried over Na SO , filtered and evaporated to dryness to give the title compound (0.046 g, 30 %) as an orange oil which was used with no further purification. MS: 184.1 (M+H ).
[B] 3-Bromo[2-(1,1-dioxo-1λ -isothiazolidinyl)-ethoxy]-pyridine Br O To a solution of 2-(2-chloro-ethyl)-isothiazolidine-1,1-dioxide (0.046 g, 0.253 mmol) and -bromopyridinol (0.04 g, 0.230 mmol) in DMF (1 mL) was added K CO (0.064 g, 0.46 mmol), followed by KI (0.008 g, 0.046 mmol) and the reaction mixture was heated to 60 °C and stirred over night. The mixture was diluted with EtOAc, poured into a sat.
NaHCO solution (5 mL) and the aqueous layer was extracted with EtOAc (2 x 10 mL).
Combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to % MeOH-DCM gradient to give the title compound (0.015 g, 20 %) as a yellow oil which was used with no further purification. MS: 321.3 and 323.2 (M+H ).
Intermediate A-52 N-((5-Bromomethylpyridinyl)methyl)ethanesulfonamide Br S In analogy to the procedure described for the preparation of intermediate A-11, 5-bromo- 4-methyl-pyridinecarbaldehyde has been reacted first with ethanesulfonamide, followed by reduction of the thus formed imine with NaBH4 in MeOH to give the title compound as an off-white solid. MS: 293.1 and 295.3 (M+H ).
Intermediate A-53 N-((5-Bromochloropyridinyl)methyl)ethanesulfonamide In analogy to the procedure described for the preparation of intermediate A-11, 5-bromo- 4-chloro-pyridinecarbaldehyde has been reacted first with ethanesulfonamide, followed by reduction of the thus formed imine with NaBH in MeOH to give the title compound as a light orange solid. MS: 313.2 and 315.1 (M+H ).
Intermediate A-54 tert-Butyl (trans)(5-bromopyridinyloxy)cyclohexylcarbamate Br O In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (cis)-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless solid. MS: 371.3 and 373.3 (M+H ).
Intermediate A-55 (R)((5-Bromopyridinyloxy)methyl)pyrrolidinecarboxylic acid tert-butyl ester Br O In analogy to the procedure described for the preparation of intermediate A-7, 5- bromopyridinol was reacted with (R)(hydroxymethyl)pyrrolidinecarboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as an orange oil. MS: 357.3 and 359.3 (M+H ).
Intermediate A-56 N-((5-Bromopyridinyl)methyl)chloropicolinamide In analogy to the procedure described for the preparation of example 75, coupling of (5- bromopyridinyl)methanamine with 3-chloro-pyridinecarboxylic acid gave the title compound as off-white solid. MS: 326.2 and 328.2 (M+H ).
Intermediate A-57 N-((5-Bromopyridinyl)methyl)chloro-N-methylpicolinamide In analogy to the procedure described for the preparation of intermediate A-41, N-((5- bromopyridinyl)methyl)chloropicolinamide (intermediate A-56) was reacted with MeI in presence of NaH (60 % in mineral oil) to give the title compound as a dark brown oil. MS: 340.2 and 342.2 (M+H ).
Intermediate A-58 (R)-N-((5-Bromochloropyridinyl)methyl)methylpropanesulfinamide Cl O Chiral Br S (R)Methyl-propanesulfinic acid 1-(5-bromochloro-pyridinyl)-meth-(E)- ylideneamide, prepared from (R)methylpropanesulfinamide and 5-bromochloro- pyridinecarbaldehyde in analogy to procedure described for the preparation of intermediate A-35 [A], has been reduced with NaBH in MeOH in analogy to the procedure described for the preparation of intermediate A-35 [B] to give the title compound as a yellow oil. MS: 325.2 (M+H ).
Intermediate A-59 (R)Methyl-propanesulfinic acid (5-bromomethyl-pyridinylmethyl)-amide Chiral Br S (R)Methyl-propanesulfinic acid 1-(5-bromomethyl-pyridinyl)-meth-(E)- ylideneamide, prepared from (R)methylpropanesulfinamide and 5-bromomethyl- pyridinecarbaldehyde in analogy to procedure described for the preparation of intermediate A-35 [A], has been reduced with NaBH in MeOH in analogy to the procedure described for the preparation of intermediate A-35 [B] to give the title compound as colorless solid. MS: 305.3 and 307.4 (M+H ).
Intermediate A-60 (R)Methyl-propanesulfinic acid [(R or S)(5-bromomethyl-pyridinyl)- ethyl]-amide Chiral Br S (R or S) (R)Methyl-propanesulfinic acid 1-(5-bromomethyl-pyridinyl)-meth-(E)- ylideneamide, prepared from (R)methylpropanesulfinamide and 5-bromomethyl- pyridinecarbaldehyde in analogy to procedure described for the preparation of intermediate A-35 [A], has been reacted with methylmagnesium bromide in analogy to the procedure described for the preparation of intermediate A-49 from the corresponding imine intermediate to give the title compound as light yellow amorphous solid. MS: 319.2 and 321.3 (M+H ).
Intermediate A-61 (R)Methyl-propanesulfinic acid [(R or S)(5-bromochloro-pyridinyl)- ethyl]-amide Cl O Chiral Br S (R or S) (R)Methyl-propanesulfinic acid 1-(5-bromochloro-pyridinyl)-meth-(E)- ylideneamide, prepared from (R)methylpropanesulfinamide and 5-bromochloro- pyridinecarbaldehyde in analogy to procedure described for the preparation of intermediate A-35 [A], has been reacted with methylmagnesium bromide in analogy to the procedure described for the preparation of intermediate A-49 from the corresponding imine intermediate to give the title compound as orange oil. MS: 341.2 (M+H ).
Example 1 Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yl]-amide To a solution of 6-(5-amino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (intermediate A-2, 0.02 g, 0.079 mmol) in DCM (0.5 mL) was added triethylamine (0.024 g, 0.237 mmol) followed by ethanesulfonyl chloride (0.01 g, 0.079 mmol) and the reaction mixture was stirred at room temperature for 1h. The mixture was diluted with DCM, poured into water (5 mL) and the aqueous layer was extracted with DCM (2 x 20 mL).
Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10 % MeOH- DCM gradient to give the title compound (0.007 g, 23 %) as a brown solid. MS: 346.0 (M+H ).
Example 2 Acetic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylcarbamoyl]-methyl ester To a solution of 6-(5-amino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride (intermediate A-2, 0.045 g, 0.155 mmol) in DCM (1.5 mL) was added TEA (0.039 g, 0.388 mmol) followed by 2-chlorooxoethyl acetate (0.017 g, 0.124 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2h. The mixture was diluted with DCM, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with DCM (2 x 25 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5 % MeOH-DCM gradient to give the title compound (0.025 g, 46 %) as a light brown solid. MS: 354.2 (M+H ).
Example 3 2-Hydroxy-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]- acetamide To a solution of acetic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin- 3-ylcarbamoyl]-methyl ester (example 2, 0.025 g, 0.071 mmol) in MeOH (1 mL) was added a 1M aqueous solution of Na CO (0.354 mL) and the reaction mixture was stirred at room temperature for 1h. The mixture was evaporated to dryness, the residue dissolved in EtOAc (20 mL) and washed with aq. NaHCO (5 mL). The organic layer was separated, dried over Na SO , filtered and evaporated to dryness to give the title compound (0.02 g, 91%) as light brown solid. MS: 312.1 (M+H ).
Example 4 6-[5-(2-Hydroxy-ethylamino)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone [A] 6-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-pyridinyl}methyl-3,4- dihydro-1H-quinolinone N Si To a solution of 6-(5-amino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride (intermediate A-2, 0.062 g, 0.214 mmol) in MeOH (1.5 mL) was added AcOH (0.154 g, 2.57 mmol), followed by 2-(tert-butyldimethylsilyloxy)acetaldehyde (0.039 g, 0.225 mmol) and the reaction mixture was stirred at room temperature for 1h.
Then, NaBH CN (0.027 g, 0.428 mmol) in THF (0.6 mL) was added to the reaction mixture and stirring at room temperature was continued for 2h. The mixture was diluted with EtOAc, poured into aq. NaHCO (10 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). Combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5 % MeOH-DCM gradient to give the title compound (0.06 g, 68 %) as a yellow solid. MS: 412.3 (M+H ).
[B] 6-[5-(2-Hydroxy-ethylamino)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone To solution of 6-{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridinyl} methyl-3,4-dihydro-1H-quinolinone (0.06 g, 0.146 mmol) in MeOH (2.5 mL) was added 4M HCl in dioxane (0.255 ml, 1.02 mmol) and the reaction mixture was stirred at room temperature for 2h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (20 mL) and washed with aq. NaHCO3 (5 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 2 % MeOH(1% NH4OH)-DCM gradient to give the title compound (0.01 g, 22 %) as an off white solid. MS: 298.3 (M+H ).
The following compounds listed in Table 1 were prepared in analogy to the procedure described for the preparation of example 4 [B] using appropriate starting materials Table 1 Ex Name and Structure Starting Materials Aspect (M+H ) 6-[5-((S) Hydroxymethyl-pyrrolidin- 6-{5-[(S)(tert-Butyl- 1-yl)-pyridinyl] dimethyl- methyl-3,4-dihydro-1H- silanyloxymethyl)- Light quinolinone pyrrolidinyl]-pyridin yellow 338.2 yl}methyl-3,4-dihydro- solid 1H-quinolinone (intermediate A-3) Ex Name and Structure Starting Materials Aspect (M+H ) 6-[5-((R) Hydroxymethyl-pyrrolidin- 6-{5-[(R)(tert-Butyl- 1-yl)-pyridinyl] dimethyl- methyl-3,4-dihydro-1H- silanyloxymethyl)- Light quinolinone pyrrolidinyl]-pyridin yellow 338.2 yl}methyl-3,4-dihydro- solid 1H-quinolinone (intermediate A-4) 6-[5-((S) Hydroxymethyl-pyrrolidin- 6-{5-[(S)(tert-Butyl- 1-ylmethyl)-pyridinyl]- dimethyl- 1-methyl-3,4-dihydro-1H- silanyloxymethyl)- Off white quinolinone 7 pyrrolidinylmethyl]- waxy 352.3 pyridinyl}methyl- solid 3,4-dihydro-1H-quinolin- 2-one (intermediate A-16) 6-[5-((S) 6-{5-[(S)(tert-Butyl- Hydroxymethyloxo- dimethyl- pyrrolidinylmethyl)- silanyloxymethyl)oxo- pyridinyl]methyl-3,4- pyrrolidinylmethyl]- dihydro-1H-quinolinone White 8 366.2 pyridinyl}methyl- Foam 3,4-dihydro-1H-quinolin- 2-one (intermediate A-18) Example 9 6-[5-((S)Ethylaminomethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone [A] 6-[5-((S)Chloromethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone In analogy to the procedure described for the preparation of intermediate A-5 [B], 6-[5- ((S)hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one (example 5) has been reacted with thionyl chloride to give the title compound as an orange oil. MS: 356.1 (M+H ).
[B] 6-[5-((S)Ethylaminomethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone In a sealed tube, a solution of 6-[5-((S)chloromethyl-pyrrolidinyl)-pyridinyl] methyl-3,4-dihydro-1H-quinolinone (0.066 g, 0.185 mmol) in CH3CN (2.5 mL) was mixed with K2CO3 (0.064 g, 0.464 mmol), TEA (0.188 g, 1.85 mmol), sodium iodide (0.028 g, 0.185 mmol) and ethanamine hydrochloride (0.151 g, 1.85 mmol). The reaction mixture was then heated to 80 °C over night. The mixture was diluted with EtOAc, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with EtOAc (2 x 20 mL).
Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography, eluting with a 0 to % MeOH(1% NH4OH)-DCM gradient to give the title compound (0.02 g, 30 %) as an orange gum. MS: 365.2 (M+H ).
Example 10 6-[5-((S)Methoxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone In analogy to the procedure described for the preparation of intermediate A-3 [C], 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to 3-bromo((S)methoxymethyl-pyrrolidinyl)- pyridine (intermediate A-6) to give the title compound as a yellow oil. MS: 352.3 (M+H ).
The following compounds listed in Table 2 were prepared in analogy to the procedure described for the preparation of intermediate A-3 [C], using the appropriate starting materials.
Table 2 Ex Name Starting Materials Aspect (M+H ) 3-Bromo((S) [1,2,4]triazol 1-Methyl[5-((S) ylmethyl-pyrrolidin- [1,2,4]triazolylmethyl- 1-yl)-pyridine pyrrolidinyl)-pyridinyl]- (intermediate A-5) Light 3,4-dihydro-1H-quinolinone and 1-methyl brown 389.1 O N (4,4,5,5-tetramethyl- foam [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Benzyl-(5-bromo- pyridinyl)-amine 6-(5-Benzylamino-pyridinyl)- (intermediate A-8) 1-methyl-3,4-dihydro-1H- and 1-methyl quinolinone White 12 (4,4,5,5-tetramethyl- 344.1 solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (S)(5-Bromo- pyridinyl) 6-[5-((S)Hydroxymethyl hydroxymethyl- oxo-pyrrolidinyl)-pyridin pyrrolidinone yl]methyl-3,4-dihydro-1H- (intermediate A-9) White quinolinone and 1-methyl yellow 352.3 (4,4,5,5-tetramethyl- foam [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) 1-(5-Bromo-pyridin- 3-yl)-pyrrolidin 1-Methyl[5-(2-oxo- one (intermediate A- pyrrolidinyl)-pyridinyl]- ) and 1-methyl 3,4-dihydro-1H-quinolinone White 14 (4,4,5,5-tetramethyl- 322.1 solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ethanesulfonic acid (5-bromo-pyridin Ethanesulfonic acid [5-(1- ylmethyl)-amide methyloxo-1,2,3,4- (intermediate A-11) tetrahydro-quinolinyl)- and 1-methyl White pyridinylmethyl]-amide 360.1 (4,4,5,5-tetramethyl- foam [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) Ethanesulfonic acid (5-bromo-pyridin Ethanesulfonic acid [5-(7- ylmethyl)-amide fluoromethyloxo-1,2,3,4- (intermediate A-11) tetrahydro-quinolinyl)- and 7-fluoro White pyridinylmethyl]-amide methyl(4,4,5,5- 378.2 solid O N F tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) Ethanesulfonic acid (5-bromo-pyridin Ethanesulfonic acid [5-(1,4,4- ylmethyl)-amide trimethyloxo-1,2,3,4- (intermediate A-11) tetrahydro-quinolinyl)- and 1,4,4-trimethyl- Off white pyridinylmethyl]-amide 17 6-(4,4,5,5- 388.1 solid tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-23) Ex Name Starting Materials Aspect (M+H ) 1-(5-Bromo-pyridin- 3-ylmethyl)- 1-Methyl[5-(2-oxo- pyrrolidinone pyrrolidinylmethyl)-pyridin- (intermediate A-12) 3-yl]-3,4-dihydro-1H-quinolin- and 1-methyl Brown 2-one 336.4 (4,4,5,5-tetramethyl- foam [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) 1-(5-Bromo-pyridin- 3-ylmethyl)- 1-Methyl[5-(2-oxo-piperidin- piperidinone 1-ylmethyl)-pyridinyl]-3,4- (intermediate A-13) dihydro-1H-quinolinone and 1-methyl White 19 350.3 (4,4,5,5-tetramethyl- solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) 4-(5-Bromo-pyridin- 3-ylmethyl)- 6-[5-(1,1-Dioxo-1λ - thiomorpholine 1,1- thiomorpholinylmethyl)- dioxide pyridinyl]methyl-3,4- (intermediate A-14) dihydro-1H-quinolinone White and 1-methyl 386.2 solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) 3-Bromo((S) methoxymethyl- 6-[5-((S)Methoxymethyl- pyrrolidin pyrrolidinylmethyl)-pyridin- ylmethyl)-pyridine 3-yl]methyl-3,4-dihydro-1H- (intermediate A-15) quinolinone Colorless and 1-methyl 366.3 (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) (S)(5-Bromo- pyridinylmethyl)- (S)[5-(1-Methyloxo- pyrrolidine 1,2,3,4-tetrahydro-quinolin carboxylic acid yl)-pyridinylmethyl]- methyl ester pyrrolidinecarboxylic acid (intermediate A-17) methyl ester 22 Brown oil 380.3 and 1-methyl (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) 3-Bromo[(S) 1-Methyl{5-[(S)(2,2,2- (2,2,2-trifluoro- trifluoro-ethoxymethyl)- ethoxymethyl)- pyrrolidinylmethyl]-pyridin- pyrrolidin 3-yl}-3,4-dihydro-1H-quinolin- ylmethyl]-pyridine 2-one (intermediate A-19) Corlorless 434.4 and 1-methyl waxy solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) 2-(6-Chloro- pyrazinylamino)- 6-[6-(2-Hydroxy-ethylamino)- ethanol pyrazinyl]methyl-3,4- (intermediate A-20) Light dihydro-1H-quinolinone and 1-methyl 24 brown 299.2 (4,4,5,5-tetramethyl- solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Benzyl-(6-chloro- pyrazinyl)-amine 6-(6-Benzylamino-pyrazin (intermediate A-21) yl)methyl-3,4-dihydro-1H- and 1-methyl Light quinolinone (4,4,5,5-tetramethyl- yellow 345.1 [1,3,2]dioxaborolan- solid 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) 2-(6-Chloro- pyrazinylamino)- 7-Fluoro[6-(2-hydroxy- ethanol ethylamino)-pyrazinyl] (intermediate A-20) methyl-3,4-dihydro-1H- and 7-fluoro White quinolinone methyl(4,4,5,5- 317.1 solid O N F tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) Benzyl-(6-chloro- pyrazinyl)-amine 6-(6-Benzylamino-pyrazin (intermediate A-21) yl)fluoromethyl-3,4- and 7-fluoro dihydro-1H-quinolinone methyl(4,4,5,5- Yellow 27 362.9 O N F tetramethyl- solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) Ex Name Starting Materials Aspect (M+H ) 6-(6-Chloro- pyrazinyl)-2,6- diaza- 6-[6-(1-Methyloxo-1,2,3,4- spiro[3.3]heptane tetrahydro-quinolinyl)- carboxylic acid tert- pyrazinyl]-2,6-diaza- butyl ester spiro[3.3]heptanecarboxylic Off white (intermediate 24) 436.1 acid tert-butyl ester solid and 1-methyl (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) 6-(5-Bromo-pyridin- 3-yl)-2,6-diaza- 6-[5-(1-Methyloxo-1,2,3,4- spiro[3.3]heptane tetrahydro-quinolinyl)- carboxylic acid tert- pyridinyl]-2,6-diaza- butyl ester spiro[3.3]heptanecarboxylic (intermediate 25) Brown 29 435.3 acid tert-butyl ester and 1-methyl waxy solid (4,4,5,5-tetramethyl- N [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Example 30 6-[5-((R)Hydroxymethylmethyl-propylamino)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone [A] 6-{5-[(R)(tert-butyl-dimethyl-silanyloxymethyl)methyl-propylamino]-pyridin yl}methyl-3,4-dihydro-1H-quinolinone In analogy to the procedures described for the preparation of intermediate A-3 [B] and A-3 [C]: i) (R)(tert-butyl-dimethyl-silanyloxymethyl)methyl-propylamine has been reacted with 3,5-dibromopyridine to give (5-bromo-pyridinyl)-[(R)(tert-butyl- dimethyl-silanyloxymethyl)methyl-propyl]-amine; ii) subsequent condensation with 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) gave the title compound as light yellow amorphous solid. MS: 454.3 (M+H ).
[B] 6-[5-((R)Hydroxymethylmethyl-propylamino)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone In a 10 mL round-bottomed flask, 6-{5-[(R)(tert-butyl-dimethyl-silanyloxymethyl) methyl-propylamino]-pyridinyl}methyl-3,4-dihydro-1H-quinolinone (60 mg, 132 µmol) was dissolved in THF (1.5 mL) to give a light yellow solution and cooled down to 0 °C. TBAF, 1 M sol. in THF (132 µl, 132 µmol) was added dropwise. The solution was stirred at 0 °C for 1.5 h and partitioned between aqueous sat. NaHCO3 solution and AcOEt (3 x). The organic layers were collected, dried over Na2SO4 and evaporated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 100% EtOAc followed by 1% MeOH in EtOAc) to give the title compound (22 mg, 49%) as a light yellow foam. MS: 340.2 (M+H ).
Example 31 6-[6-((R)Hydroxymethylmethyl-propylamino)-pyrazinyl]methyl-3,4- dihydro-1H-quinolinone In analogy to the procedures described for the preparation of intermediate A-20 and A-3 [C]: i) (R)aminomethyl-butanol has been reacted with 2,6-dichloropyrazine to give (R)(6-chloro-pyrazinylamino)methyl-butanol; ii) subsequent condensation with 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolin- 2-one (intermediate A-1) gave the title compound as a light yellow solid. MS: 341.2 (M+H ).
