PYRIDONE AND PYRIDAZINONE DERIVATIVES AS MCH ANTAGONISTS

The present invention relates to pyridone and pyridazinone derivatives, the physiologically acceptable salts thereof as well as their use as MCH antagonists and their use in preparing a pharmaceutical preparation which is suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way. The invention also relates to the use of a compound according to the invention for influencing eating behaviour and for reducing body weight and/or for preventing any increase in body weight in a mammal. It further relates to compositions and medicaments containing a compound according to the invention and processes for preparing them.

Background to the Invention

The intake of food and its conversion in the body is an essential part of life for all living creatures. Therefore, deviations in the intake and conversion of food generally lead to problems and also illness. The changes in the lifestyle and nutrition of humans, particularly in industrialised countries, have promoted morbid overweight (also known as corpulence or obesity) in recent decades. In affected people, obesity leads directly to restricted mobility and a reduction in the quality of life. There is the additional factor that obesity often leads to other diseases such as, for example, diabetes, dyslipidaemia, high blood pressure, arteriosclerosis and coronary heart disease. Moreover, high body weight alone puts an increased strain on the support and mobility apparatus, which can lead to chronic pain and diseases such as arthritis or osteoarthritis. Thus, obesity is a serious health problem for society.

The term obesity means an excess of adipose tissue in the body. In this connection, obesity is fundamentally to be seen as the increased level of fatness which leads to a health risk. There is no sharp distinction between normal individuals and those suffering from obesity, but the health risk accompanying obesity is presumed to rise continuously as the level of fatness increases. For simplicity's sake, in the present invention, individuals with a Body Mass Index (BMI), which is defined as the body weight measured in kilograms divided by the height (in metres) squared, above a value of 25 and more particularly above 30, are preferably regarded as suffering from obesity.

Apart from physical activity and a change in nutrition, there is currently no convincing treatment option for effectively reducing body weight. However, as obesity is a major risk

factor in the development of serious and even life-threatening diseases, it is all the more important to have access to pharmaceutical active substances for the prevention and/or treatment of obesity. One approach which has been proposed recently is the therapeutic use of MCH antagonists (cf. inter alia WO 01/21577, WO 01/82925).

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is synthesised predominantly in the hypothalamus in mammals and from there travels to other parts of the brain by the projections of hypothalamic neurones. Its biological activity is mediated in humans through two different G-protein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, namely the MCH receptors 1 and 2 (MCH-1R, MCH-2R).

Investigations into the function of MCH in animal models have provided good indications for a role of the peptide in regulating the energy balance, i.e. changing metabolic activity and food intake [1 ,2]. For example, after intraventricular administration of MCH in rats, food intake was increased compared with control animals. Additionally, transgenic rats which produce more MCH than control animals, when given a high-fat diet, responded by gaining significantly more weight than animals without an experimentally altered MCH level. It was also found that there is a positive correlation between phases of increased desire for food and the quantity of MCH mRNA in the hypothalamus of rats. However, experiments with MCH knock-out mice are particularly important in showing the function of MCH. Loss of the neuropeptide results in lean animals with a reduced fat mass, which take in significantly less food than control animals.

The anorectic effects of MCH are presumably mediated in rodents through the G _αs -coupled MCH-1R [3-6], as, unlike primates, ferrets and dogs, no second MCH receptor subtype has hitherto been found in rodents. After losing the MCH-1 R, knock-out mice have a lower fat mass, an increased energy conversion and, when fed on a high fat diet, do not put on weight, compared with control animals. Another indication of the importance of the MCH system in regulating the energy balance results from experiments with a receptor antagonist (SNAP- 7941 ) [3]. In long term trials the animals treated with the antagonist lose significant amounts of weight.

In addition to its anorectic effect, the MCH-1 R antagonist SNAP-7941 also achieves additional anxiolytic and antidepressant effects in behavioural experiments on rats [3]. Thus, there are clear indications that the MCH-MCH-1 R system is involved not only in regulating the energy balance but also in affectivity.

Literature:

1. Qu ₁ D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature, 1996. 380(6571 ): p. 243-7. 2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.

3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a melanin- concentrating hormone-1 receptor antagonist. Nat Med, 2002. 8(8): p. 825-30.

4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002.

143(7): p. 2469-77.

5. Marsh, DJ. , et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99(5): p. 3240-5. 6. Takekawa, S., et al., T-226296: A novel, orally active and selective melanin- concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): p. 129-35.

In the patent literature (WO 01/21577, WO 01/82925) amine compounds of the general formula formula are proposed as MCH antagonists for the treatment of obesity.

Further patent publication related to amine compounds with MCH antagonistic activity are for example: WO 04/024702, WO 04/039780, WO 04/039764, WO 05/063239, WO 05/085221 , WO 05/103031 , WO 05/103032, WO 05/103029, WO 05/100285, WO 05/103002, WO 05/85200, WO 2007/048802.

In the WO 03/068230, WO 2005/018557 (Pharmacia Corp.) substituted pyridinones are described. The WO 2004/087677 (Pharmacia Corp.) is related to pyrimidone derivatives and the WO 03/059891 as well as the WO 2005/007632 (Pharmacia Corp.) refer to pyridazinone derivatives. These compounds are described as modulators of p38 MAP kinase.

In the EP 1741703 A1, EP 1916239 A1, EP1939194, EP 1921065 A1 and WO 2007/142217 (Banyu Pharmaceuticals) pyridone derivatives are described as antagonists of the MCH receptor.

In the WO 2008/022979 (Boehringer Ingelheim), published 28.02.2008, pyridone derivatives with MCH antagonistic activity are described.

Aim of the invention

The aim of the present invention is to identify compounds which are especially effective as MCH antagonists. Another aim of this invention is to provide compounds which are effective as MCH antagonists and which possess advantageous pharmacokinetic properties. The invention also sets out to provide compounds which can be used to influence the eating habits of mammals and achieve a reduction in body weight, particularly in mammals, and/or prevent an increase in body weight.

The present invention further sets out to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally connected to MCH. In particular, the aim of this invention is to provide pharmaceutical compositions for the treatment of metabolic disorders such as obesity and/or diabetes as well as diseases and/or disorders which are associated with obesity and diabetes. Other objectives of the present invention are concerned with demonstrating advantageous uses of the compounds according to the invention. The invention also sets out to provide a process for preparing the compounds according to the invention. Other aims of the present invention will be immediately apparent to the skilled man from the foregoing remarks and those that follow.

Object of the invention

In a first aspect the present invention relates to one or more compounds selected from the group consisting of the following pyridone and pyridazinone derivatives

4-Benzyloxy-1-{2-[4-(1-dimethylaminomethyl-cyclopropyl)-p henyl]-2-oxo-ethyl}- 1 H-pyridin-2-one

4-Benzy!oxy-1 -[2-(3-methy!-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1 H- pyridin-2-one

4-Benzyloxy-1 -[2-(2,3-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]- 1 H-pyridin-2-one

5-Benzyloxy-2-[2-(3-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2H- pyridazin-3-one

5-Benzyloxy-2-[2-(2,3-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]- 25.2

2H-pyridazin-3-one

„. 4-Benzyloxy-1 -[2-oxo-2-(5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-ethyl]-1 H- 26.1 . ,. _ pyrιdιn-2-one

4-Benzyloxy-1-[2-(6-methyl-5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-2-oxo-ethyl]-

1 H-pyridin-2-one

5-Benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2H-pyridazin-3- one

5-Benzyloxy-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-2-oxo-ethyl]-2H- pyridazin-3-one

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]- 28.1

2H-pyridazin-3-one

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6- Zo. Z yl)-ethyl]-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]- 2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6- yl)-ethyl]-2H-pyridazin-3-one

5-Benzyloxy-2-(2-{4-[2-(4-hydroxy-4-methyl-piperidin-1-yl )-ethyl]-phenyl}-2-oxo- ethyl)-2H-pyridazin-3-one

1-[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-4-(4-fluoro - benzyloxy)-1 H-pyridin-2-one

⁴ -(4- ^F|uor o-benzyloxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2- oxo-ethyl]-1 H-pyridin-2-one

2-[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-5-(4-fluoro - benzyloxy)-2H-pyridazin-3-one

5-(4-Fluoro-benzyloxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2- oxo-ethyl]-2H-pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 2H-pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7- yl)-ethyl]-2H-pyridazin-3-one

1-[2-Oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-4-(5-tnfluorometh yl-pyridin- 2-ylmethoxy)-1 H-pyridin-2-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- 35.1 ethyl]-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin- 7-yl)-ethyl]-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-cyclopropylmethyl -1 ,2,3,4-tetrahydro- isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl) -1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[2-(2-methoxy-ethyl) -1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[2-(2-fluoro-ethyl)- 1 ,2,3,4-tetrahydro- 35.6 isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-cyclopropyl-1 ,2,3,4-tetrahydro- 35.7 isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 36.1

1 H-pyridin-2-one

_^n 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin- 36.2.

7-yl)-ethyl]-1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7- 36.3 yl)-ethyl]-1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-{2-[2-(2-hydroxy-ethyl )-1 ,2,3,4-tetrahydro-

36.4 isoquinolin-7-yl]-ethyl}-1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-{2-[2-(2-fluoro-ethyl) -1 ,2,3,4-tetrahydro- 36.5 isoquinolin-7-yl]-ethyl}-1 H-pyridin-2-one

2-[2-(2-Ethyl-1 ,2,3 _> 4-tetrahydro-isoquinolin-7-yl)-ethyl]-5-(5-fluoro-pyridin-2- ylmethoxy)-2H-pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-isopropyl-1,2,3, 4-tetrahydro-isoquinolin- 7-yl)-ethyl]-2H-pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl )-1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 38.1

1 H-pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7- 38 2 yl)-ethyl]-1 H-pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin- 38 3

7-yl)-ethyl]-1 H-pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-{2-[2-(2-hydroxy-ethyl)-1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-1 H-pyridin-2-one o _o - _r ¹ -{2-[2-(2-Fluoro-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-4-(5-fluoro- 38 5 pyridin-2-ylmethoxy)-1 H-pyridin-2-one

4-(4-Fluoro-benzyloxy)-1 -[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin- 39.1

2-one

4-(4-Fluoro-benzyloxy)-1 -[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1 H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(2-propyl-1 ,2,3,4-tetrahydro- isoquinolin-7-yl)-ethyl]-1 H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin- 7-yl)-2-oxo-ethyl]-1 H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- 2-oxo-ethyl]-1 H-pyridin-2-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-oxo-2-(2-propyl-1 ,2,3,4-tetrahydro- isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- 2-oxo-ethyl]-2H-pyridazin-3-one

4-(4- ^f: l'Joro-benzyloxy)-1-{2-[2-(2-hydroxy-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7- yl]-2-oxo-ethyl}-1 H-pyridin-2-one

4-(4-Fluoro-benzyloxy)-1 -{2-[2-(2-methoxy-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7- yl]-2-oxo-ethyl}-1 H-pyridin-2-one

5-(4-Fluoro-benzyloxy)-2-{2-[2-(2-methoxy-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7- yl]-2-oxo-ethyl}-2H-pyridazin-3-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)- ethyl]-1 H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6- yl)-2-oxo-ethyl]-1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)- ethyl]-1 H-pyridin-2-one

4-Benzyloxy-1 -[2-oxo-2-(5,6,7,8-tetrahydro-1 ,6-naphthyridin-2-yl)-ethyl]-1 H- pyrιdιn-2-one

4-Benzyloxy-1-[2-(6-methyl-5,6,7 _> 8-tetrahydro-1 _l 6-naphthyridin-2-yl)-2-oxo-ethyl]- 1 H-pyridin-2-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(1,2,3,4-tetrahydro -isoquinolin-6-yl)-ethyl]- 2H-pyridazin-3-one

5-(5-Fluoro-pyndin-2-ylmethoxy)-2-[2-(2-methyl-1,2,3,4-te trahydro-isoquinolin-6- yl)-ethyl]-2H-pyridazin-3-one

while in each of the above-mentioned compounds one or more C atoms may additionally be mono- or polysubstituted by F, and in each case one or two C atoms independently of one another may additionally have a substituent selected from the group Cl, Br ₁ cyano, d-4-alkyl, C- _M -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, acetylamino, aminocarbonyl, difluoromethoxy, and trifluoromethoxy, and

an H atom bound to an N atom may in each case be replaced by a group which can be cleaved in vivo,

the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

The invention also relates to the compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids. The subject of the invention also includes the compounds according to the invention, including their salts, wherein one or more hydrogen atoms are replaced by deuterium.

This invention also includes the physiologically acceptable salts of the compounds according to the invention as described above and hereinafter.

Also covered by this invention are compositions containing at least one compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients.

Also covered by this invention are pharmaceutical compositions containing at least one compound according to the invention and/ or a salt according to the invention optionally together with one or more inert carriers and/or diluents.

This invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for influencing the eating behaviour of a mammal.

The invention further relates to the use of at least one compound according to the invention and/or a salt according to the invention, for reducing the body weight and/ or for preventing an increase in the body weight of a mammal.

The invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition with an MCH receptor-antagonistic activity, particularly with an MCH-1 receptor-antagonistic activity.

This invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.

A further object of this invention is the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.

The invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of diseases and/or disorders associated with obesity, particularly diabetes, especially type Il diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.

In addition the present invention relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective

disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.

The invention also relates to the use of at least one compound according to the invention and/or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of urinary problems, such as for example urinary incontinence, overactive bladder, urgency, nycturia and enuresis.

The invention further relates to the use of at least one compound according to the invention and/ or a salt according to the invention, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of dependencies and/or withdrawal symptoms.

The invention also relates to a pharmaceutical composition containing a first active substance which is selected from the compounds according to the invention and/or the corresponding salts, as well as a second active substance which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of dyslipidaemia or hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and/or diluents.

The starting materials and intermediate products used in the synthesis of one or more of the compounds according to the invention are also a subject of this invention.

Detailed description of the invention

The compounds listed in the experimental section, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, are preferred according to the invention.

According a preferrred first embodiment the invention relates to one or more of the compounds comprising an 2-oxoethyl-spacer linked to the pyridinone or pyridazinone group wherein said compounds are selected from the group consisting of 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11 , 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 3.1 , 3.2, 3.3, 4.1 , 4.2, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 6.1 , 6.2, 6.3,

7.1 , 7.2, 7.3, 7.4, 7.5, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 10.1 , 10.2, 11.1 , 11.2, 12.1 , 12.2, 13.1 , 13.2, 14.1 , 14.2, 15.1 , 15.2, 16.1 , 16.2, 16.3, 16.4, 16.5,

17.1 , 17.2, 17.3, 23, 24.1 , 24.2, 25.1 , 25.2, 26.1 , 26.2, 27.1 , 27.2, 30, 31.1 , 31.2, 32.1 , 32.2, 34, 40.1 , 40.2, 40.3, 41.1 , 41.2, 42.1 , 42.2, 43.1, 44.1 , 44.2, 45.1 , 45.2, 53, 54, 55, 56, and 62, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

According to said first embodiment a preferred subset relates to one or more of the compounds comprising an amino-group which is not part of an azabicyclic moiety wherein said compounds are selected from the group consisting of 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, 1.11 , 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21 , 1.22, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 3.1 , 3.2, 3.3, 4.1 , 4.2, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 6.1, 6.2, 6.3, 7.1, 7.2, 7.3, 7.4, 7.5, 8.1 , 8.2, 8.3, 8.4, 8.5, 8.6, 9.1 , 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 10.1 , 10.2, 11.1 ,

11.2, 12.1 , 12.2, 23, 30, 53, 54, 55, 56, and 62 including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

According to said first embodiment another preferred subset relates to one or more of the compounds comprising an azabicyclic moiety wherein the compounds are selected from the group consisting of 13.1 , 13.2, 14.1 , 14.2, 15.1 , 15.2, 16.1 , 16.2, 16.3, 16.4, 16.5, 17.1, 17.2, 17.3, 24.1, 24.2, 25.1 , 25.2, 26.1, 26.2, 27.1, 27.2, 31.1, 31.2, 32.1, 32.2, 34, 40.1 , 40.2, 40.3, 41.1 , 41.2, 42.1 , 42.2, 43.1 , 44.1 , 44.2, 45.1 , and 45.2, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

According a preferrred second embodiment the invention relates to one or more of the compounds comprising an azabicyclic moiety which is linked to the pyridinone or pyridazinone group via an an optionally substituted ethylene spacer wherein said compounds are selected from the group consisting of 18.1 , 18.2, 19.1 , 19.2, 20.1 , 20.2, 21.1 , 21.2, 21.3, 21.4, 21.5, 22.1, 22.2, 28.1, 28.2, 29.1, 29.2, 33.1 , 33.2, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 36.1 , 36.2, 36.3, 36.4, 36.5, 37.1 , 37.2, 37.3, 38.1 , 38.2, 38.3, 38.4, 38.5, 39.1 , 39.2, 46.1 , 46.2, 47.1 , 47.2, 48, 49.1 , 49.2, 49.3, 49.4, 50.1 , 50.2, 51.1 , 51.2, 57, 58, 59, 60, 61 , 63, 64, 65, 66, 78, and 79, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

According to said second embodiment a preferred subset relates to one or more of the compounds comprising an azabicyclic moiety which is linked to the pyridinone or pyridazinone group via a not further substituted ethylene spacer wherein said compounds are

selected from the group consisting of 18.1 , 18.2, 19.1 , 19.2, 20.1 , 20.2, 21.1 , 21.2, 21.3, 21.4, 21.5, 22.1, 22.2, 28.1 , 28.2, 29.1 , 29.2, 33.1 , 33.2, 35.1 , 35.2, 35.3, 35.4, 35.5, 35.6, 35.7,

36.1 , 36.2, 36.3, 36.4, 36.5, 37.1 , 37.2, 37.3, 38.1 , 38.2, 38.3, 38.4, 38.5, 39.1 , 39.2, 46.1 ,

46.2, 47.1 , 47.2, 49.1 , 49.2, 49.3, 49.4, 50.1, 50.2, 51.1, 51.2, 65, 66, 78, and 79, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

According to said second embodiment another preferred subset relates to one or more of the compounds comprising an azabicyclic moiety which is linked to the pyridinone or pyridazinone group via an 1 ,1-difluoroethylene spacer wherein said compounds are selected from the group consisting of 57, 58, 59, 60, 61 , including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.

The compounds according to the invention as described hereinbefore and hereinafter may optionally be substituted. In case a compound of the invention is additionally substituted one or more C atoms are additionally mono- or polysubstituted by F, and/or one or two C atoms independently of one another additionally have a substituent selected from the group Cl, Br, cyano, d-4-alkyl, CWalkoxy, difluoromethyl, trifluoromethyl, hydroxy, acetylamino, aminocarbonyl, difluoromethoxy, and trifluoromethoxy. Preferred substituents are F, Cl, cyano, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, hydroxy, acetylamino, aminocarbonyl, difluoromethoxy, and trifluoromethoxy, most preferably F, Cl, cyano, methyl, methoxy, difluoromethyl, trifluoromethyl, and hydroxy,

Most preferably the compounds according to the invention do not possess any additional substituents.

Some expressions used hereinbefore and below to describe the compounds according to the invention will now be defined more fully.

The term "optionally substituted" used in this application indicates that the group thus designated is either unsubstituted or mono- or polysubstituted by the substituents specified. If the group in question is polysubstituted, the substituents may be identical or different.

The H atom bound to an N atom (imino or amino group) may in each case be replaced by a group which can be cleaved in vivo. By a group which can be cleaved in vivo from an N atom is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a Ci.i6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or

hexanoyl group, an allyloxycarbonyl group, a Cviε-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-Cvβ-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a d-s-alkylsulphonyl-C _∑ ^-alkoxycarbonyl, Ci. ₃ -alkoxy- C ₂ - ₄ -alkoxy-C ₂ - ₄ -alkoxycarbonyl or R _e CO-O-(R _f CRg)-O-CO- group wherein

Re denotes a Ci. ₈ -alkyl, C ₅ -7-cycloalkyl, phenyl or phenyl- Ci_ ₃ -alkyl group,

R _f denotes a hydrogen atom, a Ci. ₃ -alkyl, C ₅ . ₇ -cycloalkyl or phenyl group and

Rg denotes a hydrogen atom, a Ci _-3 -alkyl or R ₈ CO-O-(R _f CR _h )-O group wherein R _e and R _f are as hereinbefore defined and R _h is a hydrogen atom or a Ci _-3 -alkyl group,

while the phthalimido group is an additional possibility for an amino group.

The residues and substituents described above may be mono- or polysubstituted by fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulphinyl and alkylsulphonyl groups are trifluoromethylsulphinyl and trifluoromethylsulphonyl.

The compounds according to the invention may have basic groups such as e.g. amino functions. The compounds according to the invention may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) inter alia.

The compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained as described in the experimental section.

Stereoisomeric compounds according to the invention may chiefly be separated by conventional methods. The diastereomers are separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high

pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.

Racemates of compounds according to the invention may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (- )-tartaric acid, (+) or (-)-diacetyl tartaric acid, (+) or (-)-monomethyl tartrate or (+)-cam- phorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemate of a compound according to the invention is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. with dilute hydrochloric acid or aqueous methanesulphonic acid and in this way the corresponding free compound is obtained in the (+) or (-) form.

The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds according to the invention may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.

As already mentioned, the compounds according to the invention may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds according to the invention with inorganic or organic acids. The acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Moreover, mixtures of the above mentioned acids may be used.

The compounds according to the present invention, including the physiologically acceptable salts, are effective as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit good affinity in MCH receptor binding studies. Pharmacological test systems for MCH- antagonistic properties are described in the following experimental section.

As antagonists of the MCH receptor the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way. Generally the compounds according to the invention have low toxicity, they are well absorbed by oral route and have good intracerebral transitivity, particularly brain accessibility. Compounds of the invention predominantly have a good to excellent efficacy on body weight reduction in preclinical models of obesity and/or have advantageous pharmacokinetic properties, in particular AUC (plasma) (AUC = area under the curve), AUC (brain), brain to plasma ratio which can be expressed as AUC (brain)/AUC (plasma), cerebrospinal fluid (CSF) levels, clearance, half life (ti _/2 ), in each case in particular in preclinical species such as for example rat, monkey, dog, pig, etc.. The procedures to determine said pharmacokinetic properties are well known to the one skilled in the art and are described in textbooks and literature.

Compounds and pharmaceutical compositions according to this invention can be tested for their efficacy on body weight reduction in rats with diet-induced obesity. To this end, obesity is induced in female HanWistar rats by feeding them a cafeteria diet in addition to their standard diet for 4 to 8 weeks. The cafeteria diet consists of a mixture of palatable commercially available supermarket foods to stimulate energy intake. The rats with diet-induced obesity are treated once or twice daily for for example 2 to 4 weeks by oral administration of either one or more compound according to this invention or vehicle which is usually 0.5% aqueous hydroxyethylcellulose. Prior to start of treatment, the animals are randomized for body weight and the cafeteria diet feeding is continued throughout the study. At the end of the study, the body weight of animals treated with compounds according to this invention is compared to vehicle treatment.

Therefore, MCH antagonists which contain at least one compound according to the invention are particularly suitable in mammals, such as for example rats, mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and/or prevention of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.

Diseases caused by MCH or otherwise causally connected with MCH are particularly metabolic disorders, such as for example obesity, and eating disorders, such as for example bulimia, including bulimia nervosa. The indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity. This range of indications also includes cachexia, anorexia and hyperphagia.

Compounds according to the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiation.

In addition, the diseases caused by MCH or otherwise causally connected with MCH also include hyperlipidaemia, cellulitis, fatty accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affectivity disorders, depression, anxiety states, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.

Compounds according to the invention are also suitable as active substances for the prevention and/or treatment of other illnesses and/or disorders, particularly those which accompany obesity, such as for example diabetes, diabetes mellitus, particularly type Il diabetes, hyperglycaemia, particularly chronic hyperglycaemia, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.

MCH antagonists and formulations according to the invention may advantageously be used in combination with a dietary therapy, such as for example a dietary diabetes treatment, and exercise.

Another range of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of micturition disorders, such as for example urinary incontinence, hyperactive bladder, urgency, nycturia, enuresis, while the hyperactive bladder and urgency may or may not be connected with benign prostatic hyperplasia.

Generally speaking, the compounds according to the invention are potentially suitable for preventing and/or treating dependencies, such as for example alcohol and/or nicotine dependency, and/or withdrawal symptoms, such as for example weight gain in smokers coming off nicotine. By "dependency" is generally meant here an irresistible urge to take an addictive substance and/or to perform certain actions, particularly in order to either achieve a feeling of wellbeing or to eliminate negative emotions. In particular, the term "dependency" is used here to denote a dependency on an addictive substance. By "withdrawal symptoms" are meant here, in general, symptoms which occur or may occur when addictive substances are withdrawn from patients dependent on one or more such substances. The compounds according to the invention are potentially suitable particularly as active substances for reducing or ending tobacco consumption, for the treatment or prevention of a nicotine dependency and/or for the treatment or prevention of nicotine withdrawal symptoms, for reducing the craving for tobacco and/or nicotine and generally as an anti-smoking agent. The compounds according to the invention may also be useful for preventing or at least reducing the weight gain typically seen when smokers are coming off nicotine. The substances may also be suitable as active substances which prevent or at least reduce the craving for and/or relapse into a dependency on addictive substances. The term addictive substances refers particularly but not exclusively to substances with a psycho-motor activity, such as narcotics or drugs, particularly alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates.

The dosage required to achieve such an effect is conveniently, by intravenous or subcutaneous route, 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, and by oral or nasal route or by inhalation, 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight, in each case 1 to 3 x daily.

For this purpose, the compounds prepared according to the invention may be formulated, optionally in conjunction with other active substances as described hereinafter, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments or suppositories.

In addition to pharmaceutical compositions the invention also includes compositions containing at least one compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients. Such compositions may also be for example foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.

For the above mentioned combinations it is possible to use as additional active substances particularly those which for example potentiate the therapeutic effect of an MCH antagonist according to the invention in terms of one of the indications mentioned above and/or which make it possible to reduce the dosage of an MCH antagonist according to the invention. Preferably one or more additional active substances are selected from among active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, - active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of hyperlipidaemia, including arteriosclerosis, active substances for the treatment of dyslipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, - active substances for the treatment of anxiety states, active substances for the treatment of depression.

