TW200538102A - New alkyne compounds with mch antagonistic activity and medicaments comprising these compounds - Google Patents

Abstract

The present 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 given in claim 1. Moreover the invention relates to pharmaceutical compositions containing at least one alkyne according to the invention. By virtue of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity and diabetes.

Description

200538102 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel alkyne compound, a physiologically acceptable salt thereof, and its use as an MCH antagonist, and its use in the preparation of pharmaceutical preparations, The medicinal preparation is suitable for the prevention and / or treatment of the symptoms and / or diseases caused by MCH or connected to MCH for some other reason. The present invention also relates to a compound according to the present invention for use in mammals to affect eating behavior and reduce weight and / or prevent any weight gain. It further relates to compositions and medicaments containing a compound according to the invention and to a process for their preparation. Other aspects of the invention relate to a method for preparing a compound according to the invention. [Prior art] Food intake and its transformation in the body are an essential part of all living organisms. Therefore, deviations in food intake and conversion generally cause problems and disease. In recent decades, and especially in industrialized countries, changes in human lifestyles and nutrition have contributed to over-incidence (also known as obesity or obesity). Among those who already suffer, obesity directly results in restricted mobility and a reduction in quality of life. Menopausal fat is another factor that can lead to other diseases such as diabetes, dyslipidemia, hypertension, arterial stiffness, and Zhao-like heart disease. Furthermore, high weight alone can increase support for moving and supporting organs, which can lead to chronic pain and disease, such as inflammation or osteoarthritis. Therefore, obesity is a major health issue in society. Obesity-The word means excess fat tissue in the body. In this connection, obesity is basically considered as an increased level of fat, which can lead to health risks 100779 200538102 =. There is no clear difference between a normal individual and a person with obesity, but when the oil level is increased, the health risk associated with obesity is assumed to continue to rise / for simplicity's sake. In the present invention, there is a physical Mass index (bmi) (/, is defined as weight in kilograms divided by height (expressed in meters) squared) individuals with the same value as 25 'and, more specifically, above 30, are considered priority There is obesity. Except for changes in physical activity and nutrition, there are currently no effective treatment options for reducing body weight. However, since obesity is a major risk factor for severe and even life-threatening disease development, it is important to obtain A medicinal active substance for the prevention and / or treatment of obesity. One of the recently proposed pathways is the therapeutic use of MCH antagonists (see especially WO 01/21577, WO 01/82925). Melanin-aggregating hormone (MCH) It is a cyclic neuropeptide containing 19 amino acids. It is mainly synthesized in the hypothalamus of mammals, and runs from there to other parts of the brain through the protruding part of the neural crest in the lower thalamus. It Biological • daughter activity is mediated by two different G_protein coupled receptors (GpcR) in humans. This receptor system comes from the rhodopsin-related GpCR family, meaning MCH receptors 1 and 2 (MCH-1R, MCH- 2R). In animal mode, exploration of MCH function has provided a good indication of the role of peptides in regulating energy balance, which means changing metabolic activity and food intake [1_2]. For example, after MCH was administered indoors in rats, versus Food intake was increased compared to control animals. In addition, transgenic large white milk that produced more MCH than control animals, when given a high-fat diet, significantly increased body weight by increasing the weight of animals compared to animals without experimentally altered MCH content In response to @ 100779 200538102, it has also been found that in the hypothalamus of rats, there is a positive correlation between the stage of increasing food demand and the amount of MCH mRNA. However, experiments using MCH to eliminate mice are particularly important in confirming MCH function. The loss of neuropeptides causes lean animals to have reduced fat mass, which consumes significantly less food than control animals.

In rodents, the appetite-reducing effect of MCH is presumed to be mediated by GVs-coupled MCH-1R [3-6], because, unlike primates, white runners, and dogs, it has not yet been found in rodents. A second MCH receptor subtype was found. After losing MCH-1R, culled mice had lower fat mass, increased energy conversion, and did not gain weight when compared to control animals when fed a high-fat diet. Another indication of the importance of the MCH system in regulating energy balance is derived from experimental results using a receptor antagonist (SNAP-7941) [3]. In long-term trials, animals treated with antagonists lose significant amounts of body weight. In addition to its appetite-reducing effect, the MCH-1R antagonist SNAP-7941 also achieved other anxiolytic and antidepressant effects in behavioral experiments on rats [3]. Therefore, the MCH-MCH-1R system has clear indications, showing that it involves not only regulating energy balance, but also emotion. References: \ · Scapular shoulder of melanin-concentrating hormone in central regulation of eating behavior. Nature, 1996 · 380 (6571): 243-7. 2. Shimada, M., et al., Si Fei, Black Patty's peasant attack on the old rot of the father is green society and no public nature / 1998, 396 (6712) · · 670 · 4. Y 莼 k, anti-suppression, rubbing shoulders and reducing appetite of melanin-aggregating hormone-1 receptor antagonists · Nat Med, 2002 · 8 (8): 825-30 100779 200538102 1 Chm, Y. 専k. The disintegration of melanin aggregation hormone receptor-1 as a target can cause overeating and resistance to diet-induced obesity. 2002 · 143 (7): 2469-77. 5_ Marsh, D.J., et al., / 黑 芑 # 衮 桌 骏 # / 受 ## Pan of the old Yu 4 Lean, over-active and over-eating, and has a changing metabolic effect.

Proc Natl Acad Sci USA, 2002. 99 (5): page 3240_5. 6 · Specialty, T-226296 ·· Novel oral activity and selective melanin 衮 褰 Jun # f 礼 # # 斋. Eur J Pharmacol, 2002. 438 (3) · · pp. 129-35. In the patent literature, certain amine compounds have been proposed as MCH antagonists. Therefore, WO 01/21577 (Takeda) describes the compound of the formula r1 A "1-X-Ar-Y-N [R2 where Ar1 represents a cyclic group, X represents a spacer, and Y represents a bond or spacer. Ar represents an aromatic ring, which can be fused with a non-aromatic ring, R1 and R2 independently represent fluorene or a hydrocarbon group, and R1 and R2 and adjacent N atoms can form an N-containing heterocyclic ring together, and R2 and Ar can also form Spiral ring, R can form an N-containing heterocyclic ring with adjacent N atoms and Y, and is used as an MCH antagonist to treat obesity. Furthermore, WO 01/82925 (Takeda) also describes a compound of the formula r1

Ar1-X-Ar-Y-N:

R wherein Ar1 represents a cyclic group, X and Y represent spacers, Ar represents optionally substituted fused polycyclic aromatic ring, R1 and R2 independently represent fluorene or a hydrocarbon group, and R1 and R2 and adjacent N Atoms can form N-containing heterocycles together, and R2 can form N-containing heterocycles with adjacent N atoms and fluorene, as MCH antagonists especially for treating fat @ 100779 200538102 fat. WO 2004/024702 proposes a phosphonium amine compound of the carboxylic acid formula

Among them, Y, A, and B may represent a cyclic group, and X, Z, and W may represent a bridging group or a bond as MCH-antagonists.

WO 04/039780 A1 describes acetylene compounds of formula I, R \ .NXY— Z — = — WAB | R2 where Y, A and B can represent cyclic groups, and X, z and W can represent bridge groups or bonds As an MCH-antagonist. The following materials are specifically mentioned: (1- {5- [5_ (4-chlorophenyl) -erim-2-ylethynyl] ^ bit-2-ylbtetrahydroϊτ ratio π each -3- ) -Dimethyl-amine, 545- (4-Gaphenyl) -pyridin-2-ylethynyl] -3-tetrahydropyrrole-1-yl-3,4,5,6_tetrahydro-2H -[l, 2f] bipyridyl, Γ- {5- [5 · (4-Gaphenyl) -pyridin-2-ylethynyl] -pyridin_2_yl}-[ι, 3,] bistetra Hydropyrrolyl, {5- [5- (4-Gaphenyl) -pyridine_2_ylethynyl] • pyridine_2_yl} _ (2_tetrahydropyridine each small group_propyl) -amine '5- (4-Gasphenyl) -2- [4- (1-fluorenyl-2-hexahydropyridin-1-yl · ethoxy) _phenylethynyl] -pyridine, 5- (4 -Chlorophenyl) -2- [4- (3-hexahydropyridin-1-yl-tetrahydropyrrole small group) _phenylethoxy] -pyridine, 5- (4-chlorophenyl) -2- {4-〇 (4-fluorenyl-hexahydropyridine + yl)> propoxy] -phenylacetylene 100779 -10- 1) 200538102 group} -say σ, ^ {545- (4-Gaphenyl) -Pyridine_2-ylethynyl] -pyridin-2-yl, tetrahydropyrrole, 4-methylhexaazine, b σd '5- (4-Gaphenyl) -2- [4- ( 2-methyl-2-hexahydror than p--1-yl-propoxy) -phenylethynyl] -pyridine, 5- (4-phenyl) -2- {4- [3 -(4-methyl-hexahydrop ratio -1-yl) -cyclohexyl] -phenylethynyl] σ,

5- (4-Gasphenyl) -2- {4- [3- (4-methyl-hexahydropyridin-1-yl) -cyclohex-1-enyl] -phenylethoxy} σ-determined, 5- (4-Gaphenyl) _2- {4- [3- (4-methyl-hexahydroρ ratio α-de-1-yl) -cyclopent-1-enyl] -phenylacetylene Gibbon sigma, 5- (4-chlorophenyl) _2- {4- [3- [4- (3-methyl-hexahydroρ ratio 11 aden-1-yl) -cyclopentyl] -phenylethynyl } -Determined by sigma, 5- (4-chlorophenyl) -2- [4- (3-tetrahydroρbiloxyl-propenyl) -phenylethynyl] -exopyridine, ... 5- (4-Gasphenyl) -2- [4- (3-tetrahydroex i: 11 each-1-yl-prop-1-ynyl) -phenylethoxy] -p is determined. WO 04/039764 A1 describes a amine compound of formula I R1 \

2 / Ν-X-Υ— Zn —fjJ-0-WA--B b I where Υ, A, and B may represent a cyclic group, and X represents an alkylene bridge group, and ζ represents a bridge group or a bond, And W are selected from the group consisting of -CR6aR6b-0-, -CR7a = CR7c-, -CR6aR6b-NR8-, -CR7aR7b-CR7cR7d-, and -NR8-CR6aR6b- as MCH-antagonists. 100779 -11 · 200538102 [Summary of the invention] The object of the present invention is to identify novel alkyne compounds, especially those effective as MCH antagonists. The invention also states that a novel block compound is provided which can be used in mammalian diets and achieve weight loss, especially in mammals, and / or prevent weight gain. _

The present invention further states the provision of novel pharmaceutical compositions that are suitable for the prevention and / or treatment of money and / or diseases caused by SMCH or otherwise reasonably connected to MCH. In particular, the object of the present invention is to provide a pharmaceutical composition for the treatment of metabolic disorders such as obesity and / or glucosomiasis and diseases and / or disorders associated with obesity and diabetes. Other objects of the invention relate to the advantages of the compounds according to the invention. The invention also states to provide a method for preparing the amidine compounds according to the invention. Other purposes of this invention will be immediately apparent to the skilled person from the foregoing and subsequent discussions.

In the first aspect, R1 \ Ν—Χ—γ— z. R2

'The present invention relates to acetylene compounds of the general formula I-~ W-A-BI where R1 and R2 independently represent fluorene, alkyl, c3_7-cycloalkyl, or phenyl or pyridyl, which may be the same or different as appropriate The group R20 is mono- or poly-substituted, and / or mono-substituted with a nitro group. At the same time, the alkyl or cycloalkyl group may be mono- or poly-substituted with the same or different groups R11, and may be 6_ or 7_ _CH2-group seven-, _S-, or -NR13- substitution at the 3 or 4 position of a member ring ring group, or

100779 • 12- 200538102 R1 and R2 form a C3 _ 8 -secondary radical bridge group, in which the -CH2- group of the N atom that is not adjacent to the ri r2n_ group can be replaced by (h = N-, -CH = CH-, -〇-, -S-, -SO-,-(S02)-, -CO-, -C (= CH2)-or -NR13 _, and at the same time, in the alkylene bridge group defined above,- One or more fluorene atoms may be replaced by the same or different group R14, and the secondary alkyl bridge group defined by the text may be substituted by one or two same or different carbocyclic or heterocyclic group Cy, so that The bond between the secondary alkyl bridge group and the group Cy is made in the following manner-via a single or double bond,-via a shared C atom, forming a spiral ring system,-via two shared adjacent C and / Or N atom, forming a fused bicyclic ring system, or-forming a bridged ring system via three or more C and / or N atoms; represents Cl_6_ secondary alkyl bridge group, which contains one or more The substituents are independently selected from fluorine, gas, hydroxyl, cyano, CF3, alkyl, -Cn alkyl, Cy cycloalkyl and -alkyloxy. At the same time, two alkyl substituents can be joined together. To form C3-7_cycloalkyl, or C2-4 ~ Benzyloxy or C; 2-4-secondary imidinyl bridge group, at the same time, the imino group can be substituted by (^ _4-alkylene group, and in which the alkylene unit contains one or more substituents, each independently selected Self-fluorine, CF3, mesogen-Ci -4 · alkynyl, Ch -alkynyl, and C3_6 -cycloalkyl, at the same time, two

100779 -13- 200538102 Alkyl groups can be joined together to form a c3 7-cycloalkyl group, or if alkyl groups are attached to an imine group, they can also be joined together to form a ring-C4-6-imines. Or C3 -6 -pyridinyl or C3 -6 -hyperquidyl bridge group, which are unsubstituted or contain one or more substituents, and are independently selected from fluorine, chlorine, CF3, and hydroxy-Ch. , Ch_alkyl and c3_6-cycloalkyl, at the same time, two alkyl substituents can be joined together to form a cycloalkyl or C5-7-cyclodiluted group, and the W and Z systems independently represent a single bond or Ci _2-alkylene bridge group, at the same time, two adjacent C atoms can be joined with another C4-alkylene bridge group, and one or two C atoms can be independently of each other by one or two The same or different Cl 3 -alkyl groups are substituted, and at the same time, two alkyl groups can be joined together to form a carbocyclic ring, and the Y and A systems are independently selected from the bivalent cyclic group, and the phenyl 'P ratio is a tr-based group , • Pyrimidinyl, pyrimidinyl, dahenyl, fluorenyl, tetrahydronaphthyl, pyrimyl, -one mouse, noise group, plinyl, two rat Junlinyl, tetrahydro P quelinyl Isopropyl quinolyl, two Hydroisocylenyl, tetrahydroisolyl, benzoisocyanato, benzoinyl, phenyl, keto-4-keto, pyrimidinyl, furanyl, benzopyrimyl, or Benzofuranyl, at the same time, the above cyclic group may be mono- or poly-substituted by the same or different group R20 at one or more C atoms, and in the case of a benzene ring, it may also be mono-substituted by a nitro group , And / or one or more NH groups may be substituted by R21, 100779 -14- 200538102

B has one of the meanings given to Y and A, or represents C6-alkyl, Cyalkenyl, α · 6-alkynyl, Cycycloalkyl C5 · 7 ^ alkenyl, c3_7-cycloalkyl- Cl_3_alkyl, Talkenyl seven M * " alkyl, C3_7_cycloalkyl-Cy-alkenyl or C37,% alkyl-Ch-block, in which one or more c atoms can be independently of each other. Prime mono- or poly-substituted, and / or mono- or cyano

弋 and / or cyclic groups may be mono- or poly-substituted by the same or different groups r 2,

Cy represents a carbocyclic or heterocyclic group, selected from one of the following meanings-saturated 3- to 7-membered carbocyclic group,-unsaturated 4- to 7-membered carbocyclic group,-phenyl , A saturated 4- to 7-membered or unsaturated 5- to '-membered heterocyclic group, having one N, 0 or S atom as a heteroatom,

_Saturated or unsaturated 5- to 7-membered heterocyclic group, having two or more N atoms, or having one or two n atoms and one N, 0 or S atom as a hetero atom,-aromatic hetero A cyclic 5- or 6-membered group having one or more of the same or different heteroatoms selected from N, 0 and / or s, and the same, the aforementioned saturated 6- or 7-membered group may also have an imine Group, imino group, methylene group, (Ch 噍 group) _methylene group or bis- (Cn group) · methylene bridge group ring bridge system exists, and the above cyclic group may be in one or more C atom, is the same or one, J00779 ㊣ -15- 200538102 R "

R13 R14

R15 R16 different groups R2 G mono- or poly-substituted, in the case of phenyl, it may be additionally mono-substituted by Schottky, and / or one or more NH groups may be substituted by R 21, which means halogen, Cn-alkyl , C2-6-alkenyl, C2-6-alkynyl, R15-0-, R15-aco-, R15-C0_0-, cyano, r16r17n-, R1 SR19N-CO- or Cy, and, among the above groups, One or more C atoms may be substituted independently of each other by a substituent selected from the group consisting of halogen, OH, CN, CF3, CV3-alkyl, and hydroxy-Cu-alkyl; it has one of the meanings given for R17 and represents halogen , Cyano, Ci-6-alkynyl, C2-6-diluted, C2-6-alkynyl, R15-0-, R15-0-C0-, R15_CO-, r15-co-o-, Rl6R17N_, R18R19N_C 〇_, R15_〇_C r alkyl, R1 5 -O-CO-Ci _ 3 -alkyl, R15 -SO-NH-, R1 5 -O-CO-NH-C, 3-alkyl, R15_S02-NH-C 3-alkyl, Rb-cO-C 3-alkyl, R15-C0-0-C 3-alkyl, R16R17N_Ci 3-alkyl, R18R19N-CO-C 3-alkyl Or Cy-Cy alkyl, which represents fluorene, Ci_4-alkyl, C3_7-cycloalkyl, c3_7_cycloalkyl-Ch-alkyl, phenyl, phenylhydrazone_3-alkyl, estilbyl or p Specific bite base 3-burned base , Represents fluorene, Ci _ 6-courtyard, C 3 7 _ cycloalkenyl, c3 · 7-cycloalkenyl -C〗-3 _ alkyl, C4_7-cycloalkenyl, C4-7-cycloalkenyl — Cu — Carboyl, ω-Cycloyl-C2_3 · Carbonyl, ω-ίΑ · 4-Carbonyloxy) hepta-2_3_alkanyl, Amino-C2_6-alkyl, Ch-Carbonyl-Amino-7-6-alkyl, Two- (Cn

100779 -16-200538102 alkyl) -amino-ον6 · alkyl or cyclo_C36_iminoimidoalkyl, R has one of the meanings given for R16, or represents phenyl, phenyl-Ch- Alkyl, pyridyl, Cl_4-alkoxycarbonyl, hydroxycarbonyl oxo-3-alkyl, Cn-oxycarbonyl, cw-alkoxycarbonyl-Cn alkyl, Cw-carbonylcarbonylamino-c2_3-alkyl, N_ (Ci 4_ Alkylcarbonyl) -N-((^ _ 4 · alkyl) -amino-c2_3_alkyl, Cl 4-alkylsulfonylamino group, CH-alkylsulfonylamino group_C2-3_alkyl group, or N- (Ch-alkylsulfonyl) _N (-(^-4-alkyl) -amino-C2-3-alkyl; R18 and R19 independently represent ^ 1 or (: , R2 ° means pixel, hydroxyl, cyano, Cm • alkyl, c2-6-alkenyl, fluorene 2-6 " " fast group, € 3-74 alkyl group, 3-7-cycloalkyl group 1-3-alkyl, hydroxy-Cu-alkyl, R22-C3-alkyl, or one of the meanings given for R22, R represents C! -4 ** alkyl, 60-carboxyl < 2 -6_alkenyl, _4-codooxy_ -C〗 -6 -alkenyl, -4 -hexyl-amino < 2-6 -alkenyl, bis- (Ci-4 -alkenyl) -amine ≪ 2-6 -alkylene, ring-splitting < 3-6 -secondary imino < 2-6-alkylene, benzene , Phenyl < 1-3-alkyl, 1-4-alkyl, carbamoyl, Ci_4-co-oxy, phenyl, 4-alkyl, methyl, amine, sulfonyl, Cn Group, di-Ch-alkylaminosulfofluorenyl or cyclic-C3_6-alkylidene-imino-continuous fluorenyl, R2 2 represents? Than stilbyl, phenyl, phenyl-Cl-3 _ alkoxy , Soil < 3-6-

Secondary imido-C2-4-carboxy, 0HC-, H0-N = HC-, Ck alkoxy-N = HC-, Ck oxy, Cn thio, carboxyl, 100779 -17- 200538102

Cn-alkylcarbonyl, Ci_4-alkoxycarbonyl, aminocarbonyl, c ^ -alkylaminocarbonyl, di- (Cn alkyl) _aminocarbonyl, cyclo-C3f alkyl-amino carbon, soil-C3- 6-Syridinyl-Imino, Phenylaminocarbonyl, Cyclo-C3-6-Similenimine-C2_4-Alkyl-Aminocarbonyl, Ci-4-Syridinyl-Sulphone, C! -4 -Alkyl * " Substitutyl, Ci_ 4 -Alkyl-sulfoamidoamino, amine, Ciy alkylamino, di- (Cn • alkyl) -amine, C4- Alkyl Province-Amine, Cyclo-C3_6-alkylimine, Phenyl-Cy alkylamino, NKCh-alkyl) -Phenyl-Cu-alkylamino, Acetylamino, Propylamino Group, phenylcarbonyl group, phenylcarbonylamino group, benzyl-anorylmethylamino group, mesityl-C2-3 -aminoaminocarbanyl group, (4-morpholinyl) carbonyl group, (1-tetrahydro (Pyrrolyl) carbonyl, (Iαhydrogen stilbyl) fluorenyl, (hexahydro-1-azaheptafluorenyl) carbonyl, (4-methyl- small hexahydrogeryl) carbonyl, methylenedioxy, amine Carbonylamino group or Ci_4-aminoamino group, at the same time, in the above-mentioned groups and atomic groups, especially in W, z, R13 to R2 2 in each case One or more C atoms may additionally be mono- or poly-substituted by F, and / or in each case one or two C-atomic systems may be additionally mono-substituted by ci or Br independently of each other, and / or in each case, a Or more benzene rings may further independently contain one, two or three substituents selected from the group F, C1, βΓ, I, cyano, C4-alkyl, alkoxy, difluoromethyl , Trifluoromethyl, hydroxyl, amino, Ch-alkylamino, di- (Cl-r alkyl) > amino, acetamido, aminocarbonyl, difluoromethoxy, trifluoromethoxy , Aminoalkyl, alkylamino-Ci-r alkyl, and di- (Cl_3_alkyl) _amino_Ci3_alkyl, and / or may be mono-substituted by nitro, and

100779 -18- 200538102 Any fluorene atom of carboxyl group or H atom bonded to N atom can be replaced in each case by a group which can be split in vivo, its tautomers, diastereomers , Palmar isomers, mixtures and their 'However, the following compounds are not included in the present invention ... (1- {5- [5- (4-chlorophenyl) _pyridin-2-ylethynyl] _ Pyridine_2_ylbu tetrahydropyrrole_3_yl) -dimethyl · amine, 5-[5- (4-Anaphthyl) _pyridinylethynyl] _3-tetrahydropyridine-1_yl -3,4,5, Bu tetrahydro-2H- [1,2 '] Lian'e. Given, 1-{5- [5- (4-Anaphthyl X αAdenyl-2-ylethynyl] -Benton_2-yl}-[1,3,] bistetrahydro each outer dagger, { 5- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -pyridin-2-yl}-(2-tetrahydro, slightly more + yl-propyl) -amine '5- (4 -Phenyl) -2- [4- (1-methyl-2-hexahydroemetyl_ethoxy) _phenylethynyl] -sigma, 5- (4-Phenyl) -2- [4- (3-Hexahydroρ ratio -1--1-yl-tetrahydroρ ratio π each- 丨 _yl) · phenylethoxy] -pyridine, 5- (4-Gaphenyl) _2 -{4- [2- (4 • methyl-hexahydropyridin-1-yl) -propoxy] • phenylethynyl ratio, (1- {5- [5- (4-chlorophenyl) -Ango-2-ylethynyl] pyridin-2-yltetrahydropyridine. Each; group) -4-methylhexahydropyridine, 5- (4-chlorophenyl) -2 · [4- (2-methyl-2-hexahydroexternal I: bite-1-yl-propoxy) _benzylethyl, blockyl] -ρ ratio bite, 5- (4-Gaphenyl) -2- {4 -[3- (4-methyl-hexahydro p is smaller than π-determined small group) _cyclohexyl] _benzylidene 100779 -19- 200538102 pyridine, 5- (4-chlorophenyl) -2- { 4- [3- (4-methyl-hexahydroex 1: 1: stilbyl-1-yl) -cyclohex-1-diyl] -phenylethynyl} -pyridine, 5- (4-aminophenyl) -2- {4 · [3- (4-methyl-hexahydroρ Bite small group) -Cyclopentene-alkenyl] -phenylethynyl} bit ratio, 5- (4-Gaphenyl) -2- {4- [3- (4-methyl-hexahydroρ Specific sulfan-1-yl) -cyclopentyl] -phenylethynyl} -pyridine, 5- (4-phenyl) -2- [4- (3-tetrahydroeroxoyl-propenyl) _Benzylethenyl] pyridine, 5- (4-aminophenyl) -2_ [4- (3-tetrahydropyrrole small group-prop small alkynyl) _phenylethynyl] _pyridine. According to The compounds of the present invention, including physiologically acceptable salts, are particularly effective as antagonists of mch receptors, especially MOW receptors, compared to compounds known to be structurally similar, and in MCH receptor binding studies, Does not exhibit very good affinity. In addition, the compounds according to the present invention have high to very high selectivity for mch receptors. In general, the compounds according to the present invention have low toxicity, are well absorbed by the oral route, and have Good intra-brain transport, especially brain acceptability. The present invention also relates to compounds that are in the form of individual optical isomers, and individual mixtures of palmar isomers or racemates' are in the form of tautomers, and Presented by: 'Or a corresponding acid addition salt with a pharmacologically acceptable acid. The subject matter of the invention also includes compounds according to the present invention, including the salts thereof, in which one or more hydrogen atoms are replaced by deuterium. Ben Sheming also Includes a physiologically acceptable salt of $ 100779 -20-200538102 of the alkyne compound according to the present invention, as described above and below. The blade and the jujube invention f is a composition containing at least one compound of the fast type and / or a salt according to the present invention, optionally accompanied by one or more physiologically acceptable positions. "It is also covered by the present invention as a medicinal composition, which contains at least one fast compound according to the present invention, or a salt according to this compound, optionally accompanied by one or more inert carriers. And / or thinner.

This month also relates to the use of at least one acetylenic compound according to the present invention and / or a salt according to the present invention for influencing the feeding behavior of mammals. This test is related to at least one fast-acting compound according to the present invention and / or a salt according to the present invention for use in reducing the weight of a mammal and / or preventing an increase in body weight. The present invention also relates to the use of at least one acetylenic compound according to the present invention and / or a salt according to the present invention for the preparation of a pharmaceutical composition, which has MCH receptor-antagonistic activity, and in particular has MCH- 丨 receptor β Antagonistic activity. The invention also relates to the use of at least one acetylenic compound according to the invention and / or a salt according to the invention for the preparation of a pharmaceutical composition, which is suitable for the prevention and / or treatment of MCH caused or otherwise Symptoms and / or diseases associated with the MCH by cause.

A further object of the present invention is the use of at least one acetylenic compound according to the present invention and / or a salt according to the present invention for the preparation of a pharmaceutical composition, which is suitable for preventing and / or treating metabolic disorders and / or eating disorders In particular, obesity, bulimia, bulimia nervousness, cachexia, anorexia, anorexia nervosa, and overeating. 100779 -21-200538102 The present invention also relates to the use of at least one acetylenic compound according to the present invention and / or a salt according to the present invention for the preparation of a pharmaceutical composition, which is suitable for preventing and / or treating an association with obesity Diseases and / or conditions, especially diabetes mellitus, especially type 2 diabetes, diabetic complications, including retinopathy in diabetic patients, neuropathy in diabetic patients, nephropathy in diabetic patients, insulin resistance, pathological glucose tolerance, brain Bleeding, cardiac insufficiency, cardiovascular disease, especially arteriosclerosis and hypertension 'arthritis and knee arthritis. In addition, the present invention relates to the use of at least one alkyne compound according to the present invention and / or the salt according to the present invention for the preparation of a pharmaceutical composition, which is suitable for the prevention and / or treatment of hyperlipidemia, bee sting Fibritis, fat accumulation, malignant measles measles, systemic measles measles, affective disorder, emotional disorder, 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 acetylenic compound according to the invention and / or a salt according to the invention for the preparation of a pharmaceutical composition for the prevention and / or treatment of urinary problems, such as incontinence, bladder Excessive activity, urgency, nocturnal symptoms, and enuresis. The invention further relates to the use of at least one acetylenic compound according to the invention and / or a salt according to the invention for the preparation of a pharmaceutical composition which is suitable for the prevention and / or treatment of dependence and / or withdrawal symptoms. The invention further relates to a method for preparing a pharmaceutical composition according to the invention, characterized in that by means of non-chemical methods, at least one alkyne compound according to the invention and / or a salt according to the invention is incorporated into one or more inert carriers And 100779 -22- 200538102 / or thinner. Ben Sheming also talks about the doctor 'Pan Qi and Ren Bi 7, Ganren »Le, and mouthpieces that contain the first active substance selected from block compounds and / or their corresponding salts according to Ben Maoming, and The second active substance is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, and active substances for the treatment of obesity. Active substance for blood pressure, active substance for treating dyslipidemia or hyperlipidemia (including arteriosclerosis) • f 'Active substance for treating arthritis, active substance for treating anxiety, and for The therapeutically active substance is optionally accompanied by one or more inert carriers and / or diluents. Furthermore, in one aspect, the invention relates to a method for preparing an acetylenic compound of formula A5. R1 R2 NXYC = CWAB (A.5) Meanwhile, in the formulas A · l, A.2, A · 3, A · 4, and A · 5, R1, R2, χ, γ, w, A, and B all have One of the meanings given above and below, φ is the halogen compound of formula A.1 HO-XY-Hal (A.1) where Hal represents gas, bromine or iodine, preferably bromine or iodine, and formula α · 2 acetylenic compound HC tri-CWAB (A.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide in a suitable solvent, and the obtained compound A.3 of the compound HO-XYC three CWAB (Α.3) ⑧ 100779 -23 200538102 reacts with methanesulfonium chloride (MsCl) to produce the methane sulfonate derivative A 4, MsO-XYC ξ CWAB (A.4) and its formula H-NR1 R2 The amine reacts further to form the final product A :. The present invention further relates to a method for preparing acetylenic compounds of formula B.5 R1 R2 N-X_Y-ZC tri CAB (B.5) Meanwhile, in formulas B · 1, B.2, B.3, B · 4 and B_5 , Rl, R2, X, γ, z, A and B all have one of the meanings given in the foregoing and in the following, wherein the halogen compound of formula B.1 Hal-A_B (B.1) where Hal represents gas, bromine or Iodine, preferably bromine or iodine, is reacted with an acetylene compound of the formula β · 2 HO-XHCeC-H (B.2) in the presence of a suitable palladium catalyst, a suitable base, and copper (I) iodide in a suitable solvent. And react the formed compound H.mc. CAB (B.3) of formula B.3 with gasified pinanesulfonium sulfonium (MsCl) to form pinanesulfonate derivative B 4, MsO_X_Y_Z-C tri-C_A- B (B.4) further reacts with the amine of formula H-NR1 R2 to form the final product B.5. In addition, the present invention relates to a method for preparing an acetylenic compound of formula C.3 R1 R2 NXYC tri-C-W_A_B (C.3) Meanwhile, in formulas C.1, C2 and C3, 1 ^, 112, also 乂 \ ¥ , 8 and 6 have one of the meanings given above and below, where the halogen compound of formula C.1 is 100779 ⑧ -24- 200538102 R1 R2N-XY-Hal (Cl) where Hal represents chlorine, bromine or iodine, compared with It is preferably bromine or iodine, and further reacts with an acetylenic compound of formula c.2 HC = CWAB (C.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide to produce a final product. C.3. In another aspect, the present invention relates to a method for preparing an alkyne compound of formula D.3 R1 R2 N-X_Y_Z-C tri CAB (D.3) Meanwhile, in formulas D1, D.2 and D.3, R1, R2, X, γ, Z, a, and B all have one of the meanings given above and below, where the halogen compound of formula D.2 Hal-AB (D.2) is used, where Hal represents gas, bromine, or iodine. Preferably bromine or iodine, and acetylene compounds of formula dj

Wr ^ N-X-Y-Z-CEC-H (D.1) is reacted in an appropriate solvent 'in the presence of a suitable catalyst, a suitable base, and copper (I) iodide to form the final product D.3. The starting materials and intermediates used in the synthesis according to the invention are also the subject of the invention. Detailed description of the invention Unless otherwise specified, groups, residues and substituents, especially A, β 1 and 2,0% 111,1 {2,1111,1 ^ 3 to 仏 22, all have the previously given Meaning. If groups, residues and / or substitutions occur more than once in a compound, they may have the same or different meanings in each case. 100779 -25- 200538102 If R1 and R2 are not joined together through an alkylene bridge group, "and ^ preferably represents Cl s_alkyl or cycloalkyl independently of each other, and is monopolized by the same or different group R11 Or more substitutions', at the same time, the -CH2 · group at the 3 or 4 position of the 5 ... or 7_M ring alkyl group can be replaced by s_4_NRi3_, or phenyl or pyridyl, optionally the same or different groups R2 〇Single or multiple substitution, and / or mono-substitution, and at the same time, one or both of the groups Ri and R2 may also represent Η. The preferred meaning of the group R11 is F, C1, Br, Ci 6_ Alkyl, alkenyl, C2-6-alkynyl, R15-0-, cyano, Ri6Ri7N-Q plant cycloalkyl, cyclo_Cy alkylideneimine, tetrahydropyrrolyl, N- (Ci4_alkyl ) _Tetrahydropyrrolyl, hexahydropyridyl, N-((^ alkyl) _hexahydropyridyl, phenyl, and pyridyl, and at the same time, among the groups and atomic groups mentioned above, one or more C atoms may be mono- or poly-substituted by F, Cn alkyl or hydroxy alkyl, and / or one or two C atoms may be mono-substituted by a, Br, 0H, cf3 or CN independently of each other, and The above cyclic group may be one or more Here, it may be mono- or poly-substituted by the same or different groups R20, or in the case of phenyl, it may be additionally mono-substituted by nitro, and / or one or more NH groups may be substituted by R2 1. If R11 has the meaning of one of R15-〇_, cyano, R16R17N or cyclo- ^ alkylimino, the alkyl atom of cycloalkyl or cycloalkyl substituted by R11 is preferably not directly connected to a heteroatom, for example Group -NX. The groups R1 and R2 preferably independently represent fluorene, Cu-alkyl, C3-5-alkenyl, c3-5-alkynyl, c3_7_cycloalkyl, hydroxy_c3_7_cycloalkane. Group, 〇3_7_cycloalkyl group-Cn alkyl group, (hydroxy_c3 7_cycloalkyl group) 〇13 • alkyl, .hydroxyalkyl group, ω-NC-Cw alkyl group, Cw-alkoxy_C2 4 · Carbonyl, hydroxy_Ci 4-

100779 -26- 200538102 alkoxy-C2-4_alkyl, alkoxy-weiylalkyl, alkyl-Cn alkyl, amine-C2_4-alkyl, ch-alkyl-amino-c2_4- Alkyl, di- (Ch_alkyl) -amino-C2-4 -alkyl, cyclic -C3 -6-secondary imilide -C2-4 -alkyl, tetrahydroexo-3-yl, N- (Ci _4 -Carbonyl) -tetrahydropyrrolidine_3_ group, tetrahydropyrrolidine 12 groups-Cb; 3 alkynyl group, NA · 4--carbyl group) -tetrahydroerlocyl-Ch _Yuan Ji, hexahydro p ratio 唆 -3-yl,

Hexahydroxylpyridin-4-yl, N- (C] [_4 -alkynyl) -hexahydrogerim-3-yl, N- (Cb 4 _alkynyl) -hexahydropyridin-4-yl, hexa Hydropyridylalkyl, N-CCVr alkyl) -hexahydropyridyl stilbyl-Ci_3_alkyl, tetrahydroxan-3-yl, tetrahydroxan-4-yl, phenyl, phenyl- C! _3 -Alkenyl, Eπyl, or Etyl & _ 3 Alkenyl, and at the same time, in the above-mentioned groups and atomic groups, one or more C atoms can be independently F, C ^ -alkyl or Hydroxy-Ci — 3-alkyl is mono- or poly-substituted, and / or one or two c atoms may be mono-substituted by Cl, Br, OH, CF 3 or CN independently of each other, and the above-mentioned cyclic group may be one or more At the C atoms, it is mono- or poly-substituted by the same or different group r2O. In the case of a phenyl group, it may also be mono-substituted by a nitro group, and / or one or more NH groups may be substituted by R2! . The above-mentioned preferred substituents of phenyl or pyridyl are selected from the group consisting of F, Cl, Br, I, cyano, Cl_4-alkyl, Cl-4_alkoxy, monofluoromethyl, trifluoromethyl, and hydroxy , Amino, Cl_3-alkylamino, di- (Ch-alkyl) -amino, acetamido, aminocarbonyl, difluorofluorenyloxy, trifluoromethoxy, amino-Cy alkyl, c 3_Alkylamino_Ci_3_alkyl and di. alkyl) -amino-C ^ 3-alkyl, at the same time, phenyl can be mono-substituted by nitro. A particularly good definition of the group R1 and / or R2 is selected from the group consisting of H, C14_alkyl, Cetyl-Cb4-alkyl, c3_5-alkenyl, c3_5-alkynyl, c3_7-cycloalkyl, hydroxy-C3 -7 · Cycloalkyl, diacyl_c3_6_alkyl, c3_7_cycloalkyl_Cyalkyl, tetrahydropiperanyl, tetrahydropiperanyl, (hydroxy-C3-7 · cycloalkyl ) -C 3 -alkane 100779 -27- 200538102 group, alkoxy group) -c2_3-alkyl, pyridyl and benzyl, meanwhile, alkyl, cycloalkyl or cycloalkyl-alkyl may be additionally / Or hydroxy-Cbr alkyl mono- or di-substituted, and / or mono- or poly-substituted by ^ or ^ -alkyl, and / or mono-substituted by CF3, Br, C1 or CN. The most preferred group R1 and / or R2 is selected from the group consisting of fluorene, methyl, ethyl, n-propyl, iso-propyl, prop-2-enyl, but-2-enyl, prop-2- Alkynyl, but-2-ynyl, 2-methyllactylethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-C3_7-cycloalkyl, (Hydroxy-0 ^ 3-alkyl) -hydroxy (3 · 7-cycloalkyl, dihydroxy-Cyalkyl, (1-hydroxy-c3_6-cycloalkyl) -methyl, tetrahydrofuran-3_ Group, tetrahydrosulfan-4-yl group, 2-hydroxyethyl group, 3-hydroxypropyl group, fluorenyl group, and fluorenyl group, and at the same time, the above-mentioned groups may be mono- or multi- Substituted 'and the phenyl and aryl groups may be substituted as specified. Therefore, examples of the most preferred groups R1 and / or R2 are fluorene, methyl, ethyl, n-propyl, iso-propyl, Prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-cyclo Amyl, hydroxy-cyclohexyl, (via methyl > hydroxycyclopentyl, (hydroxymethyl > hydroxy-cyclohexyl), 2,3-dihydroxypropyl, 2-hydroxy-1-haimethyl ethyl U-di (hydroxymethyl -Ethyl, (1-hydroxy-cyclopropyl) _methyl, tetrahydropiperan-3-yl, tetrahydropiperan-4-yl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl and Pyridyl. Particularly preferred is at least one of the groups R1 and R2, and most preferred is that both groups have a meaning other than Η. If R and R2 form an alkylene bridge group, it is preferably q_times Alkyl bridge or C3-7-alkylene bridge, especially C3 6-alkylene bridge, in which -CH2- group which is not adjacent to the N atom of R1 R2N- group is _CH = N ·, _CH = CH_, 100779 -28-

200538102 _〇_, -s-, -CO- or -NR13- substitution. At the same time, one or more H atoms may be replaced by the same or different groups R14 in the alkylidene bridge group defined above, and the foregoing The defined alkylene bridge group may be substituted with a carbocyclic or heterocyclic group Cy in a manner such that the bond between the alkylene bridge group and the group Cy is made in the following manner-via a single Or a double bond,-via a shared C atom, to form a spirocyclic ring system,-via two shared adjacent C and / or N atoms, to form a fused bicyclic ring system, or-via three or more C and And / or N atoms to form a bridged ring system. R1 and R2 also preferably form an alkylene bridge group, so that Ri R2N_ represents a group selected from the group consisting of mononitrotetrahydropyrene, tetrahydropyrrole, hexahydropyridine, monoazathiopyridine, 2,5- 1 氲 -1Η_ρ each, 1,2,3,6-tetrahydropyridine, 2,3,4,7_ tetrahydro-1H-nitrogen heptadine, 2,3,6,7-tetrahydro _1Η-—Nine heptamidine, hexahydro ρ ratio ρ well, in which the free-state imine functional group is replaced by R13, hexahydropyridine_4_one, morpholin and thiomorpholine, especially preferred From tetrahydropyrrole, hexahydropyridine, and hexahydropyridine, in which the free-state imine functional group is replaced by Ri3, and morpholin, and according to the general definition of R1 and R2, one or more fluorene atoms can be the same Or different groups R14 are substituted, and / or the above groups may be substituted by one or two same or different carbocyclic or heterocyclic non-group Cy according to the manner specified by the general definition of Han 2. At the same time, the group The group Cy may be mono- or polysubstituted by R 2 0. Particularly preferred group Cy is C3_7-cycloalkyl, nitrogen-C4_7-cycloalkyl, especially ring 100779 -29- ⑧ 200538102 bis_6 alkylimine, and alkyl i_C4 7_cycloalkyl, and The group Cy may be mono- or polysubstituted by r2O. C3-8-alkylene bridge formed by R1 and R2, wherein the _CH2_ group may be substituted as specified, and may be substituted by one or two same or different carbocyclic or heterocyclic groups as described above The group Cy is substituted, and the group Cy may be substituted as specified above.