Example 32 Ethanesulfonic acid [5-(5-methyloxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)- pyridinylmethyl]-amide [A] 6-Bromonitro(toluenesulfonylmethyl)-pyridine Br N and 2-bromonitro(toluenesulfonylmethyl)-pyridine Br N To a stirred solution of 2-bromonitro-pyridine (3.4 g, 25.0 mmol) and 1- chloromethanesulfonylmethyl-benzene (3.4 g, 25 mmol) in THF (100 mL) was added t- BuOK solution (1.0 M in THF, 55 mL) at -78 C. After stirring for 30 minutes, AcOH (3.0 mL) was added to the above solution and the reaction mixture was allowed to warm up to RT and stirred for additional 20 minutes. After extraction of the reaction mixture with EtOAc, the organic layer was washed with brine, dried over anhy. Na SO , filtered and concentrated in vacuo to give a suspension (50 mL), which after filtration gave 2-bromo nitro(toluenesulfonylmethyl)-pyridine as a pale white solid (3.25 g, 35%); the filtrate was concentrated in vacuo to afford 6-bromonitro(toluenesulfonylmethyl)- pyridine as a light yellow solid (4.2 g, 45%). MS: 371.1 & 373.1 (M+H ).
[B] 3-(6-Bromonitro-pyridinyl)(toluenesulfonyl)-propionic acid methyl ester Br N A mixture of 6-bromonitro(toluenesulfonylmethyl)-pyridine (3.3 g, 9.0 mmol), bromo-acetic acid methyl ester (2.1 mL, 22.5 mmol) and K CO (8.4 g, 60.8 mmol) were suspended in DMF (18.0 mL) and stirred at 40 C for 1 hour before pouring into water (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na SO , filtered and concentrated in vacuo to give 3-(6-bromonitro-pyridinyl)- 3-(toluenesulfonyl)-propionic acid methyl ester (3.9 g, quant.) as a light yellow solid.
MS: 443.1 & 445.1 (M+H ).
[C] 6-(2-Methoxycarbonyl-vinyl)nitro-[2,3']bipyridinyl-5'-carboxylic acid methyl ester 3-(6-Bromonitro-pyridinyl)(toluenesulfonyl)-propionic acid methyl ester (1.2 g, 2.7 mmol), Pd(PPh ) Cl (190 mg, 0.27 mmol), Na CO (572 mg, 5.4 mmol) and 3- 3 2 2 2 3 (methoxycarbonyl)pyridineboronic acid pinacol ester (926 mg, 3.5 mmol) were dissolved in 1,4-dioxane (4.0 mL) and the resulting reaction mixture was heated at 120 C for 3 hours before it was poured into H O (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na SO , filtered and concentrated in vacuo to give 6-(2-methoxycarbonyl-vinyl)nitro-[2,3']bipyridinyl-5'-carboxylic acid methyl ester (926 mg, quant.) as a light yellow solid. MS: 344.1 (M+H ).
[D] 5-(6-Oxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)-nicotinic acid methyl ester 6-(2-Methoxycarbonyl-vinyl)nitro-[2,3']bipyridinyl-5'-carboxylic acid methyl ester (926 mg, 2.7 mmol), 10% Pd/C (300 mg) and AcOH (1.3 mL) were suspended in methanol (300 mL) and the reaction mixture was stirred at 50 C under 50 psi H pressure for 13 hours. After filtration, the reaction mixture was concentrated in vacuo to give a crude product of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)-nicotinic acid methyl ester (500 mg, 65.4%) as a light yellow solid. MS: 284.1 (M+H ).
[E] 5-(5-Methyloxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)-nicotinic acid methyl ester To a stirred solution of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)-nicotinic acid methyl ester (430 mg, 1.52 mmol) in THF (15.0 mL) was added 60% NaH (91 mg, 2.28 mmol) at 0 C and the reaction mixture was stirred at 2-5 °C for 0.5 h before CH I (0.3 mL, 4.56 mmol) was added. After stirring overnight at RT, it was poured into water (5.0 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na SO , filtered and concentrated in vacuo to give 5-(5-methyloxo-5,6,7,8- tetrahydro-[1,5]naphthyridinyl)-nicotinic acid methyl ester (383.7 mg, 85%) as a light yellow solid. MS: 298.1 (M+H ).
[F] 6-(5-Hydroxymethyl-pyridinyl)methyl-3,4-dihydro-1H-[1,5]naphthyridinone HO N To a stirred solution of 5-(5-methyloxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)- nicotinic acid methyl ester (270 mg, 0.91 mmol) in MeOH (10 mL) was added sodium borohydride (300 mg, 8.0 mmol) at RT. After stirring overnight, the reaction mixture was quenched by adding water (5.0 mL). It was then concentrated in vacuo to give a light yellow oil. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(5-hydroxymethyl- pyridinyl)methyl-3,4-dihydro-1H-[1,5]naphthyridinone (190 mg, 77.6%) as a white solid. MS: 270.1 (M+H ).
[G] 6-(5-Chloromethyl-pyridinyl)methyl-3,4-dihydro-1H-[1,5]naphthyridinone Cl N At 0 °C, 6-(5-hydroxymethyl-pyridinyl)methyl-3,4-dihydro-1H-[1,5]naphthyridin one (170 mg, 0.63 mmol) in DCM (15 mL) was treated with thionyl chloride (0.32 mL, 4.0 mmol). After the addition, the reaction mixture was allowed to stir at 2-5 °C for 2 hours before it was poured into satd. aq. NaHCO solution (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na SO , filtered and concentrated in vacuo to give 6-(5-chloromethyl-pyridinyl)methyl-3,4-dihydro-1H- [1,5]naphthyridinone (156 mg, 86.3%) as yellow oil. MS: 288.1 (M+H ).
[H] Ethanesulfonic acid [5-(5-methyloxo-5,6,7,8-tetrahydro-[1,5]naphthyridinyl)- pyridinylmethyl]-amide To a stirred solution of ethanesulfonic acid amide (118 mg, 1.08 mmol) in DMF (5.0 mL) was added 60% NaH (35 mg, 0.81 mmol) at RT and the resulting reaction mixture was stirred for 0.5 hour before 6-(5-chloromethyl-pyridinyl)methyl-3,4-dihydro-1H- [1,5]naphthyridinone (156 mg, 0.54 mmol) was added. After continued stirring at RT for additional 2 hours, water (1.0 mL) was added. After extraction with EtOAc, 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 give title compound (15 mg, 7.7%) as a light yellow solid. MS: 361.1 (M+H ).
Example 33 6-Pyridinyl-3,4-dihydro-1H-[1,5]naphthyridinone In analogy to the procedures described for the preparation of example 32 (steps [C] to [D]), the title compound was prepared using 3-(6-bromonitro-pyridinyl)(toluene- 4-sulfonyl)-propionic acid methyl ester and 3-pyridine boronic acid as corresponding starting materials. MS: 226.1(M+H ).
Example 34 1-Methylpyridinyl-3,4-dihydro-1H-[1,5]naphthyridinone In analogy to the procedures described for the preparation of example 32 (step [E]), the title compound was prepared using 6-pyridinyl-3,4-dihydro-1H-[1,5]naphthyridinone (example 33) as corresponding starting material. MS: 240.2 (M+H ).
Example 35 1-Methylpyridinyl-3,4-dihydro-1H-[1,7]naphthyridinone In analogy to the procedures described for the preparation of example 32 (steps [B] to [E]), the title compound was prepared using 2-bromonitro(toluenesulfonylmethyl)- pyridine (example 32 [A]) and 3-pyridine boronic acid as corresponding starting materials.
MS: 240.1 (M+H ).
Example 36 6-(5-Aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone A round-bottomed flask was charged with 5-bromo-pyridinyl-methylamine (0.5 g, 2.67 mmol), 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone (intermediate A-1, 0.845 g, 2.94 mmol) and EtOH (48 mL). Then, tetrakis(triphenylphosphine)palladium(0) (0.093 g, 0.080 mmol), followed by aqueous Na CO solution (8 mL, 0.312 g, 2.94 mmol) were added and the reaction mixture heated to 85 °C over night. The mixture was evaporated to dryness, the residue was taken up in EtOAc, filtered through Dicalite and washed with EtOAc (2 x 50 mL). The filtrate was evaporated to dryness. Then, the residue was purified by silica gel flash chromatography eluting with a 0 to 20% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.7 g, 94 %) as an off white solid. MS: 268.2 (M+H ).
Example 37 N-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- propionamide To a solution of 6-(5-aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (example 36, 0.05 g, 0.187 mmol) in dry DMF (1 mL) were added EDCI (0.039 g, 0.206 mmol), Hünig’s base (0.060 g, 0.468 mmol) and propionic acid (0.021 g, 0.282 mmol) and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NH Cl solution (5 mL) and extracted with EtOAc (2 x 10 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness.
The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH OH)-DCM gradient to give the title compound (0.029 g, 48 %) as a white solid. MS: 324.4 (M+H ).
Example 38 Propanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin- 3-ylmethyl]-amide To a solution of 6-(5-aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (example 36, 0.05 g, 0.187 mmol) in DCM (1 mL) cooled to 0 °C were added triethylamine (0.038 g, 0.374 mmol) and isopropylsulfonylchloride (0.029 g, 0.206 mmol).
The resulting suspension was stirred at 0 °C for 4h and then allowed to warm up to room temperature and stirring was continued for 2h. The reaction mixture was diluted with DCM, poured into H O (5 mL) and extracted with DCM (2 x 10 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH OH)-DCM gradient to give the title compound (0.023 g, 33 %) as a white foam. MS: 374.1 (M+H ).
Example 39 {2-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- carbamic acid tert-butyl ester In analogy to the procedure described for the preparation of intermediate A-3 [C], 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to [2-(5-bromo-pyridinyloxy)-ethyl]-carbamic acid tert-butyl ester (intermediate A-7) to give the title compound as a white solid. MS: 398.1 (M+H ).
Example 40 3-Methoxy-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide To a solution of 6-(5-aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (example 36, 0.05 g, 0.187 mmol) in dry DCM (1 mL) were added EDCI (0.039 g, 0.206 mmol), hydroxybenzotriazole (0.032 g, 0.206 mmol), Hünig’s base (0.060 g, 0.468 mmol) and 3-methoxy-isoxazolecarboxylic acid (0.040 g, 0.281 mmol) and the resulting solution was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO solution (5 mL) and extracted with EtOAc (2 x 10 mL).
Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH(1% NH OH)-DCM gradient to give the title compound (0.03 g, 41 %) as a white solid. MS: 393.1 (M+H ).
Example 41 Cyclopropanecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 37, 6-(5- aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (example 36) has been reacted with cyclopropanecarboxylic acid to give the title compound as a white solid.
MS: 336.3 (M+H ).
Example 42 6-[5-(2-Amino-ethoxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride H Cl To a solution of {2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- ethyl}-carbamic acid tert-butyl ester (example 39, 0.06 g, 0.151 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.151 mL, 0.604 mmol) and the reaction mixture was stirred at room temperature over night. The resulting suspension was filtered off and the solid material was triturated in diethyl ether, filtered off and further dried in a high vacuum to give the title compound (0.046 g, 91 %) as a white solid. MS: 298.3 (M+H ).
Example 43 N-{2-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- propionamide In analogy to the procedure described for the preparation of example 37, 6-[5-(2-amino- ethoxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 42) has been reacted with propionic acid to give the title compound as a white solid. MS: 354.3 (M+H ).
Example 44 6-[5-(1,1-Dioxo-1λ -[1,2]thiazinanylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone In analogy to the procedure described for the preparation of intermediate A-12 [B] and to the procedure described for the preparation of intermediate A-3 [C], [1,2]thiazinane 1,1- dioxide was reacted with 3-bromochloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give 2-(5-bromo-pyridinylmethyl)-[1,2]thiazinane 1,1-dioxide, which was subsequently reacted with 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- 2-yl)-3,4-dihydro-1H-quinolinone (intermediate A-1) to give the title compound as a off-white solid. MS: 386.2 (M+H ).
Example 45 (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]- azetidinecarboxylic acid tert-butyl ester Chiral A sealed tube was charged with (S)(5-bromo-pyridinyloxymethyl)-azetidine carboxylic acid tert-butyl ester (intermediate A-26, 0.260 g, 0.76 mmol), 1-methyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1, 0.239 g, 0.83 mmol) and DMF (3 mL). Then, bis(triphenylphosphine)palladium(II)chloride (0.053 g, 0.076 mmol), followed by 1N aqueous Na CO solution (2.27 mL, 2.27 mmol) were added and the reaction was heated to 110 °C (pre-heated oil bath) for 1h. The mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (20 mL). The resulting filtrate was poured into aq. NaHCO (20 mL) and the aqueous layer was extracted with EtOAc (20 mL).
Combined organics were washed with brine, dried over Na SO , filtered and evaporated.
The residue was purified by silica gel flash chromatography eluting with a 0 to 100 % EtOAc-heptane gradient to give the title compound (0.277 g, 86%) as a light brown foam.
MS: 424.1 (M+H ).
The following compounds listed in Table 3 were prepared in analogy to the procedure described for the preparation of example 45, using the appropriate starting materials.
Table 3 Ex Name Starting Materials Aspect (M+H ) Ex Name Starting Materials Aspect (M+H ) (R)(5-Bromo- pyridinyloxy)- pyrrolidine (R)[5-(7-Fluoromethyl carboxylic acid tert- oxo-1,2,3,4-tetrahydro-quinolin- butyl ester 6-yl)-pyridinyloxy]- (intermediate A-27) pyrrolidinecarboxylic acid Colorless and 7-fluoro 442.3 tert-butyl ester solid methyl(4,4,5,5- O N F tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) 3-(5-Bromopyridin- 3-[5-(1-Methyloxo-1,2,3,4- 3-yloxy)-azetidine- tetrahydro-quinolinyl)- 1-carboxylic acid pyridinyloxy]-azetidine tert-butyl ester carboxylic acid tert-butyl ester (intermediate A-28) Colorless 47 and 1-methyl 410.5 solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (S)(5-Bromo- pyridinyloxy)- (S)[5-(1-Methyloxo- pyrrolidine 1,2,3,4-tetrahydro-quinolin carboxylic acid tert- yl)-pyridinyloxy]- butyl ester pyrrolidinecarboxylic acid (intermediate A-29) Colorless tert-butyl ester 424.1 and 1-methyl solid O N (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) (S)- 3-(5- Bromopyridin (S)[5-(1-Methyloxo- yloxy)-piperidine 1,2,3,4-tetrahydro-quinolin carboxylic acid tert- yl)-pyridinyloxy]-piperidine- butyl ester 1-carboxylic acid tert-butyl ester (intermediate A-30) Colorless 49 438.3 and 1-methyl oil (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) 4-(5-Bromopyridin- 3-yloxy)-piperidine- 4-[5-(1-Methyloxo-1,2,3,4- 1-carboxylic acid tetrahydro-quinolinyl)- tert-butyl ester pyridinyloxy]-piperidine (intermediate A-31) Colorless carboxylic acid tert-butyl ester and 1-methyl amorphou 438.3 (4,4,5,5-tetramethyl- s solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) (S)((5- Bromopyridin (S)[5-(1-Methyloxo- yloxy)methyl)pyrrol 1,2,3,4-tetrahydro-quinolin idinecarboxylic yl)-pyridinyloxymethyl]- acid tert-butyl ester pyrrolidinecarboxylic acid (intermediate A-32) Colorless 51 438.5 tert-butyl ester and 1-methyl solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (S)(5-Bromo- pyridinyloxy)- (S)[5-(7-Fluoromethyl pyrrolidine oxo-1,2,3,4-tetrahydro-quinolin- carboxylic acid tert- 6-yl)-pyridinyloxy]- butyl ester pyrrolidinecarboxylic acid (intermediate A-29) Colorless tert-butyl ester and 7-fluoro n.d. solid methyl(4,4,5,5- O N F tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) (R)(5-Bromo- pyridinyloxy)- (R)[5-(1-Methyloxo- pyrrolidine 1,2,3,4-tetrahydro-quinolin carboxylic acid tert- yl)-pyridinyloxy]- butyl ester pyrrolidinecarboxylic acid (intermediate A-27) Colorless tert-butyl ester 53 424.2 and 1-methyl solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- N 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (R)-N-(3-(5- Bromopyridin (R)Methyl-propane yl)oxetanyl) sulfinic acid {3-[5-(1-methyl methylpropane oxo-1,2,3,4-tetrahydro-quinolin- sulfinamide Amorphou 6-yl)-pyridinyl]-oxetan (intermediate A-33) s brown 414.4 yl}-amide and 1-methyl solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ethanesulfonic acid (5-bromo-pyridin Ethanesulfonic acid [5-(2-oxo- ylmethyl)-amide 1,2,3,4-tetrahydro-quinolin (intermediate A-11) yl)-pyridinylmethyl]-amide and 6-(4,4,5,5- Amorphou 55 tetramethyl-1,3,2- s colorless 346.1 dioxaborolanyl)- solid 3,4- dihydroquinolin- 2(1H)-one (intermediate A-34) Ex Name Starting Materials Aspect (M+H ) (R)Methyl- propanesulfinic (R)Methyl-propane acid [(S and R) sulfinic acid {(S or R)[5-(1- (5-bromo-pyridin methyloxo-1,2,3,4- yl)-ethyl]-amide tetrahydro-quinolinyl)- (intermediate A-35) Amorphou pyridinyl]-ethyl}-amide and 1-methyl s colorless 386.1 (4,4,5,5-tetramethyl- solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- N 1H-quinolinone (intermediate A-1) (S or R) followed by HPLC separation.
(R)Methyl- propanesulfinic acid [(S and R) (R)Methyl-propane (5-bromo-pyridin sulfinic acid {(R or S)[5-(1- yl)-ethyl]-amide methyloxo-1,2,3,4- (intermediate A-35) tetrahydro-quinolinyl)- Amorphou and 1-methyl pyridinyl]-ethyl}-amide 57 s colorless 386.1 (4,4,5,5-tetramethyl- O solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (R or S) (intermediate A-1) followed by HPLC separation.
Ex Name Starting Materials Aspect (M+H ) tert-Butyl (trans) {(trans)[5-(1-Methyloxo- (5-bromopyridin 1,2,3,4-tetrahydro-quinolin yloxy)cyclohexylcar yl)-pyridinyloxy]- bamate cyclohexyl}-carbamic acid tert- (intermediate A-54) Off-white butyl ester and 1-methyl 452.5 solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1).
Example 59 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone [A] Methyl 1-(5-bromopyridinyl)cyclopropanecarboxylate To a solution of methyl 2-(5-bromopyridinyl)acetate (4 g, 17.4 mmol) in DMF (80 mL), cooled at 0 °C with an ice bath, was added 60 % NaH in mineral oil (0.918 g, 38.3 mmol) and the reaction mixture was stirred at 0 °C for 15 min. Then, a solution of 1,2- dibromoethane (3.27 g, 17.4 mmol) in DMF (16 mL) was added at 0 °C. After the addition, the mixture was stirred at room temperature for 1h. Two other portions of 60 % NaH in mineral oil (2 x 0.2 g) were added sequentially, until conversion was complete.
Then, the reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (3 x 125 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated to dryness to give the title compound (4.764 g, 99 %) as a brown oil, which was used with no further purification. MS: 256.0 and 258.0 (M+H ).
[B] Potassium 1-(5-bromopyridinyl)cyclopropanecarboxylate Br O To a solution of methyl 1-(5-bromopyridinyl)cyclopropanecarboxylate (4.764 g, 18.6 mmol) in THF (190 mL) was added 90 % potassium trimethylsilanolate (2.65 g, 18.6 mmol) and the reaction mixture was stirred at room temperature over night. Then, the mixture was filtered and washed with THF to give the desired product (2.668 g) as a light brown solid. The mother liquors were concentrated to around 50 mL of THF. Another portion of 90 % potassium trimethylsilanolate (0.43 g) was added and stirring was continued for 5 h at room temperature. Then, the mixture was filtered and washed again with THF to give a second batch of desired product (0.953 g) which was combined with the first batch to give the title compound (3.621 g, 59.1 %) as a light brown solid.
MS:242.0 and 244.1 (M+H ).