The above mentioned categories of active substances will now be explained in more detail by means of examples.

Examples of active substances for the treatment of diabetes are insulin sensitisers, insulin secretion accelerators, biguanides, insulins, α-glucosidase inhibitors, β3 adreno-receptor agonists.

Insulin sensitisers include glitazones, particularly pioglitazone and its salts (preferably hydrochloride), troglitazone, rosiglitazone and its salts (preferably maleate), JTT-501 , GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702 and GW- 1929.

Insulin secretion accelerators include sulphonylureas, such as for example tolbutamide, chloropropamide, tolazamide, acetohexamide, glyclopyramide and its ammonium salts,

glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.

Biguanides include metformin, buformin and phenformin.

Insulins include those obtained from animals, particularly cattle or pigs, semisynthetic human insulins which are synthesised enzymatically from insulin obtained from animals, human insulin obtained by genetic engineering, e.g. from Eξscherichi coli or yeasts. Moreover, the term insulin also includes insulin-zinc (containing 0.45 to 0.9 percent by weight of zinc) and protamine-insulin-zinc obtainable from zinc chloride, protamine sulphate and insulin. Insulin may also be obtained from insulin fragments or derivatives (for example INS-1 , etc.).

Insulin may also include different kinds, e.g. with regard to the onset time and duration of effect ("ultra immediate action type", "immediate action type", "two phase type",

"intermediate type", "prolonged action type", etc.), which are selected depending on the pathological condition of the patient.

α-Glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.

β ₃ Adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.

Active substances for the treatment of diabetes other than those mentioned above include ergoset, pramlintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide.

Active substances for the treatment of diabetes or diabetic complications furthermore include for example aldose reductase inhibitors, glycation inhibitors and protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-2 analogues and SGLT-2 inhibitors.

Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.

An example of a glycation inhibitor is pimagedine.

Protein Kinase C inhibitors are for example NGF, LY-333531.

DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541 , 823093 and 825964 (all GlaxoSmithkline).

GLP-1 analogues are for example Liraglutide (NN2211 ) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin).

SGLT-2 inhibitors are for example AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson&Johnson).

Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).

Active substances for the treatment of obesity, preferably other than MCH antagonists, include lipase inhibitors and anorectics.

A preferred example of a lipase inhibitor is orlistat.

Examples of preferred anorectics are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, baiamine, (S)-sibutramine, SR-141716, NGD-95-1.

Active substances other than those mentioned above for the treatment of obesity include lipstatin.

Moreover, for the purposes of this application, the active substance group of anti- obesity active substances also includes the anorectics, of which the β ₃ agonists, thyromimetic active substances and NPY antagonists should be emphasised. The range of substances which may be considered as preferred anti-obesity or anorectic active substances is indicated by the following additional list, by way of example: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as for example sibutramine), a sympathomimetic active substance, a serotonergic active substance (such as for example dexfenfluramine, fenfluramine, a 5-HT2C agonist such as BVT.933 or APD356, or duloxetine), a dopamine antagonist (such as for example

bromocriptine or pramipexol), a melanocyte-stimulating hormone receptor agonist or mimetic, an analogue of melanocyte-stimulating hormone, a cannabinoid receptor antagonist (Rimonabant, ACOMPLIA TM), an MCH antagonist, the OB protein (hereinafter referred to as leptin), a leptin analogue, a fatty acid synthase (FAS) antagonist, a leptin receptor agonist, a galanine antagonist, a Gl lipase inhibitor or reducer (such as for example orlistat). Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the Glucagon-like Peptide-1 receptor, such as for example exendin, AC 2993, CJC- 1131 , ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors, such as for example axokines. In this context mention should also be made of the forms of therapy which produce weight loss by increasing the fatty acid oxidation in the peripheral tissue, such as for example inhibitors of acetyl-CoA carboxylase.

Active substances for the treatment of high blood pressure include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers and angiotensin Il antagonists.

Inhibitors of angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).

Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.

Potassium channel openers include levcromakalim, L-27152, AL0671, NIP-121.

Angiotensin Il antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.

Active substances for the treatment of hyperlipidaemia, including arteriosclerosis, include HMG-CoA reductase inhibitors, fibrate compounds.

HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, itavastatin, ZD-4522 and their salts.

Fibrate compounds include fenofibrate, bezafibrate, clinofibrate, clofibrate and simfibrate.

Active substances for the treatment of dyslipidaemia, including arteriosclerosis, include e.g. medicaments which raise the HDL level, such as e.g. nicotinic acid and derivatives and preparations thereof, such as e.g. niaspan, as well as agonists of the nicotinic acid receptor.

Active substances for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), particularly COX2 inhibitors, such as for example meloxicam or ibuprofen.

Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.

Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.

The dosage for these active substances is conveniently 1/5 of the lowest normal recommended dose up to 1/1 of the normal recommended dose. 4

In another embodiment the invention also relates to the use of at least one compound according to the invention and/ or a salt according to the invention for influencing the eating behaviour of a mammal. This use is particularly based on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiety. The eating behaviour is advantageously influenced so as to reduce food intake. Therefore, the compounds according to the invention are advantageously used for reducing body weight. Another use according to the invention is the prevention of increases in body weight, for example in people who had previously taken steps to lose weight and are interested in maintaining their lower body weight. A further use may be the prevention of weight gain in a co-medication with a substance generally causing weight gain (such a glitazones). According to this embodiment it is preferably a non- therapeutic use. Such a non-therapeutic use might be a cosmetic use, for example to alter the external appearance, or an application to improve general health. The compounds according to the invention are preferably used non-therapeutically for mammals, particularly humans, not suffering from any diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and/or no diagnosed micturition disorders, particularly urinary incontinence. Preferably, the

compounds according to the invention are suitable for non-therapeutic use in people whose BMI (body mass index), defined as their body weight in kilograms divided by their height (in metres) squared, is below a level of 30, particularly below 25.

Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.

Preliminary remarks: As a rule, ¹ H-NMR and/or mass spectra have been obtained for the compounds prepared. The R _f values are determined using ready-made silica gel 60 TLC plates F254 (E. Merck,

Darmstadt, Item no. 1.05714) without chamber saturation or using ready-made aluminium oxide 60 F254 TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The ratios given for the eluents relate to units by volume of the solvent in question. The units by volume for NH ₃ relate to a concentrated solution of NH ₃ in water. Silica gel made by Millipore (MATREX™, 35-70 my) is used for chromatographic purification. Alox (E. Merck, Darmstadt, aluminium oxide 90 standardised, 63-200 μm, Item no. 1.01097.9050) is used for chromatographic purification. Purity data given for compounds are based on ¹ H-NMR.

The HPLC data given are measured under the following parameters:

mobile phase A: waterformic acid 99.9:0.1 mobile phase B: acetonitrile:formic acid 99.9:0.1 mobile phase C: water:NH ₄ OH 99.9:0.1 mobile phase D: acetonitrile: NH ₄ OH 99.9:0.1

method A: analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 3.5 μm; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min 0.00 95.0 5.0 1.60

4.50 10.0 90.0 1.60

5.00 10.0 90.0 1.60

5.50 95.0 5.00 1.60

method B: analytical column: Zorbax column (Agilent Technologies), Bonus-RP

C14; 3.5 μm; 4.6 mm x 75 mrr i; column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

4.00 50.0 50.0 1.60

4.50 10.00 90.00 1.60

5.00 10.00 90.00 1.60

5.50 95.0 5.0 1.60

method C: analytical column: Waters Svr nmetrv - C18: 3.5 urn: 4.6 mm x 75 mn temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

4.00 50.0 50.0 1.60

4.50 10.00 90.00 1.60

5.00 10.00 90.00 1.60

5.50 95.0 5.0 1.60

method D: analytical column: Waters SunFire - temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

4.00 50.0 50.0 1.60

4.50 10.0 90.0 1.60

5.00 10.0 90.0 1.60

5.50 95.0 5.0 1.60

method E: analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 3.5 μm; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min 0.00 95.0 5.0 1.60

2.00 10.0 90.0 1.60

5.00 10.0 90.0 1.60 5.50 95.0 5.0 1.60

method F: analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 3.5 μm; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

4.00 50.0 50.0 1.60

4.50 10.0 90.0 1.60

5.00 10.0 90.0 1.60

5.50 95.0 5.0 1.60

method G: analvtical column: Waters SunFire - C18: 3.5 urn: 4.6 mm x 75 mm: column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

4.50 10.0 90.0 1.60

5.00 10.0 90.0 1.60

5.50 95.0 5.00 1.60

method H: analytical column: Waters Symmetry - C18; 3.5 μm; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

4.50 10.0 90.0 1.60

5.00 10.0 90.0 1.60

5.50 95.0 5.00 1.60

method I: analytical column: Waters XBridge - C18; 3.5 μm; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %C %D flow rate in ml/min

0.00 95.0 5.0 1.60

4.50 10.0 90.0 1.60

5.00 10.0 90.0 1.60

5.50 95.0 5.00 1.60

method J: analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 1.8 μm; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

0.10 95.0 5.00 1.60

1.75 5.0 95.0 1.60

1.90 5.0 95.0 1.60

1.95 95.0 5.0 1.60

2.00 95.0 5.0 1.60

method K: analytical column: Waters XBridge - C18; 2.5 μm; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %C %D flow rate in ml/min

0.00 95.0 5.0 1.40

1.80 10.0 90.0 1.40

2.00 10.0 90.0 1.40

2.20 95.0 5.00 1.40

method L: analytical column: Zorbax column (Agilent Technologies), SB (Zorbax stable bond) - C18; 1.8 μm; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.60

1.00 10.0 90.0 1.60

2.50 10.0 90.0 1.60

2.75 95.0 5.0 1.60

method M: analytical column: Waters XBridge - C18; 2.5 μm; 3.0 mm x 30 mm; column temperature: RT

gradient: time in min %C %D flow rate in ml/min 0.00 95.0 5.0 1.40 0.80 10.0 90.0 1.40 2.00 10.0 90.0 1.40 2.20 95.0 5.00 1.40

method N: analytical column: Gemini - C18; 3.0 μm; 3.0 mm x 30 mm; column temperature: RT gradient: time in min %C %D flow rate in ml/min

0.00 95.0 5.0 1 .40

1.80 10.0 90.0 1 .40

2.00 10.0 90.0 1 .40

2.20 95.0 5.00 1 .40

method O: analytical column: XBridge C18; 3.0 μm; 4.6 mm x 75 mm; column temperature: RT gradient: time in min %A flow rate in ml/min

0.00 95.0 5.0 1.60

1.00 10.0 90.0 1.60

2.50 10.0 90.0 1.60

2.75 95.0 5.0 1.60

method P: analytical column: Water X-terra MS C18; 2.5 μm; 4.6 mm x 30 mm; column temperature: RT gradient: time in min %A %B flow rate in ml/min

0.00 95.0 5.0 1.00

0.10 95.0 5.0 1.00

3.10 2.00 98.0 1.00

4.50 2.00 98.0 1.00

5.00 95.0 5.0 1.00

The following abbreviations for the eluent mixtures are used hereinafter when giving the Rf values:

(A): silica gel, DCM/MeOH/ammonia (9:1 :0.1 )

(B): silica gel, DCM/ MeOH /ammonia (9.5:0.5:0.05)

(C): silica gel, PE/EtOAc (8:2)

(D) silica gel, DCM/MeOH (9:1 )

(E) silica gel, PE/EtOAc (1 :1)

(F): silica gel, Cyclohexane/EtOAc (8:2)

(G): silica gel, EtOAc/ MeOH /ammonia (8:2:0.2)

(H): silica gel, Chloroform/MeOH/ammonia (9:1 :0.1)

(I): silica gel, PE/EtOAc (6:4)

(J): silica gel, Cyclohexane/EtOAc (6:4)

The following abbreviations are used above and hereinafter:

BOC fert-Butylcarbonate cal. Calculated

CDI 1 ,1'-Carbonyl-di-imidazole#

CO Carbon monoxide DCM Dichloromethane

DMAP Dimethyl-pyridin-4-yl-amine

DMF λ/,λ/-Dimethylformamide

DMSO Dimethylsulfoxide

EII Electron impact ionisation ESI Electron spray ionisation

EtOAc Ethyl acetate h Hour

HCI Hydrochloric acid

Hg Mercury hPa hecto Pascale

HPLC High pressure liquid chromatography

KHSO ₄ Potassium hydrogen sulfate

MeOH Methanol

MgSO ₄ Magnesium sulfate min Minutes

Na ₂ CO ₃ Sodium carbonate

NaHCO ₃ Sodiumhydrogencarbonate

NH ₄ OH Ammonium hydroxide

OMe Methoxy

Pd/C Palladium on charcoal PE Petrolether

RT Ambient temperature (approx. 20 ⁰ C)

TFA Trifluoro acidic acid

THF Tetrahydrofuran

Preparation of starting materials:

Preparation 1 : 4-Benzyloxy-1-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

1a 2-Bromo-1-(4-hydroxymethyl-phenyl)-ethanone

To 7.00 g (46.6 mmol) 1-(4-hydroxymethyl-phenyl)-ethanone in 100 ml. THF is added 22.5 g (46.6 mmol) tetrabutylammonium-tribromide dissolved in MeOH/THF. The reaction mixture is stirred 1 h at RT and the solvent is evaporated. The residue is dissolved with water and tert- butylmethylether. The organic phase is washed eight times with water. The combined organic phase is dried over MgSO ₄ , filtered and the solvent is evaporated. The residue is elutriated with diisopropylether and the precipitate is collected and dried. Yield: 8.10 g (76% of theory); ESI Mass spectrum: [M+H] ⁺ = 229/231 Revalue: 0.2 (silica gel, mixture I).

1b 4-Benzyloxy-1 -[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

To 3.29 g (16.4 mmol) 4-benzyloxy-1 /-/-pyridin-2-one in 16 mL DMF is added 13.3 g (40.9 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 3.75 g (16.4 mmol) 2- bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 1a) is added and is stirred 2 h at RT. Water is added, the precipitate is collected, washed with water and dried. Yield: 5.30 g (93% of theory); ESI Mass spectrum: [M+H] ⁺ = 350 Retention time HPLC: 3.0 min (method A).

1 c 4-Benzyloxy-1 -[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

To 3.00 g (8.59 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2- one (preparation 1b) in 20 mL of DCM and 20 mL THF is added 0.81 mL (8.59 mmol) phosphorus tribromide at 0 ⁰ C. The cooling bath is removed and the mixture is stirred 1 h at RT in an ultrasound bath. The precipitate is collected, washed with diisopropylether and water and is dried. Yield: 3.40 g (96% of theory); ESI Mass spectrum: [M+H] ⁺ = 412/414 Retention time HPLC: 4.0 min (method H).

Preparation 2: 5-Benzyloxy-2H-pyridazin-3-one

2a 5-Hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one

To 14.3 g (62.0 mmol) 4-chloro-5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3- one in 200 mL MeOH and 8.71 mL (62.0 mmol) triethylamine is added 5.00 g 10% Pd/C. The reaction mixture is stirred under a hydrogen atmosphere of 1700 hPa at RT for 16 h. The catalyst is removed by filtration and the solvent is evaporated. 200 mL water is added to the residue, the precipitate is collected, washed with water and dried (fraction A, 7.80 g). The aqueous phase is concentrated and the residue is directly added to a reverse HPLC for purification (Waters xbridge; water (0.15% NH ₄ OH)/acetonitril 95:5 to 10:90) to afford fraction B (4.2 g) which is combined with fraction A.

Yield: 12.O g (99% of theory); ESI Mass spectrum: [M-H]- = 195 Retention time HPLC: 2.4 min (method A).

2b 5-Benzyloxy-2-(tetrahydro-pyran-2-yl)-2/-/-pyridazin-3-one To 500 mg (2.55 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2/-/-pyridazin-3-one (preparation 2a) in THF is added at 0 ⁰ C subsequently 315 mg (2.80 mmol) potassium-tert-butylate, 47 mg (0.13 mmol) tetra-butylammonium-iodide and 0.45 mL (3.82 mmol) benzylbromide. The reaction mixture is stirred overnight at RT and is diluted with EtOAc and 1 M aqueous sodium hydroxide solution. The organic phase is separated, washed with water and dried over MgSO ₄ . After filtration, the solvent is evaporated and the residue is elutriated in tert- butylmethylether. The precipitate is collected and dried. Yield: 500 mg (69% of theory); ESI Mass spectrum: [M+H] ⁺ = 287 Retention time HPLC: 4.0 min (method A).

2c 5-Benzyloxy-2/-/-pyridazin-3-one

To 500 mg (1.75 mmol) 5-benzyloxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 2b) in 10 mL MeOH is added 8.73 mL (8.73 mmol) 1M aqueous HCI solution and the reaction mixture is stirred overnight at RT and 10 h at reflux. MeOH is evaporated, to the residual aqueous phase is added saturated aqueous NaHCO ₃ -solution until the solution is basic. The aqueous phase is extracted with EtOAc, the combined organic phase is washed with water, dried over MgSO ₄ , filtered and evaporated to afford the product. Yield: 200 mg (57% of theory); ESI Mass spectrum: [M+H] ⁺ = 203 Retention time HPLC: 3.2 min (method G).

Preparation 3: 5-Benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2W-pyri dazin-3-one

3a 5-Benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2/-/- pyridazin-3-one 5-Benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2/-/- pyridazin-3-one is prepared following preparation 1 b from 5.20 g (25.7 mmol) 5-benzyloxy-2H-pyridazin-3-one

(preparation 2) and 7.70 g (28.6 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone

(preparation 1a) using DMSO as solvent.

Yield: 9.40 g (94% of theory); ESI Mass spectrum: [M+H] ⁺ = 351 Retention time HPLC: 0.9 min (method L).

3b 5-Benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2/-/-py ridazin-3-one 5-Benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2A7-pyr idazin-3-one is prepared following preparation 1c from 9.40 g (26.8 mmol) 5-benzyloxy-2-[2-(4-hydroxymethyl-phenyl)- 2-oxo-ethyl)-2H-pyridazin-3-one (preparation 3a) and 2.52 mL (26.8 mmol) phosphorus tribromide.

Yield: 10.0 g (90% of theory); ESI Mass spectrum: [M+H] ⁺ = 413/415 Retention time HPLC: 1.6 min (method J).

Preparation 4:

4-Benzyloxy-1-[2-(4-bromomethyl-2-fluoro-phenyl)-2-oxo-et hyl]-1H-pyridin-2-one

4a 1 -(4-Bromomethyl-2-fluoro-phenyl)-ethanone

A solution of 2-fluoro-4-methylacetophenone (17.6 g, 112 mmol) and N-bromosuccinimide (21.6 g, 178 mmol) in tetrachloromethane (150 mt_) is refluxed for 2 h while irradiating with a Hg lamp. After filtration, the reaction mixture is adsorbed onto silica gel and purified chromatographically (silica gel, 10% ethyl acetate in hexanes). Yield: 15.7 g (59% of theory); ESI Mass spectrum: [M+H] ⁺ = 231/233.

4b Acetic acid 4-acetyl-3-fluoro-benzyl ester A mixture of 1-(4-Bromomethyl-2-fluoro-phenyl)-ethanone (preparation 4a, 15.7 g, 68 mmol) and sodium acetate (22.3 g, 200 mmol) in acetic acid (150 ml_) is heated at reflux for 4 h. The reaction mixture is poured into ice water and extracted with te/t-butylmethylether. The organic layer is washed with aqueous sodium carbonate solution and water, dried over MgSO ₄ and evaporated in vacuo. Yield: 13.1 g (92% of theory); ESI Mass spectrum: [M+H] ⁺ = 211.

4c 1 -(2-Fluoro-4-hydroxymethyl-phenyl)-ethanone

A solution of acetic acid 4-acetyl-3-fluoro-benzyl ester (preparation 4b, 13.1 g, 62 mmol) in methanol (100 ml_) and 4N aqueous sodium hydroxide solution (31.2 ml_, 125 mmol) is heated at reflux for 2h. After cooling, the reaction mixture is poured into ice water and extracted several times with tert-butylmethylether. The organic layer is washed with water, dried over MgSO ₄ and evaporated in vacuo. Yield: 10.1 g (96% of theory); ESI Mass spectrum: [M+H] ⁺ = 169.

4d 2-Bromo-1-(2-fluoro-4-hydroxymethyl-phenyl)-ethanone

To 10.1 g (60 mmol) 1-(2-fluoro-4-hydroxymethyl-phenyl)-ethanone (preparation 4c) in 100 mL DCM and 10 ml_ MeOH is added 29.0 g (60 mmol) tetrabutylammonium-tribromide. The reaction mixture is stirred 2 h at RT and the solvent is evaporated. The remaining residue is treated with water and extracted several times with DCM. The combined organic layer is dried over MgSO ₄ and evaporated in vacuo. The remaining oil is adsorbed onto silica gel and purified chromatographically (silica gel, 30% ethyl acetate in hexanes). Yield: 10.4 g (70% of theory); ESI Mass spectrum: [M+H] ⁺ = 245/247.

4e 4-Benzyloxy-1 -[2-(2-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one To 1.00 g (4.97 mmol) 4-benzyloxy-1 H-pyridin-2-one in 5 mL DMSO is added 4.05 g (12.4 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 1.23 g (4.97 mmol) 2- bromo-1-(2-fluoro^-hydroxymethyl-phenyl)-ethanone (preparation 4d) is added and the reaction mixture is stirred 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.

Yield: 1.40 g (77% of theory); ESI Mass spectrum: [M+H] ⁺ = 368 Retention time HPLC: 1.41 min (method J).

4f 4-Benzyloxy-1-[2-(4-bromomethyl-2-fluoro-phenyl)-2-oxo-ethyl ]- 1 H -pyridin-2-one

To a solution of 1.40 g (2.86 mmol) 4-benzyloxy-1-[2-(2-fluoro-4-hydroxymethyl-phenyl)-2- oxo-ethyl]-1 /-/-pyridin-2-one (preparation 4e) in 20 mL of DCM is added 0.54 mL (5.72 mmol) phosphorus tribromide at 0 ⁰ C. The cooling bath is removed and the mixture is stirred 5 h at RT. Under cooling, the reaction mixture is quenched by addition of sodium bicarbonate solution and extracted with dichloromethane. The organic layer is washed with water, dried over MgSO ₄ and evaporated under reduced pressure. The remaining solid is purified by preparative reverse phase HPLC (Gilson, Waters Symmetry C18, 7μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH, 120 mL/min). Yield: 0.60 g (49% of theory); ESI Mass spectrum: [M+H] ⁺ = 430/432 Retention time HPLC: 1.57 min (method J).

Preparation 5: 4-Benzyloxy-1-[2-(4-bromomethyl-3-methoxy-phenyl)-2-oxo-ethy l]-1 /-/-pyridin-2-one

5a 4-Hydroxymethyl-3-methoxy-benzoic acid

A solution of methyl 4-bromomethyl-3-methoxy-benzoate (Trans World Chemicals, 5.18 g, 20 mmol) in 50 mL dioxane, 15 mL water and 50 mL 1 N aqueous sodium hydroxide is heated at reflux for 6 h. The reaction mixture is neutralized with 50 mL 1 N hydrochloric acid and extracted several times with ethyl acetate. The organic layer is washed with water, dried over MgSO ₄ and evaporated under reduced pressure.

Yield: 3.40 g (93 % of theory); ESI Mass spectrum: [M-H] ^" = 181 Retention time HPLC: 0.81 min (method J).

5b 4-Hydroxymethyl-3,N-dimethoxy-N-methyl-benzamide (Weinreb amide of 5a) A solution of 4-hydroxymethyl-3-methoxy-benzoic acid (preparation 5a, 3.30 g, 18.1 mmol), N,O-dimethylhydroxylamine hydrochloride (2.12 g, 21.7 mmol) and 4-methylmorpholine (3.99 mL, 36.2 mmol) is stirred for 10 min at RT. Then, 4-(4,6-dimethoxy[1 ,3,5]triazin-2-yl)-4- methylmorpholinium chloride hydrate (Acros, 5.51 g, 19.9 mmol) is added and the reaction mixture is stirred for 3 h at ambient temperature. The reaction mixture is concentrated in vacuo and purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min). Yield: 2.80 g (69 % of theory); ESI Mass spectrum: [M+H] ⁺ = 226 Retention time HPLC: 1.10 min (method K).

5c 1 -(4-Hydroxymethyl-3-methoxy-phenyl)-ethanone

At 0 ⁰ C, methylmagnesium bromide (12 mL of a 3M solution in diethyl ether, 36 mmol) is added to a solution of Weinreb amide 5b (4-Hydroxymethyl-3,N-dimethoxy-N-methyl- benzamide, 2.70 g, 12.0 mmol) in anhydrous THF (50 mL). After stirring for 1.5 h at 0 ⁰ C, another 2 equivalents of methylmagnesium bromide (8 mL) are added to the reaction mixture. After 30 min, the reaction mixture is carefully poured into saturated aqueous ammonium chloride solution and extracted several times with tert-butylmethylether. The combined organic layer is washed with water, dried over MgSO ₄ and evaporated in vacuo. The resulting oil is purified chromatographically (silica gel, gradient from 10% to 30% MeOH in DCM). Yield: 1.60 g (76 % of theory); ESI Mass spectrum: [M+H] ⁺ = 181 R _f value = 0.64 (silica gel, mixture D).

5d 2-Bromo-1 -(4-hydroxymethyl-3-methox-phenyl)-ethanone To 400 mg (2.2 mmol) 1-(4-hydroxymethyl-3-methoxy-phenyl)-ethanone (preparation 5c) in 8 mL dioxane is added at 35 ⁰ C a solution of 0.12 mL bromine (2.3 mmol) in 2 mL DCM. After 10 min, the reaction mixture is quenched with aqueous sodium thiosulfate solution and extracted several times with DCM. The combined organic layer is dried over MgSO ₄ and evaporated in vacuo. The resulting oil is purified by preparative HPLC (Gilson, Zorbax Stablebond C18, 7 μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH, 120 mL/min).

Yield: 150 mg (26% of theory); ESI Mass spectrum: [M+H] ⁺ = 259/261 Retention time HPLC: 1.12 min (method J).