In the case where the secondary alkyl bridge group is linked to the group Cy via a single bond, Cy is preferably selected from the group consisting of C: 3 · 7 · cycloalkyl, cyclo-Cycidinimine, imidazole, and pyrimidinyl. And phenyl. In the case where the long-burned bridging group is linked to the group Cy via a common C atom to form a spiro-like ring system, Cy is preferably selected from the group consisting of C: 3-7-cycloalkyl, nitrogen C4-8% alkyl, The same applies to oxygen-C4-8-bad-burning group and 2,3-dihydro_1 嗤 · ρquelinline_4_g. In the case where the alkylene bridge group is connected to the group Cy via two shared adjacent C and / or ν atoms to form a fused bicyclic ring system, Cy is preferably selected from the group consisting of C4-7-cycloalkyl , Phenyl, fluorenyl. In the case where the alkylene bridge group is connected to the group Cy via three or more C and / or N atoms to form a bridged ring system, Cy is preferably a cycloalkyl or nitrogen-C4_8-cycloalkane base. In the case where the heterocyclic group RiR2N · is substituted by the group Cy, the group & is preferably connected to the group RiR2 汴 via a single bond, and at the same time, Cy is preferably selected from the group consisting of Chr cycloalkyl and ring < 3-6-alkyleneimine, and at the same time, these groups may be substituted as specified, and are preferably substituted with fluorine, CF3, Cl3-alkyl, hydroxyheptyl, and alkyl.

Therefore, the group 100779 -30- 200538102 is particularly defined according to one of the following chemical formulas

100779 -31-200538102

Wherein one or more fluorene atoms formed by the group W1 ^ N- may be replaced by the same or different group R14, and

100779 -32- 200538102 The miscellaneous release i π ^ ^ m formed by the group Ri R2 N- can be replaced by one or two, preferably a c3-7-cyclohexyl group to replace 'same day seizure' The cycloalkyl group may be mono- or poly-substituted by r20 and linked to a heterocyclic ring formed by the radical ①, which may be 'mono- or poly-substituted' on the benzene ring at one or more c atoms. In this case, it may be additionally mono-substituted by nitro, and

… /,… All have the meanings given above and below. If the heterocyclic system formed by the group RiR2N- is substituted with one or two cycloalkyl groups as specified by R2o or more, the substituents r20 preferably independently represent Ch- Radical, Cl.4 · oxybutynyl, mesityl_Ch_ radical, mesyl, fluorine, gas, bromine or CF3, especially mesyl. R1-N > Therefore, the group R2

The most preferred is one of the following chemical formulas based on Cn- ^

Especially 100779 -33- 200538102

Among them, R13 has the meaning given above and later, and the heterocyclic ring formed by the group R ^ N- can be C3 6_cycloalkyl, hydroxy_c ^ -cycloalkyl, or (hydroxy (3_6_ Cycloalkyl) _Ci3_alkyl substituted, and the heterocyclic ring formed by the group WWN- may be substituted with the same or different groups ^ single, di- or tri. The substituents R14 are preferably represented independently of each other? , Α, Br, OH, Cw alkyl, Cwioxy, alkyloxy_Ci3_ courtyard, hydroxy-Ch-alkyl or CF3, especially hydroxy, Ci3_alkyl, CF3 or hydroxy " Cl-3 -Yuanji. Some of the chemical formulas not mentioned above are substituted as specified, then the following meanings of the group RR N- are particularly good. · Hydroxytetrahydropyrrolyl, hydroxyhexahydroeryl, 3 , 4-Dioxetyltetrahydropyridine, each radical, 3,4 dioxetylhexahydrocarbyl,% dioxetylhexazyl, phenyl, methyl) _tetrahydropyrrolyl, fluorenyl) _six Nitrogen, stilbyl, (stilbenzyl) -sweetyl-tetrahydropyrrolyl, (hydroxymethylstilbyl_hexahydropyridyl), and at the same time 'in the specified group' via a methyl group, at 0 atom Can be early- or di-substituted by methyl at the same time, two methyl substituted Can be joined together to form a cyclopropyl group, and the substituents are independently selected from the group consisting of g ^^ k mesh, hydroxy, and c3-alkyl radical CF3. At the same time, 'in one or two meridian' 经 atoms can be Methyl substitution, and the specified group does not have any other substituents, or has—or two hydroxy-C—3-alkyl groups,

100779 -34-200538102 The following chemical formulas are defined for the above heterocyclic groups:

Best

100779 -35- 200538102

N- hct hct

H〇 N-

HO HO

The specified group is not further substituted, in which the fluorenyl or ethyl group may be formed by one or more fluorene atoms of the heterocyclic ring -WN- with fluorine, which are bonded to each other independently by carbon, Gas, CN,%, Cl.3-Carbonyl, Carbo-Ci.3-Carboyl, especially oxo-3-alkyl or eh, preferably substituted by fluorenyl, ethyl, cF3. In the preferred and particularly preferred meanings of RiR2N- listed above, the substituents are preferably defined by the following four: F, a, Br, cyano, Ci 4_alkyl, C2 4_alkenyl, Ch -Quick group, Cw cycloalkyl, c37 · cycloalkyl_Ch_alkyl, hydroxydisubstituted, and wherein via a group group, via group_Ch-alkyl, C4-alkoxy, ω- (〇b 4-alkoxy) _〇b 3-alkynyl, q_4 · alkynyl, qetyl, q_4 said oxy-kisyl, mesyl-carbonyl_Ci_3-alkyl, Ch- Carboxycarbonyl-Cl_3 · carbo, q_4-alkoxy-weilylamino, Ch-carbolactylamino-Ci_3 -carbo, amine, Ci_4 -carbo · amino, C3 -7 ^ cycloalkyl-amino, N- (C3-7-cycloalkyl) _N-((ν4-alkyl) -amino, di- (Ch-alkyl) -amino, cyclic-C3_6 _ Alkyleneimino, amine-Cb3-alkyl, Ci-4-alkyl-amino-Cyalkyl, C3-7-cycloalkyl-amino-Cyalkyl, N- (C3-7 -Cyclo 100779 -36-200538102 Alkyl) -N- (C4-alkyl) -amino-Ch-alkyl, di- (Cl 4-alkylamino heptyl) ~ ring core ^ -times Alkyleneimine ^: fluorenyl-carbyl ~ aminocarbonyl, alkynyl-amino-carbonyl, Cycycloalkyl-amino-carbonyl, N- (C3_7-cycloalkane ) -N_ (Cw alkyl) -amino group, di_ (Ch_alkyl) -amino-amino group, p-sigmayl-oxy group, P ratio α-amino group, ermine group-C1 -3 -alkyl-amino. The particularly preferred meaning of the substituent R14 is F, Cl, Br, Ch-alkyl, hydroxy, hydroxy-C, 3-alkyl, Ch_alkoxy, 6 > (Ch- (Alkoxy) -Ch-alkyl, φaminoalkyl, Ci · 4 · alkyl-aminoA-3-alkyl, C3-7-cycloalkyl-amino_Ch-alkyl, N- (C3 · 7 · cycloalkyl) -N_ (Ch_alkyl) -amino_C3-alkyl, mono- (Ck alkyl) · amino-Ch-alkyl, cyclo_c3-6- Hymethyleneimino-Ch-alkyl, aminocarbonyl and pyridylamino. In the preferred meaning of R14 above, in each case one or more c atoms may be additionally mono- or poly-substituted by F, and / Or In each case, one or two. The atoms may be independently substituted by C1 or Br independently of each other. Therefore, the preferred meaning of rM also includes, for example, -CF3, -〇CF3, CF3_CO-, and CF3 -CHOH- The most preferred meaning of the substituent R is q_3 -alkyl, meridian_c1-3 -alkyl, methoxymethyl, hydroxyl, CF3, CF3_CHOH_, especially hydroxyl, fluorenyl, ethyl , CF3 and methylol. Secondary alkyl or secondary alkoxy group imine defined after the bridging group X are as hereinbefore or 'This abutment arranged to cause the system via line linked to a heteroatom group γ. If the bridging group X is an alkenylene group, the double bond is not directly connected to the group R1R2N_. The alkylene group in the group X representing an alkylene group, an alkyleneoxy group, an alkylimino group, and an alkylene group is unbranched and does not have a designated substituent. According to a first specific embodiment of the present invention, the bridging group X represents a Cl_6-sulfanyl 100779 -37- 200538102 base bridging group, especially a c2_4-alkylidene bridging group, which has one, two, three or more, It is preferably one, two or three substituents independently selected from fluorine, chlorine, cyano, CF3, hydroxyl, C4-alkyl, hydroxy-Ch-alkyl, c3-6-cycloalkyl and Ch -Alkoxy is preferably selected from Cn alkyl and cyclopropyl. At the same time, the two alkyl substituents can be joined together to form 03-7-cycloalkyl. The bridging group X is preferably a propylene bridge, which may be substituted as specified.

The alkylidene bridge group preferably has 1, 2 or 3 substituents. The preferred substituents here are fluorine, chlorine, hydroxyl, C3-alkyl and cyclopropyl, especially Ci_3-alkyl and cyclopropyl. At the same time, two alkyl substituents can be joined together to form C3_6 -Cycloalkyl. According to this first embodiment, the preferred definition of the bridge base X is selected from the group consisting of

100779 -38- 200538102

Including According to this first embodiment, the best definition of the bridge base χ is selected

According to a second specific embodiment of the present invention, the bridging group χ represents a 匸 2 tenth alkoxy bridge group, especially a C2_3_ alkoxy bridge group, which has 1, 2, 3 or more, preferably Is one, two or three substituents, independently selected from fluorine, CF3, Ci · 4 · alkyl, hydroxyalkyl, and Cs_6 · cycloalkyl, preferably selected from C! _3_alkyl and cyclopropyl At the same time, two alkyl substituents can be connected to form a C3_7-cycloalkyl group.

The bridging group X is preferably a ethoxyl bridging group, which may be substituted as specified. The alkylene unit preferably has i, 2 or 3 substituents. The preferred substituents here are fluoro'Ci-3-alkyl and cyclopropyl, especially methyl, ethyl and isopropyl. At the same time, two alkyl substituents can be joined together to form C3_6_cycloalkane ^ , 'Especially cyclopropyl. According to this second specific T embodiment, the preferred definition of the bridge base is selected from the group including 100779 -39 · 200538102

According to this second specific embodiment, a particularly good definition of the bridge base X is selected from the group consisting of

According to a third specific embodiment of the present invention, the bridging group χ represents a C24 · methyleneimine bridge group, especially a C2_3_methyleneimine bridge group, in which the imine group may be substituted by ^ -4-alkyl And wherein the alkylene unit contains i, 2, 3 or more, preferably one, two or three substituents, which are independently selected from fluorine, CF3,

Ch-alkyl, hydroxy_Ci_4_alkyl and cycloalkyl are preferably selected from Ch · Cycyl and cyclopropyl. At the same time, two alkyl groups can be joined at-to form c3-7 ·% alkyl Or, if the alkyl group is linked to the imino group, they can also be joined together to form a cyclic-6-iminoimino group. The imino group is preferably unsubstituted or substituted with a #Ci 3-alkyl group, and more preferably a methyl group. X is more ethimimine bridge than it, which may be substituted as specified. The alkylene unit preferably has 1, 2 or 3 substituents. The preferred substituents here are murine, Cl_3_alkyl and cyclopropyl, especially methyl, ethyl and iso_100779 -40-200538102 propionate. At the same time, two alkyl substituents can be joined together, A C3 6-cycloalkyl group is formed, in particular a cyclopropyl group, or if the alkyl group is linked to an imino group, it is also 5 ′ together to form a tetrahydro P ratio U or a hexahydrofluorene ratio σ. According to this third embodiment, the preferred definition of the bridge base X is selected from the group consisting of

According to this third embodiment, a particularly good definition of the bridge base x is selected from the group consisting of

N

< ^ NV According to the fourth specific embodiment of the present invention, the bridge group X represents C36-alkenylene bridge group 'especially G_4-sub-fine bridge group' which is unsubstituted or contains one or two , Three or more, preferably one, two or three substituents independently selected from fluorine, chlorine, CF3, C3-6-cycloalkyl, (^ · 4-alkyl and hydroxy_Ci-4 The alkyl group is preferably selected from c ^ 3-alkyl and cyclopropyl groups. At the same time, the two alkyl groups are taken from 100779 -41-200538102 and can be bonded together to form c3_7-cycloalkyl or c5_7-cycloolefin. The bridging group X is preferably -ch2-ch = ch- bridging group, which may be substituted as specified. The alkenyl bridging group is preferably unsubstituted, or has 1, 2 or 3 substituents. The preferred substituents are (^ _3-alkyl and cyclopropyl. At the same time, two alkyl substituents can be joined together to form a C3_6-cycloalkyl or C5_6-cycloalkenyl. According to this fourth specific implementation For example, the preferred definition of bridge base X is selected from the group consisting of

According to this fourth embodiment, a particularly good definition of the bridge base X is selected from the group consisting of

100779 -42- 200538102 Regarding X representing a substituted alkenylene, only one of the two possible E / Z configurations is shown above. Obviously, another of these two E / z configurations is also included according to the present invention.

According to a fifth specific embodiment of the present invention, the bridging group X represents a C36-alkynyl bridge group, especially a C3.4-4-alkynyl bridge group, which is unsubstituted or contains one, two, three or more Multiple, preferably one, two or three substituents, independently selected from the group consisting of fluorine, gas, CF3, c3_6-cycloalkyl, Ch.alkyl and hydroxy-Cl q_3_alkyl and cyclopropyl, at the same time, two alkyl substituents can be joined together to form c3-7-cycloalkyl. The bridging group X is preferably a -CH ^ CSC- bridging group, which may be substituted as specified. The alkynyl bridging group is preferably unsubstituted or has one, two or three substituents. The preferred substituents are Cn alkyl and cyclopropyl. At the same time, two alkyl substituents can be joined together to form a C3 6-cycloalkyl. According to the fifth specific embodiment above, the preferred definition of the bridge base x is selected from the group consisting of

衢 丞 W #parent is a single bond or I ==, and its bridge group z is preferably a single bond or ethynyl group, which can be two or two !: Generation group, which can be joined at-from, Cyclopropyl is formed. z super good series table early key. The group Y preferably has a meaning selected from the group consisting of a base, a stilbyl group, and a stilbyl group selected from the following divalent cyclic groups: benzene, ethyl, sphyl, triphenyl, tetrahydrothecyl, 100779 -43 -200538102 ♦ Fruit base, dihydro ♦ dolyl, jun, lin, lin, dihydro such as lin, tetrachlorolinyl, isofluorinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzo , Azolyl, benzoyl sallyl, sakilyl, keto 4.keto, benzyl or benzoyl, particularly preferably phenyl, pyridyl, pyrimidinyl, pyridoyl, Aryl, fluorenyl, pinen-4-one, and at the same time, the above cyclic group may be mono- or poly-substituted by the same or different group r20 at one or more c atoms, or in the benzene ring. situation

In this case, it may be additionally mono-substituted by nitro, and / or may be substituted by R21 at one or more N atoms. If the group Y is a 6-membered cyclic or heterocyclic group, the bridge group parent and 2 are preferably connected to the group Y in a para position. μ

100779 -44- 200538102

And γ especially has one of the following meanings

100779 -45- 200538102

〇

γ The best line has one of the following meanings

At the same time, the above-mentioned cyclic group may be mono- or poly-substituted by one or more C atoms at the same or different groups, and in the case of a benzene ring, it may be additionally nitro. Mono-substituted and / or one or more NH groups may be substituted by R21. The group Y is preferably unsubstituted or mono- or di-substituted. A particularly preferred substituent R20 of the group Y is selected from the group consisting of fluorine, chlorine, bromine, cyano, acyl, Ch-alkyl, c2-6-alkenyl, hydroxyl, 0-acyl-Ch-alkyl, Ch -Alkoxy, trimethyl, trifluoromethoxy, C24_alkynyl, c4-alkoxycarbonyl, WCnalkyl) -Cl_3_alkynyl, Ci 4-alkoxy_ several amines Group, amine group, Cn alkyl group-amino group, di_ (Ch_alkyl group) -amino group, amino group carbonyl group, alkyl group-amino group-amino group, and alkyl group> amino group. The most preferred substituent r20 of the group γ is selected from the group consisting of fluorine, gas, bromine, cyano, Cyalkyl, Cl_3-alkoxy, Ci 4 | oxycarbonyl, trimethylol, difluoro Ethoxy, or in the case of a benzene ring, is also nitro. The most preferred group Y is a substituted phenylene group of the following chemical formula 100779 -46- 200538102

Preferably, it is F, Cl, Br, I, methyl, ethyl, vinyl, ethynyl, cf3, 0CH3, 0CF3, -CO-CH3, -C00CH3, CN or N02, or represents Η. take

The most preferred meaning of the substituent L1 is η, f, Cl, Br, methyl, ethyl, ethyl, ethyl or methoxy, especially fluorenyl or fluorenyl. The group A is preferably selected from the following divalent cyclic groups, phenyl, pyridyl, cerato, ceryl or M, which may be at the same or different groups at one or more C atoms. Mission R2. Mono- or poly-substituted, and in the case of a benzene ring, may be additionally mono-substituted by a nitro group.

N-N

N—N 100779 • 47- 200538102 At the same time, the listed groups may be substituted as specified above. Particularly preferred substituents R20 of group A are independent of each other, said, gas, desert, amine, CF3, methoxy and Ch-alkyl. The group A is preferably unsubstituted or monosubstituted by R2O, as specified. According to the preferred specific supplement of item-, the preferred definition of the group gjB is selected from the group consisting of phenyl, fluorenyl, sedenyl, and succinyl. Group B is particularly preferably phenyl. As specified, defined Group B can be the same or different group

R20 mono- or poly-substituted 'phenyl' may also be mono-substituted with sulyl. The group B is preferably unsubstituted or mono-, di- or tri-substituted, especially unsubstituted or mono- or di-substituted. In the case of a single substitution, the substituent is preferably in the para position to the group A. The preferred substituent r2 of group B is selected from the group consisting of fluorine, gas, bromine, cyano, nitro, Ch_alkyl, hydroxyl, CHF2, CHF2_〇_, hydroxyl (fluorenyl-carbyl, Cw-alkane). Oxy, trifluoromethyl, trifluoromethoxy, c2 decaynyl, carboxyl, Ch-alkoxycarbonyl, alkoxy > (: 3-alkynyl, CH_alkoxy-quinylamino , Amine, Ch-Alkyl · Amino, Di_ (Ci4_Alkyl) _Amine, Cyclic_C36_Methyleneimine, Amine Carbonyl, CM · Alkyl-Amine · Ethyl and Di_ (CHi group) -amino group-jiki. A particularly preferred substituent R2 of group B is selected from the group consisting of fluorine, chlorine, bromine, cyano, CI? And trifluoromethoxy. The most preferred substituent r2 of group B is selected from the group consisting of gas, bromine and methoxy. According to the second embodiment, the definition of group B is preferably selected from Radical, C2-6-alkenyl, C2-6-alkenyl, 03-7-cycloalkyl, A? -Cycloalkenyl, C3-7-cycloalkyl_Ch-alkyl, C3_7-cycloalkenylcyclobutanyl , Cycloalkyl 100779 -48 · 200538102

Cl-3-alkenyl, C3-7-cycloalkyl-C1_3- fast group, and at the same time, the atom in the group mentioned in the foregoing regarding B may be mono- or poly-substituted by fluorine. According to the specific embodiment described above, in the cyclic group, one or more C atoms may be substituted by 圮 0. According to this specific embodiment, particularly preferred are the groups C3 γ alkyl, C3_6-alkenyl, C3 + alkynyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptyl Alkenyl, cyclopentylalkyl, cyclopentenyl_C ^ alkyl, cyclohexylalkyl, cyclohexenyl-Ch-alkyl, cycloheptyl_Cl_3_alkyl, cycloheptenyl-C Bu 3 -alkyl, meanwhile, one or more C atoms in the groups mentioned in the above may be mono- or poly-substituted by fluorine, and in the cyclic group, one or more C atoms may be the same Or different groups R2O substitution. According to this second specific embodiment, the most preferred B is cyclohexenyl, which is unsubstituted or contains 1, 2 or 3 identical or different substituents R 2 0, especially methyl. The following are preferred definitions of other substituents according to the present invention: • The substituent R13 is preferably one of the meanings given to R16. R! 3 is particularly preferably represented by Cw alkyl, Cw cycloalkyl, Cw cycloalkyl heptyl, ω_hydroxy_C2_3_alkyl, and alkoxyalkyl. The most preferred Rl3 is HSCi-4 · alkyl. The alkyl group specified above may be mono-substituted by α, or mono- or poly-substituted by F. The preferred meanings of the substituent R15 are fluorene, ClM-alkyl, 03-cycloalkyl, and C3-7-cycloalkyl-Ch-alkyl, and, as defined above, in each case, one or more The C atom may be additionally mono- or poly-substituted by F, and / or in each case one or two c-atoms may be additionally substituted independently by € 1 or 玢. 100779 -49- 200538102 R15 is particularly preferably H, eh, methyl, ethyl, propyl or butyl. Substituent R is the same as Η, Ch · Yuan, Cy, alkyl, cycloalkyl, ω_hydroxy-CM-alkyl, or (Ch_alkoxy) _c ^ alkyl, and As defined above, in each case, one or more c atoms may be additionally mono- or poly-substituted by F, and / or in each case, one or two c atoms may be additionally mono-substituted by C 1 or Br independently of each other. Ri6 is particularly preferably H, CF3, Ch-alkyl, c36 cycloalkyl or Gy cycloalkyl. The substituent R17 preferably has one of the meanings given to Ri6 as preferred, or represents a phenyl group, a phenylalkyl group, a pyridyl group, or a Ci_4-alkylcarbonyl group. Rl? Extraordinary is one of the meanings given to ri 6 as better. One or both of the substituents R18 and R19, preferably independently of each other, represent nitrogen or ^ -4 · alkyl, especially hydrogen. The substituent R20 preferably represents a halide, a mesityl group, a cyano group, a Ci4 · alkynyl group, a c24_alkenyl group, a c2-4-block group, a c3_7-cyclohexyl group, a c3-7_cyclohexyl-c ^ _ group Radical, hydroxy-earth Cl -_4 alkyl, R_Cl · 3-alkyl, or one of the meanings as preferred for R22, and, as previously defined, in each case, one or more c atoms may be additionally F is mono- or poly-substituted, and / or in each case one or two C atoms may be additionally mono-substituted by C 1 or Br independently of each other. The m group is particularly preferably defined as halogen, mesityl, cyano, 14.xyl, c3-7_imidyl, Q-3-methyl, and c ^ 4_ol, and, as previously defined, In each case,-or more c atoms may be additionally mono- or poly-substituted by F, and / or in each case,-or two c-atoms may be additionally substituted by 0 or mono-independently. R2. Most preferred are F, Cl, Br, butyl, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, ethyl 100779 -50- 200538102 fluorenyl , Methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or isopropoxy. The substituent R22 preferably represents a C1-4-alkoxy group, a Ciy alkylthio group, a carboxyl group, a Ck alkylcarbonyl group, a cw-alkoxycarbonyl group, an aminocarbonyl group, a Ci 4-alkylaminocarbonyl group, and a di- (Cn alkyl group). ) -Aminocarbonyl, Ci4-alkyl tellurium, Ci γalkyl_sulfinamilide, Ch-alkyl-phenylamino, amino, Ci-4_amino, dialkyl -Amine, C4-Alkyl-Weiyl_Amine, Warmyl Aminocarbonyl, ΦAminocarbonylamino or C1_4-Alkylaminocarbonyl-Amine, and, as defined above, in each case In this case, one or more C atoms may be additionally mono- or poly-substituted by F, and / or in each case, one or two C atoms may be additionally mono-substituted by C 1 or Br independently of each other. The most preferable meaning of R22 is 014-alkoxy group, Ci3 · alkoxy group, amine group, Cw alkylamino group, dijCn alkyl group, and amine group, in which one or more fluorene atoms may be replaced by fluorine. The preferred definition of the group R21 is Ci_4-alkyl, Ci alkylcarbonyl, c ^ _alkylsulfonyl, -so2-nh2, -S〇2_nh_Ch forming group ... s〇2_N (CHi group) 2 • and bad < 3-6-Methinimino-acidyl, and, as previously defined, in each case one or more C atoms may be additionally mono- or poly-substituted by F, and / or in each case, one Or two c atoms may be additionally monosubstituted by C1 or Br independently of each other. The most preferred R21 is Ci-4_alkyl4CF3.

Cy preferably represents a cycloalkyl group, in particular a cycloalkyl group, particularly a cycloalkyl group, a 7-cyclodiluted nw group, a m-based group, a hexahydrocarbyl group, a morpholinyl group, a stone quaternary muffalinyl group, an aryl group or a heteroaryl group In addition, the above cyclic group may be mono- or poly-substituted at one or more C atoms with the same or different groups, or it may be mono-substituted in the It group of the phenyl group, and / Or one or more 畑 100779 -51-200538102 groups may be substituted by R2i. The most preferred group of the group Cy: Chlorine: a gas, which can be as specified = cyclohexyl, tetragonal-the column preferably represents phenyl or theophyl, especially benzyl. Heteroaryl-words preferably include cleavyl, ahyl, fluorenyl, and benzazolyl

Preferred compounds according to the present invention are those in which one or more radicals, radicals, substituents, and / or indices have previously been designated as preferred sound meanings. Preferred compounds according to the present invention can be obtained by the general formula na, iib, nc , Ii (^ ° trace R \

It is best described by the formulas Ila and lib, (L1), R2 / N-X

Ila

R \ R2 / N-X lib

Among them, κ, ι2, χ, and z all have one of the meanings given above, and L3, independently of each other have the meanings given by R2 0 100779 200538102 m, n, p independently represent the values 0, 丨, or 2, And p can also represent 3. In particular, in formulae IIa, IIb, IIc and IId, preferably formulas and melons, Z represents a single bond, and L1 represents fluorine, chlorine, bromine, cyano, Ci y alkyl, Cy alkoxy, C Bu 4_ oxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, m represents 0 or 1, L2 represents fluorine, chlorine, bromine, CN, amine, CF3, methoxy and c ^ 3 _ Alkyl, η represents 0 or 1, and L3 has a meaning independently selected from the group consisting of fluorine, gas, bromine, cyano, nitro, Cyalkyl, hydroxyl, and ω-hydroxy_c1-3- Alkyl, Cl.4-alkoxy, trifluorofluorenyl, tris-fluorenyl, c2_4-quickyl, retarder, Ch-oxyalkyl, alkoxyalkyl, Chalkoxy-a Amino, amino, Cl_4-alkyl-amino, di- (Ci -4 -alkyl) -amino, cyclic -C3-6-secondary imilide, aminoamino, Cw alkyl Amine-Weiyl or di- (C4-Alkyl) _amino-Weiyl, particularly preferred are fluorine, gas, bromine, cyano, CF3, Ch-alkyl, Ch_oxy and difluoro The alkoxy group is subject to the condition that the benzene ring can only be mono-substituted by Schottky, and P represents 0, 1, 2 or 3, especially 1 or 2. In the best case, in the formulas Ila, Ilb, IIc, and lid, especially in the formulas Ila and lib, R and R independently represent Ci-4 * burning base, light base-Ci-4 _ Yuanji, C3- 5 Alkenyl, C3-5-alkynyl, C3-7-cycloalkyl, hydroxy-c3_7-cycloalkyl, mono-Cg-6-alkyl, C3-7-¾alkyl-Cl-3 Group, tetrazolium group 200538102 sulfan-3-yl group, tetrahydropiperan_4 group, (Cyclo_Cw cycloalkyl group) ((^ _fluorenyl group, ω-% · 4 · alkoxy group) -Cw Alkyl, pyridyl, or fluorenyl, while the 'alkyl, cycloalkyl, or cycloalkyl_alkyl group may be additionally mono- or di-substituted by hydroxy and / or. Alkyl, and / or by F or c 3_ Alkyl is mono- or poly-substituted, and / or mono-substituted by C] p3, Br, C1 or CN, and one or both, preferably one of the groups R1 and R2 may also represent fluorene, and phenyl and pyridine The radicals may be mono- or poly-substituted by the same or different groups R2 0. At the same time, the phenyl may be mono-substituted by nitro, or R1 and R2 may be bonded together and form a heterocyclic ring with the N atoms to which they are bound. Group, which is selected from the group consisting of tetrahydropyrrole, hexahydropyridine, 8-nitro-bicyclo [3 · 2 · 1] octane, and hexahydropyridine, in which the free state The amine functional group is substituted by R13 and morpholine, in which one or more fluorene atoms may be replaced by the same or different groups rM, and at the same time, the heterocyclic group defined above may pass through a single bond and be carbocyclic Or heterocyclic group Cy substitution, at the same time, Cy is selected from the group consisting of c3_7-cycloalkyl and cyclo_CS_6-sulfenimine, at the same time, Cy can be mono- or poly-substituted by the same or different groups R2, Wherein R20 is as defined above, and is preferably selected from fluorine, Cf3, < ^-alkyl, hydroxyalkyl, and hydroxy, and R14 is selected from F, Cl, Br, Ch-alkyl, and hydroxy , Hydroxy-c 3-alkyl, C 4 4-alkoxy, 6> (Ch · alkoxyalkyl, amine Ch-alkyl, Ciy alkyl-amino-C3-alkyl, C3-7_Cyclosyl-Amine-C! -3 -Cyclosyl, N- (Qj-7 -Cycloalkyl-4 -Cyloyl) _Amino-O1-3-Cycloyl, Di ^ 1 4-Alkyl) -amino-O1-3-alkyl, cyclic- (1; 3-6-imino-imidino-Cb3-alkyl, amine-based and erylamino, the same 100779 -54- 200538102 In the above sense, one or more C atoms may each be additionally substituted by F alone or more, and / or in each case one or two c atoms May be further independently substituted with C1 or Br independently of each other, and X represents a C2_4-alkylidene bridge group, which contains 1, 2 or 3 substituents, which are independently selected from q · 3-dyne and cyclopropyl, and , Two alkyl substituents can be joined together to form a c3 6-cycloalkyl, or 02-3 alkylene bridge group, which contains 1, 2 or 3 substituents, which are independently described from the Cn alkyl group and Cyclopropyl, at the same time, two alkyl substituents can be joined together to form a C3_6-cycloalkyl, or a C2-3_iminoimido bridge, where the imine can be substituted by Ci 4_ alkyl, and where The alkylene unit contains 1, 2 or 3 substituents, which are independently selected from Ci3 · alkyl and cyclopropyl. At the same time, the two alkyl groups can be joined together to form a C3 ^ cycloalkyl group, or a alkynyl group. Linked to an imine group, they can also be joined together to form a tetrahydropyrrole or hexahydropyridine, or a C3_4_alkenyl or C3_4_ alkynyl bridge, which is unsubstituted or contains 1, 2 or Three substituents are independently selected from alkyl and cyclopropyl. At the same time, two alkyl substituents can be joined together to form q-cycloalkyl or ^ cycloalkenyl. According to the present invention, the compounds listed in the experimental paragraphs preferably include tautomers, diastereomers, para-isomers, mixtures, and salts thereof. Now, some of the wording used to describe the compounds according to the invention will be defined more fully in the foregoing and in the following. The term halogen of Br, I, and especially f, C1, and Br means an atom selected from F, C1 200538102.

The term Ci-n-alkynyl, wherein n has a value of 3 to 8, means that a saturated branched or unbranched meridian 'has 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, second-butyl, third-butyl, n-pentyl, isopentyl, Neo-pentyl, tertiary-pentyl, n-hexyl, isohexyl and the like. The term Qn-secondary radical, where η may have a value of 1 to 8, is a saturated branched or unbranched hydrocarbon bridge group having 1 to η (: atoms. Examples of such groups include methylene (-CH2-), ethylidene (_CH2-CH2-), 1-methyl-ethylidene (-CH (CH3) -CH2 ·), 1,1 · dimethylethylidene (_C (CH3) 2_CH2_), n-propylidene 1,3-yl (_CH2 -CH2 -CH2-), 1-methylidene-i, 3-yl (_CH (CH3) _CH2 -CH2-), 2-methylidene- 1,3-based (-CH2_CH (CH3) -¾-), etc., and its corresponding mirror-pair.

The term Crn-alkenyl, wherein n has a value of 3 to 6, represents a branched or unbranched hydrocarbon group, has 2 to n C atoms, and has at least one O < > double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2.methacryl,丨 _pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, μhexenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, 5-hexenyl, and the like. The term C2_n-alkynyl, wherein η has a value of 3 to 6, represents a branched or unbranched cyano group, has 2 to η C atoms, and a CeC reference bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl , Μpentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-fluorenylbutynyl, 1-hexynyl, 2-hexynyl, 200538102 3-hexyl Base, 4-hexyl, 5-hexyl and the like.

The term Cl-n-alkyloxy refers to a C ^ n-alkyl-O- group, where Ckalkyl is as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second-butoxy, di-butoxy , N-pentyloxy, isopentyloxy, neo-pentyloxy, third-pentyloxy, n-hexyloxy, isohexyloxy and the like.

The term Ci-n-sulfanyl refers to each group of Ci-n-sulfanyl, where Ci-n-sulfanyl is as defined above. Examples of such groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, second_butylthio, third-butylthio , N-pentylthio, isopentylthio, neo-pentylthio, third-pentylthio, n-hexylthio, isohexylthio, and the like.

The term Ci-n-alkylcarbonyl refers to a -c (= 0)-group, where Ck alkyl is as defined above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, second-butylcarbonyl, third-butylcarbonyl , N-pentylcarbonyl, isopentylcarbonyl, neo-pentylcarbonyl, tertiary-pentylcarbonyl, n-fluorenylcarbonyl, isohexylcarbonyl, and the like.

The term Cm-cycloalkyl refers to a saturated mono-, bi-, tri- or spiro carbocyclic group, preferably a monocarbocyclic group, having from 3 to 11 (: atoms. Examples of such groups include Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [W] octyl, spiro [4,5] decyl, n Pingyl, n-sulyl, n-carboxyl, adamantyl, etc. The term Qn-cycloalkenyl refers to a monounsaturated mono-, bi-, tri- or spiro carbocyclic group, preferably a monocarboxylic acid, having 5 sn C atoms. Examples of such groups include 200538102, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc. The term C3-η-tasselyl Represents the R A η / J group as a non-alkyl_c (== 〇) group, in which the C3-η -cycloalkyl group is as defined above. Aryl-word system means carbocyclic and aromatic ring systems, For example, phenyl, biphenyl, fluorenyl, sulfanyl, phenanthryl, fluorenyl, fluorenyl, indyl, sulphonyl, dibenzyl, biphenyl, etc. "aryl" is particularly preferably phenyl. (: The term 3_6_ alkylimine refers to a 4_ to 'membered ring, which contains 3 to 6 The methylene unit, as well as the imine group, meanwhile, the bond to the molecular residues is made via the imine group. The term cyclo-Cycidinimine- several groups refers to the ring (3-6 as defined above) -An alkylideneimine ring, which is connected to several groups via an imino group. The term heteroaryl as used in this application means a heterocyclic, aromatic ring system other than at least one C atom , Containing one or more heteroatoms selected from N, 0 and / or S. Examples of such groups are furyl, thiobenzyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isosalyl Base, isothiopentyl, diamyl, 1,3,5-diamidyl, sulfanyl, sigmadinyl, pentyl, pyrimidinyl, pyrimidinyl, 1,2,3-trigenyl, 1,2,4-trigenyl, 1,3,5-trisyl, 1,2,3-4diazolyl, 1,2,4-diazolyl, 1,2,5- Oxazolyl, m-pyridoxazolyl, 1,2,3-pyrimadiazole, 1,2,4-oxadiazolyl, i, 2,5-thiadiazolyl, 1,3,4_oxadi Mouth base, tetrasalyl, soul two well bases, this bow base, isomer, base and sigma south base, stupid thiophenyl (thienyl), K 丨 phenyl, benzene Benzene group, benzopyrazolyl group, benzoisoxazolyl group, benzoinzolyl group, benzoisosialyl group, purinyl group, 4zolyl group, 4colinyl group, behenyl group, Isopentyl group, if ^^ 100779 -58- 200538102 linyl fluorenyl, pyridinyl, carbazolyl, monoazaheptenyl, diazaheptenylazine, etc. Heteroaryl one The term also includes partially hydrogenated heterocyclic aromatic% systems', especially those listed above. Examples of such partially hydrogenated ring systems are 2,3 · dihydrobenzyl, dihydrofluorenyl, Dihydro esialyl, dihydro? 丨 wood-based tetrakis π oxazolyl, dihydrooxazolyl, oxazaheptenyl, etc. Heterophylla is preferably a heteroaromatic mono- or bicyclic ring system. "Surgery" such as C3_7-Cycloalkyl-Cl-n · alkynyl, Heteroaryl-Ci-n-alkyl radicals are prepared as described above, and they are cycloalkyl radicals. , Aryl or heteroaryl. Many of the terms given above can be reused in the definition of a chemical formula or group, and in each case, have one of the meanings given above independently of each other. For example, in the group di-C! _4-alkyl-amino, two alkyl groups may have the same or different meanings. The term "pi unsaturated" is used, for example, in "unsaturated carbocyclic groups" or "unsaturated hetero% private groups +" as used in particular in the definition of the group Cy, except In addition to saturated groups, they include their corresponding fully unsaturated groups, but especially mono- and di-unsaturated groups. The term "as appropriate, substituted" as used in this application indicates that it is so private The group is referred to as either unsubstituted or mono- or poly-substituted by a specific substituent. If the groups in question are polysubstituted, the substituents may be the same or different. The type < used in Liwen and later, depends on the substituent group shown to be directed toward the center of the cyclic group in the cyclic group, unless otherwise mentioned, it means this substituent Can be bound to any free position of the cyclic group 100779 -59- 200538102 with H atom. Therefore, in instance r20

In any of the free positions of the present invention, the substituent R2 0, where s = 1, can be bound: where s = 2, the selected substituents R20 can be independently bonded to different free positions of the stupid ring.

The H atom of any carboxyl group present or the pyrene atom bonded to a 1 ^ atom (imino or hydrazone) may be replaced in each case by a group that can be split in vivo. The so-called group that can be split from an N atom in vivo means, for example, a locino group, a fluorenyl group, such as a benzyl group or an onium group, or a (^ _16-sulfonyl group, such as a fluorenyl group, Ethenyl, propionyl, butyryl, pentamyl, or hexamethylene, allyloxycarbonyl, C1-u-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Butoxycarbonyl, tertiary butoxycarbonyl, pentyloxy, hexyloxycarbonyl, octyloxycarbonyl, nonoxycarbonyl, decyloxycarbonyl, undecyloxyquinyl, dodecyloxycarbonyl or hexadecyloxycarbonyl, Phenyl (16-alkoxysulfanyl) such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl, Cn alkylsulfonyl < 2_4-alkoxycarbonyl, Cl_3-alkoxy-C2_4-alkane Oxy-C2-4_alkyloxycarbonyl or R ^ CO-CKRfCRgHKX)-group, where I represents a Cn alkyl, C5_7-cycloalkyl, phenyl or phenyl (dialkyl,

Rf represents a hydrogen atom, a Cn alkyl group, a c5-7-cycloalkyl group, or a phenyl group, and

Rg represents a hydrogen atom, a q · 3-alkynyl group or a Re C0-0- (Rf CRg) -〇 group, wherein Re to Rg are as defined above, and the phthalimide group is an amino group. Another possibility, and the above-mentioned ester group can also be used as a group which can be converted into a carboxyl group in vivo 100779 -60-200538102. The above-mentioned residues and substituents may be mono- or poly-substituted with fluorine as described. Preferred fluorinated alkyls are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethyl alcohols. The compounds of the general formula I according to the present invention may have acid groups, mainly reciprocal groups, and / or basic groups, such as amine functional groups. Therefore, the compound of the general formula I may exist in the following manner, with internal salts, and inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid) or organic acids (such as maleic acid, fumaric acid) Acid, citrate-like acid, tartaric acid or acetic acid), or pharmaceutically acceptable salts of alkalis, such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides, or organic Amines, such as in particular diethylamine, triethylamine, and triethanolamine. The compounds according to the invention can be obtained using synthetic methods known in principle. These compounds are preferably obtained by a preparation method similar to that explained more fully later. The following two reaction schemes A and B illustrate the synthesis of compounds A.5 and B · 5 according to the present invention, and at the same time, ^,, ^, jie 'eight and ㈣ have one of the meanings described above. Hal means gas, bromine or tritium, especially bromine or iodine, particularly preferred. According to the reaction plan A, the halogen compound A1 and the block compound A2 are made to have a molar ratio of about L5: ⑴: 15 'in a protective gas atmosphere in the presence of a suitable catalyst, a suitable catalyst, and ㈣_, in Suitable for reaction in solvents. 100779 -61-200538102 The preferred amount of copper (i) iodide is 丨 0 /. R p, 5 mol /. , Especially within the target range of 5 to 10 mol / 0, based on the isolate A.1. ^ # ^ ", J ^ Pd (PPh3 ^ ^ Pd2 (dba) 3 ^ Pd (OA〇2.

Pd (PPh3) 2Cl2 > Pd (CH3CN) 2Cl2 ^ Pd (dppf) Cl2 〇 ^ ^ ^ ^ # ^!