[C] 1-(5-(1-Methyloxo-1,2,3,4-tetrahydroquinolinyl)pyridin-3yl)cyclopropane- carboxylic acid A flask was charged with potassium 1-(5-bromopyridinyl)cyclopropanecarboxylate (0.5 g, 1.52 mmol), 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone (intermediate A-1, 0.479 g, 1.67 mmol) and DMF (7 mL). Then, bis(triphenylphosphine)palladium(II)chloride (0.106 g, 0.152 mmol), followed by 1N aqueous Na2CO3 solution (3.64 mL, 2.4 mmol) were added and the reaction was heated to 120 °C (pre-heated oil bath) for 1h. The mixture was evaporated to dryness and the residue purified by silica gel flash chromatography eluting with a 0 to 15 % MeOH-DCM gradient to give the title compound (0.551 g, 100%) as a brown solid. MS: 323.4 (M+H ).
[D] 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone To solution of 1-(5-(1-methyloxo-1,2,3,4-tetrahydroquinolinyl)pyridin yl)cyclopropanecarboxylic acid (0.551 g, 1.52 mmol) in toluene (20 mL) were added TEA (0.185 g, 1.83 mmol) and diphenylphosphoryl azide (0.419 g, 1.52 mmol) and then the reaction mixture was heated to reflux for 4h. After cooling to 0 °C, a 1 M solution of sodium trimethylsilanoate in THF (3.04 mL, 3.04 mmol) was added and the mixture was stirred for 45 min at room temperature. After quenching with 0.1 M aq. HCl (40 mL), the aqueous solution was washed with ether (2 times), then basified with 1 M aq. NaOH and then extracted with DCM (2 x 100 mL). The combined organics were washed with brine, dried over Na SO , filtered and evaporated to dryness to give the title compound (0.333 g, 71%) as a yellow foam. MS: 294.4 (M+H ).
The following compounds listed in Table 4 were prepared by treatment of the appropriate starting material with HCl in methanol in analogy to the procedure described for the preparation of example 42 (isolation of the compounds as HCl salts by direct evaporation or by basic extraction followed by silica gel or reverse phase chromatography): Table 4 Ex Name Starting Materials Aspect (M+H ) 1-Methyl[5-((S)-pyrrolidin- (S)[5-(1-Methyl- 3-yloxy)-pyridinyl]-3,4- 2-oxo-1,2,3,4- dihydro-1H-quinolinone tetrahydro-quinolin- hydrochloride 6-yl)-pyridin Yellow 60 324.3 yloxy]-pyrrolidine- solid 1-carboxylic acid tert-butyl ester (example 48) (S)[5-(1-Methyl- 1-Methyl[5-((S)-piperidin- 2-oxo-1,2,3,4- 3-yloxy)-pyridinyl]-3,4- tetrahydro-quinolin- Colorless dihydro-1H-quinolinone 6-yl)-pyridin 61 amorphou 338.3 yloxy]-piperidine s solid carboxylic acid tert- butyl ester (example Ex Name Starting Materials Aspect (M+H ) 4-[5-(1-Methyl 1-Methyl[5-(piperidin oxo-1,2,3,4- yloxy)-pyridinyl]-3,4- tetrahydro-quinolin- dihydro-1H-quinolinone Light 6-yl)-pyridin hydrochloride 62 yellow 338.4 yloxy]-piperidine solid carboxylic acid tert- butyl ester (example (S)[5-(1-Methyl- 6-[5-((S)Azetidin 2-oxo-1,2,3,4- ylmethoxy)-pyridinyl] tetrahydro-quinolin- methyl-3,4-dihydro-1H- 6-yl)-pyridin Light quinolinone 63 yloxymethyl]- 324.2 yellow oil O N azetidine carboxylic acid tert- butyl ester (example Ex Name Starting Materials Aspect (M+H ) 6-[5-((S or R)Amino- (R)Methyl- ethyl)-pyridinyl]methyl- propanesulfinic 3,4-dihydro-1H-quinolin acid {(S or R)[5- one hydrochloride (1-methyloxo- Colorless 64 282.1 1,2,3,4-tetrahydro- solid quinolinyl)- pyridinyl]-ethyl}- amide (example 56) (S or R) 6-[5-((R or S)Amino- (R)Methyl- ethyl)-pyridinyl]methyl- propanesulfinic 3,4-dihydro-1H-quinolin acid {(R or S)[5- one hydrochloride (1-methyloxo- Colorless 65 282.1 O N 1,2,3,4-tetrahydro- solid quinolinyl)- pyridinyl]-ethyl}- amide (example 57) (R or S) Ex Name Starting Materials Aspect (M+H ) (S)[5-(1-Methyl- 1-Methyl[5-((S) 2-oxo-1,2,3,4- pyrrolidinylmethoxy)- tetrahydro-quinolin- pyridinyl]-3,4-dihydro-1H- 6-yl)-pyridin Yellow quinolinone hydrochloride 66 yloxymethyl]- 338.2 solid pyrrolidine carboxylic acid tert- butyl ester (example (R)[5-(7-Fluoro- 7-Fluoromethyl[5-((R)- 1-methyloxo- pyrrolidinyloxy)-pyridin 1,2,3,4-tetrahydro- yl]-3,4-dihydro-1H-quinolin- quinolinyl)- Light 2-one hydrochloride 67 pyridinyloxy]- yellow 342.3 pyrrolidine solid O N F carboxylic acid tert- butyl ester (example Ex Name Starting Materials Aspect (M+H ) 1-Methyl[5-((R)- (R)[5-(1-Methyl- pyrrolidinyloxy)-pyridin 2-oxo-1,2,3,4- yl]-3,4-dihydro-1H-quinolin- tetrahydro-quinolin- 2-one hydrochloride 6-yl)-pyridin Yellow 68 324.5 yloxy]-pyrrolidine- solid 1-carboxylic acid tert-butyl ester (example 53) (R)Methyl- 6-[5-(3-Amino-oxetanyl)- propanesulfinic pyridinyl]methyl-3,4- acid {3-[5-(1- dihydro-1H-quinolinone methyloxo- Light hydrochloride 69 1,2,3,4-tetrahydro- yellow 310.2 quinolinyl)- solid pyridinyl]- oxetanyl}-amide N ClH (example 54) Ex Name Starting Materials Aspect (M+H ) 6-[5-(Azetidinyloxy)- 3-[5-(1-Methyl pyridinyl]methyl-3,4- oxo-1,2,3,4- dihydro-1H-quinolinone tetrahydro-quinolin- hydrochloride 6-yl)-pyridin Yellow 70 310.3 yloxy]-azetidine solid carboxylic acid tert- butyl ester (example 6-[5-((trans)Amino- {(trans)[5-(1- cyclohexyloxy)-pyridinyl]- Methyloxo- 1-methyl-3,4-dihydro-1H- 1,2,3,4-tetrahydro- quinolinone hydrochloride quinolinyl)- Yellow 71 pyridinyloxy]- 352.5 solid cyclohexyl}- N NH carbamic acid tert- butyl ester (example Example 72 6-[5-(1-Aminomethyl-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone [A] Methyl 2-(5-bromopyridinyl)methylpropanoate Br O To a solution of methyl 2-(5-bromopyridinyl)acetate (0.7 g, 3.04 mmol) in DMF (14 mL) cooled at 0 °C with an ice bath was added 60 % NaH in mineral oil (0.244 g, 6.09 mmol) and the reaction mixture was stirred for 15 min. Then, a solution of MeI (0.864 g, 6.09 mmol) in DMF (16 mL) was added dropwise at 0 °C. After the addition, the mixture was stirred at room temperature for 1h. An other portion of 60 % NaH in mineral oil (0.073 g) was added to the mixture which was stirred at room temperature for 1h. The reaction mixture was poured into H O (15 mL) and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na SO , filtered and evaporated to dryness to give the title compound (0.617 g, 75 %) as a brown oil which was used with no further purification. MS: 258.2 and 260.3 (M+H ).
[B] Potassium 2-(5-bromopyridinyl)methylpropanoate Br O In analogy to the procedure described for the preparation of example 59 [B], methyl 2-(5- bromopyridinyl)methylpropanoate (example 72 [A]) was reacted with 90 % potassium trimethylsilanolate to give the title compound as a light brown solid. MS: 244.3 (M+H ).
[C] 2-Methyl(5-(1-methyloxo-1,2,3,4-tetrahydroquinolinyl)pyridinyl)propan- oic acid In analogy to the procedure described for the preparation of example 59 [C], potassium 2- (5-bromopyridinyl)methylpropanoate (example 72 [B]) was reacted with 1-methyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) in presence of bis(triphenylphosphine)palladium(II)chloride and Na CO (1M aq. solution) to give the title compound as a brown foam. MS: 325.4 (M+H ).
[D] 6-[5-(1-Aminomethyl-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of example 59 [D], 2-methyl (5-(1-methyloxo-1,2,3,4-tetrahydroquinolinyl)pyridinyl)propanoic acid (example 72 [C]) was reacted with diphenylphosphoryl azide in presence of TEA and then sodium trimethylsilanoate (1 M in THF) to give the title compound as a light brown amorphous solid. MS: 296.5 (M+H ).
Example 73 6-(5-Aminomethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of example 45, reaction of 3- aminomethylbromopyridine and 7-fluoromethyl(4,4,5,5-tetramethyl- [1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-22) gave the title compound as a light yellow solid. MS: 286.7 (M+H ).
Example 74 6-{6-[6-(3-Methoxy-isoxazolecarbonyl)-2,6-diaza-spiro[3.3]heptyl]-pyrazin yl}methyl-3,4-dihydro-1H-quinolinone To a solution of 6-(6-(2,6-diazaspiro[3.3]heptanyl)pyrazinyl)methyl-3,4- dihydroquinolin-2(1H)-one 2,2,2-trifluoroacetate (intermediate A-36, 0.030 g, 0.067 mmol) in DCM (1 mL) were added 3-methoxyisoxazolecarboxylic acid (0.014 g, 0.1 mmol) and TBTU (0.024 g, 0.073 mmol) followed by Hünig’s base (0.022 g, 0.167 mmol) and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO solution (5 mL) and extracted with EtOAc (2 x 10 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to % MeOH-DCM gradient to give the title compound (0.007 g, 20 %) as a yellow solid.
MS: 461.3 (M+H ).
Example 75 3,5-Dimethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide To a solution of 6-(5-aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (example 36, 0.047 g, 0.177 mmol) in DMF (1 mL) were added 3,5-dimethylisoxazole carboxylic acid (0.037 g, 0.266 mmol) and TBTU (0.063 g, 0.195 mmol) followed by Hünig’s base (0.048 g, 0.372 mmol) and the reaction mixture was stirred at room temperature over night. The mixture was purified directly by reverse phase HPLC on a Gemini-NX column, eluting with a 20 to 98% MeOH-H2O (0.05 % TEA) gradient to give the title compound (0.041 g, 59 %) as a colorless solid. MS: 391.3 (M+H ).
Example 76 6-[5-((S)Cyclopropanecarbonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone To a solution of 1-methyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride (example 60, 0.05 g, 0.139 mmol) in dry DCM (1.5 mL) was added cyclopropanecarbonyl chloride (0.015 g, 0.139 mmol) followed by TEA (0.035 g, 0.347 mmol) and the reaction mixture was stirred at room temperature for 1h. Then, the reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 20 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 5% MeOH-DCM gradient to give the title compound (0.032 g, 59 %) as a colorless foam. MS: 392.2 (M+H ).
The following compounds listed in Table 5 were prepared by treatment of the appropriate starting materials under the appropriate coupling conditions as described in examples 40, 74, 75 or 76.
Table 5 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 3-Methyl-N-[5-(1-methyl solid 6-(5-Aminomethyl- oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-butyramide 352.4 1H-quinolinone O (example 36) and 3- methyl-butyric acid expl. 74 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to 3,3,3-Trifluoro-N-[5-(1- Colorless methyloxo-1,2,3,4- solid 6-(5-Aminomethyl- tetrahydro-quinolinyl)- pyridinyl) pyridinylmethyl]- methyl-3,4-dihydro- propionamide 1H-quinolinone 378.3 (example 36) and 3,3,3-trifluoro- propionic acid expl. 74 Colorless 2-Hydroxymethyl-N-[5-(1- solid methyloxo-1,2,3,4- 6-(5-Aminomethyl- tetrahydro-quinolinyl)- pyridinyl) pyridinylmethyl]- methyl-3,4-dihydro- propionamide 79 1H-quinolinone 354.3 (example 36) and 2- hydroxymethyl- propionic acid expl. 74 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to -Methyl-[1,3,4]oxadiazole- Colorless 6-(5-Aminomethyl- 2-carboxylic acid [5-(1- solid pyridinyl) methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide 378.3 (example 36) and 5- O methyl- [1,3,4]oxadiazole expl. 75 carboxylic acid 1-Methyl[5-((S) Orange propionyl-piperidinyloxy)- amorphou pyridinyl]-3,4-dihydro- 1-Methyl[5-((S)- s solid 1H-quinolinone piperidinyloxy)- pyridinyl]-3,4- 81 dihydro-1H- 394.1 quinolinone (example 61) and propionic acid expl. 74 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 2-Methoxy-pyrimidine 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone 404.3 ylmethyl]-amide (example 36) and 2- O methoxy- pyrimidine expl. 75 carboxylic acid Colorless 1-Methyl-1H-imidazole 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone 83 376.2 ylmethyl]-amide (example 36) and 1- methyl-1H- imidazole expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless -Trifluoromethyl-furan amorphou 6-(5-Aminomethyl- carboxylic acid [5-(1-methyl- s solid pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 430.4 (example 36) and 5- trifluoromethyl- furancarboxylic expl. 75 acid Colorless solid Pyridazinecarboxylic acid 6-(5-Aminomethyl- [5-(1-methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]-amide 85 1H-quinolinone 374.3 N (example 36) and pyridazine N carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light brown Pyrimidinecarboxylic acid 6-(5-Aminomethyl- solid [5-(1-methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]-amide 1H-quinolinone 374.3 (example 36) and pyrimidine N carboxylic acid expl. 75 Colorless 1-Methyl-1H-pyrazole 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 87 376.4 (example 36) and 1- methyl-1H- pyrazole expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Orange 1-Methyl[5-(1-propionyl- amorphou 1-Methyl[5- piperidinyloxy)-pyridin s solid (piperidinyloxy)- yl]-3,4-dihydro-1H-quinolin- pyridinyl]-3,4- 2-one dihydro-1H- 394.1 quinolinone hydrochloride (example 62) and expl. 74 propionic acid Colorless amorphou Pyridazinecarboxylic acid 6-(5-Aminomethyl- s solid [5-(1-methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]-amide 89 1H-quinolinone 374.3 (example 36) and pyridazine carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light 1-Methyl[5-((S)- 1-Methyl[5-((S) yellow oil pyrrolidinyloxy)- propionyl-pyrrolidin pyridinyl]-3,4- yloxy)-pyridinyl]-3,4- dihydro-1H- dihydro-1H-quinolinone 380.3 quinolinone O hydrochloride (example 60) and expl. 74 propionic acid Off-white 6-[5-((S) amorphou 6-[5-((S) Azetidin s solid Cyclopropanecarbonyl- ylmethoxy)-pyridin- azetidinylmethoxy)- 3-yl]methyl-3,4- pyridinyl]methyl-3,4- 91 dihydro-1H- 392.2 dihydro-1H-quinolinone quinolinone (example 63) and cyclopropanecarbon expl. 76 yl chloride Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light brown 3-Methyl-isoxazole 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone 377.1 ylmethyl]-amide (example 36) and 3- methyl-isoxazole carboxylic acid expl. 75 Colorless 4-Fluoro-2,6-dimethyl-N-[5- solid (1-methyloxo-1,2,3,4- 6-(5-Aminomethyl- tetrahydro-quinolinyl)- pyridinyl) pyridinylmethyl]- methyl-3,4-dihydro- benzamide 93 1H-quinolinone 418.3 O N (example 36) and 4- fluoro-2,6-dimethyl- F benzoic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light 6-[5-((S) yellow oil 1-Methyl[5-((S) Azetidin propionyl-azetidin ylmethoxy)-pyridin- ylmethoxy)-pyridinyl]-3,4- 3-yl]methyl-3,4- 380.3 dihydro-1H-quinolinone dihydro-1H- quinolinone (example 63) and expl. 76 propionyl chlorde Colorless 3,6-Dichloro-pyridazine amorphou 6-(5-Aminomethyl- carboxylic acid [5-(1-methyl- s solid pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 95 442.3 (example 36) and O Cl 3,6-dichloro- pyridazine expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to 3-Cyclopropyl(2,2,2- trifluoro-ethyl)-1H-pyrazole- Colorless 6-(5-Aminomethyl- 4-carboxylic acid [5-(1- solid pyridinyl) methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide (example 36) and 3- 484.4 cyclopropyl (2,2,2-trifluoro- ethyl)-1H-pyrazole- expl. 75 4-carboxylic acid Colorless Pyridinecarboxylic acid solid 6-(5-Aminomethyl- [5-(1-methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]-amide 97 1H-quinolinone 373.3 (example 36) and pyridine carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 1,3-Dimethyl-1H-pyrazole amorphou 6-(5-Aminomethyl- carboxylic acid [5-(1-methyl- s solid pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 390.3 (example 36) and 1,3-dimethyl-1H- pyrazole expl. 75 carboxylic acid Colorless Pyrimidinecarboxylic acid solid 6-(5-Aminomethyl- [5-(1-methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]-amide 99 1H-quinolinone 374.3 (example 36) and pyrimidine carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 6-Methoxy-pyridazine 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone 404.5 ylmethyl]-amide (example 36) and 6- O methoxy- pyridazine expl. 75 carboxylic acid -Methyl-isoxazole Colorless carboxylic acid [5-(1-methyl- solid 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 101 1H-quinolinone 377.1 (example 36) and 5- methyl-isoxazole O carboxylic acid expl. 40 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light 6-[5-(2-Amino- 3,5-Dimethyl-isoxazole yellow ethoxy)-pyridin carboxylic acid {2-[5-(1- solid yl]methyl-3,4- methyloxo-1,2,3,4- dihydro-1H- tetrahydro-quinolinyl)- quinolinone pyridinyloxy]-ethyl}-amide 421.1 hydrochloride (example 42) and H 3,5-dimethyl- expl. 75 isoxazole carboxylic acid 6-[5-(2-Amino- Colorless 1-Methyl-1H-pyrazole ethoxy)-pyridin solid carboxylic acid {2-[5-(1- yl]methyl-3,4- methyloxo-1,2,3,4- dihydro-1H- tetrahydro-quinolinyl)- quinolinone pyridinyloxy]-ethyl}-amide 103 406.4 hydrochloride (example 42) and 1- methyl-1H- expl. 75 pyrazole carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 6-Chloro-pyridazine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 1H-quinolinone 408.3 (example 36) and 6- chloro-pyridazine carboxylic acid expl. 40 3-Chloromethyl- Colorless 6-(5-Aminomethyl- pyridazinecarboxylic acid solid pyridinyl) [5-(1-methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide 105 422.0 (example 36) and 3- chloromethyl- pyridazine expl. 40 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless amorphou 1-Methyl[5-((S)- 1-Methyl[5-((S) s solid 1-pyrrolidin propionyl-pyrrolidin ylmethoxy)-pyridin- ylmethoxy)-pyridinyl]-3,4- 3-yl]-3,4-dihydro- dihydro-1H-quinolinone 394.3 1H-quinolinone hydrochloride (example 66) and expl. 76 propionyl chlorde Colorless -Cyclopropyl-isoxazole amorphou 6-(5-Aminomethyl- carboxylic acid [5-(1-methyl- s solid pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 107 403.3 (example 36) and 5- cyclopropyl- isoxazole expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to 2-Methyltrifluoromethyl- Colorless 6-(5-Aminomethyl- oxazolecarboxylic acid [5- solid pyridinyl) (1-methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide (example 36) and 2- 445.3 methyl trifluoromethyl- oxazole expl. 75 carboxylic acid Off-white 2-Methyl-oxazole solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- 109 ylmethyl]-amide 1H-quinolinone 377.4 N (example 36) and 2- methyl-oxazole N carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless -Cyclopropyl-oxazole amorphou 6-(5-Aminomethyl- carboxylic acid [5-(1-methyl- s solid pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone 403.6 ylmethyl]-amide (example 36) and 5- cyclopropyl- oxazole N expl. 75 carboxylic acid Colorless 