5e 4-Benzyloxy-1 -[2-(4-hydroxymethyl-3-methoxy-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one

To 117 mg (0.58 mmol) 4-benzyloxy-1H-pyridin-2-one in 3 ml_ DMSO is added 472 mg (1.45 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 150 mg (0.5 mmol) 2- bromo-1-(4-hydroxymethyl-3-methox-phenyl)-ethanone (preparation 5d) is added and the reaction mixture is stirred for 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.

Yield: 160 mg (73% of theory); ESI Mass spectrum: [M+H] ⁺ = 380 Retention time HPLC: 1.26 min (method J).

5f 4-Benzyloxy-1 -[2-(4-bromomethyl-3-methoxy-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one To 160 mg (0.42 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-3-methoxy-phenyl)-2-oxo-et hyl]- 1 /-/-pyridin-2-one (preparation 5e) in 5 mL of DCM is added 28 μl_ (0.3 mmol) phosphorus tribromide at O ⁰ C. The cooling bath is removed and the mixture is stirred 2 h at RT. Under cooling, the reaction mixture is quenched by addition of sodium bicarbonate solution and extracted with dichloromethane. The organic layer is washed with water, dried over MgSO ₄ and evaporated under reduced pressure.

Yield: 140 mg (75% of theory); ESI Mass spectrum: [M+H] ⁺ = 442/444 Retention time HPLC: 2.77 min (method E).

Preparation 6: 4-Benzyloxy-1 -[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one

6a (4-Bromo-2-fluoro-benzyloxy)-tert-butyl-dimethyl-silane

To 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) fert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO ₄ , filtered and the solvent is evaporated. Yield: 7.70 g (97% of theory); R _r value: 0.9 (silica gel, mixture C).

6b te/t-Butyl-(2-fluoro-4-iodo-benzyloxy)-dimethyl-silane

To 7.70 g (24.1 mmol) (4-bromo-2-fluoro-benzyloxy)-terf-butyl-dimethyl-silane (preparation 6a) in 8 mL 1 ,4-dioxane is added 937 mg (4.82 mmol) Cu(l)-iodide. The reaction mixture is flushed with argon and 7.23 g (48.2 mmol) sodium iodide and 1.03 mL (9.65 mmol) N ₁ N-

dimethylethylen-diamine are added. The mixture is stirred at 12O ⁰ C for 7 h in a sealed tube. The reaction mixture is diluted at RT with 5% aqueous NH ₃ -solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed a few times with water, dried over MgSO ₄ , filtered and the solvent is evaporated. Yield: 7.80 g (88% of theory); Retention time HPLC: 4.2 min (method E).

6c 4-(ferf-Butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid methyl ester

To 3.00 g (8.19 mmol) tert-butyl-(2-fluoro-4-iodo-benzyloxy)-dimethyl-silane (preparation 6b) in 20 mL MeOH and 20 mL DMF is added 455 mg (0.82 mmol) 1 ,1-bis(-diphenylphosphino)- ferrocene, 184 mg (0.82 mmol) Pd(ll)-acetate and 2.27 mL (16.3 mmol) triethylamine. The reaction mixture is stirred under a CO atmosphere (4000 hPa) at 50 ⁰ C for 24 h. The solvent is evaporated, the residue is dissolved in DMF and is purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 85:5 to 0:100). Yield: 1.46 g (60% of theory); Retention time HPLC: 3.8 min (method E).

6d 4-(fe/?-Butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid

To 2.20 g (7.37 mmol) 4-(fert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid methyl ester (preparation 6c) in 30 mL EtOH is added 12 mL 1 M aqueous NaOH-solution. The mixture is stirred 1 h at RT, additional 4 mL 1 M aqueous NaOH-solution are added and the reaction mixture is stirred an additional hour. The solvent is evaporated, the residue is acidified with 1 M aqueous HCI-solution. The precipitate is collected and dried. Yield: 540 mg (26% of theory); ESI Mass spectrum: [M-H] ^" = 283 Retention time HPLC: 4.9 min (method A).

6e 1 -[4-(fert-Butyl-dimethyl-silanyloxymethyl)-3-fluoro-phenyl]- ethanone

A solution of 540 mg (1.90 mmol) 4-(ferf-butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid (preparation 6d) in 20 mL THF is degassed and cooled to -3O ⁰ C. 3.56 mL (5.67 mmol) 1.6 M methyl-lithium solution in diethylether is added, the mixture is stirred 2 h at -3O ⁰ C and 3.12 mL (24.7 mmol) trimethyl-chloro-silane is added. The mixture is stirred 2 min and is transferred to a pH 7 buffer solution (0°C). The aqueous phase is extracted with EtOAc and diethylether. The combined organic phase is washed with water, dried over MgSO ₄ , filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (9:1) as eluent. Yield: 280 mg (52% of theory); ESI Mass spectrum: (M+H) ⁺ = 283 R _f -value: 0.5 (silica gel, mixture C).

6f 2-Bromo-1 -(3-fluoro-4-hydroxymethyl-phenyl)-ethanone

2-Bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone is prepared following preparation 1a from 280 mg (0.99 mmol) 1-[4-(tert-butyl-dimethyl-silanyloxyrnethyl)-3-fluoro-phenyl ]- ethanone (preparation 6e) and 478 mg (0.99 mmol) tetrabutylammonium-tribromide. Yield: 230 mg (94% of theory); R _r value: 0.3 (silica gel, mixture J).

6g 4-Benzyloxy-1 -[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one 4-Benzyloxy-1 -[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one is prepared following preparation 1b from 193 mg (0.93 mmol) 4-benzyloxy-1 H-pyridin-2-one and 230 mg (0.93 mmol) 2-bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone (preparation 6f). Yield: 240 mg (70% of theory); ESI Mass spectrum: (M+H) ⁺ = 368 Retention time HPLC: 3.2 min (method A).

6h 4-Benzyloxy-1 -[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one 4-Benzyloxy-1-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl ]-1 H-pyridin-2-one is prepared following preparation 1c from 240 mg (0.65 mmol) 4-benzyloxy-1-[2-(3-fluoro-4- hydroxymethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 6g) and 0.43 mL (4.57 mmol) phosphorus tribromide.

Yield: 210 mg (75% of theory); ESI Mass spectrum: (M+H) ⁺ = 430/432 Retention time HPLC: 2.4 min (method E).

Preparation 7: 5-Benzyloxy-2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl ]-2H-pyridazin-3-one

7a 5-Benzyloxy-2-[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-eth yl]-2H-pyridazin-3-one 5-Benzyloxy-2-[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-eth yl]-2H-pyridazin-3-one is prepared following preparation 1b from 1.64 g (8.1 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 2) and 2.00 g (8.1 mmol) 2-bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone (preparation 6f).

Yield: 1.40 g (47% of theory); ESI Mass spectrum: (M+H) ⁺ = 369 Retention time HPLC: 1.34 min (method J).

7b 5-Benzyloxy-2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl ]-2/-/-pyridazin-3-one 5-Benzyloxy-2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl ]-2H-pyridazin-3-one is prepared following preparation 1c from 1.40 g (3.80 mmol) 5-benzyloxy-2-[2-(3-fluoro-4- hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 7a) and 0.71 mL (7.60 mmol) phosphorus tribromide.

Yield: 1.40 g (85% of theory); ESI Mass spectrum: (M+H) ⁺ = 431/433 Retention time HPLC: 1.58 min (method J).

Preparation 8 2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-N-methoxy-N-methyl-ace tamide

8a (4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-acetic acid methyl ester

(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-acetic acid methyl ester is prepared following preparation 1b from 10.0 g (49.7 mmol) 4-benzyloxy-1H-pyridin-2-one and 4.96 mL (52.2 mmol) methyl bromoacetate, employing DMSO as the solvent.

Yield: 12.7 g (94% of theory); ESI Mass spectrum: (M+H) ⁺ = 274 Retention time HPLC: 1.12 min (method J).

8b (4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-acetic acid A solution of (4-benzyloxy-2-oxo-2H-pyridin-1-yl)-acetic acid methyl ester (preparation 8a, 12.0 g, 43 mmol) in 150 mL ethanol and 22 mL 4N aqueous sodium hydroxide solution is stirred for 18 h at room temperature. The reaction mixture is diluted with water and acidified with 4N aqueous HCI. The formed precipitate is filtered off, washed with hot acetonitrile and tert-butylmethylether and dried in vacuo. Yield: 9.30 g (82 % of theory); ESI Mass spectrum: [M+H] ⁺ = 260 Retention time HPLC: 1.13 min (method J).

8c 2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-N-methoxy-N-methyl-ace tamide 2-(4-Benzyloxy-2-oxo-2/-/-pyridin-1-yl)-N-methoxy-N-methyl-a cetamide is prepared following preparation 5b from (4-benzyloxy-2-oxo-2H-pyridin-1-yl)-acetic acid (preparation 8b, 5.19 g, 20 mmol).

Yield: 4.60 g (76 % of theory); ESI Mass spectrum: [M+H] ⁺ = 303 Retention time HPLC: 1.16 min (method J).

Preparation 9 4-Benzyloxy-1-[2-(5-bromomethyl-pyridin-2-yl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

9a 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-iodo-pyridine To a solution of 2-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine (1.51 g, 5.00 mmol, preparation according to J. Org. Chem. 69 (2), 250-262, 2004) in dioxane (5 mL) is added CuI (98 mg, 0.5 mmol), sodium iodide (1.5 g, 10 mmol) and N,N'-dimethyl ethylenediamine (0.11 mL, 1.0 mmol). The reaction mixture is heated for 3 h at 100°C. After cooling, the reaction mixture is poured into 5% aqueous ammonia solution and extracted with tert- butylmethylether. The organic layer is washed with water, dried over MgSO ₄ and evaporated under reduced pressure. The remaining oil is adsorbed onto silica gel and purified chromatographically (silica gel, gradient from 0% to 20% ethyl acetate in cyclohexane). Yield: 1.50 g (86% of theory); ESI Mass spectrum: [M+H] ⁺ = 350 Rf-value: 0.75 (silica gel, mixture F).

9b 4-Benzyloxy-1 -[2-(5-hydroxymethyl-pyridin-2-yl)-2-oxo-ethyl]-1 H-pyridin-2-one To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-iodo-pyridine (preparation 9a, 1.22 g, 3.50 mmol) in anhydrous THF (20 mL) is added at -20 ⁰ C a solution of isopropylmagnesium chloride and lithium chloride ("Turbo Grignard", 2.69 mL of 14% solution in THF). After 10 min, the Grignard solution is added to a suspension of the Weinreb amide 2-(4-benzyloxy-2- oxo-2H-pyridin-1-yl)-N-methoxy-N-methyl-acetamide (preparation 8, 1.06 g, 3.50 mmol) in THF (20 mL), while keeping the temperature below 0 ⁰ C. After stirring for 5 h at room temperature, the reaction mixture is poured into 1 N aqueous HCI, tert-butylmethylether is added and the mixture is stirred for 2 h at room temperature. The formed precipitate is filtered off, washed with terf-butylmethylether and dried in vacuo.

Yield: 250 mg (20 % of theory); ESI Mass spectrum: [M+H] ⁺ = 351 Retention time HPLC: 1.19 min (method J).

9c 4-Benzyloxy-1 -[2-(5-bromomethyl-pyridin-2-yl)-2-oxo-ethyl]-1 H-pyridin-2-one 4-Benzyloxy-1-[2-(5-bromomethyl-pyridin-2-yl)-2-oxo-ethyl]-1 H-pyridin-2-one is prepared following preparation 1c from 300 mg (0.86 mmol) 4-benzyloxy-1-[2-(5-hydroxymethyl-pyridin- 2-yl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 9b) and 41 μL (0.43 mmol) phosphorus tribromide.

Yield: 250 mg (71 % of theory).

Preparation 10.1 4-(4-Fluoro-benzyloxy)-1H-pyridin-2-one

To 1.40 g (7.41 mmol) 1 -bromomethyl-4-fluoro-benzene in 20 mL acetonitrile is added 822 mg (7.40 mmol) 2,4-dihydroxy pyridine and 2.05 g (14.8 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5 mL of DMF is added and the reaction is stirred overnight. After filtration and evaporation of the solvent, is the residue purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95). Yield: 600 mg (37% of theory); ESI Mass spectrum: [M+H] ⁺ = 220 Retention time HPLC: 2.8 min (method A).

Preparation 10.2 4-(4-Chloro-benzyloxy)-1 H-pyridin-2-one

4-(4-Chloro-benzyloxy)-1/-/-pyridin-2-one is prepared as described for preparation 10.1, employing 1-bromomethyl-4-chloro-benzene as the alkylating agent. Yield: 43% of theory; ESI Mass spectrum: [M+H] ⁺ = 236/238 Retention time HPLC: 1.1 min (method K).

Preparation 10.3 4-(5-Bromo-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared as described for preparation 10.1 , employing 2-Bromomethyl-5-bromo-pyridine as the alkylating agent. Yield: 46% of theory; ESI Mass spectrum: [M+H] ⁺ = 281/283 Retention time HPLC: 2.5 min (method A).

Preparation 10.4 5-(5-Chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one

10.4a 5-(5-Chloro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2 /-/-pyridazin-3-one

To 5.00 g (25.5 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2/-/-pyridazin-3-one (see preparation 2a) and 4.03 g (28.0 mmol) (5-chloro-pyridin-2-yl)-methanol in 25 mL THF and 15 mL DCM is added molecular sieve and then 12.7 g (38.2 mmol) of polymer bound triphenylphosphane (3 mmol/g). The reaction mixture is cooled to 0 ⁰ C and 7.53 mL (38.2 mmol) diisopropyl azodicarboxylate is added. The mixture is stirred 10 min at O ⁰ C and 30 min at RT. The reaction mixture is filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1 % formic acid)/acetonitrile (0.1 % formic acid) 95:5 to 10:90). Yield: 5.50 g (67% of theory); ESI Mass spectrum: [M+H] ⁺ = 322/324 Retention time HPLC: 3.3 min (method A).

10.4b 5-(5-Chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one

To 5.50 g (17.1 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2 /-/- pyridazin-3-one (preparation 10.4a) in 50 mL MeOH is added 7.1 mL cone. HCI and the reaction mixture is refluxed for 2 h. The solvent is evaporated, the precipitate collected and added to 50 mL of water. The mixture is neutralized with saturated aqueous NaHCO ₃ - solution. The precipitate is collected, washed with water and dried.

Yield: 3.00 g (74% of theory); ESI Mass spectrum: [M+H] ⁺ = 238/240

Retention time HPLC: 1.0 min (method J).

Preparation 10.5

5-(5-Bromo-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one

10.5a 5-(5-Bromo-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H -pyridazin-3-one To 3.29 g (16.7 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2/-/-pyridazin-3-one (preparation 2a) in acetonitrile is added at RT subsequently 4.63 g (33.4 mmol) potassium-carbonate and

4.20 g (16.7 mmol) 5-bromo-2-bromomethyl-pyridine. The reaction mixture is stirred 3 h at RT and 5 mL DMF is added. The reaction mixture is stirred overnight and the solvent is evaporated. To the residue water and terf-butylmethylether is added. The precipitate is collected and dried. Yield: 5.30 g (86% of theory); ESI Mass spectrum: [M+H] ⁺ = 366/368 Retention time HPLC: 3.7 min (method A).

10.5b 5-(5-Bromo-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 10.4b from 5.30 g (14.5 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H - pyridazin-3-one (preparation 10.5a).

Yield: 4.20 g (103% of theory); ESI Mass spectrum: [M+H] ⁺ = 282/284 Retention time HPLC: 2.8 min (method A).

Preparation 10.6

4-(5-Chloro-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one is prepared following preparation 10.1 , employing 2-bromomethyl-5-chloro-pyridine as the alkylating agent. Yield: 39% of theory; ESI Mass spectrum: [M+H] ⁺ = 237/239 Retention time HPLC: 1.05 min (method J).

Preparation 10.7 4-(4-Methoxy-benzyloxy)-1/-/-pyridin-2-one

4-(4-Methoxy-benzyloxy)-1H-pyridin-2-one is prepared as described for preparation 10.1 , employing 4-methoxybenzyl chloride as the alkylating agent and DMSO as solvent. The reaction mixture is poured into water under vigorous stirring, the formed precipitate is filtered off, washed with tert-butylmethylether and dried. The solid is triturated with acetonitrile, collected and dried.

Yield: 24% of theory; ESI Mass spectrum: [M+H] ⁺ = 232

Retention time HPLC: 1.07 min (method K).

Preparation 10.8

5-(4-Fluoro-benzyloxy)-2H-pyridazin-3-one

10.8a 5-(4-Fluoro-benzyloxy)-2-(tetrahydro-pyran-2-yl)-2/-/-pyrida zin-3-one 5-(4-Fluoro-benzyloxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazi n-3-one is prepared following preparation 10.5a from 8.00 g (40.8 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2/-/-pyridazin- 3-one (preparation 2a) and 5.4 ml_ (44.9 mmol) i-chloromethyl-4-fluoro-benzene. Yield: 10.5 g (85% of theory); ESI Mass spectrum: [M+H] ⁺ = 305 Retention time HPLC: 3.6 min (method A).

10.8b 5-(4-Fluoro-benzyloxy)-2H-pyridazin-3-one 5-(4-Fluoro-benzyloxy)-2/-/-pyridazin-3-one is prepared following preparation 10.4b from 10.5 g (34.5 mmol) 5-(4-fluoro-benzyloxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazi n-3-one

(preparation 10.8a).

Yield: 7.30 g (96% of theory); ESI Mass spectrum: [M+H] ⁺ = 221

Retention time HPLC: 2.7 min (method A).

Preparation 10.9

5-(5-Fluoro-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one

10.9a 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2 H-pyridazin-3-one 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2 H-pyridazin-3-one is prepared following preparation 10.4a from 2.4Og (12.2 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H- pyridazin-3-one (preparation 2a) and 1.56 g (12.2 mmol) (5-fluoro-pyridin-2-yl)-methanol Yield: 800 mg (21% of theory); ESI Mass spectrum: (M+H) ⁺ = 306 Retention time HPLC: 3.0 min (method A).

10.9b 5-(5-Fluoro-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 10.4b from 800 mg (2.62 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2 /-/- pyridazin-3-one.

Yield: 350 mg (60% of theory); ESI Mass spectrum: [M+H] ⁺ = 222 Retention time HPLC: 2.0 min (method A).

Preparation 10.10 4-(5-Trifluoromethyl-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one

10.10a 2-Bromomethyl-5-trifluoromethyl-pyridine

To an ice-cooled solution of (5-trifluoromethyl-pyridin-2-yl)-methanol (300 mg, 1.69 mmol) in

DCM (10 mL) is added phosphoros tribromide (96 μl_, 1.02 mmol) and the reaction mixture is stirred for 2 h at room temperature. The reaction mixture is quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over MgSO ₄ and evaporated under reduced pressure.

Yield: 350 mg (86% of theory); ESI Mass spectrum: [M+H] ⁺ = 239

Retention time HPLC: 1.37 min (method J).

10.10b 4-(5-Trifluoromethyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one

4-(5-Trifluoromethyl-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one is prepared following preparation

10.1 , employing 2-bromomethyl-5-trifluoromethyl-pyridine as the alkylating agent.

Yield: 14% of theory; ESI Mass spectrum: [M+H] ⁺ = 271 Retention time HPLC: 1.17 min (method J).

Preparation 10.11 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one

10.11a 4-Benzyloxy-1-(tetrahydro-pyran-2-yl)-1 /-/-pyridin-2-one

To 45.2 g (225 mmol) 4-benzyloxy-1/-/-pyridin-2-one in 200 mL THF is added 63.4 mL (84.1 mmol) 3,4-dihydro-2H-pyran and 4.27 g (22.5 mmol) toluene-4-sulfonic acid mono hydrate. The reaction mixture is stirred 2 h at reflux and additional 4.00 mL (5.30 mmol) 3,4-dihydro- 2H-pyran is added. After 2 h at reflux, additional 4.00 mL (5.30 mmol) 3,4-dihydro-2/-/-pyran is added and the reaction mixture is stirred 2 h at reflux and then overnight at RT. The reaction mixture is concentrated in vacuo and the residue is diluted with EtOAc. The organic phase is washed with an aqueous sodium hydroxide solution (1M). The organic phase is washed with water, dried over MgSO ₄ and evaporated in vacuo. The residue is purified chromatographically (silica gel, PE:EtOAc 1 :1 to EtOAc). Yield: 73% of theory; ESI Mass spectrum: [M+H] ⁺ = 286 Retention time HPLC: 1.10 min (method L).

10.11b 4-Hydroxy-1-(tetrahydro-pyran-2-yl)-1A-/-pyridin-2-one

To 47.0 g (165 mmol) 4-benzyloxy-1-(tetrahydro-pyran-2-yl)-1 /-/-pyridin-2-one in 700 mL ethanol and 30.1 mL (214 mmol) triethylamine is added 5.00 g 10% Pd/C. The reaction mixture is stirred under a hydrogen atmosphere at 40 ⁰ C for 1.5 h. The catalyst is removed by filtration and the solvent is evaporated. 200 mL water and pH 5 buffer solution is added to the residue. The precipitate is collected, washed with water and dried at 50 ⁰ C. Yield: 30.4 g (95% of theory); ESI Mass spectrum: [M+H] ⁺ = 196 Retention time HPLC: 0.98 min (method J).

10.11c 4-(5-Fluoro-pyridin-2-ylmethoxy)-1-(tetrahydro-pyran-2-yl)-1 /-/-pyridin-2-one 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -(tetrahydro-pyran-2-yl)-1 H-pyridin-2-one is prepared following preparation 10.4a from 4.61 g (23.6 mmol) 4-hydroxy-1-(tetrahydro-pyran-2-yl)-1H- pyridin-2-one (preparation 10.11b) and 3.00 g (23.6 mmol) (5-fluoro-pyridin-2-yl)-methanol. Yield: 2.90 g (40% of theory); ESI Mass spectrum: [M+H] ⁺ = 305 Retention time HPLC: 1.46 min (method K).

10.11d 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one 4-(5-Fluoro-pyridin-2-ylmethoxy)-1 H-pyridin-2-one is prepared following preparation 10.4b from 2.90 g (9.53 mmol) 4-(5-fluoro-pyridin-2-ylmethoxy)-1-(tetrahydro-pyran-2-yl)-1 H-pyridin-

2-one (preparation 10.11c).

Yield: 2.20 g (105% of theory); ESI Mass spectrum: [M+H] ⁺ = 221

Retention time HPLC: 1.10 min (method K).

Preparation 11.1

4-(4-Fluoro-benzyloxy)-1 -{2-[4-(1 -hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one

11.1a 2-Bromo-1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone

2-Bromo-1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone is prepared following preparation 1a from 600 mg (3.65 mmol) 1-[4-(1-hydroxy-ethyl)-phenyl]-ethanone.

Yield: 750 mg (84% of theory); ESI Mass spectrum: [M+H] ⁺ = 243/245 R _f -value: 0.5 (silica gel, mixture E).

11.1b 4-(4-Fluoro-benzyloxy)-1-{2-[4-(1-hydroxy-ethyl)-phenyl]-2-o xo-ethyl}-1/-/-pyridin-2 -one 4-(4-Fluoro-benzyloxy)-1-{2-[4-(1-hydroxy-ethyl)-phenyl]-2-o xo-ethyl}-1H-pyridin-2-one is prepared following preparation 1 b (DMSO as solvent) from 400 mg (1.83 mmol) 4-(4-fluoro- benzyloxy)-1H-pyridin-2-one (preparation 10.1 ) and 626 mg (2.19 mmol) 2-bromo-1-[4-(1- hydroxy-ethyl)-phenyl]-ethanone (preparation 11.1a).

Yield: 415 mg (60% of theory); ESI Mass spectrum: [M+H] ⁺ = 382 Retention time HPLC: 1.62 min (method K).

Preparation 11.2

4-(4-Chloro-benzyloxy)-1 -{2-[4-(1 -hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one

4-(4-Chloro-benzyloxy)-1 -{2-[4-(1 -hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-1 /-/-pyridin-2-one is prepared as described for preparation 11.1b starting from 4-(4-chloro-benzyloxy)-1 /-/-pyridin- 2-one (preparation 10.2, 319 mg, 1.15 mmol). Yield: 0.50 g (48% of theory); ESI Mass spectrum: [M+H] ⁺ = 398 Retention time HPLC: 1.71 min (method K).

Preparation 11.3 1-{2-[4-(1-Hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-methoxy- benzyloxy)-1 H-pyridin-2-one

1-{2-[4-(1-Hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-methoxy- benzyloxy)-1H-pyridin-2-one is prepared as described for preparation 11.1b starting from 4-(4-methoxy-benzyloxy)-1 H- pyridin-2-one (preparation 10.7, 400 mg, 1.73 mmol). Yield: 0.47 g (69% of theory); ESI Mass spectrum: [M+H] ⁺ = 394 Retention time HPLC: 1.61 min (method K).

Preparation 12.1 1-{2-[4-(1-Bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-fluoro-ben zyloxy)-1/-/-pyridin-2-one

1-{2-[4-(1-Bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-fluoro- benzyloxy)-1/-/-pyridin-2-one is prepared following preparation 1c from 415 mg (1.09 mmol) 4-(4-fluoro-benzyloxy)-1-{2-[4-(1- hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-1/-/-pyridin-2-one (preparation 11.1) and 72 μl_ phosphoros tribromide (0.76 mmol).

Yield: 328 mg (68% of theory); ESI Mass spectrum: [M+H] ⁺ = 444/446

Retention time HPLC: 1.57 min (method J).

Preparation 12.2

1 -{2-[4-(1 -Bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-chloro-benzyloxy)-1 /-/-pyridin-2-one

1-{2-[4-(1-Bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-chloro-ben zyloxy)-1 /-/-pyridin-2-one is prepared following preparation 1c from 216 mg (0.54 mmol) 4-(4-chloro-benzyloxy)-1-{2-[4-(1- hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-1H-pyridin-2-one (preparation 11.2) and 36 μL phosphoros tribromide (0.38 mmol). Yield: 110 mg (44% of theory; 85% purity); ESI Mass spectrum: [M+H] ⁺ = 460/462/464

Retention time HPLC: 1.63 min (method J).