To 15 mol. /. In particular, the amount of 5 mol% is based on the isolated substance μ. Suitable bases are in particular amines' such as triethylamine or ethylamine, and Cs2C03. The test is preferably based on at least an equal molar amount (based on the isolate μ), excess or as a solvent. Furthermore, the appropriate formamidine or 'e.g. tetrahydrobran' includes the acetylene compounds A.3 obtained in a range of about 2 to 24 hours for a period of about 2 to 24 hours, either directly or in advance It is then reacted with gasified methanesulfonium to form a methanesulfonate derivative A · 4. The required reaction conditions are known to the skilled person. Beneficial solvents are toothed hydrocarbons, such as digas methane. The appropriate reaction temperature is usually in the range of 0 to 3 (Γ (:.) The reaction solution containing the methanesulfonic acid ester derivative A · 4 or the purified formic acid derivative A · 4 which has been dissolved in an appropriate solvent is made. React with amine h_nrir2 to produce the final product A.5, and then purify it as appropriate. If the amine H_NRl R2 has another primary or secondary amine functional group, it is advantageous to have a protecting group in advance, which may be at the end of the reaction After that, it is split again using methods known in the literature. The product thus obtained can be converted into the salt form by, for example, reaction with the corresponding acid. The preferred molar ratio of the derivative A.4 to the amine compound is 1_5: In the range of 1 to 1: 1.5. A suitable solvent is dimethylmethaneamine or amines, such as tetrahydrofuran, including mixtures thereof. The reaction used to form product A.5 is advantageously in the temperature range of about 20 to 9〇

100779 -62- 200538102 C. Reaction plan A: HO-X-Y-Hal + H-C three C-W-A seven (A.1) (A.2)

Cul [Pd] μ ΗΟ-Χ.γ—c = C-W-A-B (Α.3)

MsCI γ

MsO-X-Y-c = C-W-A-B (A.4) HNR1R2

T φ R1R2N— XY—CSCIA_B (A5) According to reaction plan B, the prime compound B · 2 and the alkyne compound bi are used, with a molar ratio of about U: 1 to 1: i · 5, under a protective gas atmosphere In the presence of a suitable 1 bar catalyst, a suitable test and the presence of copper (I) moth, the reaction is carried out in a suitable solvent. For information on appropriate reaction conditions, including catalysts, assays, and solvents, see the explanation of Reaction Plan A. The obtained fast-type compound B.3 is directly or after being purified in advance, and reacts with the gasified tornite page 1 to form a pinanesulfonate derivative B.4. The reaction conditions to be respected can be referred again to the discussion attached to Figure A. 100779 -63- 200538102 The reaction solution containing methanesulfonate derivative B4 or purified methanesulfonate derivative B · 4 which has been dissolved in a suitable solvent is reacted with amine h_nr1r2 to form the final product B.5, and then , Purify as appropriate. Here again, the discussion of Figure A applies. Reaction plan B: HO-X-Y-Z-C three C-H + Hal-A-B (B.1) (B.2) Φ Cul [Pd] (Β · 3)

Η〇-Χ-Υ-Z · C Three OA-B MsCI

Ms〇-X-Y-Z- CEC-A_B (B.4)

HNR1R2 R1R2N—XYZ-CEC-AB (B.5) According to another reaction plan c, the halogen compound C1 and the acetylenic compound C.2 are used, with a molar ratio of about h5: 丨 to i: 15, for protection In a gaseous atmosphere, in the presence of a suitable medium, a suitable test, and the presence of Emei copper ①, it reacts in a suitable solvent to directly form the product C.3. For information on appropriate reaction conditions, including catalysts, bases, and solvents, see the explanatory discussion attached to Reaction Plan A. 100779 -64- 200538102 Reaction plan c: R1R2N— X-Y-Hal + H-C ^ C-W-A-B (c.1) (C.2)

Cul [Pd] u R1R2N— X-Y-C = C-W-A-B (C.3) An alternative synthetic method for this is shown in Reaction Plan D. According to this method, the halogen compound D.2 and the acetylenic compound Di are used at a Mozun ratio of about 1.5: 1 to 1: ι · 5 under a protective gas atmosphere under a suitable palladium catalyst, a suitable base, and iodination. In the presence of copper (I), it is reacted in a suitable solvent to directly form the product D · 3. Again, for information on appropriate reaction conditions, including catalysts, bases, and solvents, see the explanatory discussion attached to Reaction Plan A. Reaction plan D: r1r2N-XU CEC-H + Hal-A-B (D.1) (D.2)

Cul [Pd] R1R2N-XYZ- CEOA-B (D.3) According to plans A, B, C and D, the reaction system is particularly advantageous with its corresponding agamine compounds A_1, B.2, C.1 and D.2 get on. In the case where Hal represents bromine in compound A · 1, B.2, C.1 or D.2, it can be advantageously converted in advance to its corresponding iodine compound. A particularly advantageous method is the aryl-Finkelstein reaction (Klapars, Artis; Buchwald, Stephen L. Copper-catalyzed halogens in aryl halides 100779 -65- 200538102 Element exchange · Aromatic Finkdstein reaction American Chemical Society Periodicals (Science, 124 (50), 14844-14845). Therefore, for example, the halogen compounds α ι, β · 2, or D.2 and sodium iodide can be used in combination with N, NL dimethyl-ethylenediamine and In the presence of copper iodide①, it reacts in an appropriate solvent to form its corresponding interfering compound. The favorable molar ratio of the halide compound to sodium iodide is 1: 18 to 1: 2 · 3. N, n, -dimethylformate The ethylene · diamine system is advantageously used at a molar ratio of 10 to 30% by mole, based on the compound A · 1'B · 2, C.1 or D.2. Comparison of copper iodide① The optimum amount is in the range of 5 to 20 mol φ / °, based on the halogen compounds A · 1, B · 2, C.1, or D.2. A suitable solvent is, for example, 1,4-dioxolane The appropriate reaction temperature is in the range of about 20 to 11.0. The reaction is essentially completed after 2 to 72 hours. The compounds according to the invention can be obtained using synthetic methods known in principle. Substances are preferably obtained by preparation methods that are more fully explained in similar experimental paragraphs. Stereoisomers of formula (I) can be mainly separated by conventional methods. Diastereomers are separated according to their different physicochemical properties, For example, from a suitable solvent, by fractional crystallization, by high pressure liquid or column chromatography, a palmitic or preferably non-palatable stationary phase is used. A racemate covered by general formula (I) may For example, by HPLC on a suitable stationary phase (e.g., chiralpakAD). A racemate containing a basic or acidic functional group can also be separated via a diastereomeric optically active salt. Associated with an optically active acid such as (+) or osmium-tartaric acid, (+) or (-)-diethyltartaric acid, osmium or osmium-tartaric acid monomethyl ester or osmium_camphorsulfonic acid 'or an optically active base such as R) _ (+) small phenylethylamine, fluorene +) small phenylethylamine or (S) -papayaine is prepared by reaction.

100779 »66- 200538102 racemic compounds of formula (I)

Unload, or carefully neutralize with an appropriate acid, such as dilute hydrochloric acid or methanesulfonic acid, and in this way, obtain its corresponding free form in the form of hydrazone or (_). One of the aforementioned optically active acids or bases. A single fluorene or hydrazone palmitrium or a mixture of two optically active diastereoisomeric compounds of the general formula (I) can also be obtained by performing the above synthesis with appropriate reaction ingredients in the (R) or fluorene configuration. . As already mentioned, compounds of formula (I) can be converted into their salts, especially for medical use, into their physiologically and pharmacologically acceptable salts. The four salts may exist on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compound of formula (I) and inorganic or organic acids. On the other hand, in the case of binding hydrogen in an acidic manner, the compound of formula (I) can also be converted into a physiologically and pharmacologically acceptable salt by reacting with an inorganic base, having an alkali metal or alkaline earth metal cation as Counter ion. The acid addition salt can be used, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, structuric acid, methanesulfuric acid, ethanoic acid, toluenesulfonic acid, stearic acid, acetic acid, fumaric acid, succinic acid, lactic acid, Made from citric, tartaric or maleic acid. Furthermore, a mixture of the aforementioned acids can be used. In order to prepare an alkali gold 100779 -67- 200538102 metal salt having a compound of formula (I) that binds hydrogen in an acidic manner, it is preferred to use metal test and earth test metal oxide oxides, and metal test hydroxides and hydrogenation. Chemicals, especially steel-based potassium lice emulsions and hydrides are preferred, while sodium hydroxide and potassium are preferred. The compounds according to the present invention, including physiologically acceptable salts, are agonists for the receptors, specifically receive viscera, and show good affinity in the plastid body binding study. A pharmacological test system for MCH-antagonistic properties is described in the experimental paragraph below. As antagonists of the MOI receptor, the compounds according to the invention are advantageously suitable as rhenium active substances to prevent and / or treat the symptoms and / or diseases caused by CH or some other way connected to rhenium . L In general, the compound according to the present invention has low toxicity, which is fully absorbed by the oral cavity Γ. J has good intra-brain transportability, and particularly easy access to the brain. Knife therefore 'mch antagonists containing at least one compound according to the invention are particularly suitable for use in mammals, such as rats, mice, guinea pigs, hares, dogs, cats, golden sheep, horses, pigs, cattle, monkeys and humans. In the treatment and / or prevention of symptoms and / or diseases caused by MCH or directly connected with MCH for other reasons. Diseases caused by or otherwise reasonably connected to the viscera due to MCH, especially metabolic disorders, such as obesity, and eating disorders, such as bulimia, including bulimia neuropathy. Indications for obesity include, inter alia, obesity due to obesity, excessive obesity due to Tengdaosu, excessive spleen due to plasma, ^ ^ overweight obesity, insufficient plasma obesity, insufficient thyroid function obesity, obesity under the thalamus, obesity symptoms, childhood obesity, upper body obesity, Obesity due to nutritional obesity, hypogonadism, and central 100779 -68-200538102 obesity. The indications in this area also include cachexia, lack of food and excessive food intake. The compounds according to the invention can be particularly suitable for reducing hunger, suppressing appetite, controlling eating behavior and / or causing lameness. In addition, diseases caused by MCH or otherwise reasonably connected to mch also include hyperlipidemia, bee sting fibritis, fat accumulation, malignant ramie therapy, systemic ramie therapy, emotional disorders, Emotional disorders, depression, anxiety states, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia, and hormonal disorders. The compounds according to the invention are also suitable as active substances for the prevention and / or treatment of other diseases and / or disorders, especially those with obesity, such as polyuria 'diabetes, especially type II diabetes, hyperglycemia, especially chronic Hyperglycemia, complications of diabetes, including retinopathy in diabetic patients, neuropathy in diabetic patients, nephropathy in diabetic patients, etc., insulin resistance, pathological glucose tolerance, cerebral hemorrhage, cardiac insufficiency, cardiovascular disease, especially arteriosclerosis With hypertension, arthritis and knee arthritis. The MCH antagonists and formulations according to the present invention can advantageously be combined with dietary therapy ', such as dietary diabetes therapy and exercise. Another range of indications to which compounds according to the invention are advantageously suitable is for the prevention and / or treatment of urinary disorders, such as urinary incontinence, overactive bladder activity, nocturnal enuresis, and enuresis, while overactive bladder activity may or may not be associated with urinary incontinence Benign Prostatic Hyperplasia Connection. In general 'compounds according to the invention are potentially suitable for the prevention and / or treatment of dependence, such as alcohol and / or nicotine dependence, and / or withdrawal symptoms 100779 -69- 200538102 like' Weight gain among smokers. The so-called "dependence" here generally refers to the inability to resist the urge to take addictive substances and / or perform certain activities, especially to achieve either a sense of tranquility or to eliminate negative emotions. In particular, " The term "dependence" is used here to indicate dependence on addictive substances. The so-called " withdrawal symptoms " here means generally the symptoms that occur or may occur when an addictive substance is withdrawn from a patient who depends on one or more such substances. The φ compound according to the present invention is Potentially particularly suitable as an active substance for reducing or stopping tobacco consumption, treating or preventing nicotine dependence and / or treating or preventing symptoms of nicotine withdrawal, reducing tobacco and / or nicotine addiction, and generally as an anti-smoking agent The compounds according to the invention can also be used to prevent or at least reduce the weight gain typically seen when a smoker leaves the final test. These substances are also suitable as active substances which prevent or at least reduce habituation and / or relapse into The dependence of addictive substances is 1 *. The term addictive substances specifically, but not exclusively, refers to substances with psychomotor activity, such as narcotics or drugs, especially alcohol_fine, final test, coca test, amphetamine , Opioids, benzodiazepines and barbiturates. The dose required to achieve this effect, suitably by intravenous or subcutaneous route, may be zero. 30 mg / kg body weight, preferably 0.0 mg / kg body weight, and 001 to 50 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, by oral or nasal route or by inhalation ' In each case, 1 to 3 times per day. For this project, the compounds made according to the present invention can be formulated with other active substances as described below, as appropriate, and one or more 100779 • 70- 200538102 Inert customary carriers and / or silk ^ a diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, Shi Chengcheng Yueyuezhen, polyvinyl four atmosphere ratio Roth, citric acid, tartaric acid, water, ruler / ethanol, water / glycerin, water / anthanol, water / = ethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose, Or fats such as hard fats or their suitable mixtures to make custom galenicals such as plain or coated tablets, capsules, dragees, powders, granules, lotions, emulsions, ingredients, Inhaling aerosol, ointment or suppository0

In addition to the pharmaceutical composition, the present invention also includes a composition containing at least one acetylenic compound according to the present invention and / or a salt according to the present invention, optionally with a physiologically acceptable excipient. Such a composition may also be, for example, a food product, which may be a solid or a liquid in which a compound according to the present invention is incorporated. Regarding the combination mentioned above, it can be used together with other active substances, in particular, for example, those who will enhance the efficacy of the MCH antagonist according to the present invention, the above

One of the indications is an opinion, and / or one that enables it to reduce the dose of the MCH antagonist according to the present invention. One or more other active substances are preferably selected from the group consisting of active substances for treating diabetes, active substances for treating diabetic complications, active substances for treating obesity, preferably active substances for treating hypertension other than MCH antagonists, and treatment. Active substances for hyperlipidemia (including arteriosclerosis),> Active substances for the treatment of arthritis, 100779 -71-200538102-Active substances for the treatment of anxiety,-Active substances for the treatment of depression. The types of active substances mentioned above will now be explained in more detail using examples. Examples of active substances for treating diabetes are insulin sensitizers, insulin secretion accelerators, biguanides, insulin, α-glucosidase inhibitors, and adrenergic receptor activators.

Insulin sensitizers include glitazones, especially pioglitazone and its salts (preferably the hydrochloride), troglitazone, José Gatazon ( 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 accelerating agents include carbamyl ureas, such as toluazol, chloropropamide, chlorpromazine, acetazol, cyclohexyl urea, glycosyl I: glyclopyramide, and its recordings. Salt, glibenclamide, gliclazide, glimepiride. Other examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229), and JTT-608. Double contractions include metformin, buformin, and phenformin. Insulin includes animals derived from animals, especially from cattle or pigs. Semi-synthetic human insulin, which is based on Enzyme method, synthesis from animal-derived insulin, and genetic engineering from humans such as E. coli or yeast 100779-72-200538102 insulin. Furthermore, the term insulin also includes insulin-zinc (containing 0.45 to 0.9% by weight zinc), and protamine-insulin-zinc, which is available from zinc chloride, protamine sulfate, and insulin. Insulin can also be obtained from insulin fragments or derivatives (such as INS-1, etc.).

Insulin can also include different types, such as the spreading time and duration of action (π super immediate action type π, π immediate action type π, π two-stage type "," intermediate type "," long-acting type ", etc.), which The choice is based on the pathological symptoms of the patient. Alpha-glucosidase inhibitors include acarbose, voglibose, miglitol, and emiglitate Cold 3 adrenergic receptor activators include AJ-9677, BMS-196085, SB-226552, AZ40140. Active substances used for the treatment of diabetes except those mentioned above include ergoset , Pramlintide, Lepain test, BAY-27-9955, and inhibitors of liver glucose phosphorylase, anthocyanin dehydrogenase inhibitor, protein tyrosine phosphatase 1B inhibitor, dipeptide Protease inhibitors, glipazide, glyburide. Active substances for the treatment of diabetic complications, including, for example, aldose reductase inhibitors, saccharification inhibitors and protein kinase C inhibitors, DPPIV blocker, GUM or GLP-2 Analogs and SGLT-2 inhibitors. Aldose reductase inhibitors are, for example, tolrestat, epalrestat, imirestat, zenarestat ), SNK-860, zopolrestat, ARI-50i,

100779 -73- 200538102 An example of a saccharification inhibitor is pimagedine. Protein kinase C inhibitors are, for example, NGF, LY-333531. DPPIV blockers are, for example, LAF237 (Novartis), MK431 (Merck), and 815541, 823093, and 825964 (all available from GlaxoSmithkline). GUM analogs are, for example, liraglutide (NN2211) (Novordisk)

, CJC1131 (Conjuchem), exenatide (Amylin). SGLT-2 inhibitors are, for example, AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson & Johnson). Active substances used to treat complications of diabetes except those mentioned above, including Apstar Alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl pentacarbonate, memantine, pimagadine (Pimagedine) (ALT-711) The active substance for treating obesity is preferably other than MCH antagonists, including lipase inhibitors and anorectics. A preferred example of a lipase inhibitor is orlistat. Examples of preferred anorectics are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, and bait Baiamine, (S) -sibutramine, SR-141716, NGD-95-1. Active substances used to treat obesity except those mentioned above include lipostatin.

Furthermore, for the purpose of this application, the active substance group of anti-obesity active substances also includes anorectics, of which / 53 activator, pseudoformate 100779 -74- 200538102 glandular active substance and NPY antagonist should be Emphasize. Substances that can be considered as better anti-obesity or anorectic substances, the scope of which is indicated by the following additional list as examples: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, Gallbladder peptide-A (hereinafter referred to as CCK-A) activator, monoamine reuptake inhibitor (such as sibutramine), sympathomimetic active substance, serotonergic active substance (such as Difen Dexfenfluramine, fenfluramine, or 5-HT2C activator, such as BVT.933 or APD356, or Duosy, duuloxetine), dopamine antagonists (such as bromoergin Or pramipexol), melanocyte-stimulating hormone receptor agonists or mimetics, melanocyte-stimulating hormone analogs, cannabinoid receptor antagonists (rimonabant, ACOMPLIATM), MCH antagonists, OB protein (hereafter referred to as lapatenine), lapatenine analogs, fatty acid synthase (FAS) antagonists, rapateline receptor activators, galangal curcumin antagonists, GI lipase inhibitors or reducers (such as oriista t)). Other anorectics, including bombesin activators, dehydroepiandrosterone or its analogs, corticoid receptor activators and antagonists, orexin receptor antagonists, Urine voxel-binding protein antagonists, like glucagon peptide-1 receptor activators, such as exendin, AC2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors, and ciliary neurotrophy Factors, such as axokine. In this connection, mention should also be made of therapeutic forms that result in weight loss by increasing fatty acid oxidation in peripheral tissues, such as ethyl-CoA intactase inhibitors. 100779 -75- 200538102 Active substances for treating hypertension, including angiotensin-converting enzyme inhibitors, calcium antagonists, potassium channel openers, and angiotensin II antagonists. Angiotensin-converting enzyme inhibitors, including captopril, enalapril, aracepril, delapril (hydrochloride), lixinop Lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, Manidipine (hydrochloride). Examples of mamma antagonists are nifedipine, amlodipine, efonidipine, nicardipine ° de-channel opener, including levcromakalim , L-27152, AL0671, NIP-121. Angiotensin II antagonists, including telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan ), CS-866, E4177. Active substances for treating hyperlipidemia (including arteriosclerosis), including HMG-CoA reductase inhibitors, fibrate compounds. HMG-CoA reductase inhibitors, including pravastatin, simvastatin, lovastatin, atorvastatin, fulvastatin Fluvastatin, Lipantil, Cerivastatin, Itavastatin, ZD-4522 and its salts. Sulfuric acid compounds, including bezafibrate, clonoficol 100779 -76- 200538102, clinofibrate, dobutramine (doflbra (R), and propylene glycol lowering esters. Treatment of dyslipidemia ( Active substances including arteriosclerosis) include, for example, agents that increase HDL content, such as nicotinic acid and derivatives and their preparations, such as niaspan, and activators of nicotinic acid receptors. Active substances for inflammation, including NSAID (non-steroidal anti-inflammatory drugs), especially COX2 inhibitors, such as meloxicam or ibuprofen. Active substances for treating anxiety, including methylamine diazepam , Benzodiazepine, 4 oxozolam, oxazolam, cloxazolam, bromodiazepine, lorazepam, aprazolam, Fludiazepam. Active substances for the treatment of depression, including fluoxetine, fluvoxamine, propofol 1, paroxetine, sertraline. These active substances The dose may conveniently be between 1/5 of the lowest normal recommended dose and up to 1/1 of the normal recommended dose. In another specific embodiment, the invention also relates to at least one acetylenic compound according to the invention and / or according to The use of the salt of the present invention to influence the feeding behavior of mammals. This use is based in particular on the fact that the compounds according to the present invention are suitable for reducing hunger, suppressing appetite, controlling eating behavior and / or causing lameness. Eating behavior The compounds are advantageously affected so that food intake can be reduced. Therefore, the compounds according to the present invention are advantageously used for weight loss. Another use according to the present invention is to prevent weight gain, such as when weight loss steps have been previously taken And among those interested in maintaining their low weight. According to this embodiment, it is preferably non-therapeutic

100779 -77- 200538102 Use. Such non-therapeutic uses can be aesthetic applications, such as applications that change appearance and improve general health. The compounds according to the present invention are preferably used in a non-therapeutic manner in mammals, especially humans, who have not been diagnosed with any eating disorder, without being diagnosed with obesity, bulimia, diabetes, and / or without having been diagnosed with urination (particularly incontinence). The compound according to the invention is on its face (body mass index X is defined as its weight (expressed in kilograms) divided by its height

Degrees (expressed in meters) squared) to less than 30 ', and especially to those who are less than one' are preferably suitable for non-therapeutic use. [Embodiments] The following examples are intended to illustrate the present invention: Advance Remarks Generally, IR, 1H-NMR and / or mass spectra of the prepared compound have been obtained. Unless otherwise mentioned, Rf values were measured using off-the-shelf silicone 60 TLC plates 65 4 (E. Merck, Darmstadt, item number L05714), and were not saturated with unrolled grooves. The Rf value obtained under the guidance of Alox was measured using an off-the-shelf oxide Go TLC plate 65 4 (E. Merck, Darmstadt, item number 1.05713), and was not saturated with a spreading groove. For chromatographic purification, a silica gel manufactured by Messrs Millipore OL \ TREXtm, 35 'micron) or Alox (E. Merck, Darmstadt, standardized oxide 90, 63-200 micron, item number: 1.01097.9050) was used. The ratio specified for the eluent is based on the volume ratio of the solvent in question. The specific volume ratio unit of Nh3 solution refers to the concentrated solution of NH3 in water. Unless otherwise mentioned, the acid, base and salt solutions used to process the reaction solution are aqueous systems of a specified concentration. Specific HPLC data is measured under the parameters indicated below: 100779 -78- 200538102 Analytical column: Zorbax column (Agilent technology), SB (Stable Bond)-C18, 3.5 micron; 4.6 x 75 mm; column Temperature: 30 ° C; flow rate · 0.8 ml / min; injection volume: 5 µl; detection at 254 nm (methods A, B, and F). Analytical column · Zorbax column (Agilent technology), Beta-RPC14; 3.5 micron; 4.6 X 75 mm; column temperature: 30 ° C; flow rate: 0.8 ml / min; injection volume · 5 Microliter; detection at 254 nm (methods C, D, and E). Method A:

Time (minutes) Volume percentage of water (with 0.1% formic acid) Volume percentage of acetonitrile (with 0.1% formic acid) __ 一 95 5 __9_ 10 90 _ ^ ^ _10 10 90 ____— 90 10 _J Method B:

Time (minutes) Volume percent of water (with 0.1% formic acid) Volume percent of acetonitrile (with 0.1% formic acid) _ __0 95___ —5 ~ ___ 4 10___ 90 _ ^-10 ___ 90 __ ^ 90 __— 10 ___J Method C: Time (minutes) Volume percentage of water (with 0.1% formic acid) acetonitrile (with 0.1% formic acid). Volume percentage olfactory ^ __ 95 95 ___ 5 10__ 90 10 __— 90 ^ __ 13 90 —1 〇100779 -79- 200538102 Method D: Time (minutes) Volume percentage of water (with 0_1% formic acid) Volume percentage of acetonitrile (with 0.1% formic acid) 0 95___ 5 9 10 90 10 10 90 11 90 10 — Method E: time (minutes) volume percentage of water (with 0.1% formic acid) acetonitrile (with 0.1% formic acid) 0 95 5 4 10 90 10 10 90 .11 90 10 Method F: time (minutes) water (with 0.1 % Formic acid) 1% by volume of acetonitrile (with 0.1% formic acid) 0 95 5 9 10 90 12 10 90 13 __ 90 10 Preparation column: Zorbax column (Agilent technology), SB (Stable Bond)-C18; 3.5 microns; 30 x 100 mm; column temperature: ambient Degree; flow rate: 3〇 mL / min; detection at 254 nm lower. In preliminary HPLC purification, the same gradient is usually used, which is used when obtaining analytical HPLC data. The products were collected under quality control, and the product-containing fractions were combined and lyophilized. Hypeiprep layer 100779 -80-200538102 manufactured by Messrs Thermohypersil, Darmstadt. Purification: stationary phase HS C18; 8 microns (eluent A (water + 0.15% HCOOH), eluent B (methanol)). Temperature is expressed in degrees Celsius (° C); time is generally expressed in minutes (min), hours (h), or days (d). Without specific information about the configuration, it is not clear whether there are pure palmar isomers, or whether partial or even complete racemization has occurred. The following abbreviations are used above and below:

AcOH

CDI 1, Γ-carbonyldiimidazole DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPE diisopropyl ether DMF dimethylformamide dppf 1, Γ-bis (diphenylphosphino) bicyclo Iron pentadiene

EtOAc ethyl acetate cone. Concentrated

MeOH Methanol PE Petroleum ether RT Ambient temperature TBAF Tetrabutylammonium trihydrate TBME Tertiary-butyl methyl ether THF Tetrahydrofuran ~ > * Representation of bonding positions of groups General experimental method I (Sonogashira coupling) Under argon atmosphere , Suitable palladium catalyst (such as Pd (PPh3) 4 (5 mole%), 100779 -81-200538102 d (PPh3) 2Cl2 (5% ^ 〇 / 0). Pd (CH3CN) Cl2 (5 ^ ^ 〇 / 〇) ^ Pd (dppf) Cl2 (5 or 10 moles / 〇)), appropriate base (such as carbonate shavings (1.5 equivalents) or triethylamine (1.5 equivalents)) and Cul (5 or 10 moles) %) Continuously added to the solution of aryl or heteroaryl iodide or bromide (1.0 equivalent) and acetylene (105 equivalent) in TIIF or dmf. The reaction solution was stirred at room temperature to 9 ° C, between 2-24 hours, filtered, and the solvent was removed in vacuo. Further purification was performed by column chromatography or by purification using HPLC-MS. General experiments Method II (bromine-Angstrom exchange) Under argon, Nal (2.0 equivalents), N, N, -dimethyl-ethylenediamine (0.2 equivalents) and Cul (0.1 equivalents) are continuously added to the aryl or Heteroaryl bromide (10 equivalents) in a solution of 1,4-dioxourethane. The reaction was stirred at room temperature to ° C for 2-72 hours, and then diluted with nh3. The aqueous phase was extracted with DCM, the organic phase was dried over MgS04, and the solvent was removed in vacuo. If necessary, further purification was performed by column chromatography. Component 1 5- (4-Gasyl) -2 -Equivalent base ratio

BSla 5-bromo-2-[(Third-butyl-dimethyl-lithium) -ethynyl] ^

Under argon atmosphere, add 0.80 g (4.20 mmol) of Cul and 2.90 g (4.13 mmol) of bis-triphenylphosphine-vaporized palladium to 49.90 g (201.0 mmol) of 2,5- Dibromopyridine and 43.0 ml (225.6 mmol) of tertiary-butyl-ethynyl-dimethyl-lithoxane in 500 ml of anhydrous THF and 120 ml of triethylamine -7 ° C 100779- 82 · 200538102 solution, and the mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was stirred for another 3.5 hours at room temperature, then filtered, and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 1 liter of EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over Na2S04, and evaporated to dryness in vacuo. The crude product was further reacted without purification. Yield: 59.5 g (quantitative yield) 〇! 3 Η! 8 BrNSi (M = 296.278) Calculated value: Molecular peak (M + H) +: 296/298 (Br) Found: Molecular peak (M + H) +: 296/298 (Br)

Rf value: 0.75 (silicone, cyc / EtOAc8: 1) BSlb 2-[(Second-butyl-dimethyl-calcinyl) _ethanediyl] -5- (4-wind ^ phenyl) · Outside Add 250 ml of MeOH, 220 ml of 2 NNa2C03 solution and 1.80 g (2.46 mmol) of PdCl2 (dppf) to 59.5 g (201.0 mmol) of 5-bromo-2-[(third-butyl -Dimethyl-lithium alkyl) -ethynyl] -pyridine and 36.5 g (233.4 mmol) of 4-p-phenylphenyl boric acid in 600 ml of 1,4-dioxolane, and the mixture was refluxed 1 hour. The reaction mixture was evaporated to dryness in vacuo and diluted with EtOAc. The organic phase was washed with water and a half-saturated NaHC03 solution, dried over Na2S04, and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, cyc / EtOAc 9: 1). Yield: 38.5 g (58% of theory) C19H22ClNSi (M = 327.923) Calculated value: Molecular peak (M + H) +: 328/330 (Cl) Measured value: Molecular peak (M + Η) +: 328/330 (Cl) Section 100779 -83-

V U 200538102

Rf value: 0.60 (Shi Xijiao, cyc / EtOAc 8: 1) BSlc 5- (4-chlorophenyl) -2-ethoxyl ratio σ is set at room temperature, 43.66 g (156.0 mmol) ) TBAF was added to 46.50 g (142.0 mmol) of 2-[(Third-Butyl-Dimethyxylethynyl] _5_ (4-Gaphenyl) -batch σ was determined in 1 liter of DCM The solution was allowed to stir for 2 hours. The organic phase was washed with water, dried over Na2S04, and evaporated to dryness in vacuo. The residue was stirred with DIPE, the precipitate was filtered off, and washed with pe. Yield : 26.0 g (86% of theory) C13H8C1N (M = 213.662) Calculated value: Molecular peak (M + H) +: 214/216 (Cl) Measured value: Molecular peak (M + H) +: 214/216 ( Cl)

Rf value: 0.30 (silicone, CyC / EtOAc 4: 1) · Amine 2,1,2,2-trifluoro-1-hexahydro τι, hydrazone, ethanol

Ala 4_ (2,2,2-trifluoro-1 · Cyclo-ethyl) -hexahydroanidine α-1-1-metanoate Add 0.46 g (3.0 mmol) of fluoride to 7.42 G (30.0 mmol) of 4-fluorenylhexahydropyridine-1-carboxylic acid ethyl ester in 120 ml of THF, the mixture was allowed to cool to -1 (TC, 18.0 ml (36 · ml) was slowly added 〇mmol) trimethyl-trifluoromethyl-lithoxane (2.5 M in THF), the mixture was stirred at -UTC for 1.5 hours and at room temperature for 1.5 hours 120 ml of 1N HC1 was added dropwise, and the mixture was stirred for 1 hour. The organic phase was separated and dried over Na2S04. After the desiccant and solvent had been removed, the residue was purified by chromatography (silica 100779 -84- 200538102 gum, cyc / EtOAc 4: 1). Yield: 4.15 g (44% of theory)

Ci5H18F3N〇3 (M = 317.304) Calculated: Molecular peak (M + H) +: 318 Found: Molecular peak (m + H) +: 318 HPLC-MS: 8.3 minutes (Method A).

Alb 2,2,2-digas-1-hexamethylenestilbidine-4-yl-ethanol makes 3-11 grams (9.80 millimoles) of 4- (2,2,2-trifluoro small hydroxyl · ethyl)- A suspension of hexahydropyridine-1-carboxylic acid ethyl ester and 300 mg of 10% Pd / C in 30 ml of MeOH was hydrogenated at room temperature under a pressure of 3 bar hydrogen for 4 hours. The catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. Yield: 1.82 g (quantitative yield) C7H12F3NO (M = 183.172) Calculated value: molecular peak (M + H) +: 184 found: molecular peak (m + h) +: 184 Rf value: 0.20 (silicone, EtOAc / MeOH / NH350: 50: 5) Amine A2 4-methyl-1 · tetrahydroerol-3-yl-hexahydro

A2a benzyl-tetrahydroe 11--3-yl) -4-methyl-hexahydrohydroxide: 13.0 g (61.5 mmol) sodium triethoxylate borohydride with 2.37 ml (41.44 mmol) Ear) AcOH, added to 6.0 ml (50.7 millimoles) of 4-methylhexahydro leaf dagger σ 疋 with 8.14 liters (50.7 house mole) 1-Epi-tetrahydroepi_3 · A solution of the ketone in 200 ml of THF, and the reaction solution was stirred at room temperature overnight. A saturated NaHC03 solution was added to the reaction mixture, and it was thoroughly extracted with EtOAc 100779-85-200538102, and the combined organic phases were dehydrated and dried with MgS04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, DCM / MeOH / NH3 90: 10: 1) ° Yield: 6.58 g (50% of theory)

Ci 7 H26N2 (M = 258.402) Calculated value: molecular peak (M + H) +: 259 found: molecular peak (M + H) +: 259 Rf value: 0.45 (silicone, DCM / MeOH / NH390: 10: 1 ) A2b 4-methyl-1-tetraki ρ bilo-3-yl hexarat π specific bite 6.58 g (25.46 mmol) 1- (1-fluorenyl-tetrahydropyrrole-3-yl) A solution of ice methyl-hexahydropyridine in 60 ml of MeOH was combined with 0.6 g of 10% Pd / C and hydrogenated at room temperature and 4 bar until the theoretical amount of hydrogen had dissolved (4 hours). The catalyst was filtered off, washed with MeOH, and the solvent was evaporated to dryness in vacuo. Yield: 3.09 g (72% of theory) C10H20N2 (M = 168.279) Calculated value: Molecular peak (M + H) +: 169 Found: Molecular peak (M + H) +: 169 Retention time HPLC: 1.0 minute ( Method A). Example 1 5- (4-Gasphenyl) -2- {4- [3- (3,5-dimethyl-hexazine.den-1-yl) -cyclohexyl] -phenyl B-quick}}? set

100779 -86- 200538102 la 3- (4-Bromophenyl) -cyclohex-2-dione Add about 0.1 liters of dibromoethane to 3.91 g (161 mmol) of magnesium flakes and 3.80 g ( 16.1 mol), a suspension of 4-dibromobenzene in 700 ml of ether, and heated to 35 ° C. Then, the remaining dibromobenzene (34.2 g, 144.9 mmol) k k was added dropwise to 400 ml of ether, and the reaction was refluxed for 1 hour. [G (128 mmol) > methoxy-cyclohex-2-enone was slowly added dropwise in 25 ml of ether, and the reaction was stirred at room temperature for 1 hour, then, added To 1000 ml of 1 M sulfuric acid. The aqueous phase was extracted three times with TBME. The organic phase was washed twice with 500 ml of water and dried over MgS04. After filtration through activated carbon, the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (PE to PE / EtOAc 7: 3). Yield: 15.7 g (40.4% of theory) 〇ι2ϋιιΒτΟ (Μ = 251.100) Calculated value: molecular peak (M + Η) +: 251/253 (Br) Found: molecular peak (M + Η) +: 251 / 253 (Br)

Rf value: 0.25 (silicone, PE / EtOAc8: 2). Lb 3- (4-benzylphenyl) -cyclohexanol at -5 ° C, 7.00 ml (7.00 mmol) of 1 M hydrogenated in THF The lithium aluminum solution was added dropwise to a solution of 1.76 g (7.00 mmol) of 3 probromophenyl) -cyclohex-2-enone in 50 ml of THF. The reaction solution was warmed to room temperature. After treatment and filtration by the Fieser / Fieser method, the organic phase was dehydrated and dried with MgS04. After filtration through activated carbon, the solvent was removed in vacuo and the crude product was allowed to react further without any further purification. Yield: 1.70 g (95.0% of theory) 100779 -87-

200538102 C12H15BrO (M = 255.200) Calculated: Molecular peak (M-H20): 236/238 (Br) Found: Molecular peak (M-H20): 236/238 (Br)

Rf value: 0.57 (silicone, PE / EtOAc 6: 4) · lc 3- (4-iodo-phenyl) -cyclohexanol According to General Method II, prepared from 3- (4-bromophenyl) -cyclohexanol ( ι · 90 grams, 7.45 millimoles). Yield: 2.10 grams (93.3% of theory)

Ci2Hi5I〇 (M = 302.151) Calculated value: Molecular peak (M) +: 302 Measured value · Molecular peak (M) +: 302 1 ^ Value: 0.60 (silicone, PE / EtOAc6: 4) ·

Id 3- {4- [5 · (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -cyclohexanol was prepared from 3- (4-diphenyl)- Cyclohexanol (755 mg, 2.50 mmol) and 5- (4-chlorophenyl) -2-ethynyl than fluorene (534 mg, 2.50 mmol). Yield: 520 mg (53.6% of theory) C25H22C1N0 (M = 387.901) Calculated value: Molecular peak (M + H) +: 388/390 (Cl) Measured value: Molecular peak (M + H) +: 388/390 (Cl)

Rf value: 0.07 (silicone, PE / EtOAc 8: 2). Le 3 · {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenylcyclohexyl sulfonate Add 0.22 ml of pyridine (2.70 mmol) and 0.21 ml (2.68 mmol) of sulforanesulfonium chloride at 0 ° C to 520 mg (1.34 mmol) of 3- {4 -[5- (4-

100779 -88- 200538102 Phenyl) -pyridin-2-ylethynyl] -phenylbucyclohexanol in a solution of 20 ml Dcm. The reaction solution was stirred at room temperature for 2 hours, and a conversion rate of 10% was detected. Add another 1.21 ml (15-44 millimoles) of methanesulfonium chloride and 0.55 milliliters (6.22 millimoles) of pyridine. After the reaction was completed, water was added and the organic phase was washed with a dilute NaHC03 solution. The organic phase was dehydrated and dried over MgS04, and after filtering through activated carbon, the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM / EtAcAc 8: 2). Yield: 300 mg (48.0% of theory) ^ 2 6 ^ 2 4C1N03 S (M = 465.992) Calculated value: Molecular peak (M + H) +: 466/468 (Cl) Measured value: Molecular peak (M + H ) +: 466/468 (Cl)

Rf value: 0.90 (silicone, DCM / EtOAc9: 1). Lf 5_ (4_chlorophenyl > 2- {4-1 > (3,5_dimethyl · hexahydropyridine-i_yl) _ring Hexyl] -benzylpyridyl ratio σ is determined to be 119 gram (ΐ · 05 mol) 3,5-dimethyl hexahydrofluorene ratio. It is added to 100 mg (0.21 mmol) methane A solution of sulfonic acid 3_ {4_ [5_ (4 • chlorophenyl > pyridine 1ylethynyl] _benzyl} -cyclohexyl ester in 2.0 ml DMF, and the reaction solution was stirred at 60 ° C overnight And stirred at 90 ° C for another 8 hours. The reaction mixture was cooled to -10 ° C, and after filtration, the residue was stirred with tbme. Yield: 8.5 mg (8.0% of theory) C32H3 5 C1N2 ( M = 483.086) Calculated value: Molecular peak (M + H) +: 483/485 (Cl) Measured value: Molecular peak (M + H) +: 388/390 (Cl)

Rf value: 0.47 (silicone, EtOAc / MeOH / NH38: 2).

100779 89- 200538102 Example 2 l '-{4- [5- (4-chlorophenyl) -pyridin-2-ylethynylphenyl group 4-methylu] dihexahydro

2a 1L benzyl-4-methyl- [1,3,] dihexahydropyridine 3.82 g (18.0 mmol) of NaBH (OAc) 3 was added to 1.78 ml (15.0 mmol) of 4-methylhexahydro A solution of pyridine and 3.66 g (150 mmol) of N-benzylhexahydropyridine-3_one hydrochloride hydrochloride in 100 ml of butyl HF, and the solution was slightly acidified with glacial acetic acid. The reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was combined with saturated NaHC0 solution. The aqueous phase was extracted twice with EtOAc, and the organic phase was washed with a saturated NaHC0 solution, dried over MgS04, and the solvent was removed in vacuo. Further purification was performed by column chromatography on stone gum (after DCM / MeOH 8: 2, DCM). Yield: 500 mg (12.2% of theory)

Ci 8 H2 8 Ν2 (M = 272.428) Calculated value: Molecular peak (M + Η) +: 273 Measured value ·· Molecular peak (μ + Η) +: 273 Rf value: 0.18 (silicone, DCM / Me〇H / NH39: 1: 〇.ι). 2b 4-Methenyl_ [1,3 '] bishexahydropyridine 500 mg (1.84 mmol) 1,4-methyl-4-methyl- [1,3, ] The solution of bishexahydropyridine in 25 ml of methanol is combined with 100 mg of 10% Pd (OH) 2 and hydrogenated in an autoclave at room temperature 100779 -90- 200538102 and 3 bar% until the theoretical amount The hydrogen has been dissolved to suck the catalyst through the data, and the filtrate is concentrated by evaporation. The crude product was allowed to react without any further purification. 0.35 g (99.4% of theory: 95% of content) C1 ι 22N2 (M = 182.306) calculated. Molecular peak (M + Η) +: 183 found: molecular peak (μ + η) +: ⑻ Heart value. 0.08 (Shi Xijiao, Et〇Ac / Me〇H / NH39: 1: 0.1). 2〇 丨 _ (4-bromophenyl) _4 · methyl- [U '] bishexa Hydropyridine is based on argon atmosphere. 566 mg (2.00 mmol) 4-bromoiodobenzene, 7.6 mg (0.04 mmol) CuI, 849 mg (400 mmol) potassium phosphate and 248 mg ( 4.00 moles) ethane_2, 2-diol, added to 350 mg (1% millimoles) 'methyl- [1,3,] dihexahydrofluorene in 2.G ml isopropanol Inside the solution. The reaction mixture was searched overnight at 8 ° C. and then combined with 100 ml of segment 。. = organic phase was extracted twice with α5% NHΗ3 ⑧ solution, and the aqueous phase was extracted once with 3 () ml. MgS04 was dehydrated and dried, and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel ^^ to DCM / MeOH / NH39: 1: 〇 · ΐ) 〇 Yield: 100 mg (theory 15.4% of the value) C17H25BrN2 (M = 337.298)

Rf value: 0.68 (silicone, DCM / MeOH / NH39: 1: 〇ι) Retention time HPLC: 4.52 minutes (Method B) · 2d 1L (4-filled phenyl) ice methyl- [1,3 '] bis Hexahydropyridyl is prepared from Γ- (4-benzylmethylm] bishexahydropyridyl (100 mg, 0.30 mmol) according to General Method II. 100779 -91 · 200538102 Producing tritium: 120 mg (theory Value of 100%; 95% content)

Cl 7 H2 5IN2 (M = 384.298) Extraordinary value: molecular peak (M) +: 385 measured value · molecular peak (M) +: 385 retention time HPLC: 4_64 minutes (method B) · 2e 1 '-{4 -〇 (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -4-methyl- [l, 3f] dihexahydro p ratio was determined according to General Method I and was prepared from 1,- (4-Polyphenyl) -4-methyl- [1,3,] bishexahydropyridyl (120 mg, 0.30 mmol) and 5- (4-Gaphenyl) -2-acetylene 4-pyridine (69 mg, 0.30 mmol). Yield: 50 mg (36.0% of theory) C30H32CIN3 (M = 470.048) Calculated value: Molecular peak (M + H) +: 470/472 (Cl) Measured value: Molecular peak (M + H) +: 470/472 (Cl)

Rf value: 0 · 28 (silicone, DCM / MeOH9: 1).

