JP2006507246A - Novel carboxamide compounds having MCH antagonistic activity, pharmaceutical compositions containing these compounds and methods for their production - Google Patents

Abstract

（式中、基Ａ、Ｂ、Ｗ、Ｘ、Ｙ、Ｚ、R¹、R²、R³、及びｋは請求項１に示された意味を有する）
のカルボキサミド化合物に関する。また、本発明は前記カルボキサミド化合物の製造方法及び少なくとも一種の本発明のカルボキサミドを含む薬物に関する。本発明の薬物はそのMCH-受容体拮抗活性のために代謝障害及び／又は食事障害、特に肥満、多食症、拒食症、過食症、及び糖尿病を治療するのに適している。The present invention relates to general formula (I)
[Chemical 1]

(Wherein the groups A, B, W, X, Y, Z, R ¹ , R ² , R ³ , and k have the meanings given in claim 1).
Of the carboxamide compound. The present invention also relates to a method for producing the carboxamide compound and at least one drug containing the carboxamide of the present invention. The drugs of the present invention are suitable for treating metabolic and / or dietary disorders, particularly obesity, bulimia, anorexia nervosa, bulimia, and diabetes because of their MCH-receptor antagonist activity.

Description

  The present invention provides novel carboxamide compounds, methods for their preparation and their physiologically acceptable salts, as well as prevention and / or prevention of symptoms and / or diseases caused by MCH or in some other manner causally associated with MCH. Or relates to their use in preparing pharmaceutical formulations suitable for therapy. Furthermore, the present invention relates to the use of the compounds of the present invention to affect dietary behavior and to reduce mammal weight and / or prevent weight gain. The invention also relates to compositions and drugs comprising the compounds of the invention, and methods for their preparation.

Food intake and its conversion in the body are an integral part of the life of all living organisms. Therefore, deviations in food intake and conversion generally lead to problems and also illness. Changes in human lifestyle and nutrition, especially in industrialized countries, have promoted obesity in recent decades. In affected people, obesity directly leads to limited exercise and poor quality of life. There are additional factors that obesity often leads to other diseases such as diabetes, dyslipidemia, hypertension, arteriosclerosis and coronary heart disease. Furthermore, high body weight alone adds increased strain to the support and exercise apparatus, which can lead to chronic pain and disease, such as arthritis or osteoarthritis. Thus, obesity is a serious health problem for society.
The term obesity means excess adipose tissue. In this regard, obesity should basically be seen as an increased level of obesity that poses a health risk. While past analysis does not allow an accurate picture of the distinction between normal and obese individuals, it is estimated that the health risks associated with obesity continually increase as obesity levels increase. For simplicity, in the present invention, the body mass index (BMI) above the value of 25, more particularly above 30 (this is the measured body weight in kilograms divided by the squared height in meters) It is preferred that an individual with) is considered to suffer from obesity.
Aside from physical activity and nutritional changes, there are currently no definitive treatment options for effectively losing weight. However, since obesity is a major risk factor in the development of serious and even life threatening diseases, it is more important to obtain pharmaceutically active substances for the prevention and / or treatment of obesity. One very recently proposed approach is the therapeutic use of MCH antagonists (see inter alia WO 01/21577, WO 01/82925).

Melamine-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is synthesized primarily in the mammalian hypothalamus, from where it travels to the rest of the brain by the processes of hypothalamic neurons. Its biological activity is mediated in humans by two different glycoprotein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, namely MCH receptors 1 and 2 (MCH-1R, MCH-2R) .
Studies on the function of MCH in animal models have given good indications on the role of peptides in regulating energy balance, ie in changing metabolic activity and food intake [1,2]. For example, after intraventricular administration of MCH in rats, food intake was increased compared to control animals. Furthermore, transgenic rats that produced more MCH than control animals responded by obtaining a significantly higher body weight when fed a high fat diet than animals that did not produce experimentally altered MCH levels. It was also found that there was a significant correlation between the stage of increased desire for food and the amount of MCH mRNA in the rat hypothalamus. However, experiments with MCH knockout mice are particularly important to demonstrate MCH function. Neuropeptide loss results in lean animals with reduced fat mass, which consume significantly less food than control animals.
The appetite-suppressing effect of MCH is mediated by G _As -linked MCH-1R in rodents [3-6]. Unlike primates, white weasels and dogs, secondary receptors have not been previously found in rodents. After losing MCH-1R, knockout mice have a lower fat mass, increased energy conversion and do not gain weight when fed on a high fat diet compared to control animals. Another indication of the importance of the MCH-MCH-1R system in regulating energy balance comes from experiments with a receptor antagonist (SNAP-7941) [3]. In long-term studies, animals treated with antagonists lose a significant amount of weight.

In addition to its appetite suppression effect, the MCH-1R antagonist SNAP-7941 also exerts additional anxiolytic and antidepressant effects in behavioral experiments on rats [3]. Thus, there is a clear indication that the MCH-MCH-1R system not only regulates energy balance, but is also related to emotionality.
Reference:
1. Qu, D. et al., “Role of melanin-concentrating hormone in key regulation of feeding behavior” Nature, 1996. 380 (6571): 243-7
2. Shimoda, M. et al., “Mice lacking melanin-concentrating hormone are thin and thin” Nature, 1998. 396 (6712): 670-4
3. Borowsky, B. et al., “Antidepressant, anxiolytic and appetite-suppressing effects of melanin-concentrating hormone-1 receptor antagonist” Nat Med, 2002. 8 (8): 825-30
4. Chen, Y. et al., “Target-severing melanin-concentrating hormone receptor-1 results in increased feeding and tolerance to diet-induced obesity” Endocrinology, 2002. 143 (7): 2469-77
5. Marsh, DJ et al., “Melanin-concentrating hormone 1 receptor-deficient mice are thin, hyperactive, have a thin diet and have altered metabolism” Proc Natl Acad Sci USA, 2002. 99 (5): 3240- 5 pages
6. Takekawa, S. et al., “T-226296: Novel, orally active and selective melanin-concentrating hormone receptor antagonist” Eur J Pharmacol, 2002. 438 (3): 129-35. Certain amine compounds have been proposed as MCH antagonists. Thus, WO 01/21577 (Takeda) has been formulated as an MCH antagonist for the treatment of obesity