Preparation 12.3 1-{2-[4-(1-Bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-methoxy-be nzyloxy)-1/-/-pyridin-2-one

1 -{1 -{2-[4-(1 -Bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-methoxy-benzyloxy)-1 /-/-pyridin-2-one is prepared following preparation 1c from 472 mg (1.20 mmol) 1-{2-[4-(1-hydroxy-ethyl)-phenyl]- 2-oxo-ethyl}-4-(4-methoxy-benzyloxy)-1 H-pyridin-2-one (preparation 11.3) and 79 μl_ phosphoros tribromide (0.84 mmol). Yield: 241 mg (26% of theory; 60% purity); ESI Mass spectrum: [M+H] ⁺ = 456/458 Retention time HPLC: 1.56 min (method J).

Preparation 13

5-[2-(Toluene-4-sulfonyloxy)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

13a 5-(2-Hydroxy-ethyl)-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester To a solution of di-prop-2-ynyl-carbamic acid tert-butyl ester (1.91 g, 9.84 mmol) and 3-butin- 1-ol (3.00 mL, 39.5 mmol) in anhydrous EtOH is added chloro tris(triphenylphosphin) rhodium (I) (Wilkinson catalyst). Caution: In larger scale preparations (> 10 g) strong exothermia is observed. The reaction mixture is heated to reflux shortly. After cooling, the reaction mixture is purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH, 120 mL/min). Yield: 1.47 g (56% of theory); ESI Mass spectrum: [M+H] ⁺ = 264 Retention time HPLC: 1.39 min (method J).

13b 5-[2-(Toluene-4-sulfonyloxy)-ethyl]-1,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester At 0 ⁰ C ₁ a solution of 4-methylbenzenesulfonyl chloride (1.17 g, 6.14 mmol) in DCM (5 mL) is added dropwise to a stirred solution of 5-(2-hydroxy-ethyl)-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (preparation 13a, 1.47 g, 5.58 mmol) in DCM (15 mL) and pyridine (0.66 mL). The reaction mixture is stirred for 3 h at RT. An additional 0.12 g 4-

methylbenzenesulfonyl chloride plus 0.07 mL pyridine is added and the reaction mixture is stirred overnight. The reaction mixture is poured into ice water and extracted with dichloromethane. The organic layer is dried over MgSO ₄ and evaporated in vacuo. The remaining residue is purified chromatographically (silica gel, gradient from 20% to 50% ethyl acetate in cyclohexane).

Yield: 770 mg (33% of theory); ESI Mass spectrum: [M+NH ₄ ] ⁺ = 435 Retention time HPLC: 2.05 min (method K).

Preparation 14 5-[2-(4-Benzyloxy-2-oxo-2/-/-pyridin-1-yl)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

5-[2-(4-Benzyloxy-2-oxo-2/-/-pyridin-1 -yl)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester is prepared following preparation 1b (DMSO as solvent) from 174 mg (0.86 mmol) 4-benzyloxy-1/-/-pyridin-2-one and 360 mg (0.86 mmol) 5-[2-(toluene-4-sulfonyloxy)-ethyl]- 1 ,3-dihydro-isoindole-2-carboxylic acid terf-butyl ester (preparation 13). Yield: 350 mg (91% of theory); ESI Mass spectrum: [M+H] ⁺ = 447 Retention time HPLC: 1.92 min (method K).

Preparation 15

5-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin- 1-yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid te/t-butyl ester

5-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl] -ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester is prepared following preparation 1 b (DMSO as solvent) from 242 mg (0.86 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one (preparation 10.3) and 360 mg (0.86 mmol) 5-[2-(toluene-4-sulfonyloxy)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid fert-butyl ester (preparation 13). Yield: 120 mg (26% of theory); ESI Mass spectrum: [M+H] ⁺ = 526/528

Retention time HPLC: 1.87 min (method K).

Preparation 16

5-[2-(4-Benzyloxy-6-oxo-6A7-pyridazin-1-yl)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester

5-[2-(4-Benzyloxy-6-oxo-6H-pyridazin-1-yl)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid tert- butyl ester is prepared following preparation 1b (DMSO as solvent) from 174 mg (0.86 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 2) and 360 mg (0.86 mmol) 5-[2-(toluene-4- sulfonyloxy)-ethyl]-1 ,3-dihydro-isoindole-2-carboxylic acid fert-butyl ester (preparation 13). Yield: 360 mg (70% of theory); ESI Mass spectrum: [M+H] ⁺ = 448 Retention time HPLC: 2.01 min (method K).

Preparation 17 5-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1 -yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester

5-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin- 1-yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid fert-butyl ester is prepared following preparation 1b (DMSO as solvent) from 243 mg (0.86 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 10.3) and 360 mg (0.86 mmol) 5-[2-(toluene-4-sulfonyloxy)-ethyl]-1,3-dihydro-isoindole-2- carboxylic acid terf-butyl ester (preparation 13).

Yield: 180 mg (40% of theory); ESI Mass spectrum: [M+H] ⁺ = 527/529

Retention time HPLC: 1.95 min (method K).

Preparation 18

5-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-6-oxo-6A7-pyridazi n-1-yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid terf-butyl ester

S^-^^S-Chloro-pyridin^-ylmethoxyVβ-oxo-θH-pyridazin-i-y ll-ethylJ-I .S-dihydro-isoindole^- carboxylic acid fe/t-butyl ester is prepared following preparation 1b (DMSO as solvent) from 205 mg (0.86 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 10.4) and 360 mg (0.86 mmol) δ-p^toluene^-sulfonyloxyJ-ethylJ-I .S-dihydro-isoindole^-carboxylic acid tert-butyl ester (preparation 13).

Yield: 360 mg (87% of theory); ESI Mass spectrum: [M+H] ⁺ = 483/485 Retention time HPLC: 1.93 min (method K).

Preparation 19

4-Benzyloxy-1-{2-[3-methyl-2-(2 _l 2,2-trifluoro-acetyl)-1 ,2,3 _l 4-tetrahydro-isoquinolin-7-yl]-2-oxo- ethyl}-1 H-pyridin-2-one

19a N-[2-(4-Bromo-phenyl)-1 -methyl-ethyl]-2,2,2-trifluoro-acetamide To an ice-cooled solution of 2-(4-bromo-phenyl)-1-methyl-ethylamine (0.80 g, 3.74 mmol) in DCM (5 ml.) is added trifluoroacetic acid anhydride (0.57 mL, 4.11 mmol) and the reaction mixture is stirred for 1 h at RT. The reaction mixture is quenched with aqueous sodium bicarbonate solution and extracted twice with DCM. The organic layer is dried over MgSO ₄ and evaporated in vacuo. Yield: 1.2 g (quantitative); ESI Mass spectrum: [M+H] ⁺ = 310/312 Retention time HPLC: 0.92 min (method J).

19b 1-(7-Bromo-3-methyl-3,4-dihydro-1/-/-isoquinolin-2-yl)-2,2,2 -trifluoro-ethanone Under cooling, sulphuric acid (15 mL) is added to glacial acetic acid (23 mL). The mixture is allowed to warm to room temperature and N-[2-(4-bromo-phenyl)-1-methyl-ethyl]-2,2,2- trifluoro-acetamide (preparation 19a, 9.00 g, 29 mmol) is added. After 10 min, paraformaldehyde (1.50 g) is added and the reaction mixture is stirred for 18 h at 40 ⁰ C. Another portion of paraformaldehyde (1.50 g) is added and the reaction mixture is stirred for an additional 2 h at 40 ⁰ C. The reaction mixture is poured into ice water and extracted twice

with ethyl acetate. The organic layer is dried over MgSO ₄ and evaporated in vacuo. The resulting residue is purified chromatographically (silica gel, 20% ethyl acetate in hexanes). Yield: 6.7 g (72% of theory); ESI Mass spectrum: [M+H] ⁺ = 322/324 Retention time HPLC: 1.72 min (method J).

19c 1-(7-lodo-3-methyl-3,4-dihydro-1/-/-isoquinolin-2-yl)-2,2 _l 2-trifluoro-ethanone 1-(7-lodo-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr ifluoro-ethanone is prepared following preparation 9a from 1.00 g 1-(7-bromo-3-methyl-3,4-dihydro-1/-/-isoquinolin-2-yl)- 2,2,2-trifluoro-ethanone (preparation 19b, 3.10 mmol). Yield: 0.86 g (75% of theory); ESI Mass spectrum: [M+H] ⁺ = 370 Retention time HPLC: 1.80 min (method J).

19d 1 -[7-(2-Chloro-acetyl)-3-methyl-3,4-dihydro-1 /-/-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone To a solution of 1-(7-iodo-3-methyl-3,4-dihydro-1/-/-isoquinolin-2-yl)-2,2,2- trifluoro-ethanone (preparation 19c, 860 mg, 2.33 mmol) in anhydrous THF (20 mL) is added at -20 ⁰ C a solution of isopropylmagnesium chloride and lithium chloride ("Turbo Grignard", 1.79 mL of 14% solution in THF). After 10 min, the Grignard solution is added to a solution of 2-chloro-N- methoxy-N-methylacetamid (320 mg, 2.33 mmol) in THF (20 mL), keeping the temperature below 0 ⁰ C. After stirring for 30 min (temperature increases to 5°C), the reaction mixture is poured into pH 7 buffer and extracted with tert-butylmethylether. The organic layer is washed with water, dried over MgSO ₄ and concentrated in vacuo. Yield: 550 mg (74 % of theory); R _f value: 0.29 (silica gel, 30% ethyl acetate in hexanes).

19e 4-Benzyloxy-1 -{2-[3-methyl-2-(2,2,2-trif luoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2- oxo-ethyl}-1/-/-pyridin-2-one

4-Benzyloxy-1-{2-[3-methyl-2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo- ethyl}-1 /-/-pyridin-2-one is prepared following preparation 1 b from 350 mg (1.72 mmol) 4- benzyloxy-1H-pyridin-2-one and 550 mg (1.72 mmol) 1-[7-(2-chloro-acetyl)-3-methyl-3,4- dihydro-1/-/-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (preparation 19d), employing DMSO as solvent.

Yield: 80 mg (10% of theory); Retention time HPLC: 1.58 min (method J).

Preparation 20: 1-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin -2-ylmethoxy)-1H-pyridin-2-one

20a 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1 H-pyridin- 2-one

To 2.50 g (10.6 mmol) 4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 10.6) in 11 mL DMSO is added 8.6 g (26.4 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then, 3.75 g (16.4 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 1a) is added and the reaction mixture is stirred for 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.

Yield: 3.30 g (81 % of theory); ESI Mass spectrum: [M+H] ⁺ = 385/387 Retention time HPLC: 1.18 min (method J).

20b 1-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]^-(5-chloro-pyridin- 2-ylmethoxy)-1/-/-pyridin-2- one

1-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyri din-2-ylmethoxy)-1/-/-pyridin-2-one is prepared following preparation 1c from 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2-(4- hydroxymethyl-phenyl)-2-oxo-ethyl]-1/-/-pyridin-2-one (preparation 20a, 3.10 g, 8.06 mmol).

After cooling, the reaction mixture is quenched with aqueous sodium bicarbonate solution.

The organic layer is washed with water and dried over MgSO ₄ . The volatiles are removed in vacuo and the resulting residue is purified via preparative reverse HPLC chromatography (Gilson, Stable Bond C18, 7μm, gradient from 10% to 95% acetonitrile in water + 0.1%

HCOOH, 120 ml_/min).

Yield: 1.30 g (36% of theory); ESI Mass spectrum: [M+H] ⁺ = 447/449/451

Retention time HPLC: 1.08 min (method L).

Preparation 21 :

1-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyrid in-2-ylmethoxy)-1H-pyridin-2-one

21a 4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl )-2-oxo-ethyl]-1H-pyridin- 2-one

To 1.00 g (3.56 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 10.3) in 4 mL DMSO is added 2.90 g (8.90 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 0.82 g (3.60 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 1a) is added and the reaction mixture is stirred 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.

Yield: 1.30 g (64% of theory); ESI Mass spectrum: [M+H] ⁺ = 429/431 Retention time HPLC: 1.32 min (method J).

21b 1 -[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2 -ylmethoxy)-1 /-/-pyridin-2- one

1-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyrid in-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1c from 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(4- hydroxymethyl-phenyl)-2-oxo-ethyl]-1/-V-pyridin-2-one (preparation 21a, 1.30 g, 2.27 mmol).

After cooling, the reaction mixture is quenched with aqueous sodium bicarbonate solution. The organic layer is washed with water, dried over MgSO ₄ and concentrated in vacuo. The resulting solid is triturated with acetonitrile, the precipitate is filtered off and dried.

Yield: 670 mg (60% of theory); ESI Mass spectrum: [M+H] ⁺ = 491/493/495

Retention time HPLC: 1.49 min (method J).

Preparation 22

5-Benzyloxy-2-{2-[3-methyl-2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo- ethyl}-2H-pyridazin-3-one

5-Benzyloxy-2-{2-[3-methyl-2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo- ethyl}-2/-/-pyridazin-3-one is prepared following preparation 1b from 126 mg 5-benzyloxy-2H- pyridazin-3-one (preparation 2, 0.63 mmol) and 200 mg (0.63 mmol) 1-[7-(2-chloro-acetyl)-3- methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-etha none (preparation 19d), employing

DMSO as solvent.

Yield: 60 mg (20% of theory); Retention time HPLC: 1.63 min (method J).

Preparation 23

2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyri din-2-ylmethoxy)-2H-pyridazin-3- one

23a 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-pheny l)-2-oxo-ethyl]-2H- pyridazin-3-one

To 4.20 g (17.7 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 10.4) in 20 mL DMSO is added 14.4 g (44.2 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 4.45 g (19.4 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 1a) is added and the reaction mixture is stirred for 2 h at RT. Water is added, the precipitate is collected, washed with water and dried. Yield: 6.80 g (100% of theory); ESI Mass spectrum: [M+H] ⁺ = 386 Retention time HPLC: 1.18 min (method J).

23b 2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin -2-ylmethoxy)-2/-/-pyridazin-

3-one

2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyri din-2-ylmethoxy)-2/-/-pyridazin-3- one is prepared following preparation 1c from 5-(5-chloro-pyridin-2-ylmethoxy)-2-[2-(4- hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 23a, 6.80 g, 17.6 mmol).

After cooling, the reaction mixture is treated with diisopropyl ether. The formed precipitate is filtered off and dried. The solid is dissolved in DCM and small amounts of MeOH, filtered over aluminium oxide and the filtrated is concentrated in vacuo. Yield: 5.50 g (70% of theory); ESI Mass spectrum: [M+H] ⁺ = 448/450/452

Retention time HPLC: 1.08 min (method L).

Preparation 24

2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyrid in-2-ylmethoxy)-2H-pyridazin-3- one

24a 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl )-2-oxo-ethyl]-2H- pyridazin-3-one

To 500 mg (1.77 mmol) 5-(5-bromo-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 10.5) in 2 mL DMSO is added 1.44 g (4.42 mmol) cesium carbonate and the mixture is stirred

15 min at RT. Then 406 mg (1.77 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 1a) is added and the reaction mixture is stirred for 2 h at RT. Water is added, the precipitate is collected, washed with water and dried. Yield: 600 mg (71% of theory); ESI Mass spectrum: [M+H] ⁺ = 430/432 Retention time HPLC: 1.36 min (method J).

24b 2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin- 2-ylmethoxy)-2/-/-pyridazin-

3-one

2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin- 2-ylmethoxy)-2H-pyridazin-3- one is prepared following preparation 1c from 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(4- hydroxymethyl-phenyl)-2-oxo-ethyl]-2/-/-pyridazin-3-one (preparation 24a, 600 mg, 1.40 mmol). After cooling, the reaction mixture is quenched with aqueous sodium bicarbonate solution. The organic layer is washed with water, dried over MgSO ₄ and concentrated in vacuo. The resulting solid is triturated with acetonitrile, the precipitate is filtered off and dried. Yield: 688 mg (73% of theory); ESI Mass spectrum: [M+H] ⁺ = 492/494/496 Retention time HPLC: 1.56 min (method J).

Preparation 25

5-Benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2 _I 3,4-tetrahydro-isoquinolin-7-yl]-ethyl}- 2H-pyridazin-3-one

5-Benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-t etrahydro-isoquinolin-7-yl]-ethyl}- 2/-/-pyridazin-3-one is prepared following preparation 1b (DMSO as solvent) from 2.02 g (10.0 mmol) 5-benzyloxy-2/-/-pyridazin-3-one (preparation 2) and 3.21 g (10.0 mmol) 1-[7-(2-chloro- acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-eth anone (prepared according to WO2005/66165). Water is added to the reaction mixture and the formed precipitate is filtered off. The crude material is purified via reverse HPLC chromatography (Gilson; Stablebond C18; water (0.15% formic acid) / acetonitrile (0.15% formic acid) 95:5 to 5:95; 120 mL/min). Yield: 2.50 g (53% of theory); ESI Mass spectrum: [M+H] ⁺ = 472 Retention time HPLC: 1.56 min (method J).

Preparation 26:

6-[2-(Toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert-butyl ester

26a 6-lodo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester To 13.0 g (41.6 mmol) 6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid /erf-butyl ester in 42 mL 1 ,4-dioxane is added 817 mg (4.21 mmol) copper(l)-iodide under argon. After flushing with argon, 0.89 mL (8.33 mmol) λ/,λ/-dimethylethylen-diamine and 12.5 g (83.3 mmol) sodium iodide is added at RT. The reaction mixture is stirred 14 h at 110°C, is cooled to RT and is diluted with 5% aqueous ammonia-solution. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water and is dried over MgSO ₄ , filtered and the solvent is evaporated to give the product. Yield: 14.0 g (94% of theory); EII Mass spectrum: [M] ⁺ = 359 R _f -value: 0.8 (silica gel, mixture C).

26b 6-(2-Hydroxy-ethyl)-3,4-dihydro-1/-/-isoquinoline-2-carboxyl ic acid tert-butyl ester

To 1.80 g (5.00 mmol) 6-iodo-3,4-dihydro-1/-/-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 26a) in 5.0 mL THF at -20 ⁰ C is added 6.34 g (5.50 mmol) of a THF-solution of 14% isopropylmagnesium-chloride ^* lithiumchloride under argon. The mixture is warmed to 0 ⁰ C and stirred 1 h at 0 ⁰ C. The reaction mixture is cooled to -6O ⁰ C and 0.88 g (20.0 mmol) oxirane in 2.0 mL THF is added. The cooling bath is removed and the reaction is warmed to RT. The reaction mixture is poured into 50 mL aqueous ammonium chloride solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO ₄ . After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95). Yield: 47% of theory; R _r value: 0.4 (silica gel, mixture D).

26c 6-[2-(Toluene^-sulfonyloxy)-ethyl]-3,4-dihydro-1/-/-isoquino line-2-carboxylic acid tert- butyl ester

To 1.60 g (5.76 mmol) 6-(2-hydroxy-ethyl)-3,4-dihydro-1/-/-isoquinoline-2-carboxyl ic acid tert- butyl ester (preparation 26b) in 20 mL DCM is added at O ⁰ C subsequently 0.68 mL (8.66 mmol) pyridine and 1.21 g (6.34 mmol) 4-methyl-benzenesulfonyl chloride in 10.0 mL DCM. The reaction mixture is warmed to RT and is stirred 5 h at RT. Additional 0.68 mL (8.66 mmol) pyridine and 1.21 g (6.34 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM are added and the mixture is stirred overnight. The reaction mixture is poured into ice-water and the organic phase is separated, washed with aqueous KHSO ₄ -solution and aqueous

NaHC0 ₃ -solution, dried over MgSO ₄ . After evaporation of the solvent, the residue is purified via chromatography (silica gel; cyclohexane/EtOAc 8:2 to 1 :1 ). Yield: 1.30 g (52% of theory); ESI Mass spectrum: [M+NH ₄ ] ⁺ = 449 R _f -value: 0.4 (silica gel, mixture C).

Preparation 27

7-[2-(Toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid fert-butyl ester

27a 7-Bromo-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester To 10.0 g (40.2 mmol) 7-bromo-1 ,2,3,4-tetrahydro-isoquinoline hydrochloride in 250 mL DCM and 50 mL (101 mmol) 2M aqueous Na ₂ CO ₃ -solution is added a solution of 9.27 g (42.5 mmol) BOC-anhydride in DCM. The reaction is stirred 1 h at RT and is diluted with 100 mL water. The organic phase is washed with water, dried over MgSO ₄ , filtered and the solvent is evaporated. To the residue is added PE and the mixture is cooled to -30 ⁰ C. The precipitate is collected, washed with cold PE and dried.

Yield: 10.3 g (82% of theory); ESI Mass spectrum: [M+H] ⁺ = 312/314 Rf-value: 0.5 (silica gel, mixture C).

27b 7-lodo-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester To 11.0 g (35.2 mmol) 7-bromo-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester (preparation 27a) in 35 mL 1 ,4-dioxane is added 692 mg (3.56 mmol) copper(l)-iodide under argon. After flushing with argon, 0.75 mL (7.05 mmol) λ/,λ/-dimethylethylen-diamine and 10.6 g (70.5 mmol) sodium-iodide is added at RT. The reaction mixture is stirred 14 h at 110 ⁰ C, cooled to RT and diluted with 5% aqueous ammonia-solution. The aqueous phase is extracted with EtOAc and the combined organic phase is washed with water, dried over MgSO ₄ . After filtration and evaporation of the solvent, the residue is purified via chromatography (silica gel; Cyclohexane/EtOAc 85/15). Yield: 10.8 g (purity 75% (contains compound 27a), 78% of theory) ESI Mass spectrum: [M+H] ⁺ = 360; Rf-value: 0.6 (silica gel, mixture F).

27c 7-(2-Hydroxy-ethyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid fert-butyl ester

To 1.80 g (5.00 mmol) 7-iodo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid terf-butyl ester (preparation 27b) in 5.0 mL THF at -20 ⁰ C is added 6.34 g (5.50 mmol) of a THF-solution of 14% isopropylmagnesium-chlorideTithiumchloride under argon. The mixture is warmed to O ⁰ C and stirred 1 h at O ⁰ C. The reaction mixture is cooled to -60 ⁰ C and 0.88 g (20.0 mmol) oxirane in 2.0 mL THF is added. The cooling bath is removed and the reaction is warmed to RT. The reaction mixture is poured into 50 mL aqueous ammonium chloride solution and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with water, dried over MgSO ₄ . After filtration and evaporation of the solvent, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).

Yield: 800 mg (58% of theory); ESI Mass spectrum: [M+H] ⁺ = 278 Retention time HPLC: 2.6 min (method E).

27d 7-[2-(Toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinol ine-2-carboxylic acid tert- butyl ester

To 800 mg (2.88 mmol) 7-(2-hydroxy-ethyl)-3,4-dihydro-1/-/-isoquinoline-2-carboxyl ic acid tert- butyl ester (preparation 27c) in 10 mL DCM is added at 0 ⁰ C subsequently 0.34 mL (4.33 mmol) pyridine and 605 mg (3.17 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM. The reaction mixture is warmed to RT and is stirred 5 h at RT. Additional 0.34 mL (4.33 mmol) pyridine and 605 mg (3.17 mmol) 4-methyl-benzenesulfonyl chloride in 5.0 mL DCM are added and the mixture is stirred over night. The reaction mixture is poured into ice-water and the organic phase is separated, washed with aqueous KHSO ₄ -solution and aqueous NaHCO ₃ -solution, dried over MgSO ₄ . After evaporation of the solvent, the residue is purified via chromatography (silica gel; cyclohexane/EtOAc 8:2 to 1 :1 ). Yield: 1.10 g (88% of theory); ESI Mass spectrum: [M+H] ⁺ = 432 Rf-value: 0.4 (silica gel, method F).

Preparation 28

5-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1 -yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid fert-butyl ester

5-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1 -yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester is prepared following preparation 1b (DMSO as solvent) from

400 mg (1.69 mmol) 4-(5-chloro-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one (preparation 10.6) and 706 mg (1.69 mmol) δ-p^toluene^-sulfonyloxyJ-ethyll-I .S-dihydro-isoindole^-carboxylic acid tert-butyl ester (preparation 13).

Yield: 460 mg (57% of theory); ESI Mass spectrum: [M+H] ⁺ = 482/484 Retention time HPLC: 1.84 min (method K).

Preparation 29

5-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin -1-yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid terf-butyl ester

5-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1 -yl]-ethyl}-1 ,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester is prepared following preparation 1 b (DMSO as solvent) from 300 mg (1.36 mmol) 4-(5-fluoro-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one (preparation 10.11) and 569 mg (1.36 mmol) S-β-ftoluene^-sulfonyloxyJ-ethyll-I .S-dihydro-isoindole^-carboxylic acid tert-butyl ester (preparation 13).

Yield: 340 mg (54% of theory); ESI Mass spectrum: [M+H] ⁺ = 466 Retention time HPLC: 1.57 min (method J).

Preparation of example compounds of the invention:

Example 1.1

4-Benzyloxy-1-{2-[4-(4-methoxy-4-methyl-piperidin-1-ylmet hyl)-phenyl]-2-oxo-ethyl}-1H- pyridin-2-one

To 247 mg (0.60 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-ethyl]-1/-/-pyridin- 2-one (preparation 1) in 2.00 mL of DMF is added 194 mg (1.50 mmol) 4-methoxy-4-methyl- piperididine. The reaction mixture is stirred for 18 h at RT and is directly purified by HPLC (Stable Bond C 18; 7 μm; water (0.1% formic acid) / acetonitrile (0.1% formic acid) 95:5 to 10:90). Yield: 105 mg (38% of theory)

ESI Mass spectrum: [M+H] ⁺ = 461 Retention time HPLC: 1.77 min (method K).

The following examples are prepared as described for Example 1.1. For the preparation of example 1.7, 4 equivalents of triethylamine are added to the reaction mixture. For the preparation of example 1.12 and 1.13, the hydrochloride salt of the amine reagent plus 5 equivalents of Hϋnig's base (N-ethyl-diisopropylamine) are employed.