Example 3 JL phen-sec-fluorenyl) H2-ylethynyl) -benzylcyclohexyl) -4-fluorenyl-hexahydropyridin-4-ol

3.1a 3- (4-Bromophenyl) -cyclohex-2-enol to 10_0 3.00 g (79.4 millimoles) of sodium borohydride were added in portions at 100 779 -92- 200538 102 g (39.8 House Morr) 3- (4- > Stinky phenyl) -cyclohex-2-dilute-S with (Cang Yue la) in 500 ml

In MeOH. The reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The reaction solution was added to 150 ml of a 10% gasified ammonium solution so that the temperature did not exceed 10 ° C. The aqueous phase was thoroughly extracted with DIPE, and the combined organic extracts were washed three times with water. The organic phase was dried over MgS04 and the solvent was removed in vacuo. The crude product was reacted further without any further purification. Yield: 9.5 g (94.2% of theory) C12H13BrO (M = 253.135) Calculated value: Molecular peak (M + H-H2 0) +: 235/237 (Br) Measured value: Molecular peak (M + Η-Η20) +: 235/237 (Br0Rf value: 0.65 (silicone, DCM / MeOH 9: 1) · 3.1b 3- (4-iodophenyl) -cyclohex-2-enol, prepared from 3- according to General Method II (4-Bromophenyl) -cyclohex-2-enol (10.8 g, 42.7 mmol). Yield: 9.80 g (76.5% of theory) C12H13IO (M = 300.135)

Rf value 0.40 (silicone, PE / EtOAc 6: 4) 3-lc l- [3- (4- mothyl) -cyclohex-2-enyl] -4-fluorenyl-hexahydro p ratio. N--4-ol Add 0.20 ml (2.13 mmol) of phosphorus tribromide in 5.0 ml of TBME to 600 mg (2.00 mmol) 3- (4 pain phenyl) at -10 ° C. -A solution of cyclohex-2-enol in 20 ml of TBME. The reaction solution was stirred at -100 ° C for 2 hours, combined with 50 ml of ice water, and made alkaline with a dilute NaHC03 solution. The organic phase was dried over MgS04 in the cold, and immediately 461 mg (S) 100779 -93- 200538102 (4.00 pen moles) of 4-fluorenyl-hexahydropyridine was added. The reaction mixture was heated to room temperature 'then' and washed three times with 5% Na2C03 solution. The organic phase was washed with water, dried over MgS04, and the solvent was removed in vacuo. The crude product was further reacted 'without any further purification. Yield: 500 mg (62 · 9% of theory) ci 8 H2 4 ΙΝΟ (M = 397.294) Calculated value: Molecular peak (M + Η) +: 398 Found: Molecular peak (M + Η) +: 398 Retention time HPLC: 4.50 minutes (Method B) · 3 · M 1- (3- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -cyclohex-2-ene Group) -4 • methyl · hexahydrostilbene-4_ol according to General Method I, prepared from 1- [3- (4-iodophenyl) -cyclohex-2-enyl] -4-methyl -Hexahydropyridol (397 mg, 100 mmol) and 5- (4-phenyl) -2-ethynyl-exopyridine (214 mg, 1.00 mmol). Yield: 5.0 mg (1.0% of theory) C31H3! C1N2 0 (M = 483.043) Calculated value: Molecular peak (M + Η) +: 483/485 (Cl) Found: Molecular peak (M + Η) +: 483/485 (Cl) retention time HPLC: 8.4 minutes (method A). Example 3.2 5- (4-Gasphenyl) -2- {4- [3_ (3,5-dimethyl-hexadecane Hydropyridine small group) -cyclohex-1-enyl] -benzyl-ethenyl ratio σ fixed / 100779 -94- 200538102

3.2a l- [3- (4-Fephenyl) · cyclohex-2-enyl] -3,5-dimethyl-hexahydropyridine Similar to Example 3.1c, the product was obtained from 600 mg (200 mmol) Mol) 3 (4-mothyl) -cyclohex-2-enol and L20 g (10.6 mmol) of 3,5-dimethylhexahydropyridine. Yield: 500 mg (63.2% of theory) C19H26IN (M = 395.321) Calculated value: Molecular peak (M + H) +: 396 Found: Molecular peak (M + H) \ 3% Retention time HPLC: 5.4 minutes ( Method B). 3_2b 5- (4 · Phenylphenyl) -2 · {4- [3- (3,5_dimethyl-hexahydropyridine small group cyclohex-1-enyl] -phenyl-ethyl Fastyl. According to General Method I, prepared from 1- [3- (4- mothphenyl) -cyclohex-2-enyl] -3,5-dimethyl-hexahydropyridine (395 mg, 1.00 mmol) and 5- (4-chlorophenyl) -2-ethynyl-pyridine (214 mg, 1.00 mmol). Yield: 310 mg (64% of theory) C3 2H33C1N2 (M = 481.071) Calculated molecular peak (M + H) + · 481/483 (C1) Measured molecular peak (M + H) +: 481/483 (Cl) Retention time HPLC: XX minutes (Method A). 100779 -95- 200538102 Example 3.3 [(S) -1- (3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenyl} -cyclohex-2-enyl ) -Tetrahydropyrrole-2-yl] -methanol

3.3a {(S) -l- [3_ (4-iodophenyl) -cyclohex-2-enyl] -tetrahydropyrrole-2-yl} -methanol Similar to Example 3.1c, the product was obtained from 600 mg ( 2.00 millimolar) 3- (4- mothyl) -cyclohex-2-enol and U6 ml (10.6 millimolar) of S-fluoren-2-hydroxyfluorenyltetrahydropyridine. Yield: 500 mg (65.2% of theory) C17H22INO (M = 383.267) Calculated: Molecular peak (M + H) +: 384 Found: Molecular peak (M + H) +: 384 Retention time HPLC: 4.44 minutes ( Method B) · 3.3b [(S) -l- (3- {4- [5- (4-Gaphenyl) -p is more than 2-phenylethynyl] -phenylcyclohex-2-yl ) -Tetradrum ρ bilo-2-yl] methanol according to General Method I, prepared from {(S) -l- [3- (4-iodophenyl) _cyclohexenyl] _tetrahydroerro- 2-yl} -methanol (383 mg, 1.00 mmol) and 5- (4-fluorophenyl) -2-ethynyl · eridine (214 mg, 1.00 mmol). Yield: 50 mg (11% of theory) C3〇H29C1N20 (M = 469.017) Calculated value: molecular peak (M + H) +: 469/471 (Cl) 100779 -96- 200538102 found: molecular peak (M + H) +: 469/471 (Cl)

Rf value: 0 · 30 (silicone, DCM / MeOH / NH39: 1: 〇 · 1). Example 4.1 1- (3- {4- [5- (4-Gaphenyl) _pyridylethynyl] -benzene } _Cyclopentyl) · hexahydropyridine-4-carboxylic acid amidine

4.1a 3- (4-Bromobenzyl) cyclopentenone is similar to Example 1a. The product was obtained from 40.0 g (169 mmol) of 1,4-dibromobenzene and 4.13 g (170 mmol) of magnesium. Tablets and 20.0 grams (158 millimoles) of 3-ethoxy_2 • cyclopentane-1-steel. Yield: 3.5 g (8_7% of theory) C !! H9BrO (M = 237.093) Calculated value: Molecular peak (M + H) +: 237/239 (Br) Measured value: Molecular peak (M + H) +: 237/239 (Br)

Rf value: 0.35 (silicone, PE / EtOAc 6: 4). 4 · lb 3- (4-bromophenyl) -cyclopentanol is similar to the example lb. The product was obtained from L66 g (7000 mmol) in THF. ) 3_ (4-Methenyl) -cyclopent-2-enone with 10.0 ml (10.0 mmol) of a lithium aluminum hydride solution. Yield: 800 mg (47.4% of theory; content 60%; 40% debrominated product) CnH13BrO (M = 241.124) 100779 -97- 200538102 Calculated value: molecular peak (M + H) +: 240 / 242 (Br) Found: Molecular peak (Μ + Η) +: 240/242 (Br)

Rf value: 0.6 (silica gel, DCM / MeOH 9: 1). 4.1c 3- (4-iodophenyl) -cyclopentanol Prepared from 3- (4-bromophenyl) -cyclopentane according to General Method II. Alcohol (800 mg, 3.32 mmol). Yield: 1.00 g (52.3% of theory; content 50%)

CnH13IO (M = 288.125) Calculated value: Molecular peak (M) + · 288 Measured value · Molecular peak (M) +: 288 Retention time HPLC: 5.4 minutes (Method B) · 4.1d 3- {4- [5 -(4-Gasphenyl) -pyridin-2-ylethynyl] -phenylcyclopentyl alcohol, prepared from 3- (4-phenylene) -cyclopentanol (650 mg, 2.26 mmol) according to General Method I Mol) and 5- (4-Gaphenyl) -2-ethynyl-pyridine (483 mg, 2.26 mmol). Yield: 420 mg (49.7% of theory) C24H20C1NO (M = 373.874) Calculated value: Molecular peak (M + H) + ·· 374/376 (Cl) Measured value: Molecular peak (M + H) +: 374 / 376 (Cl)

Rf value: 0.6 (silica gel, DCM / MeOH9: 1). 4-le methanesulfonic acid 3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenylbenzene Cyclopentyl ester is similar to Example le, the product was obtained from 400 mg (1.07 mmol) of 3- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenylcyclopentyl Alcohol, 1-28 ml (6.8 mmol) of methanesulfonium and 0.40 ml (5.0 mmol) of pyridine. 100779 -98- 200538102 Yield: 400 mg (82.7% of theory) C2 5 H2 2 C1N03 S (M = 451.966) Calculated value: Molecular peak (M + H) + ·· 452/454 (Cl) Measured value: molecule Peak (M + H) +: 452/454 (Cl)

Rf value: 0.4 (silicone, PE / EtOAc 1: 1), 4.1f l- (3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenyl}- Cyclopentyl) _hexahydropyridine-4-carboxylic acid

Add 83 mg (0.61 mmol) hexahydroisonicotinamine to 60 mg (0.13 mmol) methanesulfonic acid 3- {4- [5- (4-Gaphenyl) -pyridin-2-yl A solution of ethynyl] -phenyl} -cyclopentyl ester in 2.0 ml of DMF, and the reaction solution was stirred at 80 ° C for 24 hours. The reaction mixture was directly purified by HPLC-MS (water: acetonitrile: acetic acid 95: 5: 0.1 to 10: 90: 0.1). Yield ·· 6.5 mg (10.0% of theory) C3 ο Η3 〇C1N3 〇 (M = 484.032) Calculated value: molecular peak (M + Η) +: 484/486 (Cl) Found: molecular peak (M + Η ) +: 484/486 (Cl) Retention time HPLC: 4.9 minutes (Method B) · Example 4.2 1- (3- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl]- Phenyl} _cyclopentyl) winter methyl-hexahydropyridin-4-ol

Η〇

100779 -99- 200538102 Similar to 4.1f, the product was obtained from 60 mg (〇13mmol) methanesulfonic acid 3_ {dong [5- (4-chlorophenyl) -pyridin_2_ylethynyl] _benzene Base} -cyclopentyl ester and mg (0.39 ^: mol) 4-methyl-hexahydroe.定 _4- 醇. Yield: 10 mg (16% of theory) c3 〇H3! C1N2 ο (M = 471.033) Calculated value: Molecular peak (M) +: 470/472 (Cl) Found: Molecular peak (M) +: 470 / 472 (Cl) Retention time HPLC: 5.64 minutes (Method C) · Example 4.3 5- (4-Gaphenyl) -2- {4- [3- (4-methoxy-hexahydropyridine_1_ ) _Cyclopentyl] _Phenylethyl

Similar to 4.1f, the product was obtained from 60 mg (0.13 mmol) of methyl pyroic acid 3 {4- [5- (4-chlorobenzyl-2-ylethynyl] -phenylcyclopentane And is mg (0.65 mmol) 4-methoxy-hexahydropyridine. Yield: 10 mg (16.3% of theory) c3 〇H3! C1N2 〇 (M = 471.033) calculated value: molecular peak (M + Η) +: 471/473 (Cl) found: molecular peak (Μ + Η) +: 471/473 (Cl) retention time HPLC: 5.4 minutes (Method A). 100779 -100- 200538102 Example 4.4 [(SH -(3- {4- [5- (4-Gaphenyl) _pyridin-2-ylethynyl] -phenylbucyclopentyl) -tetrahydropyrrole-2-yl] -methanol

The HO-like 4.1f 'product was obtained from 60 mg (0.13 mmol) of methyl benzoate 3- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl}- Cyclopentyl ester and 71 microliters (0.65 mmol) S _ (+)-2 • via methyltetrahydroerox. Yield ··························································································· 毫克 ·· + H) + ·· 457/459 (Cl) Retention time HPLC: 5.2 minutes (Method A). Example 5.1 1- (1- {4- [5- (4-chlorophenyl) -pyridin-2-ylacetylene Phenyl] -phenyl tetrahydropyrrole_3-ylM-fluorenyl-hexamethylp-pyrim-4-ol

100779 -101-200538102 5.1a 1- (4-bromophenyl) -tetrahydrop-bilo-3_ol Similar to Example 2c. The product was obtained from 871 mg (10.0 mmol) of 3-tetrahydropyrrolidone. With 2.83 g (10.0 mmol) 4-bromo-benzene. Yield: 1.30 g (53.7% of theory) C10H12BrNO (M = 242.112) Calculated value: Molecular peak (M + H) +: 242/244 CBr) Measured value: Molecular peak (M + H) +: 242/244 〇 Br) Retention time HPLC: 7.77 minutes (Method A). 5.1b 1 · (4-Ephenyl) -tetrahydropyrrole-3-ol. Prepared from 1- (4 · bromophenyl) according to General Method II. -Tetrahydropyrrolidol (1.30 g, 5.37 mmol). Yield 1.30 g (83.7% of theory)

Ci 〇Hi 2INO (M = 289.113) Calculated: Molecular peak (M + H) +: 2 90 Found: Molecular peak (m + H) +: 290 Retention time HPLC: 8.14 minutes (Method A). 5.1 c l- {4- [5- (4-Phenyl)-? °° -2-ylethenyl] -phenylbtetrahydrop-bilo-3_ol According to General Method I, prepared from 1 -(4-Methenyl) -tetrahydropyrrole-3-enzyme (1.30 g, 4.50 mmol) and 5- (4-aminophenyl) -2-ethynyl-pyridine (1.03 g, 4.50 Mol). Yield: 1.40 g (83.1% of theory) C2 3 Hi 9 C1N2 〇 (M = 374.863) Calculated value: Molecular peak (M + Η) +: 375/377 (Cl) Measured value: Molecular peak (M + Η) +: 375/377 (Cl)

100779-102- 200538102

Rf value 0.47 (silicone, DCM / MeOH / NH39: 1: 〇 · 1). 5-ld methanesulfonic acid l- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl ] -Phenyl} -tetramethylpyrrol-3-yl is similar to Example le, and the product was obtained from 1.40 g (3.74 mmol) of l- {4- [5- (4-phenyl) -pyridine 2-ylethynyl] -phenyl} -tetrahydropyrrole-3-ol, 2.61 ml (33.6 mmol) of vaporized methane hydrazone and 3.62 ml (44.4 mmol) of pyridine. Yield: 900 mg (53.2% of theory) c2 4 H2! C1N2 〇3 s (M = 452.954) Calculated value: Molecular peak (M + H) +: 453/455 (Cl) Measured value: Molecular peak (M + H) +: 453/455 (Cl) Retention time HPLC: 6-26 minutes (Method B) _ 5.1e 1- (1- {4- [5 · (4-Gaphenyl) -u than fluoren-2-ylethyl Fastyl] -Phenyltetrahydro p ratio 17 each-3-yl) -4 · methyl-hexahydropi ratio than lake 4-ol 104 mg (0.90 mmol) 4-methyl-hexahydropyridine 4-alcohol added to 82 mg (0.18 mmol) methanesulfonic acid 1- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -tetrahydro A solution of p-bilo-3-yl vinegar in 2.0 ml of DMF, and the reaction solution was stirred at 70 ° C. for 24 hours, and further stirred at 60 ° C. for 60 hours. The reaction mixture was diluted with 2.0 ml of water, and After filtration, the residue was applied to silica gel. Further purification was performed by column chromatography on silica gel (DCM toward DCM / MeOH 9: 1). Yield: 14.0 mg (16.5% of theory) C2 9 Η30αΝ3Ο (Μ = 472.021) Calculated value: Molecular peak (Μ + Η) +: 472/474 (Cl) Found: Molecular peak (M + H) +: 472/474 (Cl) 100779 -103- s) 200538102 Hysteresis Retention time HPLC: 5.03 minutes (method b). Example 5.2 1 · (1- {4- [5_ (4-Gaphenylphenylpyridin-2-ylethynyl] -phenyl} _tetrahydropyrrole-3- Group) -Hexahydrogenation

Similar to 5.1e, the product was obtained from 82 mg (0.18 mmol) of methanesulfonic acid 1- {4- [5- (4-aminobenzyl) -enidine · 2-ylethoxy] -phenylbenzene Tetrahydroeyiyi dagger with 115 mg (0.90 mmol) hexahydroisonicotinamine. Yield: 22 mg (25.2% of theory) C2 9 H2 9 C1N40 (M = 485.020) Calculated value: Molecular peak (M + H) +: 485/487 (Cl) Measured value: Molecular peak (M + H) + : 485/487 (Cl) Retention time HPLC: 4.83 minutes (Method B). Example 5.3 ((S) -1 '-{4_ [5- (4-Gaphenyl) _pyridine_2_ylethynyl]- Benzylbyryl-2-yl) -methanol'bistetrahydropyridine 100779 -104-

200538102

Similar to 5.1e, the product was obtained from 82 mg (0 18 mmol) of methanesulfonic acid 1- {4- [5- (4-chlorobenzyl-2-ylethynyl] -phenyl} -tetrakis The ratio of hydrogen p is slightly larger than g and 91 g (0.90 ^: mol) (s)-(+)-2-by methyltetrahydro p. The yield is 10 mg (12.1% of theory) 8 H2 8 C1N3 〇 (M = 457.994) Calculated: Molecular peak (M + Η) +: 458/460 (Cl) Found: Molecular peak (M + H) +: 458/460 (Cl) Retention time HPLC: 5.08 minutes (Method B) · Example 5.4 5 · (4 · Phenyl) · 2- {4- [3- (4- (Hydroxyoxy-hexahydrop) pyridin-1-yl) · Tetrahydro? ] _ Phenylethynyl} -pyridine

Similar to 5.1e, the product was obtained from 82 mg (0.18 mmol) of methanesulfonic acid 1- {4- [5- (4-Gaphenyl) -erb-2-ylethynyl] -phenyl tetrahydro Erloyl ester with 104 mg (0.90 mmol) of 4-methoxyhexahydropyridine. 100779 -105- 200538102 Yield: 32 mg (36.4% of theory) c2 9 H3 〇C1N3 〇 (M = 472.021) Calculated value: Molecular peak (Μ + Η) +: 472/474 (Cl) Measured value: Molecular peak (Μ + Η) +: 472/474 (Cl) Retention time HPLC: 5.25 minutes (Method B). Example 5.5 5- (4_ 气 本 基) -2_ {4_ [3- (4-methyl_ Hexahydroebitene-1_yl) _tetrahydro p ratio is slightly smaller] • phenylethoxy group ratio. set

Similar to 5.1e, the product was obtained from 82 mg (0.18 mmol) of methanesulfonic acid M4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenyl tetrahydropyrrole · 3_ Ester with 89 mg (0.90 mmol) of 4-methylhexahydropyridine. Yield: 38 mg (46.3% of theory) c2 9 Η3 〇C1N3 (M = 456.021) Calculated value: molecular peak (M + H) +: 456/458 (Cl) found: molecular peak (M + Η) + : 456/458 (Cl) retention time HPLC: 5.50 minutes (method B). Example 6.1 ⑻-1 · (1- {5 · [5- (4-Gaphenyl) -pyridin-2-ylethynyl]- Pyridin-2-yl} _tetrahydropyridine 11 each-3-yl) -4-fluorenyl-hexahydroepinenol 100779 -106- 200538102

6.1a (Magic-1- (5- > stinky-mouth-biting-2-yl) -tetrazol p-bilo-3 gastric alcohol at 140 ° C, 5.00 g (56.2 mmol) (R) -(+) _ Tetrahydropyrrolitol and 13.6 g (56.2 mmol) of 2,5_dibromopyridine were stirred in the melt for 1 hour. The reaction mixture was cooled, combined with EtOAc, and saturated NaHC. 3 solution washed the organic phase. The organic phase was dehydrated and dried with MgSO and the solvent was removed in vacuo. The residue was developed in DIPE and dried after filtration. Further column chromatography on silica gel was performed for further Purified (DCM / MeOH 9: 1). Yield: 5_70 mg (41.7% of theory) C9 Hi 1 ΒγΝ〗 〇 (M = 243 · 101) Calculated: Molecular peak (M + H) +: 243/245 ( Br) Found: Molecular peak (M + H) +: 243/245 (Br)

Rf value: 0.37 (silicone, DCM / MeOH9: 1). 6.1b (R) -l- (5-iodo-pyridin-2-yl) -tetrahydropyrrole-3-enzyme According to General Method II, prepared from ( R) -l- (5-Bromo-pyridin-2-yl) -tetrapyrrol-3-ol (5.50 g, 22.6 mmol). Yield: 4.80 g (66.6% of theory; content: 91%) C9HuIN20 (M = 290.101) Calculated value: molecular peak (M) +: 291 found: molecular peak (M) +: 291 retention time HPLC: 1.69 minutes (Method A).

100779 -107 · 200538102 6.1c ⑻-H5- [5- (4-chlorophenyl) -pyridin-2-ylethynyl p-pyridinyl tetrahydropyrrole-3-ol according to General Method I, prepared from (R ) -l_ (5-pyridin-2-yl) _tetrahydropyrrolidol (4.80 mg, 91% content, 15.1 mmol) and 5- (4-chlorophenyl > 2_ethynyl_pyridine (3.22 grams, 15.1 millimoles). Yield: 5.00 grams (88.4% of theory) C2 2H! 8C1N3 Ο (Μ = 375.851) Calculated value: molecular peak (Μ + Η) +: 376/378 (Cl) found Value: molecular peak (M + H) +: 376/378 (Cl) retention time HPLC: 6.90 minutes (method A). 6 * ld fluorene-methanesulfonic acid 1- {5- [5- (4-gasbenzene) Group) -pyridin-2-ylethynyl] -pyridine stilbyl-2-yl} -tetrahydropyrene ratio σ each 3-yl-g purpose similar to Example le, the product was obtained from 920 mg (2.45 mmol) Ear XR) small {5- [5- (4-Gabenzyl) -erb-2-ylethynyl] a ratio π a _2-yl} -tetrahydro ττ bilo-3-ol, 1.72 ml ( 22.0 millimoles) gasified methanesulfonium, 051 milliliters (3.68 millimoles) triethylamine and 0.50 milliliters (6.13 millimoles) of pyridine. Yield: 870 milligrams (62.6% of theory; content: 80 %) 3 Η2 〇C1N3 〇3 S (M = 453.942) Calculated value Molecular peak (M + H) +: 454/456 (Cl) Found: Molecular peak (M + H) +: 454/456 (Cl) Retention time HPLC: 5.66 minutes (Method B). 6.1e ⑻-l_ ( l- {5_ [5- (4-Gaphenyl) > pyridin-2-ylethynyl] -pyridine-2 · kibtetrahydropyrrole-3-yl) -4-methyl-hexahydropyridine-4- Add 101 mg (0.88 mmol) of 4-methyl-hexahydropyridol to 100 mmol

100779 -108-200538 102 g (0.18 mmol, 60% content) (R) -methanesulfonic acid l- {5- [5- (4-chlorophenyl) -pyridin-2-ylethynyl]- A solution of pyridin-2-yl} -tetrahydropyrrole-3-yl ester in 1.0 ml of DMF, and the reaction solution was stirred at 70 ° C for 48 hours. The reaction mixture was directly purified by column chromatography by HPLC-MS (water: acetonitrile: formic acid 80: 20: 0.1 to 75: 25: 0.1). Yield: 9.0 mg (10.8% of theory) C2 8 Η2 9 C1N40 (M = 473.009) Calculated value: Molecular peak (M + H) +: 473/475 (Cl) Measured value: Molecular peak (M + Η) + : 473/475 (Cl) Retention time HPLC: 4.94 minutes (Method A). Example 6.2 ⑻-5- (4-Gaphenyl) -2- {6- [3_ (4-methyl · hexahydropyridine small group) ) -Tetrahydropyrrole small group] -pyridin-3-ylethynyl

Similar to 6.1e, the product was obtained from 80 mg (0.14 millimolar; 80% content) of (R) -methanesulfonic acid 1- {5- [5- (4-Gaphenyl) -ϊτbibit-2- Diethylpyridyl] pyridin-2-yl} -tetrahydropyrrole-3-yl ester with 0.17 ml (1.41 mmol) of 4-methylhexahydropyridine. Yield: 16 mg (24.8% of theory) 8 H2 9 C1N4 (M = 457.010) Calculated value: Molecular peak (M + Η) +: 457/459 (Cl) 100779 -109 · 200538102 Found: Molecular peak (M + H) +: 457/459 (Cl) Retention time HPLC: 4.85 minutes (Method B). Example 6.3 (8) -1- (1- {5- [5- (4-Gaphenyl) -pyridine-2 -Ylethynyl] -pyridin_2-yl} -tetrahydropyridine 11 each -3-yl) -hexahydroρ ratio change -4-ammonium

Similar to 6.1e, the product was obtained from 100 mg (0.88 mol; 80% content) of (R) -pyrhotite lutein 1- {5- [5- (4-phenyl) -merbite- 2-ylethynyl] -pyridine j-yl} -tetrahydrop-pyrrol-3-yl ester with 116 g (0.88 mmol) of hexahydro p-ratio p-dio-4amine. Yield: 9.0 mg (10.5% of theory) c2 8 H2 8 C1N5 〇 (M = 486.008) Calculated value: Molecular peak (M + Η) +: 486/488 (Cl) Measured value: Molecular peak (M + Η) +: 486/488 (Cl)

Rf value: 0.16 (silicone, DCM / MeOH9: 1). Example 6.4 (S) -5_ (4-Gaphenyl) _2 · {6- [3_ (3,5-Difluorenyl-hexahydrofluorene gamma specific bite_ ι _)) _ tetrahydro p-specific -1-yl] -Eb-3-ylethoxy} _ρ ratio σ fixed 100779 -110- 200538102

Similar to 6.1e, the product was obtained from loo mg (0.88 millimoles; go% content) (R) _methanesulfonic acid 1_ {5- [5_ (4_Gaphenyl) -pyridin-2-ylacetylene The p-pyridin-2-yl-tetrahydroerolo-3-yl ester was mixed with 100 mg (0.88 mmol) of 3,5-dimethylhexahydropyridine. Yield: 23 mg (27.7% of theory) C29H31C1N4 (M = 471.036) Calculated value: Molecular peak (M + H) +: 471/473 (Cl) Measured value: Molecular peak (M + H) +: 471/473 (Cl)

Rf value: 0.44 (silicone, DCM / MeOH9: 1). Example 6.5 ((2S, 3 S) -1-{5- [5_ (4-Gaphenyl) _E. Ding_2 · ylethynyl] 4 Specific bite_2 · yl-tetrahydropyrrolyl_2_yl) -methanol

80% content) is similar to 6.1e '. The product was obtained from 100 mg (0 18 millimoles. Methalamic acid 1- {5_ [5- (4-Gaphenyl). Pyridylethynyl. ] _Pyridine stilbene} tetra 100779 -111-200538102 hydropyrrole 3-yl ester with 89 mg (0.88 mmol) (SH prolinol. Yield: 12 mg (theoretical value of 4. ^) C2 7 H2 7 C1N4 0 (M = 458.982) Calculated value: Molecular peak (M + H) +: 459/461 (cl) Measured value: Molecular peak (M + H) +: 459/461 (Cl)

Rf value: 0.27 (silicone, DCM / MeOH9: 1) · Example 6.6 φ tritium phenyl > 2- {6- [3_ (4_methoxy-hexahydropyridine + yl) -tetrahydropyrrole small group] • Emei-3-ylethoxy

Similar to 6.1e, the product was obtained from 100 mg (0.18 mmol; 80% content) of (R) _methyl pyroxanthate l- {5- [5- (4-phenyl)- ? Pyridin-2-ylethenyl] ^ pyridinj-yl} -tetrahydropyrrole-3-yl ester with 91 mg (0.88 mmol) 4-methoxy-hexahydropyridine. Yield: 9.0 mg (11.1% of theory) C2 7 H2 7 C1N4 〇 (M = 458.982) Calculated value: Molecular peak (M + Η) +: 459/461 (Cl) Measured value: Molecular peak (M + Η) +: 459/461 (Cl)

Rf value: 0.33 (silicone, DCM / MeOH9: 1). Example 7.1 (E) -5- (4-chlorophenyl) -2- {4_ [3_ (4-fluorenyl-hexahydrop-p-bite-i- Group) _propanyl] ^ than 0 -3--3-yl-ethenyl} ^ ratio ° 100779 112. 200538102

7_la 3_ (5- > odor than bite-2_yl) _propan-2-fast-1-ol. 2.47 ml (42.2 mmol) of prop-2-yn-1-ol and 12.3 ml (88.2 mmol) Ear) triethylamine was added to a solution of 10.0 g (42.2 mmol) of 2,5-dibromopyridine in 150 ml of THF. The reaction flask was evacuated and filled with argon. Add 88.4 mg (0.46 mmol) of Cul and stir overnight at room temperature. The mixture was diluted with EtOAc and washed twice with 100% Nh3 solution and water. The organic phase was dried over MgS04 and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (PE / EtoAc: i). Yield: 6.70 g (75% of theory) C8 H6BrN0 (M = 212.043) Calculated value: Molecular peak (M + H) +: 212/214 Measured value: Molecular peak (M + H) +: 212/214 (Br;)

Rf value: 0.40 (silicone, PE / EtOAc: 1). 7.1b (E) -M5_mo · erb-2-yl) -prop-2-en-1-ol will be 1.00 g (4.72 mmol) A solution of 3- (5-bromo-eridine_2_yl) _prop_2_yn-1-ol in 25 liters of THF was added dropwise to 4.72 ml (4 72 millimoles, 1 M in THF) lithium aluminum hydride solution so that the internal temperature does not exceed 0 ° C. The mixture was stirred for 2 hours. Then, 125 microliters of water, 125 microliters of a 15% sodium hydroxide solution, and another 375 microliters of water were added. The reaction mixture was filtered and dried over MgS04 and the solvent was removed in vacuo. 100779 -113- 200538102 Yield: 0.91 g (63% of theory) C8 H8BrNO (M = 214.059) Calculated value: Molecular peak (M + H) +: 214/216 (Br) Measured value: Molecular peak (M + H ) + ·· 214/216 (Br) Retention time HPLC: 4.18 minutes (Method B) · 7.1c (E) -3- (5-iodo-pyridin-2-yl) -prop-2-ene-1 Alcohols are prepared from (E) -3_ (5-bromo ^ pyridin-2-yl) -prop-2-en_1-ol (0.91 g, 4.25 mmol) according to General Procedure II. Yield: 0.87 g (78% of theory) C8H8INO (M = 261.060) Differential value calculated ·· Molecular peak (M + H) + ·· 262 Measured value: Molecular peak (m + h) +: 262 Retention time HPLC: 4.23 minutes (Method B) · 7,1 (1 (E) -3] 5 · [5- (4-Chlorophenylpyridin-2-ylethynyl) -esigidine_2_ylbuprop-2 -En-1-ol

According to the general method I, it is prepared from (E) -3- (5-Ang-Epidin-2-yl) -propan-2-ol (870 gram, 3.33 mol) and 5- (4- Phenyl) -2-ethoxyl-pyridine (712 mg, 3.33 mmol). Yield: 980 mg (85% of theory) C2 1Η2 5 C1N2 〇 (M = 346.809) Calculated value: Molecular peak (M + Η) +: 347/349 (Cl) Measured value ·· Molecular peak (M + Η) + ·· 347/349 (Cl) Retention time HPLC: 5.57 minutes (Method B). 7.1e (E) -5- (4-Gaphenyl) -2- {4- [3-Ga-propenyl] _ Pyridine-3_yl_ethynyl

100779 -114- 200538102 A solution of 160 microliters (1.35 mmol) of thionyl dichloride in 5 ml of DCM was slowly added dropwise to 045 g (1.330 Mol) (E) -3- {5- [5- (4-Gaphenyl) -pyridine · 2-ylethynyl > pyridine_2-ylbuprop-2-enol + 20 ml of DCM Inside the solution. The reaction solution was stirred for 30 minutes at room temperature and overnight at room temperature. After adding a saturated NaHC03 solution, the mixture was extracted with DCM. The organic phase was washed several times with water, dried over MgS04, and the solvent was removed in vacuo. Yield · 450 mg (95% of theory) C2 1H! 4 C12N2 (M = 365.255) Calculated: Molecular peak (M + H) +: 365/367/369 (2C1) Measured value: Molecular peak (M + H) 4 *: 365/367/369 (2C1) Retention time HPLC: 6.82 minutes (Method B). ΊΛί (Ε) -5- (4-Gaphenyl) _2- {4- [3- (4 -Methyl · hexahydropyridin-1-yl) -propenyl] ^-3-yl-ethynyl specific bite Add 146 microliters (1.23 millimoles) of 4-methylhexahydropyridine to 150 mg ( 0.41 millimolar) (E) _3_ {5 · [5_ (4_Atylbenzyl) · Pyridinylethynyl > pyridinyl} -allyl) -Gas in a solution of 2 ml DMF, The mixture was stirred at 70 ° C. overnight. Purified by HPLC-MS. Yield: 42.0 mg (24% of theory) C2 7 H26C1N3 (M = 427.968) Calculated value: Molecular peak (M + H) +: 428/430 (Cl) Measured value ·· Molecular peak (M + H) + · · 428/430 (Cl) retention time HPLC: 5.45 minutes (Method A). 100779 -115- 200538102 Example 7.2 1-((E) -3- {4- [5- (4-chlorophenyl)- Pyridine_2_ylethynyl] -phenyl} _allyl) Icetrifluoromethyl-hexahydrodetermined 4-ol

7.2a (E) -3- (4-Methenyl) -prop-2-en-1-ol, in a nitrogen atmosphere, mix 12.0 g (80.0 mmol) of Nal with 0.85 ml (8.0 mmol) N, Nf-dimethylethylenediamine was added to 4.26 g (20.0 mmol) (ε) -3 · (4-benzylphenyl) -prop-2-en-1-ol with 762 mg (4 Millimoles) Cul in a solution of 20 ml of 1,4-dioxolane, and the reaction mixture was shaken at 110 ° C for 17 hours. The reaction mixture was allowed to cool to room temperature, combined with 200 ml of EtOAc and 100 ml of a half-concentrated NH3 solution, stirred vigorously, the organic phase was separated, and dried over Na2SO4. After the desiccant and solvent have been removed, the residue is allowed to react further without purification. • Yield · 4.69 g (90% of theory) C9H9I02 (M = 260.072) Calculated: Molecular peak (M + H) +: 261 Measured value: Molecular peak (M + H) +: 261 HPLC-MS: 7.9 Minutes (Method A). 7.2b (E) -3- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenylbuprop-2-ene " 1-Sf * Put 3.12 g (12.0 mmol) (E) -3- (4-iodophenylpropan-2-enol, 3.33 g (15.0 Ai; Mol) 5- (4-chlorophenyl) -2 -Ethynyl-to-ratio σ and 4.31 ml (24 mmol)

100779 -116- 200538102 ear) A solution of diisopropylamine in 120 ml of anhydrous THF was evacuated three times, and then aerated with argon. Next, 45 mg (0.24 mmol) of CuI and 196 mg (0.24 mmol) of PdCl2 (dppf) were added. The reaction mixture was stirred at room temperature for 18 hours, the solvent was evaporated to dryness in vacuo, the residue was combined with 100 ml of DCM & 50 ml of a half-saturated NaHC03 solution, and stirred vigorously. The precipitate was separated, washed with water and a small amount of DCM, suspended in DIPE, suction-filtered again, and dried in a circulating air dryer at 50 ° C until a constant weight was reached. Yield: 4.23 g (quantitative yield) C22H16C1N0 (M = 345.821) Calculated value: Molecular peak (M + H) +: 346/348 (Cl) Found: Molecular peak (M + H) +: 346/348 ( Cl)

Rf value: 0.24 (Shi Xijiao, cyc / EtOAc2: 1) · 7.2c 5- (4-chlorophenyl) -2- [4-((E) -3-Ga-propenyl) -phenylacetylene [Yl] -pyridine A solution of 2.56 ml (35.28 mmol) of dithionized thionine in 10 ml of DCM was slowly added dropwise to 6.1 g (17.64 mmol) (E) -3- {4 -[5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenylbuprop-2-en-1-ol in 80 ml of DCM has been cooled to 0 ° C solution, and The reaction solution was added at 0. It was stirred for 2 hours at 0 ° C and 14 hours at room temperature. The mixture was cooled again to 0 ° C, 150 ml of a half-saturated NaHC03 solution was carefully added dropwise, the organic phase was separated, and dried over Na2S04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, cyc / EtOAc 4: 1). Yield: 3.2 g (50% of theory) C2 2 Hi 5 Cl〗 N (M == 364.267) 100779 -117- 200538102 Calculated value: molecular peak (M + H) +: 364/366/368 (2C1) found Value: Molecular peak (M + H) +: 364/366/368 (2C1)

Rf value: 0.60 (stone gum, cyc / EtOAc 2: 1). 7.2d 1 _ ((E) each {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl } -Allyl) -4-trifluoromethyl-hexahydropyridin-4-ol. 65.0 mg (0.38 mmol) of 4-trifluoromethyl-hexahydropyridine and 0.13 ml (0.77 mmol) Mol) ethyl diisopropylamine, added to 700 mg (019 mmol) 5- (4-Gabenyl) -2- [4-((E) -3-Ga-propionamidine) Group) -phenylethenyl] -ratio σ was set in a solution in 1.7 ml of DMF and shaken at 60 ° C for 19 hours. The reaction mixture was filtered through a syringe filter and purified by HPLC-MS. The residue was diluted with 20 ml of EtOAc and 10 ml of saturated NaHC03 solution. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. Then, stir it with DIpE. Yield: 40.4 mg (42.0% of theory) Q 8 H2 4 C1F3 Ν2 Ο (Μ = 496.951) Calculated value: Molecular peak (M + Η) +: 497/499 (Cl) Measured value: Molecular peak (M + H ) +: 497/499 (Cl) Retention time HPLC: 5.5 minutes (Method B). Example 7.3 ((E) _3- {4_ [5- (4-Gaphenyl) pyridin-2-ylethynyl]- Phenylallyl) · Cyclopropylmethyl · propyl · amine

100779 -118- 200538102

0.11 ml (0.77 mmol) of cyclopropylmethyl-propyl-amine and 0.13 ml (0.77 mole) of ethyl diisopropylamine were added to 7.0 mg (0 19 millimoles) 5- (4-chlorophenyl) -2- [4-((E) -3-Ga-propionyl) -phenylethynyl] ratio bite in 1 ·· ml of DMF In the solution, the mixture was shaken at 6 (rc for 3.5 hours. The reaction mixture was purified by HPLC-MS. Yield: 45_3 mg (53.0% of theory) C29H29C1N2 (M = 441.007) Calculated value: molecular peak (M + H) +: 441/443 (Cl) Found: Molecular peak (M + H) +: 441/443 (Cl) Retention time HPLC: 5.6 minutes (Method B). Example 7.4 2-((Ε) -3- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -allylamino) -2-methyl-propane-1,3 · di alcohol

80.7 mg (0.777 mmol) of 2-amino · methyl-1,3-propanediol and 0.13 ml (0.77 mmol) of ethyldiisopropylamine were added to 700 mg ( 〇19mmol 100779 -119- 200538102 ear) 5- (4-chlorophenyl) -2- [4-((E) -3-Ga-propenyl) _phenylethynyl] _pyridine at ι · 7 The solution in ml of DMF was shaken at 60 ° C for π hours. The reaction mixture was purified by HPLC-MS. Yield: 38.2 mg (46.0% of theory) c2 6 H2 5 C1N2 〇2 (M = 432.942) Calculated value: Molecular peak (M + H) +: 433/435 (Cl) Measured value: Molecular peak (M + H ) +: 433/435 (Cl)

Retention time HPLC: 4.9 minutes (Method B). Example 7.5 ((E) -3- {4_ [5- (4-Gaphenyl) -pyridine_2_ylethynyl] -phenylpropenylcyclopentane Yl-amine

