CA2558755A1 - Novel alkyne compounds having an mch-antagonistic effect, and medicaments containing said compounds - Google Patents

Abstract

The invention relates to alkyne compounds of general formula (I), wherein the groups and radicals A, B, W, X, Y, Z, R1, and R2 have the meanings indicated in claim 1. The invention further relates to medicaments containing at least one inventive alkyne. The disclosed medicaments are suitable for the treatment of metabolic disorders and/or eating disorders, particularly adiposity and diabetes, as a result of the MCH receptor antagonistic activity thereof.

Description

2 V ~ ~ 1 PCT/EP2005/003686 87055pct Novel alkyne compounds having an MCH-antagonistic effect, and medicaments containing said compounds The present invention relates to new alkyne compounds, 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. Other aspects of this invention relate to processes for preparing the compounds according to the invention.
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 (BM/), 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 very 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-1 R, 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 Gds-coupled MCH-1 R [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, 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 5. Marsh, D.J., 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 certain amine compounds are proposed as MCH
antagonists. Thus, WO 01/21577 (Takeda) describes compounds of formula Ark X-Ar-Y-N~ R

wherein Ar' denotes a cyclic group, X denotes a spacer, Y denotes a bond or a spacer, Ar denotes an aromatic ring which may be fused with a non-aromatic ring, R' and independently of one another denote H or a hydrocarbon group, while R' and R2 together with the adjacent N atom may form an N-containing hetero ring and R2 with Ar may also form a spirocyclic ring, R together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity.
Moreover WO 01/82925 (Takeda) also describes compounds of formula Ark X-Ar-Y-N

wherein Ar' denotes a cyclic group, X and Y represent spacer groups, Ar denotes an optionally substituted fused polycyclic aromatic ring, R' and R2 independently of one another represent H or a hydrocarbon group, while R' and R2 together with the adjacent N atom may form an N-containing heterocyclic ring and RZ together with the adjacent N
atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity, inter alia.
WO 2004/024702 proposes carboxylic acid amide compounds of formula I
O
iX~ /Z\
R-N Y N A-~--W~B

wherein Y, A and B may represent cyclic groups and X, Z and W may denote bridges or bonds, as MCH-antagonists.
WO 04/039780 A1 describes alkyne compounds of formula I
R' N-X-Y- Z W-A-B
R
wherein Y, A and B may denote cyclic groups and X, Z and W may denote bridges or bonds, as MCH-antagonists. The following substances are mentioned, inter alias (1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-dimethyl-amine, 5'-[5-(4-chloro-phenyl)-pyrid in-2-ylethynyl]-3-pyrrolid in-1-yl-3, 4, 5, 6-tetrahyd ro-2 H-[1,2']bipyridinyl, 1'-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-[1,3']bipyrrolidinyl, {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-propyl)-amine, 5-(4-chloro-phenyl)-2-[4-(1-methyl-2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-piperidin-1-yl-pyrrolidin-1-yl)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine, (1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-4-methylpiperidine, 5-(4-chloro-phenyl)-2-[4-(2-methyl-2-piperidin-1-yl-propoxy)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclohexyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclohex-1-enyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclopent-1-enyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclopentyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-propenyl)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylethynyl]-pyridine.

WO 04/039764 A1 describes amide compounds of formula I
R~ -Y- -N-OC-W-A Bl 2iN X Z I ~ Jb R Rs wherein Y, A and B may denote cyclic groups and X denotes an alkylene bridge, Z denotes a bridge or bond and W is selected from the group comprising -CR6aRsb-O-, _CR'a=CR'°-, -CR6aRsb_NR8-, -CR'aR'b-CR'°R'd- and -NR8-CR6aRsb-, as MCH-antagonists.
Aim of the invention The aim of the present invention is to identify new alkyne compounds, particularly those 0 which are especially effective as MCH antagonists. The invention also sets out to provide new alkyne 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 amide 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 alkyne compounds of general formula I
R' N-X-Y- Z W-A-B
so R
wherein R', Rz independently of one another denote H, C,_8-alkyl, C3_,-cycloalkyl or a phenyl or pyridinyl group optionally mono- or polysubstituted by identical or different groups R2° and/or monosubstituted by nitro, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R", and a -CHz- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR'3-, or R' and R2 form a C3~-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R'RZN- group may be replaced by -CH=N-, -CH=CH-, -O-, -S-, -SO-, -(S02)-, -CO-, -C(=CH2)- or -NR'3-, while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R'4, and the alkylene bridge defined hereinbefore may be substituted by one or two identical or different carbo- or heterocyclic groups Cy such that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system;
X denotes a C»-alkylene bridge which comprises one or more substituents selected independently of one another from fluorine, chlorine, hydroxy, cyano, CF3, C»-alkyl, hydroxy-C,_4-alkyl, C3_6-cycloalkyl and C,_4-alkoxy, while two alkyl substituents may be joined together forming a C3_,-cycloalkyl group, or a C2_4-alkylenoxy or CZ_4-alkyleneimino bridge, while the imino group may be substituted by a C,~-alkyl group, and wherein the alkylene unit comprises one or more substituents selected independently of one another from fluorine, CF3, hydroxy-C~_4-alkyl, C~_4-alkyl and C3~-cycloalkyl, while two alkyl groups may be joined together forming a C3_~-cycloalkyl group or if an alkyl group is linked to the imino group, may also be joined together to form a cyclo-C4_6-alkyleneimino group, or a C3_6-alkenylene or C3_6-alkynylene bridge which is unsubstituted or comprises one or more substituents selected independently of one another from fluorine, chlorine, CF3, hydroxy-C~_4-alkyl, C,_4-alkyl and C3_6-cycloalkyl, while two alkyl substituents may be joined together forming a C3_,-cycloalkyl or C5_~-cycloalkenyl group, and W, Z independently of one another denote a single bond or a C,_2-alkylene bridge, while two adjacent C atoms may be joined together with an additional C~_4-alkylene bridge, and one or two C atoms independently of one another may be substituted by one or two identical or different C~_3-alkyl groups, while finro alkyl groups may be joined together to form a carbocyclic ring, and Y, A independently of one another are selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, thienyl, furanyl, benzothienyl or benzofuranyl, while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R2°, in the case of a phenyl ring may also additionally be monosubstituted by vitro, and/or one or more NH groups may be substituted by R2', B has one of the meanings given for Y, A or denotes C,~-alkyl, C,~-alkenyl, C,~-alkynyl, C3_,-cycloalkyl, C5_,-cycloalkenyl, C3_,-cycloalkyl-C,_3-alkyl, C3_,-cycloalkenyl-C,_3-alkyl, C3_,-cycloalkyl-C~_3-alkenyl or C3_,-cycloalkyl-C,_3-alkynyl, wherein one or more C atoms independently of one another may be mono-or polysubstituted by halogen and/ or may be monosubstituted by hydroxy or cyano and/ or cyclic groups may be mono- or polysubstituted by identical or different groups R2o, Cy denotes a carbo- or heterocyclic group selected from one of the following meanings - a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as heteroatom, - a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, while the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, (C,_4-alkyl)-imino, methylene, (C,_4-alkyl)-methylene or di-(C,_4-alkyl)-methylene bridge, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R2°, in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R2', R" denotes halogen, C,_6-alkyl, C2~-alkenyl, C2_6-alkynyl, R'S-O-, R'S-O-CO-, R'S-CO-O-, cyano, R'6R"N-, R'8R'9N-CO- or Cy, while in the above-mentioned groups one or more C atoms may be substituted independently of one another by substituents selected from halogen, OH, CN, CF3, C~_3-alkyl, hydroxy-C~_3-alkyl;
R'3 has one of the meanings given for R", R'4 denotes halogen, cyano, C»-alkyl, C2~-alkenyl, CZ_6-alkynyl, R'S-O-, R'S-O-CO-, R'S-CO-, R'S-CO-O-, R'6R"N-, R'8R'9N-CO-, R'S-O-C,_3-alkyl, R'S-O-CO-C~_3-alkyl, R'S-SOz-NH-, R'S-O-CO-NH-C~_3-alkyl, R'S-S02-NH-C~_3-alkyl, R'S-CO-C,_3-alkyl, R'S-CO-O-C,_3-alkyl, R'6R"N-C~_3-alkyl, R'$R'9N-CO-C,_3-alkyl or Cy-C,_3-alkyl, R'S denotes H, C~_4-alkyl, C3_,-cycloalkyl, C3_,-cycloalkyl-C~_3-alkyl, phenyl, phenyl-C,_3-alkyl, pyridinyl or pyridinyl-C,_3-alkyl, R'6 denotes H, C,~-alkyl, C3_~-cycloalkyl, C3_,-cycloalkyl-C,_3-alkyl, C4_~-cycloalkenyl, C4_,-cycloalkenyl-C,_3-alkyl, c°-hydroxy-C2_3-alkyl, w-(C,~-alkoxy)-C2_3-alkyl, amino-Cz~-alkyl, C,_4-alkyl-amino-C2_s-alkyl, di-(C,_4-alkyl)-amino-C2_6-alkyl or cyclo-C3~-alkyleneimino-C2~-alkyl, R" has one of the meanings given for R'6 or denotes phenyl, phenyl-C,_3-alkyl, pyridinyl, C,_4-alkylcarbonyl, hydroxycarbonyl-C,_3-alkyl, C,_4-alkoxycarbonyl, C,_4-alkoxycarbonyl-C,_3-alkyl, C,_4-alkylcarbonylamino-C2_3-alkyl, N-(C,~,-alkylcarbonyl)-N-(C,_4-alkyl)-amino-CZ_3-alkyl, C,~-alkylsulphonyl, C,_4-alkylsulphonylamino-C2_3-alkyl or N-(C,~-alkylsulphonyl)-N(-C,_4-alkyl)-amino-CZ_3-alkyl;
R'8, R'9 independently of one another denote H or C,~-alkyl, RZ° denotes halogen, hydroxy, cyano, C,.~-alkyl, C2_6-alkenyl, CZ~-alkynyl, C3_,-cycloalkyl, C3_,-cycloalkyl-C,_3-alkyl, hydroxy-C,_3-alkyl, R22-C,_3-alkyl or has one of the meanings given for RZZ, R2' denotes C,_4-alkyl, w-hydroxy-C2~-alkyl, c~-C,_4-alkoxy-C2_6-alkyl, w-C,_4-alkyl-amino-C2_6-alkyl, cu-di-(C,_4-alkyl)-amino-CZ~-alkyl, cu-cyclo-C3_6-alkyleneimino-C2_6-alkyl, phenyl, phenyl-C,_3-alkyl, C,_4-alkyl-carbonyl, C,_4-alkoxy-carbonyl, C,_4-alkylsulphonyl, aminosulphonyl, C,_4-alkylaminosulphonyl, di-C,_4-alkylaminosulphonyl or cyclo-C3~-alkylene-imino-sulphonyl, R22 denotes pyridinyl, phenyl, phenyl-C,_3-alkoxy, cyclo-C3~-alkyleneimino-C2_4-alkoxy, OHC-, HO-N=HC-, C,_4-alkoxy-N=HC-, C,_4-alkoxy, C,_4-alkylthio, carb-oxy, C,_4-alkylcarbonyl, C,~-alkoxycarbonyl, aminocarbonyl, C,~-alkylamino-carbonyl, di-(C,~-alkyl)-aminocarbonyl, cyclo-C3~-alkyl-amino-carbonyl, cyclo-C3_6-alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C3~-alkyleneimino-C2_ 4-alkyl-aminocarbonyl, C,_4-alkyl-sulphonyl, C,_4-alkyl-sulphinyl, C,_4-alkyl-sulphonylamino, amino, C,_4-alkylamino, di-(C,~-alkyl)-amino, C,_4-alkyl-carbonyl-amino, cyclo-C3_6-alkyleneimino, phenyl-C,_3-alkylamino, N-(C,_ 4-alkyl)-phenyl-C,_3-alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C2_3-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or C~_4-alkylaminocarbonylamino, while in the above-mentioned groups and radicals, particularly in W, Z, R4, R'3 to R22, in each case one or more C atoms may additionally be mono- or polysubstituted by F
and/or in each case one or two C atoms independently of one another are additionally monosubstituted by CI
or Br and/or in each case one or more phenyl rings independently of one another may additionally comprise one, two or three substituents selected from the group F, CI, Br, I, cyano, C~~-alkyl, C»-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C,_3-alkylamino, 1 o di-(C~_3-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino C,_3-alkyl, C~_3-alkylamino-C,_3-alkyl and di-(C~_3-alkyl)-amino-C,_3-alkyl and/or may be monosubstituted by vitro, and the H atom of any carboxy group present or 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, while the following compounds are not included in the invention:
(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-dimethyl-amine, 5'-[5-(4-chloro-phenyl )-pyridin-2-ylethynyl]-3-pyrrol id in-1-yl-3, 4, 5, 6-tetrahyd ro-2H-(1,2'jbipyridinyl, 1'-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynylj-pyridin-2-yl}-[1,3']bipyrrolidinyl, {5-[5-(4-chloro-phenyl)-pyrid in-2-ylethynylj-pyrid i n-2-yl}-(2-pyrrolidin-1-yl-propyl)-amine, 5-(4-chloro-phenyl)-2-[4-(1-methyl-2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-piperidin-1-yl-pyrrolidin-1-yl)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine, ( 1-{5-[5-(4-chloro-phenyl )-pyridin-2-yleth ynyl]-pyridin-2-yl}-pyrrolidin-3-yi )-4-methylpiperidine, 5-(4-chloro-phenyl)-2-[4-(2-methyl-2-piperidin-1-yl-propoxy)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclohexyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclohex-1-enyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclopent-1-enyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclopentylj-phenyiethynyi}-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-propenyl)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylethynyl]-pyridine.

The compounds according to the present invention, including the physiologically acceptable salts, are especially effective, compared with known, structurally similar compounds, as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit very good affinity in MCH receptor binding studies. In addition, the compounds according to the invention have a high to very high selectivity with regard to the MCH
receptor. 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.
The invention also relates to the compounds in the form of the individual optical isomers, 1o 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.
15 This invention also includes the physiologically acceptable salts of the alkyne compounds according to the invention as described above and hereinafter.
Also covered by this invention are compositions containing at least one alkyne compound according to the invention and/ or a salt according to the invention optionally together with 20 one or more physiologically acceptable excipients.
Also covered by this invention are pharmaceutical compositions containing at least one alkyne 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 alkyne 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 alkyne 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 alkyne 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 alkyne 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 alkyne 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 alkyne 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 II 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 alkyne 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 alkyne 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 alkyne 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 further relates to processes for preparing for preparing a pharmaceutical composition according to the invention, characterised in that at least one alkyne compound according to the invention and/ or a salt according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
The invention also relates to a pharmaceutical composition containing a first active substance which is selected from the alkyne 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.
Moreover, in one aspect, the invention relates to a process for preparing alkyne compounds of formula A.5 R'R2N-X-Y-C=C-W-A-B (A.5) while in formulae A.1, A.2, A.3, A.4 and A.5 R', R2, X, Y, W, A and B have one of the meanings given hereinbefore and hereinafter, wherein a halogen compound of formula A.1 3o HO-X-Y-Hal (A.1 ) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula A.2 H-C=C-W-A-B(A.2) . WO 2005/103032 14 PCT/EP2005/003686 in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the compound of formula A.3 obtained HO-X-Y-C=C-W-A-B (A.3) is reacted with methanesulphonic acid chloride (MsCI) to produce the methanesulphonate derivative A.4, Ms0-X-Y-C=C-W-A-B (A.4) which is further reacted with an amine of formula H-NR'RZ to form the end product A.S.
This invention further relates to a process for preparing alkyne compounds of formula B.5 R'R2N-X-Y-Z-C=C-A-B (B.5) while in formulae B.1, B.2, B.3, B.4 and B.5 R', R2, X, Y, Z, A and B have one of the meanings given hereinbefore and hereinafter, wherein a halogen compound of formula B.1 Hal-A-B (B.1 ) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula B.2 HO-X-Y-Z-C=C-H (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the resulting compound of formula B.3 HO-X-Y-Z-C=C-A-B (B.3) is reacted with methanesulphonic acid chloride (MsCI) to form the methanesulphonate derivative B.4, Ms0-X-Y-Z-C=C-A-B (B.4) which is reacted further with an amine of formula H-NR'R2 to form the end product B.S.
In addition, the invention relates to a process for preparing alkyne compounds of formula C.3 R'RzN-X-Y-C=C-W-A-B (C.3) while in formulae C.1, C.2 and C.3 R', R2, X, Y, W, A and B have one of the meanings given hereinbefore and hereinafter, wherein a halogen compound of formula C.1 R' R2N-X-Y-Hal (C.1 ) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is further reacted with an alkyne compound of formula C.2 H-C=C-W-A-B ( C.2 ) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to yield the end product C.3.
In another aspect the invention relates to a process for preparing alkyne compounds of formula D.3 R'R2N-X-Y-Z-C=C-A-B (D.3) while in formulae D.1, D.2 and D.3 R', R2, X, Y, Z, A and B have one of the meanings given hereinbefore and hereinafter, wherein a halogen compound of formula D.2 Hal-A-B (D.2) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula D.1 R'RzN-X-Y-Z-C=C-H (D.1 ) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the end product D.3.
The starting materials and intermediate products used in the synthesis according to the invention are also a subject of this invention.
Detailed description of the invention Unless otherwise specified, the groups, residues and substituents, particularly A, B, W, X, Y, Z, Cy, R', R2, R", R'3 to R22, have the meanings given hereinbefore.
If groups, residues and/or substituents occur more than once in a compound, they may have the same or different meanings in each case.
If R' and R2 are not joined together via an alkylene bridge, R' and R2 independently of one another preferably denote a C~_8-alkyl or C3_,-cycloalkyl group mono- or polysubstituted by identical or different groups R", while a -CHZ- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR'3-, or a phenyl or pyridinyl group optionally mono- or polysubstituted by identical or different groups R2° and/or monosubstituted by nitro, while one or both of the groups R' and R2 may also represent H.
Preferred meanings of the group R" are F, CI, Br, C»-alkyl, C2_6-alkenyl, Cz_6-alkynyl, R'S-O-, cyano, R'6R"N-, C3_~-cycloalkyl, cyclo-C3_6-alkyleneimino, pyrrolidinyl, N-(C~_4-alkyl)-pyrrolidinyl, piperidinyl, N-(C,_4-alkyl)-piperidinyl, phenyl and pyridyl, while in the above-mentioned groups and radicals one or more C atoms may be mono- or polysubstituted independently of one another by F, C~_3-alkyl or hydroxy-C~_3-alkyl, and/or one or two C
atoms may be monossubstituted independently of one another by CI, Br, OH, CF3 or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R2°, or in the case of a phenyl group may also additionally be monosubstituted by vitro, and/or one or more NH groups may be substituted by R2'. If R" has one of the meanings R'S-O-, cyano, R'6R"N or cyclo-C3_6-alkyleneimino, the C
atom of the alkyl or cycloalkyl group substituted by R" is preferably not directly connected to a heteroatom, such as for example the group -N-X.
Preferablythe groups R', R2 independently of one another represent H, C,_6-alkyl, C3_5-alkenyl, C3_5-alkynyl, C3_,-cycloalkyl, hydroxy-C3_~-cycloalkyl, C3_,-cycloalkyl-C~_3-alkyl, (hydroxy-C3_,-cycloalkyl)-C,_3-alkyl, hydroxy-C2~-alkyl, co-NC-CZ_3-alkyl, C,_4-alkoxy-C2_4-alkyl, hydroxy-C~.~-alkoxy-C2_4-alkyl, C»-alkoxy-carbonyl-C~~-alkyl, carboxyl-C~_4-alkyl, amino-C2_4-alkyl, C,_4-alkyl-amino-C2_4-alkyl, di-(C,_4-alkyl)-amino-C2_4-alkyl, cyclo-C3_6-alkyleneimino-C2_4-alkyl, pyrrolidin-3-yl, N-(C,_4-alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C~_3-alkyl, N-(C,_4-alkyl)-pyrrolidinyl-C,_3-alkyl, piperidin-3-yl, piperidin-4-yl, N-(C,_4-alkyl)-piperidin-3-yl, N-(C,_4-alkyl)-piperidin-4-yl, piperidinyl-C~_3-alkyl, N-(C,_4-alkyl)-piperidinyl-C,_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, phenyl, phenyl-C,_3-alkyl, pyridyl or pyridyl-C,_3-alkyl, while in the above-mentioned groups and radicals one or more C atoms independently of one another may be mono- or polysubstituted by F, C~_3-alkyl or hydroxy-C,_3-alkyl, and/or one or two C atoms independently of one another may be monosubstituted by CI, Br, OH, CF3 or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C
atoms by identical or different radicals R2°, in the case of a phenyl group may also additionally be monosubstituted by vitro, and/or one or more NH groups may be substituted by Rz'. Preferred substituents of the above-mentioned phenyl or pyridyl groups are selected from the group F, CI, Br, I, cyano, C,~-alkyl, C,~-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C,_3-alkylamino, di-(C,_3-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl and di-(C~_3-alkyl)-amino-C,_3-alkyl, while a phenyl group may also be monosubstituted by vitro.
Particularly preferred definitions of the groups R' and/or R2 are selected from the group consisting of H, C,~-alkyl, hydroxy-C~_4-alkyl, C3_5-alkenyl, C3_5-alkynyl, C3_~-cycloalkyl, hydroxy-C3_~-cycloalkyl, dihydroxy-C3_6-alkyl, C3_~-cycloalkyl-C,_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (hydroxy-C3_,-cycloalkyl)-C,_3-alkyl, c~-(C,_4-alkoxy)-C2_3-alkyl, pyridyl and benzyl, while an alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and/or hydroxy-C,_3-alkyl, and/or mono- or polysubstituted by F or C,_3-alkyl and/or monosubstituted by CF3, Br, CI or CN.

Most particularly preferred groups R' and/or R2 are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-C3_,-cycloalkyl, (hydroxy-C,_3-alkyl)-hydroxy-C3_,-cycloalkyl, dihydroxy-C3_5-alkyl, (1-hydroxy-C3~-cycloalkyl)-methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl, while the above-mentioned groups may be mono- or polysubstituted by F and/or C,_3-alkyl, and the phenyl and pyridyl rings may be substituted as specified.
Examples of most particularly preferred groups R' and/or RZ are therefore H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-cyclopentyl, hydroxy-cyclohexyl, (hydroxymethyl)-hydroxy-cyclopentyl, (hydroxymethyl)-hydroxy-cyclohexyl, 2,3-dihydroxypropyl, 2-hydroxy-1-(hydroxymethyl)-ethyl, 1,1-di(hydroxymethyl)-ethyl, (1-hydroxy-cyclopropyl)-methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and pyridyl.
Particularly preferably, at least one of the groups R', R2, and most particularly preferably both groups, have a meaning other than H.
If R' and R2 form an alkylene bridge, this is preferably a C3_,-alkylene bridge or a C3_~-alkylene bridge, particularly a C3~-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R'R2N- group is replaced by -CH=N-, -CH=CH-, -O-, -S-, -CO- or -NR'3-, while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R'4, and the alkylene bridge defined hereinbefore may be substituted with a carbo- or heterocyclic group cy in such a way that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C- and/or N atoms forming a fused bicyclic ring system or - via three or more C- and/or N atoms forming a bridged ring system.
Preferably also, R' and R~ form an alkylene bridge such that R'RzN- denotes a group which is selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6 tetrahydro-pyridine, 2,3,4,7-tetrahydro-1 H-azepine, 2,3,6,7-tetrahydro-1 H-azepine, piperazine in which the free imine function is substituted by R'3, piperidin-4-one, morpholine and thiomorpholine, is particularly preferably selected from pyrrolidine, piperidine, piperazine in which the free imine function is substituted by R'3, and morpholine, while according to the general definition of R' and R2 one or more H atoms may be replaced by identical or different groups R'4, and/ or the above-mentioned groups may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in a manner specified according to the general definition of R' and R2, while the group Cy may be mono- or polysubstituted by R2°
Particularly preferred groups Cy are C3_~-cycloalkyl, aza-Cue,-cycloalkyl, particularly cyclo-C3~-alkyleneimino, as well as 1-C,~-alkyl-aza-C4_~-cycloalkyl, while the group Cy may be mono- or polysubstituted by RZ°
The C3_$-alkylene bridge formed by R' and R2, wherein -CH2- groups may be replaced as specified, may be substituted, as described, by one or two identical or different carbo- or heterocyclic groups Cy, which may be substituted as specified hereinbefore.
In the event that the alkylene bridge is linked to a group Cy through a single bond, Cy is preferably selected from the group consisting of C3_,-cycloalkyl, cyclo-C3~-alkyleneimino, 1 H-imidazol, thienyl and phenyl.
In the event that the alkylene bridge is linked to a group Cy via a common C
atom forming a spirocyclic ring system, Cy is preferably selected from the group consisting of C3_,-cycloalkyl, aza-C4_$-cycloalkyl, oxa-C4_8-cycloalkyl, 2,3-dihydro-1 H-quinazolin-4-one.
In the event that the alkylene bridge is linked to a group Cy via two common adjacent C
and/or N atoms forming a fused bicyclic ring system, Cy is preferably selected from the group consisting of C4_,-cycloalkyl, phenyl, thienyl.
In the event that the alkylene bridge is linked to a group Cy via three or more C and/or N
atoms forming a bridged ring system, Cy preferably denotes C4_$-cycloalkyl or aza-C4_8-cycloalkyl.

In the event that the heterocyclic group R'R2N- is substituted by a group Cy, the group Cy is preferably linked to the group R'RZN- through a single bond, while Cy is preferably selected from the group consisting of C3_~-cycloalkyl and cyclo-C3~-alkyleneimino, while these groups may be substituted as specified, preferably by fluorine, CF3, C,_3-alkyl, hydroxy-C,_3-alkyl and hydroxy.
Particularly preferably, the group R~ N~' R
is therefore defined according to one of the following partial formulae v ~ v , , 'N
N -r , N ; , ; , , , N--r \ N
N~ , , . , , , N-r , N ~ , R, a ~N
~ , , N-; , ~ ~ N N--~ , U ' N ~ \ , N ' ' , , N
, O N--. , ~ \N-; , ~ N-; , \~ . , R2v N--T N
, , , N ' R2~ N N ; \N ;
R2~~N
\ \
~N N-; , N N
R2? N
N
N . N , -.
N
N ' \ , N . N ~.
N N
R2' \N
N-T
R2' N , RZ? N \J~~N ~.
v N ' \N , N N
R2~ i N
N . R2~ N N

\ . / \
' ~ N-~_ \ N ' ' ~ N . , .
S ' ~ ~ , N~ N-', N
, , , N ~, wherein one or more H atoms of the heterocycle formed by the group R'R2N- may be replaced by identical or different groups R'4, and the heterocycle formed by the group R'R2N- may be substituted by one or two, preferably one C3_,-cycloalkyl group, while the cycloalkyl group may be mono- or polysubstituted by R2°, and the ring linked to the heterocycle formed by the group R'R2N- may be mono- or polysubstituted at one or more C atoms by R2°, and in the case of a phenyl ring may also additionally be monosubstituted by vitro and wherein R'3, R'4, RZ°, R2' have the meanings given above and hereinafter.
If the heterocycle formed by the group R'R2N- is substituted as specified by one or two cycloalkyl groups mono- or polysubstituted by R2°, the substituents RZ° independently of one another preferably denote C,~-alkyl, C,_4-alkoxy-C,_3-alkyl, hydroxy-C,_3-alkyl, hydroxy, fluorine, chlorine, bromine or CF3, particularly hydroxy.
/', Most particularly preferably the group R' is therefore defined according to one of the following partial formulae v . v . , N
N ~ , N-r , ; , v -rt N~ , I .N . , O N-J R'3 N N
~ . , N , ' \ , N--~- N
particularly ' N-y N-r , ; , where R'3 has the meanings given above and hereinafter, and the heterocycle formed by the group R'R2N- may be substituted by C3_6-cycloalkyl, hydroxy-C3_6-cycloalkyl or (hydroxy-C3_6-cycloalkyl)-C,_3-alkyl, and the heterocycle formed by the group R'RZN- may be mono-, di- or trisubstituted by identical or different radicals R'4. The substituents R'4 preferably denote independently of one another F, CI, Br, OH, C~_4-alkyl, C,_4-alkoxy, C,_4-alkoxy-C~_3-alkyl, hydroxy-C,_4-alkyl or CF3, particularly hydroxy, C,_3-alkyl, CF3 or hydroxy-C~_3-alkyl.
If the partial formulae shown above are substituted as specified, the following definitions of the group R'RzN- are particularly preferred: hydroxypyrrolidinyl, hydroxypiperidinyl, 3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl)-pyrrolidinyl, (hydroxymethyl)-piperidinyl, (hydroxymethyl)-hydroxy-pyrrolidinyl, (hydroxymethyl)-hydroxy-piperidinyl, while in the groups specified a hydroxymethyl group at the C atom may be mono-or disubstituted by methyl, while two methyl substituents may be joined together, forming a cyclopropyl group, and while in one or two hydroxy groups the H atom may be replaced by a methyl group, and the groups specified do not have any other substituents or have one or two substituents selected independently of one another from fluorine, hydroxy, C,_3-alkyl, hydroxy-C~_3-alkyl, CF3.
The following partial formulae are most particularly preferred definitions of the above-N~, 1o mentioned heterocyclic group R
N~ N~ , -._ ' ' N ' HO ~NT HO N ; HO N-T
~ , HO N-; N-T F3C N-OH OH
O N~ HO--~N-' ~ HO ' HO HO HO
N . , \ . . N-T , HO N
HO ' HO
HO HO HO
v . ~ ~ ' ' v HO N ; HO N~ HO N
FsC