Example 1.20

4-Benzyloxy-1-[2-(4-{[(2,2-difluoro-ethyl)-methyl-amino]- methyl}-phenyl)-2-oxo-ethyl]-1H- pyridin-2-one

To 100 mg (0.24 mmol) 4-benzyloxy-1-(2-{4-[(2,2-difluoro-ethylamino)-methyl]-pheny l}-2-oxo- ethyl)-1 H-pyridin-2-one (example 1.19) in 5 mL THF is added 79 μl_ (0.97 mmol) 37% aqueous formaldehyde solution and 103 mg (0.49 mmol) sodium triacetoxy-borohydride. The mixture is acidified with pH 5 buffer solution (1 mL) and stirred for 48 h at RT. The reaction mixture is quenched with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer is dried over MgSO ₄ and concentrated in vacuo. The resulting residue is purified via preparative reverse HPLC chromatography (Zorbax Stable Bond C18, 7 μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH ₁ 120 ml_/min). Yield: 50 mg (48% of theory) ESI Mass spectrum: [M+H] ⁺ = 427 Retention time HPLC: 1.26 min (method J).

Examples 1.21 and 1.22 are prepared as described for Example 1.20, starting from examples 1.9 and 1.7, respectively.

Example 2.1 5-Benzyloxy-2-{2-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-2 -oxo-ethyl}-2H-pyridazin-3-one

To 500 mg (1.21 mmol) 5-benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2/-/-py ridazin- 3-one (preparation 3) in 10 mL of DMF is added 415 mg (3.63 mmol) 1-ethylpiperazine. The reaction mixture is stirred for 18 h at RT and is directly purified by HPLC (Waters Symmetry C18; 7 μm; water (0.1% formic acid) / acetonitrile (0.1% formic acid) 95:5 to 10:90). Yield: 280 mg (52% of theory) ESI Mass spectrum: [M+H] ⁺ = 447 Retention time HPLC: 2.90 min (method C).

The following examples are prepared as described for Example 2.1.

The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1-[2-(4-bromomethyl-3-methoxy-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one (preparation 5).

The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1-[2-(4-bromomethyl-2-fluoro-phenyl)-2-oxό-ethyl]-1H-pyridi n-2-one (preparation 4).

The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1 -[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one (preparation 6).

The following examples are prepared as described for Example 2.1 starting from 5-benzyloxy- 2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-2H-pyridaz in-3-one (preparation 7).

The following examples are prepared as described for Example 1.1 starting from 4-benzyloxy- 1 -[2-(5-bromomethyl-pyridin-2-yl)-2-oxo-ethyl]-1 H-pyridin-2-one (preparation 9).

The following examples are prepared as described for Example 1.1 starting from 1-{2-[4-(1- bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-fluoro-benzyloxy)-1 H-pyridin-2-one (preparation 12.1 , R ³ = F), 1-{2-[4-(1-bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-chloro-ben zyloxy)-1 /-/-pyridin-2-one (preparation 12.2, R ³ = Cl) and 1-{2-[4-(1-bromo-ethyl)-phenyl]-2-oxo-ethyl}-4-(4-methoxy- benzyloxy)-1 H-pyridin-2-one (preparation 12.3, R ³ = MeO).

The following examples are prepared as described for Example 1.1 starting from 1-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmet hoxy)-1 /-/-pyridin-2-one (preparation 20).

The following examples are prepared as described for Example 1.1 starting from 2-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmet hoxy)-2/-/-pyridazin-3-one (preparation 23).

The following examples are prepared as described for Example 1.1 starting from 1-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmeth oxy)-1 H-pyridin-2-one (preparation 21 ).

The following examples are prepared as described for Example 1.1 starting from 2-[2-(4- bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-bromo-pyridin-2-ylmeth oxy)-2/-/-pyridazin-3-one (preparation 24).

Example 13.1:

4-Benzyloxy-1-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2 _l 3,4-tetrahydro-isoquinolin-7-yl]-ethyl}- 1 H-pyridin-2-one

To 600 mg (2.98 mmol) 4-benzyloxy-1/-/-pyridin-2-one in 6 mL THF is added at 0 ⁰ C 368 mg (3.28 mmol) potassium terf-butylate and 55 mg (0.15 mmol) te/t-butylammonium iodide. After 5 min 1.00 g (3.28 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1/-/-isoquinolin-2-yl]-2, 2,2-trifluoro- ethanone (prepared according to WO2005/66165) is added. After 2 h additional 600 mg (1.97 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2, 2-trifluoro-ethanone is added and the mixture is stirred an additional hour. The reaction mixture is diluted with EtOAc and the organic phase is washed with water, filtered, dried over MgSO ₄ and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond; water (0.15% formic acid)/acetonitrile (0.15% formic acid) 95:5 to 5:95). Yield: 600 mg (43% of theory) ESI Mass spectrum: [M+H] ⁺ = 471 Retention time HPLC: 3.9 min (method A).

Example 13.2

1 -[2-(2-Acetyl-1 ,2, 3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-4-benzyloxy-1 H-pyridin-2-one

13.2a 4-Benzyloxy-1 -[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin-2-one

To 600 mg (1.28 mmol) 4-benzyloxy-1-{2-oxo-2-[2-(2 _I 2 _l 2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-1 H-pyridin-2-one (example 13.1) in 20 mL MeOH is added 10.6 mL (10.6 mmol) aqueous 1 M sodium hydroxide solution. The reaction mixture is stirred 3 h at RT. The solvent is evaporated and the residue is triturated with a small amount of water. The formed precipitate is filtered off, washed with water and dried in vacuo. Yield: 220 mg (46% of theory) ESI Mass spectrum: [M+H] ⁺ = 375 Retention time HPLC: 1.04 min (method J).

13.2b 1-[2-(2-Acetyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-4-benzyloxy -1 H-pyridin- 2-one

To a solution of 4-benzyloxy-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin- 2-one (example 13.2a, 75 mg, 0.20 mmol) in acetic acid (1 mL) is added acetic anhydride (47 μl_, 0.50 mmol). After stirring for 1 h at room temperature, the reaction mixture is quenched with water and adjusted to basic pH with concentrated aqueous ammonia solution. The mixture is extracted with DCM ₁ the organic layer is dried over MgSO ₄ and concentrated in vacuo.

Yield: 62 mg (74% of theory) ESI Mass spectrum: [M+H] ⁺ = 417 Retention time HPLC: 1.27 min (method J).

Example 14.1

4-Benzyloxy-1 -{2-[2-(2-hydroxy-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo-ethyl}-1 H- pyridin-2-one

To a solution of 4-benzyloxy-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin- 2-one (example 13.2a, 780 mg, 2.08 mmol) in ethanol is added potassium carbonate (575 mg, 4.00 mmol) and the mixture is stirred for 10 min at 60 ⁰ C. Then chloroethanol (168 μL, 2.00 mmol) is added and the reaction mixture is stirred at 60 ⁰ C. After 2 h and 4 h, more chloroethanol (168 μL, 2.00 mmol) is added and the reaction mixture is left stirring overnight at 50 ⁰ C. The reaction mixture is concentrated under reduced pressure, triturated with DCM and filtered. The filtrate is concentrated in vacuo and purified chromatographically (silica gel, 10% MeOH in DCM). Yield: 330mg (38% of theory) ESI Mass spectrum: [M+H] ⁺ = 419 Retention time HPLC: 1.10 min (method J).

Example 14.2 4-Benzyloxy-1-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1/-/-pyridi n-2-one

To 2.00 g (5.34 mmol) 4-benzyloxy-1-[2-oxo-2-(1,2,3,4-tetrahydro-isoquinolin-7-yl) -ethyl]-1/-/- pyridin-2-one (example 13.2a) in 25 mL THF is added 332 μL (5.88 mmol) acetaldehyde and

1.36 g (6.41 mmol) sodium triacetoxy-borohydride. The mixture is acidified with pH 5 buffer solution (10 ml_) and stirred 48 h at RT. The reaction mixture is quenched with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer is dried over MgSO ₄ and concentrated in vacuo. The resulting residue is purified via preparative reverse HPLC chromatography (Zorbax Stable Bond C18, 7μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH, 120 mL/min). Yield: 1.30 g (61 % of theory) ESI Mass spectrum: [M+H] ⁺ = 403 Retention time HPLC: 1.10 min (method J).

Example 15.1 5-Benzyloxy-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyrida zin-3-one

15.1a 5-Benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one 5-Benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one is prepared following example 13.2a from 5-benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-

1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-2/-/-pyridazin-3- one (preparation 25, 1.40 g, 2.97 mmol).

Yield: 550 mg (49% of theory) ESI Mass spectrum: [M+H] ⁺ = 376

Retention time HPLC: 1.05 min (method J).

15.1b 5-Benzyloxy-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2H-pyridazi n-

3-one 5-Benzyloxy-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyrida zin-3-one is prepared following example 14.2 from 5-benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro- isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-one (example 15.1a, 187 mg, 0.50 mmol).

Yield: 50 mg (25% of theory)

ESI Mass spectrum: [M+H] ⁺ = 404 Retention time HPLC: 1.13 min (method J).

Example 15.2

5-Benzyloxy-2-{2-[2-(2-hydroxy-ethyl)-1 _l 2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo-ethyl}-2H- pyridazin-3-one

5-Benzyloxy-2-{2-[2-(2-hydroxy-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo-ethyl}-2/-/- pyridazin-3-one is prepared following the procedure for the preparation of example 14.1 from 5-benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one (example 15.1a, 113 mg, 0.30 mmol). The crude product is purified via preparative reversed phase HPLC (Zorbax Stable Bond C18, 7μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH, 120 mL/min). Yield: 55 mg (44% of theory)

ESI Mass spectrum: [M+H] ⁺ = 420 Retention time HPLC: 1.65 min (method J).

Example 16.1 4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H- pyridin-2-one

16.1a 4-(5-Chloro-pyridin-2-ylmethoxy)-1-{2-oxo-2-[2-(2,2,2-triflu oro-acetyl)-1 ,2,3,4- tetrahydro-isoquinolin-7-yl]-ethyl}-1 H-pyridin-2-one 4-(5-Chloro-pyridin-2-ylmethoxy)-1-{2-oxo-2-[2-(2,2,2-triflu oro-acetyl)-1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-1 /-/-pyridin-2-one is prepared following preparation 1b from 700 mg

(2.96 mmol) 4-(5-chloro-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one (preparation 10.6) and 904 mg

(2.96 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2, 2-trifluoro-ethanone, employing DMSO as solvent. Yield: 1.2 g (80% of theory)

ESI Mass spectrum: [M+H] ⁺ = 506/508

Retention time HPLC: 1.46 min (method J).

16.1b 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 _l 2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H- pyridin-2-one is prepared following example 13.2a from 4-(5-chloro-pyridin-2-ylmethoxy)-1-{2- oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2 _l 3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-1/-/-pyridin-2-one

(example 16.1a, 1.20 g, 2.37 mmol).

Yield: 800 mg (82% of theory)

ESI Mass spectrum: [M+H] ⁺ = 410/412

Retention time HPLC: 1.07 min (method J).

Example 16.2 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo- ethyl]-1 /-/-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo- ethyl]-1 /-/-pyridin-2-one is prepared following example 14.2 from 4-(5-chloro-pyridin-2- ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin-2-one (example

16.1a, 200 mg, 0.49 mmol) and 79 μL 37% aqueous formaldehyde solution instead of acetaldehyde.

Yield: 130 mg (63% of theory)

ESI Mass spectrum: [M+H] ⁺ = 424/426

Retention time HPLC: 1.53 min (method K).

The following examples are prepared as described for Example 16.2 starting from 4-(5- chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin- 2-one (example 16.1a), employing the corresponding aldehyde in the reductive amination step.

Example 17.1

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo- ethyl]-2/-/-pyridazin-3-one

17.1a 5-(5-Chloro-pyridin-2-ylmethoxy)-2-{2-oxo-2-[2-(2,2 _l 2-trifluoro-acetyl)-1 ,2,3,4- tetrahydro-isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one

5-(5-Chloro-pyridin-2-ylnnethoxy)-2-{2-oxo-2-[2-(2,2,2-tr ifluoro-acetyl)-1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one is prepared following preparation 1b from 700 mg

(2.95 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10.4) and 900 mg (2.95 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1/-/-isoquinolin-2-yl]-2, 2,2-trifluoro- ethanone, employing DMSO as solvent.

Yield: 1.40 g (94% of theory) ESI Mass spectrum: [M+H] ⁺ = 507/509

Retention time HPLC: 1.52 min (method J).

17.1b 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-oxo-2-(1,2,3,4-tetrahy dro-isoquinolin-7-yl)-ethyl]-

2/-/-pyridazin-3-one

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H- pyridazin-3-one is prepared following example 13.2a from 5-(5-chloro-pyridin-2-ylmethoxy)-2-

{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-2/-/-pyridazin-3- one (example 17.1a, 1.40 g, 2.76 mmol).

Yield: 800 mg (71% of theory)

ESI Mass spectrum: [M+H] ⁺ = 411/413

Retention time HPLC: 1.09 min (method J).

17.1c S^S-Chloro-pyridin^-ylmethoxy^-^^-ethyl-I ^.S^-tetrahydro-isoquinolin-T-yl)^- oxo-ethyl]-2H-pyridazin-3-one

S^S-Chloro-pyridin^-ylmethoxy^-^^-ethyl-I ^.S^-tetrahydro-isoquinolin-y-yO^-oxo- ethyl]-2/-/-pyridazin-3-one is prepared following example 14.2 from 5-(5-chloro-pyridin-2- ylmethoxy)-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one

(example 17.1b, 200 mg, 0.49 mmol).

Yield: 80 mg (37% of theory)

ESI Mass spectrum: [M+H] ⁺ = 439/441

Retention time HPLC: 1.65 min (method K).

The following examples are prepared as described for Example 17.1 starting from 5-(5- chloro-pyridin-2-ylmethoxy)-2-[2-oxo-2-(1,2,3,4-tetrahydro-i soquinolin-7-yl)-ethyl]-2/-/- pyridazin-3-one (example 17.1b), employing 1-propanal (R = n-propyl) or acetone (R = /- propyl) instead of acetaldehyde in the reductive amination step.

Example 18.1 4-Benzyloxy-1 -[2-(2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-1 W-pyridin-2-one

To a stirred solution of 5-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-1 ,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (preparation 14, 180 mg, 0.40 mmol) in DCM (10 mL) is added

TFA (0.31 rriL, 4.03 mmol). After stiring for 5 h at 40 ⁰ C ₁ the volatiles are removed in vacuo. The resulting residue is purified via preparative reverse HPLC chromatography (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.1% HCOOH ₁ 120 mL/min). Yield: 105 mg (75% of theory) ESI Mass spectrum: [M+H] ⁺ = 347 Retention time HPLC: 1.61 min (method K).

Example 18.2 4-Benzyloxy-1-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-eth yl]-1/-/-pyridin-2-one

To 90 mg (0.26 mmol) 4-benzyloxy-1-[2-(2,3-dihydro-1A7-isoindol-5-yl)-ethyl]-1H-p yridin-2-one

(example 18.1 ) in 5 mL THF is added 31 μL 37% aqueous formaldehyde solution (0.39 mmol) and 83 mg (0.39 mmol) sodium triacetoxy-borohydride. The mixture is acidified with pH 5 buffer solution (2 mL) and stirred 48 h at RT. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified via preparative reverse HPLC chromatography (Gilson; basisch; XBridge; Standard; 120 mL/min).

Yield: 71 mg (76% of theory)

ESI Mass spectrum: [M+H] ⁺ = 361 Retention time HPLC: 1.65 min (method K).

Example 19.1

4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-1 H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(2,3-dihydro-1H-isoindo l-5-yl)-ethyl]-1H-pyridin-2-one is prepared following example 18.1 from 5-{2-[4-(5-bromo-pyridin-2-ylmethoxy)-2-oxo-2A7- pyridin-1-yl]-ethyl}-1 ,3-dihydro-isoindole-2-carboxylic acid terf-butyl ester (preparation 15, 120 mg, 0.23 mmol). Yield: 80 mg (82% of theory) ESI Mass spectrum: [M+H] ⁺ = 426/428

Retention time HPLC: 1.55 min (method K).

Example 19.2

4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-1 H- pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-1 H- pyridin-2-one is prepared following example 18.2 from 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2- (2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-1 /-/-pyridin-2-one (example 19.1, 60 mg, 0.14 mmol). Yield: 23 mg (37% of theory)

ESI Mass spectrum: [M+H] ⁺ = 440/442 Retention time HPLC: 1.58 min (method K).

Example 20.1 5-Benzyloxy-2-[2-(2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-py ridazin-3-one

5-Benzyloxy-2-[2-(2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-2/-/-pyridazin-3-one is prepared following example 18.1 from 5-[2-(4-benzyloxy-6-oxo-6/-/-pyridazin-1-yl)-ethyl]-1 ,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (preparation 16, 360 mg, 0.60 mmol). Yield: 140 mg (67% of theory) ESI Mass spectrum: [M+H] ⁺ = 348 Retention time HPLC: 2.11 min (method H).

Example 20.2

5-Benzyloxy-2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)- ethyl]-2/-/-pyridazin-3-one

5-Benzyloxy-2-[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-one is prepared following the procedure for the preparation of example 18.2 from 5-benzyloxy-2-[2- (2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-one (example 20.1 , 100 mg, 0.29 mmol). Yield: 46 mg (44% of theory) ESI Mass spectrum: [M+H] ⁺ = 362 Retention time HPLC: 1.73 min (method K).

Example 21.1 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2,3-dihydro-1H-isoindo l-5-yl)-ethyl]-2/-/-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2,3-dihydro-1/-/-is oindol-5-yl)-ethyl]-2A7-pyridazin-3-one is prepared following example 18.1 from 5-{2-[4-(5-bromo-pyridin-2-ylmethoxy)-6-oxo-6H- pyridazin-1-yl]-ethyl}-1 ,3-dihydro-isoindole-2-carboxylic acid fe/t-butyl ester (preparation 17, 180 mg, 0.34 mmol). Yield: 130 mg (89% of theory)

ESI Mass spectrum: [M+H] ⁺ = 427/429 Retention time HPLC: 1.61 min (method K).

Example 21.2 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-2/-/- pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-2,3-dihydr o-1H-isoindol-5-yl)-ethyl]-2H- pyridazin-3-one is prepared following example 18.2 from 5-(5-Bromo-pyridin-2-ylmethoxy)-2- [2-(2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-one (example 21.1 , 100 mg, 0.23 mmol).

Yield: 72 mg (70% of theory)

ESI Mass spectrum: [M+H] ⁺ = 441/443

Retention time HPLC: 1.65 min (method K).

Example 21.3

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-2 _l 3-dihydro-1H-isoindol-5-yl)-ethyl]-2/-/- pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-2,3-dihydro-1/ -/-isoindol-5-yl)-ethyl]-2/-/- pyridazin-3-one is prepared following example 18.2 from 5-(5-bromo-pyridin-2-ylmethoxy)-2- [2-(2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-one (example 21.1, 136 mg, 0.32 mmol) and acetaldehyde (27 μl_, 0.48 mmol). Yield: 13 mg (9% of theory) ESI Mass spectrum: [M+H] ⁺ = 455/457

Retention time HPLC: 1.73 min (method K).

Example 21.4

5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl) -2,3-dihydro-1H-isoindol-5-yl]- ethyl}-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl)-2, 3-dihydro-1W-isoindol-5-yl]- ethyl}-2H-pyridazin-3-one is prepared following the procedure for the preparation of example 14.1 from 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(2,3-dihydro-1/-/-isoin dol-5-yl)-ethyl]-2H- pyridazin-3-one (example 21.1 , 136 mg, 0.32 mmol). Yield: 30 mg (20% of theory) ESI Mass spectrum: [M+H] ⁺ = 471/473 Retention time HPLC: 2.64 min (method C).

Example 21.5

5-(5-Bromo-pyhdin-2-ylmethoxy)-2-[2-(2-isopropyl-2,3-dihy dro-1H-isoindol-5-yl)-ethyl]-2A7- pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-isopropyl-2,3-dihydr o-1/-/-isoindol-5-yl)-ethyl]-2H- pyridazin-3-one is prepared following the procedure for the preparation of example 14.1 (acetonitrile as solvent instead of ethanol) from 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(2,3- dihydro-1H-isoindol-5-yl)-ethyl]-2/-/-pyridazin-3-one (example 21.1 , 136 mg, 0.32 mmol) and isopropyl bromide (60 μl_, 0.64 mmol) as alkylating agent instead of chloroethanol. Yield: 5 mg (5% of theory) ESI Mass spectrum: [M+H) ⁺ = 469/471 Retention time HPLC: 2.80 min (method C).

Example 22.1 5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2,3-dihydro-1H-isoind ol-5-yl)-ethyl]-2H-pyridazin-3-one

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2,3-dihydro-1/-/-i soindol-5-yl)-ethyl]-2H-pyridazin-3-one is prepared following example 18.1 from 5~{2-[4-(5-chloro-pyridin-2-ylmethoxy)-6-oxo-6/-/- pyridazin-1-yl]-ethyl}-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (preparation 18,

360 mg, 0.75 mmol).

Yield: 190 mg (67% of theory)

ESI Mass spectrum: [M+H] ⁺ = 383/385 Retention time HPLC: 1.58 min (method K).

Example 22.2

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-2,3-dihyd ro-1A7-isoindol-5-yl)-ethyl]-2/-/- pyridazin-3-one

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-2,3-dihyd ro-1H-isoindol-5-yl)-ethyl]-2H- pyridazin-3-one is prepared following example 18.2 from 5-(5-chloro-pyridin-2-ylmethoxy)-2-

[2-(2,3-dihydro-1H-isoindol-5-yl)-ethyl]-2H-pyridazin-3-o ne (example 22.1 , 140 mg, 0.37 mmol).

Yield: 100 mg (69% of theory) ESI Mass spectrum: [M+H] ⁺ = 397/399 Retention time HPLC: 1.63 min (method K).

Example 23

4-Benzyloxy-1 -{2-[4-(1 -dimethylaminomethyl-cyclopropyl)-phenyl]-2-oxo-ethyl}-1 /-/-pyridin-2- one

23a 1 -(4-Bromo-phenyl)-cyclopropanecarbaldehyde

A solution of 1-(4-bromo-phenyl)-cyclopropanecarbonitrile (500 mg) in diethyl ether (15 mL) is cooled to -10 ⁰ C. Then, a solution of DIBAL (1.2 M in toluene, 2.44 mL, 2.93 mmol) is added in dropwise fashion. The reaction mixture is stirred for 2 h between -10 ⁰ C and 5°C, quenched by addition of 1 N aqueous HCI (6 mL) and extracted twice with ethyl acetate. The combined organic layer is washed with water, dried over MgSO ₄ and concentrated under reduced pressure.

Yield: 450 mg (89% of theory)

ESI Mass spectrum: [M+H] ⁺ = 224/226 Retention time HPLC: 1.52 min (method J).

23b [1-(4-Bromo-phenyl)-cyclopropylmethyl]-dimethyl-amine

To a solution of 450 mg (2.00 mmol) 1-(4-bromo-phenyl)-cyclopropanecarbaldehyde

(example 23a) in 15 mL THF is added 1.2 mL of a solution of dimethylamine in THF (2M, 2.40 mmol), 137 μL glacial acetic acid (137 μL, 2.40 mmol) and sodium triacetoxyborohydride (508 mg, 2.40 mmol). The mixture is stirred for 48 h at RT, quenched with aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer is dried over MgSO ₄ and concentrated in vacuo. The resulting residue is purified via preparative reverse HPLC chromatography (Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min). Yield: 250 mg (49% of theory) ESI Mass spectrum: [M+H] ⁺ = 254/256 Retention time HPLC: 2.00 min (method K).

23c [1 -(4-lodo-phenyl)-cyclopropylmethyl]-dimethyl-amine

3[1-(4-lodo-phenyl)-cyclopropylmethyl]-dimethyl-amine is prepared following preparation 9a from 250 mg (0.98 mmol) [1-(4-bromo-phenyl)-cyclopropylmethyl]-dimethyl-amine (example 23b).

Yield: 300 mg (quantitative) ESI Mass spectrum: [M+H] ⁺ = 302 Retention time HPLC: 2.07 min (method K).

23d 4-Benzyloxy-1-{2-[4-(1-dimethylaminomethyl-cyclopropyl)-phen yl]-2-oxo-ethyl}-1H- pyridin-2-one

4-Benzyloxy-1-{2-[4-(1-dimethylaminomethyl-cyclopropyl)-p henyl)-2-oxo-ethyl}-1/-/-pyridin-2- one is prepared following preparation 9b from 300 mg (1.00 mmol) [1-(4-iodo-phenyl)- cyclopropylmethyl]-dimethyl-amine. Yield: 7 mg (2% of theory)

ESI Mass spectrum: [M+H] ⁺ = 417

Retention time HPLC: 2.22 min (method H).

Example 24.1 4-Benzyloxy-1 -[2-(3-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

4-Benzyloxy-1-[2-(3-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1H-pyridin- 2-one is prepared following example 13.2a from 4-benzyloxy-1-{2-[3-methyl-2-(2,2,2-trifluoro- acetyl)-1 ,2, 3,4-tetrahydro-isoquinolin-7-yl]-2-oxo-ethyl}-1 /-/-pyridin-2-one (preparation 19, 80 mg, 0.17 mmol).

Yield: 40 mg (62% of theory)

ESI Mass spectrum: [M+H] ⁺ = 389

Retention time HPLC: 2.10 min (method H).

Example 24.2

4-Benzyloxy-1-[2-(2,3-dimethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1H-pyridin- 2- one

4-Benzyloxy-1-[2-(2,3-dimethyl-1 _l 2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1H-pyridin-2 - one is prepared following example 18.2 from 4-benzyloxy-1-[2-(3-methyl-1,2,3,4-tetrahydro- isoquinolin-7-yl)-2-oxo-ethyl]-1H-pyridin-2-one (example 24.1 , 40 mg, 0.103 mmol) and 12.5 μL 37% aqueous formaldehyde solution (0.154 mmol). Yield: 33 mg (80% of theory) ESI Mass spectrum: [M+H] ⁺ = 403 Retention time HPLC: 1.65 min (method K).