Add 0.23 ml (2.30 mmol) cyclopentylamine and 0.39 ml (2.30 mmol) ethyl diisopropylamine to 210 mg (0.58 mmol) 5- (4-Gaphenyl) A solution of -2- [4-((E) gas-propenyl) -phenylethynyl] -pyridine in 5.1 ml of DMF and shake at 60 ° C for 17 hours. The reaction mixture was purified by HPLC-MS. Yield: 107 mg (45.0% of theory) C27H2 5 C1N2 (M = 412.954) Calculated value: Molecular peak (M + H) +: 413/415 (Cl) 100779 -120- 200538102 Found: Molecular peak (M + H) +: 413/415 (α) Retention time HPLC: 5.6 minutes (method β) Example 7.6 1-((E) -3- {4- [5- (4-Gaphenyl) _pyridylethynyl ] _Phenyl dilute propyl) winter methyl-hexahydroanhydro-4 ° ol

44.2 ¢: g (0.38 mol) 4-fluorenyl-hexahydroetetra-4-ol and 0.13 ml (0.77 mmol) ethyl diisopropylamine were added to 700 mg (〇19 mmol) Moore) 5_ (4_Gaphenyl) _2- [4 _ ((E) -3-Ga-propyl) -phenylethoxyl] ^ pyridine in a solution of 17 ml of DMF, and Shake for 17 hours at 0 ° C. The reaction mixture was purified by HPLC-MS. Yield: 58.0 mg (68.0% of theory) C2 8 H2 7 C1N2 〇 (M = 442.980) Calculated value: Molecular peak (M + Η) +: 443/445 (Cl) Measured value: Molecular peak (M + Η) +: 443/445 (Cl) retention time HPLC: 5.2 minutes (Method B) · Example 7.7 2-((E) -3_ {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl ] -Phenylpropenylamino) _ propane-1,3-diol 100779 -121- 200538102

70.0 mg (0.777 mole) of 2-amino-1,3-propanediol and 0.3 ml (0.77 mmol) of ethyl diisopropylamine were added to 70.0 mg (0.99 mmol) Ear) 5- (4-chlorophenyl) -2- [4-((E) -3_Ga-propionyl) -phenylethynyl] bite into a solution in π ml of DMF 'and Shake at 60 ° C for 3.5 hours. The reaction mixture was purified by HPLC-MS. Yield: 37.6 mg (47.0% of theory) c2 5 H2 3 C1N2 〇2 (M = 418.915) Calculated value: Molecular peak (M + H) +: 419/421 (Cl) Measured value: Molecular peak (M + H ) + 419/421 (Cl) retention time HPLC: 4-9 minutes (Method B). Example 7.8 3-[((E) Each {4- [5- (4-Gaphenyl) -pyridin-2-yl [Ethynyl] _phenylphenylallyl) _Cyclofluorenyl-amino] propane " " 1-ol

61.0 μl (.68 μmol) of 3-Methyl-1-propanol and 012 ml (0.68 mmol) ethyldiisopropylamine were added to 70.0 mg (0.78 mmol) Moore) ((ε) -3- {4- [5_ (4-chlorophenyl) ^ pyridin-2-ylethynyl] -phenylpropenyl> cyclopentyl-amine at 17 100779- 122-200538102 ml of the solution in DMF and shake at 4 ° C for 17 hours. Add another 61.0 彳 liter (0.68 mol) of 3-molyl-1-propanol, and mix the mixture at 40 ° C. (Shake for 3 hours at 3 ° C. Remove the solvent in vacuo and dissolve the residue in 20 mL of Eto-Ac and 10 mL of a half-saturated NaHC03 solution. The organic phase is dried over Na2S04 and dried in vacuo. The solvent was removed from the solution. Then, the residue was stirred with TBME. Yield: 9.20 mg (theoretical value of 5 · 0/0) C3〇H31C1N20 (M = 471.033) Calculated value: molecular peak (M + H) +: 471/473 (Cl) Found: Molecular peak (M + H) +: 471/473 (Cl)

Rf value: 0.30 (silica gel, 366 nm, DCM / MeOH / NH39: 1: 0.1). Example 7.9 8-((E) -3- {4- [5- (4-chlorophenyl) -pyridine · 2 · ylethynyl; phenylballylmethyl nitrogen-bicyclo [3 · 2 · 1] oct-3-ol

Add 46.6 mg (.33 mmol) of 3-methylisonitro-bicyclo [3.2.1] oct-3-ol and 0.11 ml (0.66 mmol) of ethyldiisopropylamine to 6 〇〇mg (〇 17 mol) 5- (4-chlorophenyl) -2_ [4-((E) _3_chloro-propenyl) _phenylethoxy] _? Ratio. The solution was set in 1.7 ml of DMF and the reaction mixture was shaken at 60 ° C for 16 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in 20 ml of EtOAc and 10 ml of 5% NaHC03 solution, briefly heated to 80 (rc, separated 100779-123-200538102 organic phase, and dehydrated with Na2SO4 Dry. After the desiccant and solvent have been removed, the residue is stirred with 5 ml of isopropanol, and filtered with suction. Yield: 48.4 mg (63% of theory) c3 〇H2 9 C1N2 〇 (M = 469.017 ) Differential value: Molecular peak (M + Η) +: 469/471 (Cl) Measured value: Molecular peak (M + Η) +: 469/471 (Cl) Retention time HPLC: 4.9 minutes (Method B). Example 7.10 8-((E) _3] 4- [5- (4-chlorophenyl) -eridin-2-ylethynyl] phenylpropenyl) each ethyl nitrogen-bicyclo [3.2.1 ] Octan-3-ol

Similar to Example 7.9, the product was obtained from 60.0 mg (0.17 mmol) of chlorophenyl) -2- [4-((E) -3-gas-propenyl) -phenylethynyl] with a ratio of σ to 51.2 mg (Ο ·% mmol) 3-ethyl-8-nitro-bicyclo- [3.2.1] oct-3-ol. Yield ·· 32.9 mg (41% of theory) c31H3! C1N2 〇 (M = 483.043) Calculated value: molecular peak (M + Η) +: 483/485 (Cl) Found: molecular peak (M + Η) + : 483/485 (Cl) Retention time HPLC: 5.0 minutes (method B). 100779 -124- 200538102 Example 7.11 1-((E) -3- {4- [5- (4-chlorophenyl) x bite -2-ylethynyl] -phenyl} -dilute propyl) _4_ethyl-hexahydrobenzyl-4-ol

42.6 mg (0.33 mmol) of 4-ethyl-hexahydropyridin-4-ol and 0.08 ml (0.44 mmol) of ethyldiisopropylamine were added to 4.0 mg (〇 · Ηmmole) of 5- (4-chlorophenyl) -2- [4-((E) -3-Ga-propenyl) -phenylethynyl] -pyridine in L7 ml of DMF, The reaction mixture was allowed to shake at 60 ° C. for 5 hours. After cooling, the reaction mixture was purified by HPLC without workup. The product-containing fractions were combined with 20 ml of EtOAc and 10 ml of a 5% NaHC03 solution and stirred. The liquid phases were separated and the organic phase was dried over Na2S04. After the desiccant and solvent have been removed, the residue is triturated with a small amount of DIPE, filtered with suction, and dried. Yield: 19.9 mg (40% of theory) C2 9 H2 9 C1N2 〇 (M = 457.006) Calculated value: Molecular peak (M + Η) +: 457/459 (Cl) Measured value: Molecular peak (M + Η) +: 457/459 (Cl) Retention time HPLC: 4.9 minutes (Method B) · Example 7.12 4-methyl-1-((Ε) -3_ {4_ [5- (4-methyl · cyclohexane small) Alkenyl) -pyridin-2-ylethynyl] -phenylpropenyl) -hexahydropyridin-4-ol 100779 -125- 200538102

7.12a 1- {6-[(Third-butyldimethyl-lithium alkyl) _ethynyl p-pyridinyl M-methyl-cyclohexanol will be 9.5 ml (16.19 mmol) n-BuLi (1.6 M in THF), slowly added to 4.50 g (15.19 mmol) 5-molyl-2-[(tertiary-butyl-monomethyl-stone) under chlorine at -70 ° C (Ethyl group) -ethynyl] -fluorene 2 was fixed in a solution of 50 ml of acetone and 60 ml of THF, and after the addition was completed, the mixture was stirred for another 2 minutes. Add 1.86 ml (15.19 mmol) of 4-methylcyclohexanone, and slowly warm the mixture to room temperature. Add 150 ml of a saturated gasified ammonium solution, and extract the aqueous phase thoroughly with EtoAc. The combined organic extracts were washed with a half-saturated NaHC03 solution, dried over MgS04, and evaporated to dryness in vacuo. The residue was purified by chromatography (silica gel, PE / EtOAc 4: 1). Two kinds of dissociated fractions are separated out: Dissociated fractions 1 ·· cis-1- {6-[(Third-butyl-dimethyl · Shixyl) · Ethynyl] _ p ratio ° 定 -3- } -4-methyl-cyclohexanol Production: 1.40 g (28% of theory) C20H31NOSi (M = 329.552) Calculated value: Molecular peak (M + H) +: 330 Found: Molecular peak (M + H) +: 330 Rf value: 0 · 40 (silicone, PE / EtOAc4: 1) dissociation fraction 2: trans small {6-[(third-butyl-dimethyl_lithium alkyl) _acetylene Base] -leaf sigma-3-yl} -4_methyl-cyclohexanol Yield: 1.00 g (20% of theory) $ 100779 -126- 200538102 C2 〇H3! NOSi (M = 329.552) Calculated value ·· Molecular peak (M + H) +: 330 Measured value ·· Molecular peak (m + h) + ·· 33Rf value: 0.30 (silicone, PE / EtOAc4: 1) 7.12b 2-[(Third- Butyl_dimethylsulfenyl group> Ethylpyridyl] _5_ (4-methyl-cyclohex-1-yloxy) ratio σ will be 1.22 ml (15.78 mmol) gasification of methanesulfonium, slowly Added dropwise to 1.3 g (3.95 mol) of cis- (third-butyl-dimethyl · sylxyl) · ethynyl] -pyridin-3-ylb 4-methyl-cyclohexanol With 2.2 ml (15.78 mmol) of triethyl-amine in 30 ml of DCM has been cooled to ° C solution. After the addition has ended, remove the cooling bath and stir the reaction mixture at room temperature for 2 hours. To complete the reaction, add another 2.2 ml of triethylamine and 122 ml of gasified methanesulfonium, The mixture was stirred at room temperature overnight, and combined with 1 ml of triethylamine again. Water was added to the reaction solution, the organic phase was separated, washed with water and dried over MgS04. The desiccant and solvent had been After removal, the residue was purified by chromatography (silica gel, gradient solution PE to PE / Et〇Ac ^ 丨). Yield 0.95 g (20% of theory) C20H29NSi (M = 311.536) Value · Molecular peak (M + H) +: 312 Measured value: Molecular peak (M + H) +: 312 7.12c 2-Ethynyl-5- (4-methyl-cyclohexyl · ι · alkenyl) pyridine Add 877 mg (3.35 mmol) of TBAF to 950 mg (3_05 mmol) of 2-[(Second · butyl-dimethyl-lithium alkyl) _ethynyl] _5 · (4_methyl -Cyclohexyl + alkenyl) -pyridine in 20 ml of DCM, and the reaction solution was stirred at room temperature for 30 minutes. The mixture was combined with water, the organic phase was separated, washed twice with water, and washed with MgS 4 dried desiccant and solvent had been removed after 100779-127- 200 538 102 'The residue was purified by chromatography (Al〇x, PE / Et〇Ac 9 by:. U. Yield: 400 mg (66% of theory) C14H15N (M = 197.276) Calculated: Molecular peak (M + H) +: 198 Found: Molecular peak (M + H) +: 198 Retention time HPLC: 5.9 minutes ( Method E). 7.12d 1-Bromo_4-((E) -3-chloro-propionyl) -benzene Add 1.67 ml (20.65 mmol) of eridine and a drop of DMF to 440 g ( 20.65 mmol) (E) -3- (4-bromophenyl) -propan-2-enol in 50 ml of DCM has been cooled to o ° c solution, and then 151 ml is slowly added dropwise. (20.65 mmol) of SOC12 in 10 ml of DCM. The reaction mixture was stirred at 0 ° C for 1 hour and stirred at room temperature for 3 hours. It was carefully combined with water, the organic phase was separated, washed with water, and dried over MgS04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, pE / DCM 4: 1). Yield: 1-9 g (40% of theory) C9H8BrCl (M = 231.517) Calculated value: Molecular Peak (M + H) +: 230/232/234 (BrCl) Found: Molecular peak (M + H) +: 230/232/234 (BrCl) 7.12e H (E) -3- (4-bromobenzene) ) -Allyl] -4-fluorenyl-hexahydrop-ratio-4_ol Add 709 mg (6.16 mmol) of 4-methyl-hexahydropyridinol to 950 mg (4.10 brushes) ) 1-Molyl-4-((E) -3-chloro · propylamido) _benzene and 1.14 ml (8.21 mmol) of triethylamine in 5 ml of DMF, and the reaction mixture was brought to Stir overnight at warm temperature. It was evaporated to dryness in vacuo, the residue was dissolved in water ’was thoroughly extracted with EtOAc, the combined organic phases were washed with water, and washed with 100779 -128- 200538102

MgS04 was dried and dried. After the desiccant and solvent have been removed, the residue is dried in vacuo 'and further reacted without purification. Yield: 600 mg (47% of theory)

Cl 5 Η2 〇BrNO (M = 310.229) Calculated: Molecular peak (M + H) +: 310/312 Found: Molecular peak (M + H) +: 310/312 (Br) 7_12f H (E) -3 -(4-Brophenyl) _allyl] Icemethyl_hexamethylpyridine

Prepared according to General Experimental Method II from 600 mg (1.93 mmol) of l-[(E) -3- (4- > odorantyl) -dilute propyl] _4-methyl-hexazine p is more than cylic alcohol. Yield: 700 mg (theoretical value of 〇〇〇 / 〇)

Ci 5 Η2 〇INO (M = 357.230) Calculated value ·· Molecular peak (M + H) +: 358 Measured value: Molecular peak (M + H) +: 358 Retention time HPLC ·· 3.5 minutes (Method B). 7 * 12§ 4_Methyl_H⑹-3 · {4- [5- (4-methylcyclohexenylalkenyl) pyridine_2 · ylethynyl] -phenyl} • allyl) -hexahydrop Titanol-4-ol was prepared from 120 mg (0.34 mmol) of 1-[(E) _3- (4-heterophenyl) -allyl] -4-methyl-hexa according to General Working Method I Hydrogen ττ than n-Din-4-ol and 80 mg (0.40 mmol) 2-ethynyl-5- (4-fluorenyl-cyclohex-1-enyl) _pyridine (with pd Medium, triethylamine as base, and THF as solvent. Yield: 30 mg (21% of theory) C2 9 Η34N20 (M = 426.593) Calculated value: molecular peak (M + H) +: 427 found: molecular Peak (M + H) +: 427 Retention time HPLC: 5.6 minutes (method D). 100779 -129- 200538102 Example 7.13 5- (4-methyl-cyclohexylene) -2- {4-[(E ) · 3- (4 • methyl-hexahydropyridine small group) _propenyl] -phenylethynylpyridine

7.13a 1-[(E) -3- (4-bromophenyl) -allylfluorene-methyl-hexahydropyridine Add 1.94 ml (16.41 mmol) of 4-methylhexahydropyridine to 950 mg (4.10 mmol) of 1-bromo-4-((E) -3-chloro-propenyl) -benzene in 5 ml of DMF, and the reaction solution was stirred at room temperature overnight. It was evaporated to dryness in vacuo, the residue was dissolved in water, extracted thoroughly with EtOAc, the combined organic phases were washed with water and dried over MgS04. After the desiccant and solvent have been removed, the residue is evaporated to dryness in vacuo and further reacted without purification. Yield: 900 mg (75% of theory) C15H2〇BrN (M = 294.230) Calculated value: Molecular peak (M + H) +: 294/296 (Br) Found: Molecular peak (M + H) +: 294 / 296 (Br) 7.13b 1-[(E) -3- (4-mothenyl) -dilute propyl] -4-fluorenyl-hexazidine. According to General Experimental Method II, prepared from 900 mg ( 3.06 millimolar) -3 (Ε) -3_ (4- > stilbenzyl) -dilute propyl] -4-methyl-hexamorine ρ ratio σ. Yield: 1.0 g (96% of theory)

Ci5H2〇IN (M = 341.231)

100779 -130- 200538102 Calculated value · Molecular peak (M + H) +: 342 Measured value · Molecular peak (M + H) +: 342 Retention time HPLC: 4.0 minutes (Method B) · 7.13c 5- (4 -Methyl-cyclohex-1-enyl) -2- {4-[(E) -3_ (4-methyl-hexahydropyridine small group) -propenyl] -phenylethoxyl Prepared from 120 mg (0.34 mmol) μ [⑹-3_ (4-iodophenyl) -allyl] -4-methyl-hexahydropyridine and 83 mg (0.42 mmol) according to General Working Method I ) 2-Ethynyl-5- (4-methyl-cyclohex-1-enyl) pyridine (with Pd (dppf) Cl2 as the catalyst, triethylamine as the base, and THF as the solvent). Yield: 30 mg (21% of theory) 9 H3 4N2 (M = 410.594) Differential value: molecular peak (M + H) +: 411 found: molecular peak (M + H) +: 411 retention time HPLC: 6.0 minutes (method D). Example 7.14 Η (Ε) -3- {4- [5- (4-Gaphenylphenylpyridin-2-ylethynyl] -phenylpropenyl) -4- Methyl-Hexazine-4-ol

7.14a 2,5-Dimolyl-3-defective pi ratio. A solution of 1.78 g (25.80 mmol) of sodium nitrite in 3.5 ml of water was added dropwise to 6.50 g at -5 ° C. (25.80 mmol) of 2,5-dibromo4-pyridin-3-ylamine and 15 ml of concentrated HC1 (180.62 mmol) in 15 ml of water, and the mixture was stirred for 30 minutes. Under this condition, 11.41 ml (77.41 mmol 100779 -131-200538102 ear) of hexafluorophosphoric acid (60% in water) was added, and the mixture was stirred at 0 ° C for 1 hour. The diazonium salt formed was removed, washed with cold water, isopropanol and ether, and dried in a vacuum 'dryer. The PE (boiling range 100-100 ° C) was heated to 90 ° C and the diazonium salt was added in portions, and the mixture was stirred until no further development of gas was detected. The reaction mixture was allowed to cool to room temperature, made alkaline with a saturated Na2CO3 solution, and the aqueous phase was thoroughly extracted with TBME. The combined organic phases were washed with saturated Na2C03 solution and water, and dried over MgS04 and dried. After the desiccant and solvent have been removed, the residue is dissolved in DCM, filtered through silica gel, and the filtrate is evaporated to dryness in vacuo. Yield 3.30 (51% of theory) C5 H2 Br2 FN (M = 254.883) Calculated value: molecular peak (M + H) +: 253/255/257 (2 Br) Measured value: molecular peak (M + H ) +: 253/255/257 (2 Br)

Rf value: 0.63 (silicone, PE / EtOAc 9: 1) 7.14b Molyl_2-[(Third-butyl-dimethyl-lithium alkynyl) ethoxy] -3-gas_

Add 2.62 ml (13.81 mmol) of tertiary-butylethynyl-dimethyl-lithoxane to 3.20 g (12.56 mmol) at 15 ° C in argon atmosphere 2 , 5-dibromo-3-fluoro-eridine, 5.22 ml triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) Cul, and 220.3 mg φ · 31 mmol (bi-tri) A solution of phenylphosphine-gasified palladium hydrazone in 30 ml of anhydrous THF, and the mixture was stirred at room temperature for 2 hours. 1 ml of tert-butyl-ethynyl-dimethyl-lithoxane was added, and the mixture was stirred at room temperature for another hour. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with a half-saturated Na Guangba 100779-132-200538102 solution, a 5% NH3 solution and water, and dried over MgS04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, PE / DCM9: 1). Yield: 1.62 g (41% of theory) 〇! 3 Hi 7 BrFNSi (M = 314.269) Calculated value: Molecular peak (M + H) +: 314/316 (Br) Measured value: Molecular peak (M + H) +: 314/316 (Br) HPLC-MS: 7.9 minutes (Method B) 7.14c 2-[(Second-butyl-dimethyl-secondary alkyl) -ethoxy] -5- (4-gas Phenyl) -3_ 10 ml of MeOH, 10 ml of 2NNa2C03 aqueous solution and 94 mg (0.13 mmol) of Pd (dppf) Cl2 were added to 1.61 g (5.14 mmol) of 5-bromo-2-[(third -Butyl-dimethyl-silyl) -ethynyl] -3-fluoro-pyridine and 0.90 g (5.65 mmol) of 4-chlorophenylboronic acid in 30 ml of 1,4-dioxolane And the mixture was refluxed for 15 minutes. The reaction mixture was evaporated to dryness in vacuo and diluted with EtOAc. The organic phase was washed with water and a half-saturated Na? CO3 solution and dehydrated and dried with N & 2 SO4. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, PE / DCM1: 1). Yield: 1.25 g (70% of theory) C19H2iClFNSi (M = 345.913) Calculated value ·· Molecular peak (M + H) +: 346/348 (Cl) Measured value: Molecular peak (M + H) +: 346 / 3 ^ (Cl) HPLC-MS: 8.9 minutes (method B). 7.14d 5- (4-chlorophenyl) -2-ethoxy-3-methoxy. 100779 -133 · 200538102 At room temperature, add 1.14 g (3.61 mmol) of TBAF to 1.25 g (3.61 mmol) of 2-[(third-butyl-dimethyl-lithium) -Ethynylphenyl) -3-fluoro-eridine in 30 ml of DCM, and the mixture was stirred at room temperature for 2 hours. The organic phase was washed with water and dried over Na2S04. After the desiccant and solvent have been removed, the residue is stirred with PE, the precipitate is removed, washed with PE, and dried in air. Yield: 0.72 g (86% of theory) C13H7C1FN (M = 231.653) Calculated value ·· Molecular peak (M + H) +: 232/234 (Cl) Measured value: Molecular peak (M + H) +: 232 / 234 (Cl) HPLC-MS · 5 · 8 minutes (Method B) · 7-14e Κ (Ε) -3- {4- [5- (4- · phenylphenyl) -3-fluoro-eridine-2- Ethynyl] -phenyl} -p-propyl) -4-methyl-hexazine-4-ol. According to General Working Method I, 200 mg (0.556 mmol) 1-[( e) -3- (4_ mothphenyl) -allyl] -4-methyl-hexahydrobenzyl-4-ol with 130 mg (0.56 mmol) 5- (4-aminophenyl) -2-Ethynyl-3-fluoro-E-bite (with Pd (dppf) Cl2 as the catalyst, triethylamine as the base, and THF as the solvent). Yield: 55 mg (21% of theory) 8 6 C1FN2 Ο (M = 460.970) Calculated value: molecular peak (M + H) +: 461/463 (Cl) found. · Molecular peak (M + H) — : 461/463 (Cl) Retention time HPLC: 5.6 minutes (Method D). 100779 -134- 200538102 Example 7.15 5- (4-Gaphenyl) -3-fluoroyl-2- {4- [ (E) -3- (4-methyl-hexahydropyridin-1-yl) _propene

Phenyl] -phenyl-ethynylpyridine according to General Working Method I, 200 mg (0.59 mmol) 1-[(e) _3- (4-iodophenyl) -allyl] -4-methyl -Hexahydropyridine and 136 mg (0.59 mmol) 5- (4-Gaphenyl) -2-ethynyl-3-fluoropyridine (with Pd (dppf) Cl2 as catalyst, triethylamine As the base and THF as the solvent). Yield: 40 mg (15% of theory) C28H26C1FN2 (M = 444.971) Calculated value: Molecular peak (M + H) +: 445/447 (Cl) Measured value: Molecular peak (M + H) +: 445/447 (Cl) Retention time HPLC: 6.0 minutes (Method D) · Example 8 (E) -5- (4-Gaphenyl) -2- {4_ [2-methyl-3- (4-methyl- Hexahydrogen ρ ratio. Ding-1 · yl) _propenylbenzylethynyl} -external 1:

2- (4-bromophenylethynyl) -5_ (4-phenyl) -pyridine according to General Method I, prepared from 4-bromo-dehydrobenzene (566 mg, 2.00 mmol) and 100779 -135- 200538102 5- (4-Gaphenyl) · 2-ethynyl-pyridine (460 mg, 2.00 mmol). Yield: 600 mg (81.4% of theory) q 9 Η !! BrCIN (M = 368.654) Calculated value: Molecular peak (M + H) +: 368/370/372 (BrCl) Measured value: Molecular peak (M + H) +: 368/370/372 (BrCl)

Rf value: 0.78 (silicone, PE / DCM1: 1) · 8b 5- (4-Gaphenyl) -2- (4-iodophenylethynyl) -pyridine φ According to the general method 11, prepared from 2- (4 -Bromophenylethynyl) -5- (4-nitrophenyl) -pyridine (600 mg, 1-63 mmol). Yield: 500 mg (73.9% of theory) C19HUC1IN (M = 415.655) Calculated value: Molecular peak (M) +: 416/418 (Cl) Measured value: Molecular peak (M) +: 416/418 (Cl) Retention Time HPLC: 7.76 minutes (Method B) · 8c (E) -M4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl p-phenyl 2-methyl · # prop-2 -En-1-ol will be 195 mg (2.70 mmol) 2-fluorenyl-2-propanol, 200 mg (1.2 mmol) silver acetate, 13 mg (0.06 mmol) acetic acid ( I〗) and ηmg (0.12¾ mol) of dibenzyl phosphate burned in an argon atmosphere, and continuously added to ⑻mg (1.20 mol) 5- (4-Gaphenyl) -2- (4_ Ethylethynyl) ratio σ is set in a solution in 20 ml of DMF. The reaction mixture was shaken for 2 days at 75t. An additional 89 mg (0.55 mmol) of 2-fluorenyl-2-propenol was added, and the reaction mixture was stirred at 75 C for another 4 days. After cooling, the reaction solution was diluted with 70 ml of DCM and 30 ml of water. After filtration, the organic phase was dried over MgS04, 100779 -136-% 200538102 and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (PE to PE / EtOAc 7: 3). Yield: 60 mg (13.9% of theory) c2 3 H2〇C1NO (M = 359.85) Calculated value: molecular peak (M + H) +: 360/362 (Cl) Found: molecular peak (M + H) + : 360/362 (Cl) retention time HPLC ··· 6.30 minutes (Method B) · 8d (E) -5- (4-chlorophenyl) -2- {4- [2-methyl-3- ( 4-methyl-hexahydropyridine small group) _-propenyl] -phenylethenyl ratio σ will be 15.0 microliters (0.19 millimoles) vaporized formazan and 30 microliters (0.22 millimoles) (Ear) triethylamine, added to 60.0 mg (0_17 mmol) (E) _3- {4 · [5- (4- · phenylphenyl) -exo-2-ylethoxy] -phenyl} A solution of 2-methyl-propan-2-fluoren-1-ol in 5.0 ml of DCM. The reaction was stirred at room temperature for 4 hours, and an additional 15.0 microliters (0.19 mmol) of vaporized methanesulfonium and 30 microliters (0.22 mmol) of triethylamine were added. The reaction solution was stirred at room temperature for 2 hours, and then 0.50 ml (4,23 mmol) of 4-fluorenylhexahydropyridine was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 30 ml of DCM. The organic phase was washed three times with water, dried over MgS04, and the solvent was removed in vacuo. Further purification by column chromatography on silica gel (DCM to DCM / MeOH / NH3 9: 1: 0.1) 〇 Yield: 10 mg (13.6% of theory) C2 9 9 CIN (M = 440.988) calculation Value: Molecular peak (M + H) +: 441/443 (Cl) Found: Molecular peak (M + H) +: 441/443 (Cl) 100779 -137- 200538102 Heart value: 0.15 (silicone, DCM / MeOH) / NH395: 5: 0.5). Example 8.1 1-((E) -3- {4- [5- (4-chlorophenyl)-? Pyridin-2-ylethynyl] -phenylbenzene 2-methyl -Allyl) -4-methyl-hexazine P ratio sigma-4_ drunk

8.1a 2- [4-((E) -3-Gas-2-methyl · propenyl) phenylethynyl] _5- (4-Gaphenyl) -Ebene 0.27 ml (3.36 mmol) ) Pyridine was added to uo g (306 mmol) (E) -3 · {4- [5- (4-chlorophenyl) · pyridin-2-ylethynyl] • phenyl} _2 · fluorenyl • Propane-2 • Dilute alcohol (Example 8c) in 100 ml of DCM has been cooled to (TC solution, and then 0.25 ml (3.36 mmol) of SOC12 is slowly added dropwise. The reaction solution is allowed to warm to room temperature , And stirred for 1 hour. The mixture was combined with ice water, the organic phase was separated, washed several times with water, and dried over MgS04. After the desiccant and solvent had been removed, the residue was purified by chromatography. (Silicone, PE to DCM 1: 4). Yield: 160 mg (14% of theory). 2 3 H17C12N (M = 378.293) Calculated value: Molecular peak (M + H) +: 378/380 / 382 (2 Cl) Found: Molecular peak (M + H) +: 378/380/382 (2 Cl) Retention time HPLC: 7.9 minutes (Method F). 100779 -138- 200538102 8.1b H (E)- 3- {4- [5- (4-Phenylphenylpyridin-2-ylethynyl] · phenylphenyl 2-methyl-allyl) -4-methyl-hexahydro P ratio σ_4 _ Alcohol will 22 Mg (0.19 mmoles) of 4-methyl-hexahydroetra-4-ol added to 40 mg (0.11 mmoles) of 2- [4-((E) -3-amino-2-methyl) -Propenyl) -phenylethynyl] -5- (4-aminophenyl) -pyridine in a solution of 1 ml of DMF, and the reaction mixture was stirred at 60 ° C for 1 hour. The reaction solution was purified by HPLC No further processing is required. The fractions containing the product are combined and lyophilized. Yield: 20 mg (39% of theory) c2 9 H2 9 C1N2 〇 (M = 457.006) Calculated value: molecular peak (M + Η) +: 457/459 (Cl) Measured molecular peak (M + Η) +: 457/459 (Cl) Retention time HPLC: 7.4 minutes (Method A). The following examples are in each case from 40 Starting from 2-mg 4- [4-((E) -3-amino-2-methyl · propenylphenylethynyl] _5- (4-Gaphenyl) _pyridine, made in a similar way:

100779 -139- 200538102 8.3 OH 丄 34 c30h28cif3n2o 525/527 8.1 minutes ★ [M + H] + (A) Example 8.4 5- (4-Gaphenyl) -3-fluoro-2- {4-[(E ) _2_Methyl-3- (4-methyl-hexahydro p ratio) _propenyl] -phenylethynyl} • pyridine

8.4a (E) -3_ (4-Methenyl) -2-methyl-prop-2-en-1_ol, prepared according to General Experimental Method II, from 1.0 g (4.40 mmol) (E) -3- (4-benzyl). 2-fluorenyl-prop-2-enol. Yield: U grams (91% of theory)

Cl 〇Hi! Ίο (M = 274.098) Calculated: Molecular peak (M) +: 274 Found: Molecular peak (M) +: 274 Retention time HPLC: 5-5 minutes (method B). 8.4b 1-((Ε ) -3-Chloro-2-methyl-propenyl) -4-Ebene Similar to Example 7.12d, made from 1.10 g (4.01 mmol) (E) -3- (4-iodophenyl) · 2-methyl-propan-2-enol and 0.35 ml (4.82 mmol) of SOC12, however, to complete the reaction, the solution was stirred at room temperature overnight. Yield: 1.1 grams (94% of theory)

Ci〇H10CLi (M = 292.544) Calculated: Molecular peak (M) +: 292/294 (Cl) Found: Molecular peak (M) +: 292/294 (Cl) 100779 -140- 200538102 8.4c H (E ) -3_ (4-Linylphenyl) -2-methyl-allyl; μ-methyl-hexahydropyridine Add 0.89 ml (7.52 millimoles) of 4-methyl-hexahydropyridine to 55 mg (1.88 mmol) 1 · ((E) -3-chloro-2-methyl-propenyl) Dongabae-benzene in 5 ml of DMF, and the reaction mixture was stirred at room temperature overnight . Water was added to the reaction solution, extraction was thoroughly performed with EtOAc, and the combined organic phases were dried over MgS04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, gradient PE to PE / EtOAc 4: 1). Yield: 140 mg (21% of theory) ci 6 H2 2 IN (M = 355.257) Calculated value: Molecular peak (M + H) +: 356 Found: Molecular peak (M + H) +: 356 Retention time HPLC : 5.8 minutes (Method A). 8.4d Η4-Gasphenyl) -3-fluoro-2- {4-[(E) -2-methyl-3_ (4-methyl-hexahydroeridine-1) -Yl) -propenyl] -phenylethynylpyridine according to General Working Method I, prepared from 70 mg (0.20 millimolar) of "Phenylminyl" -2-methyl-allyl] icemethyl -Hexahydropyridine and 46 mg (0.20 mmol) 5- (4-phenyl) -2-ethynyl-3-fluoro-eridine (with Pd (dppf) Cl2 as catalyst, three Ethylamine is used as the base and THF is used as the solvent. Yield: 4 mg (4% of theory) c2 9 H2 8 C1FN2 (M = 458.997) Calculated value: Molecular peak (M + H) +: 459/461 (Cl) Measured value: Molecular peak (M + H) +: 459/461 (Cl) Retention time HPLC: 6.2 minutes (Method D). 100779 -141-200538102 Example 8.5 5- (4-methyl-cyclohexenyl) > 2_ {4- [Hydroxymethyl (4-methyl-hexahydropyridine 4-yl) -propenyl] -phenylethoxypyridine

According to General Working Method I, prepared from 70 mg (0.20 mmol) l [(e) _3- (4_ erbenyl) -2-methyl-allyl] dongmethyl-hexahydropyridine With 39 mg (0.20 mmol) 2-ethoxy-5- (4-methyl-cyclohex-1-enyl) -pyridine (using pd (dppocl2 as catalyst, triethylamine As a base and THF as a solvent) Yield 5 mg (6% of theory) C3〇H3 6 N2 (M = 424.620) Differential value: molecular peak (M + H) +: 425 measured value: molecular peak (M + H) +: 425 Retention time HPLC: 6.1 minutes (Method D). Example 8.6 1-((E) -3- {4- [5- (4-Gaphenyl) -3_Fluorine 4-bite- 2-ylethynyl] -phenyl> _2_methyl_ dilute propyl) -4-fluorenyl-hexahydroex 1: bit-4-ol

8.6a H (E) -3- (4-Ephenyl) -2-methyl · fluorenyl] -4 · fluorenyl-hexahydropyridin-4-ol will be 433 mg (3.76 mmol) 4-Amidino-hexahydropyridine_4_alcohol was added to 550 mg (1.88 mmol) of 1-((E) -3-amino-2 · fluorenyl_propyl) ice-carbon-benzene with 0.079 mmol 100779 -142- 200538 102 liters (5.64 mmol) of triethylamine in 5 ml of DMF, and the reaction mixture was stirred at room temperature overnight. It was evaporated to dryness in vacuo, the residue / grain in water 'was thoroughly extracted with EtOAc, the combined organic phases were washed twice with water' and dried over MgS04. After the desiccant and the solvent have been removed, the residue is purified by chromatography (silica gel, gradient solution (入 to ^^ & /] ^ 〇119: 1). Yield: 170 mg (theoretical value) (24%)

Ci 6 H2 2INO (M = 371.256) Calculated: Molecular peak (M + H) +: 372 Found: Molecular peak (M + H) +: 372 · 8.6b Κ (Ε) -3- {4- [5 (4-Gaphenylphenylethynyl) • phenyl} _2_methyl-allyl) _4_methyl-hexahydro p ratio_4_ol According to General Working Method I, prepared from 85 mg (〇 · 23 mmoles) ι _ [(Ε) _3 · (4_ phenylene) -2-methyl-diluted propyl] _4_methyl-hexahydropyridol and 53 mg (0.23 mmoles) 5- (4-chlorophenyl) -2-ethynyl_3-fluoro-fluorene (with Pd (dppf) Cl2 as the catalyst, triethylamine as the base, and THF as the solvent). Yield: 25 mg (23% of theory) 9 H2 8 C1FN2 〇 (M = 474.997) Calculated value: Molecular peak (M + Η) +: 475/477 (Cl) Measured value: Molecular peak (M + H) + : 475/477 (Cl) retention time HPLC: 5-8 minutes (method D). Example 8.7 4-methyl · 1 · ((Ε) _2-methyl-3- {4- [5- (4-methyl- Cyclohexylalkenyl) -pyridinylethoxy] -phenyl} -diluted propyl) -hexazine. Definition-4-Sf *

100779 -143- 200538102

Prepared from 85 mg (0.23 mmol) of 1-[(Ε) -3- (4-phenylphenyl) -2-methyl-allyl] -4-methyl-hexahydro according to General Working Method I Emei-4-ol and 45 mg (0.23 mol) 2-Ethyl-5- (4-methyl-cyclohex-1-diyl) _? Bier (as a catalyst, triethylamine As the base and THF as the solvent). Yield: 7 mg (7% of theory) C3〇H36N20 (M = 440.620) Calculated value: Molecular peak (M + H) +: 441 Found: Molecular peak (m + h) +: 441 Retention time HPLC: 5 · 7 minutes (Method D) · Example 9 5- (4-chlorophenyl) -2- {4- [2-methyl-2- (4-methyl-hexahydropyridine small group) _propoxy] _Phenyl ethyl block

Ό "9a 2-methyl orthomethyl hexahydroazetidine · 1-yl) -ethyl propionate 3.72 ml (25.0 mmol) 2-methyl 2-methyl-propionate The solution in 40 ml of 4-methylhexahydropyridine was stirred at 70 t overnight, and then the solvent was removed in vacuo. The residue was dissolved in water and water. & The organic phase was dried with dehydration, and the solvent was removed in vacuo. The crude product was reacted further without any further purification. 100779 -144- 200538102 Yield: 3.00 g (56.3% of theory)

Ci2H23N02 (M = 213.317) Calculated ·· Molecular peak (M + H) +: 214 Found: Molecular peak / GC-MS (M + H) +: 214 Retention time HPLC: 3.87 minutes (Method A). 9b 2 -Fluorenyl-2- (4-methyl-hexahydropyridin-1-yl) -propanol. 9.20 ml (9.20 mmol) of a 1 M lithium aluminum hydride solution in THF, Add dropwise to 3.00 g (9.14 millimoles) of 2-methyl-2- (4-fluorenyl-hexahydroxanthine. A solution of ethyl-1-ylpropanoate in 20 ml of THF. The reaction solution Heat to 50 ° C and stir overnight. After cooling, it is diluted with ice water and the aqueous phase is extracted with ether. The organic phase is dried over MgS04 and the solvent is removed in vacuo. The crude product is further The reaction was carried out without any further purification. Yield: Z02 g (71.0% of theory; content 55%)

Ci〇H21NO (M = 171.280) Calculated: Molecular peak (M + H) +: 172 Found: Molecular peak (M + H) +: 172 Retention time HPLC: 1.88 minutes (Method A). 9〇 ^ [以4-iodo-phenoxyb 1,1-dimethyl-ethyl] _4_methyl-hexahydropyridine will be 700 grams (3.18 mol) 4_Epan with 1.25 grams (4/77 Millimolar) triphenylphosphine, added to 1.00 g (3.21 millimolar; 55% content) of 2-methyl winter (4 • methyl_7hydropyridyl) -propanol in 20 ml of DCM Inside. While cooling 2, slowly add 1.00 ml (4.79 mmol) of DIAD. The reaction mixture was stirred at room temperature for 2 hours. Water was added, the organic phase was separated, extracted twice with water, the combined organic phases were dried over MgS04 and the solvent was removed in vacuo. 100779 -145- 200538102 Further purification was performed by column chromatography on silica (EtoAc). Yield 1.85 g (84.9% of theory; content 55%)

Ci 6 H2 4INO (M = 373.272) Differential value: molecular peak (M) +: 373 found: molecular peak (M) h 373 retention time HPLC: 6.09 minutes (method A), 9d 5- (4-chlorobenzene W4_ [2 · methyl-2_ (4-methyl-hexahydropyridine_i-yl) _propoxy] -phenylethoxy}} ratio.

Prepared from 1- [2- (4 • moth-phenoxy) -ΐ, ι-dimethyl · ethyl] icel-hexahydropyridine (200 mg, 0.54 mmol) and 5- (4-Gaphenyl) -2-ethynyl-eridine (110 mg, 0.50 mmol). Yield: 25 mg (10.1% of theory) C2 9 H3! C1N2 〇 (M = 459.022) Calculated value: Molecular peak (M + Η) +: 459/461 (Cl) Measured value: Molecular peak (M + Η) +: 459/461 (Cl) retention time HPLC ·· 5.7 minutes (Method A). Example 10 5- (4-Gasphenyl) -2- [4- (1-tetrahydropyrrole-1-yl-cyclopropane) Fluorenyloxy) _phenylethynyl] -pyridine

l〇a 1- (4-E-phenoxyfluorenyl) -cyclopropylamine 100779 -146- 200538102 While cooling with ice / isopropanol, 22.1 ml (72.7 mmol) of titanium isopropoxide ( IV) Add dropwise to a solution of 13.8 g (65.1 millimoles χ4- moth-phenoxy) -acetonitrile in 250 ml of ether. Then, at 0. A solution of 43.4 ml (130 mmol) of 3 M methyl magnesium bromide in diethyl ether was added dropwise. The reaction mixture was stirred for 30 minutes. Then, 16.5 ml (130 mmol) of boron trifluoride-ether complex was quickly added. The reaction mixture was stirred for 30 minutes, and then, while cooling with ice, 200 ml of a 1M sodium hydroxide solution was added. After one hour, the aqueous phase was extracted with 300 ml of ether. The organic phase was dried over Na2SO4 and the solvent was reduced to 400 ml in vacuo. The organic phase was washed with 180 ml of a saturated NajO3 solution and twice with 400 ml of a 0.05 M hydrochloric acid solution. The aqueous phase was made alkaline with a 30% sodium hydroxide solution, and the organic extract was extracted and dried with MgS04 in 4 ml of dcm, and removed in a vacuum. The crude product was reacted further without any further purification. Yield: 7.67 grams (48.7% of theory)

Ci〇H12BrNO (M = 242.112) Calculated: Molecular peak (M + H) +: 242/244 (Br) Measured value ·· Molecular peak (M + H) +: 242/244 (Br) Retention time HPLC: 4.96 Minutes (Method A). 10b 1- [1- (4- > Odoryl-benzyloxymethyl) -cyclopropyl] -tetrahydrop-bilolide 0.50 ml 1,4-dibromobutane With U4 g (8.26 mmol) k2C03 was added to a solution of 1.00 g (4.13 mmol) of 1- (4-iodo-phenoxymethyl) -cyclopropylamine in 50 ml of DMF. The reaction mixture was stirred at 80 ° C. for 24 hours. The solvent was removed in vacuo and the residue was combined with 100 ml of water and 200 ml of EtOAc. The organic phase was separated, dried over Na2SO4, and the solvent was removed in vacuum 100779-147-200538102. The crude product was reacted further without any further purification. Yield: 1.33 g (108.6% of theory) 〇! 4 Hi 8 BrNO (M = 296.203) Calculated value: Molecular peak (M + H) +: 296/298 (Br) Found: Molecular peak (M + Η) +: 296/298 (Βγ) retention time HPLC: 6.03 minutes (Method A).