HO
\ , \ , , N~ , N-1 HO N-T
HO -O
HO HO HO
v , v . v N~ , N . , N
, HO~ HO HO
HO
v N-~ ~ HO , N , HO I
~~N~, HO ' , ~ , , N-~- , N
HO HO
N
HO
N-; N . N
. , , HO HO ~ HO
wherein the groups specified are not further substituted, or wherein methyl or ethyl groups may be mono-, di or trisubstituted by fluorine, and wherein one or more H atoms of the heterocycle formed by the group R'RzN- which are bound to carbon may be substituted independently of one another by fluorine, chlorine, CN, CF3, C~-3-alkyl, hydroxy-C~_3-alkyl, particularly C~_3-alkyl or CF3, preferably methyl, ethyl, CF3.
Among the preferred and particularly preferred meanings of R'R2N- listed above, the following definitions of the substituent R'4 are preferred: F, CI, Br, cyano, C,_4-alkyl, C2_4-alkenyl, Cz_4-alkynyl, C3_~-cycloalkyl, C3_~-cycloalkyl-C~_3-alkyl, hydroxy, hydroxy-C~_3-alkyl, C,_ 4-alkoxy, c~-(C,_4-alkoxy)-C,_3-alkyl, C,_4-alkyl-carbonyl, carboxy, C,_4-alkoxycarbonyl, hydroxy--carbonyl-C~_3-alkyl, C~_4-alkoxycarbonyl-C~_3-alkyl, C~_4-alkoxy-carbonylamino, C,_4-alkoxy-carbonylamino-C,_3-alkyl, amino, C,~-alkyl-amino, C3_,-cycloalkyl-amino, N-(C3_,-cycloalkyl)-N-(C~_4-alkyl)-amino, di-(C,_4-alkyl)-amino, cyclo-C3_6-alkyleneimino, amino-C,_3-alkyl, C~_4-alkyl-amino-C,_3-alkyl, C3_~-cycloalkyl-amino-C,_3-alkyl, N-(C3_,-cycloalkyl)-N-(C,_4-alkyl)-amino-C,_3-alkyl, di-(C,~-alkyl)-amino-C,_3-alkyl, cyclo-C3~-alkyleneimino-C,_3-alkyl, aminocarbonyl, C,_4-alkyl-amino-carbonyl, C3_~-cycloalkyl-amino-carbonyl, N-(C3_,-cycloalkyl)-N-(C,_4-alkyl)-amino-carbonyl, di-(C,_4-alkyl)-amino-carbonyl, pyridinyl-oxy, pyridinyl-amino, pyridinyl-C~_3-alkyl-amino.
Particularly preferred meanings of the substituent R'4 are F, CI, Br, C,_4-alkyl, hydroxy, hydroxy-C~_3-alkyl, C,.~-alkoxy, cu-(C~_4-alkoxy)-C~_3-alkyl, amino-C~_3-alkyl, C,_4-alkyl-amino-C~_3-alkyl, C3_~-cycloalkyl-amino-C,_3-alkyl, N-(C3_,-cycloalkyl)-N-(C»-alkyl)-amino-C~_3-alkyl, di-(C,_4-alkyl)-amino-C~_3-alkyl, cyclo-C3~-alkyleneimino-C,_3-alkyl, aminocarbonyl and pyridylamino.
In the above-mentioned preferred meanings of R'4 in each case one or more C
atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C
atoms may independently of one another additionally be monosubstituted by CI or Br.
Thus, preferred meanings of R'4 also include for example -CF3, -OCF3, CF3-CO- and CF3-CHOH-.
Most particularly preferred meanings of the substituent R'4 are C,_3-alkyl, hydroxy-C,_3-alkyl, methoxymethyl, hydroxy, CF3, CF3-CHOH-, particularly hydroxy, methyl, ethyl, CF3 and hydroxymethyl.
If the bridge X is alkylenoxy or alkyleneimino as defined hereinbefore or hereinafter, the bridge is aligned such that the heteroatom is linked to the group Y. If the bridge X is an alkenylene group, the double bond is not directly attached to the group R'R2N-.
The alkylene group in the group X representing alkylene, alkylenoxy, alkylimino and alkenylene is unbranched without the substituents specified.
According to a first embodiment of the present invention the bridge X denotes a C~_6-alkylene bridge, particularly a C2_4-alkylene bridge, which has one, two, three or more, preferably one, two or three substituents selected independently of one another from fluorine, chlorine, cyano, CF3, hydroxy, C,_4-alkyl, hydroxy-C,_4-alkyl, C3_6-cycloalkyl and C~_4-alkoxy, preferably selected from C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_~-cycloalkyl group.
The bridge X is preferably a propylene bridge, which may be substituted as specified.
Preferably the alkylene bridge has 1, 2 or 3 substituents. Preferred substituents here are fluorine, chlorine, hydroxy, C,_3-alkyl and cyclopropyl, particularly C~_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_6-cycloalkyl group.
Preferred definitions of the bridge X according to this first embodiment are selected from the group consisting of '. , OH
, ,,, ,, , . , ,, OH
,, ~,, ,, , , , ,, , ', , ', , , , ~.,, , .' , , Particularly preferred definitions of the bridge X according to this first embodiment are selected from the group consisting of , , According to a second embodiment of the present invention the bridge X denotes a C2_4-alkylenoxy bridge, particularly a Cz_3-alkylenoxy bridge, which has 1, 2, 3 or more, preferably one, two or three substituents selected independently of one another from fluorine, CF3, C,_4-alkyl, hydroxy-C,_4-alkyl and C3_6-cycloalkyl, preferably selected from C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_,-cycloalkyl group.
The bridge X is preferably an ethylenoxy bridge, which may be substituted as specified.
Preferably the alkylene unit has 1, 2 or 3 substituents. Preferred substituents here are fluorine, C,_3-alkyl and cyclopropyl, particularly methyl, ethyl and i-propyl, while two alkyl substituents may be joined together forming a C3~-cycloalkyl group, particularly a cyclopropyl group.
Preferred definitions of the bridge X according to this second embodiment are selected from the group consisting of , p y~~0~,, , ~ ~.,' ' , , ' , O ' ., , ,, y\~0~,~ , O
O , , , ,, ~,, 0~,, ~ ,' 0~,.
, , O , O
, , , Particularly preferred definitions of the bridge X according to this second embodiment are selected from the group consisting of ,y~~0~,, , O
~/ ~. ' , , O
, , , ~y~~ O
, , ~.,, O
~,, According to a third embodiment of the present invention the bridge X denotes a C2_4-alkyleneimino bridge, particularly a C2_3-alkyleneimino bridge, wherein the imino group may be substituted by a C,_4-alkyl group, and wherein the alkylene unit comprises 1, 2, 3 or more, preferably one, two or three substituents selected independently of one another from fluorine, CF3, C,_4-alkyl, hydroxy-C~_4-alkyl and C3~-cycloalkyl, preferably selected from C~_3-alkyl and cyclopropyl, while two alkyl groups may be joined together forming a C3_,-cycloalkyl group or if an alkyl group is linked to the imino group may also be joined together to form a cyclo-C4_6-alkyleneimino group.
The imino group is preferably unsubstituted or has a C,_3-alkyl substituent, preferably a methyl group.
The bridge X is preferably an ethyleneimino bridge, which may be substituted as specified.
Preferably the alkylene unit has 1, 2 or 3 substituents. Preferred substituents here are fluorine, C~_3-alkyl and cyclopropyl, particularly methyl, ethyl and i-propyl, while two alkyl substituents may be joined together forming a C3~-cycloalkyl group, particularly a cyclopropyl group, or if an alkyl group is linked to the imino group they may also be joined together forming a pyrrolidine or piperidine group.

Preferred definitions of the bridge X according to this second embodiment are selected from the group consisting of , N Y~~N~,, , ~ ~..' ~, . N
N~,. , ~ , N~,, N , . , ,, ~.,, ~,, , ~,, , , N N N
, ~J
N N
, ~.,, , N
, N
, Particularly preferred definitions of the bridge X according to this third embodiment are selected from the group consisting of N~.., , , ,, N~,, According to a fourth embodiment of the present invention the bridge X denotes a C3_6-alkenylene bridge, particularly a C3_4-alkenylene bridge which is unsubstituted or comprises one, two, three or more, preferably one, two or three substituents selected independently of one another from fluorine, chlorine, CF3, C3~-cycloalkyl, C~_4-alkyl and hydroxy-C,_4-alkyl, preferably selected from C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_~-cycloalkyl or C5_~-cycloalkenyl group.
The bridge X is preferably a -CHZ-CH=CH- bridge, which may be substituted as specified.

Preferably the alkenylene bridge is unsubstituted or has 1, 2 or 3 substituents. Preferred substituents here are C~_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3~-cycloalkyl or C5~-cycloalkenyl group.
Preferred definitions of the bridge X according to this fourth embodiment are selected from the group consisting of ' / ~ ', / , , , '' ' , ' / ' , ., , / ' , '' ' ' ' / / ', /
~, ' / , ~ , ' , ' ,, , / , /
' ' , ' , ' / , /
', / , , ', ~.,, ~.,, ' ' , , / ' , Particularly preferred definitions of the bridge X according to this fourth embodiment are selected from the group consisting of ', / , ' , , , '' , , /
, /
For X representing substituted alkenylene, only one of the two possible E/Z
configurations is given above. Obviously, the other of the two E/Z configurations is also included according to the invention.
According to a fifth embodiment of the present invention the bridge X denotes a C3_6-alkynylene bridge, particularly a C3_4-alkynylene bridge which is unsubstituted or comprises one, two, three or more, preferably one, two or three substituents selected independently of one another from fluorine, chlorine, CF3, C3~-cycloalkyl, C,_4-alkyl and hydroxy-C~_4-alkyl, preferably selected from C~_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_~-cycloalkyl group.
The bridge X is preferably a -CHZ-C=C- bridge, which may be substituted as specified.
Preferably the alkynylene bridge is unsubstituted or has 1, 2 or 3 substituents. Preferred substituents are C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together, forming a C3~-cycloalkyl group.
Preferred definitions of the bridge X according to this fifth embodiment are selected from the group consisting of The bridge W preferably denotes a single bond or ethylene, particularly preferably a single bond.

The bridge Z preferably denotes a single bond or ethylene, which may have one or two methyl substituents, which may be joined together forming a cyclopropyl group.
Particularly preferably, Z denotes a single bond.
The group Y preferably has a meaning selected from among the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, benzothienyl, or benzofuranyl, particularly preferably phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, chromanyl, chromen-4-onyl, while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms with identical or different groups R2°, or in the case of a phenyl ring may also additionally be monosubstituted by nitro, and/or may be substituted by R2' at one or more N atoms.
If the group Y is a 6-membered cyclic or heterocyclic group, the bridges X and Z are preferably attached to the group Y in the para position.
Particularly preferably the definition of the group Y is selected from among the bivalent cyclic groups , \ / ~ , . \
N-N
N- -N
\ ~ , N N

N
\ / ' \ /
N
' N \ / ' ' ,~N \ / ' N
_ , N \ / ' ,~N \ / ' N ~
/ ~ , ,-~i ~ , ~N / ; O
~ , /
,, / ~ \ / ;
o / ' ~ , ' , o ', ', o and in particular Y has one of the following meanings / \ ~ . / \ ;

-N '.
, ' ' \
' , O
O
\
.
O
most particularly preferably Y has one of the following meanings / ~ ;
while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C
atoms by identical or different groups R2°, and in the case of a phenyl ring may also additionally be monosubstituted by vitro, and/or one or more NH groups may be substituted by R2'.
The group Y is preferably unsubstituted or mono- or disubstituted.
Particularly preferred substituents R2° of the group Y are selected from the group consisting of fluorine, chlorine, bromine, cyano, vitro, C~_4-alkyl, C2~-alkenyl, hydroxy, c~-hydroxy-C~_3-alkyl, C,_4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, C~~-alkoxy-carbonyl, c~-(C~_4-alkoxy)-C~_3-alkyl, C,_4-alkoxy-carbonylamino, amino, C,~-alkyl-amino, di-(C,_4-alkyl)-amino, aminocarbonyl, C,_4-alkyl-amino-carbonyl and di-(C~_4-alkyl)-amino-carbonyl.
Most particularly preferred substituents R2° of the group Y are selected from amorfg fluorine, chlorine, bromine, cyano, C,_3-alkyl, C~_3-alkoxy, C~_4-alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, or in the case of a phenyl ring vitro as well.
Most particularly preferably the group Y denotes substituted phenylene of the partial formula L' / ~ , wherein L' has one of the meanings given hereinbefore for R2°
preferably F, CI, Br, I, methyl, ethyl, ethenyl, ethynyl, CF3, OCH3, OCF3, -CO-CH3, -COOCH3, CN or N02, or denotes H. Most particularly preferred meanings of the substituent L' are H, F, CI, Br, methyl, ethyl, ethenyl, acetyl or methoxy, particularly H or methyl.
Preferably the group A is selected from among the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be mono- or polysubstituted at one or more C
atoms by identical or different groups R2°, and in the case of a phenyl ring may also additionally be monosubstituted by nitro.
Most particularly preferably, A is one of the groups listed below / ~ ;
. ~ , -N N
, , \ ~ . , N
-N N-/ , / ;
N N
. \ / ~ , N-N
N . . , particularly / \ \ / , or , N-N
most particularly preferably ~ , while the groups listed may be substituted as specified hereinbefore.
Particularly preferred substituents R2° of the group A, independently of one another, are fluorine, chlorine, bromine, amino, CF3, methoxy and C,_3-alkyl.
Preferably is the group A is unsubstituted or monosubstituted by R2°, as specified.
Preferred definitions of the group B according to a first preferred embodiment are selected from the group consisting of phenyl, pyridyl, thienyl and furanyl.
Particularly preferably the group B denotes phenyl. The group B defined as specified may be mono- or polysubstituted by identical or different groups R2°, a phenyl group may additionally also be monosubstituted by vitro. Preferably the group B is unsubstituted or mono-, di- or trisubstituted, particularly unsubstituted or mono- or disubstituted. In the case of a monosubstitution the substituent is preferably in the para position to the group A.
Preferred substituents R2° of the group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, vitro, C,~-alkyl, hydroxy, CHF2, CHFZ-O-, hydroxy-C~_3-alkyl, C,_ 4-alkoxy, trifluoromethyl, trifluoromethoxy, C2_4-alkynyl, carboxy, C, ~-alkoxycarbonyl, w-(C~_ 4-alkoxy)-C~_3-alkyl, C,_4-alkoxy-carbonylamino, amino, C~_4-alkyl-amino, di-(C,_4-alkyl)-amino, cyclo-C3_6-alkyleneimino, aminocarbonyl, C,~-alkyl-amino-carbonyl and di-(C,_4-alkyl)-amino-carbonyl.
Particularly preferred substituents R2° of the group B are selected from the group consisting of fluorine, chlorine, bromine, cyano, CF3, C~_3-alkyl, C~_4-alkoxy and trifluoromethoxy.
Most particularly preferred substituents R2° of the group B are selected from the group consisting of chlorine, bromine and methoxy.
According to a second embodiment the definition of the group B is preferably selected from C~_6-alkyl, C2_6-alkenyl, C2~-alkynyl, C3_~-cycloalkyl, C5_~-cycloalkenyl, C3_,-cycloalkyl-C~_3-alkyl, C3_~-cycloalkenyl-C~_3-alkyl, C3_~-cycloalkyl-C~_3-alkenyl, C3_~-cycloalkyl-C~_3-alkynyl, while one or more C atoms in the groups mentioned for B hereinbefore may be mono- or polysubstituted by fluorine. In the cyclic groups according to the above-mentioned embodiment one or more C atoms may be substituted by Rzo.

Particularly preferred according to this embodiment are the groups C3~-alkyl, C3_6-alkenyl, C3_ 6-alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclopentyl-C,_3-alkyl, cyclopentenyl-C,_3-alkyl, cyclohexyl-C~_3-alkyl, cyclohexenyl-C,_3-alkyl, cycloheptyl-C~_3-alkyl, cycloheptenyl-C~_3-alkyl, while one or more C atoms in the groups mentioned for B hereinbefore may be mono- or polysubstituted by fluorine, and in cyclic groups one or more C atoms may be substituted by identical or different groups R2°.
Most particularly preferably, according to this second embodiment B denotes cyclohexenyl, which is unsubstituted or comprises 1, 2 or 3 identical or different substituents R2°, particularly methyl.
The following are preferred definitions of other substituents according to the invention:
Preferably the substituent R'3 has one of the meanings given for R'6.
Particularly preferably R'3 denotes H, C»-alkyl, C3_~-cycloalkyl, C3_,-cycloalkyl-C,_3-alkyl, w-hydroxy-C2_3-alkyl, w-(C,~-alkoxy)-C2_3-alkyl. Most particularly preferably R'3 denotes H or C,_4-alkyl. The alkyl groups specified above may be monosubstituted by CI or mono- or polysubstituted by F.
Preferred meanings of the substituent R'S are H, C,_4-alkyl, C3_,-cycloalkyl and C3_,-cycloalkyl-C,_3-alkyl, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms may independently of one another additionally be monosubstituted by CI or Br. Particularly preferably, R'S
denotes H, CF3, methyl, ethyl, propyl or butyl.
The substituent R'6 preferably denotes H, C,_4-alkyl, C3_~-cycloalkyl, C3_,-cycloalkyl-C~_3-alkyl, w-hydroxy-C2_3-alkyl or w-(C,_4-alkoxy)-C2_3-alkyl, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms may independently of one another additionally be monosubstituted by CI
or Br. Particularly preferably R'6 denotes H, CF3, C~_3-alkyl, C3~-cycloalkyl or C3~-cycloalkyl-C,_3-alkyl.
Preferably the substituent R" has one of the meanings given as preferred for R'6 or denotes phenyl, phenyl-C,_3-alkyl, pyridinyl or C,_4-alkylcarbonyl. Particularly preferably R" has one of the meanings given as preferred for R'6.

Preferably one or both of the substituents R'8 and R'9 independently of one another denote hydrogen or C»-alkyl, particularly hydrogen.
The substituent Rz° preferably denotes halogen, hydroxy, cyano, C,~-alkyl, CZ_4-alkenyl, C2~-alkynyl, C3_7-cycloalkyl, C3_~-cycloalkyl- C~_3-alkyl, hydroxy-C,_4-alkyl, R22-C,_3-alkyl or one of the meanings given as preferred for R22, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by CI or Br.
Particularly preferred definitions of the group R2° are halogen, hydroxy, cyano, C,_4-alkyl, C3_,-cycloalkyl, C,_3-alkylcarbonyl and C~_4-alkoxy, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by CI
or Br. Most particularly preferably R2° denotes F, CI, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, acetyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.
The substituent R2Z preferably denotes C~_4-alkoxy, C,_4-alkylthio, carboxy, C~_4-alkylcarbonyl, C,_4-alkoxycarbonyl, aminocarbonyl, C,_4-alkylaminocarbonyl, di-(C,~-alkyl)-aminocarbonyl, C,_4-alkyl-sulphonyl, C~_4-alkyl-sulphinyl, C~_4-alkyl-sulphonylamino, amino, C~_4-alkylamino, di-(C,_4-alkyl)-amino, C,_4-alkyl-carbonyl-amino, hydroxy-C,_3-alkylaminocarbonyl, aminocarbonylamino or C,_4-alkylaminocarbonyl-amino, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms may independently of one another additionally be monosubstituted by CI or Br. Most particularly preferred meanings of R22 are C,_4-alkoxy, C~_3-alkylcarbonyl, amino, C~_4-alkylamino, di-(C~_4-alkyl)-amino, wherein one or more H atoms may be replaced by fluorine.
Preferred definitions of the group RZ' are C,~-alkyl, C,_4-alkylcarbonyl, C~_4-alkylsulphonyl, -S02-NH2, -S02-NH-C~_3-alkyl, -SOZ-N(C,_3-alkyl)2 and cyclo-C3_6-alkyleneimino-sulphonyl, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono-or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by CI or Br. Most particularly preferably R2' denotes C,_4-alkyl or CF3.

Cy preferably denotes a C3_,-cycloalkyl, particularly a C3_6-cycloalkyl group, a C5_~-cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R2°, or in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R2'. Most particularly preferred definitions of the group Cy are C3~-cycloalkyl, pyrrolidinyl and piperidinyl, which may be substituted as specified.
The term aryl preferably denotes phenyl or naphthyl, particularly phenyl.
The term heteroaryl preferably includes pyridyl, indolyl, quinolinyl and benzoxazolyl.
Preferred compounds according to the invention are those wherein one or more of the groups, radicals, substituents and/or indices have one of the meanings specified hereinbefore as being preferred.
Particularly preferred compounds according to the invention may be described by one of the general formulae Ila, Ilb, Ilc, Ild, most particularly preferably Ila and Ilb, ~L1 ~L2~n 1 ~m ~L3~P

R / ~ \ ~ _ Ila 2~N X Z N / \ /

R

~Ll~m ~L2y 1 ~L3~

R _ / I \ T P
Ilb R2iN X N / \ /
- Z

N

~Ll~m ~L2~n 1 ~L3~

R P
IIC

2~N X Z ~ / \

R N

~~.1 ~L2O
~m R1 ~L3~P

2~N X Z ~ /
Ild \

R N- N

wherein R', R2, X and Z have one of the meanings given above and L' , L2, L3, independently of one another have one of the meanings given for R2°, and m, n, p independently of one another represent the values 0, 1 or 2, and p may also denote 3.
In particular, in formulae Ila, Ilb, Ilc and Ild, preferably Ila and Ilb Z denotes a single bond, L' denotes fluorine, chlorine, bromine, cyano, C,_3-alkyl, C,_3-alkoxy, C,~-alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, vitro, m denotes 0 or 1, L2 denotes fluorine, chlorine, bromine, CN, amino, CF3, methoxy and C,_3-alkyl, n denotes 0 or 1, L3 independently of one another have a meaning selected from among fluorine, chlorine, bromine, cyano, vitro, C,_4-alkyl, hydroxy, c~-hydroxy-C,_3-alkyl, C,~-alkoxy, trifluoromethyl, trifluoromethoxy, CZ_4-alkynyl, carboxy, C,_4-alkoxycarbonyl, cu-(C,_4-alkoxy)-C,_3-alkyl, C,_ 4-alkoxy-carbonylamino, amino, C,~-alkyl-amino, di-(C,_4-alkyl)-amino, cyclo-C3~-alkyleneimino, aminocarbonyl, C,_4-alkyl-amino-carbonyl or di-(C,_4-alkyl)-amino-carbonyl, particularly preferably fluorine, chlorine, bromine, cyano, CF3, C,_3-alkyl, C,_4-alkoxy and trifluoromethoxy, with the proviso that a phenyl ring may only be monosubstituted by vitro, and p denotes 0, 1, 2 or 3, particularly 1 or 2.
Most particularly preferably, in the formulae Ila, Ilb, Ilc, Ild, particularly Ila and Ilb, R', R2 independently of one another denote C~_4-alkyl, hydroxy-C,~-alkyl, C3_5-alkenyl, C3_5-alkynyl, C3_,-cycloalkyl, hydroxy-C3_,-cycloalkyl, dihydroxy-C3~-alkyl, C3_,-cycloalkyl-C,_3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, (hydroxy-C3_~-cycloalkyl)-C,_3-alkyl, c°-(C,_4-alkoxy) C2_3-alkyl, pyridyl or benzyl, while an alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and/or hydroxy-C,_3-alkyl, and/or mono-or polysubstituted by F or C,_3-alkyl and/or monosubstituted by CF3, Br, CI or CN, and one or both, preferably one of the groups R' and Rz may also denote H, and phenyl and pyridyl rings may be mono- or polysubstituted by identical or different radicals R2°, while phenyl may also be monosubstituted by nitro, or R', R2 are joined together and form, together with the N atom to which they are bound, a heterocyclic group which is selected from pyrrolidine, piperidine, 8-aza-bicyclo[3.2.1]octane, piperazine, wherein the free imine function is substituted by R'3, and morpholine, wherein one or more H atoms may be replaced by identical or different groups R'4, and while the heterocyclic group defined hereinbefore may be substituted through a single bond with a carbo- or heterocyclic group Cy, while Cy is selected from the group consisting of C3_ ,-cycloalkyl and cyclo-C3_6-alkyleneimino, while Cy may be mono- or polysubstituted by identical or different radicals R2°, where R2° is as hereinbefore defined and is preferably selected from fluorine, CF3, C,_3-alkyl, hydroxy-C,_3-alkyl and hydroxy, and R'4 is selected from F, CI, Br, C,_4-alkyl, hydroxy, hydroxy-C~_3-alkyl, C~_4-alkoxy, ur(C,_ 4-alkoxy)-C~_3-alkyl, amino-C~_3-alkyl, C,_4-alkyl-amino-C,_3-alkyl, C3_,-cycloalkyl-amino-C,_3-alkyl, N-(C3_~-cycloalkyl)-N-(C,_4-alkyl)-amino-C,_3-alkyl, di-(C~_4-alkyl)-amino-C,_3-alkyl, cyclo-C3_6-alkyleneimino-C~_3-alkyl, aminocarbonyl and pyridylamino, while in the above-mentioned meanings one or more C atoms may each additionally be mono- or polysubstituted by F and/or in each case one or two C atoms may independently of one another additionally be monosubstituted by CI or Br and X denotes a C2~-alkylene bridge which comprises 1, 2 or 3 substituents selected independently of one another from C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_6-cycloalkyl group, or a C2_3-alkylenoxy bridge which comprises 1, 2 or 3 substituents selected independently of one another from C~_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3~-cycloalkyl group, or a C2_3-alkyleneimino bridge, wherein the imino group may be substituted by a C,~-alkyl group, and wherein the alkylene unit comprises 1, 2 or 3 substituents selected independently of one another from C,_3-alkyl and cyclopropyl, while two alkyl groups may be joined together forming a C3~-cycloalkyl group or if an alkyl group is linked to the imino group, they may also be joined together, forming a pyrrolidine or piperidine group, or a C3_4-alkenylene or C3_4-alkynylene bridge which is unsubstituted or comprises 1, 2 or 3 substituents selected independently of one another from C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3~-cycloalkyl or C5_6-cycloalkenyl group.
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.
Some expressions used hereinbefore and below to describe the compounds according to the invention will now be defined more fully.
The term halogen denotes an atom selected from among F, CI, Br and I, particularly F, CI and Br.
The term C,_"alkyl, where n has a value of 3 to 8, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
The term C~_~-alkylene, where n may have a value of 1 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of such groups include methylene (-CH2-), ethylene (-CHZ-CH2-), 1-methyl-ethylene (-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2-CH2-), n-prop-1,3-ylene (-CHZ-CHZ-CHZ-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop-1,3-ylene (-CH2-CH(CH3)-CH2-), etc., as well as the corresponding mirror-symmetrical forms.

The term C2_~-alkenyl, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and at least one C=C-double bond.
Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.
The term C2_"-alkynyl, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C---C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc.
The term C~_~ alkoxy denotes a C,_~ alkyl-O- group, wherein C,_~ alkyl is defined as above.
Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy etc.
The term C,_~-alkylthio denotes a C,_~ alkyl-S- group, wherein C,_~ alkyl is defined as above.
Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert-pentylthio, n-hexylthio, iso-hexylthio, etc.
The term C~_~ alkylcarbonyl denotes a C,_~-alkyl -C(=O)- group, wherein C~_~
alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tent-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.
The term C3_~ cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3,2,1]octyl, spiro[4,5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
The term C5_n-cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarboxylic group with 5 to n C atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.

The term C3_~ cycloalkylcarbonyl denotes a C3_~-cycloalkyl-C(=O) group, wherein C3_~
cycloalkyl is as hereinbefore defined.
The term aryl denotes a carbocyclic, aromatic ring system, such as for example phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. A particularly preferred meaning of "aryl" is phenyl.
The term cyclo-C3~-alkyleneimino denotes a 4- to 7-membered ring which comprises 3 to 6 methylene units as well as an imino group, while the bond to the residue of the molecule is made via the imino group.
The term cyclo-C3~-alkyleneimino-carbonyl denotes a cyclo-C3_6-alkyleneimino ring as hereinbefore defined which is linked to a carbonyl group via the imino group.
The term heteroaryl used in this application denotes a heterocyclic, aromatic ring system which comprises in addition to at least one C atom one or more heteroatoms selected from N, O and/or S. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The term heteroaryl also comprises the partially hydrogenated heterocyclic, aromatic ring systems, particularly those listed above. Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc. Particularly preferably heteroaryl denotes a heteroaromatic mono-~r bicyclic ring system.
Terms such as C3_~-cycloalkyl-C~_~ alkyl, heteroaryl-C~_~ alkyl, etc. refer to C,_~ alkyl, as defined above, which is substituted with a C3_~-cycloalkyl, aryl or heteroaryl group.
Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

Thus, for example, in the group di-C,_4-alkyl-amino, the two alkyl groups may have the same or different meanings.
The term "unsaturated", for example in "unsaturated carbocyclic group" or "unsaturated heterocyclic group", as used particularly in the definition of the group Cy, comprises in addition to the mono- or polyunsaturated groups, the corresponding, totally unsaturated groups, but particularly the mono- and diunsaturated groups.
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 style used hereinbefore and hereinafter, according to which in a cyclic group a bond of a substituent is shown towards the centre of this cyclic group, indicates unless otherwise stated that this substituent may be bound to any free position of the cyclic group carrying an H atom.
RzoJs Thus in the example ~' the substituent R2° where s = 1 may be bound to any of the free positions of the phenyl ring;
where s = 2 selected substituents R2° may independently of one another be bound to different free positions of the phenyl ring.
The H atom of any carboxy group present or an 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 C,_,s-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C~_~s-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C,_s-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C,_3-alkylsulphonyl-C2_4-alkoxycarbonyl, C,_3-alkoxy-C2_4-alkoxy-CZ_4-alkoxycarbonyl or ReCO-O-(RfCR9)-O-CO- group wherein Re denotes a C,_8-alkyl, C5_,-cycloalkyl, phenyl or phenyl- C,_3-alkyl group, Rf denotes a hydrogen atom, a C,_3-alkyl, C5_,-cycloalkyl or phenyl group and R9 denotes a hydrogen atom, a C,_3-alkyl or ReCO-O-(RfCR9)-O group wherein Re to R9 are as hereinbefore defined, while the phthalimido group is an additional possibility for an amino group, and the above-mentioned ester groups may also be used as a group which can be converted in vivo into a carboxy 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 of general formula I according to the invention may have acid groups, predominantly carboxyl groups, and/or basic groups such as e.g. amino functions.
Compounds of general formula I 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 malefic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine inter alia.
The compounds according to the invention may be obtained using methods of synthesis which are known in principle. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter.
The two reaction plans A and B that follow show the synthesis of the compounds A.5 and B.5 according to the invention, while R', R2, X, Y, Z, W, A and B have one of the meanings described hereinbefore. Hal denotes chlorine, bromine or iodine, particularly bromine or iodine, particularly preferably iodine.
According to reaction plan A the halogen compound A.1 is reacted with the alkyne compound A.2 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective has atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent.
A preferred amount of copper(I)iodide is in the range from 1 to 15 mol%, particularly 5 to 10 mol% based on the educt A.1.
Suitable palladium catalysts are for example Pd(PPh3)4, Pd2(dba)3, Pd(OAc)2, Pd(PPh3)ZCI2, Pd(CH3CN)ZCI2, Pd(dppf)CIZ. The palladium catalyst is preferably used in an amount from 1 to mol%, particularly 5 to 10 mol% based on the educt A.1.
15 Suitable bases are particularly amines, such as for example triethylamine or ethyldiisopropylamine, as well as Cs2C03. The base is preferably used in an at least equimolar amount based on the educt A.1, in excess or as the solvent.
Moreover, suitable solvents are dimethylformamide or ether, such as for example tetrahydrofuran, including the mixtures thereof. The reaction takes place over a period of about 2 to 24 hours in a temperature range of about 20 to 90°C.
The alkyne compound A.3 obtained is reacted directly or after prior purification with methanesulphonic acid chloride to form the methanesulphonate derivative A.4.
The reaction conditions required are known to the skilled man as such. Advantageous solvents are halogenated hydrocarbons, such as for example dichloromethane. Suitable reaction temperatures are usually in the range from 0 to 30°C.
The reaction solution containing the methanesulphonate derivative A.4 or the purified methanesulphonate derivative A.4, dissolved in a suitable solvent, is reacted with an amine H-NR'R2 to yield the end product A.5 and then optionally purified. If the amine H-NR'R2 has another primary or secondary amino function, this is advantageously provided with a protective group beforehand, which can be cleaved again after the reaction has ended, using methods known from the literature. The product thus obtained may for example be converted into the salt form by reaction with a corresponding acid. A preferred molar ratio of the derivative A.4 to the amine compound is in the range from 1.5 : 1 to 1 : 1.5.
Suitable solvents are dimethylformamide or ether, such as for example tetrahydrofuran, including the mixtures thereof.
The reaction to form the product A.5 is advantageously carried out in a temperature range from about 20 to 90°C.
Reaction plan A:
HO-X-Y-Hal + H-C=C-W-A-B
(A.1) (A.2) Cul [Pd]
HO-X-Y-C=C-W-A-B (A.3) MsCI
Ms0-X-Y-C=C-W-A-B (A.4) HNR~R2 R~RZN- X-Y-C-C-W-A-B (A.5) According to reaction plan B the halogen compound B.2 is reacted with the alkyne compound B.1 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent. Information on suitable reaction conditions, including catalysts, bases and solvents, may be found in the explanations of reaction plan A.