2,5-Dimethyl-oxazole 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 111 391.3 (example 36) and 2,5-dimethyl- oxazole expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless -Methyl-oxazole solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 1H-quinolinone 377.4 N (example 36) and 5- methyl-oxazole carboxylic acid expl. 75 3,5-Dimethyl-isoxazole Colorless 6-[5-(1-Amino- carboxylic acid {1-[5-(1- solid cyclopropyl)- methyloxo-1,2,3,4- pyridinyl] tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinyl]-cyclopropyl}- 113 1H-quinolinone 417.4 amide (example 59) and 3,5-dimethyl- isoxazole N expl. 40 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Off-white 6-Chloro-pyridine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 1H-quinolinone 407.2 (example 36) and 6- N Cl chloro-pyridine carboxylic acid expl. 75 Colorless 3-Methyl-pyridine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 115 1H-quinolinone 387.2 N (example 36) and 3- methyl-pyridine carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 3,6-Dichloro-pyridine 6-(5-Aminomethyl- solid carboxylic acid [5-(1-methyl- pyridinyl) 2-oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone ylmethyl]-amide 441.2 (example 36) and 3,6-dichloro- N Cl pyridine expl. 75 carboxylic acid Colorless 6-Methyl-pyridine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- 117 ylmethyl]-amide 1H-quinolinone 387.2 N (example 36) and 6- methyl-pyridine N carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Off-white 3-Chloro-pyridine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 1H-quinolinone 407.2 (example 36) and 3- chloro-pyridine carboxylic acid expl. 75 Colorless 3-Fluoro-pyridine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 119 1H-quinolinone 391.2 N (example 36) and 3- fluoro-pyridine F carboxylic acid expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Off-white -Chloromethyl-pyridine- 6-(5-Aminomethyl- solid 2-carboxylic acid [5-(1- pyridinyl) methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide 421.1 (example 36) and 5- chloromethyl- pyridine expl. 75 carboxylic acid Light yellow 1-Methyl[5-((R)- 1-Methyl[5-((R) solid pyrrolidinyloxy)- propionyl-pyrrolidin pyridinyl]-3,4- yloxy)-pyridinyl]-3,4- dihydro-1H- dihydro-1H-quinolinone 121 380.2 quinolinone hydrochloride (example 68) and expl. 76 propionyl chloride Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Yellow solid 7-Fluoromethyl[5-((S)- 7-Fluoromethyl- 1-propionyl-pyrrolidin 6-[5-((S)-pyrrolidin- yloxy)-pyridinyl]-3,4- 3-yloxy)-pyridin dihydro-1H-quinolinone yl]-3,4-dihydro-1H- 398.2 O N F quinolinone (example 146) and propionyl chloride expl. 76 Colorless -Trifluoromethyl- 6-(5-Aminomethyl- solid pyrimidinecarboxylic acid pyridinyl) [5-(1-methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide 123 442.5 (example 36) and 5- N trifluoromethyl- pyrimidine expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless -Methyl-pyrazine solid carboxylic acid [5-(1-methyl- 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 1H-quinolinone 388.3 (example 36) and 5- methyl-pyrazine carboxylic acid expl. 75 -Chloro-pyrazine Colorless carboxylic acid [5-(1-methyl- solid 6-(5-Aminomethyl- 2-oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 125 1H-quinolinone 408.4 (example 36) and 5- chloro-pyrazine N carboxylic acid N expl. 75 Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless -Trifluoromethyl-pyrazine- 6-(5-Aminomethyl- solid 2-carboxylic acid [5-(1- pyridinyl) methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone 442.4 pyridinylmethyl]-amide (example 36) and 5- trifluoromethyl- pyrazine expl. 75 carboxylic acid Colorless 3,5-Dimethyl-isoxazole 6-(5-Aminomethyl- solid carboxylic acid [5-(7-fluoro- pyridinyl) 1-methyloxo-1,2,3,4- fluoromethyl-3,4- tetrahydro-quinolinyl)- dihydro-1H- pyridinylmethyl]-amide 127 quinolinone 409.5 O N (example 73) and 3,5-dimethyl- isoxazole expl. 40 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Yellow 1-Methyl[5- solid 1-Methyl[5-((R) ((R)pyrrolidin propionyl-pyrrolidin ylmethoxy)-pyridin- ylmethoxy)-pyridinyl]-3,4- 3-yl]-3,4-dihydro- dihydro-1H-quinolinone 394.5 1H-quinolinone hydrochloride (example 148) and expl. 76 propionyl chloride Colorless 1-Methyl[5-(1-propionyl- amorphou 6-[5-(Azetidin azetidinyloxy)-pyridin s solid yloxy)-pyridin yl]-3,4-dihydro-1H-quinolin- yl]methyl-3,4- 2-one dihydro-1H- 129 366.5 quinolinone hydrochloride (example 70) and expl. 76 propionyl chloride Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless N-{3-[5-(1-Methyloxo- amorphou 6-[5-(3-Amino- 1,2,3,4-tetrahydro-quinolin s solid oxetanyl)- yl)-pyridinyl]-oxetan pyridinyl] yl}-propionamide methyl-3,4-dihydro- 366.1 O N O 1H-quinolinone hydrochloride (example 69) and expl. 76 propionyl chloride Off-white 3-Chloro-pyridine 6-(5-Aminomethyl- solid carboxylic acid [5-(7-fluoro- pyridinyl) 1-methyloxo-1,2,3,4- fluoromethyl-3,4- tetrahydro-quinolinyl)- dihydro-1H- pyridinylmethyl]-amide 131 425.4 quinolinone (example 73) and 3- chloro-pyridine expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless 3,6-Dichloro-pyridazine 6-(5-Aminomethyl- amorphou carboxylic acid [5-(7-fluoro- pyridinyl) s solid 1-methyloxo-1,2,3,4- fluoromethyl-3,4- tetrahydro-quinolinyl)- dihydro-1H- pyridinylmethyl]-amide quinolinone 460.3 O Cl (example 73) and 3,6-dichloro- pyridazine Cl expl. 40 carboxylic acid Yellow 7-Fluoromethyl- 7-Fluoromethyl[5-((R)- solid 6-[5-((R)-pyrrolidin- 1-propionyl-pyrrolidin 3-yloxy)-pyridin yloxy)-pyridinyl]-3,4- yl]-3,4-dihydro-1H- dihydro-1H-quinolinone 133 398.5 quinolinone O N F hydrochloride (example 67) and expl. 76 propionyl chloride Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Yellow -Chloromethoxy- amorphou 6-(5-Aminomethyl- pyrazinecarboxylic acid [5- s solid pyridinyl) (1-methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide 438.1 (example 36) and 5- chloromethoxy- pyrazine O N Cl expl. 75 carboxylic acid 6-[5-((R or S) Colorless 3,5-Dimethyl-isoxazole Amino-ethyl)- solid carboxylic acid {(R or S) pyridinyl] [5-(1-methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinyl]-ethyl}-amide 135 405.5 hydrochloride O (example 65) and 3,5-dimethyl- expl. 74 isoxazole (R or S) carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to 3-Methyltrifluoromethyl- Off-white 6-(5-Aminomethyl- isoxazolecarboxylic acid solid pyridinyl) [5-(1-methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone pyridinylmethyl]-amide (example 36) and 3- 445.5 methyl trifluoromethyl- isoxazole expl. 40 carboxylic acid 3-Chloro-pyridine Off-white carboxylic acid {1-[5-(1- 6-[5-(1-Amino- solid methyloxo-1,2,3,4- cyclopropyl)- tetrahydro-quinolinyl)- pyridinyl] pyridinyl]-cyclopropyl}- methyl-3,4-dihydro- 137 433.5 amide 1H-quinolinone N (example 59) and 3- chloro-pyridine expl. 75 Cl carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Off-white 3-Chloro-pyridine amorphou 6-[5-(1-Amino carboxylic acid {1-methyl s solid methyl-ethyl)- [5-(1-methyloxo-1,2,3,4- pyridinyl] tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinyl]-ethyl}-amide 435.5 1H-quinolinone (example 72) and 3- chloro-pyridine expl. 75 carboxylic acid Off-white 3,5-Dimethyl-isoxazole 6-[5-(1-Amino solid carboxylic acid {1-methyl methyl-ethyl)- [5-(1-methyloxo-1,2,3,4- pyridinyl] tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinyl]-ethyl}-amide 139 1H-quinolinone 419.5 O N (example 72) and 3,5-dimethyl- isoxazole expl. 40 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light yellow 3-Chloro-pyridine 6-(5-Aminomethyl- solid carboxylic acid [5-(2-oxo- pyridinyl)-3,4- 1,2,3,4-tetrahydro-quinolin dihydro-1H- yl)-pyridinylmethyl]-amide H quinolinone 393.5 (example 149) and 3-chloro-pyridine N Cl carboxylic acid expl. 75 Colorless 3,5-Dimethyl-isoxazole 6-(5-Aminomethyl- solid carboxylic acid [5-(2-oxo- pyridinyl)-3,4- 1,2,3,4-tetrahydro-quinolin dihydro-1H- yl)-pyridinylmethyl]-amide quinolinone 141 377.5 (example 149) and 3,5-dimethyl- isoxazole expl. 40 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Light 3-Chloro-pyridine brown 6-[5-(1-Amino- carboxylic acid {1-[5-(7- amorphou cyclopropyl)- fluoromethyloxo- s solid pyridinyl] 1,2,3,4-tetrahydro-quinolin fluoromethyl-3,4- yl)-pyridinyl]- dihydro-1H- 451.5 cyclopropyl}-amide quinolinone (example 150) and 3-chloro-pyridine expl. 75 carboxylic acid 3-Methyl-pyridine Colorless carboxylic acid {1-[5-(1- 6-[5-(1-Amino- solid methyloxo-1,2,3,4- cyclopropyl)- tetrahydro-quinolinyl)- pyridinyl] pyridinyl]-cyclopropyl}- methyl-3,4-dihydro- 143 413.5 amide 1H-quinolinone N (example 59) and 3- methyl-pyridine expl. 75 carboxylic acid Aspect Ex Name Starting Materials Prep. by (M+H ) analogy to Colorless N-{(trans)[5-(1-Methyl 6-[5-((trans) solid oxo-1,2,3,4-tetrahydro- Amino- quinolinyl)-pyridin cyclohexyloxy)- yloxy]-cyclohexyl}- pyridinyl] propionamide methyl-3,4-dihydro- 408.5 1H-quinolinone hydrochloride (example 71) and expl. 76 propionyl chloride Light brown -Trifluoromethyl-isoxazole- 6-(5-Aminomethyl- amorphou 4-carboxylic acid [5-(1- pyridinyl) s solid methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone 145 431.5 pyridinylmethyl]-amide (example 36) and 5- trifluoromethyl- H isoxazole expl. 40 F carboxylic acid Example 146 7-Fluoromethyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone O N F In analogy to the procedure described for the preparation of example 42, reaction of (S) [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid tert-butyl ester (example 52) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 342.1 (M+H ).
Example 147 (R)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]- pyrrolidinecarboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of example 45, reaction of (R) ((5-bromopyridinyloxy)methyl)pyrrolidinecarboxylic acid tert-butyl ester (intermediate A-55) and 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4- dihydro-1H-quinolinone (intermediate A-1) gave the title compound as a colorless solid. MS: 438.6 (M+H ).
Example 148 1-Methyl[5-((R)pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro-1H-quinolin- 2-one hydrochloride In analogy to the procedure described for the preparation of example 42, reaction of (R) [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]-pyrrolidine- 1-carboxylic acid tert-butyl ester (example 147) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 338.2 (M+H ).
Example 149 6-(5-Aminomethyl-pyridinyl)-3,4-dihydro-1H-quinolinone In analogy to the procedure described for the preparation of example 45, reaction of 3- aminomethylbromopyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,4- dihydroquinolin-2(1H)-one (intermediate A-34) gave the title compound as a light yellow amorphous solid. MS: 254.4 (M+H ).
Example 150 6-[5-(1-Amino-cyclopropyl)-pyridinyl]fluoromethyl-3,4-dihydro-1H- quinolinone O N F In analogy to the procedures described for the preparation of example 59, potassium 1-(5- bromopyridinyl)cyclopropanecarboxylate (example 59 [B]) has been reacted with 7- fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone (intermediate A-22) and subsequently with diphenylphosphoryl azide and sodium trimethylsilanolate to give the title compound as a light yellow oil. MS: 312.5 (M+H ).
The following compounds listed in Table 6 were prepared in analogy to the procedure described for the preparation of example 38, using the appropriate starting materials.
Table 6 Ex Name Starting Materials Aspect (M+H ) 6-[5-(2-Amino- Ethanesulfonic acid {2-[5-(1- ethoxy)-pyridin methyloxo-1,2,3,4- yl]methyl-3,4- tetrahydro-quinolinyl)- dihydro-1H- pyridinyloxy]-ethyl}-amide Colorless 151 quinolinone 390.1 hydrochloride H (example 42) and ethanesulfonyl chlorde Ex Name Starting Materials Aspect (M+H ) 3-Chloro-N-[5-(1-methyl oxo-1,2,3,4-tetrahydro- 6-(5-Aminomethyl- quinolinyl)-pyridin pyridinyl) ylmethyl]- methyl-3,4-dihydro- Light benzenesulfonamide 1H-quinolinone 152 yellow 442.2 (example 36) and 3- solid chloro- benzenesulfonyl chloride 6-Methoxy-pyridine sulfonic acid [5-(1-methyl 6-(5-Aminomethyl- oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- Light ylmethyl]-amide 153 1H-quinolinone yellow 439.3 (example 36) and 6- solid methoxy-pyridine sulfonyl chloride Ex Name Starting Materials Aspect (M+H ) 3,5-Dimethyl-isoxazole 6-(5-Aminomethyl- sulfonic acid [5-(1-methyl pyridinyl) oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin 1H-quinolinone Yellow ylmethyl]-amide 154 427.2 (example 36) and solid 3,5-dimethyl- isoxazolesulfonyl chloride Cyclopropanesulfonic acid 6-(5-Aminomethyl- [5-(1-methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]-amide Off-white 155 1H-quinolinone 372.2 solid (example 36) and cyclopropanesulfon yl chloride 3,4-Dichloro-N-[5-(1-methyl- 2-oxo-1,2,3,4-tetrahydro- 6-(5-Aminomethyl- quinolinyl)-pyridin pyridinyl) ylmethyl]- methyl-3,4-dihydro- Light benzenesulfonamide 1H-quinolinone 156 yellow 476.1 (example 36) and solid 3,4-dichloro- benzenesulfonyl chloride Cl Cl Ex Name Starting Materials Aspect (M+H ) 1-Methyl-1H-imidazole sulfonic acid [5-(1-methyl 6-(5-Aminomethyl- oxo-1,2,3,4-tetrahydro- pyridinyl) quinolinyl)-pyridin methyl-3,4-dihydro- ylmethyl]-amide 1H-quinolinone Off-white 157 412.3 (example 36) and 1- solid S methyl-1H- imidazole sulfonyl chloride 6-Chloro-pyridinesulfonic acid [5-(1-methyloxo- 6-(5-Aminomethyl- 1,2,3,4-tetrahydro-quinolin pyridinyl) yl)-pyridinylmethyl]-amide methyl-3,4-dihydro- Light O 1H-quinolinone yellow 443.2 (example 36) and 6- solid chloro-pyridine sulfonyl chloride 1-Methyl-1H-pyrazole 6-(5-Aminomethyl- sulfonic acid [5-(1-methyl pyridinyl) oxo-1,2,3,4-tetrahydro- methyl-3,4-dihydro- quinolinyl)-pyridin Light 1H-quinolinone ylmethyl]-amide 159 brown 412.2 (example 36) and 1- solid methyl-1H- pyrazolesulfonyl chloride Ex Name Starting Materials Aspect (M+H ) 6-[5-((S)Ethanesulfonyl- 1-Methyl[5-((S)- piperidinyloxy)-pyridin piperidinyloxy)- yl]methyl-3,4-dihydro-1H- pyridinyl]-3,4- quinolinone dihydro-1H- Colorless 160 430.1 quinolinone solid (example 61) and N N ethanesulfonyl chloride 1-Methyl[5- 6-[5-(1-Ethanesulfonyl- (piperidinyloxy)- piperidinyloxy)-pyridin pyridinyl]-3,4- yl]methyl-3,4-dihydro-1H- dihydro-1H- Colorless quinolinone 161 quinolinone amorphou 430.1 hydrochloride s solid (example 62) and ethanesulfonyl chloride 2,2,2-Trifluoro- 6-(5-Aminomethyl- ethanesulfonic acid [5-(1- pyridinyl) methyloxo-1,2,3,4- methyl-3,4-dihydro- tetrahydro-quinolinyl)- 1H-quinolinone Colorless pyridinylmethyl]-amide 414.1 (example 36) and solid 2,2,2-trifluoro- ethanesulfonyl N chloride Ex Name Starting Materials Aspect (M+H ) C,C,C-Trifluoro-N-[5-(1- 6-(5-Aminomethyl- methyloxo-1,2,3,4- pyridinyl) tetrahydro-quinolinyl)- methyl-3,4-dihydro- pyridinylmethyl]- Colorless 1H-quinolinone methanesulfonamide 163 amorphou 400.0 (example 36) and s solid trifluoro- methanesulfonyl chloride 1-Methyl[5-((S)- 6-[5-((S)Ethanesulfonyl- pyrrolidinyloxy)- pyrrolidinyloxy)-pyridin pyridinyl]-3,4- yl]methyl-3,4-dihydro-1H- dihydro-1H- Colorless quinolinone 164 quinolinone amorphou 416.1 hydrochloride s solid (example 60) and S ethanesulfonyl chloride 6-[5-((S) 6-[5-((S)Ethanesulfonyl- Azetidin azetidinylmethoxy)- ylmethoxy)-pyridin- pyridinyl]methyl-3,4- 3-yl]methyl-3,4- Colorless dihydro-1H-quinolinone 165 dihydro-1H- 416.1 solid quinolinone N (example 63) and N ethanesulfonyl chloride Ex Name Starting Materials Aspect (M+H ) Ethanesulfonic acid {1-[5-(1- 6-[5-(1-Amino- methyloxo-1,2,3,4- cyclopropyl)- tetrahydro-quinolinyl)- pyridinyl] pyridinyl]-cyclopropyl}- methyl-3,4-dihydro- Off-white amide 166 386.3 1H-quinolinone solid (example 59) and ethanesulfonyl chloride 1-Methyl[5-((S)- 1-pyrrolidin 6-[5-((S)Ethanesulfonyl- ylmethoxy)-pyridin- pyrrolidinylmethoxy)- 3-yl]-3,4-dihydro- Colorless pyridinyl]methyl-3,4- 167 1H-quinolinone amorphou 430.5 dihydro-1H-quinolinone O N hydrochloride s solid N (example 66) and ethanesulfonyl chloride 7-Fluoromethyl- 6-[5-((R)Ethanesulfonyl- 6-[5-((R)-pyrrolidin- pyrrolidinyloxy)-pyridin 3-yloxy)-pyridin yl]fluoromethyl-3,4- yl]-3,4-dihydro-1H- Off-white dihydro-1H-quinolinone 168 quinolinone 434.4 solid O N F hydrochloride (example 67) and ethanesulfonyl chloride Ex Name Starting Materials Aspect (M+H ) 6-[5-((R)Ethanesulfonyl- 1-Methyl[5-((R)- pyrrolidinyloxy)-pyridin pyrrolidinyloxy)- yl]methyl-3,4-dihydro-1H- pyridinyl]-3,4- quinolinone dihydro-1H- Colorless 169 quinolinone 416.4 hydrochloride (example 68) and ethanesulfonyl chloride 6-[5-(Azetidin 6-[5-(1-Ethanesulfonyl- yloxy)-pyridin azetidinyloxy)-pyridin yl]methyl-3,4- yl]methyl-3,4-dihydro-1H- dihydro-1H- Colorless quinolinone quinolinone amorphou 402.5 hydrochloride s solid N (example 70) and ethanesulfonyl chloride Ethanesulfonic acid {1-[5-(7- 6-[5-(1-Amino- fluoromethyloxo- cyclopropyl)- 1,2,3,4-tetrahydro-quinolin pyridinyl] yl)-pyridinyl]- fluoromethyl-3,4- Brown cyclopropyl}-amide 171 dihydro-1H- amorphou 404.5 O N F quinolinone s solid (example 150) and ethanesulfonyl chloride Ex Name Starting Materials Aspect (M+H ) 6-[5-((trans) Ethanesulfonic acid {(trans)- Amino- 4-[5-(1-methyloxo-1,2,3,4- cyclohexyloxy)- tetrahydro-quinolinyl)- pyridinyl] pyridinyloxy]-cyclohexyl}- Yellow methyl-3,4-dihydro- amide amorphou 444.4 1H-quinolinone s solid hydrochloride (example 71) and ethanesulfonyl chloride 6-[5-((R or S) Ethanesulfonic acid {(R or Amino-ethyl)- S)[5-(1-methyloxo- pyridinyl] 1,2,3,4-tetrahydro-quinolin methyl-3,4-dihydro- Colorless yl)-pyridinyl]-ethyl}-amide 173 1H-quinolinone amorphou 374.1 O O hydrochloride s solid (example 65) and ethanesulfonyl (R or S) chloride 6-[5-((S or R) Ethanesulfonic acid {(S or Amino-ethyl)- R)[5-(1-methyloxo- pyridinyl] 1,2,3,4-tetrahydro-quinolin methyl-3,4-dihydro- Colorless yl)-pyridinyl]-ethyl}-amide 1H-quinolinone amorphou 374.0 hydrochloride s solid (example 64) and ethanesulfonyl (S or R) chloride The following compounds listed in Table 7 were prepared in analogy to the procedure described for the preparation of example 45, using the appropriate starting materials.