10c E-phenoxyfluorenyl) -cyclopropyl] -tetrahydroekou, each prepared from 1- [1- (4-bromo-phenoxymethyl) _cyclopropyl] -tetrahedron according to General Method II Hydropyrrole (1.22 g, 4.12 mmol). Yield: 473 mg (33.5% of theory) 4 g ΓΝΟ (Μ = 343.209) Calculated value: Molecular peak (M + Η) +: 344 Found: Molecular peak (M + Η) +: 344 Retention time HPLC: 6.17 minutes (Method A) · 10d 5- (4-Gaphenyl) -2- [4- (l-tetrahydropyrrole small group-cyclopropylmethoxy) -phenylethoxy] -ρ ratio according to the general Method I, prepared from 1- [1- (4-Anglo-phenoxymethyl) -cyclopropyl] -tetrahydroerrole (100 mg, 0.29 mmol) and 5- (4-phenyl) -2-Ethynylpyridine (78 mg, 0.36 mmol). Yield: 15 mg (12.0% of theory) c2 7 H25C1N20 (M = 428.953) Calculated value: Molecular peak (M + H) + ·· 429/431 (Cl) Measured value: Molecular peak (M + H) +: 429/431 (Cl) retention time HPLC: 8 · 28 minutes (Method A). 100779 -148- 200538102 Example 11.1 (R) -5- (4-chlorophenyl) -2- {4- [2- (4 -Methyl · hexahydropyridine small group > propoxy] _phenylethynyl

11-la (R) -2- [2- (4-Et-phenoxy) -1-methyl-ethyl] _isopropane_ι, 3_dione in a nitrogen atmosphere, 40 ml of THF 5.40 g (26.3 mmol) of (R) -2- (2-Cyclo_1-methyl-ethyl) -isoxindole 4,3_dione, added to 8.8 g (3 (00mmol)) 4-Homophenol and 10.5 g (4.0 mmol) of triphenylphosphine in 180 ml of THF. The reaction solution was cooled to 0. 0, and 7.93 liters (40.0 mmol) of DIAD in 20 ml of thF was added, the ice bath was removed, and the mixture was stirred at room temperature overnight. An additional 10.5 g (40.0 mmol) of triphenylphosphine and 60 ml (30.3 mmol) of DIAD were added, and the mixture was stirred for another 4 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was washed twice with a half-saturated Na2co3 solution, dried over MgS04, and the solvent was removed in vacuo. The residue was combined with TBME and DIPE. After filtration, the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (pE / EtoAc 9 · 1 to PE / EtOAc 6: 4). The residue was dissolved in EtOAc, washed twice with 1] y [sodium hydroxide solution, the organic phase was dried over MgS04, and the solvent was removed in vacuo. Yield: 6.60 g (61.60 / theoretical value) ci 7 Hi 4 IN〇3 (M = 407.202) 100779 -149- 200538102 Calculated value: molecular peak (M + H) +: 408 found: molecular peak (M + H) +: 408 Retention time HPLC: 6.41 minutes (Method B) · lUb ⑻-2- (2- {4_ [5_ (4-chlorophenyl) -pyridin-2-ylethynyl] -phenoxy } _I_methyl-ethyl) -iso-1-hexyl-1,3-difluorene, prepared according to General Method I from (R) -2- [2- (4-iodo · phenoxy) -1-fluorenyl -Ethyl] -isoindole-1,3-dione (1.00 g, 2.46 mmol) and 5- (4-Gaphenyl) -2-ethynyl-eridine (643 mg, 2.80 mmol) ). Yield: 700 mg (57.8% of theory) ^ 3 〇H21C1N2 〇3 (M = 492.952) Calculated value: Molecular peak (M + H) +: 493/495 (Cl) Measured value: Molecular peak (M + H) +: 493/495 (Cl)

Rf value: 0.60 (silicone, PE / EtOAc 6: 4). 11-lc (R) -2- {4- [5- (4-Gaphenyl) -pyridine_2_ylethynyl] -phenoxy} Small methyl-ethylamine 3.0 ml of methylamine (40% in water) was added to 700 mg (1.42 mmol) (R) -2- (2- {4-〇 (4-Gabenzene Group) ^ pyridin_2_ylethynyl group> phenoxyfluorenylethyl) -isopyrene-1,3-dione in 3.0 ml of toluene, and the reaction solution was stirred overnight. The reaction mixture was combined with 80 ml of DCM, extracted twice with water 'and dried over MgS04, and the solvent was removed in vacuo. The residue was stirred with TBME, and after filtering, it was dried in air. Only part of the number is opened. Therefore, the residue was combined with 50 ml of 40% methylamine and 50 ml of toluene, and stirred at 60 ° C for 3 days in a sealed container. The reaction mixture was diluted with 120 liters of DCM. The organic phase was extracted three times with water, dried over MgS04, and the solvent was removed in vacuo. The residue was stirred with tbme 100779 -150- 200538102 and EtOAc-and after the transition, dried in air. Yield: 250 mg (48.5% of theory) C2 2 Hi 9 C1N2 〇 (M = 362.852) Calculated value: Molecular peak (M + Η) +: 363/365 (Cl) Measured value: Molecular peak (M + Η) +: 363/365 (Cl)

Rf value: 0.08 (silicone, DCM / MeOH9: 1). Ll.ld (R) -5- (4-Gaphenyl) -2- {4- [2- (4-methyl-hexahydropyridine small ) -Propoxy] -phenylethynylpyridine will be 61 _0 g (0.25 mol) 1,5-diaphthyl-3-methylpentanol and 75.0 mg (0.54 mmol) K2C03, Add to 80.0 mg (0.22 mmol) (R) _2- {4- [5- (4-Gaphenyl) -Exo-1: hydradin-2-ylethoxy] -phenoxy} -ΐ · A solution of methyl-ethylamine in 2000 ml of DMF. The mixture was shaken at 50 ° C overnight. After cooling, a precipitate formed, which was combined with some water. After filtration, the mixture was washed with water and iso-propanol. Further purification was performed by column chromatography on Shixi gum (DCM / MeOH / NH39: 1: 0.1) 〇 Yield: 24 mg (25.0% of theory) C2 8 H2 9 C1N2 0 (M = 444.995) calculation Value: Molecular peak (M + Η) +: 445/447 (Cl) Found: Molecular peak (M + H) +: 445/447 (Cl)

Rf value: 0.12 (silicone, DCM / MeOH / NH395: 5: 0.5) · Examples 11.2 and 11.3 11.2: (R)-(2- {4- [5- (4-Gaphenyl group fluoren-2-ylethyl Fastyl] -phenoxyfluorenyl-ethyl) -cyclopropylmethyl-amine

100779 -151-200538102

11 · 3: (RH2- {4- [5- (4 · chlorophenyl) -pyridin-2-ylethynyl] -phenoxy} -ΐ-methyl-ethyl) -bis-cyclopropylmethyl Yl-amine

11_2 and 11.3 190 mg (0.52 millimoles) of (R) -2_ {4- [5- (4-_phenylphenylpyridin-2-ylethynyl] -phenoxy} berberyl-ethylamine with A solution of 0.06 ml (0.80 mmol) of cyclopropane benzaldehyde in 75 ml of THF was stirred at room temperature for 1 hour. Then, 339 mg (1.60 mmol) of NaBH (OAc) 3 and 0 · were added. 〇1 ml (0. 25 mmol) glacial acetic acid. The reaction mixture was stirred at room temperature for 2 hours. A portion of the solvent was removed in vacuo and the residue was diluted with 50 ml of EtOAc and 30 ml of saturated NaHC03 solution. The organic phase was extracted with water, dried over MgS04, and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM to DCM / MeOH / NH39: 1: 0.1). The dissolved fractions were evaporated to dryness, and the individual residues were triturated with TBME and DIPE, and dried in the air after the transition. 11.2: (R)-(2- {4- [5- (4-Gaphenyl) _ Pyridine_2_ylethynyl] _phenoxy} _μmethyl-ethyl) _cyclopropylmethyl-amine 100779 -152- 200538102 Yield: 27 mg (12.4% of theory) c2 6 H2 5 C1N2 ο (Μ = 416.942) Calculated: Molecular peak Μ + Η) +: 417/419 (Cl) Found: molecular peak (Μ + Η) +: 417/419 (Cl)

Rf value: 0.56 (silicone, DCM / MeOH / NH39: 1: 〇 · 1) · 11_3: (R)-(2- {4- [5- (4-chlorophenyl) -outer b ° Ding-2- Ethynyl] -phenoxy} -1-methyl-ethyl) -bis-cyclopropylmethyl-amine: Yield: 58 mg (23.5% of theory) C3 〇H31C1N2 〇 (M = 471.033) calculation Value: Molecular peak (M + Η) +: 471/473 (Cl) Found: Molecular peak (M + Η) +: 471/473 (Cl)

Rf value: 0.87 (silicone, DCM / MeOH / NH39: 1: 0.1) · Example 12.1 (S) -5- (4-chlorophenyl) -2- {4- [2- (4-methyl -Hexahydroρ than fluoren-1-yl) -propoxy] -phenylethynylpyridine

12_la (S) _2- [2- (4-^ _ phenoxy) _1 · methyl · ethyl] -iso4 丨 h-i, 3-difluorene is similar to 11.1a, and the product is obtained from 6.30 g (30.7 Millimolar) (S) -2- (2-hydroxy-1-methyl-ethyl) -isoearmole-1,3-dione, 7.04 g (32.0 millimolar) 4-iodophenol, 23.6 g (90.0 mmol) triphenylphosphine and 17.8 ml (90.0 mmol) DIAD. Yield: 2.50 grams (20.0% of theory)

(D 100779-153-200538102 C17H14IN〇3 (M = 407.202) Calculated value · Molecular peak (M + H) +: 408 Found: Molecular peak (m + H) + · 408 Retention time HPLC: 6.41 minutes ( Method B) · 12.1b (S) -2_ (2- {4- [5- (4-Gaphenyl) _pyridine_2_ylethynyl] -phenoxy} -ΐ · methyl-ethyl) -Isbutol-1,3-di_ According to General Method I, (R) -2_ [2- (4-iodo-phenoxy) -1-methyl-ethyl]. , 3-diketone (2.50 g, 6.14 mmol) and 5- (4-phenyl)> 2-ethynyl-pyridine (1-49 g, 6.50 mmol). Yield: 1.30 g (43.0% of theory) ) c3 〇H2! C1N2 〇3 (M = 492.952) Calculated value: molecular peak (M + H) +: 493/495 (Cl) Found: molecular peak (M + H) +: 493/495 (Cl) retention Time HPLC: 7.18 minutes (Method a). 12, lc (S) _2- {4X4-Gaphenyl) · pyridin-2-ylethynyl] • phenoxyb 1-methyl-ethylamine is similar to 11.1c, The product was obtained from U0 g (2.64 mmol) of water (s) _2_ (2 · {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] _phenoxy} _ 丨 -methyl_ethyl) _isoindole · 1,3-dione and 6 ml of 40% methylamine solution. Yield: 650 milligrams (67.9% of theory) C2 2 9 C1N2 〇 (M = 362.852) Calculated value: molecular peak (M + Η) +: 363/365 (Cl) Measured value: molecular peak (M + H) +: 363/365 (Cl) Retention time HPLC: 4.87 minutes (Method B). 100779 -154- 200538102 12.1d (s) -5- (4-Gaphenyl) -2- {4- [2- (4-methyl-hexa The hydrogen p ratio is 1-yl) · propoxy] -phenylethynyl} -pyridine is similar to ll.ld 'product was obtained from 100 mg (.28 mol) (s) -2- { 4- [5- (4_chlorobenzyl) -p than σd_2_2ylethoxy] -phenoxy} small methyl-ethylamine with% mg (0.31 mol) Methyl-3-methylfluorene. Yield: 20 mg (16.3% of theory) C2 8 H2 9 C1N2 〇 (M = 444.995)

Calculated: Molecular peak (M + Η) +: 445/447 (Cl) Measured value: Molecular peak (M + Η) + ·· 445/447 (Cl)

Rf value: 0.48 (silicone, DCM / MeOH / NH39: 1: 0.1) · Example 12.2 and 12.3 12.2:

12.3: (S)-(2- {4- [5- (4-Gaphenylphenylpyridin-2-ylethynyl] -phenoxy} micromethyl-ethyl) -cyclopropylmethyl-amine

(S)-(2- {4- [5- (4-chlorophenyl ratio sigma-2-ylethynyl] -phenoxy} -1-methyl-ethyl) -bis-¾propylfluorene Yl-amine

12.2 with 12.3 100779 -155- 200538102 will be 290 mg (0.80 mmol) (S) _2- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenoxy} small A solution of methyl-ethylamine and 0.09 ml (1.20 mmol) of cyclopropanecarboxaldehyde in 75 ml of THF was stirred at room temperature for 1 hour. Then, 509 mg (2.40 mmol) of NaBH (OAc) 3 and 0.02 ml (0-40 mmol) of glacial acetic acid were added. The reaction mixture was stirred at room temperature for 2 hours. Part of the solvent was removed in vacuo and the residue was diluted with 50 ml of EtOAc and 30 ml of a saturated NaHC03 solution. The organic phase was washed with water, dried over MgS04, and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM to DCM / MeOH / NH3 9: 1: 0.1). The desired fractions were evaporated to dryness and the individual residues were triturated with TBME and filtered and dried in air. 12.2: (S) _ (2- {4- [5_ (4-chlorophenyl) -pyridin-2-ylethynyl] -phenoxy} small methyl-ethyl) -¾propylmethyl-amine Yield: 56 mg (16.8% of theory) C2 6 H2 5 C1N2 〇 (M = 416.942) Calculated value: Molecular peak (M + Η) +: 417/419 (Cl) Measured value: Molecular peak (M + Η) +: 417/419 (Cl)

Rf value: 0.48 (silicone, DCM / MeOH / NH39: 1: 0.1) · 12.3: (S)-(2- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -Phenoxy} small methyl-ethyl) -bis-cyclopropylmethyl_amine Yield: 32 mg (9.0% of theory) C30H3iC1N20 (M = 471.033) Calculated value: Molecular peak (M + H ) +: 471/473 (Cl) found. · Molecular peak (M + H) +: 471/473 (C1)

Rf value: 0.82 (silicone, DCM / MeOH / NH39: 1: 0.1). 100779 -156- 200538102 Example 13 (R) -5- (4-Gaphenyl) _2- {4- [3-methyl-2 -(4-methyl-hexahydropyridin-1-yl) -butoxy] -phenylethoxy

13a (R) -3-methyl-2- (4-methyl-hexahydropyridine small group) -butyrol will be 1.32 g (5.40 mmol) 1,5-dibromo · 3-methylpentyl Alkane and 1.55 g (11.2 mmol) of K2C03 were added to a solution of 0.50 g (4.85 mmol) of R-(-)-2-amino-3-methyl-1-butanol in 10 ml of DMF. The reaction mixture was stirred at 50 ° C overnight. After cooling, it was diluted with 50 ml of EtOAc and the bars were washed three times with a half-saturated NaHC03 solution. The organic phase was dried over MgS04 and the solvent was removed in vacuo. The residue was filtered through a silica gel bed (DCM to DCM / MeOH 8: 2). Yield: 350 mg (39.0% of theory)

CnH23NO (M = 185.306) Calculated value · Molecular peak (M + H) +: 186 Measured value: Molecular peak (M + H) + · 186 Rf value: 0_30 (silicone, DCM / MeOH9: 1). 13b ( R) -HH4 · Mo-phenoxymethyl) _2 · methyl-propyl] Hydroxymethyl-hexahydro will be 0.54 g (1.90 mol) 4-mo-broken, 1 24 g (3.80 Mol) CsfO3, 68.0 mg (0.38 mol) 1,10-diazephene and 36 mg (〇19 mmol 100779 -157- 200538102 mol) Cul, added to 0.35 g (1.89 mmol) Ear) (R) _3_methyl winter (4-methyl-hexahydroemen-1-yl) -but-1-ol in 3.0 ml of toluene. The reaction mixture was shaken at 110 ° C for 36 hours. After cooling, it was diluted 'with 40 ml of EtoAc and washed twice with 30 ml of water. The organic phase was dried over MgS04 and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM to DCM / MeOH 9: 1). Yield: 100 mg (16.0% of theory) C! 7 H2 6 BrNO (M = 340.298) Calculated value: Molecular peak (M + H) +: 340/342 (Br) Measured value: Molecular peak (M + H) +: 340/342 (Br) retention time HPLC: 4.93 minutes (Method B). 13c (R) -HH4-E-phenoxymethyl) -2-methyl · propyl] -4-methyl-hexa Hydropyridine was prepared from (R) minor [1- (4-bromophenoxymethyl)> 2-fluorenyl-propyl> 4-methyl-hexahydropyridine (0.10 g, 〇29mmol). Yield: 60 mg (53.0% of theory)

Ci7H26INO (M = 387.299) Calculated: Molecular peak (M + H) +: 388 Found: Molecular peak (m + H) +: 388 Retention time HPLC: 7.54 minutes (Method A). 13d (R)- 5- (4_Gaphenyl) -2- {4- [3-methyl-2_ (4-methyl-hexahydroπ ratio σ-i-yl) · butoxy] -phenylethynyl} -Pyridine according to General Method I, prepared from (R) -l-〇 (4-iodo-phenoxymethyl) -2-methyl-propyl] < methyl-hexahydropyridine (60.0 mg, 〇 · 16 mmol) and 5- (4-aminophenyl) -2-ethynyl-pyridine (35.6 mg, 0.16 mmol). 100779

(D -158- 200538102 Yield: 4.5 mg (6.0% of theory, content: 50% per minute) c3 〇H3 3 C1N2 〇 (M = 473.049) Calculated value · Molecular peak (M + Η) +: 473 / 475 (Cl) Found: Molecular peak (M + H) +: 473/475 (Cl) Retention time HPLC: 9.65 minutes (Method A) · Example 14 (S) -5_ (4-chlorophenyl) -2 -{4- [3-methyl-2- (4-methyl-hexahydropyridin-1-yl) -butoxy] -phenylethynyl} -pyridine

14a (S) -3-methyl-2_ (4 · methyl-hexahydro p-ratio πden-1-yl) -butane; [_ alcohol is similar 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) of 1,5-dibromo-3-methylpentane, 3.10 g (22.4 mmol) (Ear) K2C03 and 20 ml DMF. Yield · 2.20 g (98.0% of theoretical value, 80%)

CnH23NO (M = 185.306) Calculated: Molecular peak (M + H) +: 186 Found: Molecular peak (M + H) +: ι86 Rf value: 0.30 (silicone, DCM / MeOH9: 1) · 14b (SW- fX4-mo-phenoxymethyl) _2_methyl-propyl] _4_methyl_hexahydropyridine is similar to 13b, and the product is obtained from 1.1 g (4.75 mmol, 80% XS) each Methyl · (4- 100779 -159- 200538102) Methyl-hexahydropyridin-1-yl) -but-1-ol, 1.34 g (4.75 mmol) 4-bromo-iodophenol, 3.10 g (9.50 millimolar) Cs2C03, 0.17 grams (0.95 millimolar) of 1,10-diazephenanthrene, 0.09 grams (0.48 millimolar) of Cul and 10 ml of toluene. Yield: 0.15 g (9.0% of theory)

Ci 7 H2 6 BrNO (M = 340.298) Calculated: Molecular peak (M + H) +: 340/342 (Br) Found: Molecular peak (M + H) +: 340/342 (Bι〇 Retention time HPLC: 7.4 minutes (Method A). 14c (S) -H1_ (4-Po · phenoxymethyl) -2-methyl-propyl] -4-methyl-hexahydrogen is determined according to General Method II, Manufactured from (S) -l- [l- (4- Mo-phenoxymethyl) _2-fluorenyl-propylmethyl-hexahydropyridine (0.5 g, 0.44 mol). Yield : 0.10 g (59.0% of theory)

Ci7H26INO (M = 387.299) Calculated: Molecular peak (M + H) +: 388 Found: Molecular peak (m + H) +: 388 Retention time HPLC ·· 4.96 minutes (Method D). 14d (S) -5 -(4-Gasphenyl) -2 · {4- [3_methyl · 2- (4-fluorenyl-hexahydrop-pyridyl) · butoxy] -phenylethynylpyridine according to the general method I, produced from (S) -l- [l- (4 · iodine-phenoxymethyl) -2_methyl · propyl] methyl-hexahydropyridine (100 mg, 0.26 mmol) and 5- (4-Anaphthyl) _2_ethynylpyridine (61.0 mg, 0.28 mmol). Yield: 20.0 mg (13.0% of theoretical value, 80%) c3 〇 H3 3 C1N2 ο (M = 473.049) Calculated value: molecular peak (M + Η) +: 473/475 (Cl)

100779 -160 · 200538102 Found: Molecular peak (M + H) +: 473/475 (Cl) Retention time HPLC ···· 1 minute (Method D) · Example 15.1 (E)-(R) -3_ {4_ [5- (4-Chlorophenyl) -pyridine_2_ylethynyl] -phenylbut 1-methyl_but-2-

15.1a [(E)-(R) _3- (4-Bromophenyl) -1-methyl-but-2-fluorenyl] -aminocarboxylic acid tertiary alkenylamine at room temperature in 20 minutes 27.7 ml (27.7 millimoles, i M in n-hexane) of a bell-bis- (trimethylsilyl) _amine solution was added dropwise to 14.6 grams (27.7 millimoles ^-( Winter Molybdenyl) _ethyl] triphenylmolybdenum scale in a suspension of 250 ml of ether while cooling gently with water. The mixture was stirred for 4 hours and cooled to (TC. Dropwise addition 4 A solution of 80 g (27 7 millimoles-2-one-ethyl) -carbamic acid tertiary-butyl ester in 50 ml of ether. The mixture was stirred at room temperature for another 20 hours. After The diatomite transition reaction mixture was removed in vacuo. The residue was purified by gravity: gel column (cyclohexane / EtOAc 4: 1). Low yield: 1.90 g (20.1% of theory)

Ci 6 H2 2 ΒγΝ02 (M = 340.255) Calculated value: Molecular peak (Μ + Η) +: 340/342 (Br) 100779 -161-200538102 Found: Molecular peak (M + H) +: 340/342 (Βι 〇Rf value: 0.56 (silicone, cyclohexane / EtOAc 4: 1). 15.1b [(E)-(R) _3- (4-iodophenyl) -1_methyl-butylenyl] -aminocarboxylic acid Third-Butyl Ester Prepared from [(E)-(R) -3- (4-bromophenyl) _1-methyl-but-2 · alkenyl l · aminocarboxylic acid according to General Method II Ester (1.90 g, 5.58 mmol). Yield: 1.87 g (86.7% of theory) C16H22IN〇2 (M = 387.256) Calculated value: molecular peak (M + H) + ·· 388 measured value: molecular peak ( M + H) +: 388 Retention time HPLC: 6.71 minutes (Method B) · 15.1c ((E)-(R) _3- {4_ [5- (4-Gaphenyl) -pyridin-2-ylethynyl ] -Phenyl} berberyl-butylenyl) -aminocarboxylic acid tertiary-butyl ester according to General Method I, prepared from [(E)-(R) -3- (4-iodophenyl) _1-methyl -But-2-enyl] -aminocarboxylic acid tertiary-butyl ester (1.87 g, 4.84 mmol) and 5 · (4-phenyl) -2-ethynyl-pyridine (1.35 g, 5.80 millimolar). Yield: 1.36 g (59.4% of theory) C2 9 H2 9 C1N2 〇2 (M = 473.00 6) Calculated: Molecular peak (M + H) +: 473/475 (Cl) Measured value: Molecular peak (M + H) + ·· 473/475 (Cl)

Rf value: 0.09 (silicone, 366 nm, DCM). 15.1d (EMR) -3_ {4 _ [> (4-chlorophenyl) · pyridin-2-ylethynyl] · phenyl} small methyl- Butan-2-diylamine added 6.59 ml of trifluoroacetic acid to 1.36 g (2.87 mmol) ((E)-(R) -3- {4- [5- (4-chlorophenyl) -pyridine- 2-ylethynyl] -phenyl} -l-methyl-but-2-enyl) -amine € 100779-162- 200538102 A solution of tert-butyl carboxylic acid in 70 ml of DCM and the mixture Stir at room temperature for 15 hours. The reaction mixture was tested with 15% sodium hydroxide solution. The organic phase was dried over Na 2 SO 4 and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM / MeOH / NH3 19: 1: 0.1). Yield: 610 mg (57% of theory). C24H21C1N2 (M = 372.890) Calculated value: Molecular peak (M + H) +: 373/375 (Cl) Measured value ·· Molecular peak (M + H) +: 373/375 (Cl)

Rf value: 0.25 (silicone, 366 nm, DCM / MeOH / NH39: 1: 0.1). Example 15.2 (E)-(R-) 5- (4-Gaphenyl) · 2- {4- [1- Methyl-3- (4-methyl-hexahydropyridin-1-yl) -but-alkenyl] -phenylethenyl} -P ratio

58.3 mg (0.38 mmol) of 1,5-dibromo-3-methylpentane and 0.13 ml (0.75 mmol) of ethyl diisopropylamine were added to 700 mg (0.19 mmol) (Mole) (E)-(R) -3- {4- [5- (4-Gaphenyl) -eridine_2_ylethynyl] -phenyl} small methyl_butenylamine Within 1.7 ml of the solution in DMF, the mixture was shaken at 80 ° C for 3.5 hours. The solvent was removed in vacuo. The residue was dissolved in 20 ml of dcm and washed with 1 ml of a half-saturated NaHC03 solution. The organic phase was dried by dehydration and the solvent was removed in vacuo. By column chromatography on silica gel 100779 -163-

200538102

Further purification was performed (DCM / MeOH / NH3 99: 1: 0.1). Stir the residue with DIPE. Yield: 24.4 mg (29% of theory) C3〇H31ClN2 (M = 455.033) Calculated value: Molecular peak (M + H) +: 455/457 (Cl) Found: Molecular peak (M + H) +: 455 / 457 (Cl)

Rf value 0.20 (silicone, DCM / MeOH / NH39: 1: 0.1). Examples 15.3 and 15.4 15.3: ((EHR) _3- {4- [5- (4-Gaphenyl) -pyridin-2-yl Ethynyl] phenyl} small methyl-but-2-enyl) _cyclopropylfluorenyl-amine

15.4: ((E) _ (R) -3- {4- [5_ (4-Gaphenyl) -Eb-2-ylethynyl] -phenylphenyl); ^ methyl-butyl-2-fluorenyl ) -Bis-cyclopropylmethyl-amine

15.3 and 15.4 325 mg (0.87 millimolar) of (E)-(R) -3- {4- [5- (4-Gaphenyl) _egnayiethynyl] -phenyl} berberyl A solution of 2-alkenylamine and 0.07 ml (0.87 mmol) of cyclopropanecarboxaldehyde in 25 ml of TtiF was stirred at room temperature for 1 hour. After 100779 • 164-200538102, 739 mg (3.49 mmol) of NaBH (OAc) 3 and 0.20 ml (3 49 mmol) of glacial acetic acid were added. The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo and the residue was diluted with 50 ml of EtOAc and 30 ml of a half-saturated & 03 solution. The organic phase was dried over NaaSO4 and the solvent was removed in vacuo. Further purification was carried out by column chromatography on silica gel (DCM / MeOH / NH319: 1: 0.1). The desired fractions were evaporated to dryness and the individual residues were triturated with DIPE and, after filtration, dried in air. φ 15,3: ((EHR) -H4- [5_ (4-chlorophenylpyridinylethynyl; I-phenyl} small methyl-but-2-fluorenyl) -cyclopropylmethylamine 190 mg (51% of theory) 8 7 CIN2 (M = 426.980) Calculated: Molecular peak (M + H) +: 427/429 (Cl) Measured value: Molecular peak (M + H) +: 427/429 (Cl)

Rf value: 0.56 (silicone, DCM / MeOH / NH319: 1: 0.1). 15.4 · ((E) -⑻_3- {4- [5- (4-Gaphenylphenyl-bite-2_ylethynyl)] -Phenyl} -1-methyl • butyl-but-2-enyl) -bis-cyclopropylmethyl-amine Yield: 11.6 mg (3% of theory) C3 2 Η3 3 CIN2 (M = 481.071) calculation Value: Molecular peak (M + H) +: 481/483 (Cl) Found: Molecular peak (M + H) +: 481/483 (C1)

Rf value 0.83 (silicone, DCM / MeOH / NH319: 1 · 0.1). Example 15 · 5 ((EKR) -3_ {4- [5- (4-chlorophenyl) -pyridin-2-ylacetylene Group] -phenyl} small methyl H alkenyl) -cyclopropylmethyl-propyl-amine 100779 -165- 200538102

Add 0.06 ml (0.70 mmol) of bromopropane and 0.13 ml (0.74 mmol) of ethyldiisopropylamine 'to 75.0 mg (0.18 mmol) ((E) _ (r) _3- {4-

A solution of? -methylmethyl-amine in L5 ml of DMF was shaken at 60 ° C for 22 hours. The reaction mixture was purified by preparative HPLC-MS. The corresponding fractions were evaporated to dryness in vacuo and combined with 10 ml of a half-saturated NaHC03 solution and 20 ml of DCM. The organic phase was dried over N ^ SO4 and the solvent was removed in vacuo. Further purification was carried out by stirring with DIPE. Yield: 10.0 mg (12% of theory) C31H33C1N2 (M = 469.060) Calculated value: Molecular peak (M + H) +: 469/471 (Cl) • Measured value: Molecular peak (M + H) +: 469 / 471 (Cl) HPLC retention time: 9.15 minutes (Method A). Example 15.6 (E)-(R) -5- (4-chlorophenyl) -2- [4_ (1-methyl-3-tetrahydropyrrole ] _Yl · butenyl) _phenylethynyl] -pyridine

100779 -166- 200538102 Add 0.09 liters (0.75 mol) of 1,4-diamobutene and 0.3 ml (0.75 mmol) of ethyl diisopropylamine to 70.0 Mg (0.19 millimoles xE) _ (R) _3_ {4- [5 · (4-Gaphenyl) -pyridin-2-ylethynyl] • phenylmethyl-butenylamine in 1.7 ml Solution in DMF, and at 60. Shake at 3.5 ° C for 3.5 hours. The reaction mixture was combined with 20 ml of half-saturated NaHC03 solution and 30 ml of EtOAc. The organic phase was dried over NaSO4 and the solvent was removed in vacuo. Further purification was performed by column chromatography on stone gum (DCM / MeOH / NH319: 1: 0.1). Evaporate the desired solvent and mix with PE. Yield: 11.7 mg (15% of theory) C2 8 7 C1N〗 (M = 426.980) Calculated value: Molecular peak (M + Η) +: 427/429 (Cl) Measured value: Molecular peak (M + H ) +: 427/429 (Cl)

Rf value: 0.32 (silicone, 366 nm, DCM / MeOH / NH39: 1: 0.1) Example 16.1 (E)-(S) _3- {4- [5- (4-Gaphenyl) -pyridine-2- Ethynyl] -phenylb-l-fluorenyl-but-2-enylamine

16.1a [(E) _ (S) -3- (4-Methenyl) -fluorene-fluorenyl-but-2-enyl] -aminocarboxylic acid tert-butyl ester 54.0 ml (54.0 mmol Moore, 1 M, in THF) Lithium-bis- (trimethylsilicon 100779 -167- 200538102 carbyl) -amine solution was slowly added dropwise to 28 4 g of ammonium ethoxylate)- Ethyl] -triphenyl-bromide scale was suspended in 500 ml of ether while cooling with ice. The mixture was stirred for another 3 hours. A solution of 949 g (548 pen moles) of ((S) -l-methyl-2-keto-ethyl) · aminocarbamic acid tert-butyl ester in 1 ml of diethyl ether was added dropwise. The mixture was stirred at room temperature for another 20 hours. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was purified by a gravity silica gel column (cyclohexane / EtOAc 4: 2). Yield: 1.29 g (6.9% of theory) ci 6 H2 2 BrN02 (M = 340.255) Calculated value: molecular peak (M + Η) +: 340/342 (Br) Found: molecular peak (M + H) + : 340/342 (Br) Retention time HPLC: 10.71 minutes (Method A). 16.1b [(E)-(S) -3- (4-Ephenyl) small methyl-but-2-enyl]- Carbamate third-butyl according to General Method II, produced from [(E)-(S) -3- (4-benzylphenyl) -1methylbut-2-enyl] -carbamic acid Tertiary-butyl ester (0.77 g, 2.26 mmol). Yield: 0.75 g (85.8% of theory)

Ci6H22IN02 (M = 387.256) Retention time HPLC: 6.82 minutes (Method B). 16.1c ((E)-(S) -3- {4- [5- (4-Gaphenyl) -E ° Ding-2- Ethynyl] -phenyl} -l-fluorenyl-but-2-enyl) -aminocarbamic acid tert-butyl ester produced from [(EMS) -3- (4- moth benzene) according to the general method I ' Group) berberyl-but-2-fluorenyl] " aminocarbamic acid tert-butyl- (1_28g's mol) with 5- (4-aminophenyl) -2-ethynyl-pyridine ( 0.84 grams, 3.63 millimoles).

100779-168- 200538102 Yield: 0.43 g (27.6% of theory) C2 5 H2 2 C1NO (M = 473.006) Calculated value: molecular peak (M + H) +: 473/475 (Cl) Found: molecular peak ( Μ + Η) +: 473/475 (Cl)

Rf value: 0.07 (silicone, 366 nm, DCM). 16.1d (E)-(S) -3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -benzene } Small methyl-but-2-diylamine Add 1.98 ml (25_9 mmol) trifluoroacetic acid to 0.43 g (0.91 mmol) ((E)-(S) -3- {4 -[5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} small methyl-but-2-enyl) -aminocarboxylic acid tert-butyl ester in 25 ml of DCM Inside the solution. The mixture was stirred at room temperature for 17 hours, and then made alkaline with a 15% sodium hydroxide solution. The organic phase was dried over Na2S04 and the solvent was removed in vacuo. Further purification was performed by column chromatography on crushed gel (DCM / MeOH / NH319: 1: 0.1 to DCM / MeOH / NH39: 1: 0.1). Yield: 520 mg (53.6% of theory) C24H21C1N2 (M = 372.890) Calculated value · Molecular peak (M + H) +: 373/375 (Cl) Measured value: Molecular peak (M + H) +: 373 / 375 (Cl)

Rf value: 0.31 (silicone, 366 nm, DCM / MeOH / NH39: 1: 0.1) · Example 16.2 (E)-(S) -5- (4-Gaphenyl) -2- {4- [1- Fluorenyl-3- (4-fluorenyl-hexahydropyridin-1-yl) -but-1-enyl] -phenylethynylpyridine 100779 -169- 200538102

37.0 mg (0.27 mmol) of k2C03 and 24.8 mg (0.16 mmol) of 1,5-dibromo-3-methylpentane were added to 500 mg (0.13 mmol) ) (E) _ (s) _3_ {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl> PhenylH • fluorenyl-but1enylamine in 1.4 ml of DMF The solution was shaken at 70 ° C for 21 hours. Remove solvents in the air. The residue was dissolved in 20 ml of EtOAc and washed with 10 ml of a half-saturated NaHC03 solution. The organic phase was dried over Na2s04 and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM / MeOH / NH3 98: 2: 0.2). Stir the residue with DIPE. Yield: 17.2 mg (28% of theory) C3〇H31ClN2 (M = 455.033) Calculated value: Molecular peak (M + H) +: 455/457 (Cl) Measured value ·· Molecular peak (M + H) +: 455/457 (Cl)

Rf value: 0.82 (silicone, 366 nm, DCM / MeOH / NH39: 1: 0.1). Examples 16.3 and 16.4 16.3: ((E)-(S) -3- {4- [5- (4-chlorobenzene ) -Pyridin-2-ylethynyl] phenyl • methyl-but-2_diyl) -L-propylpropylfluorenyl · amine

100779 -170- 200538102 16.4: butyl-but-2-diyl) -bis-cyclopropylmethyl-amine

16.3 with 16_4 will be 180 mg (0.48 mmol) (E)-(S) -3_ {4- [5- (4_chlorophenyl) _pyridine_2_ylethoxy] -phenyl} -1 -A solution of methyl-but-2-fluorenylamine and 0.04 ml (0.48 mmol) of cyclopropanecarboxaldehyde in 15 ml of THF, and stirred at room temperature for 1 hour. Then, 409 mg (1-93 mmol) of NaBH (OAc) 3 and 0.1 ml (1.93 mmol) of glacial acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. The agent was removed in vacuo and the residue was diluted with 40 litres of EtOAc and 20 ml of a half-saturated CO3 solution. The organic phase was dried over NaaSO4 and the solvent was removed in vacuo. Further purification was performed by column chromatography on Shixijia (DCM / MeOH / NH39: 1: 0.1). 〇16 · 3 · ((E)-(S) -3- {4- [5- (4 · Chlorophenyl) -ρ ratio πden-2-ylethynyl] -phenylbumethyl-but-2-enyl) _cyclopropylmethyl-amine Yield: 100 mg (49% of theory) 8 7 CIN2 (Μ = 426.980) Calculated: Molecular peak (Μ + Η) +: 427/429 (Cl) Measured value: Molecular peak (M + H) +: 427/429 (Cl)

Rf value: 0.39 (silica gel, 366 nm, DCM / MeOH / NH39: 1: 0.1). 16. ·· ((eMS) -3- {4- [5- (4-chlorophenyl) -P ratio. Dyn-2-ylethenyl] -phenylmethyl 100779 -171-

200538102 methyl-but-2-enyl) -bis-cyclopropylmethyl-amine yield: 20.3 mg (9% of theory) C3 2 H3 3 CIN〗 (M == 481.071) Calculated value: molecular peak (M + H) +: 481/483 (Cl) Found: Molecular peak (M + H) +: 481/483 (C1)

Rf value ·· 67 (Silicone, 366 nm, DCM / MeOH / NH39: 1: 0.1). Example 16.5

((E)-(S) -3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenyl} berberyl-but_2-alkenyl) -ring Propylmethyl-propyl-amine

Add 0.08 ml (0.84 mmol) 1-bromopropane and 0.4 ml (0.84 mmol) ethyl diisopropylamine to 45.0 mg (o.ii mmol) ((e ) _ (s) _3_ {4 · [5- (4-Gasphenyl) -erim-2-ylethynyl] -phenylb μmethyl_but_2_enyl) _cyclopropylfluorenyl -A solution of the amine in 1.0 ml of DMF and shaken at 60 ° C for 50 hours. The solvent was removed in vacuo. The residue was combined with 10 ml of a half-saturated NaHco solution and 20 ml of EtOAc. The organic phase It was dehydrated and dried with N% δ〇4, and was removed in a vacuum> cereals. It was purified by column chromatography on stone gum (Cyclohexane / EtOAc 1 ·· 2). ° Yield: 8.1 Mg (16% of theory) C31H3 3 C1N2 (M = 469.060) Calculated value: molecular peak (M + H) +: 469/471 (α) 100779 -172-

200538102 Found: Molecular peak (M + H) +: 469/471 (Cl)

Rf value: 0.10 (silicone, 366 nm, cyclohexane / EtOAc 1: 2). Example 17.1 1- {4- [5- (4-chlorophenyl than fluoren-2-ylethenyl] -2-methyl P-phenoxymethylcyclopropylamine

17.1a (4-Filler-2-methyl · phenoxy) -acetonitrile Add 7.447 g (53.9 mmol) & (: 03 to 13.0 g (53.9 mmol) 4_ mothyl-2- Methyl chloride was in a solution of 80.0 ml of DMF. Then, 3.70 ml (53.9 mmol) of bromoacetonitrile dissolved in 20.0 ml of DMF was slowly added dropwise. The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered. The solvent was removed in vacuo. The residue was dissolved in 400 ml of EtOAc and 200 ml of water. The organic phase was washed with 100 ml of saturated NaCl solution. The organic phase was dried over Na2S04 and removed in vacuo. Remove the solvent. Yield: 15.3 g (104% of theory) C9H8INO (M = 273.070) Differential value: molecular peak (M + H) +: 273 measured value: molecular peak (m + h) +: 273 Rf value: 0.62 (silicone, cyclohexane / EtOAc2: 1). 17.1b 1- (4-iodo-2-methyl-phenoxymethyl) _cyclopropylamine makes 14.0 g (51.3 mmol) (4 -Elkyl-2-methyl-phenoxy) · acetonitrile was dissolved in 21 liters of ethyl acetate and cooled by an ice / isopropanol bath. Then, carefully add 100779 -173- 200538102 dropwise and add 17 · 1 ml (56.4 mmol) isopropoxide (IV). Then, 34.2 ml of ethyl magnesium bromide (102.5 mmol, 3M in B) were added dropwise, and the mixture was stirred for 30 minutes. 13.0 ml (102.5 mmol) of trifluoride Shed-ether complex was quickly sucked into it with a pipette at 10 ° C. After another 2 hours, 150 ml of a 1 M sodium hydroxide solution was added dropwise and further cooled. The reaction mixture was filtered. The liquid phase of the filtrate was separated The organic phase was washed with 150 ml of saturated NaCl solution. The organic phase was dehydrated and dried with Na SO *, and the solvent was removed in vacuum φ. Further purification using a gravity silica gel column (cyclohexane /-