The alkyne compound B.3 obtained is reacted directly, or after prior purification, with methanesulphonic acid chloride to form the methanesulphonate derivative B.4.
The reaction conditions to be respected can again be found in the remarks accompanying Diagram A.
The reaction solution containing the methanesulphonate derivative B.4 or the purified methanesulphonate derivative B.4, dissolved in a suitable solvent, is reacted with an amine H-NR'R2 to form the end product B.5 and then optionally purified. Here again, the remarks concerning Diagram A apply.
Reaction plan B:
HO-X-Y-Z- C-C-H + Hal-A-B
(B.1) (B.2) Cul [Pd]
HO-X-Y-Z- C-C-A-B (B.3) MsCI
Ms0-X-Y-Z-C=C-A-B (B.4) HNR~R2 R'R2N-X-Y-Z-C=C-A-B (B.5) According to the other reaction plan C the halogen compound C.1 is reacted with the alkyne compound C.2 in a molar ratio of about 1.5 : 1 to 1 : 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the product C.3 directly. Information on suitable reaction conditions, including catalysts, bases and solvents, may be found in the explanatory remarks accompanying reaction plan A.
Reaction plan C:
R'R2N-X-Y-Hal + H-C=C-W-A-B
(C.1 ) (C.2) Cul [Pd]
R'R2N- X-Y-C-C-W-A-B (C.3) An alternative method of synthesis to this is shown in reaction plan D.
According to this, the halogen compound D.2 is reacted with the alkyne compound D.1 in a molar ratio of about 1.5 1 to 1 : 1.5 under a protective gas atmosphere in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the product D.3 directly. Once again, information on suitable reaction conditions, including catalysts, bases and solvents, may be found in the explanatory remarks accompanying reaction plan A.
Reaction plan D:
R'R2N-X-Y-Z- C=C-H + Hal-A-B
(D.1 ) (D.2) Cul [Pd]
R'R2N-X-Y-Z- C-C-A-B (D.3) The reactions according to plans A, B, C and D are particularly advantageously carried out with the corresponding iodine compounds A.1, B.2, C.1 and D.2. In the event that Hal denotes bromine in compounds A.1, B.2, C.1 or D.2, it is advantageous to convert it into the corresponding iodine compound beforehand. One particularly advantageous method is the Aryl-Finkelstein reaction (Klapars, Artis; Buchwald, Stephen L.. Copper-Catalyzed Halogen Exchange in Aryl Halides: An Aromatic Finkelstein Reaction. Journal of the American Chemical Society (2002), 124(50), 14844-14845). Thus, for example, the halogen compound A.1, B.2, C.1 or D.2 may be reacted with sodium iodide in the presence of N,N'-dimethyl-ethylenediamine and copper(I)iodide in a suitable solvent to form the corresponding iodine compound. An advantageous molar ratio of the halogen compound to sodium iodide is 1 : 1.8 to 1 : 2.3. N, N'-dimethyl-ethylenediamine is advantageously used in a molar ratio of 10 to 30 mol% based on the halogen compound A.1, B.2, C.1 or D.2. Preferred amounts of copper(I)iodide are in the range from 5 to 20 mol% based on the halogen compound A.1, B.2, C.1 or D.2. A suitable solvent is for example 1,4-dioxane. Suitable reaction temperatures are in the range from about 20 to 110°C. The reaction is substantially complete after 2 to 72 hours.
The compounds according to the invention may be obtained using methods of synthesis which are known in principle. Preferably the compounds are obtained analogously to the methods of preparation explained more fully in the experimental section.
Stereoisomeric compounds of formula (I) 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 covered by general formula (I) 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 (+)-camphorsulphonic 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 of formula (I) 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 of general formula (I) 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 of formula (I) 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 of formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen, the compound of formula (I) may also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion. 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 malefic acid.
Moreover, mixtures of the above mentioned acids may be used. To prepare the alkali and alkaline earth metal salts of the compound of formula (I) with acidically bound hydrogen the alkali and alkaline earth metal hydroxides and hydrides are preferably used, while the hydroxides and hydrides of the alkali metals, particularly of sodium and potassium, are preferred and sodium and potassium hydroxide are most preferred.
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.
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 II
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 well-being 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 sub-cutaneous 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 alkyne 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, a-glucosidase inhibitors, (33 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, 2o human insulin obtained by genetic engineering, e.g. from Escherichi 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.
a-Glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
(33 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 1 B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide.
Active substances for the treatment of diabetic complications 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 GIaxoSmithkline).
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 (33 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 GI 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 II
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 II 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, cerivastatin, itavastatin, ZD-4522 and their salts.
Fibrate compounds include 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.
In another embodiment the invention also relates to the use of at least one alkyne 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. 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.
The Examples that follow are intended to illustrate the invention:
Preliminary remarks As a rule, IR, 1 H-NMR and/or mass spectra have been obtained for the compounds prepared.
Unless otherwise stated the Rf values were determined using ready-made silica gel 60 TLC
plates F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The Rf values obtained under the heading Alox were determined using ready-made aluminium oxide 60 TLC plates F254 (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. For chromatographic purification, silica gel made by Messrs Millipore (MATREXTM, 35-70 my) or Alox (E. Merck, Darmstadt, standardised aluminium oxide 90, 63-200 pm, Item No.:
1.01097.9050) is used. The ratios specified for the eluants are based on units by volume of the solvents in question. The specified units by volume of NH3 solutions relate to a concentrated solution of NH3 in water. Unless otherwise stated the acid, base and salt solutions used for working up the reaction solutions are aqueous systems of the concentrations specified.
The HPLC data specified were measured under the parameters indicated below:
Analytical columns: Zorbax column (Agilent Technologies), SB (Stable Bond) -C18; 3.5 Nm;
4.6 x 75 mm; column temperature: 30°C; flow: 0.8 mL / min; injection volume: 5 NL; detection at 254 nm (methods A, B and F).
Analytical columns: Zorbax column (Agilent Technologies), Bonus RP C14; 3.5 um; 4.6 x 75 mm; column temperature: 30°C; flow: 0.8 mL / min; injection volume: 5 uL; detection at 254 nm (methods C, D and E) method A:
percent by volume of waterpercent by volume of acetonitrile time (min) (with 0.1 % formic acid) (with 0.1 % formic acid) method B:
time (min) percent by volume of waterpercent by volume of acetonitrile (with 0.1 % formic acid) (with 0.1 % formic acid) method C:
time (min) percent by volume of percent by volume of acetonitrile water (with 0.1% formic acid) (with 0.1% formic acid) method D:
time (min) percent by volume of percent by volume of acetonitrile water (with 0.1 % formic acid) (with 0.1 % formic acid) 10 method E:
time (min) percent by volume of water percent by volume of acetonitrile (with 0.1% formic acid) (with 0.1% formic acid) method F:
time (min) percent by volume of waterpercent by volume of acetonitrile (with 0.1 % formic acid) (with 0.1 % formic acid) Preparative column: Zorbax column (Agilent Technologies), SB (Stable Bond) -C18; 3.5 pm;
5 30 x 100 mm; column temperature: ambient temperature; flow: 30 mL / min;
detection at 254 nm.
In preparative HPLC purification, as a rule the same gradients are used which were used when obtaining the analytical HPLC data.
The products are collected under mass control, the fractions containing the product are 10 combined and freeze-dried.
Chromatographic purification with Hyperprep made by Messrs Thermohypersil, Darmstadt:
Stationary phase HS C18; 8NM (eluant A (water+0.15%HCOOH), eluant B
(methanol)).
Temperatures are given in degrees Celsius (°C) ; times are generally given in minutes (min), hours (h) or days (d). If there is no specific information as to the configuration, it is not clear whether there are pure enantiomers or whether partial or even total racemisation has taken place.
The following abbreviations are used above and hereinafter:
AcOH acetic acid CDI 1,1 '-carbonydiimidazole DCM dichloromethane DIAD diisopropylazodicarboxylate DIPE diisopropylether DMF dimethylformamide WO 2005/103032 64 PCT/EP2005/0036$6 dppf 1,1 ~-bis(diphenylphosphino)ferrocene EtOAc ethyl acetate conc. concentrated MeOH methanol PE petroleum ether RT ambient temperature TBAF tetrabutyammoniumfluorid trihydrate TBME tert-butylmethylether THF tetrahydrofuran -~* denotes the bonding site of a group General experimental method I (Sonogashira couplings) Under an argon atmosphere, a suitable palladium catalyst (e.g. Pd(PPh3)4 (5 mol%), Pd(PPh3)2C12 (5 mol%), Pd(CH3CN)CI2 (5 mol%) or Pd(dppf)CI2 (5 or 10 mol%)), a suitable base (e.g. caesium carbonate (1.5 eq) or triethylamine (1.5 eq.)) and Cul (5 or 10 mol%) are added successively to a solution of the aryl or heteroaryl iodide or bromide (1.0 eq) and the alkyne (1.05 eq) in THF or DMF. The reaction solution is stirred at RT to 90°C for between 2-24 h, filtered and the solvent is eliminated i.vac.. Further purification is carried out by column chromatography or by purification using HPLC-MS.
General experimental method II (bromine-iodine exchange) Nal (2.0 eq), N,N'-dimethyl-ethylenediamine (0.2 eq.) and Cul (0.1 eq.) are added successively to a solution of the aryl or heteroaryl bromide (1.0 eq.) in 1,4-dioxane under argon. The reaction is stirred for 2-72 h at RT to 110°C and then diluted with NH3. The aqueous phase is extracted with DCM, the organic phase is dried over MgS04 and the solvent is eliminated i.vac.. If necessary further purification is carried out by column chromatography.
Component 1 5-(4-chloro-phenyl)-2-ethynyl-pyridine ci ~J
N
BS1 a 5-bromo-2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridine Under an argon atmosphere 0.80 g (4.20 mmol) Cul and 2.90 g (4.13 mmol) bis-triphenylphosphane-palladium(II)-chloride are added to a solution of 49.90 g (201.0 mmol) 2,5-dibromopyridine and 43.0 mL (225.6 mmol) tert-butyl-ethynyl-dimethyl-silane in 500 mL
dry THF and 120 mL triethylamine at -7 °C and the mixture is stirred for 30 min at 0 °C. The reaction mixture is stirred for a further 3.5 h at RT, then filtered and the filtrate is evaporated down i. vac.. The residue is dissolved in 1 L EtOAc, the organic phase is washed with water and saturated NaCI solution, dried over Na2S04 and evaporated down i. vac..
The crude product is reacted further without purification.
Yield: 59.5 g (quant. yield) C,3H,gBrNSi (M= 296.278) Calc.: molpeak (M+H)+: 296/298 (Br) Found: molpeak (M+H)+: 296/298 (Br) Rf value: 0.75 (silica gel, cyc/EtOAc 8:1 ) BS1b 2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-5-(4-chloro-phenyl)-pyridine 250 mL MeOH, 220 mL 2 N Na2C03 solution and 1.80 g (2.46 mmol) PdCl2(dppf) are added to a solution of 59.5 g (201.0 mmol) 5-bromo-2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridine and 36.5 g (233.4 mmol) 4-chlorophenylboric acid in 600 mL 1,4-dioxane and the mixture is refluxed for 1 h. The reaction mixture is evaporated down i. vac. and diluted with EtOAc. The organic phase is washed with water and semisaturated NaHC03 solution, dried over Na2S04 and evaporated down i. vac.. The residue is purified by column chromatography (silica gel, cyc/EtOAc 9:1 ).
Yield: 38.5 g (58% of theoretical) C~9H22CINSi (M= 327.923) Calc.: molpeak (M+H)+: 328/330 (CI) Found: molpeak (M+H)+: 328/330 (CI) Rf value: 0.60 (silica gel, cyc/EtOAc 8:1 ) BS1c 5-(4-chloro-phenyl)-2-ethynyl-pyridine 43.66 g (156.0 mmol) TBAF are added at RT to a solution of 46.50 g (142.0 mmol) 2-[(tert butyl-dimethyl-silanyl)-ethynyl]-5-(4-chloro-phenyl)-pyridine in 1 L DCM and the- mixture is stirred for 2 h. The organic phase is washed with water, dried over NaZS04 and evaporated down i. vac.. The residue is stirred with DIPE, the precipitate is filtered off and washed with PE.
Yield: 26.0 g (86% of theoretical) C~3H8CIN (M= 213.662) Calc.: molpeak (M+H)+: 214/216 (CI) Found: molpeak (M+H)+: 214/216 (CI) Rf value: 0.30 (silica gel, cyc/EtOAc 4:1 ).

Amine A1 2,2,2-trifluoro-1-piperidin-4-yl-ethanol H
F3C l ~~ H
A1a benzyl4-(2,2,2-trifluoro-1-hydroxy-ethyl)-piperidine-1-carboxylate 0.46 g (3.0 mmol) caesium fluoride are added to a solution of 7.42 g (30.0 mmol) benzyl 4-formyl-piperidine-1-carboxylate in 120 mL THF, the mixture is cooled to -10°C, 18.0 mL (36.0 mmol) trimethyl-trifluoromethyl-silane (2.5 M in THF) are slowly added, the mixture is stirred for 1.5 h at -10°C and 1.5 h at RT. 120 mL of 1 N HCI are added dropwise and the mixture is stirred for 1 h. The organic phase is separated off and dried over NaZS04.
After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 4:1 ).
Yield: 4.15 g (44% of theoretical) C~5H~8F3N03 (M= 317.304) Calc.: molpeak (M+H)+: 318 Found: molpeak (M+H)+: 318 HPLC-MS: 8.3 min (method A).
A1 b 2,2,2-trifluoro-1-piperidin-4-yl-ethanol A suspension of 3.11 g (9.80 mmol) benzyl 4-(2,2,2-trifluoro-1-hydroxy-ethyl)-piperidine-1-carboxylate and 300 mg 10% Pd/C in 30 mL MeOH is hydrogenated at RT and 3 bar hydrogen pressure for 4 h. The catalyst is filtered off and the filtrate is evaporated down i.vac.
Yield: 1.82 g (quant. yield) C~H~2F3N0 (M= 183.172) Calc.: molpeak (M+H)+: 184 Found: molpeak (M+H)+: 184 Rf value: 0.20 (silica gel, EtOAc/MeOH/NH3 50:50:5).
Amine A2 4-methyl-1-pyrrolidin-3-yl-piperidine N
~NH

A2a 1-(1-benzyl-pyrrolidin-3-yl)-4-methyl-piperidine 13.0 g (61.5 mmol) sodium triacetoxyborohydride and 2.37 mL (41.44 mmol) AcOH
are added to a solution of 6.0 mL (50.7 mmol) 4-methylpiperidine and 8.14 mL (50.7 mmol) 1-benzyl-pyrrolidin-3-one in 200 mL THF and the reaction solution is stirred overnight at RT. Saturated NaHC03 solution is added to the reaction mixture, which is exhaustively extracted with EtOAc and the combined organic phases are dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM/MeOH/NH3 90:10:1 ).
Yield: 6.58 g (50% of theoretical) C»H26N2 (M= 258.402) Calc.: molpeak (M+H)+: 259 Found: molpeak (M+H)': 259 Rf value: 0.45 (silica gel, DCM/MeOH/NH3 90:10:1 ) A2b 4-methyl-1-pyrrolidin-3-yl-piperidine A solution of 6.58 g (25.46 mmol) 1-(1-benzyl-pyrrolidin-3-yl)-4-methyl-piperidine in 60 mL
MeOH is combined with 0.6 g 10% Pd/C and hydrogenated at RT and 4 bar until the theoretical amount of hydrogen has been taken up (4 h). The catalyst is filtered off, washed with MeOH and the solvent is evaporated down i.vac. .
Yield: 3.09 g (72% of theoretical) C~oH2oNz (M= 168.279) Calc.: molpeak (M+H)+: 169 Found: molpeak (M+H)+: 169 retention time HPLC: 1.0 min (method A).
Example 1 5-(4-chloro-phenyl)-2-{4-[3-(3,5-dimethyl-piperidin-1-yl)-cyclohexyl]-phenylethynyl}-pyridine 1 a 3-(4-bromo-phenyl)-cyclohex-2-enone . WO 2005/103032 68 PCT/EP2005/003686 Approx. 0.1 mL dibromoethane is added to a suspension of 3.91 g (161 mmol) magnesium chips and 3.80 g (16.1 mmol) 1,4-dibromobenzene in 700 mL diethyl ether and heated to 35°C. Then the remaining 1,4-dibromobenzene (34.2 g, 144.9 mmol) is slowly added dropwise to 400 mL ether and the reaction is refluxed for 1 h. 16.1 g (128 mmol) 3-methoxy-cyclohex-2-enone in 25 mL diethyl ether is slowly added dropwise and the reaction mixture is stirred for 1 h at RT, before being added to 1000 mL of 1 M sulphuric acid.
The aqueous phase is extracted three times with TBME. The organic phase is washed twice with 500 mL
water and dried over MgS04. After filtration through activated charcoal the solvent is removed i.vac.. Further purification is carried out by column chromatography on silica gel (PE towards PE/EtOAc 7:3).
Yield: 15.7 g (40.4 % of theoretical) C12H11Br0 (M= 251.100) Calc.: molpeak (M+H)+: 251/253 (Br) Found: molpeak (M+H)+: 251/253 (Br) Rf value: 0.25 (silica gel, PE/EtOAc 8:2).
1 b 3-(4-bromo-phenyl)-cyclohexanol 7.00 mL (7.00 mmol) einer 1 M lithium aluminium hydride solution in THF is added dropwise at -5°C to a solution of 1.76 g (7.00 mmol) 3-(4-bromo-phenyl)-cyclohex-2-enone in 50 mL
THF. The reaction solution is heated to RT. After working up by the Fieser/Fieser method and filtration the organic phase is dried over MgS04. After filtration through activated charcoal the solvent is eliminated i. vac. and the crude product is reacted further without any further purification.
Yield: 1.70 g (95.0 % of theoretical) C12H15Br0 (M= 255.200) Calc.: molpeak (M-H20): 236/238 (Br) Found: molpeak (M-H20): 236/238 (Br) Rf value: 0.57 (silica gel, PE/EtOAc 6:4).
1c 3-(4-lod-phenyl)-cyclohexanol Prepared according to general method II from 3-(4-bromo-phenyl)-cyclohexanol (1.90 g, 7.45 mmol).
Yield: 2.10 g (93.3 % of theoretical) C12H1510 (M= 302.151) Calc.: molpeak (M)+: 302 Found: molpeak (M)+: 302 Rf value: 0.60 (silica gel, PE/EtOAc 6:4).
1d 3-(4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohexanol Prepared according to general method I from 3-(4-iodo-phenyl)-cyclohexanol (755 mg, 2.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (534 mg, 2.50 mmol).
Yield: 520 mg (53.6 % of theoretical) C25H22CIN0 (M= 387.901 ) Calc.: molpeak (M+H)+: 388/390 (CI) Found: molpeak (M+H)+: 388/390 (CI) R, value: 0.07 (silica gel, PE/EtOAc 8:2).
1e 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohexyl methanesulphonate 0.22 mL pyridine (2.70 mmol) and 0.21 mL (2.68 mmol) methanesulphonic acid chloride are added at 0°C to a solution of 520 mg (1.34 mmol) 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohexanol in 20 mL DCM. The reaction solution is stirred for 2 h at RT
and a conversion of 10% is detected. Another 1.21 mL (15.44 mmol) methanesulphonic acid chloride and 0.5 mL (6.22 mmol) pyridine are added. After the reaction is complete water is added and the organic phase is washed with dilute NaHC03 solution. The organic phase is dried over MgS04 and after filtration through activated charcoal the solvent is eliminated i.
vac.. Further purification is carried out by column chromatography on silica gel (DCM/EtOAc 8:2).
Yield: 300 mg (48.0 % of theoretical) C26H24CIN03S (M= 465.992) Calc.: molpeak (M+H)+: 466/468 (CI) Found: molpeak (M+H)+: 466/468 (CI) Rf value: 0.90 (silica gel, DCM/EtOAc 9:1 ).
1f 5-(4-chloro-phenyl)-2-{4-[3-(3,5-dimethyl-piperidin-1-yl)-cyclohexyl]-phenylethynyl}-pyridine 119 mg (1.05 mmol) 3,5-dimethylpiperidine are added to a solution of 100 mg (0.21 mmol) 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohexyl methanesulphonate in 2.0 mL
DMF and the reaction solution is stirred overnight at 60°C and for a further 8 h at 90°C. The reaction mixture is cooled to -10°C and after filtration the residue is stirred with TBME.
Yield: 8.5 mg (8.0 % of theoretical) C32H35CIN2 (M= 483.086) Calc.: molpeak (M+H)+: 483/485 (CI) Found: molpeak (M+H)+: 388/390 (CI) Rf value: 0.47 (silica gel, EtOAc/MeOH/NH3 8:2).
Example 2 1'-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-4-methyl-[1,3']bipiperidinyl ~1 U
2a 1'-benzyl-4-methyl-[1,3']bipiperidinyl 3.82 g (18.0 mmol) NaBH(OAc)3 are added to a solution of 1.78 mL (15.0 mmol) 4 methylpiperidine and 3.66 g (15.0 mmol) N-benzylpiperidin-3-one hydrochloride hydrate in 100 mL THF and the solution is acidified slightly with glacial acetic acid.
The reaction solution is stirred overnight at RT. The solvent is eliminated i. vac. and the residue is combined with saturated NaHC03 solution. The aqueous phase is extracted twice with EtOAc and the organic phase is washed with saturated NaHC03 solution, dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM after DCM/MeOH 8:2).
Yield: 500 mg (12.2 % of theoretical) C18H28N2 (M= 272.428) Calc.: molpeak (M+H)+: 273 Found: molpeak (M+H)+: 273 Rf value: 0.18 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
2b 4-methyl-[1,3']bipiperidinyl A solution of 500 mg (1.84 mmol) 1'-benzyl-4-methyl-[1,3']bipiperidinyl in 25 mL methanol is combined with 100 mg 10% Pd(OH)Z and hydrogenated in the autoclave at RT and 3 bar H2 until the theoretical amount of hydrogen has been taken up. The catalyst is suction filtered and the filtrate concentrated by evaporation. The crude product is reacted further without any further purification.
Yield: 0.35 g (99.4% of theoretical; content 95%) C11 H22N2 (M= 182.306) Calc.: molpeak (M+H)+: 183 Found: molpeak (M+H)': 183 Rf value: 0.08 (silica gel, EtOAc/MeOH/NH3 9:1:0.1 ).
2c 1'-(4-bromo-phenyl)-4-methyl-[1,3']bipiperidinyl 566 mg (2.00 mmol) 4-bromiodobenzene, 7.6 mg (0.04 mmol) Cul, 849 mg (4.00 mmol) potassium phosphate and 248 mg (4.00 mmol) ethane-1,2-diol are added to a solution of 350 mg (1.92 mmol) 4-methyl-[1,3']bipiperidinyl in 2.0 mL isopropanol in an argon atmosphere.
The reaction mixture is stirred overnight at 80°C and then combined with 100 mL EtOAc. The organic phase is extracted twice with 5% NH3 solution and the aqueous phase is extracted once with 30 mL EtOAc. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM
towards DCM/MeOH/NH3 9:1:0.1 ).
Yield: 100 mg (15.4 % of theoretical) C17H25B~2 (M= 337.298) Rf value: 0.68 (silica gel, DCM/MeOH/NH3 9:1:0.1 ) retention time HPLC: 4.52 min (method B).
2d 1'-(4-iodo-phenyl)-4-methyl-[1,3']bipiperidinyl Prepared according to general method II from 1'-(4-bromo-phenyl)-4-methyl-[1,3']bipiperidinyl (100 mg, 0.30 mmol).
Yield: 120 mg (100 % of theoretical; 95% content) C17H251N2 (M= 384.298) Calc.: molpeak (M)+: 385 Found: molpeak (M)+: 385 retention time HPLC: 4.64 min (method B).
2e 1'-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-4-methyl-[1,3']bipiperidinyl Prepared according to general method I from 1'-(4-iodo-phenyl)-4-methyl-[1,3']bipiperidinyl (120 mg, 0.30 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (69 mg, 0.30 mmol).
Yield: 50 mg (36.0 % of theoretical) C30H32CIN3 (M= 470.048) Calc.: molpeak (M+H)+: 470/472 (CI) Found: molpeak (M+H)+: 470/472 (CI) Rf value: 0.28 (silica gel, DCM/MeOH 9:1 ).
Example 3.1 1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohex-2-enyl)-4-methyl-piperidin-4-0l 3.1a 3-(4-bromo-phenyl)-cyclohex-2-enol 3.00 g (79.4 mmol) sodium borohydride are added batchwise at 0°C to a solution of 10.0 g (39.8 mmol) 3-(4-bromo-phenyl)-cyclohex-2-en-one (see 1a) in 500 mL MeOH. The reaction mixture is heated to RT and stirred for 1 h at RT. The reaction solution is added to 150 mL
10% ammonium chloride solution, so that the temperature does not exceed 10°C. The aqueous phase is exhaustively extracted with DIPE and the combined organic extracts are washed three times with water. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. The crude product is reacted further without any further purification.
1o Yield: 9.5 g (94.2 % of theoretical) C12H13Br0 (M= 253.135) Calc.: molpeak (M+H-H20)+: 235/237 (Br) Found: molpeak (M+H-Hz0)+: 235/237 (Br) Rf value: 0.65 (silica gel, DCM/MeOH 9:1 ).
3.1 b 3-(4-iodo-phenyl)-cyclohex-2-enol Prepared according to general method II from 3-(4-bromo-phenyl)-cyclohex-2-enol (10.8 g, 42.7 mmol).
Yield: 9.80 g (76.5 % of theoretical) C12H131O (M= 300.135) Rf value: 0.40 (silica gel, PE/EtOAc 6:4).
3.1c 1-[3-(4-iodo-phenyl)-cyclohex-2-enyl]-4-methyl-piperidin-4-of 0.20 mL (2.13 mmol) phosphorus tribromide in 5.0 mL TBME are added at -10°C to a solution of 600 mg (2.00 mmol) 3-(4-iodo-phenyl)-cyclohex-2-enol in 20 mL TBME. The reaction solution is stirred for 2 h at -10°C, combined with 50 mL ice water and made alkaline with dilute NaHC03 solution. The organic phase is dried over MgS04 in the cold and 461 mg (4.00 mmol) 4-methyl-piperidin-4-of are added immediately. The reaction mixture is heated to RT
and then washed three times with 5% Na2C03 solution. The organic phase is washed with water, dried over MgS04 and the solvent is eliminated i. vac.. The crude product is reacted further without any further purification.