Example 25.1

5-Benzyloxy-2-[2-(3-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyrida zin-3- one

25.1a δ-Benzyloxy^^-^-methyl^^^^-trifluoro-acetyO-I ^.S^-tetrahydro-isoquinolin^-yl]-

2-oxo-ethyl}-2H-pyridazin-3-one

5-Benzyloxy-2-{2-[3-methyl-2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo- ethyl}-2H-pyridazin-3-one is prepared following preparation 1b from 127 mg (0.63 mmol) 5- benzyloxy-2/-/-pyridazin-3-one (preparation 2) and 200 mg (0.63 mmol) 1-[7-(2-chloro-acetyl)- 3-methyl-3,4-dihydro-1/-/-isoquinolin-2-yl]-2,2,2-trifluoro- ethanone (preparation 19d), employing DMSO as solvent.

Yield: 60 mg (20% of theory)

Retention time HPLC: 1.63 min (method J).

25.1b 5-Benzyloxy-2-[2-(3-methyl-1,2,3,4-tetrahydro-isoquinolin-7- yl)-2-oxo-ethyl]-2/-/- pyridazin-3-one

5-Benzyloxy-2-[2-(3-methyl-1,2,3,4-tetrahydro-isoquinolin -7-yl)-2-oxo-ethyl]-2/-/-pyridazin-3- one is prepared following example 13.2a from 5-benzyloxy-2-{2-[3-methyl-2-(2,2,2-trifluoro- acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-2-oxo-ethyl}-2/-/-pyrida zin-3-one (example 25.1a, 60 mg, 0.124 mmol).

Yield: 32 mg (67% of theory) ESI Mass spectrum: [M+H] ⁺ = 390 Retention time HPLC: 1.65 min (method K).

Example 25.2

5-Benzyloxy-2-[2-(2,3-dimethyl-1,2,3,4-tetrahydro-isoquin olin-7-yl)-2-oxo-ethyl]-2H-pyridazin-

3-one

5-Benzyloxy-2-[2-(2,3-dimethyl-1 ,2,3 _l 4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyridazin- 3-one is prepared following example 18.2 from 5-benzyloxy-2-[2-(3-methyl-1,2,3,4-tetrahydro- isoquinolin-7-yl)-2-oxo-ethyl]-2/-/-pyridazin-3-one (example 25.1 , 88 mg, 0.23 mmol) and 37% aqueous formaldehyde solution (28 μL, 0.34 mmol).

Yield: 60 mg (66% of theory)

ESI Mass spectrum: [M+H] ⁺ = 404 Retention time HPLC: 1.65 min (method K).

Example 26.1

4-Benzyloxy-1 -[2-oxo-2-(5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-ethyl]-1 H-pyridin-2-one

26.1a 3-lodo-7,8-dihydro-5/-/-[1 ,6]naphthyridine-6-carboxylic acid terf-butyl ester

3-lodo-7,8-dihydro-5H-[1 ,6]naphthyridine-6-carboxylic acid fert-butyl ester is prepared following preparation 9a from 3-bromo-7,8-dihydro-5/-/-[1 ,6]naphthyridine-6-carboxylic acid tert-butyl ester (7.00 g, 22.4 mmol). Yield: 7.80 g (97% of theory) ESI Mass spectrum: [M+H] ⁺ = 361

Retention time HPLC: 1.56 min (method J).

26.1b 4-Benzyloxy-1-[2-oxo-2-(5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-ethyl]-W-pyridin-2- one

4-Benzyloxy-1-[2-oxo-2-(5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-ethyl]-1 H-pyridin-2-one is prepared following preparation 9b from 3-iodo-7,8-dihydro-5H-[1 ,6]naphthyridine-6-carboxylic acid tert-butyl ester (example 26.1a, 1.00 g, 2.78 mmol). Yield: 36 mg (4% of theory) ESI Mass spectrum: [M+H] ⁺ = 376

Retention time HPLC: 2.09 min (method H).

Example 26.2

4-Benzyloxy-1-[2-(6-methyl-5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-2-oxo-ethyl]-1/-/-pyridin- 2-one

4-Benzyloxy-1-[2-(6-methyl-5,6,7,8-tetrahydro-[1 ,6]naphthyridin-3-yl)-2-oxo-€thyl]-1/-/-pyridin- 2-one is prepared following example 18.2 from 4-benzyloxy-1-[2-oxo-2-(5,6,7,8-tetrahydro- [1 ,6]naphthyridin-3-yl)-ethyl]-1H-pyridin-2-one (example 26.1 , 60 mg, 0.160 mmol) and 37% aqueous formaldehyde solution (19.5 μl_, 0.24 mmol). Yield: 53 mg (85% of theory) ESI Mass spectrum: [M+H] ⁺ = 390 Retention time HPLC: 1.45 min (method K).

Example 27.1

5-Benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2/-/-pyridazin-3- one

27.1a 6-(Methoxy-methyl-carbamoyl)-3,4-dihydro-1AV-isoquinoline-2- carboxylic acid te/t-butyl ester e^Methoxy-methyl-carbamoylJ-S^-dihydro-IH-isoquinoline^-carb oxylic acid tert-butyl ester is prepared following preparation 5b from 3,4-dihydro-1/-/-isoquinoline-2,6-dicarboxylic acid 2- tert-butyl ester (2.80 g, 10.1 mmol).

Yield: 2.20 g (68% of theory)

ESI Mass spectrum: [M+H] ⁺ = 321 Retention time HPLC: 1.42 min (method J).

27.1b 6-Acetyl-3,4-dihydro-1/-/-isoquinoline-2-carboxylic acid ferf-butyl ester θ-Acetyl-Sλ-dihydro-I H-isoquinoline^-carboxylic acid fert-butyl ester is prepared following preparation 5c from Weinreb amide 6-(methoxy-methyl-carbamoyl)-3,4-dihydro-1H- isoquinoline-2-carboxylic acid fert-butyl ester (example 27.1a, 2.20 g, 6.87 mmol). Yield: 1.50 g (79% of theory) ESI Mass spectrum: [M+H] ⁺ = 276 Retention time HPLC: 1.52 min (method J).

27.1c 6-(2-Bromo-acetyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid fert-butyl ester

6-(2-Bromo-acetyl)-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester is prepared following preparation 4d (mixture of 20% MeOH in THF as solvent) from 6-acetyl-3,4-dihydro- 1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester (example 27.1b, 1.50 g, 5.45 mmol). Yield: 1.00 g (44% of theory) ESI Mass spectrum: [M+H] ⁺ = 354/356

Retention time HPLC: 1.91 min (method K).

27.1d 6-[2-(4-Benzyloxy-6-oxo-6A7-pyridazin-1-yl)-acetyl]-3,4-dihy dro-1/-/-isoquinoline-2- carboxylic acid fert-butyl ester 6-[2-(4-Benzyloxy-2-oxo-2/-/-pyridin-1 -yl)-acetyl]-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester is prepared following preparation 1b (DMSO as solvent) from 6-(2-bromo- acetyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid fert-butyl ester (example 27.1c, 1.00 g,

2.82 mmol) and 5-Benzyloxy-2H-pyridazin-3-one (570 mg, 2.82 mmol).

Yield: 700 mg (52% of theory) ESI Mass spectrum: [M+H] ⁺ = 476

Retention time HPLC: 1.96 min (method K).

27.1e 5-Benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2/-/-pyridazin-3- one 6-[2-(4-Benzyloxy-6-oxo-6AV-pyridazin-1-yl)-acetyl]-3,4-dihy dro-1H-isoquinoline-2-carboxylic acid fert-butyl ester (example 27.1d, 700 mg, 1.47 mmol) is dissolved in DCM (10 mL) and TFA (1.13 mL) is added. The reaction is stirred for 18 h at room temperature. The volatiles are removed in vacuo and the resulting residue is purified via preparative reverse HPLC chromatography (Gilson, XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min). Yield: 500 mg (91% of theory) ESI Mass spectrum: [M+H] ⁺ = 376

Retention time HPLC: 1.59 min (method K).

Example 27.2

5-Benzyloxy-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-2-oxo-ethyl]-2H-pyridazi n-3- one

5-Benzyloxy-2-[2-(2-methyl-1, ,3,4-tOetrahydro-isoquinolin-6-yl)-2-oxo-ethyl]-2H-pyridazin -3- one is prepared following example 18.2 from 5-benzyloxy-2-[2-oxo-2-(1 ,2,3,4-tetrahydro- isoquinolin-6-yl)-ethyl]-2/-/-pyridazin-3-one (example 27.1 , 350, 0.932 mmol) and 105 μl_ 37% aqueous formaldehyde solution (0.24 mmol). Yield: 322 mg (89% of theory) ESI Mass spectrum: [M+H] ⁺ = 390 Retention time HPLC: 2.80 min (method C).

Example 28.1

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2H-pyridazin- 3-one

28.1 a 6-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-6-oxo-6/-/-pyridazin- 1 -yl]-ethyl}-3,4-dihydro-1 H- isoquinoline-2-carboxylic acid tert-butyl ester

6-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1- yl]-ethyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid terf-butyl ester is prepared following preparation 1b from 5-(5- chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10.4, 238 mg, 1.00 mmol) and 6- [2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1/-/-isoquinol ine-2-carboxylic acid terf-butyl ester (preparation 26, 432 mg, 1.00 mmol). Yield: 175 mg (35% of theory) ESI Mass spectrum: [M+H] ⁺ = 497/499 Retention time HPLC: 1.71 min (method J).

28.1b S^δ-Chloro-pyridin^-ylmethoxy^-^^I ^.Sλ-tetrahydro-isoquinolin-θ-ylJ-ethyl]^/-/- pyridazin-3-one

S^S-Chloro-pyridin^-ylmethoxy^-^^I ^.S^-tetrahydro-isoquinolin-θ-yO-ethyl^H-pyridazin- 3-one is prepared following example 18.1 from 6-{2-[4-(5-chloro-pyridin-2-ylmethoxy)-6-oxo- 6H-pyridazin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carb oxylic acid terf-butyl ester (example 28.1a, 175 mg, 0.35 mmol). Yield: 100 mg (62% of theory) ESI Mass spectrum: [M+H] ⁺ = 397/399 Retention time HPLC: 1.05 min (method J).

Example 28.2

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1,2,3,4-t etrahydro-isoquinolin-6-yl)-ethyl]-2/-/- pyridazin-3-one

5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2/-/- pyridazin-3-one is following example 18.2 from 5-(5-chloro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4- tetrahydro-isoquinolin-6-yl)-ethyl]-2H-pyridazin-3-one (example 28.1 , 70 mg, 0.18 mmol). Yield: 23 mg (29% of theory) ESI Mass spectrum: [M+H] ⁺ = 411/413 Retention time HPLC: 1.15 min (method J).

Example 29.1

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(1,2,3,4-tetrahydro- isoquinolin-6-yl)-ethyl]-2/-/-pyridazin-

3-one

29.1a 6-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1-y l]-ethyl}-3,4-dihydro-1/-/- isoquinoline-2-carboxylic acid fert-butyl ester

6-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin- 1-yl]-ethyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid fert-butyl ester is prepared following preparation 1b from 5-(5- bromo-pyridin-2-ylmethoxy)-2/-/-pyridazin-3-one (preparation 10.5, 282 mg, 1.00 mmol) and 6-

[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 26, 432 mg, 1.00 mmol). Yield: 140 mg (26% of theory) ESI Mass spectrum: [M+H] ⁺ = 541/543 Retention time HPLC: 1.52 min (method J).

29.1b 5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2H- pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(1,2,3,4-tetrahydro- isoquinolin-6-yl)-ethyl]-2H-pyridazin- 3-one is prepared following the preparation of example 18.1 from 6-{2-[4-(5-bromo-pyridin-2- ylmethoxy)-6-oxo-6H-pyridazin-1 -yl]-ethyl}-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert- butyl ester (example 28.1a, 140 mg, 0.26 mmol).

Yield: 90 mg (68% of theory)

ESI Mass spectrum: [M+H] ⁺ = 441/443 Retention time HPLC: 1.10 min (method J).

Example 29.2

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1,2,3,4-te trahydro-isoquinolin-6-yl)-ethyl]-2/-/- pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-2H- pyridazin-3-one is following example 18.2 from 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(1 , 2,3,4- tetrahydro-isoquinolin-6-yl)-ethyl]-2/-/-pyridazin-3-one (example 29.1 , 60 mg, 0.14 mmol). Yield: 20 mg (29% of theory) ESI Mass spectrum: [M+H] ⁺ = 455/457

Retention time HPLC: 1.17 min (method J).

Example 30

5-Benzyloxy-2-(2-{4-[2-(4-hydroxy-4-methyl-piperidin-1-yl )-ethyl]-phenyl}-2-oxo-ethyl)-2H- pyridazin-3-one

30a 5-Ben2yloxy-2-{2-[4-(2-chloro-ethyl)-phenyl]-2-oxo-ethyl}-2/ -/-pyridazin-3-one

5-Benzyloxy-2-{2-[4-(2-chloro-ethyl)-phenyl]-2-oxo-ethyl} -2/-/-pyridazin-3-one is prepared following preparation 1b (DMSO as solvent) from 1.00 g (3.82 mmol) 2-bromo-1-[4-(2-chloro- ethyl)-phenyl]-ethanone (preparation according to J. Med. Chem. 34, 6, 1991 , 1860-1866) and 0.773 g (3.82 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 2).

Yield: 570 mg (32% of theory, 80% purity)

ESI Mass spectrum: [M+H] ⁺ = 383/385

30b 5-Benzyloxy-2-(2-{4-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-e thyl]-phenyl}-2-oxo-ethyl)-2H- pyridazin-3-one

To a solution of 5-benzyloxy-2-{2-[4-(2-chloro-ethyl)-phenyl]-2-oxo-ethyl}-2/ -/-pyridazin-3-one

(example 30a, 110 mg, 0.29 mmol) in DMF (2 mL) is added 4-hydroxy-4-methyl-piperidine (66 mg, 0.58 mmol) and tetrabutylammonium iodide (106 mg, 0.29 mmol). The reaction mixture is heated for 5 min to 120 ⁰ C in the microwave. The crude reaction mixture is purified via preparative reverse phase HPLC (Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min).

Yield: 5 mg (4% of theory) ESI Mass spectrum: [M+H] ⁺ = 462

Retention time HPLC: 1.70 min (method J).

Example 31.1

1 -[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-4-(4-fluoro -benzyloxy)-1 H- pyridin-2-one

31.1a 4-(4-Fluoro-benzyloxy)-1-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl )-1 ,2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-1H-pyridin-2-one

4-(4-Fluoro-benzyloxy)-1-{2-oxo-2-[2-(2 _l 2 _> 2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7- yl]-ethyl}-1H-pyridin-2-one is prepared following preparation 1b from 330 mg (1.51 mmol) 4- (4-fluoro-benzyloxy)-1H-pyridin-2-one (preparation 10.1 ) and 460 mg (1.51 mmol) 1-[7-(2- chloro-acetyl)-3,4-dihydro-1/-/-isoquinolin-2-yl]-2,2,2-trif luoro-ethanone, employing DMSO as solvent.

Yield: 0.40 g (54% of theory) ESI Mass spectrum: [M+H] ⁺ = 489 Retention time HPLC: 1.52 min (method J).

31.1b 4-(4-Fluoro-benzyloxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1W- pyridin-2-one

4-(4-Fluoro-benzyloxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl)-1H-pyridin-2-one is prepared following example 13.2a from 4-(4-fluoro-benzyloxy)-1-{2-oxo-2-[2-(2,2,2-trifluoro- acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-1H-pyridin-2-one (example 31.1a, 0.40 g, 0.82 mmol).

Yield: 0.28 g (87% of theory)

ESI Mass spectrum: [M+H] ⁺ = 393

Retention time HPLC: 1.11 min (method J).

31.1c 1-[2-(2-Ethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-eth yl]-4-(4-fluoro-benzyloxy)-1/-/- pyridin-2one

1 -[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-4-(4-fluoro -benzyloxy)-1 H- pyridin-2-one is prepared following example 14.2 from 4-(4-fluoro-benzyloxy)-1-[2-oxo-2-

(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1/-/-pyridin-2-on e (example 31.1b, 70 mg, 0.18 mmol) and 11 μL acetaldehyde.

Yield: 35 mg (75% of theory)

ESI Mass spectrum: [M+H] ⁺ = 421

Retention time HPLC: 1.15 min (method J).

Example 31.2

4-(4-Fluoro-benzyloxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1 /-/- pyridin-2-one

4-(4-Fluoro-benzyloxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-1/-/- pyridin-2-one is prepared following example 14.2 from 4-(4-fluoro-benzyloxy)-1-[2-oxo-2- (1,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1A7-pyridin-2-o ne (example 31.1 b, 70 mg, 0.18 mmol) and 14 μl_ acetone instead of acetaldehyde. Yield: 6 mg (8% of theory)

ESI Mass spectrum: [M+H] ⁺ = 435 Retention time HPLC: 1.19 min (method J).

Example 32.1 2-[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-5-(4-fluoro -benzyloxy)-2H- pyridazin-3-one

32.1a 5-(4-Fluoro-benzyloxy)-2-{2-oxo-2-[2-(2,2 _l 2-trifluoro-acetyl)-1 ₎ 2,3,4-tetrahydro- isoquinolin-7-yl]-ethyl}-2/-/-pyridazin-3-one

5-(4-Fluoro-benzyloxy)-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl )-1 _l 2,3,4-tetrahydro-isoquinolin-7- yl]-ethyl}-2H-pyridazin-3-one is prepared following preparation 1 b from 660 mg (3.00 mmol) 5- (4-fluoro-benzyloxy)-2/-/-pyridazin-3-one (preparation 10.8) and 917 mg (3.00 mmol) 1-[7-(2- chloro-acetyl)-3,4-dihydro-1/-/-isoquinolin-2-yl]-2,2,2-trif luoro-ethanone, employing DMSO as solvent.

Yield: 1.35 g (92% of theory) ESI Mass spectrum: [M+H] ⁺ = 490 Retention time HPLC: 1.57 min (method J).

32.1 b 5-(4-Fluoro-benzyloxy)-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H- pyridazin-3-one

5-(4-Fluoro-benzyloxy)-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one is prepared following example 13.2a from 5-(4-fluoro-benzyloxy)-2-{2-oxo-2-[2-(2,2,2- trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-2/-/-pyridazin-3- one (example 32.1a, 1.3O g, 2.66 mmol).

Yield: 1.03 g (99% of theory)

ESI Mass spectrum: [M+H] ⁺ = 394

Retention time HPLC: 1.12 min (method J).

32.1 c 2-[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-5-(4-f luoro-benzyloxy)-2H- pyridazin-3-one

2-[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-5-(4-fluoro -benzyloxy)-2/-/- pyridazin-3-one is prepared following example 14.2 from 5-(4-fluoro-benzyloxy)-2-[2-oxo-2- (1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-on e (example 32.1b, 100 mg, 0.25 mmol) and 16 μl_ acetaldehyde. Yield: 30 mg (28% of theory) ESI Mass spectrum: [M+H] ⁺ = 422 Retention time HPLC: 1.16 min (method J).

Example 32.2

5-(4-Fluoro-benzyloxy)-2-[2-(2-isopropyl-1,2,3,4-tetrahyd ro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/- pyridazin-3-one

5-(4-Fluoro-benzyloxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-2-oxo-ethyl]-2/-/- pyridazin-3-one is prepared following example 14.2 from 5-(4-fluoro-benzyloxy)-2-[2-oxo-2- (1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-on e (example 32.1b, 100 mg, 0.25 mmol) and 21 μl_ acetone instead of acetaldehyde. Yield: 20 mg (18% of theory)

ESI Mass spectrum: [M+H] ⁺ = 436 Retention time HPLC: 1.20 min (method J).

Example 33.1 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2λy-pyridazin- 3-one

33.1a 7-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-6-oxo-6H-pyridazin-1- yl]-ethyl}-3,4-dihydro-1tf- isoquinoline-2-carboxylic acid tert-butyl ester

7-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-6-oxo-6/-/-pyridazin- 1-yl]-ethyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 1b from 5-(5- fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10.9, 80 mg, 0.36 mmol) and 7- [2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid terf-butyl ester (preparation 27, 156 mg, 0.36 mmol). Yield: 160 mg (92% of theory) ESI Mass spectrum: [M+H] ⁺ = 481 Retention time HPLC: 1.89 min (method K).

33.1b 5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(1,2,3,4-tetrahydro-is oquinolin-7-yl)-ethyl]-2H- pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-

3-one is prepared following example 18.1 from 7-{2-[4-(5-fluoro-pyridin-2-ylmethoxy)-6-oxo-

6H-pyridazin-1-yl]-ethyl}-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (example 33.1a, 160 mg, 0.33 mmol).

Yield: 160 mg

ESI Mass spectrum: [M+H] ⁺ = 381

Retention time HPLC: 1.53 min (method K).

Example 33.2

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1,2,3,4-t etrahydro-isoquinolin-7-yl)-ethyl]-2H- pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/- pyridazin-3-one is prepared following example 18.2 from 5-(5-fluoro-pyridin-2-ylmethoxy)-2-

[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2A7-pyridazin-3-o ne (example 33.1 , 30 mg, 0.08 mmol).

Yield: 27 mg (87% of theory)

ESI Mass spectrum: [M+H] ⁺ = 395 Retention time HPLC: 1.58 min (method K).

Example 34

1-[2-Oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-4-(5-trifluoromet hyl-pyridin-2- ylmethoxy)-1 /-/-pyridin-2-one

34a 1 -{2-Oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-4-(5- trifluoromethyl-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one

1-{2-Oxo-2-[2-(2,2,2-trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethylH-(5- trifluoromethyl-pyridin-2-ylmethoxy)-1 H-pyridin-2-one is prepared following preparation 1b from 110 mg (0.41 mmol) 4-(5-trifluoromethyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one

(preparation 10.10) and 137 mg (0.45 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H- isoquinolin-2-yl]-2,2,2-trifluoro-ethanone, employing DMSO as solvent.

Yield: 0.30 g (ca. 70% pure, ca. 96% of theory)

ESI Mass spectrum: [M+H] ⁺ = 540 Retention time HPLC: 1.53 min (method J).

34b 1 -[2-Oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-4-(5-trifluoromet hyl-pyridin-2- ylmethoxy)-1 H-pyridin-2-one

1-[2-Oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-4-(5-trifluoromet hyl-pyridin-2- ylmethoxy)-1 H-pyridin-2-one is prepared following example 13.2a from 1-{2-oxo-2-[2-(2,2,2- trifluoro-acetyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-4-(5-trifluoromet hyl-pyridin-2- yimethoxy)-1 /-/-pyridin-2-one (example 34a, 0.30 g, 70% pure, 0.39 mmol).

Yield: 7 mg (4% of theory)

ESI Mass spectrum: [M+H] ⁺ = 444 Retention time HPLC: 1.23 min (method J).

Example 35.1

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/- pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/- pyridazin-3-one is prepared following example 14.2 from 5-(5-bromo-pyridin-2-ylmethoxy)-2- [2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one (for preparation see WO 08/022979; 150 mg, 0.34 mmol) and acetaldehyde (30 mg, 0.68 mmol). Yield: 21 mg (13% of theory) ESI Mass spectrum: [M+H] ⁺ = 469/471 Retention time HPLC: 1.79 min (method K).

Example 35.2

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-

2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 2/-/-pyridazin-3-one is prepared following example 14.2 from 5-(5-bromo-pyridin-2-ylmethoxy)- 2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-on e (for preparation see WO 08/022979; 1.90 g, 4.31 mmol) and acetone (0.63 ml_, 8.61 mmol). Yield: 1.00 g (48% of theory) ESI Mass spectrum: [M+H] ⁺ = 483/485 Retention time HPLC: 1.90 min (method K).

Example 35.3

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-cyclopropylmethyl -1 ,2,3,4-tetrahydro-isoquinolin-7- yl)-ethyl]-2H-pyridazin-3-one

5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(2-cyclopropylmethyl-1 ,2,3,4-tetrahydro-isoquinolin-7- yl)-ethyl]-2/-/-pyridazin-3-one is prepared following example 14.2 from 5-(5-bromo-pyridin-2- 5 ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3- one (for preparation see WO 08/022979; 150 mg, 0.34 mmol) and cyclopropanecarbaldehyde (48 mg, 0.68 mmol). Yield: 70 mg (42% of theory) ESI Mass spectrum: [M+H] ⁺ = 495/497 0 Retention time HPLC: 1.91 min (method K).

Example 35.4

5-(5-Bromo-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl) -1 ,2,3,4-tetrahydro-isoquinolin-7-yl]- ethyl}-2H-pyridazin-3-one

To a solution of 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(1,2,3,4-tetrahydro-iso quinolin-7-yl)- ethyl]-2H-pyridazin-3-one (for preparation see WO 08/022979, 130 mg, 0.30 mmol) in 4.0 mL

THF is added potassium carbonate (103 mg, 0.74 mmol) and bromoethanol (25 μL, 0.35 0 mmol). The reaction mixture is stirred overnight at 60 ⁰ C ₁ diluted with MeOH and after filtration directly subjected to preparative reverse HPLC chromatography (Waters XBridge 5 μm, gradient from 10% to 100% acetonitrile in water + 0.3% NH ₄ OH).

Yield: 76 mg (53% of theory)

ESI Mass spectrum: [M+H] ⁺ = 485/487 5 Retention time HPLC: 1.57 min (method K).

The following examples are prepared as described for Example 35.4 starting from 5-(5- bromo-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3- one (for preparation see WO 08/022979).

Example 35.7 δ^δ-Bromo-pyridin^-ylmethoxy^-^^-cyclopropyl-I ^.S^-tetrahydro-isoquinolin^-yl)- ethyl]-2/-/-pyridazin-3-one

To a solution of 5-(5-bromo-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- ethyl]-2H-pyridazin-3-one (for preparation see WO 08/022979, 300 mg, 0.54 mmol) in 5.0 mL MeOH is added (i-ethoxy-cyclopropoxy)-trimethyl-silane (0.12 mL, 0.60 mmol). The reaction mixture is stirred 40 min at RT and sodium cyano-borohydride (41 mg, 0.65 mmol) is added. After stirring overnight at 8O ⁰ C, aqueous half saturated NaHCO ₃ -solution is added. The aqueous phase is extracted two times with DCM, the combined organic phase is dried over MgSO ₄ and evaporated in vacuo. The residue is purified via preparative reversed HPLC chromatography (Waters XBridge 5 μm, gradient from 10% to 100% acetonitrile in water + 0.3% NH ₄ OH). Yield: 27 mg (10% of theory) ESI Mass spectrum: [M+H] ⁺ = 481/483

Retention time HPLC: 1.92 min (method K).