After EtOAc 2: 1, it was cyclohexane / EtOAc 4: 1). Yield: 9.06 g (58.3% of theory)

CnH14IN0 (M = 303.139) Calculated value: molecular peak (M + H) +: 304 found: molecular peak (M + H) +: 30% Rf value: 0.07 (silicone, cyclohexane / EtOAc2: 1). 17.1c l- {4- [5- (4-Phenylphenyl);-pyridin-2-ylethynyl] -2-methyl-phenoxymethyl cyclopropylamine, according to General Method I, Manufactured from 1- (4-mothyl-2-methyl-phenoxymethyl) _cyclopropylamine (2_00 g, 6_60 mmol) and 5_ (4_aminophenyl) -2-ethynyl- Eridine (1.53 g, 6.60 mmol). Yield: 1.73 g (67% of theory) C2 4 H21C1N20 (M = 388.889) Calculated value: Molecular peak (M + H) +: 389/391 (Cl) Measured value: Molecular peak (M + H) +: 389 / 391 (Cl)

Rf value: 0.59 (silicone, DCM / MeOH / NH39: 1: 0.1). Examples 17.2 and 17.3 100779. 174- 200538102 17.2: (l- {4- [5- (4-chlorophenyl) -pyridine- 2-ylethynyl] -2-methyl-phenoxyfluorenyl} -badpropyl) -¾propylmethyl-yuean

17.3 · (1- {4- [5- (4-Gaphenyl) -p than fluorene · 2-ylethynyl] _2_fluorenyl-phenoxymethylcyclopropyl) -bis-cyclopropyl Methylamine

17.2 and 17.3 1.00 g (2.57 millimoles) of 1_ {4- [5- (4-Gaphenyl) _pyridine 1ylethynyl] -2-fluorenyl-phenoxyfluorenyl} -cyclopropene A solution of propylamine and 019 ml (2.57 mmol) of cyclopropanecarboxaldehyde in 75 ml of THF was stirred at room temperature for 1 hour. Then, 2.18 g (10.3 mmol) of NaBH (OAC) 3 and 0.59 ml (10.3 mmol) of glacial acetic acid were added. The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the residue was diluted with 100 ml of Et0Ac and 50 ml of a half-saturated K2CO3 solution. The organic phase was dried over NaaSO4 and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM / MeOH / NH3 98: 2: 0.2). The desired fractions were evaporated to dryness and the individual residues were triturated with tbme. 100779 -175- 200538102 17 · 2: ((E)-(R) -3- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -benzyl 1 methyl · But-2-enyl) -cyclopropylmethyl-amine yield: 505 mg (44% of theory) C2 8 H2 7 C1N2 〇 (M = 442.980) Calculated value: molecular peak (M + Η) +: 443 / 445 (Cl) Found: Molecular peak (M + H) +: 443/445 (Cl)

Rf value: 0.21 (silicone, DCM / MeOH / NH398: 2: 0.2). 17 · 3: (1- {4- [5- (4-chlorophenylpyridin-2-ylethynyl) -2- Methyl-benzyloxymethyl} -cyclopropyl) -bis-cyclopropylmethyl-amine Yield: 57.7 mg (5% of theory) c3 2 H3 3 C1N2 〇 (M = 497.070) Calculated: Molecular Peak (Μ + Η) +: 497/499 (Cl) Measured value: Molecular peak (Μ + Η) + ··· 497/499 (Cl) Retention time HPLC ·· 10-15 minutes (Method A). Example 17.4 (1- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxymethylcyclopropyl) -cyclopentyl-cyclopropylfluorenyl-amine

At room temperature, 0.07 ml (0.72 mmol) of cyclopentanone was added to 80.0 mg (0.18 mmol) ((E)-(R) _3- {4- [5- (4-gas Phenyl) -pyridin-2-ylethynyl] -phenylfluorenyl-but-2-enyl) -cyclopropylfluorenyl-amine in 80 ml of THF 100779 -176- 200538102 liquid. After 15 minutes, 162 mg (0.72 mmol) of NaBH (〇Ac) 3 and-ml (0.72 mmol) of glacial acetic acid were added. After 3 hours (wherein complete dissolution was not achieved) '6 ml of DCM was added. After another 26 hours, add 6 ml of MeOH, 0.07

Ml (0.72 mmol) of cyclopentanone, 162 mg (0.72 mmol) of NaBH (OAc) 3 and 0.04 ml (0.72 mmol) of glacial acetic acid. After another 20 hours (dissolved, no reaction), 45.0 mg (0.72 mmol) of NaBH3 CN and 0.07 ml (0.72 mmol) of cyclopentanone were added. After the weekend with stirring, the solvent was removed in vacuo. Mix the residue with DIPE. Further purification was performed by column chromatography on stone gum (cyclohexane / EtOAc 4: 1). Yield · 15.2 mg (16% of theory) 5 H2 2 C1NO (M = 511.097) Calculated: Molecular peak (M + H) +: 511/513 Found: Molecular peak (M + H) +: 511 / 513 Rf value: 0.63 (silicone, cyclohexane / EtOAc2: 1) · Example 17.5 5- (4_Gaphenyl) -2- {3 · fluorenyl_4- [1_ (4-methyl-hexahydroe n-determined) cyclopropylmethoxy] -phenylethoxy} -17 than π-determined

71.0 mg (0.51 mmol) of K2C03 and 47.8 mg (0.31 mmol) of 5,5 dibromo-3-methylpentane were added to 100 mg (0.26 mmol) of ( e) _ (R) Each [5- (4-chlorophenyl) -erb-2-ylethenyl] -phenylmethyl_but_2_enyl) · cyclopropane 100779 -177-

200538102 A solution of methylmethyl-amine in 3.0 ml of DMF and shaken at 70 ° C for 20 hours. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was diluted with 20 ml of EtOAc and 10 ml of a half-saturated κ2co3 solution. The organic phase was dried over Na2s04 and the solvent was removed in vacuo. Further purification was performed by preparative HPLC-MS. The desired fractions were evaporated to dryness and the residue was triturated with pE. Yield: 3.2 mg (3% of theory) c3 〇H3! C1N2 ο (Μ = 471.033) Calculated value: molecular peak (M + Η) +: 471/473 (Cl) found: molecular peak (M + Η) +: 471/473 (Cl) retention time HPLC: 9.60 minutes (Method A) _ Example 17.6 (1- {4- [5- (4-Gaphenyl) · pyridin-2-ylethynyl] -2-methyl -Phenoxymethylcyclopropyl) -cyclopropylmethyl · propyl-amine

0.07 ml (0.72 mmol) of bromopropane and 0.04 ml (0.72 mmol) of ethyldiisopropylamine were added to 800 mg (〇18 mmol) ((e ) _ (r) _3_ {4_ [5- (4-Gasphenyl) _pyridinoethynyl] • phenyl 丨 small methyl_butynyl) _cyclopropylfluorenyl-amine in 1.7 ml DMF The solution was shaken at 7 ° C for 4 hours. The solvent was removed in vacuo. The residue was diluted with 30 ml of EtOAc and 10 ml of a half-saturated K ^ CO3 solution. The organic phase was dried over ν々304 and dried. The solvent was removed in vacuo. Further purification was performed by preparative HPLC-MS. 100779 -178- 200538102 Yield: 17.8 mg (20% of theory) C31H3 3 C1N2 0 (M = 485.059) Calculated value: molecular peak (M + H) +: 485/487 (Cl) Measured molecular peak (M + H) + · 485/487 (Cl) Retention time HPLC: 6.60 minutes (Method A) · Example 17.7 (1- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -2-methyl-phenoxyfluorenyl} -ring

Propyl) -cyclopentyl-amine

0.46 ml (5.17 mmol) of cyclopentanone was added to 50 mg (129 mmol) of 1 · {4- [5 · (4-chlorophenyl) -pyridin-2-ylethynyl] -2- A solution of methyl-phenoxymethylcyclopropylamine in 50 ml of THF, and the mixture was stirred at room temperature for 15 minutes. Then, 15 g (5.17 mmol) of sodium triethoxyborohydride and 0.30 ml (5-17 mmol) of Ac0H were added. The reaction solution was stirred at room temperature for 48 hours, then, neutralized with 30 ml of a half-saturated NaHC03 solution, extracted with 40 ml of EtOAc, and the organic phase was dried and dried. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, cyc / EtOAc 2: 1). The product-containing fractions were evaporated to dryness in vacuo, the residue was triturated with isopropanol, filtered under suction, and dried. Yield: 210 mg (58% of theory) C2 9 H2 9 C1N2 Ο (Μ = 457.006) 100779 -179- 200538102 Calculated value: molecular peak (M + H) +: 457/459 (Cl) found: molecular peak (M + H) +: 457/459 (Cl)

Rf value: 0 · 18 (silicone, cyclohexane / EtOAc2: 1). Example 18.1 5- (4-Gaphenyl) -2- [4-((S) -2-tetrahydropyrrolidine-1- Methyl_tetrahydro p is slightly smaller than) _phenylethynyl] -edian

4.00 g (9.62 millimoles) of 5- (4-phenyl) -2- (4-erphenylphenylethynyl) -exopyridine (Example 8b), 3.00 g (19.4 millimoles) (SH +) -(2-tetrahydropyrrolyl-methyl) _ tetrahydropyrrole, 187 mg (0.96 mmol) of CuI and 0.74 g (3.85 mmol) of N, N-diethyl-2-meryl-benzyl A suspension of amidine in 10 ml of DMF was evacuated several times and filled with argon. Then, 4.72 g (19.2 mmol) of phosphoric acid monohydrate was added, the mixture was evacuated and filled with argon. The mixture was stirred overnight at 1000c. The reaction mixture was diluted with DCM and washed three times with 5% NH3 solution and several times with water. The organic phase was dried over MgS04, filtered through activated carbon, and the solvent was removed in vacuo. Further purification was performed by column chromatography on silica gel (DCM / MeOH 9: 1). Yield: 2.50 g (59.0% of theory) C28H28C1N3 (M = 441.995) Calculated value: molecular peak (M + H) + · 442/444 (Cl) found: molecular peak (M + H) +: 442/444 (Cl) 100779-180- 200538102

Rf value: 0.35 (silicone, DCM / MeOH9: 1). Example 18.2 5- (4-Gabenyl) -2- {4- [3- (4-methyl-hexamethylene ρ ratio σ fixed -1_ group ) -Prop-1-yl]] phenylethynylpyridine

18.2a 2- (4 · > styrenylethenyl) · 5_ (4-chlorophenyl) -amizidine According to General Method I, 4-bromo-xylbenzene (6.27 g, 21.5 Millimoles) and 5- (4-aminophenyl) -2.ethynyl-eridine (5.0 g, 21.5 millimoles). Yield: 8.10 g (quantitative yield) 9 Η !! BrCIN (M = 368.654) Calculated value: Molecular peak (M + H) +: 368/370/372 (BrCl) Found: Molecular peak (M + H) +: 368/370/372 (BrCl)

Rf value: 0.73 (silicone, DCM / PE1: 1). 18.2b 2- (4-iodophenylethynyl) -5- (4-phenyl) -pyridine Prepared from 2- (4 according to General Method II) -Bromophenylethynyl) -5- (4-fluorophenyl) -pyridine (8.10 g, 22.0 mmol). Yield: 6.80 grams (74% of theory)

Ci9HuClIN (M = 415.665) Calculated: Molecular peak (M + H) +: 416/418 (Cl) Found: Molecular peak (M + H) +: 416/418 (Cl) Retention time HPLC: 7.9 minutes (method B) · 100779 -181-200538102 18.2c 3] 4- [5- (4-chlorophenyl p-pyridinylethynyl] phenylpropynyl small alcohol will be 0.70 g (L68 mmol) 2_ (4 _Iodophenylethynyl) _5_ (4_Gaphenyl) _Toxidine, 98.3 microliters (1.68 millimoles) propane_2 • alkyne + alcohol, 0.49 milliliters (3.54 millimoles) triethyl A solution of amine in ίmL of acetonitrile was evacuated and filled with argon. 151 μg (0.02 mmol) of PdCl2 (dppf) and 3.53 mg (0.02 mmol) of CuI were added, and the mixture was pumped again Gas, and fill with argon. The reaction was stirred at room temperature overnight. Purified by column chromatography on silica gel (pE / Et〇Ac 丨: 丨). Yield · 430 mg (74% of theory) ) c2 2 4 C1NO (M = 343.805) Differential value: molecular peak (M + H) + · 344/346 (Cl) found: molecular peak (M + H) +: 344/346 (Cl)

Rf value: 0.57 (silicone, PE / EtOAc: 1) · 18.2d 5- (4-Gaphenyl) -2- [4_ (3-Ga-prop-1_alkynyl) _phenylethynyl] ^ ratio A solution of 39.6 microliters of digassed thionine in 2 ml of DCM was added to 150 mg (0.44 mmol) 3- {4- [5- (4 -Phenyl) -pyridin-2-ylethynyl] -phenylbuprop-2-yn-1-ol in 5 ml of DCM. The reaction solution was stirred at 0 ° C for 30 minutes and at room temperature overnight. 5 ml of saturated NaHC03 solution were added, and the mixture was extracted with DCM. The organic phase was dehydrated to dryness and the solvent was removed in vacuo. Yield: 145 mg (92% of theory). 2 2 吒 3 C12N (M = 362.251) Calculated value · Molecular peak (M + H) +: 362/364/366 (2C1) Measured value: Molecular peak (M + H) +: 362/364/366 (2C1 ) Retention time HPLC: 7.49 minutes (method B). 100779 -182- 200538102 18.2e 5- (4-chlorophenyl) -2- {4- [3- (4-methyl-hexahydroepithione) _Propanyl] -phenylethynyl} -p specific bite 142 microliters (1.20 mmol) 4-methylhexahydropyridine was added to 145 mg (0.40 mmol) 5- (4-chloro Phenyl) -2- [4- (3-chloro-prop-1 · alkynyl> phenylphenylethynyl] · eridine in a solution of 2 ml of DMF and stirred at 70 ° C overnight. After cooling, a solid precipitated out and filtered out. Yield: 46.0 mg (27.0% of theory) 8 5 CIN2 (M = 424.964) Calculated value: Molecular peak (M + H) +: 425/427 (Cl) Measured Value: Molecular peak (M + Η) +: 425/427 (Cl) Retention time HPLC: 6.01 minutes (Method a) · Example 18.3 (S) -lf- {4- [5- (4-Gaphenyl) ) -Pyridin-2-ylethynyl] -phenyl} ice methylbishexahydro

18.3a ⑸-Η4 · bromophenyl) -hexahydropiridine · 3 · ylamine Will 1.00 g (5.00 t mole) of ⑻-hexahydro? ratio. Aj-yl-aminocarbamic acid third butyl ester, 97.2 g (0.50 mmol) Qil, 2.12 g (10.0 mmol) potassium phosphate and 0.56 l (10.0) Mol) ethane, 2-diol, added to a solution of 141 g (50 mol) 4- > odor-Ebenzene in 10 ml of isopropanol, aspirated several times, and

100779 -183. 200538102 Argon filling. The mixture was stirred at 90 ° C overnight. 100 ml of 1/3 concentrated HC1 was added at room temperature, and the mixture was stirred for 1 hour. It was then extracted twice with TBME. The aqueous phase was made alkaline with NH3 solution and extracted several times with TBME. The organic phase was washed with a small amount of water, dried over MgS04, filtered through activated carbon, and the solvent was removed in vacuo. The residue was dissolved in 2 ml of DCM and purified by column chromatography (Hyperprep, gradient: 10% B to 90% B in 12 minutes, then 90% B in 5 minutes). The residue was then dissolved in a small amount of water, neutralized with NaHC03, and extracted with DCM. The organic phase was dried over MgS04 and the solvent was removed in vacuo. Yield: 250 mg (20% of theory)

CnH15BrN2 (M = 255.200) Calculated: Molecular peak (M + H) +: 255/257 (Br) Measured value: Molecular peak (M + H) +: 255/257 (Br) Retention time HPLC: 6.46 minutes (Method B) 18.3b (S) -1 '-(4-Bromophenyl) _4-methyl- [1,3] bishexahydropyridine φ will be 286 mg (1.18 mmol) 1,5-di Bromo-3-methylpentane with 325 mg (2.35 mmol) of K2C03 added to 250 mg (0.98 mmol) of (S) -1- (4-bromophenyl) -hexahydropyridin-3-yl A solution of amine in 10 ml of DMF and the mixture was stirred at 50 ° C overnight. The solvent was removed in vacuo. The residue was dissolved in water, made alkaline with a 2N sodium hydroxide solution, and extracted with TBME. The organic phase was dried over MgS04 and the solvent was removed in vacuo. Purification was performed by column chromatography (Hyperprep, gradient: 10% B to 90% B in 12 minutes and then 90% B in 5 minutes). The residue was dissolved in water again, made alkaline with 2N sodium hydroxide solution, and extracted with TBME. Yuzan 100779 -184- 200538102 was dehydrated and dried with MgS04, and the solvent was removed in vacuo. Yield: 125 mg (38% of theory) C17H2 5 BrN2 (M = 337.298) Calculated: Molecular peak (M + H) +: 337/339 (Br) Measured value: Molecular peak (M + H) +: 337 / 339 (Br)

Rf value: 0.40 (silicone, DCM / MeOH / NH39: 1: 0.1). 18-3c ⑻1 (4-Diphenyl) -4-methyl- [1,3 '] bishexahydropyridyl Method II, prepared from (S) -lf- (4-mophenyl) -4-methyl- [1,3 丨] bispyridyl (125 mg, 0-37 mmol). Yield: 120 mg (84% of theory)

Ci7H25IN2 (M = 384.298) Calculated: Molecular peak (M + H) +: 385 Found: Molecular peak (m + h) +: 385 Retention time HPLC: 6.7 minutes (Method A). 18,3 (1 (S ) -1L {4_ [5_ (4 · Phenyl) -pyridine-2_ylethynyl] · Phenyl-4-methyl_ [1,3 '] bishexahydroerenyl (S) -l,-(4-iodophenyl) winter methyl- [1,3,] bishexahydropyridyl (120 μg ′ 0.31 mmol) and 5- (4-Gabenzene Base) -2-Ethylpyridine-Löbidadine (66 · 8 mg, 0.31 mmol). Yield: 10.0 mg (70% of theory). 3 0H3 2 QN3 (M = 470.048) Calculated value: Molecular peak (M + Η) +: 470/472 (Cl) Found: Molecular peak (M + H) +: 470/472 (Cl) Retention time HPLC: 6.0 minutes (Method A). 100779 -185- 200538102 Example 18.4 (R) -1 '-{4- [5- (4-chlorophenyl) -pyridin_2-ylethynyl] • phenylη-methyl- [1,3 ,] Double six hydrogen said to bite

184a [(R) -H4_bromophenyl) _hexahydropyridine_3_yl] aminobutyric acid tert-butyl ester 2.00 g (10.0 mmol) Tert-butyl gallate, 194 mg (1.00 mmol) Cul, 4.25 g (20.0 mmol) potassium potassium acid and U3 ml (20.0 mmol) ethane β1,2, diol, added to 2 · 83 g (10.0 mmol) of 4-brook-carbonbenzene in 20 ml of isopropanol, evacuated several times, and filled with argon. Stir overnight at 90 ° C. At room temperature 100 ml of 1/3 concentrated HC1 was added, and the mixture was stirred for 1 hour. Then, it was extracted twice with TBME. The aqueous phase was made alkaline with NH3 solution and extracted several times. The organic phase was washed with a small amount of water, Dehydrate and dry with MgS04, filter through activated carbon, and remove the solvent in vacuum. Yield: 1-00 grams (28% of theory)

Cj 6 H2 3 ΒΓΝ2 〇2 (M = 355.270) Calculated: Molecular peak (M + Η) +: 355/357 (Br) Found: Molecular peak (M + H) +: 355/357 (Βι〇18.4b) (R) -l- (4-Methenyl) -hexamidine p-ratio. 3-Methylamine 5.00 ml of trifluoroacetic acid was added to ι.00 g (2.82 mmol) _ 丨 (4 ,, smelly

100779 -186- 200538102 Phenyl) -hexahydroeming: -3-yl] -aminocarboxylic acid tert-butyl ester in 50 ml of dcM 'and stirred overnight. The solvent was removed in vacuo. The residue was dissolved in DCM 'and made alkaline with a 2 N sodium hydroxide solution while cooling. The organic phase was washed with water, dried over MgS04, and the solvent was removed in vacuo. Yield · 750 home grams (quantitative yield)

CnH15BrN2 (M = 255.154) Calculated: Molecular peak (M + H) +: 255/257 (Br) Measured value: Molecular peak (M + H) +: 255/257 (Br)

Rf value · 0.15 (Shi Xijiao, DCM / MeOH / NH39: 1: 0.1) · 18.4c ⑻-1H4-bromophenyl) ice methyl- [1,3,] dihexahydropyridine will be 832 mg (3.41 ^ : Moore) 1,5-diamoyl-3 · methylpentanol with 943 mg (6.82 mmol) K: 2C03, added to 725 mg (2.84 mmol) (R) -i- ( 4 · Bromophenyl) -hexahydropyridin-3-ylamine in 50 ml of DMF and the mixture was stirred at 50 C overnight. The reaction mixture was diluted with 50 ml of Etoac and washed three times with half-saturated NaHC0 solution. The organic phase was dried over MgS04 and the solvent was removed in vacuo. Yield: 125 mg (13% of theory) C17H25BrN2 (M = 337.298) Calculated value: Molecular peak (M + H) —: 337/339 (Br) Measured value: Molecular peak (M + H) +: 337/339 (Br) 18.4d ⑻-Γ- (4-Ephenyl) -4-methyl- [1,3,] bishexahydropyridine prepared from (R) -1H4-bromophenyl) ice according to General Procedure II Methylbishexahydropyridine (125 mg, 0.37 mmol). .⑩ 100779-187- 200538102 Yield: 110 mg (77% of theory) C17H25lN2 (M = 384.298) Calculated value: Molecular peak (M + H) +: 385 Measured value: Molecular peak (M + H) +: 385 Retention time HPLC: 4.7 minutes (Method B). 18-4e (R) -lL {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -4 · methyl _ [1,3 '] bishexahydropyridine is prepared from (R) -1' _ (4-iodophenyl) -4-methyl- [1,3,] bishexahydropyridine (110 Mg, 0.29 mmoles) and 5- (4-aminophenyl) -2-ethynyl 4 pyridine (66.8 mg, 0.31 mmoles). Yield: 20.0 mg (15.0% of theory) C30H32C1N3 (M = 470.048) Calculated value: Molecular peak (M + H) +: 470/472 (Cl) Measured value: Molecular peak (M + H) +: 470/472 (Cl)

Rf value: 0.47 (silicone, DCM / MeOH9: 1). Example 19.1 5- (4-Gaphenyl) -2- {3-fluoroyl-4- [3- (4-fluorenyl-hexahydrop-specific ratio) -1-yl) -tetrahydro eicosyl] -phenylethenyl} -o °

19.1a Sinyl-2-aminophenyl) -tetrahydroπ ratio π each _3_yl] -4-fluorenyl-hexahydroρ ratio bite in argon atmosphere, 17.9 mg (0.08 mmol) palladium acetate (II) Added to 800 mg (2.66 mmol) 4. Molyl-2-fluoro-1-an-benzene, 447 mg (3.0 mmol 100779 -188 · 200538102

Ear) 4-methyl-1-tetrapyrrole_3-yl-hexahydropyridine (amine A2), 121 g (400 mmol) carbonate shavings and 49.7 mg (0.08 mmol) 2 , 2, _bis_ (dibenzylphosphino) -1, Γ-bifluorene in a suspension of 15 ml of i, 4-dioxolane, and the reaction mixture was stirred at 50 ° C overnight. An additional 49.7 mg (0.8 mmol) of 2,2'-birenylphosphinonaphthalene and 17.9 mg (008 mmol) of acetic acid (II) were added, and the mixture was refluxed for 3 days. After cooling, mix it with water and dress 08. Combine, separate the liquid phases, wash the organic phase several times with water, and dry over Na2S04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, DCM / MeOH / NH3 95: 5: 0.5). Yield: 250 mg (28.0% of theory)

Cl 6 H2 2 BrFN2 (M = 341.262) Calculated value: Molecular peak (M + H) +: 341/343 (Br) Measured value ·· Molecular peak (M + H) +: 341/343 (Br) Retention time HPLC : 6_2 minutes (Method A). 19.1b oxy-4 · moth phenyl) -tetrahydrob0 each-3-yl] -4-methyl-hexahydro p ratio 唆 According to the general experimental method II, produced from 250 Mg (0.73 mmol) of 1- [1- (4-bromo-2-fluorophenyl) -tetrahydropyrrole-3-yl] -4-methyl-hexahydropyridine. Yield: 135 mg (47% of theory)

Ci6H22FIN2 (M = 388.262) Calculated: Molecular peak (M + H) +: 389 Found: Molecular peak (M + H) +: 389 Retention time HPLC: 6.0 minutes (Method A). 19.1c 5- (4- Phenyl) -2- {3-Gasyl-4- [3- (4-methyl-hexamethylenestilbene-1-yl) -tetra

(D rat b-l-l-yl) -phenylethenyl, specific ratio According to the general working method I, made from 135 mg (0.35 mmol) 1- [1- (2-fluoro 100779 -189- 200538102 yl-4-iodophenyl) · tetrahydropyrrole_3_yl] -4-fluorenyl · hexahydropyridine with 74 mg (0.35 mmol) 5- (4-aminophenyl) -2-ethynyl ^ Bipyridine (with Pd (dppf) Cl2 as catalyst, triethylamine as base, and acetonitrile as solvent). Yield: 22 mg (13% of theory) C29H29C1FN3 (M = 474.012) Calculated value: molecular peak (M + H) +: 474/476 (Cl) Measured value: Molecular peak (M + H) +: 474/476 (Cl) Retention time HPLC: 6.0 minutes (Method A). Example 20.1 5- (4-Gaphenyl) ) -2- {4-[(Ε) -1-fluorenyl-3- (4-methyl-hexahydro p ratio fluoren-1-yl) _propenyl] -phenylethynyl 丨 -u ratio 唆

20.1a (E) -3- (4-Benzophenyl) -butane · 2-dilute acid in an argon atmosphere, 31.6 mg (0.14 mmol) acetic acid (π) and 171 mg (. 56 millimoles) tri-o-tolyl-squamane, added to "I (14.1 millimoles) l-bromo-4-iodo-benzene, L51 g (18.0 millimoles) (E) -butane A solution of 2-enoic acid and 3.91 ml (28.1 mmol) of triethylamine in 40 ml of acetonitrile, and the reaction mixture was refluxed overnight. After cooling, 20 ml of 1 M HC1 was added dropwise, the mixture was thoroughly extracted with EtOAc, and the combined organic phases were dried over MgS04 and dried. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, gradient PE / EtOAc 9: 1 to 7: 3).

100779 -190- 200538102 Yield: 700 mg (14% of theory) C10H9BrO2 (M = 241.081) Calculated value: Molecular peak (MH) ·: 239/241 (Br) Measured value: Molecular peak (M-Η) ·: 239/241 (Br) retention time HPLC: 5.7 minutes (method E). 20.1 lb (E) · 3- (4-benzylphenyl) -but-2-enol, 659 mg (4.07 mmol) Mol) CDI was added to a solution of 700 mg (2.03 mmol) (E) -3- (4-bromophenyl) -but-2-enoic acid in 10 ml of anhydrous THF, and the reaction mixture was added to 70 Stir at ° C until gas evolution has stopped. An additional 659 mg of CDI was added, and the mixture was stirred at 60 ° C for another 2 hours. After cooling, the reaction solution was added to a solution of 307 mg (8.13 mmol) of sodium hydrogenated in 10 ml of water (exothermic reaction), and stirred at room temperature overnight. The reaction mixture was acidified with dilute KHS04 solution, thoroughly extracted with EtOAc, and the combined organic phases were dried over MgS04. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, PE / EtOAc 7: 3). Yield: 250 mg (54% of theory) C10HnBrO (M = 227.098) Calculated value: Molecular peak (M) +: 226/228 (Br) Measured value ·· Molecular peak (M) +: 226/228 (Br) 20.1c 1-Molyl-4-((E) -3-amino-1-methyl-propyl) -benzene 107 microliters (1.32 millimoles) of pyridine and one drop of DMF were added to 250 mg ( 1.10 pen mole) of a solution of (E) -3- (4-benzylphenyl) -but-2-fluoren-1-ol in 5 ml of DCM. After cooling in an ice bath, the solution was slowly combined with 96 microliters (1.32 millimoles) of SOC12, and the reaction mixture was stirred at this temperature for 1 hour and at room temperature 100779 • 191-200538102 overnight. This was combined with a half-saturated NaHC0 solution, thoroughly extracted with dCm, and the combined organic phases were washed with water several times and dehydrated and dried with MggO4. After the desiccant and solvent have been removed, the residue is allowed to react further without purification. Yield: 240 mg (89% of theory)

Ci 〇Hi 〇BrCl (M = 245.543) Calculated: Molecular peak (M) +: 244/246/248 (BrCl) Found: Molecular peak (M) +: 244 /; 246/248 (BrCl) 20.1d H (E) _3- (4-Bromophenyl) -but_2-alkenyl] -4-fluorenyl-hexahydropyridine will be 0.23 liters (1.96 mmol) 4-methyl-hexahydro Ebene was added to a solution of 240 mg (0.98 mmol) of 1-molyl-4 _ ((E > 3-aminomethyl-propenyl) · benzene in 2 ml of DMF, and the reaction solution was dissolved in 45 ml. It was stirred at 0 ° C for 2 hours and overnight at room temperature. It was evaporated to dryness in vacuo, the residue was combined with water, extracted thoroughly with EtOAc, the combined organic phases were washed twice with water and with MgS. 4 Dehydration and drying. After the desiccant and solvent have been removed, the residue is allowed to react further without purification. Yield: 260 mg (86% of theory)

Ci6H22BrN (M = 308.257) Calculated: Molecular peak (M + H) + ·· 308/310 (Br) Measured value: Molecular peak (M + Η) +: 308/310 (Br) Retention time HPLC ·· 4 · 1 minute (Method B) · 20.1e 1-[(E) _3- (4-iodophenyl > but-2-enyl] -4-methyl-hexahydropyridine, prepared according to General Experimental Method II, 260 Milligram (0.84 millimolar) 1-[(E) -3- (4- > Styrenyl) -but-2-fluorenyl] -4-methyl-hexamidine μ specific bite. 100779 -192- 200538102 Yield: 170 mg (57% of theory) ci6H22IN (M = 355.257) Calculated abnormal value · Molecular peak (M + H) +: 356 Measured value: Molecular peak (m + h) + ·· 356 Retention time HPLC: 4.3 Minutes (Method B). 2〇.lf 5- (4-Gasphenyl) _2ye_-1-methyl-3- (4-methyl · hexahydropyridine small group) _propenyl] -phenylacetylene Base} -P ratio bite

Prepared according to General Working Method I from 160 mg (0.45 mmol) 1-[(e) -3- (4-Ebenyl) -but-2-enyl] -4-methyl-hexahydrop Specific bite with 106 mg (0.50 millimolar) 5_ (4-Gaphenyl) -2-ethynyl-pyridine (with Pd (dppf) Cl2 as the catalyst, triethylamine as the test, and THF As a solvent). Yield ·· 30 mg (15% of theory) 9 H2 9 C1N2 (M = 441.007) Calculated: Molecular peak (M + H) +: 441/443 (Cl) Measured value: Molecular peak (M + H) + : 441/443 (Cl) Retention time HPLC: 9.3 minutes (Method A). Example 20.2 1-((E) -3- {4_ [5- (4-Gaphenyl) -3_fluoro · Edian 2-ylethynyl] -phenylbutin. 2-diluted M-methyl-hexahydropyridine_4-ol

20.2a 1-[(E) -3- (4-Phenyl) -but-2-enyl] -4-methyl-hexahydro p-ratio-4-ol 0.24 ml (3.07 mmol) SOC12 added to 580 mg (2.55 mmol)

100779 -193- 200538102 ear) (E) -3- (4-bromophenyl) -but-2-en-1-ol with 0-9i ml (5.H mmol) triethylamine in 10 ml DCM Within the solution, cool to -20 ° C and allow the reaction mixture to warm to 0 ° C over 30 minutes. Then, it was mixed with 882 mg (7.66 mol) of 4-methyl-hexahydroexo I :. A solution of stilbene-4-ol in 5 ml of DCM was combined, and the reaction bath was stirred at room temperature for 2 hours. 50 ml of half-saturated NaHC03 solution was added, the mixture was extracted twice with 50 ml of DCM, the combined organic phases were washed with water and dried over MgS04. After the desiccant and solvent have been removed ', the residue is further reacted without purification. Yield: 180 mg (22% of theory)

Cl 6 H2 2 BrNO (M = 324.256) Calculated value: molecular peak (M + Η) +: 324/326 CBr) Found: molecular peak (M + H) +: 324/326 Br) Retention time HPLC: 5 5 minutes (method A). 20.2b l-[(E) -3_ (4- mothphenyl) -but_2-fluorenyl] -4-fluorenyl hexahydro p than fluoren-4-ol according to general experiments Method II, prepared from 180 mg (0.56 mmol) of 1-[(E) -3- (4-aubenyl) -but-2-diyl] -4-methyl-hexahydropi -alcohol. Yield: 180 mg (87% of theory)

Ci6H22INO (M = 371.256) Calculated: Molecular peak (M + H) + ·· 372 Found: Molecular peak (M + H) +: 372 Retention time HPLC: 5.7 minutes (Method A). 20.2c K (E) -3- {4- [5- (4-Gaphenyl) -3-fluoro4pyridin-2-ylethynyl] -phenyl}-

But_2_2alkenyl) _4 • fluorenylhexahydropyridin-4-ol according to General Working Method I, prepared from 80 mg (0.22 mmol) 1-[(E) _3- (4-iodophenyl)- But-2-enyl] _4-methyl-hexahydropyridin-4-ol with 50 mg (0.22 mmol 100779 -194- 200538102 er) 5- (4-Gaphenyl) -2-ethynyl-3- Fluoride 4 than pyridine (with Pd (dppf) Cl2 as catalyst, hexahydrogen as test, and acetonitrile as solvent). Yield: 37 mg (36% of theory) c2 9 H2 8 C1FN2 〇 (M = 474.997) Calculated value: Molecular peak (M + Η) +: 475/477 (Cl) Measured value: Molecular peak (M + Η) + ·· 475/477 (Cl) residence time HPLC ··· 5.0 minutes (method B). Example 20.3 4-methyl-1-((Ε) -3- {4- [5_ (4_fluorenyl- Cyclohexyl-fluorenyl-alkenyl) · eridin-2-ylethynyl] -phenylbutene-2-enyl) -hexahydroρ-ratio-4-ol

Prepared according to General Working Method I from 80 mg (0.22 mmol) of l-[(E) -3- (4-pyridyl) -but-2-enyl] -4-methyl-hexahydro Pyridine-4 · ol was contacted with 50 mg (85%, 0-22 mmol) 2-ethynyl-5- (4-fluorenyl-cyclohex-1-enyl) _pyridine (with pd (dpp〇cl2 as the contact Medium, hexahydropyridine as the base, and acetonitrile as the solvent. Yield: 13 mg (14% of theory) C30H36N20 (M = 440.620) δ ten-singular value: molecular peak (M + H) +: 441 found : Molecular peak (m + H) +: 441 Heart value: 0.10 (silicone, DCM / MeOH9: 1). 100779 -195- 200538102 Example 21.1 (E) -5- (4-Gabenzyl) -2- {4 -[3- (4,4- ^ monofluorenyl-hexamethylpyridin-1-yl) -propionyl] • lipidin-3-yl-ethynylpyridine

φ Add 121 mg (1.06 mmol) 4,4-dimethyl-hexahydropyridine to 130 mg (0.36 mmol) (ε) -5- (4-Gaphenyl) -2- A solution of {4- [3-gas-propenyl] -pyridin-3-yl · ethynyl} -pyridine (Example 7.1e) in 3 ml of DMF, and the reaction mixture was stirred at 60 ° C for 2 hours. After the reaction solution has been cooled, the product is crystallized out, then filtered and dried. Yield: 18 mg (11% of theory) c2 8 H2 8 C1N3 (M = 441.995) Juice value: molecular peak (M + H) +: 442/444 (α) φ measured value ·· molecular peak (M + Η) +: 442/444 (Cl) Retention time HPLC: 5.0 minutes (Method A) · The following examples are in each case from 100 mg (Ε) _5_ (4_ 气 phenyl) _2 · {4_ [ 3. · Ga-propenyl] _pyridine_3-yl_ethynylpyridine, made in a similar manner, and the reaction solution was stirred at 60 ° C overnight, and after cooling, #HPLC was purified without any need Further processing. 100779 200538102

Example R Yield (%) Experimental Mass HPLC Retention time (method) 21.2 21 C28H28C1N3 442/444 [M + H] + 5.6 minutes 21.3 H 39 c26h24cin3 414/416 [M + H] + 5.4 minutes (A) 21.4 OH * 47 c28h25cif3n3o 512/514 [M + H] + 5.5 minutes㈧ 21.5 HO * 21 C27H23C1F3N30 498/500 [M + H] + 7.7 minutes㈧ 21.6 HO * 41 C28H28C1N30 458/460 [M + H] + 5.3 minutes㈧ 21.7 OH it 36 c28h28cin3o 458/460 [M + H] + 5.1 minutes㈧ 21.8 41 c28h28cin3 442/444 [M + H] + 5.6 minutes㈧ 21.9 HO < x ★ 12 C27H26C1N30 444/446 [M + H] + 5.1 Min-100779 -197- 200538102 Example 22.1 trans-5- (4-chlorophenyl) _2_ {4 _ [(2_ (4_methyl-hexahydropyridine small methylcyclopropyl] -phenylethynyl} -Pyridine

22.1a Trans-2_ (4-bromophenyl) -cyclopropanecarboxylic acid ethyl ester 5.7 g (55% in mineral oil, 129.5 mmol) NaH was added in portions to 344 g (153.0 mmol) Mol) A solution of trimethylsulfanium iodide in 45 ml of anhydrous DMS. After 1 hour, a solution of 300 g (117.6 millimoles) of p-molyl cinnamate in 400 ml of DMSO was slowly added dropwise, while the temperature was raised to 30 ° C. The reaction mixture was stirred at room temperature for 70 hours, poured onto j liters of saturated NaCl solution, extracted twice with 800 ml of EtOAc, and the organic phase was dried over NadO4 and dried. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, Cyc). Yield: 17.7 g (56% of theory) C12H13Br02 (M = 269.134) Calculated value: Molecular peak (M + H) +: 269/271 丨 Bila. Found: Molecular peak (M + H) +: 269/271 (; Br)

Rf = 0.13 (Shi Xijiao, cyc) Retention time (HPLC): 6_3 minutes (Method B). 22.1b trans- [2- (4-bromophenyl) -cyclopropyl] -methanol at -10 ° C 20.7 g (76.9 mmol) trans-bromophenyl) _cyclo-propane

100779 -198- 200538102 A solution of ethyl alkanoate in 250 ml of THF was added dropwise to a solution of 100 ml (100 mmol, 1 M in THF) of a lithium aluminum hydride solution in 15 ml of THF And the reaction mixture was stirred at 0 t for 1 h. The reaction solution was slowly combined with 20% KOH, while being cooled in an ice bath, stirred for one hour, and transitioned to remove insoluble materials. The liquid phase of the filtrate was separated, the organic phase was dried over Na2S04 and evaporated to dryness in vacuo. Yield: 16.7 g (95% of theory) C10HuBrO (M = 227.098) Calculated value: Molecular peak (M-Η) ·: 225/227 (Br) Measured value: Molecular peak (M-Η)-: 225/227 (Br)

Rf = 0.47 (Shi Xijiao, EtOAc / cyc 1: 1). 22.1c Trans- [2- (4-_phenylphenyl) cyclopropyl] fluorenol in a nitrogen atmosphere, 12.0 (52.8 mmol) A solution of trans- [2- (4-bromophenyl) -cyclopropyl] -methanol and 2.0 (10.6 mmol) Cul in 52 ml of 1,4-dioxolane, and 23.8 g (158.5 mmol) Mol) NaI and 2.3 ml (2U mmol) of N, N, -dimethylethylenediamine were combined. The reaction solution was shaken at 110 ° C for 15 hours, combined with 100 ml of half-concentrated NH3 and 300 ml of EtOAc, the liquid phases were separated, and the organic phase was dried over NasSO4 and dried. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, gradient cyc / EtOAc 3: 1 to 2: 1). Yield: 10.0 g (69% of theory) C10HnIO (M = 274.098) Calculated value: Molecular peak (MH)-= 273 Found: Molecular peak (μ · Η)-= 273 Rf = 0.55 (Shi Xijiao, EtOAc / cycl: 1).