Yield: 500 mg (62.9 % of theoretical) C18H241N0 (M= 397.294) Calc.: molpeak (M+H)+: 398 Found: molpeak (M+H)+: 398 retention time HPLC: 4.50 min (method B).
3.1d 1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohex-2-enyl)-4-methyl-piperidin-4-of Prepared according to general method I from 1-[3-(4-iodo-phenyl)-cyclohex-2-enyl]-4-methyl-piperidin-4-of (397 mg, 1.00 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (214 mg, 1.00 mmol).
Yield: 5.0 mg (1.0 % of theoretical) C31 H31 CIN20 (M= 483.043) Calc.: molpeak (M+H)+: 483/485 (CI) Found: molpeak (M+H)+: 483/485 (CI) retention time HPLC: 8.4 min (method A).
Example 3.2 5-(4-chloro-phenyl )-2-{4-[3-(3, 5-d imethyl-piperidin-1-yl)-cyclohex-1-enyl]-phenyl-ethynyl}-pyridine 3.2a 1-[3-(4-iodo-phenyl)-cyclohex-2-enyl]-3,5-dimethyl-piperidine Analogously to Example 3.1 c the product is obtained from 600 mg (2.00 mmol) 3-(4-iodo-phenyl)-cyclohex-2-enol and 1.20 g (10.6 mmol) 3,5-dimethylpiperidine.
Yield: ~ 500 mg (63.2 % of theoretical) C1 gH261N (M= 395.321 ) Calc.: molpeak (M+H)+: 396 Found: molpeak (M+H)+: 396 retention time HPLC: 5.4 min (method B).
3.2b 5-(4-chloro-phenyl)-2-{4-[3-(3,5-dimethyl-piperidin-1-yl)-cyclohex-1-enyl]-phenyl-ethynyl}-pyridine Prepared according to general method I from 1-[3-(4-iodo-phenyl)-cyclohex-2-enyl]-3,5-dimethyl-piperidine (395 mg, 1.00 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (214 mg, 1.00 mmol).
Yield: 310 mg (64 % of theoretical) C32H33CIN2 (M= 481.071 ) Calc.: molpeak (M+H)+: 481/483 (CI) Found: molpeak (M+H)+: 481/483 (CI) retention time HPLC: xx min (method A).
Example 3.3 [(S)-1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohex-2-enyl)-pyrrolidin-2-yl]-methanol HO~
3.3a {(S)-1-[3-(4-iodo-phenyl)-cyclohex-2-enyl]-pyrrolidin-2-yl}-methanol Analogously to Example 3.1 c the product is obtained from 600 mg (2.00 mmol) 3-(4-iodo-phenyl)-cyclohex-2-enol and 1.16 mL (10.6 mmol) S-(+)-2-hydroxymethylpyrrolidin.
Yield: 500 mg (65.2 % of theoretical) C17H221N0 (M= 383.267) Calc.: molpeak (M+H)+: 384 Found: molpeak (M+H)+: 384 retention time HPLC: 4.44 min (method B).
3.3b [(S)-1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclohex-2-enyl)-pyrrolidin-2-yl]-methanol Prepared according to general method I from {(S)-1-[3-(4-iodo-phenyl)-cyclohex-2-enyl]-pyrrolidin-2-yl}-methanol (383 mg, 1.00 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (214 mg, 1.00 mmol).
Yield: 50 mg (11 % of theoretical) C3pH2gCIN20 (M= 469.017) Calc.: molpeak (M+H)+: 469/471 (CI) Found: molpeak (M+H)+: 469/471 (CI) Rf value: 0.30 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
Example 4.1 1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentyl)-piperidin-4-carboxylic acid amide HZN
/~~N
~O
4.1a 3-(4-bromo-phenyl)-cyclopent-2-enon Analogously to Example 1a the product is obtained from 40.0 g (169 mmol) 1,4-dibromobenzene, 4.13 g (170 mmol) magnesium chips and 20.0 g (158 mmol) 3-ethoxy-2-cyclopenten-1-one.
Yield: 3.5 g (8.7 % of theoretical) C11 HgBrO (M= 237.093) Calc.: molpeak (M+H)+: 237/239 (Br) Found: molpeak (M+H)+: 237/239 (Br) Rf value: 0.35 (silica gel, PE/EtOAc 6:4).
4.1 b 3-(4-bromo-phenyl)-cyclopentanol Analogously to Example 1 b the product is obtained from 1.66 g (7.00 mmol) 3-(4-bromo-phenyl)-cyclopent-2-enone and 10.0 mL (10.0 mmol) 1 M lithium aluminium hydride solution in THF.
Yield: 800 mg (47.4 % of theoretical; content 60%; 40% debrominated product) C11 H13Br0 (M= 241.124) Calc.: molpeak (M+H)+: 240/242 (Br) Found: molpeak (M+H)+: 240/242 (Br) Rf value: 0.6 (silica gel, DCM/MeOH 9:1 ).
4.1 c 3-(4-iodo-phenyl)-cyclopentanol Prepared according to general method II from 3-(4-bromo-phenyl)-cyclopentanol (800 mg, 3.32 mmol).
Yield: 1.00 g (52.3 % of theoretical; content 50%) C11H1310 (M= 288.125) Calc.: molpeak (M)+: 288 Found: molpeak (M)+: 288 retention time HPLC: 5.4 min (method B).
4.1d 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentanol Prepared according to general method I from 3-(4-iodo-phenyl)-cyclopentanol (650 mg, 2.26 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (483 mg, 2.26 mmol).
Yield: 420 mg (49.7 % of theoretical) C24H20CIN0 (M= 373.874) Calc.: molpeak (M+H)+: 374/376 (CI) Found: molpeak (M+H)+: 374/376 (CI) Rf value: 0.6 (silica gel, DCM/MeOH 9:1 ).
4.1 a methanesulphonate 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentylester Analogously to Example 1e the product is obtained from 400 mg (1.07 mmol) 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentanol, 1.28 mL (6.8 mmol) methanesulphonic acid chloride and 0.40 mL (5.00 mmol) pyridine.
Yield: 400 mg (82.7 % of theoretical) C25H22CIN03S (M= 451.966) Calc.: molpeak (M+H)+: 452/454 (CI) Found: molpeak (M+H)+: 452/454 (CI) R, value: 0.4 (silica gel, PE/EtOAc 1:1 ).
4.1f 1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentyl)-piperidin-4 carboxylic acid amide 83 mg (0.61 mmol) isonipecotamide are added to a solution of 60 mg (0.13 mmol) 3-{4-(5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopenty1 methanesulphonate in 2.0 mL DMF
and the reaction solution is stirred for 24 h at 80°C. The reaction mixture is purified directly by HPLC-MS (water:acetonitrile:formic acid 95:5:0.1 towards 10:90:0.1 ).
Yield: 6.5 mg (10.0 % of theoretical) C30H30CIN30 (M= 484.032) Calc.: molpeak (M+H)+: 484/486 (CI) Found: molpeak (M+H)+: 484/486 (CI) retention time HPLC: 4.9 min (method B).
Example 4.2 1-(3-{4-(5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentyl)-4-methyl-piperidin-4-of HC
Analogously to 4.1f the product is obtained from 60 mg (0.13 mmol) 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopenty1 methanesulphonate and 45 mg (0.39 mmol) 4-methyl-piperidin-4-ol.
Yield: 10 mg (16 % of theoretical) C30H31 CIN20 (M= 471.033) Calc.: molpeak (M)+: 470/472 (CI) Found: molpeak (M)+: 470/472 (CI) retention time HPLC: 5.64 min (method C).
Example 4.3 5-(4-chloro-phenyl)-2-{4-[3-(4-methoxy-piperidin-1-yl)-cyclopentyl]-phenylethynyl}-pyridine ,N
Analogously to 4.1f the product is obtained from 60 mg (0.13 mmol) methanesulphonate 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentyl and 75 mg (0.65 mmol) 4-methoxy-piperidine.
Yield: 10 mg (16.3 % of theoretical) C30H31CIN20 (M= 471.033) Calc.: molpeak (M+H)+: 471/473 (CI) Found: molpeak (M+H)+: 471/473 (CI) retention time HPLC: 5.4 min (method A).
Example 4.4 [(S)-1-(3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopentyl)-pyrrolidin-2-yl]-methanol CN
HO
Analogously to 4.1f the product is obtained from 60 mg (0.13 mmol) 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopenty1 methanesulphonate and 71 gL (0.65 mmol) S-(+)-2-hydroxymethylpyrrolidine.
Yield: 6.5 mg (10.9 % of theoretical) C2gH2gCIN20 (M= 457.006) Calc.: molpeak (M+H)+: 457/459 (CI) Found: molpeak (M+H)+: 457/459 (CI) retention time HPLC: 5.2 min (method A).
Example 5.1 1-( 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl)-4-methyl-piperidin-4-of HC
5.1a 1-(4-bromo-phenyl)-pyrrolidin-3-of Analogously to Example 2c the product is obtained from 871 mg (10.0 mmol) 3-pyrrolidinone and 2.83 g (10.0 mmol) 4-bromo-iodobenzene.
Yield: 1.30 g (53.7 % of theoretical) C10H12BrN0 (M= 242.112) Calc.: molpeak (M+H)+: 242/244 (Br) Found: molpeak (M+H)+: 242/244 (Br) retention time HPLC: 7.77 min (method A).
5.1 b 1-(4-iodo-phenyl)-pyrrolidin-3-of Prepared according to general method II from 1-(4-bromo-phenyl)-pyrrolidin-3-of (1.30 g, 5.37 mmol).
Yield: 1.30 g (83.7 % of theoretical) C10H121N0 (M= 289.113) Calc.: molpeak (M+H)+: 290 Found: molpeak (M+H)+: 290 retention time HPLC: 8.14 min (method A).
5.1c 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-of Prepared according to general method I from 1-(4-iodo-phenyl)-pyrrolidin-3-of (1.30 g, 4.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.03 g, 4.50 mmol).
Yield: 1.40 g (83.1 % of theoretical) C23H1gCIN20 (M= 374.863) Calc.: molpeak (M+H)+: 375/377 (CI) Found: molpeak (M+H)+: 375/377 (CI) Rf value: 0.47 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
5.1d 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl methanesulphonate Analogously to Example 1e the product is obtained from 1.40 g (3.74 mmol) 1-{4-[5-(4-chloro phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-ol, 2.61 mL (33.6 mmol) methanesulphonic acid chloride and 3.62 mL (44.4 mmol) pyridine.
Yield: 900 mg (53.2 % of theoretical) C24H21 CIN203S (M= 452.954) Calc.: molpeak (M+H)+: 453/455 (CI) Found: molpeak (M+H)+: 453/455 (CI) retention time HPLC: 6.26 min (method B).
5.1e 1-(1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl)-4-methyl-piperidin-4-of 104 mg (0.90 mmol) 4-methyl-piperidin-4-of are added to a solution of 82 mg (0.18-mmol) 1 {4-[5-(4-chloro-phenyl)-pyridin-2-ylethynylJ-phenyl}-pyrrolidin-3-yl methanesulphonate in 2.0 mL DMF and the reaction solution is stirred for 24 h at 70°C and for a further 60 h at 60°C.
The reaction mixture is diluted with 2.0 mL water and after filtration the residue is applied to silica gel. Further purification is carried out by column chromatography on silica gel (DCM
towards DCM/MeOH 9:1 ).
Yield: 14.0 mg (16.5 % of theoretical) C2gH3pCIN30 (M= 472.021 ) Calc.: molpeak (M+H)+: 472/474 (CI) Found: molpeak (M+H)+: 472/474 (CI) retention time HPLC: 5.03 min (method B).
Example 5.2 1-(1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl)-piperidin-4-carboxylic acid amide ci Analogously to 5.1 a the product is obtained from 82 mg (0.18 mmol) 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl methanesulphonate and 115 mg (0.90 mmol) isonipecotamide.
Yield: 22 mg (25.2 % of theoretical) C2gH2gCIN40 (M= 485.020) Calc.: molpeak (M+H)+: 485/487 (CI) Found: molpeak (M+H)+: 485/487 (CI) retention time HPLC: 4.83 min (method B).
Example 5.3 ((S)-1'-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-[1,3']bipyrrolidinyl-2-yl)-methanol CN N
l HO
Analogously to 5.1e the product is obtained from 82 mg (0.18 mmol) 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl methanesulphonate and 91 mg (0.90 mmol) (S)-(+)-2-hydroxymethylpyrrolidine.
Yield: 10 mg (12.1 % of theoretical) C28H28CIN30 (M= 457.994) Calc.: molpeak (M+H)+: 458/460 (CI) Found: molpeak (M+H)+: 458/460 (CI) retention time HPLC: 5.08 min (method B).
Example 5.4 5-(4-chloro-phenyl)-2-{4-[3-(4-methoxy-piperidin-1-yl)-pyrrolidin-1-yl]-phenylethynyl}-pyridine ~~N
Analogously to 5.1e the product is obtained from 82 mg (0.18 mmo!) 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl methanesulphonate and 104 mg (0.90 mmol) 4-methoxypiperidine.
Yield: 32 mg (36.4 % of theoretical) C2gH3pCIN30 (M= 472.021 ) Calc.: molpeak (M+H)+: 472/474 (C!) Found: molpeak (M+H)+: 472/474 (CI) retention time HPLC: 5.25 min (method B).
Example 5.5 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidi n-1-yl)-pyrrolid i n-1-yl]-phenylethynyl}-pyridine Analogously to 5.1e the product is obtained from 82 mg (0.18 mmol) 1-{4-[5-(4-chloro phenyl)-pyridin-2-ylethynyl]-phenyl}-pyrrolidin-3-yl methanesulphonate and 89 mg (0.90 mmol) 4-methylpiperidine.
Yield: 38 mg (46.3 % of theoretical) C2gH3pClN3 (M= 456.021 ) Calc.: molpeak (M+H)+: 456/458 (CI) Found: molpeak (M+H)+: 456/458 (CI) retention time HPLC: 5.50 min (method B).

Example 6.1 (S )-1-( 1-{5-[5-(4-chloro-phenyl )-pyrid i n-2-ylethynyl]-pyrid in-2-yl}-pyrrol id in-3-yl)-4-methyl-piperidin-4-of ci N " N
HO~\
G
6.1a (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-of 5.00 g (56.2 mmol) (R)-(+)-pyrrolidinol and 13.6 g (56.2 mmol) 2,5-dibromopyridine are stirred for 1 h in a melt at 140°C. The reaction mixture is cooled, combined with EtOAc and the organic phase is washed with saturated NaHC03 solution. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. The residue is triturated in DIPE
and dried after filtration. Further purification is carried out by column chromatography on silica gel (DCM/MeOH 9:1 ).
Yield: 5.70 mg (41.7 % of theoretical) CgHl1 BrN20 (M= 243.101 ) Calc.: molpeak (M+H)+: 243/245 (Br) Found: molpeak (M+H)+: 243/245 (Br) R, value: 0.37 (silica gel, DCM/MeOH 9:1 ).
6.1 b (R)-1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-of Prepared according to general method II from (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-of (5.50 g, 22.6 mmol).
Yield: 4.80 g (66.6 % of theoretical; content:91%) CgHl1 IN20 (M= 290.101 ) Calc.: molpeak (M)+: 291 Found: molpeak (M)+: 291 retention time HPLC: 1.69 min (method A).
6.1c (R)-1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-of Prepared according to general method I from (R)-1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-of (4.80 mg, 91 % content, 15.1 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (3.22 g, 15.1 mmol).
Yield: 5.00 g (88.4 % of theoretical) C22H18CIN30 (M= 375.851 ) Calc.: molpeak (M+H)+: 376/378 (CI) Found: molpeak (M+H)+: 376/378 (CI) retention time HPLC: 6.90 min (method A).
6.1d (R)-methanesulphonate 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl-ester Analogously to Example 1e the product is obtained from 920 mg (2.45 mmol) (R)-1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-ol, 1.72 mL
(22.0 mmol) methanesulphonic acid chloride, 0.51 mL (3.68 mmol) triethylamine and 0.50 mL
(6.13 mmol) pyridine.
Yield: 870 mg (62.6 % of theoretical; content: 80%) C23H2pCIN303S (M= 453.942) Calc.: molpeak (M+H)+: 454/456 (CI) Found: molpeak (M+H)+: 454/456 (CI) retention time HPLC: 5.66 min (method B).
6.1e (S)-1-(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-4-methyl-piperidin-4-of 101 mg (0.88 mmol) 4-methyl-piperidin-4-of are added to a solution of 100 mg (0.18 mmol, 60% content) 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl (R)-methanesulphonate in 1.0 mL DMF and the reaction solution is stirred for 48 h at 70°C. The reaction mixture is purified directly by column chromatography by HPLC-MS
(water:acetonitrile:formic acid 80:20:0.1 towards 75:25:0.1 ).
Yield: 9.0 mg (10.8 % of theoretical) C28H2gCIN40 (M= 473.009) Calc.: molpeak (M+H)+: 473/475 (CI) Found: molpeak (M+H)+: 473/475 (CI) retention time HPLC: 4.94 min (method A).
Example 6.2 (S)-5-(4-chloro-phenyl)-2-{6-[3-(4-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-pyrid-3-ylethynyl}-pyridine ,.

. . WO 2005/103032 84 PCT/EP2005/003686 Analogously to 6.1 a the product is obtained from 80 mg (0.14 mmol; 80%
content) 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl (R)-methanesulphonate and 0.17 mL (1.41 mmol) 4-methylpiperidine.
Yield: 16 mg (24.8% of theoretical) C28H2gCIN4 (M= 457.010) Calc.: molpeak (M+H)+: 457/459 (CI) Found: molpeak (M+H)+: 457/459 (CI) retention time HPLC: 4.85 min (method B).
Example 6.3 (S)-1-(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-piperidin-4-carboxylic acid amide HZN
N,""
Analogously to 6.1e the product is obtained from 100 mg (0.18 mmol; 80%
content) 1-{5-[5 (4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl (R)-methanesulphonate and 116 mg (0.88 mmol) piperidin-4-carboxylic acid amide.
Yield: 9.0 mg (10.5% of theoretical) C28H28CIN50 (M= 486.008) Calc.: molpeak (M+H)+: 486/488 (CI) Found: molpeak (M+H)+: 486/488 (CI) Rf value: 0.16 (silica gel, DCM/MeOH 9:1 ).
Example 6.4 (S )-5-(4-chloro-phenyl )-2-{6-[3-(3, 5-d imethyl-piperid in-1-yl )-pyrrolidin-1-yl]-pyrid-3-ylethynyl}-pyridine ci r-~

. WO 2005/103032 85 PCT/EP2005/003686 Analogously to 6.1e the product is obtained from 100 mg (0.18 mmol; 80%
content) 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl (R)-methanesulphonate and 100 mg (0.88 mmol) 3,5-dimethylpiperidine.
Yield: 23 mg (27.7% of theoretical) C2gH31 CIN4 (M= 471.036) Calc.: molpeak (M+H)+: 471/473 (CI) Found: molpeak (M+H)+: 471/473 (CI) Rf value: 0.44 (silica gel, DCM/MeOH 9:1 ).
Example 6.5 ((2S,3'S)-1'-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(1,3']bipyrrolidinyl-2-yl)-methanol CN",..
l HO
Analogously to 6.1e the product is obtained from 100 mg (0.18 mmol; 80%
content) 1-{5-[5 (4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl (R)-methanesulphonate and 89 mg (0.88 mmol) (S)-(+)-prolinol.
Yield: 12 mg (14.9% of theoretical) C27H27CIN40 (M= 458.982) Calc.: molpeak (M+H)+: 459/461 (CI) Found: molpeak (M+H)+: 459/461 (CI) Rf value: 0.27 (silica gel, DCM/MeOH 9:1 ).
Example 6.6 (S)-5-(4-chloro-phenyl )-2-{6-[3-(4-methoxy-piperid in-1-yl )-pyrrolid i n-1-yl]-pyrid-3-ylethynyl}-pyridine Analogously to 6.1e the product is obtained from 100 mg (0.18 mmol; 80%
content) 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl (R)-methanesulphonate and 91 mg (0.88 mmol) 4-methoxy-piperidine.
Yield: 9.0 mg (11.1% of theoretical) C27H27CIN40 (M= 458.982) Calc.: molpeak (M+H)+: 459/461 (CI) Found: molpeak (M+H)+: 459/461 (CI) Rf value: 0.33 (silica gel, DCM/MeOH 9:1 ).
Example 7.1 (E)-5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-propenyl]-pyrid-3-yl-ethynyl}-pyridine 7.1a 3-(5-bromo-pyridin-2-yl)-prop-2-yn-1-of 2.47 mL (42.2 mmol) prop-2-yn-1-of and 12.3 mL (88.2 mmol) triethylamine are added to a solution of 10.0 g (42.2 mmol) 2,5-dibromopyridine in 150 mL THF. The reaction flask is evacuated and charged with argon. 88.4 mg (0.46 mmol) Cul are added and stirred overnight at RT. The mixture is diluted with EtOAc and washed twice with 10% NH3 solution and water.
The organic phase is dried over MgS04 and the solvent is eliminated i. vac..
Further purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1 ).
Yield: 6.70 g (75 % of theoretical) C8H6BrN0 (M= 212.043) Calc.: molpeak (M+H)+: 212/214 (Br) Found: molpeak (M+H)+: 212/214 (Br) Rf value: 0.40 (silica gel, PE/EtOAc 1:1 ).
7.1b (E)-3-(5-bromo-pyridin-2-yl)-prop-2-en-1-of A solution of 1.00 g (4.72 mmol) 3-(5-bromo-pyridin-2-yl)-prop-2-yn-1-of in 25 mL THF is added dropwise at -5°C to 4.72 mL (4.72 mmol, 1 M in THF) of a lithium aluminium hydride solution such that the internal temperature does not exceed 0°C. The mixture is stirred for 2 h. Then 125 NL water, 125 NL 15% sodium hydroxide solution and another 375 NL
water are added. The reaction mixture is filtered, dried over MgS04 and the solvent is eliminated i. vac..
Yield: 0.91 g (63 % of theoretical) C8H8BrN0 (M= 214.059) Calc.: molpeak (M+H)+: 214/216 (Br) Found: molpeak (M+H)+: 214/216 (Br) retention time HPLC: 4.18 min (method B).
7.1c (E)-3-(5-iodo-pyridin-2-yl)-prop-2-en-1-of Prepared according to general method II from (E)-3-(5-bromo-pyridin-2-yl)-prop-2-en-1-of (0.91 g, 4.25 mmol).
Yield: 0.87 g (78 % of theoretical) C8H81N0 (M= 261.060) Calc.: molpeak (M+H)+: 262 Found: molpeak (M+H)+: 262 retention time HPLC: 4.23 min (method B).
7.1d (E)-3-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-prop-2-en-1-of Prepared according to general method I from (E)-3-(5-iodo-pyridin-2-yl)-prop-2-en-1-of (870 mg, 3.33 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (712 mg, 3.33 mmol).
Yield: 980 mg (85 % of theoretical) C21 H 15CIN20 ( M= 346.809) Calc.: molpeak (M+H)+: 347/349 (CI) Found: molpeak (M+H)+: 347/349 (CI) retention time HPLC: 5.57 min (method B).
7.1e (E)-5-(4-chloro-phenyl)-2-{4-[3-chloro-propenyl]-pyrid-3-yl-ethynyl}-pyridine A solution of 160 NL (1.35 mmol) thionyl chloride in 5 mL DCM is slowly added dropwise at 10°C to a solution of 0.45 g (1.30 mmol) (E)-3-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]
pyridin-2-yl}-prop-2-en-1-of in 20 mL DCM. The reaction solution is stirred for 30 min at 0°C
and overnight at RT. After the addition of saturated NaHC03 solution the mixture is extracted with DCM. The organic phase is washed several times with water, dried over MgS04 and the solvent is eliminated i. vac..
Yield: 450 mg (95 % of theoretical) C21 H14CI2N2 (M= 365.255) , WO 2005/103032 88 PCT/EP2005/003686 Calc.: molpeak (M+H)+: 365/367/369 (2C1) Found: molpeak (M+H)+: 365/367/369 (2C1) retention time HPLC: 6.82 min (method B).
7.1f (E)-5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-propenyl]-pyrid-3-yl-ethynyl}-pyridine 146 NL (1.23 mmol) 4-methylpiperidine are added to a solution of 150 mg (0.41 mmol) (E)-3-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-allyl)-chloride in 2 mL DMF and the mixture is stirred overnight at 70°C. The purification is carried out by HPLC-MS.
Yield: 42.0 mg (24 % of theoretical) C27H26CIN3 (M= 427.968) Calc.: molpeak (M+H)+: 428/430 (CI) Found: molpeak (M+H)+: 428/430 (CI) retention time HPLC: 5.45 min (method A).
Example 7.2 1-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-4-trifluoromethyl-piperidin-4-of 7.2a (E)-3-(4-iodo-phenyl)-prop-2-en-1-of Under a nitrogen atmosphere 12.0 g (80.0 mmol) Nal and 0.85 mL (8.0 mmol) N,N~-dimethylethylenediamine are added to a solution of 4.26 g (20.0 mmol) (E)-3-(4-bromo-phenyl)-prop-2-en-1-of and 762 mg (4 mmol) Cul in 20 mL 1,4-dioxane and the reaction mixture is shaken for 17 h at 110°C. The reaction mixture is cooled to RT, combined with 200 mL -EtOAc and 100 mL semiconc. NH3 solution, vigorously stirred, the organic phase is separated off and dried over Na2S04. After the desiccant and solvent have been eliminated the residue is reacted further without purification.
Yield: 4.69 g (90% of theoretical) C9H9102 (M= 260.072) Calc.: molpeak (M+H)+: 261 Found: molpeak (M+H)+: 261 3D HPLC-MS: 7.9 min (method A).
7.2b (E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-prop-2-en-1-of A solution of 3.12 g (12.0 mmol) (E)-3-(4-iodo-phenyl)-prop-2-en-1-ol, 3.33 g (15.0 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 4.31 mL (24 mmol) diisopropylamine in 120 mL dry THF isevacuated three times and then gassed with argon. Then 45 mg (0.24 mmol) Cul and 196 mg (0.24 mmol) PdCl2(dppf) are added. The reaction mixture is stirred for 18 h at RT, the solvent is evaporated down i.vac., the residue is combined with 100 mL DCM and 50 mL
semisat. NaHC03 solution and stirred vigorously. The precipitate is separated off, washed with water and a little DCM, suspended in DIPE, suction filtered again and dried at 50°C in the circulating air dryer until a constant weight is achieved.
Yield: 4.23 g (quant. yield) C22H~sCINO (M= 345.821 ) Calc.: molpeak (M+H)': 346/348 (CI) Found: molpeak (M+H)': 346/348 (CI) Rf value: 0.24 (silica gel, cyc/EtOAc 2:1 ).
7.2c 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine 95 A solution of 2.56 mL (35.28 mmol) thionyl chloride in 10 mL DCM is slowly added dropwise to a solution of 6.1 g (17.64 mmol) (E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-prop-2-en-1-of in 80 ml DCM which has been cooled to 0°C and the reaction solution is stirred for a further 2 h at 0°C and 14 h at RT. The mixture is again cooled to 0°C, 150 mL
semisat. NaHC03 solution are carefully added dropwise, the organic phase is separated off 2o and dried over Na2S04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 4:1 ).
Yield: 3.2 g (50% of theoretical) CZZH~SCIzN (M= 364.267) Calc.: molpeak (M+H)+: 364/366/368 (2C/) Found: molpeak (M+H)+: 364/366/368 (2C/) 25 Rf value: 0.60 (silica gel, cyc/EtOAc 2:1 ).
7.2d 1-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-4-trifluoromethyl-piperidin-4-of 65.0 mg, (0.38 mmol) 4-trifluoromethyl-piperidin-4-o! and 0.13 mL (0:77 mmol) 30 ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and shaken for 19 h at 60°C. The reaction mixture is filtered through an injection fitter and purified by HPLC-MS. The residue is diluted with 20 mL EtOAc and 10 mL saturated NaHC03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. It is then stirred with DIPE.
35 Yield: 40.4 mg (42.0 % of theoretical) C28H24CIF3N20 (M= 496.951 ) Calc.: molpeak (M+H)+: 497/499 (CI) Found: molpeak (M+H)+: 497/499 (CI) retention time HPLC: 5.5 min (method B).
Example 7.3 ((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-cyclopropylmethyl-propyl-amine ~N
0.11 mL (0.77 mmol) cyclopropylmethyl-propyl-amine and 0.13 mL (0.77 mmol) ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and the mixture is shaken for 3.5 h at 60°C. The reaction mixture is purified by HPLC-MS.
Yield: 45.3 mg (53.0 % of theoretical) C2gH2gCIN2 (M= 441.007) Calc.: molpeak (M+H)+: 441/443 (CI) Found: molpeak (M+H)+: 441/443 (CI) retention time HPLC: 5.6 min (method B).
Example 7.4 2-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allylamino)-2-methyl-propane-1,3-diol HO
80.7 mg (0.77 mmol) 2-amino-2-methyl-1,3-propanediol and 0.13 mL (0.77 mmol) ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and shaken for 17 h at 60°C. The reaction mixture is purified by HPLC-MS.
Yield: 38.2 mg (46.0 % of theoretical) . WO 2005/103032 91 PCT/EP2005/003686 C26H25CIN202 (M= 432.942) Calc.: molpeak (M+H)+: 433/435 (CI) Found: molpeak (M+H)+: 433/435 (CI) retention time HPLC: 4.9 min (method B).
Example 7.5 ((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-cyclopentyl-amine <_r 0.23 mL (2.30 mmol) cyclopentylamin and 0.39 mL (2.30 mmol) ethyldiisopropylamine are added to a solution of 210 mg (0.58 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 5.1 mL DMF and shaken for 17 h at 60°C. The reaction mixture is purified by HPLC-MS.
Yield: 107 mg (45.0 % of theoretical) C27H25CIN2 (M= 412.954) Calc.: molpeak (M+H)+: 413/415 (CI) Found: molpeak (M+H)+: 413/415 (CI) retention time HPLC: 5.6 min (method B).
Example 7.6 1-(( E)-3-{4-[5-(4-chloro-phenyl )-pyrid in-2-ylethynyl]-phenyl}-a Ilyl )-4-methyl-piperidin-4-of 44.2 mg (0.38 mmol) 4-methyl-piperidin-4-of and 0.13 mL (0.77 mmol) ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and shaken for 17 h at 60°C. The reaction mixture is purified by HPLC-MS.
Yield: 58.0 mg (68.0 % of theoretical) C28H27CIN20 (M= 442.980) . WO 2005/103032 92 PCT/EP2005/003686 Calc.: molpeak (M+H)+: 443/445 (CI) Found: molpeak (M+H)+: 443/445 (CI) retention time HPLC: 5.2 min (method B).
Example 7.7 2-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allylamino)-propane-1,3-diol H
,N
H
70.0 mg (0.77 mmol) 2-amino-1,3-propanediol and 0.13 mL (0.77 mmol) ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) 5-(4-chloro-phenyl)-2 [4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and shaken for 3.5 h at 60°C. The reaction mixture is purified by HPLC-MS.
Yield: 37.6 mg (47.0 % of theoretical) C25H23CIN202 (M= 418.915) Calc.: molpeak (M+H)+: 419/421 (CI) Found: molpeak (M+H)+: 419/421 (CI) retention time HPLC: 4.9 min (method B).
Example 7.8 3-[((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-cyclopentyl-amino]-propan-1-0l 61.0 NL (0.68 mmol) 3-bromo-1-propanol and 0.12 mL (0.68 mmol) ethyldiisopropylamine are added to a solution of 70.0 mg (0.17 mmol) ((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-cyclopentyl-amine in 1.7 mL DMF and shaken for 17 h at 40°C. Another 61.0 NL
(0.68 mmol) 3-bromo-1-propanol are added and the mixture is shaken for 23 h at 40°C. The solvent is eliminated i. vac. and the residue is taken up with 20 mL EtOAc and 10 mL
semisaturated NaHC03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. The residue is then stirred with TBME.