Example 36.1

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin-2- one

36.1 a 7-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin-1- yl]-ethyl}-3,4-dihydro-1 H- isoquinoline-2-carboxylic acid tert-butyl ester

7-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin -1-yl]-ethyl}-3,4-dihydro-1/-/- isoquinoline-2-carboxylic acid fe/t-butyl ester is prepared following preparation 1 b (DMSO as solvent) from 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinol ine-2-carboxylic acid fe/t-butyl ester (preparation 27, 4.32 g, 10.0 mmol) and 4-(5-chloro-pyridin-2-ylmethoxy)-1/-/- pyridin-2-one (preparation 10.6, 2.37 g, 10.0 mmol).

Yield: 2.00 g (40% of theory)

ESI Mass spectrum: [M+H] ⁺ = 496/498 Retention time HPLC: 1.92 min (method K).

36.1b 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H- pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1,2,3,4-tetrahydro -isoquinolin-7-yl)-ethyl]-1/-/-pyridin-2- one is prepared following example 18.1 from 7-{2-[4-(5-chloro-pyridin-2-ylmethoxy)-2-oxo-2H- pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxyli c acid tert-butyl ester (example

36.1a, 340 mg, 0.69 mmol).

Yield: 230 mg (85% of theory)

ESI Mass spectrum: [M+H] ⁺ = 396/398 Retention time HPLC: 1.52 min (method K).

Example 36.2

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-isopropyl-1,2,3, 4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1 /-/-pyridin-2-one

To 250 mg (0.63 mmol) 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin- 7-yl)-ethyl]-1 H-pyridin-2one (example 36.1) in 10 mL MeOH is added 110 mg (1.90 mmol) acetone and 401 mg (1.90 mmol) sodium triacetoxy-borohydride. After 1 h stirring at RT, the mixture is acidified with acetic acid and stirred overnight at RT. The mixture is directly purified Wa preparative reverse HPLC chromatography (Waters XBridge 5 μm, gradient from 10% to 100% acetonitrile in water + 0.3% NH ₄ OH). Yield: 260 mg (94% of theory) ESI Mass spectrum: [M+H] ⁺ = 438/440 Retention time HPLC: 1.76 min (method K).

Example 36.3

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H- pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1,2,3,4-tetr ahydro-isoquinolin-7-yl)-ethyl]-1H- pyridin-2-one is prepared following example 14.2 from 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2- (1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 36.1 ; 100 mg, 0.25 mmol) and 37% aqueous formaldehyde solution (31 μL, 0.38 mmol). Yield: 80 mg (77% of theory) ESI Mass spectrum: [M+H] ⁺ = 410/412 Retention time HPLC: 1.59 min (method K).

The following examples are prepared as described for Example 35.4 starting from 4-(5- chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 36.1 ).

Example 37.1

2-[2-(2-Ethyl-1,2,3 _I 4-tetrahydro-isoquinolin-7-yl)-ethyl]-5-(5-fluoro-pyridin-2- ylmethoxy)-2H- pyridazin-3-one

2-[2-(2-Ethyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-5-(5-fluoro-pyrid in-2-ylmethoxy)-2/-/- pyridazin-3-one is prepared following example 14.2 from 5-(5-fluoro-pyridin-2-ylmethoxy)-2-

[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-on e (example 33.1 ; 150 mg, 0.39 mmol) and acetaldehyde (25 μl_, 0.43 mmol).

Yield: 90 mg (56% of theory)

ESI Mass spectrum: [M+H] ⁺ = 409 Retention time HPLC: 1.7 min (method K).

Example 37.2

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-

2/-/-pyridazin-3-one

To 150 mg (0.39 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3 _I 4-tetrahydro-isoquinolin- 7-yl)-ethyl]-2H-pyridazin-3-one (example 33.1) in 6.0 mL THF is added 145 μl_ (1.97 mmol) acetone and after 10 min stirring 209 mg (0.99 mmol) sodium triacetoxy-borohydride. After 4 h stirring at RT, the mixture is directly purified via preparative reverse HPLC chromatography (Waters XBridge 5 μm, gradient from 10% to 100% acetonitrile in water + 0.3% NH ₄ OH). Yield: 129 mg (77% of theory) ESI Mass spectrum: [M+H] ⁺ = 423 Retention time HPLC: 1.8 min (method K).

Example 37.3

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl )-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]- ethyl}-2H-pyridazin-3-one

5-(5-Fluoro-pyridin-2-ylmethoxy)-2-{2-[2-(2-hydroxy-ethyl)-1 ,2,3,4-tetrahydro-isoquinolin-7-yl]- ethyl}-2/-/-pyridazin-3-one is prepared following example 35.4 (EtOH as solvent) from 5-(5- fluoro-pyridin-2-ylmethoxy)-2-[2-(1 ,2,3 _f 4-tetrahydro-isoquinolin-7-yl)-ethyl]-2/-/-pyridazin-3-one (example 33.1; 1.00 g, 2.63 mmol) and bromoethanol (187 μL, 2.63 mmol). Yield: 580 mg (52% of theory) ESI Mass spectrum: [M+H] ⁺ = 425 Retention time HPLC: 1.50 min (method K).

Example 38.1 4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1,2,3,4-tetrahydro-is oquinolin-7-yl)-ethyl]-1H-pyridin-2- one

38.1a 7-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl ]-ethyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid fert-butyl ester

7-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl ]-ethyl}-3,4-dihydro-1 H- isoquinoline-2-carboxylic acid te/t-butyl ester is prepared following preparation 1 b (DMSO as solvent) from 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 27, 1.96 g, 4.54 mmol) and 4-(5-fluoro-pyridin-2-ylmethoxy)-1 H- pyridin-2-one (preparation 10.11 , 1.0O g, 4.54 mmol). Yield: 1.00 g (46% of theory) ESI Mass spectrum: [M+H] ⁺ = 480 Retention time HPLC: 1.72 min (method J).

38.1b 4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/- pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin-2- one is prepared following example 18.1 from 7-{2-[4-(5-fluoro-pyridin-2-ylmethoxy)-2-oxo-2A7- pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxyli c acid te/t-butyl ester (example 38.1a, 120 mg, 0.25 mmol).

Yield: 77 mg (81 % of theory)

ESI Mass spectrum: [M+H] ⁺ = 380

Retention time HPLC: 0.99 min (method J).

Example 38.2

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1/-/- pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H- pyridin-2-one is prepared following example 14.2 from 4-(5-fluoro-pyridin-2-ylmethoxy)-1-[2- (1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 38.1 ; 400 mg, 1.05 mmol) and 37% aqueous formaldehyde solution (128 μL, 1.58 mmol). Yield: 220 mg (53% of theory) ESI Mass spectrum: [M+H] ⁺ = 394

Retention time HPLC: 1.10 min (method K).

Example 38.3

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1 H-pyridin-2-one

4-(5-Fluoro-pyndin-2-ylmethoxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1/-/-pyridin-2-one is prepared following example 37.2 from 4-(5-fluoro-pyridin-2-ylmethoxy)-1- [2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 38.1 ; 200 mg, 0.53 mmol) and acetone (194 μl_, 2.64 mmol). Yield: 100 mg (45% of theory) ESI Mass spectrum: [M+H] ⁺ = 422

Retention time HPLC: 1.69 min (method K).

The following examples are prepared as described for Example 35.4 (for example 38.4 EtOH is used as the solvent) starting from 4-(5-fluoro-pyridin-2-ylmethoxy)-1-[2-(1,2,3,4-tetrahydro- isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 38.1 ).

Example 39.1

4-(4-Fluoro-benzyloxy)-1 -[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin-2-one

39.1a 7-{244-(4-fluoro-benzyloxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-3 _l 4-dihydro-1/-/-isoquinoline-2- carboxylic acid fert-butyl ester 7-{2-[4-(4-fluoro-benzyloxy)-2-oxo-2/-/-pyridin-1 -yl]-ethyl}-3,4-dihydro-1 /-/-isoquinoline-2- carboxylic acid fert-butyl ester is prepared following preparation 1 b (DMSO as solvent) from 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 27, 2.94 g, 6.81 mmol) and 4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (preparation 10.1, 1.50 g, 6.84 mmol). Yield: 1.50 g (46% of theory)

ESI Mass spectrum: [M+H] ⁺ = 479 Revalue: 0.2 (silica gel, mixture E).

39.1b 4-(4-Fluoro-benzyloxy)-1-[2-(1,2,3,4-tetrahydro-isoquinolin- 7-yl)-ethyl]-1/-/-pyridin-2-one 4-(4-Fluoro-benzyloxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one is prepared following example 18.1 from 7-{2-[4-(4-fluoro-benzyloxy)-2-oxo-2/-/-pyridin-1-yl]- ethyl}-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert-butyl ester (example 39.1a, 1.50 g,

3.13 mmol).

Yield: 400 mg (34% of theory) ESI Mass spectrum: [M+H] ⁺ = 379

Retention time HPLC: 1.67 min (method K).

Example 39.2

4-(4-Fluoro-benzyloxy)-1-[2-(2-isopropyl-1,2,3,4-tetrahyd ro-isoquinolin-7-yl)-ethyl]-1/-/-pyridin- 2-one

4-(4-Fluoro-benzyloxy)-1-[2-(2-isopropyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1/-/-pyridin- 2-one is prepared following example 37.2 from 4-(4-fluoro-benzyloxy)-1-[2-(1,2,3,4- tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (example 39.1 ; 600 mg, 1.59 mmol) and acetone (582 μl_, 7.93 mmol).

Yield: 280 mg (42% of theory) ESI Mass spectrum: [M+H] ⁺ = 421 Retention time HPLC: 1.86 min (method K).

Example 40.1

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(2-propyl-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- ethyl]-1 H-pyridin-2-one

To 70 mg (0.15 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1,2,3,4-tetrahyd ro- isoquinolin-7-yl)-ethyl]-1/-/-pyridin-2-one (for preparation see WO 08/022979) in 2.0 mL THF is added 10 mg (0.17 mmol) propionaldehyde and 39 mg (0.19 mmol) sodium triacetoxy- borohydride. The mixture is acidified with acetic acid and stirred 2h at RT. The mixture is directly purified via preparative reverse HPLC chromatography (Waters XBridge 5 μm, gradient from 5% to 95% acetonitrile in water + 0.3% NH ₄ OH). Yield: 25 mg (33% of theory) ESI Mass spectrum: [M+H] ⁺ = 496/498 Retention time HPLC: 1.84 min (method N).

The following examples are prepared as described for Example 40.1 starting from 4-(5- bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1H-pyridin- 2-one (for preparation see WO 08/022979).

The following examples are prepared as described for Example 40.1 starting from 5-(5- bromo-pyridin-2-ylmethoxy)-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H- pyridazin-3-one (for preparation see WO 08/022979).

The following examples are prepared as described for Example 35.4 (for example 42.2 EtOH is used as the solvent) starting from 4-(4-fluoro-benzyloxy)-1-[2-oxo-2-(1,2,3,4-tetrahydro- isoquinolin-7-yl)-ethyl]-1H-pyridin-2-one (for preparation see WO 08/022979).

The following example is prepared as described for Example 35.4 starting from 5-(4-fluoro- benzyloxy)-2-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-2H-pyridazin-3-on e (for preparation see WO 08/022979).

Example 44.1

4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1 H- pyridin-2-one

44.1a 6-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin-1-y l]-acetyl}-3,4-dihydro-1/-/- isoquinoline-2-carboxylic acid tert-butyl ester 6-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2A7-pyridin-1-yl ]-acetyl}-3,4-dihydro-1/-/- isoquinoline-2-carboxylic acid te/f-butyl ester is prepared following preparation 1b (DMSO as solvent) from 6-(2-bromo-acetyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

(for preparation see WO08/022979, 1.30 g, 3.67 mmol) and 4-(5-bromo-pyridin-2-ylmethoxy)-

1H-pyridin-2-one (preparation 10.3, 1.03 g, 3.67 mmol). Yield: 2.10 g (103% of theory)

ESI Mass spectrum: [M+H] ⁺ = 554/556

Retention time HPLC: 1.86 min (method K).

44.1b 4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]- 1 /-/-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1,2,3 _I 4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H- 5 pyridin-2-one is prepared following example 18.1 from 6-{2-[4-(5-bromo-pyridin-2-ylmethoxy)- 2-oxo-2H-pyridin-1-yl]-acetyl}-3,4-dihydro-1/-/-isoquinoline -2-carboxylic acid fert-butyl ester (example 44.1a, 2.00 g, 3.61 mmol). Yield: 650 mg (40% of theory) ESI Mass spectrum: [M+H] ⁺ = 454/456 10 Retention time HPLC: 1.50 min (method K).

Example 44.2

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-2-oxo- ethyl]-1 H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-2-oxo- ethyl]-1H-pyridin-2-one is prepared following example 40.1 from 4-(5-bromo-pyridin-2- ylmethoxy)-1 -[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1 H-pyridin-2-one (example 0 44.1 , 550 mg, 1.21 mmol) and 37% aqueous formaldehyde solution (99 μl_, 1.33 mmol). Yield: 360 mg (64% of theory) ESI Mass spectrum: [M+H] ⁺ = 468/470 Retention time HPLC: 1.58 min (method K). 5 Example 45.1

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H- pyridin-2-one

45.1a 6-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin-1- yl]-acetyl}-3,4-dihydro-1 H- isoquinoline-2-carboxylic acid tert-butyl ester

6-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin-1- yl]-acetyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid tert-butyl ester is prepared following preparation 1b (DMSO as solvent) from 6-(2-bromo-acetyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid fert-butyl ester (for preparation see WO08/022979, 700 mg, 1.48 mmol) and 4-(5-chloro-pyridin-2- ylmethoxy)-1 /-/-pyridin-2-one (preparation 10.6, 468 mg, 1.98 mmol). Yield: 140 mg (19% of theory) ESI Mass spectrum: [M+H] ⁺ = 510/512 Retention time HPLC: 1.84 min (method K).

45.1b 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-

1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1/-/- pyridin-2-one is prepared following example 18.1 from 6-{2-[4-(5-chloro-pyridin-2-ylmethoxy)-

2-oxo-2H-pyridin-1-yl]-acetyl}-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid fert-butyl ester

(example 45.1a, 140 mg, 0.28 mmol).

Yield: 70 mg (62% of theory)

ESI Mass spectrum: [M+H] ⁺ = 410/412 Retention time HPLC: 1.48 min (method K).

Example 45.2

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-2-oxo- ethyl]-1 /-/-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-2-oxo- ethyl]-1 /-/-pyridin-2-one is prepared following example 40.1 from 4-(5-chloro-pyridin-2- ylmethoxy)-1 -[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1 /-/-pyridin-2-one (example 45.1 , 750 mg, 1.83 mmol) and 37% aqueous formaldehyde solution (150 μL, 2.01 mmol). Yield: 450 mg (58% of theory) ESI Mass spectrum: [M+H] ⁺ = 424/426 Retention time HPLC: 1.56 min (method K).

Example 46.1

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H-pyridin-2- one

46.1a 6-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl ]-ethyl}-3,4-dihydro-1 H- isoquinoline-2-carboxylic acid fert-butyl ester

6-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin -1-yl]-ethyl}-3,4-dihydro-1H- isoquinoline-2-carboxylic acid fert-butyl ester is prepared following preparation 1b from 6-[2-

(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert-butyl ester

(preparation 26, 1.51 g, 3.50 mmol) and 4-(5-chloro-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one

(preparation 10.6, 828 mg, 3.50 mmol).

Yield: 420 mg (24% of theory) ESI Mass spectrum: [M+H] ⁺ = 496/498

Retention time HPLC: 1.92 min (method K).

46.1b 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1/-/- pyridin-2-one 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1/-/-pyridin-2- one is prepared following example 18.1 from 6-{2-[4-(5-chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/- pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxyli c acid tert-butyl ester (example

46.1a, 420 mg, 0.63 mmol).

Yield: 250 mg (75% of theory) ESI Mass spectrum: [M+H] ⁺ = 396/398

Retention time HPLC: 1.54 min (method K).

Example 46.2

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H- pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2 _I 3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H- pyridin-2-one is prepared following example 40.1 from 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2- (1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H-pyridin-2-one (example 46.1 , 220 mg, 0.56 mmol) and 37% aqueous formaldehyde solution (46 μl_, 0.61 mmol). Yield: 180 mg (79% of theory) ESI Mass spectrum: [M+H] ⁺ = 410/412 Retention time HPLC: 1.24 min (method J).

Example 47.1

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H-pyridin-2- one

47.1a 6-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin-1- yl]-ethyl}-3,4-dihydro-1 H- isoquinoline-2-carboxylic acid tert-butyl ester

6-{2-[4-(5-Fluoro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1 -yl]-ethyl}-3,4-dihydro-1/-/- isoquinoline-2-carboxylic acid terf-butyl ester is prepared following preparation 1b from 6-[2- (to!uene^-sulfonyloxy)-ethyl]-3,4-dihydro-1A7-isoquinoline-2 -carboxylic acid tert-butyl ester

(preparation 26, 650 mg, 1.51 mmol) and 4-(5-fluoro-pyridin-2-ylmethoxy)-1H-pyridin-2-one

(preparation 10.11 , 330 mg, 1.50 mmol).

Yield: 130 mg (18% of theory)

ESI Mass spectrum: [M+H] ⁺ = 480 Retention time HPLC: 1.84 min (method K).

47.1b 4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H- pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(1 _l 2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1/-/-pyridin-2- one is prepared following example 18.1 from 6-{2-[4-(5-fluoro-pyridin-2-ylmethoxy)-2-oxo-2H-

pyridin-1-yl]-ethyl}-3,4-dihydro-1 /-/-isoquinoline-2-carboxylic acid tert-butyl ester (example 47.1a, 130 mg, 0.27 mmol). Yield: 65 mg (63% of theory) ESI Mass spectrum: [M+H] ⁺ = 380 Retention time HPLC: 1.46 min (method K).

Example 47.2

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1H- pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-1,2,3,4-tetr ahydro-isoquinolin-6-yl)-ethyl]-1H- pyridin-2-one is prepared following example 40.1 from 4-(5-fluoro-pyridin-2-ylmethoxy)-1-[2- (1 ,2,3,4-tetrahydro-isoquinolin-6-yl)-ethyl]-1/-/-pyridin-2-on e (example 47.1 , 40 mg, 0.11 mmol) and 37% aqueous formaldehyde solution (9 μL, 0.12 mmol). Yield: 25 mg (60% of theory) ESI Mass spectrum: [M+H] ⁺ = 394 Retention time HPLC: 1.60 min (method K).

Example 48

4-Benzyloxy-1-[2-hydroxy-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1/-/-pyridin-2-on e

To 8.70 g (18.5 mmol) 4-benzyloxy-1-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-t etrahydro- isoquinolin-7-yl]-ethyl}-1/-/-pyridin-2-one (example13.1 ) in 150 mL isopropanol is added at RT 350 mg (9.25 mmol) sodium borohydride. The reaction mixture is stirred 2h at RT and is added to a pH 5 buffer-solution. After 1h the reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified via reversed HPLC chromatography (Gemini- C18 10 μM; gradient from 5% to 95% acetonitrile in water + 0.15% HCOOH). Yield: 2.10 g (30% of theory) ESI Mass spectrum: [M+H] ⁺ = 377

Retention time HPLC: 0.74 min (method O).

The following examples are prepared as described for Example 35.4 (for example 49.1 DMF is used as the solvent) starting from 4-(5-bromo-pyridin-2-ylmethoxy)-1-[2-(2,3-dihydro-1/-/- isoindol-5-yl)-ethyl]-1/-/-pyridin-2-one (example 19.1 ).

The following examples are prepared as described for Example 14.2 starting from 4-(5- bromo-pyridin-2-ylmethoxy)-1-[2-(2,3-dihydro-1/-/-isoindol-5 -yl)-ethyl]-1/-/-pyridin-2-one

(example 19.1 ). For example 49.3 1.0 eq. acetaldehyde and for example 49.4 2.0 eq acetaldehyde is used.

Example 50.1 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2,3-dihydro-1H-isoind ol-5-yl)-ethyl]-1/-/-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(2,3-dihydro-1 /-/-isoindol-5-yl)-ethyl]-1 /-/-pyridin-2-one is prepared following example 18.1 from 5-{2-[4-(5-chloro-pyridin-2-ylmethoxy)-2-oxo-2/-/- pyridin-1-yl]-ethyl}-1 ,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (preparation 28, 460 mg, 0.95 mmol). Yield: 140 mg (38% of theory)

ESI Mass spectrum: [M+H] ⁺ = 382/384 Retention time HPLC: 1.47 min (method K).

Example 50.2 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(2-methyl-2,3-dihydro- 1/-/-isoindol-5-yl)-ethyl]-1H- pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-1 H- pyridin-2-one is prepared following example 14.2 from 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2-

(2,3-dihydro-1H-isoindot-5-yl)-ethyl]-1/-/-pyridin-2-one (example 50.1 , 100 mg, 0.26 mmol) and

37% aqueous formaldehyde solution (32 μL, 0.39 mmol).

Yield: 95 mg (92% of theory)

ESI Mass spectrum: [M+H] ⁺ = 396/398 Retention time HPLC: 1.55 min (method K).

Example 51.1 1-[2-(2,3-Dihydro-1H-isoindol-5-yl)-ethyl]-4-(5-fluoro-pyrid in-2-ylmethoxy)-1H-pyridin-2-one

1 -[2-(2,3-Dihydro-1 H-isoindol-5-yl)-ethyl]-4-(5-f luoro-pyridin-2-ylmethoxy)-1 H-pyridin-2-one is prepared following example 18.1 from 5-{2-[4-(5-fluoro-pyridin-2-ylmethoxy)-2-oxo-2/-/-pyridin- 1-yl]-ethyl}-1 ,3-dihydro-isoindole-2-carboxylic acid fert-butyl ester (preparation 29, 340 mg, 0.73 mmol).

Yield: 190 mg (71% of theory) ESI Mass spectrum: [M+H] ⁺ = 366 Retention time HPLC: 0.92 min (method J).

Example 51.2

4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-1 H- pyridin-2-one

4-(5-Fluoro-pyridin-2-ylmethoxy)-1 -[2-(2-methyl-2,3-dihydro-1 H-isoindol-5-yl)-ethyl]-1 H- pyridin-2-one is prepared following example 14.2 from 1-[2-(2,3-dihydro-1H-isoindol-5-yl)- ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)-1/-/-pyridin-2-one (example 51.1, 140 mg, 0.38 mmol) and 37% aqueous formaldehyde solution (47 μl_, 0.58 mmol). Yield: 55 mg (38% of theory)

ESI Mass spectrum: [M+H] ⁺ = 380 Retention time HPLC: 1.46 min (method K).

Example 52 4-Benzyloxy-1 -[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-allyl]-1 /-/-pyridin-2-one

52a 7-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1 -yl)-acetyϊ]-3,4-dihydro-1 H-isoquinoline-2- carboxylic acid tert-butyl ester

To a solution of 4-benzyloxy-1-[2-oxo-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin-

2-one (1.50 g, 4.01 mmol; preparation according to WO 2008022979) and triethylamine (0.85 mL, 6.02 mmol) in 40 mL THF is added Boc-anhydride (0.92 g, 4.21 mmol) and the mixture is stirred for 30 min at ambient temperature. The reaction mixture is poured into water and the resulting precipitate is filtered off, washed with water and dried in vacuo.

Yield: 1.71 g (90% of theory)

ESI Mass spectrum: [M+H] ⁺ = 475.

52b 7-[1-(4-Benzyloxy-2-oxo-2H-pyridin-1-ylmethyl)-vinyl]-3,4-di hydro-1 H-isoquinoline-2- carboxylic acid tert-butyl ester

To a solution of 7-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-acetyl]-3,4-dihydro -1 H-isoquinoline-

2-carboxylic acid tert-butyl ester (example 52a, 0.20 g, 0.42 mmol) in 5.0 mL THF is added a solution of the Tebbe-Reagent (0.84 mL, 0.5 M in toluene, 0.42 mmol) and the reaction mixture is stirred for 18 h at RT. The mixture is quenched with water and extracted with ethyl acetate. The combined organic layer is washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The remaining residue is purified by flash chromatography (silica gel, 10% MeOH in dichloromethane). Yield: 0.02 g (10% of theory)

ESI Mass spectrum: [M+H] ⁺ = 473.

52c 4-Benzyloxy-1 -[2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-allyl]-1 H-pyridin-2-one A solution of 7-[1-(4-benzyloxy-2-oxo-2H-pyridin-1-ylmethyl)-vinyl]-3,4-di hydro-1 H- isoquinoline-2-carboxylic acid tert-butyl ester (example 52b, 0.10 g, 0.42 mmol) in 10 mL 4N HCI in dioxane is stirred for 1 hr at RT. The volatiles are removed under reduced pressure, the residue is triturated with diisopropyl ether, filtered off and dried in vacuo. Yield: 0.055 g (64% of theory) ESI Mass spectrum: [M+H] ⁺ = 373 Retention time HPLC: 2.07 min (method P).

Example 53 4-Benzyloxy-1-[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]-1/-/ -pyridin-2-one

53a 4-Piperidin-2-yl-benzoic acid, acetate salt

To a solution of 4-pyridin-2-yl-benzoic acid (5.00 g, 25 mmol) in 72 ml_ glacial acetic acid is added palladium on charcoal (10%, 2.00 g) and the mixture is hydrogenated in an autoclave (3 days, 3 bar hydrogen, RT). The catalyst is filtered off, the filtrate is concentrated under reduced pressure and the residue is dried in vacuo. The remaining solid is triturated with acetonitrile, filtered off and dried. Yield: 4.4 g (66% of theory) ESI Mass spectrum: [IvRH] ⁺ = 206 Retention time HPLC: 0.67 min (method J).