Table 7 Ex Name Starting Materials Aspect (M+H ) 1-Methyl-1H- 1-Methyl-1H-pyrazole pyrazole carboxylic acid [5-(7-fluoro- carboxylic acid (5- 1-methyloxo-1,2,3,4- bromo-pyridin tetrahydro-quinolinyl)- ylmethyl)-amide pyridinylmethyl]-amide (intermediate A-47) Colorless O N F and 7-fluoro 394.0 solid methyl(4,4,5,5- tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) Ex Name Starting Materials Aspect (M+H ) (rac)-N-(1-(5- Bromopyridinyl)- (rac)-Ethanesulfonic acid {2- methyl[5-(1-methyloxo- methylpropyl)ethane 1,2,3,4-tetrahydro-quinolin sulfonamide yl)-pyridinyl]-propyl}- (intermediate A-40) Yellow amide 402.5 and 1-methyl solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) (rac)-N-((5- (rac)-Ethanesulfonic acid Bromopyridin {cyclopropyl-[5-(1-methyl yl)(cyclopropyl)met oxo-1,2,3,4-tetrahydro- hyl)ethanesulfonami quinolinyl)-pyridinyl]- de (intermediate A- Colorless methyl}-amide 177 39) and 1-methyl amorphou 400.3 (4,4,5,5-tetramethyl- s solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (rac)-N-(1-(5- Bromopyridin yl)ethyl)ethanesulfo (rac)-Ethanesulfonic acid {1- namide [5-(7-fluoromethyloxo- (intermediate A-37) 1,2,3,4-tetrahydro-quinolin Colorless and 7-fluoro yl)-pyridinyl]-ethyl}-amide amorphou 392.1 methyl(4,4,5,5- O N F s solid O tetramethyl- H [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) 2-(5-Bromo-pyridin- 6-[5-(1,1-Dioxo-1λ - 3-ylmethyl)- isothiazolidinylmethyl)- isothiazolidine 1,1- pyridinyl]methyl-3,4- dioxide dihydro-1H-quinolinone (intermediate A-48) Colorless 179 and 1-methyl 372.1 solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (rac)-N-(1-(5- Bromopyridin (rac)-Ethanesulfonic acid {1- yl)propyl)ethanesulf [5-(1-methyloxo-1,2,3,4- onamide tetrahydro-quinolinyl)- Light (intermediate A-38) pyridinyl]-propyl}-amide yellow and 1-methyl 388.0 amorphou (4,4,5,5-tetramethyl- s solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) N-((5- Bromopyridin Ethanesulfonic acid ethyl-[5- yl)methyl)-N- (1-methyloxo-1,2,3,4- ethylethanesulfonam tetrahydro-quinolinyl)- Light ide (intermediate A- pyridinylmethyl]-amide yellow 181 42) and 1-methyl 388.2 amorphou (4,4,5,5-tetramethyl- s solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) N-((5- Bromopyridin Ethanesulfonic acid methyl- yl)methyl)-N- [5-(1-methyloxo-1,2,3,4- methylethanesulfona tetrahydro-quinolinyl)- mide (intermediate pyridinylmethyl]-amide A-41) and 1-methyl- Colorless 374.1 6-(4,4,5,5- solid S tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) N-(2-(5- Bromopyridin Ethanesulfonic acid {1- yl)propan methyl[5-(1-methyloxo- yl)ethanesulfonamid 1,2,3,4-tetrahydro-quinolin e (intermediate A- yl)-pyridinyl]-ethyl}-amide Colorless 183 49) and 1-methyl 388.0 solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) N-((5- Bromopyridin Ethanesulfonic acid yl)methyl)-N- isopropyl-[5-(1-methyloxo- isopropylethanesulf 1,2,3,4-tetrahydro-quinolin onamide yl)-pyridinylmethyl]-amide (intermediate A-43) Colorless 402.2 and 1-methyl solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) N-((5- Ethanesulfonic acid (2- Bromopyridin ethoxy-ethyl)-[5-(1-methyl yl)methyl)-N oxo-1,2,3,4-tetrahydro- ethoxy- quinolinyl)-pyridin ethylethanesulfonam ylmethyl]-amide ide (intermediate A- Colorless 185 432.3 O O 44) and 1-methyl solid (4,4,5,5-tetramethyl- N [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (rac)-N-(1-(5- Bromopyridin (rac)-Ethanesulfonic acid yl)ethyl)-N- methyl-{1-[5-(1-methyl methylethanesulfona oxo-1,2,3,4-tetrahydro- mide (intermediate quinolinyl)-pyridinyl]- Colorless A-45) and 1-methyl- ethyl}-amide amorphou 388.4 6-(4,4,5,5- s solid tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) (rac)-N-(1-(5- Bromopyridin (rac)-Ethanesulfonic acid yl)ethyl)-N- ethyl-{1-[5-(1-methyloxo- ethylethanesulfonam 1,2,3,4-tetrahydro-quinolin ide (intermediate A- Colorless yl)-pyridinyl]-ethyl}-amide 187 46) and 1-methyl amorphou 402.5 (4,4,5,5-tetramethyl- s solid [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) N-((5- Bromopyridin 3,5-Dimethyl-isoxazole yl)methyl)-N,3,5- carboxylic acid methyl-[5-(1- trimethylisoxazole- methyloxo-1,2,3,4- 4-carboxamide tetrahydro-quinolinyl)- (intermediate A-50) Colorless pyridinylmethyl]-amide 405.5 and 1-methyl solid (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) 3-Bromo[2-(1,1- dioxo-1λ - 6-{5-[2-(1,1-Dioxo-1λ - isothiazolidinyl)- isothiazolidinyl)-ethoxy]- ethoxy]-pyridine pyridinyl}methyl-3,4- (intermediate A-51) dihydro-1H-quinolinone Light 189 and 1-methyl 402.4 yellow oil (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) (rac)-N-(1-(5- Bromopyridin yl)ethyl)ethanesulfo namide Ethanesulfonic acid {(R or S)- (intermediate A-37) 1-[5-(7-fluoromethyl and 7-fluoro oxo-1,2,3,4-tetrahydro- methyl(4,4,5,5- Colorless quinolinyl)-pyridinyl]- tetramethyl- amorphou 392.1 ethyl}-amide [1,3,2]dioxaborolan- s solid O N F 2-yl)-3,4-dihydro- 1H-quinolinone (R or S) (intermediate A-22) followed by separation with chiral phase HPLC. (rac)-N-(1-(5- Bromopyridin yl)ethyl)ethanesulfo Ethanesulfonic acid {(S or R)- namide 1-[5-(7-fluoromethyl (intermediate A-37) oxo-1,2,3,4-tetrahydro- and 7-fluoro quinolinyl)-pyridinyl]- methyl(4,4,5,5- Colorless ethyl}-amide 191 tetramethyl- amorphou 392.1 O N F [1,3,2]dioxaborolan- s solid 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22) (S or R) followed by separation with chiral phase HPLC.
Ex Name Starting Materials Aspect (M+H ) N-((5-Bromo methylpyridin Ethanesulfonic acid [5-(7- yl)methyl)ethanesulf fluoromethyloxo- onamide 1,2,3,4-tetrahydro-quinolin (intermediate A-52) yl)methyl-pyridin and 7-fluoro Colorless ylmethyl]-amide 392.5 methyl(4,4,5,5- solid O N F tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-22).
N-((5-Bromo chloropyridin Ethanesulfonic acid [4- yl)methyl)ethanesulf chloro(1-methyloxo- onamide 1,2,3,4-tetrahydro-quinolin (intermediate A-53) yl)-pyridinylmethyl]-amide Colorless 193 and 1-methyl 394.3 solid (4,4,5,5-tetramethyl- H [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Ex Name Starting Materials Aspect (M+H ) N-((5-Bromo methylpyridin Ethanesulfonic acid [4- yl)methyl)ethanesulf methyl(1-methyloxo- onamide 1,2,3,4-tetrahydro-quinolin (intermediate A-52) yl)-pyridinylmethyl]-amide and 1-methyl Grey solid 374.4 (4,4,5,5-tetramethyl- [1,3,2]dioxaborolan- 2-yl)-3,4-dihydro- 1H-quinolinone (intermediate A-1) Example 195 Ethanesulfonic acid methyl-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyloxy]-ethyl}-amide To a solution of ethanesulfonic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-amide (example 151, 0.06 g, 0.154 mmol) in DMF (1.5 mL) cooled at 0 °C with an ice bath was added 60% NaH in mineral oil (0.008 g, 0.2 mmol) and the reaction mixture was stirred for 15 min. Then, MeI (0.026 g, 0.185 mmol) was added and the reaction mixture was stirred at 0 °C for another 30 min. The mixture was quenched with aq. ammonia (1 mL), diluted with brine (5 mL) and then extracted with EtOAc (2 x 20 mL). Combined organics were dried over Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to % MeOH-DCM gradient to give the title compound (0.050 g, 80 %) as a light yellow amorphous solid. MS: 404.4 (M+H ).
The following compounds listed in Table 8 were prepared in analogy to the procedure described for the preparation of example 195, using the appropriate starting materials.
Table 8 Ex Name Starting Materials Aspect (M+H ) 3-Chloro-pyridine carboxylic acid methyl-[5-(1- 3-Chloro-pyridine- methyloxo-1,2,3,4- 2-carboxylic acid tetrahydro-quinolinyl)- [5-(1-methyloxo- pyridinylmethyl]-amide Colorless 1,2,3,4-tetrahydro- 196 amorphou 421.4 quinolinyl)- s solid pyridinylmethyl]- N Cl amide (example 118) N-{2-[5-(1-Methyl- N-Methyl-N-{2-[5-(1-methyl- 2-oxo-1,2,3,4- 2-oxo-1,2,3,4-tetrahydro- tetrahydro-quinolin- Colorless quinolinyl)-pyridin 197 6-yl)-pyridin amorphou 368.3 yloxy]-ethyl}-propionamide yloxy]-ethyl}- s solid propionamide (example 43) Ex Name Starting Materials Aspect (M+H ) 1-Methyl-1H-pyrazole 1-Methyl-1H- carboxylic acid methyl-[5-(1- pyrazole methyloxo-1,2,3,4- carboxylic acid [5- tetrahydro-quinolinyl)- Colorless (1-methyloxo- pyridinylmethyl]-amide 198 amorphou 390.4 1,2,3,4-tetrahydro- s solid quinolinyl)- pyridinylmethyl]- amide (example 87) 3-Methyl-pyridine 3-Methyl-pyridine- carboxylic acid methyl-[5-(1- 2-carboxylic acid methyloxo-1,2,3,4- [5-(1-methyloxo- tetrahydro-quinolinyl)- Colorless 1,2,3,4-tetrahydro- pyridinylmethyl]-amide 199 amorphou 401.5 quinolinyl)- s solid pyridinylmethyl]- amide (example 115) 3-Chloro-pyridine 3-Chloro-pyridine- carboxylic acid [5-(7-fluoro- 2-carboxylic acid 1-methyloxo-1,2,3,4- [5-(7-fluoro tetrahydro-quinolinyl)- methyloxo- Off-white pyridinylmethyl]-methyl- 200 1,2,3,4-tetrahydro- amorphou 439.1 amide quinolinyl)- s solid O N F O Cl pyridinylmethyl]- amide (example 131) Ex Name Starting Materials Aspect (M+H ) 3-Chloro-pyridine carboxylic acid methyl-{1-[5- 3-Chloro-pyridine- (1-methyloxo-1,2,3,4- 2-carboxylic acid tetrahydro-quinolinyl)- {1-[5-(1-methyl Colorless pyridinyl]-cyclopropyl}- oxo-1,2,3,4- 201 amorphou 447.4 amide tetrahydro-quinolin- s solid 6-yl)-pyridinyl]- cyclopropyl}-amide (example 137) N Cl 1-Methyl-1H-pyrazole 1-Methyl-1H- carboxylic acid [5-(7-fluoro- pyrazole 1-methyloxo-1,2,3,4- carboxylic acid [5- tetrahydro-quinolinyl)- (7-fluoromethyl- Light pyridinylmethyl]-methyl- 202 2-oxo-1,2,3,4- brown 408.5 amide tetrahydro-quinolin- solid O N F 6-yl)-pyridin ylmethyl]-amide (example 175) Example 203 Ethanesulfonic acid [5-(8-chlorooxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-amide To a solution of ethanesulfonic acid [5-(2-oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-amide (example 55, 0.681 g, 0.197 mmol) in DMF (1 mL) heated to 65 °C was added N-chloro-succinimide (0.034 g, 0.256 mmol) and the reaction mixture was stirred at this temperature over night. The mixture was diluted with EtOAc, poured into water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine, dried over Na SO , filtered and evaporated. The residue was purified by reverse phase HPLC on a Gemini-NX column, eluting with a MeOH-H O (0.05 % TEA) gradient to give the title compound (0.025 g, 33 %) as a colorless amorphous solid. MS: 380.4 (M+H ).
The following compounds listed in Table 9 were prepared in analogy to the procedure described for the preparation of example 203, using the appropriate starting materials.
Table 9 Ex Name Starting Materials Aspect (M+H ) Ex Name Starting Materials Aspect (M+H ) 3-Chloro-pyridine 3-Chloro-pyridine- carboxylic acid [5-(8-chloro- 2-carboxylic acid 2-oxo-1,2,3,4-tetrahydro- [5-(2-oxo-1,2,3,4- Colorless quinolinyl)-pyridin 204 tetrahydro-quinolin- 427.4 solid ylmethyl]-amide 6-yl)-pyridin ylmethyl]-amide (example 140) N Cl 3,5-Dimethyl-isoxazole 3,5-Dimethyl- carboxylic acid [5-(8-chloro- isoxazole 2-oxo-1,2,3,4-tetrahydro- carboxylic acid [5- quinolinyl)-pyridin (2-oxo-1,2,3,4- Colorless ylmethyl]-amide 205 411.4 tetrahydro-quinolin- solid 6-yl)-pyridin ylmethyl]-amide (example 141) Example 206 6-{5-[(3-Ethyl-oxetanylamino)-methyl]-pyridinyl}methyl-3,4-dihydro-1H- quinolinone [A] 6-(5-Hydroxymethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone A microwave vial was charged with (5-bromo-pyridinyl)-methanol (376 mg, 2.0 mmol), 1-methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone (intermediate A-1) (574 mg, 2.0 mmol) and DMF (4 mL). After purging the reaction mixture with argon, bis(triphenylphosphine)palladium(II)chloride (140 mg, 0.2 mmol) and 2 N aq. Na CO solution (2.0 mL, 4 mmol) were added and the reaction was heated in the microwave at 120 °C for 50 min. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2 x 20 mL). The resulting filtrate was washed with brine, dried over anhydrous Na SO , filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to % MeOH-DCM gradient to give the title compound (198 mg, 74 %) as a white solid. MS: 269.2 (M+H ).
[B] 6-(5-Chloromethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone At 0 °C, 6-(5-hydroxymethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone (190 mg, 0.7 mmol) in DCM (15 mL) was treated slowly with thionyl chloride (0.32 mL, 4.0 mmol). After the addition, the reaction mixture was allowed to stir at 2-5 °C for 2 hours before it was poured into satd. aq. NaHCO solution (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhydrous Na SO , filtered and concentrated in vacuo to give title compound (190 mg, 93.5%) as yellow oil. MS: 287.1 (M+H ).
[C] 6-{5-[(3-Ethyl-oxetanylamino)-methyl]-pyridinyl}methyl-3,4-dihydro-1H- quinolinone To a stirred solution of 6-(5-chloromethyl-pyridinyl)methyl-3,4-dihydro-1H- quinolinone (190 mg, 0.66 mmol) in DMF (5.0 mL) was added K CO (276 mg, 2.0 mmol) and 3-ethyl-oxetanylamine (415 mg, 3.0 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for additional 12 hours. After extraction with EtOAc, the organic layer was washed with brine, dried over anhydrous Na SO , filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (35 mg, 17.2%) as a light yellow solid. MS: 352.1 (M+H ).
Example 207 Ethanesulfonic acid [5-(7-chloromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide O N Cl [A] N-(4-Bromochloro-phenyl)chloro-propionamide To a solution of 4-bromochloroaniline (6.0 g, 29. 1 mmol) and pyridine (3.45 g, 43.6 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (5.53 g, 43.6 mmol) dropwise at 15 C. After stirring for 2 hours at room temperature, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The product N-(4-bromochloro-phenyl)chloro-propionamide (8.20 g, yield: 95%) was obtained as an oil. MS: 298.0 (M+H) .
[B] 6-Bromochloro-3,4-dihydro-1H-quinolinone O N Cl A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with N-(4- bromochloro-phenyl)chloro-propionamide (1.0 g, 3.36 mmol) and aluminium chloride (0.67 g, 5.04 mmol). In a pre-heated oil bath, the flask was heated at 135~140 C for 2 hours. After cooling to room temperature, the reaction mixture was treated slowly with ice-water, then extracted with EtOAc. The organic layer was washed with water and brine in sequence and dried over anhydrous Na SO . After evaporation of the solvent, the residue was purified by recrystallization from EtOAc (2 mL) which gave title compound (0.44 g, 50%) as a solid. MS: 260.0 (M+H) .
[C] 6-Bromochloromethyl-3,4-dihydro-1H-quinolinone O N Cl Potassium tert-butoxide (0.45 g, 4.0 mmol) was added to a solution of 6-bromochloro- 3,4-dihydro-1H-quinolinone (0.52 g, 2.0 mmol) in DMF (5 mL) at 0 C. Then, the reaction mixture was stirred at 0 C for 30 min and methyl iodide (0.18 g, 1.29 mmol) was added. The resulting mixture was stirred for 2 hours before water was added. After extraction of the reaction mixture with EtOAc, the organic layer was washed with water and brine in sequence. Then, it was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give a crude product (0.49 g, 90%) as a white solid.
MS: 274.0 (M+H) .
[D] 7-Chloromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone O N Cl A mixture of 6-bromochloromethyl-3,4-dihydro-1H-quinolinone (0.1 g, 0.36 mmol), bis(pinacolato)diboron (0.13 g, 0.55 mmol), 1,1'-bis(diphenylphosphino) ferrocenedichloro-palladium (II) (14.7 mg, 0.018 mmol) and potassium acetate (0.11 g, 1.08 mmol) in dioxane (3 mL) was heated in a microwave at 100 C for 3 hours. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound (82 mg, 70%) as a white solid. MS: 322.1 (M+H) .
[E] Ethanesulfonic acid [5-(7-chloromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide A mixture of 7-chloromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4- dihydro-1H-quinolinone (20 mg, 0.06 mmol), ethanesulfonic acid (5-bromo-pyridin ylmethyl)-amide (intermediate A-11, 26 mg, 0.09 mmol), bis(triphenylphosphine)- palladium(II) chloride (4.2 mg, 0.006 mmol) and sodium carbonate (2 N aq., 0.06 mL) in DMF (1 mL) was heated in a microwave at 120 C for 30 minutes. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na SO and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title product (7.1 mg, 30%) as a white solid. MS, 394.2 (M+H) .
Example 208 Ethanesulfonic acid [5-(8-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide [A] 3-Chloro-N-(2-fluoro-phenyl)-propionamide To a solution of 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2- dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15 C. After stirring at room temperature for 2 hours, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na SO , filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as an oil. MS: 202.1 (M+H) .
[B] 8-Fluoro-3,4-dihydro-1H-quinolinone A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with 3- chloro-N-(2-fluoro-phenyl)-propionamide (5.33 g, 26.5 mmol) and aluminium chloride (5.30 g, 39.7 mmol). In a pre-heated oil bath, the flask was heated at 160 C for 1.5 hours.
After cooling to room temperature, the mixture was treated slowly with ice-water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhydrous Na SO , filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford title compound (3.1 g, 70%) as a solid. MS: 166.0 (M+H) .
[C] 6-Bromofluoro-3,4-dihydro-1H-quinolinone At 0 C, NBS (0.62 g, 3.5mmol) was added dropwise to a solution of 8-fluoro-3,4-dihydro- 1H-quinolinone (0.52 g, 3.2 mmol) in DMF (5 mL). The resulting reaction mixture was stirred at room temperature for 12 hours before it was treated with water. The precipitated solid was collected through filtration, washed with ether, and dried in a vacuum to afford title compound (0.65 g, 85%) as a white solid. MS: 244.1 (M+H) .