Yield: 9.20 mg (11.5 % of theoretical) C30H31CIN20 (M= 471.033) Calc.: molpeak (M+H)+: 471/473 (CI) Found: molpeak (M+H)+: 471/473 (CI) Rf value: 0.30 (silica gel, 366nm, DCM/MeOH/NH3 9:1:0.1 ).
Example 7.9 8-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-3-methyl-8-aza-bicyclo[3.2.1 ]octan-3-of ci H
~~~'N
46.6 mg (0.33 mmol) 3-methyl-8-aza-bicyclo[3.2.1]octan-3-of and 0.11 mL (0.66 mmol) ethyldiisopropylamine are added to a solution of 60.0 mg (0.17 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and the reaction mixture is shaken for 16 h at 60°C. The reaction mixture is evaporated down i.vac., the residue is taken up in 20 mL EtOAc and 10 mL 5% NaHC03 solution, briefly heated to 80°C, the organic phase is separated off and dried over Na2S04. After the desiccant and solvent have been eliminated the residue is stirred with 5 mL isopropanol and suction filtered.
Yield: 48.4 mg (63 % of theoretical) C3pH2gCIN20 (M= 469.017) Calc.: molpeak (M+H)+: 469/471 (CI) Found: molpeak (M+H)+: 469/471 (CI) retention time HPLC: 4.9 min (method B).
Example 7.10 8-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-3-ethyl-8-aza-bicyclo[3.2.1 ]octan-3-of OH
\\y~/~N

Analogously to Example 7.9 the product is obtained from 60.0 mg (0.17 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine and 51.2 mg (0.33 mmol) 3-ethyl-8-aza-bicyclo-[3.2.1 ]octan-3-ol.
Yield: 32.9 mg (41 % of theoretical) C31 H31 CIN20 (M= 483.043) Calc.: molpeak (M+H)+: 483/485 (CI) Found: molpeak (M+H)+: 483/485 (CI) retention time HPLC: 5.0 min (method B).
Example 7.11 1-(( E)-3-{4-[5-(4-chloro-phenyl )-pyridin-2-ylethynyl]-phenyl}-allyl )-4-ethyl-piperid in-4-of ci 42.6 mg (0.33 mmol) 4-ethyl-piperidin-4-of and 0.08 mL (0.44 mmol) ethyldiisopropylamine are added to a solution of 40.0 mg (0.11 mmol) 5-(4-chloro-phenyl)-2-[4-((E)-3-chloro-propenyl)-phenylethynyl]-pyridine in 1.7 mL DMF and the reaction mixture is shaken for 5 h at 60°C. After cooling the reaction mixture is purified by HPLC without working up. The fractions containing the product are combined with 20 mL EtOAc and 10 mL 5 % NaHC03 solution and stirred. The phases are separated and the organic phase is dried over Na2S04.
After the desiccant and solvent have been eliminated the residue is triturated with a little DIPE, suction filtered and dried.
Yield: 19.9 mg (40 % of theoretical) C2gH2gCIN20 (M= 457.006) Calc.: molpeak (M+H)+: 457/459 (CI) Found: molpeak (M+H)+: 457/459 (CI) retention time HPLC: 4.9 min (method B).
Example 7.12 4-methyl-1-(( E)-3-{4-[5-(4-methyl-cyclohex-1-enyl )-pyrid i n-2-ylethynyl]-phenyl}-al lyl )-piperid in-4-0l 7.12a 1-{6-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridin-3-yl}-4-methyl-cyclohexanol 9.5 mL (16.19 mmol) n-BuLi (1.6 M in THF) are slowly added under argon at -70°C to a solution of 4.50 g (15.19 mmol) 5-bromo-2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridine in 50 mL diethyl ether and 60 mL THF and after the addition has ended the mixture is stirred for another 2 min. 1.86 mL (15.19 mmol) 4-methylcyclohexanone are added and the mixture is slowly heated to RT. 150 mL saturated ammonium chloride solution is added and the aqueous phase is exhaustively extracted with EtOAc. The combined organic extracts are washed with semisaturated NaHC03 solution, dried over MgS04 and evaporated down i.vac..
The residue is purified by chromatography (silica gel, PE/EtOAc 4:1 ). 2 fractions are isolated:
fraction1: cis-1-{6-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridin-3-yl}-4-methyl-cyclohexanol Yield: 1.40 g (28% of theoretical) CZOH3,NOSi (M= 329.552) Calc.: molpeak (M+H)+: 330 Found: molpeak (M+H) : 330 Rf value: 0.40 (silica gel, PE/EtOAc 4:1 ) fraction 2: trans-1-{6-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridin-3-yl}-4-methyl-cyclohexanol Yield: 1.00 g (20% of theoretical) C2oH3~NOSi (M= 329.552) Calc.: molpeak (M+H)+: 330 Found: molpeak (M+H) : 330 Rf value: 0.30 (silica gel, PE/EtOAc 4:1 ) 7.12b 2-[(tent-butyl-dimethyl-silanyl)-ethynyl]-5-(4-methyl-cyclohex-1-enyl)-pyridine 1.22 mL (15.78 mmol) methanesulphonic acid chloride are slowly added dropwise to a solution cooled to 0°C of 1.3 g (3.95 mmol) cis-1-{6-[(tert-butyl-dimethyl-silanyl)-ethynyl]-pyridin-3-yl}-4-methyl-cyclohexanol and 2.2 mL (15.78 mmol) triethylamine in 30 mL DCM.
After the addition has ended the cooling bath is removed and the reaction mixture is stirred for 2 h at RT. To complete the reaction another 2.2 mL triethylamine and 1.22 mL
methanesulphonic acid chloride are added, the mixture is stirred overnight at RT and again combined with 1 mL triethylamine. Water is added to the reaction solution, the organic phase is separated off, washed with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient PE to PE/EtOAc 9:1 ).
Yield: 0.95 g (20% of theoretical) C2oH29NSi (M= 311.536) Calc.: molpeak (M+H)+: 312 Found: molpeak (M+H) : 312 7.12c 2-ethynyl-5-(4-methyl-cyclohex-1-enyl)-pyridine 877 mg (3.35 mmol) TBAF are added to a solution of 950 mg (3.05 mmol) 2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-5-(4-methyl-cyclohex-1-enyl)-pyridine in 20 mL DCM
and the reaction solution is stirred for 30 min at RT. The mixture is combined with water, the organic phase is separated off, washed three times with water and dried over MgS04.
After the desiccant and solvent have been eliminated the residue is purified by chromatography (Alox, PE/EtOAc 9:1 ).
Yield: 400 mg (66% of theoretical) C~4H,5N (M= 197.276) Calc.: molpeak (M+H)+: 198 Found: molpeak (M+H) : 198 retention time HPLC: 5.9 min (method E).
7.12d 1-bromo-4-((E)-3-chloro-propenyl)-benzene 1.67 mL (20.65 mmol) pyridine and one drop of DMF are added to a solution cooled to 0°C of 4.40 g (20.65 mmol) (E)-3-(4-bromo-phenyl)-prop-2-en-1-of in 50 mL DCM and then a solution of 1.51 mL (20.65 mmol) SOCI2 in 10 mL DCM is slowly added dropwise.
The reaction mixture is stirred for 1 h at 0°C and for 3 h at RT. It is carefully combined with water, the organic phase is separated off, washed with water and dried over MgS04.
After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, PE/DCM 4:1 ).
Yield: 1.9 g (40% of theoretical) C9H$BrCI (M= 231.517) Calc.: molpeak (M+H)+: 230/232/234 (BrCI) Found: molpeak (M+H) : 230/232/234 (BrCI) 7.12e 1-[(E)-3-(4-bromo-phenyl)-allyl]-4-methyl-piperidin-4-of 709 mg (6.16 mmol) 4-methyl-piperidin-4-of are added to a solution of 950 mg (4.10 mmol) 1 bromo-4-((E)-3-chloro-propenyl)-benzene and 1.14 mL (8.21 mmol) triethylamine in 5 mL
DMF and the reaction mixture is stirred overnight at RT. It is evaporated down i.vac., the residue is taken up in water, extracted exhaustively with EtOAc, the combined organic phases are washed with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is evaporated down i.vac. and reacted further without purification.
Yield: 600 mg (47% of theoretical) C,5H2oBrN0 (M= 310.229) Calc.: molpeak (M+H)+: 310/312 (Br) Found: molpeak (M+H) : 310/312 (Br) 7.12f 1-[(E)-3-(4-iodo-phenyl)-allyl]-4-methyl-piperidin-4-of Prepared according to general experimental method II from 600 mg (1.93 mmol) 1-[(E)-3-(4-bromo-phenyl)-allyl]-4-methyl-piperidin-4-ol.
Yield: 700 mg (100% of theoretical) C,5H2oIN0 (M= 357.230) Calc.: molpeak (M+H)+: 358 Found: molpeak (M+H) : 358 retention time HPLC: 3.5 min (method B).
7.12g 4-methyl-1-((E)-3-{4-[5-(4-methyl-cyclohex-1-enyl)-pyridin-2-ylethynyl]-phenyl}-allyl)-piperidin-4-of Prepared according to general working method I from 120 mg (0.34 mmol) 1-[(E)-3-(4-iodo phenyl)-allyl]-4-methyl-piperidin-4-of and 80 mg (0.40 mmol) 2-ethynyl-5-(4-methyl-cyclohex 1-enyl)-pyridine (with Pd(dppf)CIz as catalyst, triethylamine as base and THF
as solvent).
Yield: 30 mg (21 % of theoretical) Cz9H34N20 (M= 426.593) Calc.: molpeak (M+H)+: 427 Found: molpeak (M+H) : 427 retention time HPLC: 5.6 min (method D).
Example 7.13 5-(4-methyl-cyclohex-1-enyl)-2-{4-[(E)-3-(4-methyl-piperidin-1-yl)-propenyl]-phenylethynyl}-pyridine r 7.13a 1-[(E)-3-(4-bromo-phenyl)-allyl]-4-methyl-piperidin 1.94 mL (16.41 mmol) 4-methypiperidine are added to a solution of 950 mg (4.10 mmol) 1-bromo-4-((E)-3-chloro-propenyl)-benzene in 5 mL DMF and the reaction solution is stirred overnight at RT. It is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc, the combined organic phases are washed with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is evaporated down i.vac. and reacted further without purification.
Yield: 900 mg (75% of theoretical) C,5H2oBrN (M= 294.230) Calc.: molpeak (M+H)+: 294/296 (Br) Found: molpeak (M+H) : 294/296 (Br) 7.13b 1-[(E)-3-(4-iodo-phenyl)-allyl]-4-methyl-piperidin Prepared according to general experimental method II from 900 mg (3.06 mmol) 1-[(E)-3-(4-bromo-phenyl)-allyl]-4-methyl-piperidine.
Yield: 1.0 g (96% of theoretical) C~5H2oIN (M= 341.231 ) Calc.: molpeak (M+H)+: 342 Found: molpeak (M+H) : 342 retention time HPLC: 4.0 min (method B).
7.13c 5-(4-methyl-cyclohex-1-enyl)-2-{4-[(E)-3-(4-methyl-piperidin-1-yl)-propenyl]-phenylethynyl}-pyridine Prepared according to general working method I from 120 mg (0.34 mmol) 1-[(E)-3-(4-iodo phenyl)-allyl]-4-methyl-piperidine and 83 mg (0.42 mmol) 2-ethynyl-5-(4-methyl-cyclohex-1 enyl)-pyridine (with Pd(dppf)CIZ as catalyst, triethylamine as base and THF as solvent).
Yield: 30 mg (21 % of theoretical) C2gH34N2 (M= 410.594) Calc.: molpeak (M+H)+: 411 Found: molpeak (M+H) : 411 retention time HPLC: 6.0 min (method D).
Example 7.14 1-(( E)-3-{4-[5-(4-chloro-phenyl )-3-fluoro-pyrid in-2-ylethynyl]-phenyl}-allyl)-4-methyl-piperid in-4-0l ci . WO 2005/103032 99 PCT/EP2005/003686 7.14a 2,5-dibromo-3-fluoro-pyridine A solution of 1.78 g (25.80 mmol) sodium nitrite in 3.5 mL water is added dropwise at -5°C to a solution of 6.50 g (25.80 mmol) 2,5-dibromo-pyridin-3-ylamine and 15 mL
conc. HC/ (180.62 mmol) in 15 mL water and the mixture is stirred for 30 min. At 0 °C
11.41 mL (77.41 mmol) hexafluorophosphoric acid (60% in water) are added and the mixture is stirred for 1 h at 0 °C.
The diazonium salt formed is filtered off, washed with cold water, isopropanol and diethyl ether and dried i.vac. in the desiccator. PE (boiling range 100-140 °C) is heated to 90 °C, the diazonium salt is added batchwise and the mixture is stirred until no further development of gas can be detected. The reaction mixture is cooled to RT, made alkaline with saturated Na2C03 solution and the aqueous phase is exhaustively extracted with TBME. The combined organic phases are washed with saturated Na2C03 solution and water and dried over MgS04.
After the desiccant and solvent have been eliminated the residue is dissolved in DCM, filtered through silica gel and the filtrate is evaporated down i.vac. .
Yield: 3.30 (51 % of theoretical) C5H2BrZFN (M= 254.883) Calc.: molpeak (M+H)+: 253/255/257 (2 Br) Found: molpeak (M+H) : 253/255/257 (2 Br) Rf value: 0.63 (silica gel, PE/EtOAc 9:1 ) 7.14b 5-bromo-2-[(tert-butyl-dimethyl-silanyl)-ethynylJ-3-fluoro-pyridine Under an argon atmosphere 2.62 mL (13.81 mmol) tert-butyl-ethynyl-dimethyl-silane are added at 15°C to a solution of 3.20 g (12.56 mmol) 2,5-dibromo-3-fluoro-pyridine, 5.22 mL
triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) Cul and 220.3 mg (0.31 mmol) bis-triphenylphosphane-palladium(//)-chloride in 30 mL dry THF and the mixture is stirred for 2 h at RT. 1 mL tert-butyl-ethynyl-dimethyl-silane is added and again the mixture is stirred for 1 h at RT. The reaction mixture is evaporated down i.vac. and the residue is taken up in EtOAc.
The organic phase is washed with semisaturated Na2C03 solution, 5% NH3 solution and water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, PE/DCM 9:1 ).
Yield: 1.62 g (41 % of theoretical) C,3H"BrFNSi (M= 314.269) Calc.: molpeak (M+H)+: 314/316 (Br) Found: molpeak (M+H) : 314/316 (Br) HPLC-MS: 7.9 min (method B) 7.14c 2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-5-(4-chloro-phenyl)-3-fluoro-pyridine 10 mL MeOH, 10 mL 2 N aqueous Na2C03 solution and 94 mg (0.13 mmol) Pd(dppf)CI2 are added to a solution of 1.61 g (5.14 mmol) 5-bromo-2-[(tent-butyl-dimethyl-silanyl)-ethynyl]-3-fluoro-pyridine and 0.90 g (5.65 mmol) 4-chlorophenylboric acid in 30 mL 1,4-dioxane and the mixture is refluxed for 15 min. The reaction mixture is evaporated down i.vac.
and diluted with EtOAc. The organic phase is washed with water and semisaturated Na2C03 solution and dried over Na2S04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, PE/DCM 1:1 ).
Yield: 1.25 g (70% of theoretical) C,9H2~CIFNSi (M= 345.913) Calc.: molpeak (M+H)+: 346/348 (CI) Found: molpeak (M+H) : 3461348 (CI) HPLC-MS: 8.9 min (method B).
7.14d 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine 1.14 g (3.61 mmol) TBAF are added at RT to a solution of 1.25 g (3.61 mmol) 2-[(tert-butyl-dimethyl-silanyl)-ethynyl]-5-(4-chloro-phenyl)-3-fluoro-pyridine in 30 mL DCM
and the mixture is stirred for 2 h at RT. The organic phase is washed with water and dried over Na2S04. After the desiccant and solvent have been eliminated the residue is stirred with PE, the precipitate is filtered off, washed with PE and dried in the air.
Yield: 0.72 g (86% of theoretical) C~3H~CIFN (M= 231.653) Calc.: molpeak (M+H)+: 232/234 (CI) Found: molpeak (M+H) : 2321234 (CI) HPLC-MS: 5.8 min (method B).
7.14e 1-((E)-3-{4-[5-(4-chloro-phenyl)-3-fluoro-pyridin-2-ylethynyl]-phenyl}-allyl)-4-methyl-piperidin-4-of Prepared according to general working method I from 200 mg (0.56 mmol) 1-[(E)-3-(4-iodo phenyl)-allyl]-4-methyl-piperidin-4-of and 130 mg (0.56 mmol) 5-(4-chloro-phenyl)-2-ethynyl-3 fluoro-pyridine (with Pd(dppf)CIZ as catalyst, triethylamine as base and THF
as solvent).
Yield: 55 mg (21 % of theoretical) C28H26CIFN20 (M= 460.970) ' + -Calc.: molpeak (M+H)+: 461/463 (CI) Found: molpeak (M+H) : 461/463 (CI) retention time HPLC: 5.6 min (method D).
Example 7.15 5-(4-chloro-phenyl)-3-fluoro-2-{4-[(E)-3-(4-methyl-piperidin-1-yl)-propenyl]-phenyl-ethynyl}-pyridine Prepared according to general working method I from 200 mg (0.59 mmol) 1-[(E)-3-(4-iodo-phenyl)-allyl]-4-methyl-piperidine and 136 mg (0.59 mmol) 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine (with Pd(dppf)CI2 as catalyst, triethylamine as base and THF
as solvent).
Yield: 40 mg (15% of theoretical) C28HZ6CIFN2 (M= 444.971 ) Calc.: molpeak (M+H)': 445/447 (CI) Found: molpeak (M+H) : 445/447 (CI) retention time HPLC: 6.0 min (method D).
Example 8 (E)-5-(4-chloro-phenyl)-2-{4-[2-methyl-3-(4-methyl-piperidin-1-yl)-propenyl]-phenylethynyl}-pyridine 8a 2-(4-bromo-phenylethynyl)-5-(4-chloro-phenyl)-pyridine Prepared according to general method I from 4-bromo-iodobenzene (566 mg, 2.00 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (460 mg, 2.00 mmol).
Yield: 600 mg (81.4 % of theoretical) C1 gH11 BrCIN (M= 368.654) Calc.: molpeak (M+H)+: 368/370/372 (BrCI) Found: molpeak (M+H)+: 368/370/372 (BrCI) Rf value: 0.78 (silica gel, PE/DCM 1:1 ).
8b 5-(4-chloro-phenyl)-2-(4-iodo-phenylethynyl)-pyridine Prepared according to general method II from 2-(4-bromo-phenylethynyl)-5-(4-chloro-phenyl)-pyridine (600 mg, 1.63 mmol).
Yield: 500 mg (73.9 % of theoretical) C1gH11CIIN (M=415.655) Calc.: molpeak (M)+: 416/418 (CI) Found: molpeak (M)+: 416/418 (CI) . WO 2005/103032 102 PCT/EP2005/003686 retention time HPLC: 7.76 min (method B).
8c (E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-methyl-prop-2-en-1-of 195 mg (2.70 mmol) 2-methyl-2-propen-1-ol, 200 mg (1.20 mmol) silver acetate, 13 mg (0.06 mmol) palladium(II)acetate and 31 mg (0.12 mmol) triphenylphosphane are added successively to a solution of 500 mg (1.20 mmol) 5-(4-chloro-phenyl)-2-(4-iodo-phenylethynyl)-pyridine in 2.0 mL DMF in an argon atmosphere. The reaction mixture is shaken for 2 days at 75°C. A further 89 mg (0.55 mmol) 2-methyl-2-propen-1-of are added and the reaction mixture is stirred for a further 4 days at 75°C. After cooling the reaction solution is diluted with 70 mL DCM and 30 mL water. After filtration the organic phase is dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (PE towards PE/EtOAc 7:3).
Yield: 60 mg (13.9 % of theoretical) C23H2pCIN0 (M= 359.85) Calc.: molpeak (M+H)+: 360/362 (CI) Found: molpeak (M+H)+: 360/362 (CI) retention time HPLC: 6.30 min (method B).
8d (E)-5-(4-chloro-phenyl)-2-{4-[2-methyl-3-(4-methyl-piperidin-1-yl)-propenyl]-phenylethynyl}-pyridine 15.0 pL (0.19 mmol) methanesulphonic acid chloride and 30 pL (0.22 mmol) triethylamine are added to a solution of 60.0 mg (0.17 mmol) (E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-methyl-prop-2-en-1-of in 5.0 mL DCM. The reaction is stirred for 4 h at RT and a further 15.0 pL (0.19 mmol) methanesulphonic acid chloride and 30 pL (0.22 mmol) triethylamine are added. The reaction solution is stirred for 2 h at RT and then 0.50 mL (4.23 mmol) 4-methylpiperidine are added. The reaction mixture is stirred for 2 h at RT and then diluted with 30 mL DCM. The organic phase is washed three times with water, dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM towards DCM/MeOH/NH3 9:1:0.1 ).
Yield: 10 mg (13.6 % of theoretical) C2gH2gCIN2 (M= 440.988) Calc.: molpeak (M+H)+: 441/443 (CI) Found: molpeak (M+H)+: 441/443 (CI) Rf value: 0.15 (silica gel, DCM/MeOH/NH3 95:5:0.5).
Example 8.1 1-((E)-3-{4-(5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-methyl-allyl)-4-methyl-piperidin-4-0l HO
N
8.1a 2-[4-((E)-3-chloro-2-methyl-propenyl)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine 0.27 mL (3.36 mmol) pyridine are added to a solution cooled to 0°C of 1.10 g (3.06 mmol) (E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-methyl-prop-2-en-1-of (Example 8c) in 100 mL DCM and then 0.25 mL (3.36 mmol) SOCI2 are slowly added dropwise. The reaction solution is brought to RT gebracht and stirred for 1 h. The mixture is combined with ice water, the organic phase is separated off, washed several times with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient PE to PE/DCM 1:4).
Yield: 160 mg (14% of theoretical) C23Hi~C12N (M= 378.293) Calc.: molpeak (M+H)+: 378/380/382 (2 CI) Found: molpeak (M+H) : 378/380/382 (2 CI) retention time HPLC: 7.9 min (method F).
8.1b 1-((E)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-2-methyl-allyl)-4-methyl-piperidin-4-of 22 mg (0.19 mmol) 4-methyl-piperidin-4-of are added to a solution of 40 mg (0.11 mmol) 2-[4-((E)-3-chloro-2-methyl-propenyl)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine in 1 mL DMF
and the reaction mixture is stirred for 1 h at 60°C. The reaction solution is purified by HPLC
without any further working up. The fractions containing the product are combined and lyophilised.
Yield: 20 mg (39% of theoretical) C29H29CIN20 (M= 457.006) Calc.: molpeak (M+H)+: 457/459 (CI) Found: molpeak (M+H) : 457/459 (CI) retention time HPLC: 7.4 min (method A).
The followeing Examples are prepared analogously, in each case starting from 40 mg 2-[4-((E)-3-chloro-2-methyl-propenyl)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine:

ci ExampleR Yield Empirical formulaMass HPLC
(%) spectrum retention time (method) 8.2 ~ 42 C28HZ,CIN2 427/429 8.0 min [M+H]+ (A) N-_ .

H

8.3 " 34 C3oH28CIF3N20 525/527 8.1 min F3c ~N [M+H]+ (A) Example 8.4 5-(4-chloro-phenyl )-3-fluoro-2-{4-[( E)-2-methyl-3-(4-methyl-piperid i n-1-yl )-propenyl]-phenylethynyl}-pyridine 8.4a (E)-3-(4-iodo-phenyl)-2-methyl-prop-2-en-1-of Prepared according to general experimental method II from 1.0 g (4.40 mmol) (E)-3-(4-bromo-phenyl )-2-methyl-prop-2-en-1-of Yield: 1.1 g (91 % of theoretical) _ C~oH»10 (M= 274.098) Calc.: molpeak (M)+: 274 Found: molpeak (M) : 274 retention time HPLC: 5.5 min (method B).
8.4b 1-((E)-3-chloro-2-methyl-propenyl)-4-iodo-benzene Prepared analogously to Example 7.12d from 1.10 g (4.01 mmol) (E)-3-(4-iodo-phenyl)-2-methyl-prop-2-en-1-of and 0.35 mL (4.82 mmol) SOCI2, while in order to complete the reaction the solution is stirred overnight at RT.

. - WO 2005/103032 105 PCT/EP2005/003686 Yield: 1.1 g (94% of theoretical) C~oH~oCll (M= 292.544) Calc.: molpeak (M)+: 292/294 (CI) Found: molpeak (M) : 292/294 (CI) 8.4c 1-[(E)-3-(4-iodo-phenyl)-2-methyl-allyl]-4-methyl-piperidin 0.89 mL (7.52 mmol) 4-methyl-piperidine are added to a solution of 550 mg (1.88 mmol) 1-((E)-3-chloro-2-methyl-propenyl)-4-iodo-benzene in 5 mL DMF and the reaction mixture is stirred overnight at RT. Water is added to the reaction solution, it is exhaustively extracted with EtOAc and the combined organic phases are dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient PE to PE/EtOAc 4:1 ).
Yield: 140 mg (21 % of theoretical) C~6H221N (M= 355.257) Calc.: molpeak (M+H)+: 356 Found: molpeak (M+H) : 356 retention time HPLC: 5.8 min (method A).
8.4d 5-(4-chloro-phenyl)-3-fluoro-2-{4-[(E)-2-methyl-3-(4-methyl-piperidin-1-yl)-propenyl]-phenylethynyl}-pyridine Prepared according to general working method I from 70 mg (0.20 mmol) 1-[(E)-3-(4-iodo-phenyl)-2-methyl-allyl]-4-methyl-piperidine and 46 mg (0.20 mmol) 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine (with Pd(dppf)CIz as catalyst, triethylamine as base and THF as solvent).
Yield: 4 mg (4% of theoretical) C29H28CIFN2 (M= 458.997) Calc.: molpeak (M+H)+: 459/461 (CI) Found: molpeak (M+H) : 459/461 (CI) retention time HPLC: 6.2 min (method D).
Example 8.5 5-(4-methyl-cyclohex-1-enyl )-2-{4-[( E)-2-methyl-3-(4-methyl-piperid i n-1-yl )-propenyl]-phenylethynyl}-pyridine Prepared according to general working method I from 70 mg (0.20 mmol) 1-[(E)-3-(4-iodo-phenyl)-2-methyl-allyl]-4-methyl-piperidine and 39 mg (0.20 mmol) 2-ethynyl-5-(4-methyl-cyclohex-1-enyl)-pyridine (with Pd(dppf)CIZ as catalyst, triethylamine as base and THF as solvent).
Yield: 5 mg (6% of theoretical) CsoHssN2 (M= 424.620) Calc.: molpeak (M+H)+: 425 Found: molpeak (M+H) : 425 retention time HPLC: 6.1 min (method D).
Example 8.6 1-((E)-3-{4-[5-(4-chloro-phenyl)-3-fluoro-pyridin-2-ylethynyl]-phenyl}-2-methyl-allyl)-4-methyl-piperidin-4-of HO
N
8.6a 1-[(E)-3-(4-iodo-phenyl)-2-methyl-allyl]-4-methyl-piperidin-4-of 433 mg (3.76 mmol) 4-methyl-piperidin-4-of are added to a solution of 550 mg (1.88 mmol) 1-((E)-3-chloro-2-methyl-propenyl)-4-iodo-benzene and 0.79 mL (5.64 mmol) triethylamine in 5 mL DMF and the reaction mixture is stirred overnight at RT. It is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with EtOAc, the combined organic phases are washed twice with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient EtOAc to EtOAc/MeOH 9:1 ).
Yield: 170 mg (24% of theoretical) C~6H221N0 (M= 371.256) Calc.: molpeak (M+H)+: 372 Found: molpeak (M+H) : 372 -8.6b 1-((E)-3-{4-[5-(4-chloro-phenyl)-3-fluoro-pyridin-2-ylethynyl]-phenyl}-2-methyl-allyl)-4-methyl-piperidin-4-of Prepared according to general working method I from 85 mg (0.23 mmol) 1-[(E)-3-(4-iodo phenyl)-2-methyl-allyl]-4-methyl-piperidin-4-of and 53 mg (0.23 mmol) 5-(4-chloro-phenyl)-2 ethynyl-3-fluoro-pyridine (with Pd(dppf)CI2 as catalyst, triethylamine as base and THF as solvent).
Yield: 25 mg (23% of theoretical) C29H28CIFNzO (M= 474.997) Calc.: molpeak (M+H)+: 475/477 (CI) Found: molpeak (M+H) : 475/477 (CI) retention time HPLC: 5.8 min (method D).
Example 8.7 4-methyl-1-(( E)-2-methyl-3-{4-[5-(4-methyl-cyclohex-1-enyl )-pyrid in-2-ylethynyl]-phenyl}-allyl)-piperidin-4-of Prepared according to general working method I from 85 mg (0.23 mmol) 1-[(E)-3-(4-iodo-phenyl)-2-methyl-allyl]-4-methyl-piperidin-4-of and 45 mg (0.23 mmol) 2-ethynyl-5-(4-methyl-cyclohex-1-enyl)-pyridine (with Pd(dppf)CIz as catalyst, triethylamine as base and THF as solvent).
Yield: 7 mg (7% of theoretical) CsoHssN20 (M= 440.620) Calc.: molpeak (M+H)+: 441 Found: molpeak (M+H) : 441 retention time HPLC: 5.7 min (method D).
Example 9 5-(4-chloro-phenyl)-2-{4-[2-methyl-2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}pyridine O
Ni' \
9a ethyl2-methyl-2-(4-methyl-piperidin-1-yl)-propionate A solution of 3.72 mL (25.0 mmol) ethyl 2-bromo-2-methyl-propionate in 40 mL 4-methylpiperidine is stirred overnight at 70°C and then the solvent is eliminated i. vac.. The residue is taken up in EtOAc and water. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. The crude product is reacted further without any further purification.
Yield: 3.00 g (56.3 % of theoretical) C12H23N02 (M= 213.317) Calc.: molpeak (M+H)+: 214 Found: molpeak/GC-MS (M+H)+: 214 retention time HPLC: 3.87 min (method A).
9b 2-methyl-2-(4-methyl-piperidin-1-yl)-propan-1-of 9.20 mL (9.20 mmol) of a 1 M lithium aluminium hydride solution in THF is added dropwise at RT to a solution of 3.00 g (9.14 mmol) ethyl 2-methyl-2-(4-methyl-piperidin-1-yl)-propionate in 20 mL THF. The reaction solution is heated to 50°C and stirred overnight. After cooling it is diluted with ice water and the aqueous phase is extracted with diethyl ether.
The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. The crude product is reacted further without any further purification.
Yield: 2.02 g (71.0 % of theoretical; content 55%) C1 pH21 NO (M= 171.280) Calc.: molpeak (M+H)+ : 172 Found: molpeak (M+H)+: 172 retention time HPLC: 1.88 min (method A).
9c 1-[2-(4-iodo-phenoxy)-1,1-dimethyl-ethyl]-4-methyl-piperidine 700 mg (3.18 mmol) 4-iodophenol and 1.25 g (4.77 mmol) triphenylphosphine are added to a solution of 1.00 g (3.21 mmol; 55% content) 2-methyl-2-(4-methyl-piperidin-1-yl)-propan-1-of in 20 mL DCM. 1.00 mL (4.79 mmol) DIAD is slowly added while cooling. The reaction mixture is stirred for 2 h at RT. water is added, the organic phase is separated off, extracted twice with water, the combined organic phases are dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (EtOAc).
Yield: 1.85 g (84.9 % of theoretical; content 55%) C16H241N0 (M= 373.272) Calc.: molpeak (M)+: 373 Found: molpeak (M)+: 373 retention time HPLC: 6.09 min (method A). -9d 5-(4-chloro-phenyl)-2-{4-[2-methyl-2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}pyridine Prepared according to general method I from 1-[2-(4-iodo-phenoxy)-1,1-dimethyl-ethyl]-4-methyl-piperidine (200 mg, 0.54 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (110 mg, 0.50 mmol).
Yield: 25 mg (10.1% of theoretical) C2gH31 CIN20 (M= 459.022) Calc.: molpeak (M+H)+: 459/461 (CI) Found: molpeak (M+H)+: 459/461 (CI) retention time HPLC: 5.7 min (method A).
Example 10 5-(4-chloro-phenyl)-2-[4-(1-pyrrolidin-1-yl-cyclopropylmethoxy)-phenylethynyl]-pyridine ci C.
o 10a 1-(4-iodo-phenoxymethyl)-cyclopropylamine While cooling with ice/isopropanol, 22.1 mL (72.7 mmol) titanium(IV)-isopropoxide are added dropwise to a solution of 13.8 g (65.1 mmol) (4-iodo-phenoxy)-acetonitrile in 250 mL diethyl ether. Then 43.4 mL (130 mmol) of a 3 M ethylmagnesium bromide solution in diethyl ether are added dropwise at 0°C. The reaction mixture is stirred for 30 min.
Then 16.5 mL (130 mmol) boron trifluoride-diethyl ether complex are added quickly. The reaction mixture is stirred for 30 min and then while cooling with ice 200 mL of a 1 M sodium hydroxide solution solution are added. After an hour the aqueous phase is extracted with 300 mL
diethyl ether.
The organic phase is dried over NazS04 and the solvent is reduced i.vac. to 400 mL. The organic phase is washed with 180 mL saturated Na2S03 solution and washed twice with 400 mL of 0.05 M hydrochloric acid solution. The aqueous phase is made alkaline with 30%
sodium hydroxide solution and extracted with 400 mL DCM. The combined organic extracts are dried over MgS04 and the solvent is eliminated i. vac.. The crude product is reacted further without any further purification.
Yield: 7.67 g (48.7 % of theoretical) C1pH12BrN0 (M= 242.112) Calc.: molpeak (M+H)+: 242/244 (Br) Found: molpeak (M+H)+: 242/244 (Br) retention time HPLC: 4.96 min (method A).
10b 1-[1-(4-bromo-phenoxymethyl)-cyclopropyl]-pyrrolidine 0.50 mL of 1,4-dibromobutane and 1.14 g (8.26 mmol) K2C03 are added to a solution of 1.00 g (4.13 mmol) 1-(4-iodo-phenoxymethyl)-cyclopropylamine in 50 mL DMF. The reaction mixture is stirred for 24 h at 80°C. The solvent is eliminated i. vac.