53b 4-[1-(2,2,2-Trifluoro-acetyl)-piperidin-2-yl]-benzoic acid

To an ice-cooled solution of 4-piperidin-2-yl-benzoic acid, acetate salt (example 53a, 4.40 g,

16.6 mmol) and triethylamine (6.93 ml_, 49.8 mmol) in 100 ml_ dichloromethane is added trifluoroacetic anhydride (4.61 mL, 33.2 mmol). After warming to RT., the reaction mixture is stirred for another hour. The volatiles are removed in vacuo, the residue is dissolved in a small volume of MeOH and purified by preparative HPLC (Gilson, StableBond C18, gradient from 5% to 95% acetonitrile in water + 0.15% HCOOH, 120 mL/min).

Yield: 1.60 g (32% of theory) ESI Mass spectrum: [M-H] ⁺ = 300.

53c N-Methoxy-N-methyl-4-[1 -(2,2,2-trifluoro-acetyl)-piperidin-2-yl]-benzamide (Weinreb amide of 53b)

A solution of 4-[1-(2,2,2-trifluoro-acetyl)-piperidin-2-yl]-benzoic acid (example 53b, 1.60 g, 5.31 mmol), N,O-dimethylhydroxylamine hydrochloride (0.62 g, 6.37 mmol) and 4- methylmorpholine (1.17 mL, 10.6 mmol) in 40 mL MeOH is stirred for 10 min at RT. Then, 4- (4,6-dimethoxy[1 ,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (1.54 g, 5.58 mmol) is added and the reaction mixture is stirred for 18 h at ambient temperature. The reaction mixture is concentrated in vacuo and purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min). Yield: 1.50 g (82 % of theory) ESI Mass spectrum: [M+H] ⁺ = 345

Retention time HPLC: 1.41 min (method J).

53d 1 -(4-Piperidin-2-yl-phenyl)-ethanone

At 0 ⁰ C, methylmagnesium bromide (2.9 ml_ of a 3M solution in diethyl ether, 8.7 mmol) is added to a solution of Weinreb amide 53c (N-methoxy-N-methyl-4-[1-(2,2,2-trifluoro-acetyl)- piperidin-2-yl]-benzamide, 1.50 g, 4.36 mmol) in anhydrous THF (50 ml_). After stirring for 1 h at -5°C, another 2 equivalents of methylmagnesium bromide (2.9 mL) are added to the reaction mixture. After an additional 1 h at -5°C, the reaction mixture is carefully poured into ice-cold 1N aqueous HCI. The volatiles are removed under reduced pressure and the remaining residue is dissolved in water and purified by preparative HPLC (Gilson, Waters

XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min).

Yield: 0.74 g (84 % of theory)

ESI Mass spectrum: [M+H] ⁺ = 204 Retention time HPLC: 1.44 min (method K).

53e 1 -[2-(4-Acetyl-phenyl)-piperidin-1 -yl]-2,2,2-trifluoro-ethanone

To an ice-cooled solution of 1-(4-piperidin-2-yl-phenyl)-ethanone (example 53d, 0.60 g, 2.95 mmol) in 10 mL dichloromethane is added trifluoroacetic anhydride (0.45 mL, 3.25 mmol). After warming to RT, the reaction mixture is stirred for 18 h. The volatiles are removed in vacuo, the residue is dissolved in a small volume of MeOH and purified by preparative HPLC

(Gilson, StableBond C18, gradient from 5% to 95% acetonitrile in water + 0.15% HCOOH,

120 mL/min).

Yield: 0.50 g (57% of theory) ESI Mass spectrum: [M+H] ⁺ = 300

Retention time HPLC: 1.52 min (method J).

53f 1 -{2-[4-(2-Bromo-acetyl)-phenyl]-piperidin-1 -yl}-2,2,2-trifluoro-ethanone

To a solution of 1-[2-(4-acetyl-phenyl)-piperidin-1-yl]-2,2,2-trifluoro-ethan one (example 53e; 0.50 g, 1.67 mmol) in 10 mL THF is added tetrabutylammonium-tribromide (0.81 g, 1.67 mmol) dissolved in MeOH/THF. After stirring for 30 min at RT, the volatiles are removed in vacuo. The residue is stirred with 1N aqueous HCI and extracted with terf-butylmethylether. The organic phase is washed with 1 N aqueous HCI and water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel, 30% ethyl acetate in hexanes). Yield: 0.56 g (89% of theory)

ESI Mass spectrum: [M+H] ⁺ = 378/380.

53g 4-Benzyloxy-1-(2-oxo-2-{4-[1-(2 _l 2,2-trifluoro-acetyl)-piperidin-2-yl]-phenyl}-ethyl)-1/-/- pyridin-2-one To a solution of 4-benzyloxy-1 /-/-pyridin-2-one (149 mg, 0.74 mmol) in 2.0 ml. DMSO is added cesium carbonate (0.60 g, 1.85 mmol) and the mixture is stirred for 15 min at RT. Then, 1-{2- [4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifluoro- ethanone (example 53f, 280 mg, 0.74 mmol) is added and the reaction mixture is stirred for 1 h at RT. Water is added, the precipitate is collected, washed with water and dried. Yield: 340 mg (92% of theory) ESI Mass spectrum: [M+H] ⁺ = 499 Retention time HPLC: 1.63 min (method J).

53h 4-Benzyloxy-1 -[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]-1 H-pyridin-2-one To a solution of 4-benzyloxy-1-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperi din-2-yl]-phenyl}- ethyl)-1 /-/-pyridin-2-one (example 53g, 340 mg, 0.68 mmol) in 10 mL THF and 2.0 mL MeOH is added 1N aqueous NaOH solution (3.4 mL) and the reaction mixture is stirred for 1 h at RT.

The volatiles are removed in vacuo, the residue is dissolved in a small volume of DMF and

MeOH and purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min).

Yield: 180 mg (66% of theory)

ESI Mass spectrum: [M+H] ⁺ = 403

Retention time HPLC: 1.69 min (method K).

Example 54

5-Benzyloxy-2-[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]-2 H-pyridazin-3-one

54a 5-Benzyloxy-2-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperi din-2-yl]-phenyl}-ethyl)-2/-/- pyridazin-3-one

5-Benzyloxy-2-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-pip eridin-2-yl]-phenyl}-ethyl)-2H- pyridazin-3-one is prepared following example 53g from 5-benzyloxy-2/-/-pyridazin-3-one (150

mg, 0.74 mmol) and 1-{2-[4-(2-bromo-acetyl)-phenyl]-piperidin-1-yl}-2,2,2-trifl uoro-ethanone (example 53f, 280 mg, 0.74 mmol). Yield: 300 mg (81% of theory) ESI Mass spectrum: [M+H] ⁺ = 500 Retention time HPLC: 1.70 min (method J).

54b 5-Benzyloxy-2-[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]-2H-p yridazin-3-one 5-Benzyloxy-2-[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]-2/-/ -pyridazin-3-one is prepared following example 53h from 5-benzyloxy-2-(2-oxo-2-{4-[1-(2,2,2-trifluoro-acetyl)-piperi din-2- yl]-phenyl}-ethyl)-2H-pyridazin-3-one (example 54a, 300 mg, 0.60 mmol). Yield: 150 mg (62% of theory) ESI Mass spectrum: [M+H] ⁺ = 404 Retention time HPLC: 1.75 min (method K).

Example 55

4-Benzyloxy-1 -{2-[4-(1 -methyl-piperidin-2-yl)-phenyl]-2-oxo-ethyl}-1 H-pyridin-2-one

To a solution of 4-benzyloxy-1-[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]-1H-p yridin-2-one

(example 53, 120 mg, 0.30 mmol) in THF (5.0 mL), formaldehyde (36 μM of 37% aqueous solution, 0.45 mmol) and aqueous buffer pH 5 (2.0 mL) is added sodium triacetoxyborohydride (95 mg, 0.45 mmol) and the reaction mixture is stirred for 18 h at RT.

The volatiles are removed in vacuo, the residue is dissolved in a small volume of MeOH and purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min). Yield: 122 mg (98% of theory)

ESI Mass spectrum: [M+H] ⁺ = 417

Retention time HPLC: 1.76 min (method K).

Example 56 5-Benzyloxy-2-{2-[4-(1-methyl-piperidin-2-yl)-phenyl]-2-oxo- ethyl}-2H-pyridazin-3-one

5-Benzyloxy-2-{2-[4-(1-methyl-piperidin-2-yl)-phenyl]-2-o xo-ethyl}-2/-/-pyridazin-3-one is prepared following example 55 from 5-benzyloxy-2-[2-oxo-2-(4-piperidin-2-yl-phenyl)-ethyl]- 2/-/-pyridazin-3-one (example 54, 110 mg, 0.27 mmol). Yield: 75 mg (66% of theory)

ESI Mass spectrum: [M+H] ⁺ = 418 Retention time HPLC: 1.85 min (method K).

Example 57 4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2,2-difluoro-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1A7-pyridin-2-one

57a 7-(Ethoxycarbonyl-difluoro-methyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert- butyl ester

To a solution of 7-iodo-3,4-dihydro-1A7-isoquinoline-2-carboxylic acid terf-butyl ester (preparation 27b, 10.0 g, 27.8 mmol) and ethyl difluoroiodoacetate (8.2 mL, 56 mmol) in 40 ml. DMSO is added copper powder (Aldrich, "nano powder", 100 nm, 7.1 g,H 1 mmol) and the mixture is stirred for 18 h at RT. Another 4.0 mL of ethyl difluoroiodoacetate is added and the reaction mixture is stirred for an additional 24 h. The mixture is filtered over a pad of silica gel, washed with DCM/MeOH, concentrated under reduced pressure and purified by preparative HPLC (Agilent, Zorbax Stablebond C18, 7 μm, gradient from 5% to 95% acetonitrile in water + 0.15% HCOOH). Yield: 4.1O g (41% of theory) ESI Mass spectrum: [M+NH ₄ ] ⁺ = 373

Retention time HPLC: 1.88 min (method J).

57b 7-(1 ,1-Difluoro-2-hydroxy-ethyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert- butyl ester

To an ice-cooled solution of 7-(ethoxycarbonyl-difluoro-methyl)-3,4-dihydro-1 H-isoquinoline-2- carboxylic acid tert-butyl ester (example 57a, 4.00 g, 11.3 mmol) in 250 mL MeOH is added sodium borohydride (2.24 g, 56 mmol). The reaction mixture is stirred for 18 h at RT ₁ poured into brine and concentrated under reduced pressure. The aqueous phase is extracted with EtOAc, the organic layer is dried over MgSO ₄ , evaporated in vacuo and purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 5% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mUmin). Yield: 1.54 g (44% of theory) ESI Mass spectrum: [M+NH ₄ ] ⁺ = 314 Retention time HPLC: 1.77 min (method K).

57c 7-[1 ,1-Difluoro-2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1 H-isoquinoline-2- carboxylic acid terf-butyl ester

To a solution of 7-(1,1-difluoro-2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline -2-carboxylic acid tert-butyl ester (example 57b, 1.50 g, 4.79 mmol), triethylamine (0.81 mL, 5.8 mmol), DMAP

(58 mg, 0.48 mmol) in 30 mL dichloromethane is added p-toluenesulfonyl chloride (1.10 g,

5.75 mmol). After stirring for 1 h at RT, the reaction mixture is poured into 20 mL ice water and extracted with DCM. The combined organic layer is washed with water, dried over

MgSO ₄ and evaporated under reduced pressure. Yield: 2.20 g (98% of theory)

ESI Mass spectrum: [M+H] ⁺ = 468

Retention time HPLC: 1.38 min (method L).

57d 7-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1 -yl]-1 , 1 -difluoro-ethyl}-3,4- dihydro-1 H-isoquinoline-2-carboxylic acid fert-butyl ester

To a solution of 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (722 rήg, 2.57 mmol, preparation 10.3) in 3.0 mL DMSO is added cesium carbonate (2.09 g, 6.42 mmol) and the mixture is stirred for 15 min at RT. Then, 7-[1 ,1-difluoro-2-(toluene-4-sulfonyloxy)-ethyl]-3,4- dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 57c, 1200 mg, 2.57 mmol) is added and the reaction mixture is stirred for 4 h at 80 ⁰ C. The reaction mixture is filtered and purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 5% to 95% acetonitrile in water + 0.3% NH ₄ OH, 120 mL/min). Yield: 230 mg (16% of theory) ESI Mass spectrum: [M+H] ⁺ = 576/578 Retention time HPLC: 1.99 min (method K).

57e 4-(5-Bromo-pyridin-2-ylmethoxy)-1 -[2,2-difluoro-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- ethyl]-1 H-pyridin-2-one

To a solution of 7-{2-[4-(5-bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl] -1,1-difluoro- ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example 57d, 230 mg, 0.40 mmol) in 5.0 mL dichloromethane is added 1.5 mL trifluoroacetic acid. After stirring for 1 h at RT, the reaction mixture is evaporated in vacuo and the remaining residue is purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 5% to 95% acetonitrile in water + 0.3% NH ₄ OH ₁ 120 mL/min). Yield: 120 mg (63% of theory) ESI Mass spectrum: [M+H] ⁺ = 476/478

Retention time HPLC: 1.64 min (method K).

Example 58

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2,2-difluoro-2-(2-meth yl-1 ,2,3,4-tetrahydro-isoquinolin-7- yl)-ethyl]-1H-pyridin-2-one

4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2,2-difluoro-2-(2-methyl- 1,2,3,4-tetrahydro-isoquinolin-7- yl)-ethyl]-1A7-pyridin-2-one is prepared following example 55 from 4-(5-bromo-pyridin-2- ylmethoxyJ-i-^^-difluoro^^i^.S^-tetrahydro-isoquinolin^-yO-e thyll-IH-pyridin^-one (example 57, 70 mg, 0.15 mmol). Yield: 50 mg (69% of theory) ESI Mass spectrum: [M+H] ⁺ = 490/492 Retention time HPLC: 1.72 min (method K).

Example 59

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2,2-difluoro-2-(1 ,2,3 _I 4-tetrahydro-isoquinolin-7-yl)-ethyl]- 1H-pyridin-2-one

59a 7-{2-[4-(5-Chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1 -yl]-1 , 1 -difluoro-ethyl}-3,4- dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester y^-K^S-Chloro-pyridin^-ylmethoxy^-oxo^H-pyridin-i-ylJ-i .i-difluoro-ethylJ-a^-dihydro- IH-isoquinoline-2-carboxylic acid fert-butyl ester is prepared following example 57d from 4-(5-chloro-pyridin-2-ylmethoxy)-1 /-/-pyridin-2-one (278 mg, 1.18 mmol, preparation 10.6). Yield: 160 mg (26% of theory) ESI Mass spectrum: [M+H] ⁺ = 532/534 Retention time HPLC: 1.19 min (method O).

59b 4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2,2-difluoro-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)- ethyl]-1 H-pyridin-2-one

4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2,2-difluoro-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-

1 /-/-pyridin-2-one is prepared following example 57e from 7-{2-[4-(5-chloro-pyridin-2- ylmethoxyJ^-oxo^H-pyridin-i-yll-i .i-difluoro-ethylJ-S^-dihydro-I H-isoquinoline^-carboxylic acid tert-butyl ester (preparation 59a, 150 mg, 0.28 mmol).

Yield: 120 mg (99% of theory)

ESI Mass spectrum: [M+H] ⁺ = 432/434

Retention time HPLC: 0.76 min (method O).

Example 60

4-Benzyloxy-1-[2,2-difluoro-2-(1 ,2, 3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin-2-one

60a 7-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-1,1-difluoro-ethyl] -3,4-dihydro-1 H- isoquinoline-2-carboxylic acid /erf-butyl ester

7-[2-(4-Benzyloxy-2-oxo-2H-pyridin-1-yl)-1 ,1-difluoro-ethyl]-3,4-dihydro-1 H-isoquinoline-2- carboxylic acid tert-butyl ester is prepared following example 57d from 4-benzyloxy-1 H- pyridin-2-one (166 mg, 0.82 mmol).

Yield: 75 mg (20% of theory) ESI Mass spectrum: [M+H] ⁺ = 497.

60b 4-Benzyloxy-1 -[2,2-difluoro-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 H-pyridin-2- one

4-Benzyloxy-1 -[2,2-difluoro-2-(1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin-2-one is prepared following example 57e from 7-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-1 ,1-difluoro- ethyl]-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (example 60a, 75 mg, 0.15 mmol). Yield: 60 mg (100% of theory) ESI Mass spectrum: [M+H] ⁺ = 397 Retention time HPLC: 0.92 min (method L).

Example 61 4-Benzyloxy-1-[2,2-difluoro-2-(2-methyl-1 _l 2,3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin- 2-one

4-Benzyloxy-1 -[Z, 2-difluoro-2-(2-methyl-1 , 2, 3,4-tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin- 2-one is prepared following example 55 from 4-benzyloxy-1-[2,2-difluoro-2-(1 ,2,3,4- tetrahydro-isoquinolin-7-yl)-ethyl]-1 /-/-pyridin-2-one (example 60, 35 mg, 0.09 mmol). Yield: 25 mg (69% of theory) ESI Mass spectrum: [M+H] ⁺ = 411 Retention time HPLC: 1.78 min (method K).

Example 62

4-Benzyloxy-1 -[2-(4-imidazol-1 -ylmethyl-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

A solution of 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-1 /-/-pyridin-2-one

(preparation 1 , 250 mg, 0.61 mmol) and imidazole (124 mg, 1.82 mmol) in DMF (2.0 mL) is stirred for 2 h at RT. The reaction mixture is diluted with water, the formed precipitate is filtered off and purified by preparative HPLC (Gilson, StableBond C18, gradient from 5% to

95% acetonitrile in water + 0.15% HCOOH, 120 mL/min).

Yield: 27 mg (11% of theory)

ESI Mass spectrum: [M+H] ⁺ = 400 Retention time HPLC: 2.5 min (method A).

Example 63

4-Benzyloxy-1 -[2-(4-imidazol-1 -ylmethyl-phenyl)-ethyl]-1 H-pyridin-2-one

A solution of 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-ethyl]-1/-/-pyridin- 2-one (preparation according to WO2008022979, 239 mg, 0.60 mmol) and imidazole (163 mg, 2.40 mmol) in DMF (2.0 mL) is stirred for 2 h at RT. The reaction mixture is purified by preparative HPLC (Gilson, Waters XBridge C18, 5 μm, gradient from 10% to 95% acetonitrile in water + 0.3% NH ₄ OH ₁ 120 mL/min). Yield: 157 mg (68% of theory)

ESI Mass spectrum: [M+H] ⁺ = 386 Retention time HPLC: 1.60 min (method K).

Example 64 4-Benzyloxy-1 -{2-[4-(2-oxo-2H-pyridin-1 -ylmethyl)-phenyl]-ethyl}-1 H-pyridin-2-one

To a solution of 2-hydroxypyridine (19 mg, 0.20 mmol) in 3.0 mL THF is added potassium terf-butoxide (24 mg, 0.21 mmol) and the mixture is stirred for 20 min at RT. Then, 4- benzyloxy-1-[2-(4-bromomethyl-phenyl)-ethyl]-1 H-pyridin-2-one (preparation according to WO2008022979, 50 mg, 0.13 mmol) is added and the reaction mixture is stirred for 2 h at 50 ⁰ C. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (XTerra MS C18, gradient from 5% to 95% acetonitrile in water + 0.15% HCOOH ₁ 120 ml_/min). Yield: 23 mg (44% of theory) ESI Mass spectrum: [M+H] ⁺ = 413

Retention time HPLC: 2.81 min (method P).

The following examples can be prepared following the above described procedures:

Some test methods for determining an MCH-receptor antagonistic activity will now be described. In addition, other test methods known to the skilled man may be used, e.g. by inhibiting the MCH-receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and by biosensory measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by plasmon resonance, as described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors", Anal. Biochem. 300 (2002), 132-138. Other methods of testing antagonistic activity to MCH receptors are contained in the references and patent documents mentioned hereinbefore, and the description of the test methods used is hereby incorporated in this application.

MCH-1 receptor binding test

Method: MCH binding to hMCH-1 R transfected cells

Species: Human Test cell: hMCH-1 R stably transfected into CHO/Galpha16 cells

Results: IC50 values

Membranes from CHO/Galpha16 cells stably transfected with human hMCH-1 R are resuspended using a syringe (needle 0.6 x 25 mm) and diluted in test buffer (50 mM HEPES,

10 mM MgCI ₂ , 2 mM EGTA, pH 7.00; 0.1 % bovine serum albumin (protease-free), 0.021 % bacitracin, 1 μg/ml aprotinin, 1 μg/ml leupeptin and 1 μM phosphoramidone) to a concentration of 5 to 15 μg/ml.

200 microlitres of this membrane fraction (contains 1 to 3 μg of protein) are incubated for 60 minutes at ambient temperature with 100 pM of ¹²⁵ l-tyrosyl melanin concentrating hormone

( ¹²⁵ I-MCH commercially obtainable from NEN) and increasing concentrations of the test compound in a final volume of 250 microlitres. After the incubation the reaction is filtered using a cell harvester through 0.5% PEI treated fibreglass filters (GF/B, Unifilter Packard).

The membrane-bound radioactivity retained on the filter is then determined after the addition of scintillator substance (Packard Microscint 20) in a measuring device (TopCount of

Packard). The non-specific binding is defined as bound radioactivity in the presence of 1 micromolar

MCH during the incubation period.

The analysis of the concentration binding curve is carried out on the assumption of one receptor binding site.

Standard: Non-labelled MCH competes with labelled ¹²⁵ I-MCH for the receptor binding with an IC50 value of between 0.06 and 0.15 nM.

The KD value of the radioligand is 0.156 nM.

Relative binding of MCH (as a radioligand) at a concentration of 10 ^'7 M of a respective compound according to this invention is expressed as %CTL and is calculated from the whole concentration curve whereas total specific binding of ligand without a compound according to this invention is set 100%. Values are the mean of two separately performed experiments.

MCH-1 receptor-coupled Ca ²⁺ mobilisation test

Method: Calcium mobilisation test with human MCH (FLIPR ³⁸⁴ ) Species: Human

Test cells: CHO/ Galpha 16 cells stably transfected with hMCH-R1

Results: 1st measurement:: % stimulation of the reference (MCH 10 ^'6 M)

2nd measurement: pKB value

Reagents: HBSS (IOx) (GIBCO)

HEPES buffer (1 M) (GIBCO)

Pluronic F-127 (Molecular Probes)

Fluo-4 (Molecular Probes)

Probenecid (Sigma)

MCH (Bachem) bovine serum albumin (Serva) (protease-free)

DMSO (Serva)

Ham's F12 (BioWhittaker)

FCS (BioWhittaker)

L-Glutamine (GIBCO)

Hygromycin B (GIBCO)

PENStrep (BioWhittaker)

Zeocin (Invitrogen)

Clonal CHO/Galpha16 hMCH-R1 cells are cultivated in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; Cat.No.: BE12-615F). This contains per 500 ml 10% FCS, 1% PENStrep, 5 ml L-glutamine (200 mM stock solution), 3 ml hygromycin B (50 mg/ml in PBS) and 1.25 ml zeocin (100 μg/ml stock solution). One day before the experiment the cells are plated on a 384-well microtitre plate (black-walled with a transparent base, made by Costar) in a density of 2500 cells per cavity and cultivated in the above medium overnight at 37°C, 5% CO ₂ and 95% relative humidity. On the day of the experiment the cells are incubated with cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid have been added, at 37°C for 45 minutes. After charging with fluorescent dye the cells are washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which has been combined with 0.07% Probenicid. The test substances are diluted in Hanks buffer solution, combined with 2.5% DMSO. The background fluorescence of non-stimulated cells is measured in the presence of substance in the 384-well microtitre plate five minutes after the last washing step in the FLIPR ³⁸⁴ apparatus (Molecular Devices; excitation wavelength: 488 nm; emission wavelength: bandpass 510 to 570 nm). To stimulate the cells MCH is diluted in Hanks buffer with 0.1% BSA, pipetted into the 384-well cell culture plate 35 minutes after the last washing step and the MCH-stimulated fluorescence is then measured in the FLIPR ³⁸⁴ apparatus.

Data analysis:

1st measurement: The cellular Ca ²⁺ mobilisation is measured as the peak of the relative fluorescence minus the background and is expressed as the percentage of the maximum signal of the reference (MCH 10 ^"6 M). This measurement serves to identify any possible agonistic effect of a test substance.

2nd measurement: The cellular Ca ²⁺ mobilisation is measured as the peak of the relative fluorescence minus the background and is expressed as the percentage of the maximum signal of the reference (MCH 10 ^"6 M, signal is standardised to 100%). The EC50 values of the MCH dosage activity curve with and without test substance (defined concentration) are determined graphically by the GraphPad Prism 2.01 curve program. MCH antagonists cause the MCH stimulation curve to shift to the right in the graph plotted.

The inhibition is expressed as a pKB value: pKB=lθg(EC50(testsubstance+MCH) / ECsO(MCH) "1 ) "lθg C(testsubslance)

The compounds according to the invention, including their salts, exhibit an excellent MCH- receptor antagonistic activity in the tests mentioned above. Using the MCH-1 receptor binding test described hereinbefore the compounds according to this invention predominantly have IC50 values below 100 nM, in particular below 50 nM.

In order to illustrate that compounds according to the invention with different structural elements possess an excellent MCH-1 receptor antagonistic activity, the %CTL values of the compounds are provided in the following table wherein "Ex. No." means the compound according to the respective example number and "%CTL" means the relative binding of MCH at a concentration of 100 nM of said compound. The measurement of %CTL is described hereinbefore.

Table 1

Some examples of formulations will be described hereinafter, wherein the term "active substance" denotes one or more compounds according to the invention, including their salts. In the case of one of the combinations with one or more active substances described, the term "active substance" also includes the additional active substances.

Example A

Tablets containinq 20 mq of active substance

Composition: active substance 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg

Povidone K 25 1 8 mg

Preparation:

Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.

Example B

Capsules containing 20 mq active substance Composition: active substance 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg

Preparation: Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.

Example C

Suppositories containing 50 mq of active substance Composition: active substance 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg

Preparation: Hard fat is melted at about 38°C; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35°C it is poured into chilled moulds.

Example D

Injectable solution containing 5 mg of active substance per 5 ml Composition: active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 ml

Preparation:

Glycofurol and glucose are dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.

Example E

Injectable solution containing 10 mq of active substance per 1 ml Composition: active substance 10 mg mannitol 50 mg human serum albumin 10 mg water for injections ad 1 ml

Preparation: Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.