[D] 6-Bromofluoromethyl-3,4-dihydro-1H-quinolinone A solution of 6-bromofluoro-3,4-dihydro-1H-quinolinone (0.21 g, 0.86 mmol) in DMF (2 mL) was treated with potassium tert-butoxide (0.19 g, 1.72 mmol) at 0 C. The resulting mixture was stirred at 0 C for 30 minutes before methyl iodide (0.18 g, 1.29 mmol) was added. After stirring for 2 hours, the reaction mixture was treated with water, extracted with EtOAc, washed with water and brine in sequence, and dried over anhydrous Na SO . After removal of solvent under reduced pressure, the crude product (0.18 g, 80%) was obtained as a white solid. MS: 258.0 (M+H) .
[E] 8-Fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone A mixture of 6-bromofluoromethyl-3,4-dihydro-1H-quinolinone (0.18 g, 0.36 mmol), bis(pinacolato)diboron (0.25g, 1.05mmol), 1,1'-bis(diphenylphosphino)ferrocene- dichloropalladium (II) (28.6 mg, 0.035 mmol) and potassium acetate (0.21 g, 2.1 mmol) in dioxane (3 mL) was heated in a microwave at 100 C for 3 hours. After dilution with EtOAc, the organic layer was washed with water, dried over anhydrous Na SO and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, % ethyl acetate in hexane) to afford the title compound (0.15g, 70%) as a white solid.
MS: 306.2 (M+H) .
[F] Ethanesulfonic acid [5-(8-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide A mixture of 8-fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4- dihydro-1H-quinolinone (20 mg, 0.066 mmol), ethanesulfonic acid (5-bromo-pyridin ylmethyl)-amide (intermediate A-11, 27.4 mg, 0.098 mmol), bis(triphenylphosphine)- palladium(II) chloride (4.6 mg, 0.0066 mmol) and aq. sodium carbonate solution (2 N, 0.07 mL) in DMF (1 mL) was heated in a microwave at 120 C for 30 min. The resulting reaction mixture was then diluted with EtOAc, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (12.4 mg, 50%) as a white solid. MS: 378.1 (M+H) .
Example 209 Ethanesulfonic acid [5-(8-chloromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide [A] N-(4-Bromochloro-phenyl)chloro-propionamide Br Cl N Cl To a solution of 4-bromochloro-phenylamine (32 g, 0.15 mol) and pyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionyl chloride (21.65 g, 0.17 mol) dropwise at 15 C. After stirring at room temperature for 1 hour, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na SO , filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as a white solid.
[B] 6-Bromochloro-3,4-dihydro-1H-quinolinone A flame-dried 500-mL flask equipped with a magnetic stirring bar was charged with N-(4- bromochloro-phenyl)chloro-propionamide (29.7 g, 0.1 mol) and aluminium chloride (53.3 g, 0.4 mol). In a pre-heated oil bath, the flask was heated at 140 C for 1 hour. After cooling to room temperature, the mixture was treated slowly with ice-water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound (7.0 g, 27%) as a white solid.
[C] 6-Bromochloromethyl-3,4-dihydro-1H-quinolinone A solution of 6-bromochloro-3,4-dihydro-1H-quinolinone (7.0 g, 26.9 mmol) in DMF (100 mL) was treated with potassium tert-butoxide (6.0 g, 53.8 mmol) at 0 C portionwise. The resulting mixture was stirred at 0 C for 30 minutes before methyl iodide (5.0 g, 35.0 mmol) was added. After stirred for 12 hours, the reaction mixture was treated with water, extracted with EtOAc, washed with water and brine in sequence, and dried over anhydrous Na SO . After removal of solvent under reduced pressure, the crude product (3.3 g, 45%) was obtained as a white solid.
[D] 8-Chloromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone A mixture of 6-bromochloromethyl-3,4-dihydro-1H-quinolinone (0.23 g, 0.84 mmol), bis(pinacolato)diboron (0.255 g, 1.01mmol), 1,1'-bis(diphenylphosphino)- ferrocene-dichloropalladium (II) (30.7 mg, 0.04 mmol) and potassium acetate (0.247 g, 2.52 mmol) in dioxane (5 mL) was heated in a microwave at 80 C over night. After dilution with EtOAc, the organic layer was washed with water, dried over anhydrous Na SO and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound (0.17g, 63%) as a white solid.
[E] Ethanesulfonic acid [5-(8-chloromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide Under argon protection, bis(triphenylphosphine)palladium(II)chloride (4 mg, 0.05 mmol) followed by 1 N aqueous Na CO solution (1 mL), was added to a solution of 8-chloro methyl(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolanyl)-3,4-dihydro-1H-quinolinone (160 mg, 0.5 mmol) and ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11, 158 mg, 0.6 mmol) in DMF (3 mL). The resulting reaction mixture was then heated in a microwave at 110 °C for 45 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc (5 mL) and poured into a satd. aq. solution of NaHCO (10 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL). Combined organics were washed with water and brine (20 mL), dried over anhydrous Na SO , filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (65 mg, 45%) as a white solid. MS: 394.1 (M+H) .
Example 210 Ethanesulfonic acid [5-(5-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide [A] 3-Chloro-N-(3-fluoro-phenyl)-propionamide F N Cl To a solution of 3-fluoroanilline (10 mL, 104.02 mmol) in DCM (100 mL) was added pyridine (21 mL, 260.2 mmol) and 3-chloropropionyl chloride (12 mL, 124.4 mmol). The reaction mixture was stirred for 3 hours at room temperature until all starting material had disappeared as shown by LC-MS analysis. The reaction mixture was then diluted with H O and extracted with EtOAc. The organic layer was dried over anhydrous Na SO and concentrated in vacuo to afford the title compound as a solid. It was used in the next step without further purification.
[B] 7-Fluoro-3,4-dihydro-1H-quinolinone (compound A) and 5-fluoro-3,4-dihydro-1H- quinolinone (compound B) F N O (compound A) (compound B) A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with 3- chloro-N-(3-fluoro-phenyl)-propionamide (10 g, 49.6 mmol) and AlCl (23.1 g, 173.6 mmol). On a pre-heated oil bath, the flask was heated at 120~125 °C for 2 hours until LC- MS indicated the reaction was complete. After cooling to room temperature, the mixture was treated slowly with ice-water. After extraction with EtOAc, the combined organic layers were washed with water and brine in sequence. The organic layer was dried over anhydrous Na SO , filtered and concentrated in vacuo to afford a white solid as a crude mixture of two regioisomeric products (A:B) in a ratio of 5.3 :1. (7.63 g, 93.2%).
[C] 7-Fluoromethyl-3,4-dihydro-1H-quinolinone and 5-fluoromethyl-3,4-dihydro- 1H-quinolinone F N O (compound B) (compound A) To an ice cold solution of a mixture of 7-fluoro-3,4-dihydro-1H-quinolinone and 5- fluoro-3,4-dihydro-1H-quinolinone (16.5 g, 0.1 mol) in DMF (200 mL) was added potassium tert-butoxide (22.4 g, 0.2 mol) in 2 portions. The reaction mixture was stirred at 0 °C for 30 min before MeI (25.4 g, 0.18 mol) was added. After the addition, the reaction mixture was allowed to warm up to RT slowly and stirred at RT over night. It was then diluted with EtOAc (500 mL) and poured into 200 mL of 1 M aq. HCl. After extraction with EtOAc (200 mL, 3x), the combined organic layers were washed with brine, dried over anhydrousNa SO , filtered and concentrated in vacuo to give the crude title compounds as oil (16.0 g, 89 %). It was used in the next step without further purification.
[D] 6-Bromofluoromethyl-3,4-dihydro-1H-quinolinone and 6-bromofluoro methyl-3,4-dihydro-1H-quinolinone F N O (compound B) (compound A) To an ice cold solution of the mixture of 7-fluoromethyl-3,4-dihydro-1H-quinolinone and 5-fluoromethyl-3,4-dihydro-1H-quinolinone (16.0 g, 89.4 mmol) in DMF (200 mL) was added NBS (16.0 g, 89.4 mmol). After the addition, the reaction mixture was warmed up to RT and stirred for 3 hours. When LC-MS indicated the completion of the reaction, the mixture was diluted with EtOAc (500 mL) and poured into 500 mL of water.
The aqueous layer was then extracted with EtOAc (200 mL, 3x). Combined organic layers were washed with brine, dried over Na SO , filtered and concentrated in vacuo to give the crude title compound as oil (18.0 g, 78 %). It was used in the next step without further purification.
[E] Ethanesulfonic acid [5-(5-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide In analogy to the procedure described for the preparation of intermediates A-1 [B], the mixture of 6-bromofluoromethyl-3,4-dihydro-1H-quinolinone and 6-bromo fluoromethyl-3,4-dihydro-1H-quinolinone was reacted with 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) in the presence of potassium acetate and PdCl (DPPF)-CH Cl and the reaction product was subsequently reacted with 2 2 2 ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11) in analogy to the procedure described for the preparation of example 45. The crude reaction product has been separated by preparative HPLC to give ethanesulfonic acid [5-(7-fluoro methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]-amide (example 16) as well as the title compound as a white solid. MS: 378.1 (M+H) .
Example 211 Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-methyl-amide To a solution of ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide (example 16, 0.15 g, 0.39 mmol) in DMF (5 mL) was added potassium tert-butoxide (67.2 mg, 0.60 mmol) at 0 C. The resulting mixture was stirred for 30 minutes at 0 C before methyl iodide (84.6 mg, 0.6 mmol) was added dropwise. After stirring for 2 hours, the mixture was treated with water, and extracted with EtOAc. The combined organic layers were then washed with water and brine in sequence, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 5% methanol in dichloromethane) to afford the title compound (93 mg, 60%) as a white solid. MS: 392.1(M+H) .
Example 212 N-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- propionamide O N F [A] N-(5-Bromo-pyridinylmethyl)-propionamide To a solution of propionamide (146 mg, 2.0 mmol) in DMF (10 mL) was added NaH (61 mg, 2.4 mmol) at 0 ºC and reaction mixture was stirred for 10 min before the addition of 3- bromochloromethyl-pyridine (intermediate A-12 [A], 412 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour before water was added. Then, the reaction mixture was extracted with EtOAc and combined organic layers were dried by anhydrous Na SO , filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give title compound (400 mg, 82%) as a solid.
[B] N-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- propionamide O N F To a mixture of 7-fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4- dihydro-1H-quinolinone (intermediate A-22, 168 g, 0.55 mmol) and N-(5-bromo- pyridinylmethyl)-propionamide (122 mg, 0.5 mmol) in DMF (3 mL), purged with argon for 1 min, was added bis(triphenylphosphine)palladium (II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na CO (2.5 mL). Then, the resulting reaction mixture was heated in a microwave at 110 °C for 45 min. After cooling to room temperature, it was diluted with EtOAc (5 mL) and poured into a satd. aq. solution of NaHCO (10 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL) and combined organics were washed with water and brine (20 mL), dried over anhydrous Na SO , filtered and concentrated in vacuo. The residue was then purified by prep-HPLC to afford the title compound (30 mg, 18%) as a white solid. MS: 342.1(M+H) .
Example 213 (rac)-N-{1-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yl]-ethyl}-propionamide A] 5-Bromo-N-methoxy-N-methyl-nicotinamide Br O To a solution of 5-bromo-nicotinic acid (2.02 g,10 mmol) and O,N-dimethyl- hydroxylamine (670 mg, 11 mmol) in DMF (100 mL) was added HOBt (400 mg, 0.3 mmol), EDCI (2.09 g, 11 mmol) and Et N ( 1.11 g, 11 mmol). The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, dried by anhydrous Na SO , filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give the title compound (2.08 g, 85%) as a solid.
[B] 1-(5-Bromo-pyridinyl)-ethanone To a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at -78 ºC. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water.
After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na SO , filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88%).
[C] (rac)(5-Bromo-pyridinyl)-ethylamine To a solution of 1-(5-bromo-pyridinyl)-ethanone (400 mg, 2 mmol) in methanolic ammonia (10 mL) was added Ti(O-iPr) (1.14 g, 4 mmol). The resulting reaction mixture was heated to reflux and stirred over night. After cooling at 0 ºC, NaBH was added into the mixture and it was allowed to warm up to room temperature and stirred for 3 hours.
Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. It was directly used in the next step without further purification.
[D] (rac)-N-[1-(5-Bromo-pyridinyl)-ethyl]-propionamide At 0 ºC, propionyl chloride (138 mg, 1.5 mmol) was added dropwise to a solution of (rac)- 1-(5-bromo-pyridinyl)-ethylamine (201 mg, 1 mmol) and Et N (153 mg, 1.5 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour before it was concentrated to dryness. The residue was redissolved in EtOAc and washed with water and brine, dried over anhydrous Na SO , filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound (200 mg, 78%).
[E] (rac)-N-{1-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yl]-ethyl}-propionamide O N F To a mixture of 7-fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4- dihydro-1H-quinolinone (intermediate A-22, 168 g, 0.55 mmol) and (rac)-N-[1-(5- bromo-pyridinyl)-ethyl]-propionamide (125 mg, 0.5 mmol) in DMF (3 mL), purged with argon for 1 min, was added bis(triphenylphosphine)palladium(II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na CO (2.5 mL). Then, the resulting reaction mixture was heated in a microwave at 100 °C for 45 min. After cooling to room temperature, it was diluted with EtOAc (5 mL), and poured into satd. aq. solution of NaHCO (10 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL) and combined organics were washed with water and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was the purified by prep-HPLC to give the title compound (35 mg, %) as a white solid. MS: 356.3 (M+H) .
Example 214 (S)[5-(2-Oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-pyrrolidine carboxylic acid tert-butyl ester Chiral In analogy to the procedure described for the preparation of example 45, 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) has been coupled to (S)(5-bromo-pyridinyloxy)-pyrrolidinecarboxylic acid tert- butyl ester (intermediate A-29) to give the title compound as a dark grey amorphous solid.
MS: 410.6 (M+H ).
Example 215 3-Chloro-pyridinecarboxylic acid methyl-[5-(2-oxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 45, 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) has been coupled to N-((5-bromopyridinyl)methyl)chloro-N-methylpicolinamide (intermediate A-57) to give the title compound as a light brown amorphous solid. MS: 407.5 (M+H ).
Example 216 3-Chloro-pyridinecarboxylic acid [5-(8-chlorooxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinylmethyl]-methyl-amide In analogy to the procedure described for the preparation of example 203, 3-chloro- pyridinecarboxylic acid methyl-[5-(2-oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-amide (example 215) was reacted with N-chloro-succinimide to give the title compound as a light brown solid. MS: 441.5 (M+H ).
Example 217 (R)Methyl-propanesulfinic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide Chiral Cl O In analogy to the procedure described for the preparation of example 45, 1-methyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to (R)-N-((5-bromochloropyridinyl)methyl) methylpropanesulfinamide (intermediate A-58) to give the title compound as an orange solid. MS: 406.4 (M+H ).
Example 218 6-(5-Aminomethylchloro-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride In analogy to the procedure described for the preparation of example 42, reaction of (R) methyl-propanesulfinic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinylmethyl]-amide (example 217) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 302.4 (M+H ).
Example 219 3,5-Dimethyl-isoxazolecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide Cl O To a solution of 6-(5-aminomethylchloro-pyridinyl)methyl-3,4-dihydro-1H- quinolinone hydrochloride (example 218, 0.05 g, 0.148 mmol) in dry DMF (1 mL) were added EDCI (0.034 g, 0.077 mmol), hydroxybenzotriazole (0.017 g, 0.077 mmol), Hünig’s base (0.057 g, 0.443 mmol) and 3,5-dimethyl-isoxazolecarboxylic acid (0.021 g, 0.148 mmol) and the resulting solution was stirred at room temperature for 2h. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 20 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 5% MeOH-DCM gradient to give the title compound (0.03 g, 48 %) as a colorless solid. MS: 425.4 (M+H ).
Example 220 3-Chloro-pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide Cl O Cl In analogy to the procedure described for the preparation of example 75, 6-(5- aminomethylchloro-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 218) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a off-white solid. MS: 441.3 (M+H ).
Example 221 (R)Methyl-propanesulfinic acid [4-methyl(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 45, 1-methyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) has been coupled to (R)methyl-propanesulfinic acid (5-bromo methyl-pyridinylmethyl)-amide (intermediate A-59) to give the title compound as a colorless amorphous solid. MS: 386.5 (M+H ).
Example 222 6-(5-Aminomethylmethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride In analogy to the procedure described for the preparation of example 42, reaction of (R) methyl-propanesulfinic acid [4-methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinylmethyl]-amide (example 221) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 282.5 (M+H ).
Example 223 3,5-Dimethyl-isoxazolecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 219, 6-(5- aminomethylmethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 222) has been coupled with 3,5-dimethyl-isoxazolecarboxylic acid to give the title compound as a off-white solid. MS: 405.5 (M+H ).
Example 224 3-Chloro-pyridinecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 75, 6-(5- aminomethylmethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 222) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a colorless solid. MS: 421.5 (M+H ).
Example 225 (R)Methyl-propanesulfinic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)methyl-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 45, 7-fluoro methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-22) has been coupled to (R)methyl-propanesulfinic acid (5-bromo methyl-pyridinylmethyl)-amide (intermediate A-59) to give the title compound as a brown amorphous solid. MS: 404.5 (M+H ).
Example 226 6-(5-Aminomethylmethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H- quinolinone hydrochloride O N F In analogy to the procedure described for the preparation of example 42, reaction of (R) methyl-propanesulfinic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)methyl-pyridinylmethyl]-amide (example 225) with hydrogen chloride (in dixoane) in methanol gave the title compound as a light brown solid. MS: 300.5 (M+H ).
Example 227 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)methyl-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 75, 6-(5- aminomethylmethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 226) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a colorless solid. MS: 439.4 (M+H ).
Example 228 3-Chloro-pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-methyl-amide Cl O Cl In analogy to the procedure described for the preparation of example 195, 3-chloro- pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide (example 220) has been reacted with sodium hydride and methyl iodide to give the title compound as off-white solid. MS: 455.1 (M+H ).
Example 229 3-Chloro-pyridinecarboxylic acid methyl-[4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 195, 3-chloro- pyridinecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide (example 224) has been reacted with sodium hydride and methyl iodide to give the title compound as light brown amorphous solid. MS: 435.5 (M+H ).
Example 230 3-Chloro-pyridinecarboxylic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide O Cl (R or S) In analogy to the procedures described for the preparation of example 74, 6-[5-((R or S)- 1-amino-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 65) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a colorless solid. MS: 421.4 (M+H ).
Example 231 5'-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-5,6-dihydro-4H- [3,3']bipyridinylcarboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of example 45, 6-(5-bromo- pyridinyl)methyl-3,4-dihydro-1H-quinolinone (prepared from 1-methyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) and 3,5-dibromo pyridine also with a procedure as used for the preparation of example 45) has been coupled to 5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolanyl)-3,4-dihydro-2H-pyridinecarboxylic acid tert-butyl ester to give the title compound as a amorphous colorless solid. MS: 420.5 (M+H ).
Example 232 {2-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- ethyl}-carbamic acid tert-butyl ester O N F In analogy to the procedure described for the preparation of example 45, 7-fluoro methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-22) has been coupled to [2-(5-bromo-pyridinyloxy)-ethyl]-carbamic acid tert-butyl ester (intermediate A-7) to give the title compound as a yellow waxy solid.
MS: 416.4 (M+H ).
Example 233 3-Chloro-pyridinecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide O Cl In analogy to the procedure described for the preparation of example 75, 6-[5-(2-amino- ethoxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 42) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a light yellow viscous oil. MS: 437.4 (M+H ).
Example 234 Ethanesulfonic acid [5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolinyl)- pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 45, 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one has been coupled to ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11) to give the title compound as a colorless amorphous solid. MS: 372.2 (M+H ).
Example 235 Ethanesulfonic acid [5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin yl)-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 45, 9-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(5H)-one (prepared from 9-bromo-1,2,6,7-tetrahydropyrido[3,2,1-ij]quinolin-3(5H)-one and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in analogy to the procedure described for the preparation of intermediate A-1 [B]) has been coupled to ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11) to give the title compound as a off-white amorphous solid. MS: 386.2 (M+H ).
Example 236 3-Chloro-pyridinecarboxylic acid [5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinolinyl)-pyridinylmethyl]-amide N Cl In analogy to the procedure described for the preparation of example 45, 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one has been coupled to N-((5-bromopyridinyl)methyl)chloropicolinamide (intermediate A-56) to give the title compound as off-white solid. MS: 419.3 (M+H ).