and the residue is combined with 100 mL water and 200 mL EtOAc. The organic phase is separated off, dried over Na2S04 and the solvent is eliminated i. vac.. The crude product is reacted further without any further purification.
Yield: 1.33 g (108.6 % of theoretical) C14H18BrN0 (M= 296.203) Calc.: molpeak (M+H)+: 296/298 (Br) Found: molpeak (M+H)+: 296/298 (Br) retention time HPLC: 6.03 min (method A).
10c 1-(1-(4-iodo-phenoxymethyl)-cyclopropyl]-pyrrolidine Prepared according to general method II from 1-[1-(4-bromo-phenoxymethyl)-cyclopropyl]-pyrrolidine (1.22 g, 4.12 mmol).
Yield: 473 mg (33.5 % of theoretical) C14H181N0 (M= 343.209) Calc.: molpeak (M+H)+: 344 Found: molpeak (M+H)+: 344 retention time HPLC: 6.17 min (method A).
10d 5-(4-chloro-phenyl)-2-[4-(1-pyrrolidin-1-yl-cyclopropylmethoxy)-phenylethynyl]-pyridine Prepared according to general method I from 1-[1-(4-iodo-phenoxymethyl)-cyclopropyl]-pyrrolidine (100 mg, 0.29 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (78 mg, 0.36 mmol).
Yield: 15 mg (12.0 % of theoretical) C27H25CIN20 (M= 428.953) Calc.: molpeak (M+H)+: 429/431 (CI) Found: molpeak (M+H)+: 429/431 (CI) retention time HPLC: 8.28 min (method A).
Example 11.1 (R)-5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine ~r°
11.1a (R)-2-[2-(4-iodo-phenoxy)-1-methyl-ethyl]-isoindol-1,3-dione 5.40 g (26.3 mmol) (R)-2-(2-hydroxy-1-methyl-ethyl)-isoindol-1,3-dione in 40 mL THF are added to a solution of 8.80 g (30.0 mmol) 4-iodophenol and 10.5 g (40.0 mmol) triphenylphosphine in 180 mL THF in a nitrogen atmosphere. The reaction solution is cooled to 0°C and 7.93 mL (40.0 mmol) DIAD in 20 mL THF are added, the ice bath is removed and the mixture is stirred overnight at RT. Another 10.5 g (40.0 mmol) triphenylphosphine and 6.0 mL (30.3 mmol) DIAD are added and the mixture is stirred for a further 4 h.
The solvent is eliminated i. vac. and the residue is taken up in EtOAc. The organic phase is washed twice with semisaturated NazC03 solution, dried over MgS04 and the solvent is eliminated i. vac..
The residue is combined with TBME and DIPE. After filtration the solvent is eliminated i. vac..
Further purification is carried out by column chromatography on silica gel (PE/EtOAc 9:1 towards PE/EtOAc 6:4). The residue is taken up in EtOAc, washed twice with 1 M
sodium hydroxide solution, the organic phase is dried over MgS04 and the solvent is eliminated i.
vac..
Yield: 6.60 g (61.6 % of theoretical) C17H141N03 (M= 407.202) Calc.: molpeak (M+H)+: 408 Found: molpeak (M+H)+: 408 retention time HPLC: 6.41 min (method B).
11.1 b (R)-2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy)-1-methyl-ethyl)-isoindol-1,3-dione Prepared according to general method I from (R)-2-[2-(4-iodo-phenoxy)-1-methyl-ethyl]-isoindol-1,3-dione (1.00 g, 2.46 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (643 mg, 2.80 mmol).
Yield: 700 mg (57.8 % of theoretical) C30H21 CIN203 (M= 492.952) Calc.: molpeak (M+H)+: 493/495 (CI) Found: molpeak (M+H)+: 493/495 (CI) Rf value: 0.60 (silica gel, PE/EtOAc 6:4).

11.1c (R)-2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylamine 3.0 mL methylamine (40% in water) are added to a solution of 700 mg (1.42 mmol) (R)-2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-isoindol-1,3-dione in 3.0 mL toluene and the reaction solution is stirred overnight. The reaction mixture is combined with 80 mL DCM, extracted three times with water, dried over MgS04 and the solvent is eliminated i. vac.. The residue is stirred with TBME and after filtration dried in the air. The succinimide has been only partially opened. Therefore the residue is combined with 5.0 mL
40% methylamine and 5.0 mL toluene and stirred for 3 days in a sealed vessel at 60°C. The reaction mixture is diluted with 120 mL DCM. The organic phase is extracted three times with 1o water, dried over MgS04 and the solvent is eliminated i. vac.. The residue is stirred with TBME and EtOAc and after filtration dried in the air.
Yield: 250 mg (48.5 % of theoretical) C22H1gCIN20 (M= 362.852) Calc.: molpeak (M+H)+: 363/365 (CI) Found: molpeak (M+H)+: 363/365 (CI) Rf value: 0.08 (silica gel, DCM/MeOH 9:1 ).
11.1d (R)-5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyrid ine 61.0 mg (0.25 mmol) 1,5-dibromo-3-methylpentane and 75.0 mg (0.54 mmol) K2C03 are added to a solution of 80.0 mg (0.22 mmol) (R)-2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]
phenoxy}-1-methyl-ethylamine in 2.00 mL DMF. The mixture is shaken overnight at 50°C.
After cooling a precipitate is formed which is combined with some water. After filtration the mixture is washed with water and i-propanol. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 9:1:0.1 ).
Yield: 24 mg (25.0 % of theoretical) C2gH2gCIN20 (M= 444.995) Calc.: molpeak (M+H)+: 445/447 (CI) Found: molpeak (M+H)+: 445/447 (CI) Rf value: 0.12 (silica gel, DCM/MeOH/NH3 95:5:0.5).
Example 11.2 and 11.3 11.2: (R)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-cyclopropylmethyl-amine 11.3: (R)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-bis-cyclopropylmethyl-amine ci 11.2 and 11.3 A solution of 190 mg (0.52 mmol) (R)-2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylamine and 0.06 mL (0.80 mmol) cyclopropanecarboxaldehyde in 75 mL THF is stirred for 1 h at RT and then 339 mg (1.60 mmol) NaBH(OAc)3 and 0.01 mL (0.25 mmol) glacial acetic acid are added. The reaction mixture is stirred for 2 h at RT.
Some of the solvent is eliminated i. vac. and the residue is diluted with 50 mL EtOAc and 30 mL saturated NaHC03 solution. The organic phase is extracted with water, dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM towards DCM/MeOH/NH3 9:1:0.1 ). The desired fractions are evaporated down and the respective residues are triturated with TBME and DIPE and after filtration dried in the air.
11.2: (R)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-cyclopropylmethyl-amine Yield: 27 mg (12.4 % of theoretical) C26H25CIN20 (M= 416.942) Calc.: molpeak (M+H)+: 417/419 (CI) Found: molpeak (M+H)+: 417/419 (CI) Rf value: 0.56 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
11.3: (R)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-bis-cyclopropylmethyl-amine:
Yield: 58 mg (23.5 % of theoretical) C30H31 CIN20 (M= 471.033) Calc.: molpeak (M+H)+: 471/473 (CI) Found: molpeak (M+H)+: 471/473 (CI) Rf value: 0.87 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
Example 12.1 (S)-5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine N
O
12.1 a (S)-2-[2-(4-iodo-phenoxy)-1-methyl-ethyl]-isoindol-1,3-dione Analogously to 11.1a the product is obtained from 6.30 g (30.7 mmol) (S)-2-(2-hydroxy-1-methyl-ethyl)-isoindol-1,3-dione, 7.04 g (32.0 mmol) 4-iodophenol, 23.6 g (90.0 mmol) triphenylphosphine and 17.8 mL (90.0 mmol) DIAD.
Yield: 2.50 g (20.0 % of theoretical) C17H141NO3 (M= 407.202) Calc.: molpeak (M+H)+: 408 Found: molpeak (M+H)+: 408 retention time HPLC: 6.41 min (method B).
12.1b (S)-2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-isoindol-1,3-dione Prepared according to general method I from (R)-2-[2-(4-iodo-phenoxy)-1-methyl-ethyl]-2o isoindol-1,3-dione (2.50 g, 6.14 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.49 g, 6.50 mmol).
Yield: 1.30 g (43.0 % of theoretical) C30H21 CIN203 (M= 492.952) Calc.: molpeak (M+H)+: 493/495 (CI) Found: molpeak (M+H)+: 493/495 (CI) retention time HPLC: 7.18 min (method A).
12.1c (S)-2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylamine Analogously to 11.1 c the product is obtained from 1.30 g (2.64 mmol) (S)-2-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-isoindol-1,3-dione and 6 mL 40%
methylamine solution in water.

Yield: 650 mg (67.9 % of theoretical) C22H1gCIN20 (M= 362.852) Calc.: molpeak (M+H)+: 363/365 (CI) Found: molpeak (M+H)+: 363/365 (CI) retention time HPLC: 4.87 min (method B).
12.1d (S)-5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine Analogously to 11.1 d the product is obtained from 100 mg (0.28 mmol) (S)-2-{4-[5-(4-chloro phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylamine and 76 mg (0.31 mmol) 1,5 dibromo-3-methylpentane.
Yield: 20 mg (16.3 % of theoretical) C28H2gCIN20 (M= 444.995) Calc.: molpeak (M+H)+: 445/447 (CI) Found: molpeak (M+H)+: 445/447 (CI) Rf value: 0.48 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
Example 12.2 and 12.3 12.2: (S)-(2-f4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-cyclopropylmethyl-amine ~H
N
O
12.3: (S)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-bis-cyclopropylmethyl-amine ci 12.2 and 12.3 A solution of 290 mg (0.80 mmol) (S)-2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethylamine and 0.09 mL (1.20 mmol) cyclopropancarboxaldehyde in 75 mL
THF is stirred for 1 h at RT. Then 509 mg (2.40 mmol) NaBH(OAc)3 and 0.02 mL (0.40 mmol) glacial acetic acid are added. The reaction mixture is stirred for 2 h at RT. Some of the solvent is eliminated i. vac. and the residue is diluted with 50 mL EtOAc and 30 mL
saturated NaHC03 solution. The organic phase is washed with water, dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM towards DCM/MeOH/NH3 9:1:0.1 ). The desired fractions are evaporated down and the respective residues are triturated with TBME and after filtration dried in the air.
12.2: (S)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-cyclopropylmethyl-amine Yield: 56 mg (16.8 % of theoretical) C26H25CIN20 (M= 416.942) Calc.: molpeak (M+H)+: 417/419 (CI) Found: molpeak (M+H)+: 417/419 (CI) Rf value: 0.48 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
12.3: (S)-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl)-bis-cyclopropylmethyl-amine Yield: 32 mg (9.0 % of theoretical) C30H31 CIN20 (M= 471.033) Calc.: molpeak (M+H)+: 471/473 (CI) Found: molpeak (M+H)+: 471/473 (CI) Rf value: 0.82 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
Example 13 (R)-5-(4-chloro-phenyl)-2-{4-[3-methyl-2-(4-methyl-piperidin-1-yl)-butoxy]-phenylethynyl}-pyridine ,a 13a (R)-3-methyl-2-(4-methyl-piperidin-1-yl)-butan-1-of 1.32 g (5.40 mmol) 1,5-dibromo-3-methylpentane and 1.55 g (11.2 mmol) K2C03 are added to a solution of 0.50 g (4.85 mmol) R-(-)-2-amino-3-methyl-1-butanol in 10 mL
DMF. The reaction mixture is stirred overnight at 50°C. After cooling it is diluted with 50 mL EtOAc and washed three times with semisaturated NaHC03 solution. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. The residue is filtered through a silica gel bed (DCM towards DCM/MeOH 8:2).
Yield: 350 mg (39.0 % of theoretical) C11 H23N0 (M= 185.306) Calc.: molpeak (M+H)+: 186 Found: molpeak (M+H)+: 186 Rf value: 0.30 (silica gel, DCM/MeOH 9:1 ).
13b (R)-1-[1-(4-bromo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidin 0.54 g (1.90 mmol) 4-bromo-iodophenol, 1.24 g (3.80 mmol) Cs2C03, 68.0 mg (0.38 mmol) 1,10-phenanthroline and 36.0 mg (0.19 mmol) Cul are added to a solution of 0.35 g (1.89 mmol) (R)-3-methyl-2-(4-methyl-piperidin-1-yl)-butan-1-of in 3.0 mL toluene.
The reaction mixture is shaken for 36 h at 110°C. After cooling it is diluted with 40 mL EtOAc and washed twice with 30 mL water. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM
towards DCM/MeOH 9:1 ).
Yield: 100 mg (16.0 % of theoretical) C17H26BrN0 (M= 340.298) Calc.: molpeak (M+H)+: 340/342 (Br) Found: molpeak (M+H)+: 340/342 (Br retention time HPLC: 4.93 min (method B).
13c (R)-1-[1-(4-iodo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidin Prepared according to general method II from (R)-1-[1-(4-bromo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidine (0.10 g, 0.29 mmol).
Yield: 60 mg (53.0 % of theoretical) C17H261N0 (M= 387.299) Calc.: molpeak (M+H)+: 388 Found: molpeak (M+H)+: 388 retention time HPLC: 7.54 min (method A).
13d (R)-5-(4-chloro-phenyl)-2-(4-[3-methyl-2-(4-methyl-piperidin-1-yl)-butoxy]-phenylethynyl}-pyridine Prepared according to general method I from (R)-1-[1-(4-iodo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidine (60.0 mg, 0.16 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (35.6 mg, 0.16 mmol).
Yield: 4.5 mg (6.0 % of theoretical, content:: min. 50%) . WO 2005/103032 118 PCT/EP2005/003686 C30H33C1N20 (M= 473.049) Calc.: molpeak (M+H)+: 473/475 (CI) Found: molpeak (M+H)+: 473/475 (CI) retention time HPLC: 9.65 min (method A).
Example 14 (S)-5-(4-chloro-phenyl)-2-{4-[3-methyl-2-(4-methyl-piperidin-1-yl)-butoxy]-phenylethynyl}-pyridine ci N~
O
14a (S)-3-methyl-2-(4-methyl-piperidin-1-yl)-butan-1-of Analogously to 13a the product is obtained from 1.00 g (9.69 mmol) S-(+)-2-amino-3-methyl-1-butanol, 2.64 g (10.8 mmol) 1,5-dibromo-3-methylpentane, 3.10 g (22.4 mmol) K2C03 and mL DMF.
Yield: 2.20 g (98.0 % of theoretical, 80%) C11 H23N0 (M= 185.306) 15 Calc.: molpeak (M+H)+: 186 Found: molpeak (M+H)+: 186 Rf value: 0.30 (silica gel, DCM/MeOH 9:1 ).
14b (S)-1-[1-(4-bromo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidine Analogously to 13b the product is obtained from 1.1 g (4.75 mmol, 80%) (S)-3-methyl-2-(4-20 methyl-piperidin-1-yl)-butan-1-ol, 1.34 g (4.75 mmol) 4-bromo-iodophenol, 3.10 g (9.50 mmol) Cs2C03, 0.17 g (0.95 mmol) 1,10-phenanthroline, 0.09 g (0.48 mmol) Cul and 10 mL toluene.
Yield: 0.15 g (9.0 % of theoretical) C17H26Bri~lO (M= 340.298) Calc.: molpeak (M+H)+: 340/342 (Br) Found: molpeak (M+H)+: 340/342 (Br) retention time HPLC: 7.4 min (method A).
14c (S)-1-[1-(4-iodo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidin Prepared according to general method II from (S)-1-[1-(4-bromo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidine (0.15 g, 0.44 mmol).
Yield: 0.10 g (59.0 % of theoretical) C17H261N0 (M= 387.299) Calc.: molpeak (M+H)+: 388 Found: molpeak (M+H)+: 388 retention time HPLC: 4.96 min (method D).
14d (S)-5-(4-chloro-phenyl)-2-{4-[3-methyl-2-(4-methyl-piperidin-1-yl)-butoxy]-phenylethynyl}-pyridine Prepared according to general method I from (S)-1-[1-(4-iodo-phenoxymethyl)-2-methyl-propyl]-4-methyl-piperidine (100 mg, 0.26 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (61.0 mg, 0.28 mmol).
Yield: 20.0 mg (13.0 % of theoretical, 80%) C30H33CIN20 (M= 473.049) Calc.: molpeak (M+H)+: 473/475 (CI) Found: molpeak (M+H)+: 473/475 (CI) retention time HPLC: 6.1 min (method D).
Example 15.1 (E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine c~
H
,N
H
15.1a tert-butyl ((E)-(R)-3-(4-bromo-phenyl)-1-methyl-but-2-enyl]-carbamate 27.7 mL (27.7 mmol, 1 M in n-hexane) lithium-bis-(trimethylsilyl)-amide solution is added dropwise at RT within 20 min, while cooling gently with water, to a suspension of 14.6 g (27.7 - mmol) [1-(4-bromo-phenyl)-ethyl]-triphenyl-phosphonium bromide in 250 mL
diethyl ether.
The mixture is stirred for 4 h and cooled to 0°C. A solution of 4.80 g (27.7 mmol) tert-butyl ((R)-1-methyl-2-oxo-ethyl)-carbamate in 50 mL diethyl ether is added dropwise.
The mixture is stirred for a further 20 h at RT. The reaction mixture is filtered through Celite and the solvent is eliminated i. vac.. The residue is purified through a gravity silica gel column (cyclohexane/EtOAc 4:1 ).
Yield: 1.90 g (20.1 % of theoretical) C16H22BrN02 (M= 340.255) 3o Calc.: molpeak (M+H)+: 340/342 (Br) Found: molpeak (M+H)+: 340/342 (Br) . r WO 2005/103032 120 PCT/EP2005/003686 Rf value: 0.56 (silica gel, cyclohexane/EtOAc 4:1 ).
15.1b tert-butyl [(E)-(R)-3-(4-iodo-phenyl)-1-methyl-but-2-enyl)-carbamate Prepared according to general method II from tert-butyl [(E)-(R)-3-(4-bromo-phenyl)-1-methyl-but-2-enyl]-carbamate (1.90 g, 5.58 mmol).
Yield: 1.87 g (86.7 % of theoretical) C16H221N02 (M= 387.256) Calc.: molpeak (M+H)+: 388 Found: molpeak (M+H)+: 388 retention time HPLC: 6.71 min (method B).
15.1c tert-butyl ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-carbamate Prepared according to general method I from tert-butyl [(E)-(R)-3-(4-iodo-phenyl)-1-methyl-but-2-enyl]-carbamate (1.87 g, 4.84 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.35 g, 5.80 mmol).
Yield: 1.36 g (59.4 % of theoretical) C2gH2gCIN202 (M= 473.006) Calc.: molpeak (M+H)+: 473/475 (CI) Found: molpeak (M+H)+: 473/475 (CI) Rf value: 0.09 (silica gel, 366 nm, DCM).
15.1d (E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine 6.59 mL trifluoroacetic acid are added to a solution of 1.36 g (2.87 mmol) tert-butyl ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-carbamate in 70 mL
DCM and the mixture is stirred for 15 h at RT. The reaction mixture is made alkaline with 15%
sodium hydroxide solution. The organic phase is dried over NaZS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel - (DCM/MeOH/NH3 19:1:0.1 ).
Yield: 610 mg (57 % of theoretical) C24H21 CIN2 (M= 372.890) Calc.: molpeak (M+H)+: 373/375 (CI) Found: molpeak (M+H)+: 373/375 (CI) Rf value: 0.25 (silica gel, 366 nm, DCM/MeOH/NH3 9:1:0.1 ).

Example 15.2 (E)-(R-)5-(4-chloro-phenyl)-2-{4-[1-methyl-3-(4-methyl-piperidin-1-yl)-but-1-enyl]-phenylethynyl}-pyridine 58.3 mg (0.38 mmol) 1,5-dibromo-3-methylpentane and 0.13 mL (0.75 mmol) ethyldiisopropylamine are added to a solution of 70.0 mg (0.19 mmol) (E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine in 1.7 mL
DMF and the mixture is shaken for 3.5 h at 80°C. The solvent is eliminated i. vac..
The residue is taken up in 20 mL DCM and washed with 10 mL semisaturated NaHC03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 99:1:0.1 ). The residue is stirred with DIPE.
Yield: 24.4 mg (29 % of theoretical) C30H31 CIN2 (M= 455.033) Calc.: molpeak (M+H)+: 455/457 (CI) Found: molpeak (M+H)+: 455/457 (CI) Rf value: 0.20 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
Example 15.3 and 15.4 15.3: ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine ci 15.4: ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-bis-cyclopropylmethyl-amine 15.3 and 15.4 A solution of 325 mg (0.87 mmol) (E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine and 0.07 mL (0.87 mmol) cyclopropanecarboxaldehyde in 25 mL THF is stirred for 1 h at RT. Then 739 mg (3.49 mmol) NaBH(OAc)3 and 0.20 mL (3.49 mmol) glacial acetic acid are added. The reaction mixture is stirred for 2.5 h at RT. The solvent is eliminated i. vac. and the residue is diluted with 50 mL EtOAc and 30 mL
semisaturated K2C03 solution. The organic phase is dried over NazS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 19:1:0.1 ). The desired fractions are evaporated down and the respective residues are triturated with DIPE and after filtration dried in the air.
15.3: ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine Yield: 190 mg (51 % of theoretical) C28H27CIN2 (M= 426.980) Calc.: molpeak (M+H)+: 427/429 (CI) Found: molpeak (M+H)+: 427/429 (CI) Rf value: 0.56 (silica gel, DCM/MeOH/NH3 19:1:0.1 ).
15.4: ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-bis-cyclopropylmethyl-amine Yield: 11.6 mg (3 % of theoretical) C32H33CIN2 (M= 481.071 ) Calc.: molpeak (M+H)+: 481/483 (CI) Found: molpeak (M+H)+: 481/483 (CI) Rf value: 0.83 (silica gel, DCM/MeOH/NH3 19:1:0.1 ).
Example 15.5 ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-propyl-amine ci 0.06 mL (0.70 mmol) 1-bromopropane and 0.13 mL (0.74 mmol) ethyldiisopropylamine are added to a solution of 75.0 mg (0.18 mmol) ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine in 1.5 mL DMF
and shaken for 22 h at 60°C. The reaction mixture is purified by preparative HPLC-MS. The corresponding fractions are evaporated down i.vac. and combined with 10 mL of semisaturated NaHC03 solution and 20 mL DCM. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by stirring with DIPE.
Yield: 10.0 mg (12 % of theoretical) C31 H33CIN2 (M= 469.060) Calc.: molpeak (M+H)+: 469/471 (CI) Found: molpeak (M+H)+: 469/471 (CI) retention time HPLC: 9.15 min (method A).
Example 15.6 (E)-(R)-5-(4-chloro-phenyl)-2-[4-(1-methyl-3-pyrrolidin-1-yl-but-1-enyl)-phenylethynyl]-pyridine C
0.09 mL (0.75 mmol) 1,4-dibromobutane and 0.13 mL (0.75 mmol) ethyldiisopropylamine are added to -a solution of 70.0 mg (0.19 mmol) (E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine in 1.7 mL DMF and shaken for 3.5 h at 60°C.
The reaction mixture is combined with 20 mL semisaturated NaHC03 solution and 30 mL
EtOAc. The organic phase is dried over Na2S04 and the solvent is eliminated i.
vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 19:1:0.1 ).
The desired fractions are evaporated down and stirred with PE.
Yield: 11.7 mg (15 % of theoretical) C28H27CIN2 (M= 426.980) Calc.: molpeak (M+H)+: 427/429 (CI) Found: molpeak (M+H)+: 427/429 (CI) Rf value: 0.32 (silica gel, 366 nm, DCM/MeOH/NH3 9:1:0.1 ) Example 16.1 (E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine H~
16.1a tert-butyl [(E)-(S)-3-(4-bromo-phenyl)-1-methyl-but-2-enyl]-carbamate 54.0 mL (54.0 mmol, 1 M in THF) lithium-bis-(trimethylsilyl)-amide solution is slowly added dropwise to a suspension of 28.4 g (54.0 mmol) [1-(4-bromo-phenyl)-ethyl]-triphenyl phosphonium bromide in 500 mL diethyl ether while cooling with ice. The mixture is stirred for a further 3 h. A solution of 9.49 g (54.8 mmol) tert-butyl ((S)-1-methyl-2-oxo-ethyl)-carbamate in 100 mL diethyl ether is added dropwise. The mixture is stirred for a further 20 h at RT. The reaction mixture is filtered and the solvent is eliminated i. vac.. The residue is purified through a gravity silica gel column (cyclohexane/EtOAc 4:2).
Yield: 1.29 g (6.9 % of theoretical) C16H22BrN02 (M= 340.255) Calc.: molpeak (M+H)+: 340/342 (Br) Found: molpeak (M+H)+: 340/342 (Br) retention time HPLC: 10.71 min (method A).
16.1b [(E)-(S)-3-(4-iodo-phenyl)-1-methyl-but-2-enyl]-carbamate tert-butyl Prepared according to general method II from tert-butyl [(E)-(S)-3-(4-bromo-phenyl)-1-methyl-but-2-enyl]-carbamate (0.77 g, 2.26 mmol).
Yield: - 0.75 g (85.8 % of theoretical) C16H221N02 (M= 387.256) retention time HPLC: 6.82 min (method B).
16.1c tert-butyl ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-carbamate Prepared according to general method I from tert-butyl [(E)-(S)-3-(4-iodo-phenyl)-1-methyl-but-2-enyl]-carbamate (1.28 g, 3.30 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (0.84 g, 3.63 mmol).
Yield: 0.43 g (27.6 % of theoretical) C25H22CIN0 (M= 473.006) Calc.: molpeak (M+H)+: 473/475 (CI) Found: molpeak (M+H)+: 473/475 (CI) Rf value: 0.07 (silica gel, 366 nm, DCM).
16.1d (E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine 1.98 mL (25.9 mmol) trifluoroacetic acid are added to a solution of 0.43 g (0.91 mmol) tert-butyl ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-carbamate in 25 mL DCM. The mixture is stirred for 17 h at RT and then made alkaline with 15% sodium hydroxide solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOHlNH3 19:1:0.1 towards DCM/MeOH/NH3 9:1:0.1 ).
Yield: 520 mg (53.6 % of theoretical) C24H21 CIN2 (M= 372.890) Calc.: molpeak (M+H)+: 373/375 (CI) Found: molpeak (M+H)+: 373/375 (CI) R, value: 0.31 (silica gel, 366 nm, DCM/MeOH/NH3 9:1:0.1 ).
Example 16.2 ( E)-(S-)5-(4-chloro-phenyl )-2-{4-[1-methyl-3-(4-methyl-piperid in-1-yl )-but-1-enyl]-phenylethynyl}-pyridine N
37.0 mg (0.27 mmol) K2C03 and 24.8 mg (0.16 mmol) 1,5-dibromo-3-methylpentane are added to a solution of 50.0 mg (0.13 mmol) (E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enylamine in 1.4 mL DMF and shaken for 21 h at 70°C. The solvent is eliminated i. vac.. The residue is taken up in 20 mL EtOAc and washed with 10 mL
semisaturated NaHC03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 98:2:0.2). The residue is stirred with DIPE.
Yield: 17.2 mg (28 % of theoretical) C30H31 CIN2 (M= 455.033) Calc.: molpeak (M+H)+: 455/457 (CI) Found: molpeak (M+H)+: 455/457 (CI) Rf value: 0.82 (silica gel, 366 nm, DCM/MeOH/NH3 9:1:0.1 ).
Example 16.3 and 16.4 16.3: ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine ~H
'-/ \~ N
16.4: ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-bis-cyclopropylmethyl-amine ci 16.3 and 16.4 A solution of 180 mg (0.48 mmol) (E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]
phenyl}-1-methyl-but-2-enylamine and 0.04 mL (0.48 mmol) cyclopropanecarboxaldehyde in 15 mL THF is stirred for 1 h at RT. Then 409 mg (1.93 mmol) NaBH(OAc)3 and 0.11 mL (1.93 mmol) glacial acetic acid are added. The reaction mixture is stirred for 16 h at RT. The solvent is eliminated i. vac. and the residue is diluted with 40 mL EtOAc and 20 mL
semisaturated K2C03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 9:1:0.1 ).

16.3: ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine Yield: 100 mg (49 % of theoretical) C28H27CIN2 (M= 426.980) Calc.: molpeak (M+H)+: 427/429 (CI) Found: molpeak (M+H)+: 427/429 (CI) Rf value: 0.39 (silica gel, 366nm, DCM/MeOH/NH3 9:1:0.1 ).
16.4: ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-bis-cyclopropylmethyl-amine Yield: 20.3 mg (9 % of theoretical) C32H33CIN2 (M= 481.071 ) Calc.: molpeak (M+H)+: 481/483 (CI) Found: molpeak (M+H)+: 481/483 (CI) Rf value: 0.67 (silica gel, 366 nm, DCM/MeOH/NH3 9:1:0.1 ).
Example 16.5 ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-propyl-amine N
0.08 mL (0.84 mmol) 1-bromopropane and 0.14 mL (0.84 mmol) ethyldiisopropylamine are added to a solution of 45.0 mg (0.11 mmol) ((E)-(S)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine in 1.0 mL DMF
and shaken for 50 h at 60°C. The solvent is eliminated i. vac.. The residue is combined with 10 mL
semisaturated NaHC03 solution and 20 mL EtOAc. The organic phase is dried over NaZS04 and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (cyclohexane/EtOAc 1:2).
Yield: 8.1 mg (16 % of theoretical) C31 H33CIN2 (M= 469.060) Calc.: molpeak (M+H)+: 469/471 (CI) Found: molpeak (M+H)+: 469/471 (CI) Rf value: 0.10 (silica gel, 366 nm, cyclohexane/EtOAc 1:2).

. . WO 2005/103032 128 PCT/EP2005/003686 Example 17.1 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropylamine H
17.1 a (4-iodo-2-methyl-phenoxy)-acetonitrile 7.447 g (53.9 mmol) KZC03 are added to a solution of 13.0 g (53.9 mmol) 4-iodo-methylphenol in 80.0 mL DMF. Then 3.70 mL (53.9 mmol) bromoacetonitrile, dissolved in 20.0 mL DMF, are slowly added dropwise. The mixture is stirred for 24 h at RT.
The reaction mixture is filtered. The solvent is eliminated i. vac.. The residue is taken up in 400 mL EtOAc and 200 mL water. The organic phase is washed with 100 mL saturated NaCI
solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac..
Yield: 15.3 g (104 % of theoretical) CgH81N0 (M= 273.070) Calc.: molpeak (M+H)+: 273 Found: molpeak (M+H)+: 273 Rf value: 0.62 (silica gel, cyclohexane/EtOAc 2:1 ).
17.1b 1-(4-iodo-2-methyl-phenoxymethyl)-cyclopropylamine 14.0 g (51.3 mmol) (4-iodo-2-methyl-phenoxy)-acetonitrile are dissolved in 210 mL diethyl ether and cooled by means of a bath of ice/isopropanol. Then 17.1 mL (56.4 mmol) titanium-(IV)-isopropoxide are carefully added dropwise. Then 34.2 mL (102.5 mmol, 3 M
in diethyl ether) are added dropwise and the mixture is stirred for 30 min. 13.0 mL
(102.5 mmol) boron trifluoride-diethyl ether complex are rapidly pipetted in at 10°C.
After another 2 h 150 mL 1 M
sodium hydroxide solution is added dropwise with further cooling. The reaction mixture is filtered. The phases of the filtrate are separated. The organic phase is washed with 150 mL
saturated i~laCl solution. The organic phase is dried over NaZS04 and the solvent is eliminated i. vac.. Further purification is carried out using a gravity silica gel column (cyclohexane/EtOAc 4:1 after cyclohexane/EtOAc 2:1 ).
Yield: 9.06 g (58.3 % of theoretical) C11H141N0 (M= 303.139) Calc.: molpeak (M+H)+: 304 Found: molpeak (M+H)+: 304 Rf value: 0.07 (silica gel, cyclohexane/EtOAc 2:1 ).

17.1c 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropylamine Prepared according to general method I from 1-(4-iodo-2-methyl-phenoxymethyl)-cyclopropylamine (2.00 g, 6.60 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.53 g, 6.60 mmol).