100779 -199- 200538102 22.1d Trans- (2- {4- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] -phenyl} -cyclopropyl) -methanol under argon atmosphere, Add 0.3 g (0.37 mmol) of Pd (dppf) Cl2 and 69.5 mg (0.37 mmol) of Cul to 5.0 g (18.2 mmol) of trans- [2- (4-Ephenyl) -ring Propyl] -methanol, 4.7 g (21.9 mmol) of 5- (4-aerophenyl) -2-ethynylpyridine and 6.5 ml (36.5 mmol) of diisopropylamine in 180 ml of THF Into the solution, and the reaction mixture was stirred at room temperature for 21 hours. After the reaction had ended, the mixture was evaporated to dryness in vacuo, the residue was combined with 150 ml of EtOAc and 300 ml of water, and filtered off. The crystals were combined with TBME, filtered with suction again, and dried. Yield: 6.68 g (100% of theory) C23H18C1N0 (M = 359.848) Calculated value: Molecular peak (M + H) + = 360/362 (Cl) Measured value: Molecular peak (M + H) + = 360/362 (Cl)

Rf = 0.38 (silica gel, EtOAc / cycl: 1) Retention time (HPLC): 6 · 2 minutes (Method B) · 22.1e trans_2- [4- (2-aminomethyl-cyclopropyl)- Phenylethenyl] _5_ (4-Gaphenyl) _Say bite Add 860 microliters (1U2 mmol) S0C12 in 5 ml of DCM to 2.0 g (5.6 mmol) of trans- ( 2- {4- [5- (4-Gaphenyl) -pyridin-2-ylethynyl] -phenyl} -cyclopropyl) -methanol in 25 ml of DCM has been cooled to 0 ° C, The reaction solution was stirred at 0 ° C. for 30 minutes and at room temperature for 1.5 hours. After the reaction was completed, the reaction mixture was combined with 40 ml of 5% NaHC03 solution and 30 ml of DCM at 0 ° C, the liquid phase was separated, and the organic phase was separated by

100779 -200- 200538102

Na2S04 is dehydrated and dried. After the desiccant and solvent have been removed, the residue is purified by chromatography (silica gel, cyc / EtOAc 9: 1). Yield: 520 mg (25% of theory) C2 3 Hi 7C12N (M = 378.293) Calculated value: Molecular peak (M + H) + = 378/380/382 (2 Cl) Measured value: Molecular peak (M + H ) + = 378/380/382 (2 Cl)

Rf = 0.43 (silicone, EtOAc / cycl: 1). 22.If trans-5- (4-gasbenzyl) -2- {4- [2_ (4-methyl-hexaplex p ratio α fixed -1 -Ylmethyl) _cyclopropyl] phenylethoxyl is 80 mg (0_2 mmol) trans-2- [4- (2-aminomethyl-cyclopropylphenylethynyl) A solution of 5- (4-phenyl) -pyridine and 100 μl (0.8 mmol) of 4-methylhexahydropyridine was combined with 144 μl of ethyldiisopropylamine, and Stir for 4 hours at 60 ° C. Purify the reaction mixture by HPLC, combine the product-containing fractions and dry the bed. Yield: 37 mg (40% of theory) C29H29C1N2 (M = 441.007) Calculated value: molecular peak (M + H) + = 441/443 (Cl) Measured value: Molecular peak (M + H) + = 441/443 (Cl) Retention time (HPLC): 8 · 2 minutes (Method A). The following compounds are based on In each case, 80 mg of trans-2- [4- (2-aminomethyl-cyclopropyl) -phenylethynyl] _5- (4-aminophenyl)-? Set the corresponding amount of amine: 100779 -201-200538102

Example R Yield (%) Experimental Mass HPLC Retention Time (Method) 22.2 Η 28 C27H25CIN2 413/415 [M + H] + 7.8 minutes (A) 22.3 QN ~ * H '34 C28H27C1N2 427/429 [M + H] + 8.3 minutes㈧ 22.4 21 C30H31C1N2 455/457 [M + H] + 8.9 minutes㈧ 22.5 ho ^^-oh ιϊ 92 C26H25C1N202 433/435 [M + H] + 7.2 minutes㈧ 22.6 HO ★ 41 C30H31C1N2O 471/473 [M + H] + 7.6 minutes 22.7 HO Waki 32 C29H29C1N20 457/459 [M + H] + 7.4 minutes ㈧ Some test methods for measuring MCH-receptor antagonistic activity will now be described. In addition, other test methods known to those skilled in the art can be used, such as inhibition of cAMP production via inhibition of MCH-receptor mediators, as shown by Hoogduijn M. et al. In π melanin and its receptor system in and on human skin Functionality, as described in Biochem. Biophys. Res Commun. 296 (2002) 698-701, and through the resonance of plasmons in the presence of antagonists, 100779 -202- 200538102 biosensor measures MCH The binding to MCH receptors, such as recombination by KarlssonOP and Lofas S on the surface of `` G-protein-coupled receptor flow medium, supplied for surface plasmon resonance biosensors '', Anal. Biochem. 300 (2002), 132-138. Other methods for testing MCH receptor antagonistic activity are included in the references and patent documents mentioned above, and the description of the test methods used is based on this and is included in this application. MCH-1 receptor binding test method: MCH binds to hMCH_lR transfected cells Species: Human test cells · Transfected with hMCH-lR stability into CHO / Galpha 16 cells Results: IC5G value makes the human hMCH-lR stable Cell membranes of transfected CHO / Galpha 16 cells were resuspended using a syringe (needle 0.6x25 mm) and tested in test buffer (50 mM HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7.00; 0.1% bovine serum albumin ( Protease-free), 0.021% bacitracin, 1 μg / ml aprotinin, 1 μg / ml Leupeptin and 1 Phosphatidone) were diluted to a concentration of 5 to 15 μg / ml. Separate 200 microliters of this cell membrane (containing 1 to 3 micrograms of protein) at ambient temperature with 100 pM of 125I-tyrosine methyl melanin aggregation hormone (125I-MCH is commercially available from NEN) and at Increasing concentrations of test compounds in a final volume of 250 microliters were incubated together for 60 minutes. After this incubation, the reaction was filtered using a cell harvester and a 0.5% PEI-treated glass fiber filter (GF / B, Unifilter Packard). Then, after adding the scintillator substance (Packard Microscint 20), the cell membrane-bound radioactivity of 100779 -203-200538102 retained on the filter was measured in a measuring device (Packard's top counter). Non-specific binding lines are defined as binding radioactivity during the culture period in the presence of 1 micromolar MCH. The analysis of the concentration binding curve is performed under the assumption that one receptor is bound. standard:

Unlabeled MCH binds to the labeled 125I-MCH competition receptor and has an IC50 value between 0.06 and 0.15 nM. The KD of the radioligand was 0.156 nM. MCH-1 receptor-coupled Ca2 + migration assay method: Calcium migration assay using human MCH (FLIPR3 84) Species: Human test cells: CHO / Galpha 16 cells stably transfected with hMCH-Rl Result: 1st metric Value:% stimulation of reference (MCH 10 · 6M)

Reagent: 2nd measurement value: ρKB value HBSS (10χ) (GIBCO) HEPES buffer (1M) (GIBCO) Pluronic F-127 (Molecular Probes) Fluo-4 (Molecular Probes) webenecid (Sigma) ) MCH (Bachem) Bovine Serum Albumin (Serva) (Protease Free) DMSO (Serva) 100779 -204- 200538102

Ham's F12 (BioWhittaker) FCS (BioWhittaker) L-glutamine (GIBCO) (GIBCO)

Hygromycin B PENStrep (BioWhittaker) Zeocin (Invitrogen)

Asexual propagation line CHO / Galpha 16 hMCH-R1 cells were cultured in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; catalog number: BE12-615F). Each 500 ml contains 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 geomycin ( zeocin) (100 μg / ml stock solution). One day before the experiment, the cells were covered with a density of 2500 cells per well on a 384-well microtiter plate (black wall, with a transparent bottom, made by Costar), at 37 ° C, 5% C02 and 95 Incubate overnight in the above medium at% relative humidity. On the day of the experiment, the cells were incubated with 2mMFluo-4 and 4.6 mM probenicid in a cell culture medium at 37 ° C for 45 minutes. After adding the fluorescent dye, the cells were washed four times with Hanks buffer solution (lxHBSS, 20mMHEPES) which had been combined with 0.07% carboxybenzamide. The test substance was diluted in Hanks buffer solution and combined with 2.5% DMSO. The background fluorescence of unstimulated cells was in the FLIPR384 device (molecular device; excitation wavelength: 488 nm; emission wavelength: spectral passband 510 to 570 nm) five minutes after the final washing step. Measured in a 384-well microtiter plate. To stimulate the cells, MCH was diluted in Hanks buffer with 0.1% BSA 35 minutes after the final washing step.

100779 -205-200538102 Pipette into a 384-well cell culture plate, and then measure the MCH-stimulated fluorescence in the FUpR384 device. Data analysis: The first degree I value: Cellular Ca2 + movement is measured as the peak value of relative fluorescence minus the background, and is expressed as a percentage of the maximum signal of the reference (MCH 10 · 6M). This measurement is used to confirm any possible urging action of the substance to be tested. The second measurement value: the cell Ca2 + movement is measured by the peak value of relative fluorescence minus the background, and is based on the reference (MCH 10-6M, the signal is normalized to 100 / >) No. ] y [The ec50 value of the CH dose activity curve 'with and without the substance to be measured (limited concentration) was measured graphically using the Graphpad Prism 2.01 curve program. MCH antagonists cause the MCH stimulation curve to shift to the right in the graph drawn. Inhibition is expressed in terms of pKB ... pKB-lOg (EC5 〇 (test substance + M c η> / ecs 〇 (M c H> -1) -log C (test substance) The compound according to the present invention, Including its salts, in the test mentioned above, it showed MCH-receptor antagonistic activity. Using the Mcjjq receptor binding assay described above, the antagonistic activity was obtained in a dose range from about 10-10 to 10.5M, particularly It is from 〇_9 to io_6m. The following IQo values are measured using the MCH- 丨 receptor binding test. 100779 -206- 200538102

The IC50 value of the compound substance name according to the following example numbers is 6.3 (8) -1- (1- {5- [5- (4-Gasphenyl)-^ biphenyl-2-ylethoxy]-卩 ratio σ 疋-2-yl} _tetrahydropyridin-3-yl) hexahydropyridine-4-carboxylic acid sulfonamide 3.7 nM 15.5 ((EHR) -3_ {4- [5- (4-Gaphenyl) -pyridine-2 -Ylethynyl] -phenyl} -1-methyl-but-2-fluorenyl) -cyclopropylmethyl-propyl-amine ---- 25 nM

Some formulation examples will be described later, where the term "active substance," means one or more compounds according to the present invention, including salts thereof. In the case of having one of a combination of a plurality of said active substances, "active The substance word also includes additional active substances.

Example A Capsules inhaled by Ken A, containing 1 active-free temporary composition: 1 capsule for powder inhalation containing: 1.0 mg 20.0 mg 5 mg of active substance lactose hard gelatin capsule 71.0 mg The active substance is ground until the active substance and The particle size needed for lactose to be inhaled uniformly. Mix the ground. Fill the mixture into hard gelatin capsules. 100779 -207- 200538102

Example B For Respimat® ^ Γ. ^ IL ίΓ Into the solution, there will be 1 mg of creative composition. 1.0 mg 0.002 mg 0.0075 mg 15.0 μl

1 spray contains: Active substance benzyl alkoxy ammonium chloride Disodium acetic acid Pure water to Preparation method: Dissolve the active substance and ammonium oxyalkanoate chloride in water and fill the Respimat® cartridge.

Example C 1 solution in a nebulizer tank, containing 1 g of active matter. Composition: 1 vial containing: active substance 0.1 g of gasified sodium 0.008 g of gasified ammonium hydroxide 0.002 g of pure water to 20.0 Preparation method for milliliters: Dissolve the active substance, sodium vaporization and vaporized benzyl alkoxide in water.

Example D: There are 1 milliseconds of active ingredients. Composition: 100779 -208- 200538102 1 spray contains: active substance 1.0 mg egg fat 0.1% propellant gas to 50.0 microliters Preparation method: make micronized active The substance is evenly suspended in the lecithin and propellant gas

In the mixture. This suspension was transferred to a pressurized container with a metering valve. Example E Contains 1 voucher. Active substance composition: 1.0 mg 0.9 mg 0.025 mg 0.05 mg 0.1 ml Active substance Sodium vaporization Oxygen ammonium oxide Oxide second steel Pure water to Preparation method:

The active substance and excipients are dissolved in water and transferred to the corresponding container. Example F

5 mg 250 mg 10 mg 250 mg Active substance Glucose Human serum albumin Sugar furanal 100779 -209- 200538102 Water for injection to 5 ml

Dissolve sugar squeegee and glucose in water for injection (Wfl); add human blood / monthly albumin; dissolve the active ingredients and heat; make up to the specified volume with wfI; transfer to ampoules under nitrogen. iJiG

Composition: Active substance 100 mg Monopotassium phosphate = KH2P〇4 12 mg Disodium hydrogen phosphate = Na2HP04 · 2H20 2 mg Sodium vaporization 180 mg Human serum albumin 50 mg Polycyanate 80 20 mg

Water for injection to 20 ml

Dissolve polycyanate 80, sodium vaporization, monopotassium phosphate, and disodium hydrogen phosphate in water for injection (Wfl); add human serum albumin; decompose the active ingredient 4 and heat; supplement with Wfl to Specified volume; transfer to ampoule. Contains ίο 亳 gram of actives! Grade: 10 mg Active substance 100779 -210- 200538102 300 mg 20 mg Mannitol Human serum albumin: Dissolve mannitol in water for injection (Single; add human serum albumin

Dissolve the active ingredients and heat; make up to the specified volume with wfI. Transfer to a vial; freeze-dry. ’Solvents for lyophilisates:

20 mg 200 mg 10 ml polyacetic acid g purpose 80 = Tween 80 mannitol water for injection to: Dissolve polycyanate 80 and mannitol in water for injection (w print; transfer to ampoules) .

Example I Only contains 20 milligrams of coupons. Live * Temporary composition: 20 mg of lactose, 120 mg of corn powder, 40 mg of magnesium stearate, 2 mg of magnesium stearate, 2 mg of Povidone K 25 Preparation: 18 mg of active substance, lactose and Corn starch is uniformly mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; -....- (/ 100779 -211-200538102 tablet weight 200 mg. Examples J Calendar i, containing 20 to 3

Preparation of active substance corn starch highly dispersed silica gel magnesium stearate: 20 mg 80 mg 5 mg 2.5 mg Mix the active substance and corn starch into ^ + Evening gum; mix with magnesium stearate, fill in capsules In the machine, fill the mixed agricultural product into the hard gelatin capsule No. 3. Example KK

Good medicine, contains 50 milliA live! Composition: Active substance hard fat (tallow fat solid) is sufficient to _ Preparation: The hard fat is melted at about 38 ° C; the milled active substance is uniformly dispersed in the molten hard fat; cooled to about 35 After ° C, pour it into a quenched mold. Example L Liquid storage, prepare 1 well with 10 mg j tongue sex 50 mg 1700 g active substance 10 mg 100779 -212- 200538102 mannitol 50 mg human serum albumin 10 mg water for injection to 1 ml Preparation: Make Mannitol is dissolved in water for injection (Wfl); human serum albumin is added; the active ingredients are dissolved and heated; make up to the specified volume with Wfl; and transferred to ampoule under nitrogen.

100779 213-

Claims (1)

200538102 Scope of patent application: R1 \ acetylene compounds of general formula I ^ / N ~ χ ~ γ— ZZ ——: —W-A—B where R1 and R2 independently represent H, C8, alkyl, C3.7-Cycloalkyl or phenyl or pyridyl, mono- or poly-substituted with the same or different groups R 2 0, and / or mono-substituted with nitro, at the same time, alkyl or cycloalkyl may be the same or Different groups R11 are mono- or poly-substituted 'and the -0ν group at the 3 or 4 position of the 5-, 6- or 7-membered ring alkyl group may be replaced by -〇-, -S- or -NR13 ·, Or R1 and R2 form a C3_s_ secondary alkyl bridge group, in which the _CH2 · group of the N atom which is not adjacent to the Wr ^ N- group can be -CH-N-, -CIKH-, -0-, -S-, -SO-,-(S〇2)-, -CO-, _C (= CH2) _ or _NR13- substitution, and at the same time, in the alkylene bridge group defined in the foregoing, one or more The fluorene atom may be replaced by the same or different group, and the alkylene bridge group defined above may be substituted by one or two same or different carbocyclic or heterocyclic group Cy, so that the alkylene bridge The bond between the group Cy and the group Cy is made in the following manner-via a single or double bond, -I is C atom, forming a spirocyclic ring system,-via two shared adjacent C and / or ^^ atoms, forming a dense 100779 200538102 bicyclic ring system, or-via three or more C and / or N atoms To form a bridged ring system; X represents a Cn · alkylene bridge group, which contains one or more substitutions Are independently selected from the group consisting of fluorine, gas, hydroxyl, cyano, cf3, C4-alkyl, per-Cle4-alkyl, C3 · 6-cycloalkyl and c_4-alkyloxy. At the same time, two Nominal substituents can be joined together to form C3_7-cycloalkyl, or C: 2 · 4 · alkynyloxy or Q-4 · imineimino bridge group, and at the same time, imine group can be C1-4 -Alkyl substituted, and wherein the secondary unit contains one or more substituents independently selected from fluorine, gas, CF3, hydroxy-Cl_4 · alkyl, Ch_alkyl, and c3 6_ cycloalkyl, and at the same time, two Alkyl groups can be joined together to form a C3_7_cycloalkyl or cyclo-c4_6-alkylimino group, or a C3_6-alkenylene or C3-6-alkynyl bridge group, which are unsubstituted or contain a Or multiple substituents independently selected from fluorine, gas, CF3, hydroxy_c1-4-alkyl, c4-alkyl, and C3_6-cycloalkyl 'At the same time, two alkyl substituents can be joined together To form a C3_7 • cycloalkyl or C5_7-cycloalkenyl group, and W and Z independently of each other represent a single bond or a C! _ 2-secondary alkyl bridge group. At the same time, two adjacent c atoms can be bonded to another (^ -4-alkylene bridges are joined together and one or two C atoms Atoms can be independently substituted by one or two identical or different Ci-3 -alkyl groups, and at the same time, two alkyl groups can be joined together to form a carbocyclic ring, and 2005 and A are independently selected from bivalent rings. Like groups, benzyl, pyridyl, pyrimidinyl, pyrimidinyl, dahenyl, naphthyl, tetrahydronaphthyl, indolyl, dihydro # 丨 inyl, fluorinyl, dihydrofluorinyl, Tetrahydroquinolyl, isofluorinyl, dihydroisofluorinyl, tetrazine-isoamyl, stilbyl stilbyl, benzo P tr, pp stilbene, pinene-4- Keto, thienyl, furyl, benzopyrimyl, or benzofuranyl, and at the same time, the above cyclic group may be mono- or polysubstituted by one or more C atoms at the same or different groups 'In the case of a benzene ring, it may be additionally mono-substituted by nitro, and / or one or more NH groups may be substituted by R21, B Cy has one of the meanings given to Y and A, or it represents Cu-alkyl, C6-alkenyl, (^ _6_quickyl, c3-7 · ring courtyard, Cw ring alkyl, Cw ring courtyard -Ch-alkenyl, Cw cycloalkenyl-C3 3-alkynyl, Ch-cycloalkyl-Ch-alkenyl, or Cw cycloalkenyl-Cw alkynyl, wherein one or more C atoms independently of one another can be replaced by The halogen is mono- or poly-substituted, and / or may be mono-substituted by a hydroxyl group or a cyano group, and / or the cyclic group may be mono- or poly-substituted by the same or different group R20, which means a carbocyclic or heterocyclic group. From one of the following meanings-a saturated 3- to 7-membered carbocyclic group,-an unsaturated 4- to 7-membered carbocyclic group, _phenyl, 100779 -Saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic groups' having N, 0 or S atoms as heteroatoms, -Saturated or unsaturated 5- to 7-membered heterocyclic groups Group having two or more N atoms, or having one or two N atoms and one N, 0 or S atom as a heteroatom,-an aromatic heterocyclic 5- or 6-membered group having one or more Same or different heteroatoms, selected from N, 0 and / or s, at the same time, the above saturated 6- or 7-membered group may also have an imine group, (Ch · alkyl) -imine group, methylene group Group, ((^^ alkyl) · methylene or di- (q · 4-alkyl) -methylene bridging ring system exists> and the above cyclic group may be at one or more C atoms Where it is mono- or poly-substituted by the same or different group R20, in the case of phenyl, 'may also be mono-substituted by nitro, and / or one or more NH groups may be substituted by r2 1, meaning halogen, Ch-Chenyl, C2-6-diluted, C2-6-alkynyl, R15_0-, Rl5_aC (>, r15-C (M >, cyano, R16R17N-, Rl8R19N_C0_4Cy, at the same time, in the above groups , One or more c atoms may be substituted independently of one another by a substituent, The substituent is selected from halogen, OH, CN, CF3, Ci-3-alkyl, hydroxy-3-alkyl; has one of the meanings given for R17, and represents halogen, cyano, Cu-alkyl, C2-6- Alkenyl, c2-6-alkynyl, R15-〇 ·, Ri 5-OC0-, R15 -CO-, R15 -COO-, -4- 200538102 R16R17N-, R18R19N-CO-, rU-O-Ch-alkyl, r15-o-co-c 3-alkyl, r15-so2-nh-, R15-O-CO-NH-Ci_3-alkyl, R15-S〇2-NH-q_3--alkyl, R15-CO-C 3-alkyl, R15-C0-0-C 3-alkyl, R16Rl7N_Ci3-alkyl, R18R19N-C0_Ci_3-alkyl or Cy-Ci_3-alkyl H, Cn-alkyl, (: 3-7_cycloalkyl, C3_7-cycloalkyl_ -Ci-3 -alkyl, phenyl, phenyl-Cl-3 -alkyl, p-phenyl or external R 定 定 定 -Ci _ 3 -alkyl, R1 6 represents fluorene, Cn-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-β-3-alkyl, β-7-bad Diluted group, fluorene 4-7-cyclo-diluted group 1-3-alkyl, ω-hydroxy-C2-3-alkyl, ωβ-fluorenyl-alkoxy) -C2-3-alkyl, amine-C2_6-alkane (V4-alkyl-amino-C2-6-alkyl), mono- (Ci-4-alkyl) -amino-C2-6-alkyl or cyclic < 3-6 _ alkyleneimine Radical-C2-6- Alkyl group, • R17 has one of the meanings given for R16, or represents phenyl, phenylfluorenyl_3_alkynyl, p-pyridyl, Ci-4-carbyl, viayl , Cn oxoyl, Cl-4- oxoyl (Bu 3 " alkynyl, Ci-4- oxoamino) < 2-3-alkyl, N- (C C 4 * " Burner group) -N_ (Ci-4_yuan) -amino group < 2-3-carbon group, Q-4-alkylsulfonyl group, Ck alkylsulfonylamino group (2 · 3_carbon Or N- (Ci—4-alkyl) —N (-Ci_4-alkyl) —amino-C2-3-alkyl; R18 and R19 independently represent H or alkyl, 100779 200538102 R20 Halogen, hydroxy, cyano, Cu-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-7-cycloalkyl, c3_7-cycloalkyl-Ch-alkyl, hydroxy-01_3-alkyl, 1122_ 〇: 1_3-alkyl, or one of the meanings given to R22, R21 • represents Ch-alkyl, ω-hydroxy_C2-6-alkyl, ω-c4-alkoxy-C2-6- Alkyl, ω-Cn alkyl-amino_c2_6-alkyl, ω-di- (Cw alkyl) -amino-C2-6-alkyl, ω ^ _〇3 · 6-hemimino-C2 -6-alkyl, phenyl, phenyl-(^ _ 3 · alkyl, Cn-alkylcarbonyl, Ciw alkoxy-carbonyl, (^ -4-Alkylsulfenyl, aminesulfenyl, Cn alkylsulfenyl, di-CVr alkylaminosulfonyl, or cyclic-C3-6-alkylidene-iminyl-benzyl Fluorenyl, R22 »represents fluorenyl than fluorenyl, phenyl, phenyl-Ci-3 -alkoxy, cyclo-C3-6 · alkylideneimino-C2_4-alkoxy, OHC-, HO-N = HC-, group, carboxyl, c ^ -alkoxycarbonyl, C ^ -alkoxycarbonyl, aminocarbonyl, Ci-4-alkylaminocarbonyl, di- (Ci-r alkyl) -amino group, ring- C3-6-Alkenyl-Amino-Phenyl, Ring " Ά-6-Trimidineimino-carbonyl, Phenylaminocarbonyl, Ring-C3-6-Trimyleneimine < 2-4 -Alkyl-amino-carbyl, Ci-4 -Alkyl-continuous, Ci-4 -Alkyl-substitutyl, Cl-4 -Alkyl-continyl-amine, Amine, Ci 4-Alkylamino, di- (Cl_4 * alanyl) _amino, (V4-alkyl-amino, cyclic-c3_6-methyleneimino, phenyl · Cn alkylamino, N- ( C phenyl group) _phenyl-Cn amine 100779 200538102 group, acetamido group, propionylamino group, phenylcarbonyl group, phenylcarbonylamino group, phenylcarbonylmethylamino group, hydroxy-C2-3- Alkylaminocarbonyl, (4-morpholinyl), phenyl, (1-tetrahydropyrrole ) Jiji, (1-Hexahydrotidinyl) Jiji, (Hexa-1--1-azaheptenyl) carbonyl, (4-methyl-1-hexahydropyridyl) carbonyl, methylene Dioxy, aminocarbonylamino or Cn-alkylaminocarbonylamino, and, among the above-mentioned groups and atomic groups, especially W, z, R13 to R22, in each case, one or more Each C atom may be additionally mono- or poly-substituted by F, and / or in each case one or two C atoms are independently mono-substituted by ci or Br, and / or The ring may additionally contain one, two or three substituents independently of one another, selected from the group F, cl, Br, I, cyano, Cyalkyl, q-4 · alkoxy, difluoromethyl, trifluoro Methyl, hydroxyl, aminoalkylamino, di- (Cl-3_alkyl), amino, acetamido, aminocarbonyl, difluoromethoxy, trifluoroamido, aminoalkyl , Ch-alkylamino-Ch-alkyl, and di- (Ch_alkyl) > amino-Ch-alkyl, and / or may be mono-substituted by a nitro group, and the fluorene atom of any of the retarding groups or The η atom bound to the n atom can be split in each case by the Group substitution, its tautomers, diastereomers, paraisomers, mixtures, and salts thereof, however, the following compounds are not included in the present invention: (1- {5- [5- (4-Phenylpyridin-2-ylethynyl) -pyrimidine · 2_yltetrahydropyrrole_3 · yl) -dimethyl_amine, 100779 200538102 545- (4-Gaphenyl) -pyridine_2_ylethynyl] _3_tetrahydropyrrole_ 丨 _yl_3,4,5 & tetrahydro-2Η- [1,2, '] bipyridine ^ Γ- {5- [5- (4-chlorophenyl) -pyridin-2-ylethynyl] _pyridin_2_ylHu,] bistetrahydropyridyl, {5- [5- (Winterchlorophenyl) -pyridin-2-ylethynyl] -pyridine_2-ylbutanyl (2 • tetrahydropyrrole I-propyl) -amine, 5- (4-chlorophenyl) -2- [ 4- (1-methyl-2-hexahydropyridine-μyl-ethoxy) _benzylethynyl] -sigma, 5- (4-Gaphenyl) -2- [4- (3- Hexahydropyridine-μyl · tetrahydropyrrole + yl) -phenylethyl block] -sigma, 5- (4-Gaphenyl) -2- {4- [2- (4-methyl-hexa Hydrogen stilbyl group) _propoxy] _benzyl ethynyl} ϋ ϋ ϋ, (1- {5- [5- (4-chlorophenyl) -pyridin-2-ylethynyl]- Pyridine_2_kib tetrahydro eicosyl) -4-methylhexahydroρ specific bite, 5- (4-phenyl) -2- [4- (2-fluorenyl-2-hexahydroe . Definite group · propoxy) -phenylethynyl] -pyridine, 5- (4-phenyl) -2- {4- [3- (4-fluorenyl-hexahydro p ratio 唆 -1- ) _Cyclohexyl] _phenylethynyl} -pyridine, 5- (4-airphenyl) -2- {4- [3- (4-fluorenyl-hexahydrop-ratio-1- ) _Cyclohexenyl] _phenylethynylpyridine, 5- (4-phenyl) -2- {4- [3- (4-methyl-hexahydropyridin-1-yl) _cyclopentyl Diluted group] -phenylethenyl} -ρ ratio bite, 5- (4-Gaphenyl) -2- {4- [3- (4-methyl-hexahydro-exo-t-d-1-yl) -Cyclopentyl] -phenylethynyl} -Samarine, 100779 200538102 5- (4-chlorophenyl) -2- [4- (3-tetrahydropyrrole-i-yl_propenyl) _phenylacetylene Group] -pyridine, 5- (4-aminophenyl) -2- [4- (3-tetrahydropyrrole-i-yl_propi-alkynyl > phenylethynyl]]. For example, the alkyne compound of claim 1, characterized in that the groups Ri and R2 are independently selected from the group consisting of fluorene, Ci · 6 · alkyl, c: 3.5 · alkenyl, c3-5-alkynyl, C3- 7-cycloalkyl, hydroxycycloalkyl, c3_7-cycloalkyl-Ch-alkyl, (hydroxy-C3-7-cycloalkyl) _Ch_alkyl, hydroxy_c2-4-alkyl, o-NC -Cw alkynyl, Cn alkoxy-C2-4-alkyl, hydroxy-Ch-alkoxy-c2_4-alkyl, (ν4-carboxy-weiyl-Ch-alkyl, carboxy_c1-4 _Alkyl, amine_C2 4-alkyl, Ch-alkyl-amino-C2-4-alkyl, di_ (c1-4-alkyl) _amino_c2-4_alkyl, ring _C3 · 6 · secondary imino-C2_4 · carbon Tetrahydropyridin-hee! Radical, N-dryl) -tetrahydropyrrolidin-3-yl, tetrahydropyrrolyl-Cu-alkyl, N-((^-4_alkyl) -tetrahydro 17 Alkyl, hexahydrou-ratio-3-yl, hexahydrop-r udin-4-yl, Ν-Α · 4-alkyl) -hexahydropyridyl, N_ (Ci-4_alkyl) _hexa Hydropyridine_4_ group, /, 疋 σ 疋 -Ci_3 -carbyl, N- (Ch -carbylhexahydrogallyl 11 amidyl-Cb 3 -carbyl, tetrahydropiperan-3-yl, Tetrahydropiperanyl, phenyl, phenyl-c ^ alkyl, bulky or pyridyl-C3-alkyl, and one or more C atoms in the above-mentioned groups and radicals may be Are mono- or poly-substituted by F, alkyl or hydroxy-Ci-3, and / or one or two c atoms may be mono-substituted by Cl, Br, OH, CFS or CN independently of each other, and phenyl Or p may be mono- or poly-substituted by the same or different group r 2 0, and in the case of phenyl, it may be additionally mono-substituted by nitro, and the group R 2 0 has the meaning given in claim 1 100779 200538102 3. The alkyne compound of Shiming seeking item 1, characterized in that R1 and R2 together with the N atom to which they are bound form a heterocyclic group, which is selected from the group consisting of In the following sense, tetrahydropyrrole, hexahydropyridine, 8-nitro_bicyclo [3H] octane, hexahydropyridine, in which the free-state imine functional group is replaced by Rl3, and morpholine, and 'one or more Each fluorene atom may be replaced by the same or different group R1 4 and / or the above heterocyclic group may be replaced by one or two same or different carbocyclic or heterocyclic groups & The bond between the alkylene bridge group and the group ~ group Cy is made in the following way: • via a single or double bond,-via a shared C atom, forming a spirocyclic ring system,-via two shared adjacent C -And / or N atoms to form a fused bicyclic bad system, or-to form a bridged ring system via three or more C- and / or N atoms; and the groups R13, RH and the Cy system As defined in claim 1. Preview 4. The alkyne compound according to any of claims 1 to 3, characterized in that X represents a propylidene bridge group, which contains 1, 2, 3 or more of the same or Different substituents are selected from fluorine, gas, hydroxyl, Cp3-alkyl and cyclopropyl. At the same time, two alkyl substituents can be joined together to form C3_6-cycloalkane Or ethoxy or ethyleneimine bridging group, wherein the imino group may be substituted by (^ -4-alkyl, which contains 1, 2, 3 or more of the same or different substituents, selected from fluorine, gas C, 3-alkyl and cyclopropyl. At the same time, two alkyl groups can be joined together to form a C3.6-cycloalkyl group, or if the alkyl group is linked to an imine group, they can also be joined together. To form tetrahydropyrrole or hexahydropyridine, or 100779 -10- 200538102 _CH2 -CH = CH- or -CH2 -C tri-C- bridge group, which is unsubstituted or contains ^, 2, 3 or more substituents, selected from fluorine, chlorine, c Alkyl and cyclopropyl. At the same time, two alkyl substituents can be joined together to form a c3 6-cycloalkyl. 5. The alkyne compound according to any one of claims 1 to 3, characterized in that z represents a single bond or an ethylidene group, and W represents a single bond. 6. The alkyne compound according to any one of claims 1 to 3, characterized in that the group γ is selected from the group consisting of a monovalent cyclic group, phenyl, pyridyl, pyrimidinyl, pyrimidinyl, φdachinyl , Tetrahydrofluorenyl, fluorinyl, dihydroquinolinyl, quinolinyl, dihydrofluorinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisofluorinyl, tetrahydro_isoquinoline Group, benzimidazolyl group, benzoxazolyl group, fluorenyl group, pinenone group, benzofluorenyl group or benzofuranyl group, and the above cyclic group may be at one or more C atoms, Mono- or poly-substituted by the same or several groups R 2 0, and in the case of a benzene ring, may also be mono- substituted by a nitro group, and / or may be substituted by R 21 at one or more N atoms, at the same time The anti-20 and the 21 all have the meaning given in claim 1. Call 7. If the alkyne compound in the item 壬 non-item in item 请求 is requested, it is characterized by the group a «from the divalent cyclic group 'phenyl" than phenyl group, sparbityl group bisphenyl group or Jingji group May be mono- or poly-substituted at one or more C atoms by the same or different group r20, and in the case of a benzene ring, it may be additionally nitrated, and R 0 has the meaning given in claim 1 . 8. The block compound according to any one of claims 1 to 3, characterized in that the group system is selected from the group consisting of phenyl, cyclohexyl, "biphenyl", sedenyl, and β-succinyl, and 'the above ring The same group can be substituted at the same or more c atoms with the same or 100779 200538102 the same group R20, or more, and in the case of a phenyl group, it can be additionally substituted with a nitro group, and R2G has a claim The meaning given in 1. 9. The acetylene compound according to any one of claims 1 to 3, wherein Y has a meaning selected from the following: And A has the meaning selected from # B represents phenyl, cyclohexenyl, pyridyl, phenenyl, and furyl, preferably phenyl. Meanwhile, Y and A are unsubstituted or monosubstituted by R2O, and B is unsubstituted Or they may be mono-, di-, or tri-substituted by R20 independently of each other, and in the case of a benzene ring, may also be mono-substituted by nitro, and tR20 has the meaning given in claim i. 10. The alkynyl compound according to any one of claims 1 to 3, wherein R20 represents 卩 ^^ Bu㈤ ^ yl'methyl ~ difluoromethyl, 100779 -12-200538102 difluoromethyl, ethyl , N-propyl, isopropyl, amino, ethenyl, methoxy, difluorofluorenyl, trifluoromethoxy, ethoxy, n-propoxy, or isopropoxy, and Recurring substituents R20 may have the same or different meanings. 11. A physiologically acceptable salt of an alkyne compound as claimed in any one of claims 1 to 10. 12. A composition comprising at least one alkyne compound as claimed in any one of claims 请求 to ⑺ and / or a salt as claimed in claim η, optionally with one or more physiologically acceptable endowments形 剂。 Shape agent. 13. A pharmaceutical composition comprising at least one alkyne compound as claimed in any one of claims i to and / or a salt as claimed in n, optionally accompanied by one or more inert carriers and / or diluents . / A kind of at least one acetylenic compound according to any one of% to 10 and / or a salt according to claim 11 for use in the preparation of a pharmaceutical composition for influencing a mammal's eating behavior. # Mouth seed as at least one kind of amidine compound according to any one of items 1 to 10 and / or a salt such as item 11 for use in the preparation of a pharmaceutical composition for reducing the weight of a mammal And / or prevent weight gain. / Zhong Shiming seeks at least one acetylenic compound according to any one of items i to 10 and / or the salt of long item 11 for use in the preparation of a pharmaceutical composition which has MCH and receptor-containing anti-activity. 17 · ~ At least one alkyne compound according to any one of items 1 to 10 and the salt of / 3, or item 11 for use in the preparation of a pharmaceutical composition, the pharmaceutical composition 100779 -13- 200538102 It is suitable for the prevention and / or treatment of symptoms and / or diseases caused by MCH or otherwise reasonably connected to MCH. 18 'at least one alkyne compound according to any one of claims 1 to 10 and / or a salt according to claim 11 for use in the preparation of a pharmaceutical composition suitable for the prevention and / or treatment of a metabolic disorder And / or eating disorders, particularly obesity, bulimia, cachexia, anorexia, anorexia nervosa, and overeating. At least one alkyne compound according to any one of 4 items 1 to 10 and / or a salt as specified in item 11 for the preparation of a pharmaceutical composition, which is suitable for the prevention and / or treatment of obesity Associated diseases and / or diseases ^ Diabetes, especially type 11 diabetes, diabetic complications, including retinopathy in patients with branuria, neuropathy in diabetic patients, heat-producing nephropathy in diabetic patients, insulin resistance, Pathology Glucose tolerance, brain, "visceral insufficiency, cardiovascular disease, especially arteriosclerosis and hypertension, arthritis and knee arthritis. At least one acetylenic compound according to any one of claims 1 to 10 and / 2 If the salt of the item u is used for the preparation of a pharmaceutical composition, the pharmaceutical combination product is used for the prevention and / or treatment of hyperlipidemia, bee sting fibritis, and fat storage and salt storage. Pigmentary anesthesia, affective disorders,: disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, psychiatric disorders, epilepsy, forms of dementia, and hormonal disorders. Or any of the items 1 to 10 At least one acetylenic compound according to one item and / or the salt according to claim 11 for use in the preparation of a pharmaceutical composition for the prevention and / or treatment of urinary disorders such as urinary incontinence, bladder 100779 -14- 200538102 2 hyperactivity, Urinary urgency, nocturnal disease, and enuresis. ^ 1 at least one alkyne compound of any one of items 1 to 10 and the salt of / 5, / month long item 11 for use in the preparation of a pharmaceutical composition, the pharmaceutical composition It is suitable for the prevention and / or treatment of dependence and / or withdrawal symptoms. 23 ·: A method for preparing a composition or a pharmaceutical composition according to any one of claims 12, 13, and 16 to 22, characterized in that at least one of any one of claims 1 to 10 is requested by a non-chemical method The alkyne compound of one item and / or the salt of claim II is incorporated into one or more inert carriers and / or diluents. 24. A pharmaceutical composition comprising a first tongue-like substance selected from the group consisting of an alkyne compound according to any one of claims 1 to 10 and / or a salt according to claim 11, and a first active substance, It is selected from active substances for treating diabetes, active substances for treating diabetic complications, active substances for treating obesity, preferably other than MCH antagonists, active substances for treating hypertension, and hyperlipidemia (including arteriosclerosis). Active substances, active substances for the treatment of arthritis, active substances for the treatment of anxiety states, and active substances for the treatment of depression, optionally with one or more inert carriers and / or diluents. 25. A method for preparing an acetylene compound of the formula α · 5, R1 R2 NXYC = CWAB (Α.5) Meanwhile, in the formulas A · 1, Α · 2, Α · 3, Α.4 and Α.5, 111, 112, ¥; and ^ ¥ ^ and 8 each have one of the meanings given in claims 1 to 10, wherein the halogen compound of formula A.1 is HO-XY-Hal (A.1), where Hal represents chlorine, Bromine or iodine, preferably bromine or iodine, is compounded with acetylene of formula A · 2 100779 -15- 200538102, H-CeC_W-AB (A.2) in a suitable palladium catalyst, a suitable base and copper iodide ( I) In the presence of a suitable solvent, the compound HO-XYC tri-CWAB (A.3) It reacts with gasified methanesulfonium (MsCl) to produce a methanesulfonate derivative A.4, MsO-X-Y-C = C-W-A-B (A.4) to further react with amine of formula H-NRiR2 to form the final product human 5. 26. A method for preparing acetylenic compounds of formula B.5, R1 R2 NX-Y_Z-C tri-CAB (B.5) At the same time, in formula (1): 8.2, 6.3, 8.4 and 5 (1), ; ^ 2,: ^, fork 2 ;, and 3 have one of the meanings given in claims 1 to 10, wherein the halogen compound of formula B.1 Hal-AB (B.1) where Hal represents gas, Bromine or iodine, preferably bromine or moth, and β-2 acetylenic compound, HO-XYZC tri-CH (B.2) in the presence of a suitable palladium catalyst, a suitable base and copper (I) iodide ^ It reacts in a solvent, and reacts the formed compound HO-X-Y_Z-C ε CAB (B.3) of the formula B.3 with gasified methanesulfonium (MsCl) to form a pinaneuronic acid derivative B · 4. MsO-XYZC tri-CAB (B.4) 100779 -16-200538102 further reacts with the amine of formula H-NRiR2 to form the final product B5. 27. — A method for preparing acetylenic compounds of formula C.3, R1 R2 NXYC tri-CWAB (C.3) At the same time, in formulas C.1, C.2 and C.3, ruler 1, 1 ^, and ¥ In the world, eight and three each have one of the meanings given in claims 1 to 10, wherein the halogen compound of formula C.1 is ^ NXY-Hal (C.1) where Hal represents gas, bromine or iodine, preferably For bromine or iodine, with the alkyne compound of formula C2, HC ^ CWAB (C.2) in the presence of a suitable catalyst, a suitable base and copper (I) iodide, further reaction in a suitable solvent to produce the final product C. 3. 28 · —A method for preparing acetylene compounds of formula D.3, R1 R2 NXYZC e CAB (D.3) Simultaneously 'in formulas D.1, D.2 and D.3' R ^ R'x, γ, ζ, a and b each have one of the meanings given in claims 1 to 10, wherein the halogen compound of formula D.2 Hal-AB (D.2) is used, wherein Hal represents gas, bromine or iodine, preferably bromine or Iodine reacts with a fast compound of formula D1, ^ NXYZC ^ CH (D.1) in the presence of a suitable palladium catalyst, a suitable base, and copper (I) iodide in a suitable solvent to form the final product D.3. 100779 -17- 200538102 7. Designated representative map: (1) Designated representative map in this case is: (none) (II) Brief description of the component symbols of this representative map: 8. If there is a chemical formula in this case, please disclose the features that can best show the invention Chemical formula: W-A-B 100779