Example 237 3-Chloro-pyridinecarboxylic acid methyl-[5-(4-oxo-1,2,5,6-tetrahydro-4H- pyrrolo[3,2,1-ij]quinolinyl)-pyridinylmethyl]-amide N Cl In analogy to the procedure described for the preparation of example 195, N-methylation of 3-chloro-pyridinecarboxylic acid [5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinolinyl)-pyridinylmethyl]-amide (example 236) gave the title compound as a light yellow solid. MS: 433.4 (M+H ).
Example 238 6-[5-(2-Amino-ethoxy)-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolin one hydrochloride O N F In analogy to the procedure described for the preparation of example 42, reaction of {2-[5- (7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- carbamic acid tert-butyl ester (example 232) with hydrogen chloride (in dixoane) in methanol gave the title compound as light yellow solid. MS: 316.5 (M+H ).
Example 239 (R)Methyl-propanesulfinic acid {(R or S)[4-methyl(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide (R or S) In analogy to the procedure described for the preparation of example 45, reaction of 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) with (R)methyl-propanesulfinic acid [(R or S)(5-bromo methyl-pyridinyl)-ethyl]-amide (intermediate A-60) gave the title compound as a dark brown amorphous solid. MS: 400.5 (M+H ).
Example 240 6-[5-((R or S)Amino-ethyl)methyl-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride (R or S) In analogy to the procedure described for the preparation of example 42, reaction of (R) methyl-propanesulfinic acid {(R or S)[4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide (example 239) with hydrogen chloride (in dixoane) in methanol gave the title compound as light brown solid. MS: 296.5 (M+H ).
Example 241 3-Chloro-pyridinecarboxylic acid {(R or S)[4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide (R or S) In analogy to the procedure described for the preparation of example 75, 6-[5-((R or S) amino-ethyl)methyl-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 240) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a colorless solid. MS: 435.6 (M+H ).
Example 242 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[4-methyl(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide (R or S) In analogy to the procedure described for the preparation of example 219, 6-[5-((R or S) amino-ethyl)methyl-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 240) has been coupled with 3,5-dimethyl-isoxazolecarboxylic acid to give the title compound as a colorless amorphous solid. MS: 419.6 (M+H ).
Example 243 Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyloxy]-ethyl}-amide O N F In analogy to the procedure described for the preparation of example 38, 6-[5-(2-amino- ethoxy)-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 238) and ethanesulfonyl chloride gave the title compound as a orange amorphous solid. MS: 408.4 (M+H ).
Example 244 3-Chloro-pyridinecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide O N F O Cl In analogy to the procedure described for the preparation of example 75, 6-[5-(2-amino- ethoxy)-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 238) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a off-white solid. MS: 455.3 (M+H ).
Example 245 N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- cyclohexyl}-methanesulfonamide In analogy to the procedure described for the preparation of example 38, 6-[5-((trans) amino-cyclohexyloxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 71) and methanesulfonyl chloride gave the title compound as a light yellow amorphous solid. MS: 430.4 (M+H ).
Example 246 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide In analogy to the procedure described for the preparation of example 219, 6-(5- aminomethylmethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 226) has been coupled with 3,5-dimethyl-isoxazolecarboxylic acid to give the title compound as a colorless solid. MS: 423.6 (M+H ).
Example 247 -(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester In analogy to the procedure described for the preparation of example 45, 6-(5-bromo- pyridinyl)methyl-3,4-dihydro-1H-quinolinone (prepared from 1-methyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) and 3,5-dibromo pyridine also with a procedure as used for the preparation of example 45) has been coupled to 4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolanyl)-3,6-dihydro-2H-pyridinecarboxylic acid tert-butyl ester to give the title compound as light yellow amorphous solid. MS: 420.5 (M+H ).
Example 248 Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyloxy]-ethyl}-methyl-amide O N F In analogy to the procedure described for the preparation of example 195, ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- ethyl}-amide (example 243) has been reacted with sodium hydride and methyl iodide to give the title compound as orange amorphous solid. MS: 422.4 (M+H ).
Example 249 (R)Methyl-propanesulfinic acid {(R or S)[4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide Cl O (R or S) In analogy to the procedure described for the preparation of example 45, reaction of 1- methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H-quinolinone (intermediate A-1) with (R)methyl-propanesulfinic acid [(R or S)(5-bromo chloro-pyridinyl)-ethyl]-amide (intermediate A-61) gave the title compound as a colorless amorphous solid. MS: 420.4 (M+H ).
Example 250 6-[5-((R or S)Amino-ethyl)chloro-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride (R or S) In analogy to the procedure described for the preparation of example 42, reaction of (R) methyl-propanesulfinic acid {(R or S)[4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide (example 249) with hydrogen chloride (in dixoane) in methanol gave the title compound as yellow solid. MS: 316.4 (M+H ).
Example 251 3-Chloro-pyridinecarboxylic acid {(R or S)[4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide Cl O Cl (R or S) In analogy to the procedure described for the preparation of example 75, 6-[5-((R or S) amino-ethyl)chloro-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 250) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a colorless solid. MS: 455.5 (M+H ).
Example 252 (R)Methyl-propanesulfinic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide O N F (R or S) In analogy to the procedure described for the preparation of example 45, reaction of 7- fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4-dihydro-1H- quinolinone (intermediate A-22) with (R)methyl-propanesulfinic acid [(R or S) (5-bromomethyl-pyridinyl)-ethyl]-amide (intermediate A-60) gave the title compound as a yellow amorphous solid. MS: 418.5 (M+H ).
Example 253 6-[5-((R or S)Amino-ethyl)methyl-pyridinyl]fluoromethyl-3,4-dihydro- 1H-quinolinone hydrochloride (R or S) In analogy to the procedure described for the preparation of example 42, reaction of (R) methyl-propanesulfinic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide (example 252) with hydrogen chloride (in dixoane) in methanol gave the title compound as light brown solid.
MS: 314.5 (M+H ).
Example 254 6-[5-((S)Acetyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone In analogy to the procedure described in example 76, 1-methyl[5-((S)-pyrrolidin yloxy)-pyridinyl]-3,4-dihydro-1H-quinolinone hydrochloride (example 60) has been reacted with acetyl chloride to give the title compound as a colorless solid. MS: 366.4 (M+H ).
Example 255 1-Methyl{5-[(S)(1-methyl-1H-pyrazolecarbonyl)-pyrrolidinyloxy]-pyridin- 3-yl}-3,4-dihydro-1H-quinolinone To a solution of 1-methyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride (0.04 g, 0.111 mmol, example 60), 1-methyl-1H-pyrazole carboxylic acid (0.021 g, 0.167 mmol) and Hunig's base (0.036 g, 0.278 mmol) in EtOAc (2 mL) was added propylphosphonic acid anhydride (cyclic trimer) solution (50% in EtOAc, 0.177 mL, 0.25 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was diluted with EtOAc, poured into a sat. NaHCO solution (5 mL) and extracted with EtOAc (2 x 20 mL). Combined organics were dried over Na SO , filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give the title compound (0.036 g, 75.1%) as a colorless amorphous solid. MS: 432.4 (M+H ).
Example 256 (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid ethyl ester In analogy to the procedure described in example 76, 1-methyl[5-((S)-pyrrolidin yloxy)-pyridinyl]-3,4-dihydro-1H-quinolinone hydrochloride (example 60) has been reacted with chloroformic acid ethyl ester to give the title compound as a light yellow amorphous solid. MS: 396.5 (M+H ).
Example 257 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[4-chloro(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide Cl O (R or S) In analogy to the procedure described for the preparation of example 219, 6-[5-((R or S) amino-ethyl)chloro-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 250) has been coupled with 3,5-dimethyl-isoxazolecarboxylic acid to give the title compound as a off-white amorphous solid. MS: 439.4 (M+H ).
Example 258 3-Chloro-pyridinecarboxylic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide (R or S) In analogy to the procedure described for the preparation of example 75, 6-[5-((R or S) amino-ethyl)methyl-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 253) has been coupled with 3-chloro-pyridinecarboxylic acid to give the title compound as a off-white solid. MS: 453.4 (M+H ).
Example 259 -Methyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)methyl-pyridinylmethyl]-amide O N F In analogy to the procedure described for the preparation of example 219, 6-(5- aminomethylmethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 226) has been coupled with 5-methyl-isoxazolecarboxylic acid to give the title compound as a off-white solid. MS: 409.6 (M+H ).
Example 260 -(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',4',5',6'-tetrahydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester 5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'- carboxylic acid tert-butyl ester (example 247, 0.128 g, 0.305 mmol) in MeOH (50 mL) was run through the H-cube for 2 h (flow rate: 0.5 mL/min; temperature: 60 °C; catalyst: % Pd/C (THS 01111); full hydrogen mode). The resulting solution was evaporated to dryness to give the title compound (0.106 g, 74 %) as a yellow amorphous solid. MS: 422.5 (M+H ).
Example 261 N-{(R or S)[4-Chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin- 3-yl]-ethyl}-propionamide Cl O (R or S) In analogy to the procedure described in example 76, 6-[5-((R or S)amino-ethyl) chloro-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 250) has been reacted with propionyl chloride to give the title compound as a colorless solid. MS: 372.5 (M+H ).
Example 262 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-1H-quinolinone To solution of 1-(5-(1-methyloxo-1,2,3,4-tetrahydroquinolinyl)pyridin yl)cyclopropanecarboxylic acid (example 59 [C], 0.3 g, 0.931 mmol) in toluene (15 mL) were added TEA (0.141 g, 1.4 mmol) and diphenylphosphoryl azide (0.384 g, 1.4 mmol) and then the reaction mixture was heated to reflux for 4 h. The mixture was concentrated in vacuo, the residue was dissolved in THF (30 mL) and the solution cooled to 0 °C. Then, a solution of KOtBu (0.627 g, 5.58 mmol) in THF (13 mL) was added and the mixture was stirred for 1 h at 0 °C and then over night at room temperature. The mixture was concentrated in vacuo, the residue was preadsorbed on silica gel and purified by silica gel flash chromatography eluting with a 0 to 10% MeOH-DCM gradient to give a yellow amorphous solid (0.104 g). This material was then further purified by reverse phase HPLC on a Gemini-NX column, eluting with a MeOH-H2O (0.05 % TEA) gradient to give the title compound (0.02 g, 7 %) as a colorless amorphous solid. MS: 292.3 (M+H ).
Example 263 Ethanesulfonic acid [5-(8-fluoromethyloxo-1,2-dihydro-quinolinyl)-pyridin- 3-ylmethyl]-amide A mixture of 8-fluoromethyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-3,4- dihydro-1H-quinolinone (example 208 [E], 20 mg, 0.066 mmol), ethanesulfonic acid (5-bromo-pyridinylmethyl)-amide (intermediate A-11, 27.4 mg, 0.098 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.6 mg, 0.0066 mmol), and aq. sodium carbonate solution (2 N, 0.07 mL) in DMF (1 mL) was heated in a microwave at 120 C for 30 minutes. After dilution of the reaction mixture with EtOAc, the organic layer was washed with water, dried over anhydrous Na SO and concentrated in vacuo. The residue was then purified by prep-HPLC to afford the title compound (2.5 mg, 10%) as a white solid. MS: 376.3 (M+H) .
Example 264 N-{(R or S)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl) methyl-pyridinyl]-ethyl}-propionamide In analogy to the procedure described in example 76, 6-[5-((R or S)amino-ethyl) methyl-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 253) has been reacted with propionyl chloride to give the title compound as a colorless amorphous solid. MS: 370.6 (M+H ).
Example 265 N-[4-Chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- propionamide Cl O In analogy to the procedure described in example 76, 6-(5-aminomethylchloro-pyridin- 3-yl)methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 218) has been reacted with propionyl chloride to give the title compound as a off-white solid. MS: 358.4 (M+H ).
Example 266 N-{(R or S)[4-Methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin- 3-yl]-ethyl}-propionamide In analogy to the procedure described in example 76, 6-[5-((R or S)amino-ethyl) methyl-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride (example 240) has been reacted with propionyl chloride to give the title compound as a colorless amorphous solid. MS: 352.5 (M+H ).
Example 267 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide O N F In analogy to the procedure described for the preparation of example 219, 6-[5-(2-amino- ethoxy)-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolinone hydrochloride (example 238) has been coupled with 3,5-dimethyl-isoxazolecarboxylic acid to give the title compound as a colorless solid. MS: 439.4 (M+H ).
Example A A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Example B A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims (67)

1. Compounds of formula (I) wherein 5 R is alkyl; R is H; R is H; R is H; R is H; 10 R is R ; R is H; 8 9 10 11 12 13 14 15 16 R is -O -(CR R ) -(CR R ) -(CR R ) -NR R ; m n p q R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; 15 R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 11 12 or R and R together with the carbon atom to which they are attached form a cycloalkyl or a heterocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 10 14 or R and R together form -(CH2)t-; R is H, alkyl, or alkoxyalkyl; 16 18 18 18 R is hydroxyalkyl, -S(O)2R , -C(O)R , or -C(O)OR ; 15 16 5 or R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, 10 wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl; 11 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted 23 24 25 heterocycloalkyl is substituted with R , R and R ; 9 15 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted heterocycloalkyl is 23 24 25 substituted with R , R and R ; R is alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, 20 substituted heteroaryl, wherein substituted aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, and halogen; 1 20 A is CR ; 2 21 25 A is CR ; 3 22 A is CR ; R is H or halogen; is H, halogen, or alkyl; R is H or halogen; 23 24 25 R , R and R are each independently selected from H, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxy, oxo, triazolylalkyl, and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom 5 with one to two substituents selected from alkyl; m is zero or 1, wherein in case m is 1, then the sum of n and p is 2, 3 or 4; n is zero, 1 or 2; p is zero, 1 or 2; q is zero, 1 or 2; 10 t is zero, 1 or 2; or pharmaceutically acceptable salts or esters.
2. A compound according to claim 1, wherein R is alkyl; R is H; 15 R is H; R is H; R is H; R is R ; R is H; 8 9 10 11 12 13 14 15 16 20 R is -Om-(CR R )n-(CR R )p-(CR R )q-NR R ; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R is H; 11 12 or R and R together with the carbon atom to which they are attached form a cycloalkyl; R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; 5 R is H; 10 14 or R and R together form -(CH2)t-; R is H, alkyl, or alkoxyalkyl,; 16 18 18 18 R is hydroxyalkyl, -S(O)2R , -C(O)R , or -C(O)OR ; 15 16 or R and R together with the nitrogen atom to which they are attached form a 10 substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to 15 two alkyl; 11 15 or R and R together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl, wherein substituted 23 24 25 heterocycloalkyl is substituted with R , R and R ; 9 15 or R and R together with the nitrogen and carbon atoms to which they are attached 20 form a substituted heterocycloalkyl, wherein substituted heterocycloalkyl is 23 24 25 substituted with R , R and R ; R is alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, wherein substituted aryl, substituted heterocycloalkyl and 25 substituted heteroaryl are substituted with one to three substituents independently selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, , and halogen; 1 20 A is CR ; 2 21 A is CR ; 3 22 A is CR ; R is H or halogen; R is H halogen, or alkyl; 5 R is H or halogen; 23 24 25 R , R and R are each independently selected from H, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxy, oxo, triazolylalkyl, and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two substituents independently 10 selected from alkyl; m is zero or 1, wherein in case m is 1, then the sum of n and p is 2, 3 or 4; n is zero, 1 or 2; p is zero, 1 or 2; q is zero, 1 or 2; 15 t is zero, 1 or 2; or pharmaceutically acceptable salts or esters.
3. A compound according to claim 1 or 2, wherein R is methyl.
4. A compound according to any one of claims 1 to 3, wherein R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl. 20
5. A compound according to any one of claims 1 to 4, wherein R is H, alkyl or cycloalkyl.
6. A compound according to any one of claims 1 to 5, wherein R is H or alkyl.
7. A compound according to any one of claims 1 to 6, wherein R is H.
8. A compound according to any one of claims 1 to 7, wherein R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl.
9. A compound according to any one of claims 1 to 8, wherein R is H or alkyl.
10. A compound according to any one of claims 1 to 9, wherein R is H. 5
11. A compound according to any one of claims 1 to 10, wherein R is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl.
12. A compound according to any one of claims 1 to 11, wherein R is H.
13. A compound according to any one of claims 1 to 12, wherein R is H. 11 12
14. A compound according to any one of claims 1 to 12, wherein R and R together 10 with the carbon atom to which they are attached form a cycloalkyl.
15. A compound according to any one of claims 1 to 14, wherein R is H.
16. A compound according to any one of claims 1 to 15, wherein R is H. 10 14
17. A compound according to any one of claims 1 to 15, wherein R and R together form -(CH2)t-. 15
18. A compound according to any one of claims 1 to 17, wherein R is H, alkyl or alkoxyalkyl.
19. A compound according to any one of claims 1 to 18, wherein R is H or alkyl.
20. A compound according to any one of claims 1 to 19, wherein R is H. 9 15
21. A compound according to any one of claims 1 to 17, wherein R and R together 20 with the nitrogen and carbon atoms to which they are attached form a substituted 23 24 heterocycloalkyl, wherein substituted heterocycloalkyl is substituted with R , R and R .
22. A compound according to any one of claims 1 to 21, wherein R is hydroxyalkyl, - 18 18 18 S(O)2R , -C(O)R or -C(O)OR . 25
23. A compound according to any one of claims 1 to 21, wherein R is hydroxyalkyl or -S(O) R .
24. A compound according to any one of claims 1 to 22, wherein R is hydroxyalkyl.
25. A compound according to any one of claims 1 to 22, wherein R is hydroxyethyl or hydroxymethylbutyl.
26. A compound according to any one of claims 1 to 22, wherein R is 5 -S(O)2R . 16 18
27. A compound according to any one of claims 1 to 22, wherein R is -C(O)R . 15 16
28. A compound according to any one of claims 1 to 17, wherein R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl or a substituted heteroaryl, wherein substituted heterocycloalkyl 10 and substituted heteroaryl are substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl. 15 16
29. A compound according to any one of claims 1 to 18 and 28, wherein R and R 15 together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two 20 alkyl. 15 16
30. A compound according to any one of claims 1 to 17, 28 and 29, wherein R and R together with the nitrogen atom to which they are attached form a substituted heterocycloalkyl wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from hydroxyalkyl and oxo. 25
31. A compound according to any one of claims 1 to 17, 29 and 30, wherein the 15 16 heterocycloalkyl formed by R and R together with the nitrogen atom to which they are attached is selected from pyrrolydinyl, piperidinyl, thiomorpholinyl, thiazinanyl, isothiazolidinyl and 2,6-diaza-spiro[3.3]heptanyl.
32. A compound according to any one of claims 1 to 17 and 29 to 31, wherein the 15 16 30 heterocycloalkyl formed by R and R together with the nitrogen atom to which they are attached is selected from pyrrolydinyl, piperidinyl, thiomorpholinyl, thiazinanyl and 2,6-diaza-spiro[3.3]heptanyl.
33. A compound according to any one of claims 1 to 17 and 29 to 32, wherein R and R together with the nitrogen atom to which they are attached form 2- 5 hydroxymethyl-pyrrolidinyl, 2- hydroxymethyloxo-pyrrolidinyl or isothiazolidinyl substituted on the sulfur atom by two oxo.
34. A compound according to any one of claims 1 to 17 and 29 to 32, wherein R and R together with the nitrogen atom to which they are attached form 2- hydroxymethyl-pyrrolidinyl or 2- hydroxymethyloxo-pyrrolidinyl. 10
35. A compound according to any one of claims 1 to 34, wherein R is alkyl, cycloalkyl, hydroxyalkyl, or alkylcarbonyloxyalkyl.
36. A compound according to any one of claims 1 to 35, wherein R is alkyl, cycloalkyl, hydroxyalkyl, or alkylcarbonyloxyalkyl.
37. A compound according to any one of claims 1 to 36, wherein R is alkyl or 15 heteroaryl substituted with one to three substituents independently selected from alkyl and halogen.