Yield: 1.73 g (67 % of theoretical) C24H21 CIN20 (M= 388.889) Calc.: molpeak (M+H)+: 389/391 (CI) Found: molpeak (M+H)+: 389/391 (CI) Rf value: 0.59 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
Example 17.2 and 17.3 17.2: (1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropyl)-cyclopropylmethyl-amine N\
17.3: (1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropyl)-bis-cyclopropylmethyl-amine 17.2 and 17.3 A solution of 1.00 g (2.57 mmol) 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropylamine and 0.19 mL (2.57 mmol) cyclopropanecarboxaldehyde in 75 mL THF is stirred for 1 h at RT. Then 2.18 g (10.3 mmol) NaBH(OAc)3 and 0.59 mL (10.3 mmol) glacial acetic acid are added. The reaction mixture is stirred for 6 h at RT. The solvent is eliminated i. vac. and the residue is diluted with 100 mL EtOAc and 50 mL
semisaturated K2C03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac..
Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 . - WO 2005/103032 130 PCT/EP2005/003686 98:2:0.2). The desired fractions are evaporated down and the respective residues are triturated with TBME.
17.2: ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynylJ-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine Yield: 505 mg (44 % of theoretical) C28H27CIN20 (M= 442.980) Calc.: molpeak (M+H)+: 443/445 (CI) Found: molpeak (M+H)+: 443/445 (CI) R, value: 0.21 (silica gel, DCM/MeOH/NH3 98:2:0.2).
17.3: (1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropyl)-bis-cyclopropylmethyl-amine Yield: 57.7 mg (5 % of theoretical) C32H33CIN20 (M= 497.070) Calc.: molpeak (M+H)+: 497/499 (CI) Found: molpeak (M+H)+: 497/499 (CI) retention time HPLC: 10.15 min (method A).
Example 17.4 ( 1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropyl)-cyclopentyl-cyclopropylmethyl-amine 0.07 mL (0.72 mmol) cyclopentanone are added at RT to a solution of 80.0 mg (0.18 mmol) (( E)-( R)-3-{4-[5-(4-chloro-phenyl )-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl )-cyclopropylmethyl-amine in 8.0 mL THF. After 15 min 162 mg (0.72 mmol) NaBH(OAc)3 and 0.04 mL (0.72 mmol) glacial acetic acid are added. After 3 h (in which total dissolution is not achieved) 6 mL DCM are added. After another 26 h 6 mL are MeOH, 0.07 mL (0.72 mmol) cyclopentanone, 162 mg (0.72 mmol) NaBH(OAc)3 and 0.04 mL (0.72 mmol) glacial acetic acid are added. After another 20 h (dissolution, no reaction) 45.0 mg (0.72 mmol) NaBH3CN
and 0.07 mL (0.72 mmol) cyclopentanone are added. After stirring over the weekend the solvent is eliminated i. vac.. The residue is stirred with DIPE. Further purification is carried out by column chromatography on silica gel (cyclohexane/EtOAc 4:1 ).
Yield: 15.2 mg (16 % of theoretical) C25H22CIN0 (M= 511.097) Calc.: molpeak (M+H)+: 511/513 Found: molpeak (M+H)+: 511/513 Rf value: 0.63 (silica gel, cyclohexane/EtOAc 2:1 ).
Example 17.5 5-(4-chloro-phenyl)-2-{3-methyl-4-[1-(4-methyl-piperidin-1-yl)-cyclopropylmethoxy]-phenylethynyl}-pyridine 71.0 mg (0.51 mmol) KZC03 and 47.8 mg (0.31 mmol) 1,5-dibromo-3-methylpentane are added to a solution of 100 mg (0.26 mmol) ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine in 3.0 mL DMF
and shaken for 20 h at 70°C. The reaction mixture is filtered and the solvent is eliminated i. vac.. The residue is diluted with 20 mL EtOAc and 10 mL semisaturated K2C03 solution.
The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by preparative HPLC-MS. The desired fractions are evaporated down and the residue triturated with PE.
Yield: 3.2 mg (3 % of theoretical) C30H31 CIN20 (M= 471.033) Calc.: molpeak (M+H)+: 471/473 (CI) Found: molpeak (M+H)+: 471/473 (CI) retention time HPLC: 9.60 min (method A).
Example 17.6 ( 1-{4-[5-(4-chloro-phenyl )-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropyl)-cyclopropytmethyl-propyl-amine 0.07 mL (0.72 mmol) 1-bromopropane and 0.04 mL (0.72 mmol) ethyldiisopropylamine are added to a solution of 80.0 mg (0.18 mmol) ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-1-methyl-but-2-enyl)-cyclopropylmethyl-amine in 1.7 mL DMF
and shaken for 4 h at 70°C. The solvent is eliminated i. vac.. The residue is diluted with 30 mL EtOAc and mL semisaturated KzC03 solution. The organic phase is dried over Na2S04 and the solvent is eliminated i. vac.. Further purification is carried out by preparative HPLC-MS.
Yield: 17.8 mg (20 % of theoretical) 5 C31 H33CIN20 (M= 485.059) Calc.: molpeak (M+H)+: 485!487 (CI) Found: molpeak (M+H)+: 485/487 (CI) retention time HPLC: 6.60 min (method A).
Example 17.7 10 (1-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropyl)-cyclopentyl-amine F
0.46 mL (5.17 mmol) cyclopentanone are added to a solution of 500 mg (1.29 mmol) 1-f4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxymethyl}-cyclopropylamine in 50 mL
THF and the mixture is stirred for 15 min at RT. Then 1.15 g (5.17 mmol) sodium triacetoxyborohydride and 0.30 mL (5.17 mmol) AcOH are added. The reaction solution is stirred for 48 h at RT, then neutralised with 30 mL semisaturated NaHC03 solution, extracted with 40 mL EtOAc and the organic phase is dried over Na2S04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 2:1 ). The fractions containing the product are evaporated down i.vac., the residue is triturated with isopropanol, suction filtered and dried.
Yield: 210 mg (58 % of theoretical) C2gH2gCIN20 (M= 457.006) Calc.: molpeak (M+H)+: 457/459 (CI) Found: molpeak (M+H)+: 457/459 (CI) R, value: 0.18 (silica gel, cyclohexane/EtOAc 2:1 ).
Example 18.1 5-(4-chloro-phenyl)-2-[4-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-phenylethynyl]-pyridine A suspension of 4.00 g (9.62 mmol) 5-(4-chloro-phenyl)-2-(4-iodo-phenylethynyl)-pyridine (Example 8b), 3.00 g (19.4 mmol) (S)-(+)-(2-pyrrolidinyl-methyl)-pyrrolidine, 187 mg (0.96 mmol) Cul and 0.74 g (3.85 mmol) N,N-diethyl-2-hydroxy-benzamide in 10 mL DMF
is evacuated several times and charged with argon. Then 4.72 g (19.2 mmol) potassium phosphate monohydrate are added, the mixture is evacuated and charged with argon. The mixture is stirred overnight at 100°C. The reaction mixture is diluted with DCM and washed three times with 5% NH3 solution and several times with water. The organic phase is dried over MgS04, filtered through activated charcoal and the solvent is eliminated i. vac.. Further purification is carried out by column chromatography on silica gel (DCM/MeOH
9:1 ).
Yield: 2.50 g (59.0 % of theoretical) C28H28CIN3 (M= 441.995) Calc.: molpeak (M+H)+: 442/444 (CI) Found: molpeak (M+H)+: 442/444 (CI) Rf value: 0.35 (silica gel, DCM/MeOH 9:1 ).
Example 18.2 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-prop-1-ynyl]-phenylethynyl}-pyridine Y' 18.2a 2-(4-bromo-phenylethynyl)-5-(4-chloro-phenyl)-pyridine Prepared according to general method I from 4-bromo-iodobenzene (6.27 g, 21.5 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (5.00 g, 21.5 mmol) in acetonitrile.
Yield: 8.10 g (quant. yield) C1 gH 11 BrCIN (M= 368.654) Calc.: molpeak (M+H)+: 368/370/372 (BrCI) Found: molpeak (M+H)+:368/370/372 (BrCI) Rr value: 0.73 (silica gel, DCMIPE 1:1 ).

18.2b 2-(4-iodo-phenylethynyl)-5-(4-chloro-phenyl)-pyridine Prepared according to general method II from 2-(4-bromo-phenylethynyl)-5-(4-chloro-phenyl)-pyridine (8.10 g, 22.0 mmol).
Yield: 6.80 g (74 % of theoretical) C1gH11CIIN (M= 415.665) Calc.: molpeak (M+H)+: 416/418 (CI) Found: molpeak (M+H)+: 416/418 (CI) retention time HPLC: 7.9 min (method B).
18.2c 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-prop-2-in-1-of A solution of 0.70 g (1.68 mmol) 2-(4-iodo-phenylethynyl)-5-(4-chloro-phenyl)-pyridine, 98.3 NL (1.68 mmol) prop-2-yn-1-ol, 0.49 mL (3.54 mmol) triethylamine in 10 mL
acetonitrile is evacuated and charged with argon. 15.1 mg (0.02 mmol) PdCl2(dppf) and 3.53 mg (0.02 mmol) Cul are added and the mixture is again evacuated and charged with argon.
The reaction is stirred overnight at RT. The purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1 ).
Yield: 430 mg (74 % of theoretical) C22H14CIN0 (M= 343.805) Calc.: molpeak (M+H)+: 344/346 (CI) Found: molpeak (M+H)+: 344/346 )CI) Rf value: 0.57 (silica gel, PE/EtOAc 1:1 ).
18.2d 5-(4-chloro-phenyl)-2-[4-(3-chloro-prop-1-ynyl)-phenylethynyl]-pyridine A solution of 39.6 NL thionyl chloride in 2 mL DCM is added at -10°C to a solution of 150 mg (0.44 mmol) 3-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynylJ-phenyl}-prop-2-yn-1-of in 5 mL
DCM. The reaction solution is stirred for 30 min at 0°C and overnight at RT. 5 mL saturated NaHC03 solution are added and the mixture is extracted with DCM. The organic phase is dried over MgS04 and the solvent is eliminated i. vac..
Yield: 145 mg (92 % of theoretical) C22H13CI2N (M= 362.251) Calc.: molpeak (M+H)+: 362/364/366 (2C/) Found: molpeak (M+H)+: 362/364/366 (2C/) retention time HPLC: 7.49 min (method B).
18.2e 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-prop-1-ynyl]-phenylethynyl}-pyridine 142 pL (1.20 mmol) 4-methylpiperidine are added to a solution of 145 mg (0.40 mmol) 5-(4-chloro-phenyl)-2-[4-(3-chloro-prop-1-ynyl)-phenylethynyl]-pyridine in 2 mL DMF
and stirred overnight at 70°C. After cooling a solid is precipitated out, which is filtered off.
Yield: 46.0 mg (27.0 % of theoretical) C28H25CIN2 (M= 424.964) Calc.: molpeak (M+H)+: 425/427 (CI) Found: molpeak (M+H)+: 425/427 (CI) retention time HPLC: 6.01 min (method A).
Example 18.3 (S)-1'-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-4-methyl-[1,3']bipiperidinyl N.,, _N
18.3a (S)-1-(4-bromo-phenyl)-piperidin-3-ylamine 1.00 g (5.00 mmol) tert-butyl (S)-piperidin-3-yl-carbamate, 97.2 mg (0.50 mmol) Cul, 2.12 g (10.0 mmol) potassium phosphate and 0.56 mL (10.0 mmol) ethane-1,2-diol are added to a solution of 1.41 g (5.0 mmol) 4-bromo-iodobenzene in 10 mL isopropanol, evacuated several times and charged with argon. The mixture is stirred overnight at 90°C.
At RT 100 mL 1/3-concentrated HCI are added and the mixture is stirred for 1 h. Then it is extracted twice with TBME. The aqueous phase is made alkaline with NH3 solution and extracted several times with TBME. The organic phase is washed with a little water, dried over MgS04, filtered through activated charcoal and the solvent is eliminated i. vac.. The residue is dissolved in 2 mL DCM and purified by column chromatography (Hyperprep, gradient: 10% B
towards 90%
B in 12 min, then 5 min 90% B). Then the residue is taken up in a little water, neutralised with NaHC03 and extracted with DCM. The organic phase is dried over MgS04 and the solvent is eliminated i. vac..
Yield: 250 mg (20 % of theoretical) C11H15BrN2 (M= 255.200) Calc.: molpeak (M+H)+: 255/257 (Br) Found: molpeak (M+H)+: 255/257 (Br) retention time HPLC: 6.46 min (method B).

18.3b (S)-1'-(4-bromo-phenyl)-4-methyl-[1,3']bipiperidinyl 286 mg (1.18 mmol) 1,5-dibromo-3-methylpentane and 325 mg (2.35 mmol) K2C03 are added to a solution of 250 mg (0.98 mmol) (S)-1-(4-bromo-phenyl)-piperidin-3-ylamine in 10 mL
DMF and the mixture is stirred overnight at 50°C. The solvent is eliminated i. vac.. The residue is taken up in water, made alkaline with 2 N sodium hydroxide solution and extracted with TBME. The organic phase is dried over MgS04 and the solvent is eliminated i. vac.. The purification is carried out by column chromatography (Hyperprep, gradient: 10%
B towards 90% B in 12 min, then 5 min 90% B). The residue is again taken up in water, made alkaline with 2 N sodium hydroxide solution and extracted with TBME. The organic phase is dried over MgS04 and the solvent is eliminated i. vac..
Yield: 125 mg (38 % of theoretical) C17H25BrN2 (M= 337.298) Calc.: molpeak (M+H)+: 337/339 (Br) Found: molpeak (M+H)+: 337/339 (Br) Rf value: 0.40 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
18.3c (S)-1'-(4-iodo-phenyl)-4-methyl-[1,3']bipiperidinyl Prepared according to general method II from (S)-1'-(4-bromo-phenyl)-4-methyl-[1,3']bipiperidinyl (125 mg, 0.37 mmol).
Yield: 120 mg (84 % of theoretical) C17H251N2 (M= 384.298) Calc.: molpeak (M+H)+: 385 Found: molpeak (M+H)+: 385 retention time HPLC: 6.7 min (method A).
18.3d (S)-1'-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-4-methyl-[1,3']bipiperidinyl Prepared according to general method I from (S)-1'-(4-iodo-phenyl)-4-methyl-[1,3']bipiperidinyl (120 mg, 0.31 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (66.8 mg, 0.31 mmol).
Yield: 10.0 mg (7.0 % of theoretical) C30H32CIN3 (M= 470.048) Calc.: molpeak (M+H)+: 470/472 (CI) Found: molpeak (M+H)+: 470/472 (CI) retention time HPLC: 6.0 min (method A).
Example 18.4 (R)-1'-{4-(5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-4-methyl-[1,3']bipiperidinyl ci ~r~
18.4a tert-butyl [(R)-1-(4-bromo-phenyl)-piperidin-3-yl]-carbamate 2.00 g (10.0 mmol) tert-butyl (R)-piperidin-3-yl-carbamate, 194 mg (1.00 mmol) Cul, 4.25 g (20.0 mmol) potassium phosphate and 1.13 mL (20.0 mmol) ethane-1,2-diol are added to a solution of 2.83 g (10.0 mmol) 4-bromo-iodobenzene in 20 mL isopropanol, evacuated several times and charged with argon. It is stirred overnight at 90°C.
At RT 100 mL 1/3-concentrated HCI are added and the mixture is stirred for 1 h. Then it is extracted twice with TBME. The aqueous phase is made alkaline with NH3 solution and extracted several times with TBME. The organic phase is washed with a little water, dried over MgS04, filtered through activated charcoal and the solvent is eliminated i. vac..
Yield: 1.00 g (28 % of theoretical) C16H23BrN2O2 (M= 355.270) Calc.: molpeak (M+H)+: 355/357 (Br) Found: molpeak (M+H)+: 355/357 (Br) 18.4b (R)-1-(4-bromo-phenyl)-piperidin-3-ylamine 5.00 mL trifluoroacetic acid are added to a solution of 1.00 g (2.82 mmol) tent-butyl [(R)-1-(4 bromo-phenyl)-piperidin-3-yl]-carbamate in 50 mL DCM and this is stirred overnight. The solvent is eliminated i. vac.. The residue is dissolved in DCM and made alkaline with 2 N
sodium hydroxide solution while being cooled. The organic phase is washed with water, dried over MgS04 and the solvent is eliminated i. vac..
Yield: 750 mg (quant. yield) C11H15BrN2 (M= 255.154) Calc.: molpeak (M+H)+: 255/257 (Br) Found: molpeak (M+H)+: 255/257 (Br) Rf value: 0.15 (silica gel, DCM/MeOH/NH3 9:1:0.1 ).
18.4c (R)-1'-(4-bromo-phenyl)-4-methyl-[1,3']bipiperidinyl 832 mg (3.41 mmol) 1,5-dibromo-3-methylpentan and 943 mg (6.82 mmol) KZC03 are added to a solution of 725 mg (2.84 mmol) (R)-1-(4-bromo-phenyl)-piperidin-3-ylamine in 50 mL
DMF and the mixture is stirred overnight at 50°C. The reaction mixture is diluted with 50 mL

EtOAc and washed three times with semisaturated NaHC03 solution. The organic phase is dried over MgS04 and the solvent is eliminated i. vac..
Yield: 125 mg (13% of theoretical) C17H25BrN2 (M= 337.298) Calc.: molpeak (M+H)+: 337/339 (Br) Found: molpeak (M+H)+: 337/339 (Br) 18.4d (R)-1'-(4-iodo-phenyl)-4-methyl-[1,3']bipiperidinyl Prepared according to general method II from (R)-1'-(4-bromo-phenyl)-4-methyl-[1,3']bipiperidinyl (125 mg, 0.37 mmol).
Yield: 110 mg (77 % of theoretical) C17H251N2 (M= 384.298) Calc.: molpeak (M+H)+: 385 Found: molpeak (M+H)+: 385 retention time HPLC: 4.7 min (method B).
18.4e (R)-1'-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-4-methyl-[1,3']bipiperidinyl Prepared according to general method I from (R)-1'-(4-iodo-phenyl)-4-methyl-[1,3']bipiperidinyl (110 mg, 0.29 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (66.8 mg, 0.31 mmol).
Yield: 20.0 mg (15.0 % of theoretical) C3pH32CIN3 (M= 470.048) Calc.: molpeak (M+H)+: 470/472 (CI) Found: molpeak (M+H)+: 470/472 (CI) Rf value: 0.47 (silica gel, DCM/MeOH 9:1 ).
Example 19.1 5-(4-chloro-phenyl)-2-{3-fluoro-4-[3-(4-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenylethynyl}-pyridine F
N ~N
19.1a 1-[1-(4-bromo-2-fluoro-phenyl)-pyrrolidin-3-yl]-4-methyl-piperidine Under an argon atmosphere 17.9 mg (0.08 mmol) palladium(//)-acetate are added to a suspension of 800 mg (2.66 mmol) 4-bromo-2-fluoro-1-iodo-benzene, 447 mg (3.0 mmol) 4-methyl-1-pyrrolidin-3-yl-piperidine (amine A2), 1.21 g (40.0 mmol) caesium carbonate and 49.7 mg (0.08 mmol) 2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene in 15 mL
1,4-dioxane and the reaction mixture is stirred overnight at 50°C. Another 49.7 mg (0.08 mmol) 2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene and 17.9 mg (0.08 mmol) palladium(II)-acetate are added and the mixture is refluxed for 3 days. After cooling it is combined with water and EtOAc, the phases are separated, the organic phase is washed several times with water and dried over Na2S04. After the desiccant and solvent have been eliminated the residue is purified by-chromatography (silica gel, DCM/MeOH/NH3 95:5:0.5).
Yield: 250 mg (28.0 % of theoretical) 1o C16H22BrFN2 (M= 341.262) Calc.: molpeak (M+H)+: 341/343 (Br) Found: molpeak (M+H)+: 341/343 (Br) retention time HPLC: 6.2 min (method A).
19.1b 1-[1-(2-fluoro-4-iodo-phenyl)-pyrrolidin-3-yl]-4-methyl-piperidine Prepared according to general experimental method II from 250 mg (0.73 mmol) 1-[1-(4-bromo-2-fluoro-phenyl)-pyrrolidin-3-yl]-4-methyl-piperidine.
Yield: 135 mg (47% of theoretical) C~6H2zFIN2 (M= 388.262) Calc.: molpeak (M+H)+: 389 Found: molpeak (M+H) : 389 retention time HPLC: 6.0 min (method A).
19.1c 5-(4-chloro-phenyl)-2-{3-fluoro-4-[3-(4-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenylethynyl}-pyridine Prepared according to general working method I from 135 mg (0.35 mmol) 1-[1-(2-fluoro-4-iodo-phenyl)-pyrrolidin-3-yl]-4-methyl-piperidine and 74 mg (0.35 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine (with Pd(dppf)CIZ as catalyst, triethylamine as base and acetonitrile as solvent).
Yield: 22 mg (13% of theoretical) Cz9H29CIFN3 (M= 474.012) Calc.: molpeak (M+H)+: 474/476 (CI) Found: molpeak (M+H) : 474/476 (CI) retention time HPLC: 6.0 min (method A).
Example 20.1 5-(4-chloro-phenyl)-2-{4-[(E)-1-methyl-3-(4-methyl-piperidin-1-yl)-propenyl)-phenylethynyl}-pyridine ci 20.1 a (E)-3-(4-bromo-phenyl)-but-2-enoic acid Under an argon atmosphere 31.6 mg (0.14 mmol) palladium(II)-acetate and 171 mg (0.56 mmol) tri-o-tolyl-phosphane are added to a solution of 4.1 (14.1 mmol) 1-bromo-4-iodo benzene, 1.51 g (18.0 mmol) (E)-but-2-enoic acid and 3.91 mL (28.1 mmol) triethylamine in 40 mL acetonitrile and the reaction mixture is refluxed overnight. After cooling 20 mL 1 M HCI
are added dropwise, the mixture is exhaustively extracted with EtOAc and the combined organic phases are dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient PE/EtOAc 9:1 to 7:3).
Yield: 700 mg (14% of theoretical) C7oH9Br02 (M= 241.081 ) Calc.: molpeak (M-H)-: 239/241 (Br) Found: molpeak (M-H) : 239/241 (Br) retention time HPLC: 5.7 min (method E).
20.1b (E)-3-(4-bromo-phenyl)-but-2-en-1-of 659 mg (4.07 mmol) CDI are added to a solution of 700 mg (2.03 mmol) (E)-3-(4-bromo-phenyl)-but-2-enoic acid in 10 mL dry THF and the reaction mixture is stirred at 70°C until the development of gas has ceased. A further 659 mg CDI are added and the mixture is stirred for a further 2 h at 60°C. After cooling the reaction solution is added to a solution of 307 mg (8.13 mmol) sodium borohydride in 10 mL water (exothermic reaction) and stirred overnight at RT. The reaction mixture is acidified with dilute KHS04 solution, exhaustively extracted with EtOAc and the combined organic phases are dried over MgS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, PE/EtOAc 7:3).
Yield: 250 mg (54% of theoretical) C~oH~~BrO (M= 227.098) Calc.: molpeak (M)+: 226/228 (Br) Found: molpeak (M)+: 226/228 (Br) 20.1c 1-bromo-4-((E)-3-chloro-1-methyl-propenyl)-benzene 107 NL (1.32 mmol) pyridine and one drop of DMF are added to a solution of 250 mg (1.10 mmol) (E)-3-(4-bromo-phenyl)-but-2-en-1-of in 5 mL DCM. After cooling in the ice bath the solution is slowly combined with 96 NL (1.32 mmol) SOCI2 and the reaction mixture is stirred for 1 h at this temperature and overnight at RT. It is combined with semisaturated NaHC03 solution, extracted exhaustively with DCM, the combined organic phases are washed several times with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is reacted further without purification.
Yield: 240 mg (89% of theoretical) C,oH,oBrCl (M= 245.543) Calc.: molpeak (M)+: 244/246/248 (BrCI) Found: molpeak (M) : 244/246/248 (BrCI) 20.1d 1-[(E)-3-(4-bromo-phenyl)-but-2-enyl]-4-methyl-piperidine 0.23 mL (1.96 mmol) 4-methyl-piperidine are added to a solution of 240 mg (0.98 mmol) 1-bromo-4-((E)-3-chloro-1-methyl-propenyl)-benzene in 2 mL DMF and the reaction solution is stirred for 2 h at 45°C and overnight at RT. It is evaporated down i.
vac., the residue is combined with water, extracted exhaustively with EtOAc, the combined organic phases are washed twice with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is reacted further without purification.
Yield: 260 mg (86% of theoretical) C~6Hz2BrN (M= 308.257) Calc.: molpeak (M+H)+: 308/310 (Br) Found: molpeak (M+H) : 308/310 (Br) retention time HPLC: 4.1 min (method B).
20.1e 1-[(E)-3-(4-iodo-phenyl)-but-2-enyl]-4-methyl-piperidine Prepared according to general experimental method II from 260 mg (0.84 mmol) 1-[(E)-3-(4-bromo-phenyl)-but-2-enyl]-4-methyl-piperidine.
Yield: 170 mg (57% of theoretical) C~6H221N (M= 355.257) Calc.: molpeak (M+H)+: 356 Found: molpeak (M+H) : 356 retention time HPLC: 4.3 min (method B).
20.1f 5-(4-chloro-phenyl)-2-{4-[(E)-1-methyl-3-(4-methyl-piperidin-1-yl)-propenyl]-phenylethynyl}-pyridine Prepared according to general working method I from 160 mg (0.45 mmol) 1-[(E)-3-(4-iodo-phenyl)-but-2-enyl]-4-methyl-piperidine and 106 mg (0.50 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine (with Pd(dppf)CI2 as catalyst, triethylamine as base and THF
as solvent).
Yield: 30 mg (15% of theoretical) C2sHzsCIN2 (M= 441.007) Calc.: molpeak (M+H)': 441/443 (CI) Found: molpeak (M+H) : 441/443 (CI) retention time HPLC: 9.3 min (method A).
Example 20.2 1-(( E)-3-{4-[5-(4-chloro-phenyl )-3-fluoro-pyridin-2-ylethynyl]-phenyl}-but-2-enyl )-4-methyl-piperidin-4-of HO
20.2a 1-[(E)-3-(4-bromo-phenyl)-but-2-enyl]-4-methyl-piperidin-4-of 0.24 mL (3.07 mmol) SOCIZ are added to a solution of 580 mg (2.55 mmol) (E)-3-(4-bromo-phenyl)-but-2-en-1-of and 0.91 mL (5.11 mmol) triethylamine in 10 mL DCM
cooled to -10°C
and the reaction mixture is brought to 0°C within 30 min. Then it is combined with a solution of 882 mg (7.66 mmol) 4-methyl-piperidin-4-of in 5 mL DCM and the reaction solution is stirred for 2 h at RT. 50 mL of semisaturated NaHC03 solution are added, the mixture is extracted twice with 50 mL DCM, the combined organic phases are washed with water and dried over MgS04. After the desiccant and solvent have been eliminated the residue is reacted further without purification.
Yield: 180 mg (22% of theoretical) C,6H22BrN0 (M= 324.256) Calc.: molpeak (M+H)+: 324/326 (Br) Found: molpeak (M+H) : 324/326 (Br) retention time HPLC: 5.5 min (method A).
20.2b 1-[(E)-3-(4-iodo-phenyl)-but-2-enyl]-4-methyl-piperidin-4-of - Prepared according to general experimental method II from 180 mg (0.56 mmol) 1-[(E)-3-(4-bromo-phenyl)-but-2-enyl]-4-methyl-piperidin-4-ol.
Yield: 180 mg (87% of theoretical) C~6H221N0 (M= 371.256) Calc.: molpeak (M+H)+: 372 Found: molpeak (M+H) : 372 retention time HPLC: 5.7 min (method A).
20.2c 1-((E)-3-{4-[5-(4-chloro-phenyl)-3-fluoro-pyridin-2-ylethynyl]-phenyl}-but-2-enyl)-4-methyl-piperidin-4-of Prepared according to general working method I from 80 mg (0.22 mmol) 1-[(E)-3-(4-iodo-phenyl)-but-2-enyl]-4-methyl-piperidin-4-of and 50 mg (0.22 mmol) 5-(4-chloro-phenyl)-2-ethynyl-3-fluoro-pyridine (with Pd(dppf)CIz as catalyst, piperidine as base and acetonitrile as solvent).
Yield: 37 mg (36% of theoretical) Cz9H28CIFNzO (M= 474.997) Calc.: molpeak (M+H)+: 475/477 (CI) Found: molpeak (M+H) : 475/477 (CI) retention time HPLC: 5.0 min (method B).
Example 20.3 4-methyl-1-(( E)-3-{4-[5-(4-methyl-cyclohex-1-enyl )-pyrid in-2-ylethynyl]-phenyl}-but-2-enyl )-piperidin-4-of Prepared according to general working method I from 80 mg (0.22 mmol) 1-[(E)-3-(4-iodo-phenyl)-but-2-enyl]-4-methyl-piperidin-4-of and 50 mg (85%, 0.22 mmol) 2-ethynyl-5-(4-methyl-cyclohex-1-enyl)-pyridine (with Pd(dppf)CI2 as catalyst, piperidine as base and acetonitrile as solvent).
Yield: 13 mg (14% of theoretical) CsoHssN20 (M= 440.620) Calc.: molpeak (M+H)+: 441 Found: molpeak (M+H) : 441 Rf value: 0.10 (silica gel, DCM/MeOH 9:1 ).
Example 21.1 ( E )-5-(4-cfi loco-phenyl )-2-{4-[3-(4,4-dimethyl-piperid i n-1-yl )-propenyl]-pyrid-3-yl-ethynyl}-pyridine . WO 2005/103032 144 PCT/EP2005/003686 121 mg (1.06 mmol) 4,4-dimethyl-piperidine are added to a solution of 130 mg (0.36 mmol) (E)-5-(4-chloro-phenyl)-2-{4-[3-chloro-propenyl]-pyrid-3-yl-ethynyl}-pyridine (Example 7.1 e) in 3 mL DMF and the reaction mixture is stirred for 2 h at 60°C. After the reaction solution has been cooled, the product crystallises out and is then filtered and dried.
Yield: 18 mg (11% of theoretical) C28Hz8CIN3 (M= 441.995) Calc.: molpeak (M+H)+: 442/444 (CI) Found: molpeak (M+H) : 442/444 (CI) retention time HPLC: 5.0 min (method A).
The following Examples are prepared analogously, in each case starting from 100 mg (E)-5-(4-chloro-phenyl)-2-{4-[3-chloro-propenyl]-pyrid-3-yl-ethynyl}-pyridine, while the reaction solution is stirred overnight at 60°C and after cooling is purified by HPLC without any further working up.
ci HPLC

Mass ExampleR Yield Empirical formula retention (%) time spectrum (method) 442/444 5.6 min ~

21.2 21 C28H28CIN3 --.. [M+H]+ (A) 414/416 5.4 min ~

21.3 39 Cz6H2aCIN3 N-.. [M+H] (A) H

512/514 5.5 min F'c 21.4 47 C28HzsCIF3N30 Ny M+H + A
[ ] () 498/500 7.7 min 21.5 F3C~N 21 Cz~Hz3CIF3N30 ~ [M+H] (A) HO

458/460 5.3 min \~

21.6 ~N 41 CZ8H28CIN30 ~ [M+H] (A) H

458/460 5.1 min . N~ M+H + A
[ 1 () 442/444 5.6 min 21.8 ~Ny , 41 C28H28CIN3 [M H]+ (A) HO
444/446 5.1 m i ~ n 21 ~N 12 C2~HZ6CIN30 . ~ [M+H]+ (A) Example 22.1 trans-5-(4-chloro-phenyl)-2-{4-[(2-(4-methyl-piperidin-1-ylmethyl)-cyclopropyl]-phenylethynyl}-pyridine \\~N
22.1 a ethyl traps-2-(4-bromo-phenyl)-cyclopropanecarboxylate 5.7 g (55% in mineral oil, 129.5 mmol) NaH are added batchwise to a solution of 34.4 g (153.0 mmol) trimethylsulphoxonium iodide in 450 mL anhydrous DMSO. After 1 h a solution of 30.0 g (117.6 mmol) ethyl p-bromocinnamate in 400 mL DMSO is slowly added dropwise, while the temperature rises to 30°C. The reaction mixture is stirred for 70 h at RT, poured onto 1 L saturated NaCI solution, extracted twice with 800 mL EtOAc and the organic phase is dried over Na2S04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, Cyc).
Yield: 17.7 g (56% of theory) C~2H~3Br02 (M= 269.134) Calc.: molpeak (M+H)+: 269/271 (Br) Found: molpeak (M+H) : 269/271 (Br) Rf = 0.13 (silica gel, cyc) retention time (HPLC): 6.3 min (method B).
22.1 b traps-[2-(4-bromo-phenyl)-cyclopropyl]-methanol At -10°C a solution of 20.7 g (76.9 mmol) ethyl trans-2-(4-bromo-phenyl)-cyclo-propanecarboxylate in 250 mL THF is added dropwise to a solution of 100 mL
(100 mmol, 1 M in THF) lithium aluminium hydride solution in 150 mL THF and the reaction mixture is stirred for 1 h at 0°C. The reaction solution is slowly combined with 20% KOH while cooling with an ice bath, stirred for 1 h and filtered to remove the insoluble matter. The phases of the filtrate are separated, the organic phase is dried over Na2S04 and evaporated down i.vac. .
Yield: 16.7 g (95% of theory) C~oH»Br0 (M= 227.098) Calc.: molpeak (M-H)-: 225/227 (Br) Found: molpeak (M-H) : 225/227 (Br) Rf = 0.47 (silica gel, EtOAc/cyc 1:1 ).
22.1 c trans-[2-(4-iodo-phenyl)-cyclopropyl]-methanol Under a nitrogen atmosphere a solution of 12.0 (52.8 mmol) trans-[2-(4-bromo-phenyl)-cyclopropyl)-methanol and 2.0 (10.6 mmol) Cul in 52 mL 1,4-dioxane is combined with 23.8 g (158.5 mmol) Nal and 2.3 mL (21.1 mmol) N,N'-dimethylethylenediamine. The reaction solution is shaken for 15 h at 110°C, combined with 100 mL semiconc.