38. A compound according to any one of claims 1 to 37, wherein R is heteroaryl substituted with one to three substituents independently selected from alkyl and halogen. 20
39. A compound according to any one of claims 1 to 38, wherein R is alkyl.
40. A compound according to any one of claims 1 to 39, wherein R is ethyl.
41. A compound according to any one of claims 1 to 40, wherein R is H.
42. A compound according to any one of claims 1 to 41, wherein R is H or alkyl.
43. A compound according to any one of claims 1 to 42, wherein R is H. 25
44. A compound according to any one of claims 1 to 43, wherein R is H. 23 24 25
45. A compound according to any one of claims 1 to 44, wherein R , R and R are each independently selected from hydrogen, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, oxo, triazolylalkyl and substituted aminoalkyl, wherein substituted aminoalkyl is substituted on the nitrogen atom with one to two alkyl. 23 24 25
46. A compound according to any one of claims 1 to 45, wherein R , R and R are each independently selected from hydrogen, hydroxyalkyl and oxo. 23 24 5
47. A compound according to any one of claims 1 to 46, wherein at least one of R , R and R is different from hydrogen.
48. A compound according to any one of claims 1 to 47, wherein m is 1.
49. A compound according to any one of claims 1 to 47, wherein m is zero.
50. A compound according to any one of claims 1 to 49, wherein n is zero or 1. 10
51. A compound according to any one of claims 1 to 50, wherein n is zero.
52. A compound according to any one of claims 1 to 51, wherein p is zero or 1.
53. A compound according to any one of claims 1 to 52, wherein q is zero or 1.
54. A compound according to any one of claims 1 to 53, wherein q is zero.
55. A compound according to any one of claims 1 to 54, wherein t is 2. 15
56. A compound according to any one of claims 1 to 54, wherein t is zero.
57. A compound according to any one of claims 1 to 56, selected from Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yl]-amide; Acetic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 20 ylcarbamoyl]-methyl ester; 2-Hydroxy-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]- acetamide; 6-[5-(2-Hydroxy-ethylamino)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 6-[5-((S)Hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((R)Hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 5 6-[5-((S)Hydroxymethyl-pyrrolidinylmethyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[5-((S)Hydroxymethyloxo-pyrrolidinylmethyl)-pyridinyl]methyl- 3,4-dihydro-1H-quinolinone; 6-[5-((S)Ethylaminomethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro- 10 1H-quinolinone; 6-[5-((S)Methoxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 1-Methyl[5-((S)[1,2,4]triazolylmethyl-pyrrolidinyl)-pyridinyl]-3,4- dihydro-1H-quinolinone; 15 6-(5-Benzylamino-pyridinyl)methyl-3,4-dihydro-1H-quinolinone; 6-[5-((S)Hydroxymethyloxo-pyrrolidinyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 1-Methyl[5-(2-oxo-pyrrolidinyl)-pyridinyl]-3,4-dihydro-1H-quinolinone; Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 20 ylmethyl]-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl[5-(2-oxo-pyrrolidinylmethyl)-pyridinyl]-3,4-dihydro-1H- quinolinone; 25 1-Methyl[5-(2-oxo-piperidinylmethyl)-pyridinyl]-3,4-dihydro-1H-quinolin- 2-one; 6-[5-(1,1-Dioxo-1λ -thiomorpholinylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-((S)Methoxymethyl-pyrrolidinylmethyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 5 (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- pyrrolidinecarboxylic acid methyl ester; 1-Methyl{5-[(S)(2,2,2-trifluoro-ethoxymethyl)-pyrrolidinylmethyl]-pyridin- 3-yl}-3,4-dihydro-1H-quinolinone; 6-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-2,6-diaza- 10 spiro[3.3]heptanecarboxylic acid tert-butyl ester ; 6-[5-((R)Hydroxymethylmethyl-propylamino)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[6-((R)Hydroxymethylmethyl-propylamino)-pyrazinyl]methyl-3,4- dihydro-1H-quinolinone; 15 6-(5-Aminomethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone; N-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]- propionamide; Propanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 20 {2-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- carbamic acid tert-butyl ester; 3-Methoxy-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Cyclopropanecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- 25 pyridinylmethyl]-amide; 6-[5-(2-Amino-ethoxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride; N-{2-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}- propionamide; 6-[5-(1,1-Dioxo-1λ -[1,2]thiazinanylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 5 and pharmaceutically acceptable salts thereof.
58. A compound according to any one of claims 1 to 56, selected from (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]- azetidinecarboxylic acid tert-butyl ester; (R)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 10 yloxy]-pyrrolidinecarboxylic acid tert-butyl ester; 3-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-azetidine- 1-carboxylic acid tert-butyl ester; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid tert-butyl ester; 15 (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- piperidinecarboxylic acid tert-butyl ester; 4-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- piperidinecarboxylic acid tert-butyl ester; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxymethyl]- 20 pyrrolidinecarboxylic acid tert-butyl ester; (S)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-pyrrolidinecarboxylic acid tert-butyl ester; (R)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid tert-butyl ester; 25 (R)- 2-Methyl-propanesulfinic acid {3-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-oxetanyl}-amide; (R)Methyl-propanesulfinic acid {(S or R)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; (R) 2-Methyl-propanesulfinic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 5 {(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- cyclohexyl}-carbamic acid tert-butyl ester; 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 1-Methyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolin 10 one hydrochloride; 1-Methyl[5-((S)-piperidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolin one; 1-Methyl[5-(piperidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolinone hydrochloride; 15 6-[5-((S)Azetidinylmethoxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((S or R)Amino-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one hydrochloride; 6-[5-((R or S)Amino-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin 20 one hydrochloride; 1-Methyl[5-((S)pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride; 7-Fluoromethyl[5-((R)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride; 25 1-Methyl[5-((R)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H-quinolin one hydrochloride; 6-[5-(3-Amino-oxetanyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride; 6-[5-(Azetidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H-quinolinone hydrochloride; 5 6-[5-((trans)Amino-cyclohexyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride; 6-[5-(1-Aminomethyl-ethyl)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 6-(5-Aminomethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H-quinolinone ; 10 3,5-Dimethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-[5-((S)Cyclopropanecarbonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 3-Methyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 15 ylmethyl]-butyramide; 3,3,3-Trifluoro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-propionamide; 2-Hydroxymethyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-propionamide; 20 5-Methyl-[1,3,4]oxadiazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-piperidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 2-Methoxy-pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- 25 quinolinyl)-pyridinylmethyl]-amide, 1-Methyl-1H-imidazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5-Trifluoromethyl-furancarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 5 Pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-(1-propionyl-piperidinyloxy)-pyridinyl]-3,4-dihydro-1H- 10 quinolinone; Pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 15 6-[5-((S)Cyclopropanecarbonyl-azetidinylmethoxy)-pyridinyl]methyl- 3,4-dihydro-1H-quinolinone; 3-Methyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 4-Fluoro-2,6-dimethyl-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- 20 pyridinylmethyl]-benzamide; 1-Methyl[5-((S)propionyl-azetidinylmethoxy)-pyridinyl]-3,4-dihydro- 1H-quinolinone; 3,6-Dichloro-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 25 3-Cyclopropyl(2,2,2-trifluoro-ethyl)-1H-pyrazolecarboxylic acid [5-(1- methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinylmethyl]-amide; Pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 1,3-Dimethyl-1H-pyrazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5 Pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 6-Methoxy-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5-Methyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- 10 quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide; 15 6-Chloro-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloromethyl-pyridazinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro- 20 1H-quinolinone; 5-Cyclopropyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 2-Methyltrifluoromethyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 25 2-Methyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5-Cyclopropyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 2,5-Dimethyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5 5-Methyl-oxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; 6-Chloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- 10 quinolinyl)-pyridinylmethyl]-amide; 3-Methyl-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,6-Dichloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 15 6-Methyl-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Fluoro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- 20 quinolinyl)-pyridinylmethyl]-amide; 5-Chloromethyl-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((R)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 25 7-Fluoromethyl[5-((S)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4- dihydro-1H-quinolinone; 5-Trifluoromethyl-pyrimidinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 5-Methyl-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5 5-Chloro-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5-Trifluoromethyl-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- 10 tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((R)propionyl-pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro- 1H-quinolinone; 1-Methyl[5-(1-propionyl-azetidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 15 N-{3-[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-oxetan yl}-propionamide; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3,6-Dichloro-pyridazinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- 20 tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 7-Fluoromethyl[5-((R)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4- dihydro-1H-quinolinone; 5-Chloromethoxy-pyrazinecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 25 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Methyltrifluoromethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-cyclopropyl}-amide; 5 3-Chloro-pyridinecarboxylic acid {1-methyl[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {1-methyl[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {1-[5-(7-fluoromethyloxo-1,2,3,4- 10 tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; 3-Methyl-pyridinecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-cyclopropyl}-amide; N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-cyclohexyl}-propionamide; 15 5-Trifluoromethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 7-Fluoromethyl[5-((S)-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; (R)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 20 yloxymethyl]-pyrrolidinecarboxylic acid tert-butyl ester; 1-Methyl[5-((R)pyrrolidinylmethoxy)-pyridinyl]-3,4-dihydro-1H- quinolinone hydrochloride; 6-(5-Aminomethyl-pyridinyl)-3,4-dihydro-1H-quinolinone; 6-[5-(1-Amino-cyclopropyl)-pyridinyl]fluoromethyl-3,4-dihydro-1H- 25 quinolinone ; Ethanesulfonic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyloxy]-ethyl}-amide ; 3-Chloro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-benzenesulfonamide; 6-Methoxy-pyridinesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 5 3,5-Dimethyl-isoxazolesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; Cyclopropanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 3,4-Dichloro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 10 ylmethyl]-benzenesulfonamide; 1-Methyl-1H-imidazolesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-Chloro-pyridinesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinylmethyl]-amide; 15 1-Methyl-1H-pyrazolesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 6-[5-((S)Ethanesulfonyl-piperidinyloxy)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-(1-Ethanesulfonyl-piperidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- 20 quinolinone; 2,2,2-Trifluoro-ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinylmethyl]-amide; C,C,C-Trifluoro-N-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-methanesulfonamide; 25 6-[5-((S)Ethanesulfonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 6-[5-((S)Ethanesulfonyl-azetidinylmethoxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; Ethanesulfonic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-cyclopropyl}-amide; 5 6-[5-((S)Ethanesulfonyl-pyrrolidinylmethoxy)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[5-((R)Ethanesulfonyl-pyrrolidinyloxy)-pyridinyl]fluoromethyl- 3,4-dihydro-1H-quinolinone; 6-[5-((R)Ethanesulfonyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro- 10 1H-quinolinone; 6-[5-(1-Ethanesulfonyl-azetidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; Ethanesulfonic acid {1-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-cyclopropyl}-amide; 15 Ethanesulfonic acid {(trans)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-cyclohexyl}-amide; Ethanesulfonic acid {(R or S)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {(S or R)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin 20 yl)-pyridinyl]-ethyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; (rac)-Ethanesulfonic acid {2-methyl[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-propyl}-amide; 25 (rac)-Ethanesulfonic acid {cyclopropyl-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-methyl}-amide; (rac)-Ethanesulfonic acid {1-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; 6-[5-(1,1-Dioxo-1λ6-isothiazolidinylmethyl)-pyridinyl]methyl-3,4-dihydro- 1H-quinolinone; 5 (rac)-Ethanesulfonic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-propyl}-amide; Ethanesulfonic acid ethyl-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid methyl-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- 10 pyridinylmethyl]-amide; Ethanesulfonic acid {1-methyl[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid isopropyl-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 15 Ethanesulfonic acid (2-ethoxy-ethyl)-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; (rac)-Ethanesulfonic acid methyl-{1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 6-yl)-pyridinyl]-ethyl}-amide; (rac)-Ethanesulfonic acid ethyl-{1-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin- 20 6-yl)-pyridinyl]-ethyl}-amide; 3,5-Dimethyl-isoxazolecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 6-{5-[2-(1,1-Dioxo-1λ6-isothiazolidinyl)-ethoxy]-pyridinyl}methyl-3,4- dihydro-1H-quinolinone; 25 Ethanesulfonic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {(S or R)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- 4-methyl-pyridinylmethyl]-amide; 5 Ethanesulfonic acid [4-chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid [4-methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid methyl-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin 10 yl)-pyridinyloxy]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; N-Methyl-N-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-ethyl}-propionamide; 15 1-Methyl-1H-pyrazolecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Methyl-pyridinecarboxylic acid methyl-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- 20 tetrahydro-quinolinyl)-pyridinylmethyl]-methyl-amide; 3-Chloro-pyridinecarboxylic acid methyl-{1-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-methyl-amide; 25 6-{5-[(3-Ethyl-oxetanylamino)-methyl]-pyridinyl}methyl-3,4-dihydro-1H- quinolinone; Ethanesulfonic acid [5-(7-chloromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; Ethanesulfonic acid [5-(5-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 5 Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-methyl-amide; N-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-propionamide; (rac)-N-{1-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin 10 yl]-ethyl}-propionamide; (S)[5-(2-Oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]-pyrrolidine carboxylic acid tert-butyl ester ; 3-Chloro-pyridinecarboxylic acid methyl-[5-(2-oxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinylmethyl]-amide ; 15 (R)Methyl-propanesulfinic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide ; 6-(5-Aminomethylchloro-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride; 3,5-Dimethyl-isoxazolecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- 20 tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; (R)Methyl-propanesulfinic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide ; 25 6-(5-Aminomethylmethyl-pyridinyl)methyl-3,4-dihydro-1H-quinolinone hydrochloride; 3,5-Dimethyl-isoxazolecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 5 (R)Methyl-propanesulfinic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide ; 6-(5-Aminomethylmethyl-pyridinyl)fluoromethyl-3,4-dihydro-1H- quinolinone hydrochloride; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- 10 tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [4-chloro(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-methyl-amide; 3-Chloro-pyridinecarboxylic acid methyl-[4-methyl(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 15 3-Chloro-pyridinecarboxylic acid {(R or S)[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 5'-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-5,6-dihydro-4H- [3,3']bipyridinylcarboxylic acid tert-butyl ester; {2-[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- 20 ethyl}-carbamic acid tert-butyl ester; 3-Chloro-pyridinecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide; 6-[5-(2-Amino-ethoxy)-pyridinyl]fluoromethyl-3,4-dihydro-1H-quinolin one hydrochloride; 25 (R)Methyl-propanesulfinic acid {(R or S)[4-methyl(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 6-[5-((R or S)Amino-ethyl)methyl-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride; 3-Chloro-pyridinecarboxylic acid {(R or S)[4-methyl(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 5 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[4-methyl(1-methyl oxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- 10 tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-cyclohexyl}-methanesulfonamide; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; 15 5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester; Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-methyl-amide; (R)Methyl-propanesulfinic acid {(R or S)[4-chloro(1-methyloxo- 20 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 6-[5-((R or S)Amino-ethyl)chloro-pyridinyl]methyl-3,4-dihydro-1H- quinolinone hydrochloride; 3-Chloro-pyridinecarboxylic acid {(R or S)[4-chloro(1-methyloxo- 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 25 (R)Methyl-propanesulfinic acid {(R or S)[5-(7-fluoromethyloxo- 1,2,3,4-tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide; 6-[5-((R or S)Amino-ethyl)methyl-pyridinyl]fluoromethyl-3,4- dihydro-1H-quinolinone hydrochloride; 6-[5-((S)Acetyl-pyrrolidinyloxy)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 5 1-Methyl{5-[(S)(1-methyl-1H-pyrazolecarbonyl)-pyrrolidinyloxy]- pyridinyl}-3,4-dihydro-1H-quinolinone; (S)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridinyloxy]- pyrrolidinecarboxylic acid ethyl ester; 3,5-Dimethyl-isoxazolecarboxylic acid {(R or S)[4-chloro(1-methyloxo- 10 1,2,3,4-tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 3-Chloro-pyridinecarboxylic acid {(R or S)[5-(7-fluoromethyloxo- 1,2,3,4-tetrahydro-quinolinyl)methyl-pyridinyl]-ethyl}-amide; 5-Methyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; 15 5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',4',5',6'-tetrahydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester ; N-{(R or S)[4-Chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinyl]-ethyl}-propionamide ; 6-[5-(1-Amino-cyclopropyl)-pyridinyl]methyl-1H-quinolinone; 20 N-{(R or S)[5-(7-Fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl) methyl-pyridinyl]-ethyl}-propionamide; N-[4-Chloro(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-propionamide; N-{(R or S)[4-Methyl(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)- 25 pyridinyl]-ethyl}-propionamide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; and pharmaceutically acceptable salts thereof.
59. A compound according to any one of claims 1 to 57, selected from 6-[5-(2-Hydroxy-ethylamino)-pyridinyl]methyl-3,4-dihydro-1H-quinolin one; 5 6-[5-((S)Hydroxymethyl-pyrrolidinyl)-pyridinyl]methyl-3,4-dihydro-1H- quinolinone; 6-[5-((S)Hydroxymethyl-pyrrolidinylmethyl)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; 6-[5-((S)Hydroxymethyloxo-pyrrolidinylmethyl)-pyridinyl]methyl- 10 3,4-dihydro-1H-quinolinone; Ethanesulfonic acid [5-(1-methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin ylmethyl]-amide; Ethanesulfonic acid [5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolinyl)- pyridinylmethyl]-amide; 15 1-Methyl[5-(2-oxo-pyrrolidinylmethyl)-pyridinyl]-3,4-dihydro-1H- quinolinone; 6-[5-((R)Hydroxymethylmethyl-propylamino)-pyridinyl]methyl-3,4- dihydro-1H-quinolinone; and pharmaceutically acceptable salts thereof. 20
60. A compound according to any one of claims 1 to 56 and 58, selected from 3,5-Dimethyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 1-Methyl[5-((S)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4-dihydro-1H- quinolinone; 25 5-Methyl-isoxazolecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid {2-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyloxy]-ethyl}-amide; 5 3-Chloro-pyridinecarboxylic acid [5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinylmethyl]-amide; 3-Chloro-pyridinecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinylmethyl]-amide; 7-Fluoromethyl[5-((R)propionyl-pyrrolidinyloxy)-pyridinyl]-3,4- 10 dihydro-1H-quinolinone; 3-Chloro-pyridinecarboxylic acid {1-[5-(1-methyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-cyclopropyl}-amide; 3-Chloro-pyridinecarboxylic acid {1-methyl[5-(1-methyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-ethyl}-amide; 15 3-Chloro-pyridinecarboxylic acid {1-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyl]-cyclopropyl}-amide; Ethanesulfonic acid {(trans)[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-cyclohexyl}-amide; 1-Methyl-1H-pyrazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- 20 tetrahydro-quinolinyl)-pyridinylmethyl]-amide; Ethanesulfonic acid {1-methyl[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyl]-ethyl}-amide; 6-{5-[2-(1,1-Dioxo-1λ6-isothiazolidinyl)-ethoxy]-pyridinyl}methyl-3,4- dihydro-1H-quinolinone; 25 Ethanesulfonic acid {(R or S)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid {(S or R)[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro- quinolinyl)-pyridinyl]-ethyl}-amide; Ethanesulfonic acid methyl-{2-[5-(1-methyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-amide; 5 Ethanesulfonic acid [5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolinyl)- pyridinylmethyl]-amide; N-{(trans)[5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-pyridin yloxy]-cyclohexyl}-methanesulfonamide; 3,5-Dimethyl-isoxazolecarboxylic acid [5-(7-fluoromethyloxo-1,2,3,4- 10 tetrahydro-quinolinyl)methyl-pyridinylmethyl]-amide; 5-(1-Methyloxo-1,2,3,4-tetrahydro-quinolinyl)-3',6'-dihydro-2'H- [3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester; Ethanesulfonic acid {2-[5-(7-fluoromethyloxo-1,2,3,4-tetrahydro-quinolin yl)-pyridinyloxy]-ethyl}-methyl-amide; 15 3,5-Dimethyl-isoxazolecarboxylic acid {2-[5-(7-fluoromethyloxo-1,2,3,4- tetrahydro-quinolinyl)-pyridinyloxy]-ethyl}-amide; 1-Methyl{5-[(S)(1-methyl-1H-pyrazolecarbonyl)-pyrrolidinyloxy]- pyridinyl}-3,4-dihydro-1H-quinolinone; and pharmaceutically acceptable salts thereof. 20
61. A process to prepare a compound according to any one of claims 1 to 60 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III); 101 2 6 4 5 4 5 R X A R R R R R (III) A B A 102 2 6 R A R O N O N 1 7 1 7 R R (II) R R 1 2 3 1 2 3 4 5 6 7 wherein A , A , A , R , R , R , R , R , R and R are as defined in claim1 and 101 102 wherein X is halogen or triflate, R and R are alkyl, cycloalkyl or together with the boron atom they are attached to form together a borolanyl. 5
62. A compound according to any one of claims 1 to 60 for use as therapeutically active substance.
63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 60 and a therapeutically inert carrier.
64. A compound according to any one of claims 1 to 60 for the treatment or prophylaxis 10 of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom.
65. The use of a compound according to any one of claims 1 to 60 for the preparation of a medicament for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrom. 15
66. A compound according to any one of claims 1 to 60, when manufactured according to a process of claim 61.
67. A pharmaceutical composition according to claim 63 substantially as herein described with reference to any example thereof.
NZ621599A 2011-09-15 2012-09-12 New dihydroquinoline-2-one derivatives NZ621599B2 (en)

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CNPCT/CN2011/079673 2011-09-15
CN2011079673 2011-09-15
PCT/EP2012/067744 WO2013037779A1 (en) 2011-09-15 2012-09-12 New dihydroquinoline-2-one derivatives

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NZ621599B2 true NZ621599B2 (en) 2016-11-01

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