NH3 and 300 mL
EtOAc, the phases are separated and the organic phase is dried over Na2S04.
After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient cyc/EtOAc 3:1 to 2:1 ).
Yield: 10.0 g (69% of theory) C~oH»10 (M= 274.098) Calc.: molpeak (M-H)- = 273 Found: molpeak (M-H)- = 273 Rf = 0.55 (silica gel, EtOAc/cyc 1:1 ).
22.1 d trans-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl)-phenyl}-cyclopropyl)-methanol Under an argon atmosphere 0.3 g (0.37 mmol) Pd(dppf)CIZ and 69.5 mg (0.37 mmol) Cut are added to a solution of 5.0 g (18.2 mmol) trans-[2-(4-iodo-phenyl)-cyclopropyl)-methanol, 4.7 g (21.9 mmol) 5-(4-chlorophenyl)-2-ethynylpyridine and 6.5 mL (36.5 mmol) diisopropylamine in 180 mL THF and the reaction mixture is stirred for 21 h at RT. After the reaction has ended the mixture is evaporated down to dryness i.vac., the residue is combined with 150 mL EtOAc and 300 mL water and filtered off. The crystals are combined with TBME, suction filtered again and dried.
Yield: 6.68 g (100% of theory) C23H~$CINO (M= 359.848) Calc.: molpeak (M+H)+ = 360/362 (CI) Found: molpeak (M+H)+ = 360/362 (CI) Rf = 0.38 (silica gel, EtOAc/cyc 1:1 ) retention time (HPLC): 6.2 min (method B).
22.1 a traps-2-[4-(2-chloromethyl-cyclopropyl)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine 860 NL (11.12 mmol) SOCI2 in 5 mL DCM are added to a solution of 2.0 g (5.6 mmol) trans-(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenyl}-cyclopropyl)-methanol in 25 mL DCM
which has been cooled to 0°C and the reaction solution is stirred for 30 min at 0°C and 1.5 h at RT. After the end of the reaction the reaction mixture is combined at 0°C with 40 mL 5%
NaHC03 solution and 30 mL DCM, the phases are separated and the organic phase is dried over NaZS04. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 9:1 ).
Yield: 520 mg (25% of theory) CZ3H~~CI2N (M= 378.293) Calc.: molpeak (M+H)+=378/380/382 (2 CI) Found: molpeak (M+H)+=378/380/382 (2 CI) Rf = 0.43 (silica gel, EtOAc/cyc 1:1 ).
22.1f traps-5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-ylmethyl)-cyclopropyl]-phenylethynyl}-pyridine A solution of 80 mg (0.2 mmol) traps-2-[4-(2-chloromethyl-cyclopropyl)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine and 100 NL (0.8 mmol) 4-methylpiperidine is combined with 144 NL
ethyldiisopropylamine and stirred for 4 h at 60°C. The reaction mixture is purified by HPLC, the fractions containing the product are combined and lyophilised.
Yield: 37 mg (40% of theory) C29Hz9CINz (M= 441.007) Calc.: molpeak (M+H)+ = 441/443 (CI) Found: molpeak (M+H)+ = 441/443 (CI) retention time (HPLC): 8.2 min (method A).
The following compounds are prepared analogously, in each case from 80 mg of traps-2-[4-(2-chloromethyl-cyclopropyl)-phenylethynyl]-5-(4-chloro-phenyl)-pyridine and the corresponding amount of amine:

HPLC

Mass Example R Yield Empirical retention (%) formula time spectrum (method) H 413/415 7.8 min 22.2 ~N-' ' 28 Cz~HzSCINz fM+HI+ (A) 427/429 8.3 min ~

22.3 34 CzsHz~CINz -,N-_ . ~M+H~+ (A) H

455/457 8.9 min 22 21 CsoHs~CINz . IM+HI (A) HO, ,-OH 433/435 7.2 min 22 ~ 92 CzsHzsCIN20z . N~ , IM+Hl+ (A) H

HO
~ 471/473 7.6 min 22.6 ~N~ 41 CsoHsiCIN20 \~

IM+H~~ (A) HO
457/459 7.4 min 22.7 ~N 32 CzsHzsCIN20 ~ IM+H~+ (A) 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 5 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, mM MgCl2, 2 mM EGTA, pH 7.00; 0.1 % bovine serum albumin (protease-free), 0.021 bacitracin, 1 Ng/ml aprotinin, 1 Ng/ml leupeptin and 1 NM phosphoramidone) to a 10 concentration of 5 to 15 Ng/ml.
200 microlitres of this membrane fraction (contains 1 to 3 Ng of protein) are incubated for 60 minutes at ambient temperature with 100 pM of'z51-tyrosyl melanin concentrating hormone (,z51_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 '251-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.
MCH-1 receptor-coupled Ca2+ mobilisation test Method: Calcium mobilisation test with human MCH (FLIPR38a) 3o Species: Human Test cells: CHO/ Galpha 16 cells stably transfected with hMCH-R1 Results: 1 st measurement:: % stimulation of the reference (MCH 10~M) 2nd measurement: pKB value Reagents: HBSS (10x) (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 Ng/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% C02 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 FLIPR384 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 FLIPR384 apparatus.
Data analysis:
1 st measurement: The cellular Caz+ 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~M). This measurement serves to identify any possible agonistic effect of a test substance.
2nd measurement: The cellular Ca2+ 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~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=log(ECSO(testsubstance+MCH)/ EC50(MCH) -1 ) -10g C(testsubstance) The compounds according to the invention, including their salts, exhibit an MCH-receptor antagonistic activity in the tests mentioned above. Using the MCH-1 receptor binding test described above an antagonistic activity is obtained in a dosage range from about 10-'° to 10-5 M, particularly from 10-9 to 10~ M.
The following IC50 values were determined using the MCH-1 receptor binding test described above:
Compound IC50 value according to Name of substance Example no.
6.3 ~ (S)-1-(1-{5-(5-(4-chloro-phenyl)-pyridin-2- ~ 3.7 nM
ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-piperidin-4 carboxylic acid amide 15.5 ~ ((E)-(R)-3-{4-[5-(4-chloro-phenyl)-pyridin-2- ~ 25 nM
ylethynyl]-phenyl}-1-methyl-but-2-enyl) cyclopropylmethyl-propyl-amine 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
Capsules for powder inhalation containing 1 mq active substance Composition:
1 capsule for powder inhalation contains:
active substance 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg Method of preparation:
The active substance is ground to the particle size required for inhalation.
The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules.
Example B
Inhalable solution for Respimat~ containinct 1 ma active substance Composition:

1 spray contains:

active substance 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg purified water ad 15.0 NI

Method of preparation:
The active substance and benzalkonium chloride are dissolved in water and packed into Respimat~ cartridges.

Example C
Inhalable solution for nebulisers containing 1 mg active substance Composition:

1 vial contains:

active substance 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water ad 20.0 ml Method of preparation:
The active substance, sodium chloride and benzalkonium chloride are dissolved in water.
Example D
Propellant type metered dose aerosol containing 1 mg active substance Composition:
1 spray contains:
active substance 1.0 mg lecithin 0.1 propellant gas ad 50.0 NI
Method of preparation:
The micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.
Example E
Nasal spray containing 1 mg active substance Composition:
active substance 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg purified water ad 0.1 ml Method of preparation:
The active substance and the excipients are dissolved in water and transferred into a corresponding container.
Example F
Inlectable solution containinct 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 (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into ampoules under nitrogen gas.
Example G
Iniectable solution containing 100 mg_of active substance per 20 ml Composition: -3o active substance 100 mg monopotassium dihydrogen phosphate = KH2P0412 mg disodium hydrogen phosphate = Na2HP04~2H202 mg sodium chloride 180 mg human serum albumin 50 mg Polysorbate 80 20 mg water for injections ad 20 ml Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into ampoules.
Example H
Lyophilisate containing 10 mq of active substance Composition:
Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg Preparation:
Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into vials; freeze-dried.
Solvent for lyophilisate:
Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad 10 ml Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);
transferred into ampoules.
Example I
Tablets containing 20 mg 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 J
Capsules containinct 20 ma 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 K
Suppositories containing 50 ma 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 L
I~ectable solution containing 10 mg 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 (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl;
transferred into ampoules under nitrogen gas.

Claims (28)

1. Alkyne compounds of general formula I
wherein R1, R2 independently of one another denote H, C1-8-alkyl, C3-7-cycloalkyl or a phenyl or pyridinyl group optionally mono- or polysubstituted by identical or different groups R20 and/or monosubstituted by nitro, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R11, and a -CH2- group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by -O-, -S- or -NR13-, or R1 and R2 form a C3-8-alkylene bridge, wherein a -CH2- group not adjacent to the N atom of the R1R2N- group may be replaced by -CH=N-, -CH=CH-, -O-, -S-, -SO-, -(SO2)-, -CO-, -C(=CH2)- or -NR13-, while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R14, and the alkylene bridge defined hereinbefore may be substituted by one or two identical or different carbo- or heterocyclic groups Cy such that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C and/or N atoms forming a fused bicyclic ring system or - via three or more C and/or N atoms forming a bridged ring system;
X denotes a C1-6-alkylene bridge which comprises one or more substituents selected independently of one another from fluorine, chlorine, hydroxy, cyano, CF3, C1-4-alkyl, hydroxy-C1-4-alkyl, C3-6-cycloalkyl and C1-4-alkoxy, while two alkyl substituents may be joined together forming a C3-7-cycloalkyl group, or a C2-4-alkylenoxy or C2-4-alkyleneimino bridge, while the imino group may be substituted by a C1-4-alkyl group, and wherein the alkylene unit comprises one or more substituents selected independently of one another from fluorine, chlorine, CF3, hydroxy-C1-4-alkyl, C1-4-alkyl and C3-6-cycloalkyl, while two alkyl groups may be joined together forming a C3-7-cycloalkyl group or a cyclo-C4-s-alkyleneimino group, or a C3-6-alkenylene or C3-6-alkynylene bridge which is unsubstituted or comprises one or more substituents selected independently of one another from fluorine, chlorine, CF3, hydroxy-C1-4-alkyl, C1-4-alkyl and C3-6-cycloalkyl, while two alkyl substituents may be joined together forming a C3-7-cycloalkyl or C5-7-cycloalkenyl group, and W, Z independently of one another denote a single bond or a C1-2-alkylene bridge, while two adjacent C atoms may be joined together with an additional C1-4-alkylene bridge, and one or two C atoms independently of one another may be substituted by one or two identical or different C1-3-alkyl groups, while two alkyl groups may be joined together to form a carbocyclic ring, and Y, A independently of one another are selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, thienyl, furanyl, benzothienyl or benzofuranyl, while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R20, in the case of a phenyl ring may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R21, B has one of the meanings given for Y, A or denotes C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl, C5-7-cycloalkenyl, C3-7-cycloalkyl-C1-3-alkyl, C3-7-cycloalkenyl-C1-3-alkyl, C3-7-cycloalkyl-C1-3-alkenyl or C3-7-cycloalkyl-C1-3-alkynyl, wherein one or more C atoms independently of one another may be mono-or polysubstituted by halogen and/ or may be monosubstituted by hydroxy or cyano and/ or cyclic groups may be mono- or polysubstituted by identical or different groups R20, Cy denotes a carbo- or heterocyclic group selected from one of the following meanings a saturated 3- to 7-membered carbocyclic group, - an unsaturated 4- to 7-membered carbocyclic group, - a phenyl group, - a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as heteroatom, a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms, - an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S, while the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, (C1-4-alkyl)-imino, methylene, (C1-4-alkyl)-methylene or di-(C1-4-alkyl)-methylene bridge, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R20, in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R21, R11 denotes halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15S-O-, R15-O-CO-, R'S-CO-O-, cyano, R16R17N-, R18R19N-CO- or Cy, while in the above-mentioned groups one or more C atoms may be substituted independently of one another by substituents selected from halogen, OH, CN, CF3, C1-3-alkyl, hydroxy-C1-3-alkyl;
R13 has one of the meanings given for R17, R14 denotes halogen, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, R15-O-, R'S-O-CO-, R15-CO-, R15-CO-O-, R16R17N-, R18R19N-CO-, R15-O-C1-3-alkyl, R15-O-CO-C1-3-alkyl, R15-SO2-NH-, R15-O-CO-NH-C1-3-alkyl, R15-SO2-NH-C1-3-alkyl, R15-CO-C1-3-alkyl, R15-CO-O-C1-3-alkyl, R16R17N-C1-3-alkyl, R18R19N-CO-C1-3-alkyl or Cy-C1-3-alkyl, R15 ~denotes H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, pyridinyl or pyridinyl-C1-3-alkyl, R16 ~denotes H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, C4-7-cycloalkenyl, C4-7-cycloalkenyl-C1-3-alkyl, .omega.-hydroxy-C2-3-alkyl, .omega.-(C1-4-alkoxy)-C2-3-alkyl, amino-C2-6-alkyl, C1-4-alkyl-amino-C2-6-alkyl, di-(C1-4-alkyl)-amino-C2-6-alkyl or cyclo-C3-6-alkyleneimino-C2-6-alkyl, R17 ~has one of the meanings given for R16 or denotes phenyl, phenyl-C1-3-alkyl, pyridinyl, C1-4-alkylcarbonyl, hydroxycarbonyl-C1-3-alkyl, C1-4-alkoxycarbonyl, C1-4-alkoxycarbonyl-C1-3-alkyl, C1-4-alkylcarbonylamino-C2-3-alkyl, N-(C1-4-alkylcarbonyl)-N-(C1-4-alkyl)-amino-C2-3-alkyl, C1-4-alkylsulphonyl, C1-4-alkylsulphonylamino-C2-3-alkyl or N-(C1-4-alkylsulphonyl)-N(-C1-4alkyl)-amino-C2-3-alkyl;

R18, R19 independently of one another denote H or C1-6-alkyl, R20 ~denotes halogen, hydroxy, cyano, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl, hydroxy-C1-3-alkyl, R22-C1-3-alkyl or has one of the meanings given for R22, R21 ~denotes C1-4-alkyl, .omega.-hydroxy-C26-alkyl, .omega.-C1-4-alkoxy-C2-6-alkyl, .omega.-C1-4-alkyl-amino-C2-6-alkyl, .omega.-di-(C1-4-alkyl)-amino-C2-6-alkyl, .omega.-cyclo-C3-6-alkyleneimino-C2-6-alkyl, phenyl, phenyl-C1-3-alkyl, C1-4-alkyl-carbonyl, C1-4-alkoxy-carbonyl, C1-4-alkylsulphonyl, aminosulphonyl, C1-4-alkylaminosulphonyl, di-C1-4-alkylaminosulphonyl or cyclo-C3-6-alkylene-imino-sulphonyl, R22 ~denotes pyridinyl, phenyl, phenyl-C1-3-alkoxy, cyclo-C3-6-alkyleneimino-alkoxy, OHC-, HO-N=HC-, C1-4-alkoxy-N=HC-, C1-4-alkoxy, C1-4-alkylthio, carb-oxy, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-aminocarbonyl, cyclo-C3-6-alkyl-amino-carbonyl, cyclo-C3-6-alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl-aminocarbonyl, C1-4-alkyl-sulphonyl, C1-4-alkyl-sulphinyl, C1-4-alkyl-sulphonylamino, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C1-4-alkyl-carbonyl-amino, cyclo-C3-6-alkyleneimino, phenyl-C,-3-alkylamino, N-(C,-4-alkyl)-phenyl-C1-3-alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C2-3-alkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino or C1-4-alkylaminocarbonylamino, while in the above-mentioned groups and radicals, particularly in W, Z, R13 to R22, in each case one or more C atoms may additionally be mono- or polysubstituted by F
and/or in each case one or two C atoms independently of one another are additionally monosubstituted by Cl or Br and/or in each case one or more phenyl rings independently of one another may additionally comprise one, two or three substituents selected from the group F, Cl, Br, I, cyano, C1-4-alkyl, C1-4-alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl and di-(C1-3-alkyl)-amino-C1-3-alkyl and/or may be monosubstituted by nitro, and the H atom of any carboxy group present or 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, while the following compounds are not included in the invention:
(1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-dimethyl-amine, 5'-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl, 1'-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-[1,3']bipyrrolidinyl, {5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-(2-pyrrolidin-1-yl-propyl)-amine, 5-(4-chloro-phenyl)-2-[4-( 1-methyl-2-piperidin-1-yl-ethoxy)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-piperidin-1-yl-pyrrolidin-1-yl)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-{4-[2-(4-methyl-piperidin-1-yl)-propoxy]-phenylethynyl}-pyridine, (1-{5-[5-(4-chloro-phenyl )-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-yl)-4-methylpiperidine, 5-(4-chloro-phenyl)-2-[4-(2-methyl-2-piperidin-1-yl-propoxy)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclohexyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclohex-1-enyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclopent-1-enyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-{4-[3-(4-methyl-piperidin-1-yl)-cyclopentyl]-phenylethynyl}-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-propenyl)-phenylethynyl]-pyridine, 5-(4-chloro-phenyl)-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylethynyl]-pyridine.

2. Alkyne compounds according to claim 1, characterised in that the groups R1, independently of one another are selected from the group consisting of H, C1-6-alkyl, C3-5-alkenyl, C3-5-alkynyl, C3-7-cycloalkyl, hydroxy-C3-7-cycloalkyl, C3-,-cycloalkyl-C1,-3-alkyl, (hydroxy-C3-,-cycloalkyl)-C,-3-alkyl, hydroxy-C2-4-alkyl, .omega.-NC-C2-

3-alkyl, C1-

4-alkoxy-C2-4-alkyl, hydroxy-C1-4-alkoxy-C2-4-alkyl, C1-4-alkoxy-carbonyl-C1-4-alkyl, carboxyl-C1-4-alkyl, amino-C2-4-alkyl, C1-4-alkyl-amino-C2-4-alkyl, di-(C1-4-alkyl)-amino-C2-4-alkyl, cyclo-C3-6-alkyleneimino-C2-4-alkyl, pyrrolidin-3-yl, N-(C1-4-alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C1-3-alkyl, N-(C1-4-alkyl)-pyrrolidinyl-C1-3-alkyl, piperidin-3-yl, piperidin-4-yl, N-(C1-4-alkyl)-piperidin-3-yl, N-(C1-4-alkyl)-piperidin-4-yl, piperidinyl-C1-3-alkyl, N-(C1-4-alkyl)-piperidinyl-C1-3-alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, phenyl, phenyl-C1-3-alkyl, pyridyl or pyridyl-C1-3-alkyl, while in the above-mentioned groups and radicals one or more C atoms independently of one another may be mono- or polysubstituted by F, C1-3-alkyl or hydroxy-C1-3-alkyl, and/or one or two C
atoms independently of one another may be monosubstituted by Cl, Br, OH, CF3 or CN, and the phenyl or pyridyl group may be mono- or polysubstituted by identical or different groups R20, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and the group R20 has the meaning given in claim 1.
3. Alkyne compounds according to claim 1, characterised in that R1 and R2 together with the N atom to which they are bound form a heterocyclic group which is selected from the meanings pyrrolidine, piperidine, 8-aza-bicyclo[3.2.1]octane, piperazine, wherein the free imine function is substituted by R13, and morpholine, while one or more H atoms may be replaced by identical or different groups R14, and/
or the above-mentioned heterocyclic groups may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is made - via a single or double bond, - via a common C atom forming a spirocyclic ring system, - via two common adjacent C- and/or N atoms forming a fused bicyclic ring system or via-three or more C- and/or N atoms forming a bridged ring system;
and the groups R'3, R'4 and the group Cy are defined as in claim 1.
4. Alkyne compounds according to one or more of the preceding claims, characterised in that X denotes a propylene bridge which comprises 1, 2, 3 or more identical or different substituents selected from fluorine, chlorine, hydroxy, C~_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together forming a C3_6-cycloalkyl group, or an ethoxy or an ethyleneimino bridge, wherein the imino group may be substituted by C~_4-alkyl, which comprises 1, 2, 3 or more identical or different substituents selected from fluorine, chlorine, C,_3-alkyl and cyclopropyl, while two alkyl groups may be joined together forming a C3_6-cycloalkyl group or if an alkyl group is linked to an imino group they may also be joined together to form a pyrrolidine or piperidine group, or a -CHZ-CH=CH- or -CHz-C=C- bridge which is unsubstituted or comprises 1, 2, 3 or more substituents selected from fluorine, chlorine, C,_3-alkyl and cyclopropyl, while two alkyl substituents may be joined together, forming a C3~-cycloalkyl group.

5. Alkyne compounds according to one or more of the preceding claims, characterised in that Z denotes a single bond or ethylene and W denotes a single bond.

6. Alkyne compounds according to one or more of the preceding claims, characterised in that the group Y is selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydronaphthyl, indolyl, dihydroindolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, benzoxazolyl, chromanyl, chromen-4-onyl, benzothienyl, or benzofuranyl, while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or several groups R20, and in the case of a phenyl ring may also additionally be monosubstituted by vitro, and/or may be substituted at one or more N
atoms by R21, while R20 and R21 have the meanings given in claim 1.

7. Alkyne compounds according to one or more of the preceding claims, characterised in that the group A is selected from the group of the bivalent cyclic groups phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, which may be mono- or polysubstituted at one or more C
atoms by identical or different groups R20, and in the case of a phenyl ring may also additionally be monosubstituted by nitro, and R20 has the meaning given in claim 1.

8. Alkyne compounds according to one or more of the preceding claims, characterised in that the group B is selected from phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C
atoms by identical or different groups R20, and in the case of a phenyl group may also additionally be monosubstituted by nitro, and R20 has the meanings given in claim 1.

9. Alkyne compounds according to one or more of the preceding claims, characterised in that Y has a meaning selected from and A has a meaning selected from or , and B denotes phenyl, cyclohexenyl, pyridyl, thienyl and furanyl, preferably phenyl, while Y and A are unsubstituted or monosubstituted by R20, and B is unsubstituted or mono-, di- or trisubstituted independently of one another by R20, and in the case of a phenyl ring may also additionally be monosubstituted by nitro, and wherein R20 has the meaning given in claim 1.

10. Alkyne compounds according to one or more of the preceding claims, characterised in that R20 denotes F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, amino, acetyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy, while substituents R20 occurring repeatedly may have identical or different meanings.

11. Physiologically acceptable salts of the alkyne compounds according to one or more of claims 1 to 10.

12. Composition, containing at least one alkyne compound according to one or more of claims 1 to 10 and/ or a salt according to claim 11, optionally together with one or more physiologically acceptable excipients.

13. Pharmaceutical compositions, containing at least one alkyne compound according to one or more of claims 1 to 10 and/ or a salt according to claim 11, optionally together with one or more inert carriers and/or diluents.

14. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/ or a salt according to claim 11 for influencing the eating behaviour of a mammal.

15. Use of at least one amide compound according to one or more of claims 1 to and/or a salt according to claim 11, for reducing the body weight and/ or for preventing an increase in the body weight of a mammal.

16. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition with an MCH-receptor-antagonistic activity.

17. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.

18. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.

19. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating diseases and/or disorders associated with obesity, particularly diabetes, especially type II 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.

20. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating 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.

21. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating micturition disorders, such as for example urinary incontinence, hyperactive urinary bladder, urgency, nycturia and enuresis.

22. Use of at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 for preparing a pharmaceutical composition which is suitable for preventing and/or treating dependencies and/or withdrawal symptoms.

23. Process for preparing a composition or a pharmaceutical composition according to one or more of claims 12, 13 and 16 to 22, characterised in that at least one alkyne compound according to one or more of claims 1 to 10 and/or a salt according to claim 11 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

24. Pharmaceutical composition, containing a first active substance which is selected from the alkyne compounds according to one or more of claims 1 to 10 and/or a salt according to claim 11, and a second active substance 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 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.

25. Process for preparing alkyne compounds of formula A.5 R1R2N-X-Y-C.ident.C-W-A-B (A.5) while in formulae A.1, A.2, A.3, A.4 and A.5 R1, R2, Y, X, W, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula A.1 HO-X-Y-Hal (A.1) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula A.2 H-C.ident.C-W-A-B (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the compound of formula A.3 obtained HO-X-Y-C.ident.C-W-A-B (A.3) is reacted with methanesulphonic acid chloride (MsCl) to produce the methanesulphonate derivative A.4, MsO-X-Y-C.ident.C-W-A-B (A.4) which is further reacted with an amine of formula H-NR1R2 to form the end product A.5.

26. Process for preparing alkyne compounds of formula B.5 R1R2N-X-Y-Z-C.ident.C-A-B (B.5) while in formulae B.1, B.2, B.3, B.4 and B.5 R1, R2, X, Y, Z, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula B.1 Hal-A-B (B.1) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula B.2 HO-X-Y-Z-C.ident.C-H (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent, and the resulting compound of formula B.3 HO-X-Y-Z-C.ident.C-A-B (B.3) is reacted with methanesulphonic acid chloride (MsCl) to form the methanesulphonate derivative B.4, MsO-X-Y-Z-C.ident.C-A-B (B.4) which is reacted further with an amine of formula H-NR1R2 to form the end product B.5.

27. Process for preparing alkyne compounds of formula C.3 R1R2N-X-Y-C.ident.C-W-A-B (C.3) while in formulae C.1, C.2 and C.3 R1, R2, X, Y, W, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula C.1 R1R2N-X-Y-Hal (C.1) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is further reacted with an alkyne compound of formula C.2 H-C.ident.C-W-A-B (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to yield the end product C.3.

28. Process for preparing alkyne compounds of formula D.3 R1R2N-X-Y-Z-C.ident.C-A-B (D.3) while in formulae D.1, D.2 and D.3 R1, R2, X, Y, Z, A and B have one of the meanings given in claims 1 to 10, wherein a halogen compound of formula D.2 Hal-A-B (D.2) wherein Hal denotes chlorine, bromine or iodine, preferably bromine or iodine, is reacted with an alkyne compound of formula D.1 R1R2 N-X-Y-Z-C.ident.C-H (D.1) in the presence of a suitable palladium catalyst, a suitable base and copper(I)iodide in a suitable solvent to form the end product D.3.