(Wherein Ar ¹ represents a cyclic group, X represents a spacer, Y represents a bond or a spacer, Ar represents an aromatic ring that may be condensed with a non-aromatic ring, R ¹ and R ² Independently represents H or a hydrocarbon group, R ¹ and R ² together with adjacent N atoms may form an N-containing heterocycle, and R ² also forms a spirocyclic ring with Ar. R may combine with the adjacent N atom and Y to form an N-containing heterocycle)
Are described.
Furthermore, WO 01/82925 (Takeda) is also formulated as an MCH antagonist for the treatment of obesity

(In the formula, Ar ¹ represents a cyclic group, X and Y represent a spacer group, Ar represents a condensed polycyclic aromatic ring which may be optionally substituted, and R ¹ and R ² are independent of each other. R ¹ and R ² together with the adjacent N atom may form an N-containing heterocycle, and R ² together with the adjacent N atom and Y may form an N-containing heterocycle A ring may be formed)
Are described.
Other amine compounds having MCH antagonist activity have been proposed in WO 02/057233 (Schering Corp.). These compounds have the general formula

Wherein Ar ¹ , Ar ² , Ar ³ represent in particular aryl or heteroaryl, X represents O, S or N—CN, Y represents a single bond or C _1-4 -alkylene, and R ¹ And R ² is as defined in the description)
to go into.
In addition, MCH antagonist activity is

Wherein W represents a specially defined aminocarbonyl group or carbonylamino group, X represents —CHR ⁸ , —CO, —C (═NOR ⁹ ) or —CR ⁸ ═, Y represents CH, C (OH), C (C _1-4 -alkoxy), or in the case of a C double bond, R ² represents a substituted aryl group or a heteroaryl group, R ¹⁰ is H, C _1-6 -alkyl Or represents aryl, and other groups are as defined in the specification)
Are described in WO 02/051809 (Schering Corp.).
Caroxamide as an antagonist of the human 11CBy receptor has been proposed in WO 02/10146 (Smithkline Beecham). These compounds have the general structural formula

(In the formula, A represents H, alkyl, alkoxy, alkenyl, acyl, halogen, OH, CN or CF ₃ , R ³ represents H, methyl or ethyl, and R ⁴ represents an optionally substituted aromatic. Represents a group carbocyclic ring or heterocyclic ring, Z represents O, S, NH, CH ₂ or a single bond, R ⁵ represents an optionally substituted aromatic, saturated or unsaturated carbocyclic ring or Represents a heterocycle, Q represents a group —XY—NR ¹ (R ² ), and according to different embodiments, X may represent O, S or N, and Y represents an alkylene group or a cycloalkylene group (these are R ¹ and R ² may also represent alkyl or phenyl-alkyl, R ¹ and R ² , R ¹ and Y or R ¹ and X may also be described. Can be linked together to form a ring system)
It is an example.
Other compounds with MCH antagonistic properties were proposed in published applications WO 03/035055, WO 03/033480, WO 02/06245, WO 02/04433, WO 01/87834, WO 01/21169 and JP 2001/226269. ing.
General formula

Quinazolinone compounds are described in WO 01/23365 (Merck) (wherein Z represents a bond or phenylene), and WO 01/23364 (Merck) (wherein Z represents cyclohexylene). Furthermore, Y represents a bond or C _2-4 -alkenyl and R ⁴ represents an aryl, cycloalkyl, phenylalkyl or heterocyclic ring system. These compounds have been described as GPIbIX inhibitors, in particular as inhibitors of this receptor with von Willebrand factor (vWF) ligand.
Aromatic compounds that may contain amide bridges and amine groups are also proposed in the literature for other indications. Thus, a compound of the general formula Ar-AE, wherein Ar represents an optionally substituted aromatic monocyclic or bicyclic group, A represents an amide bridge or an amine bridge, and E represents In particular, a phenyl group (which represents a para-position and is substituted by a substituted aminoalkylene group via a spacer group B) is described in WO 99/01127 (Smithkline Beecham Corp.). These compounds have been proposed as CCR5 receptor ligands, especially for the treatment of asthma, atopic diseases and rheumatoid arthritis.
WO 01/72712 (Cor Therapeutics Inc.) has the following formula

(In the formula, A represents an optionally substituted amino group or amidino group, Z represents a bond or an alkyl spacer group, a cycloalkyl spacer group, an alkenyl spacer group, an alkynyl spacer group or an aryl spacer group; And n represents 0 to 3, D represents a bond or a specific bridge, X represents NR ¹² or CHR ¹² , p represents 0 to 3, E represents a specific ether group, amine group, amide group and carboxyl Represents a bond in addition to a group, J represents a bond, a cycloalkylene group, a phenylene group, a naphthylene group or a heteroaryl group, G represents a more strictly specified amide group, imino group or amidino group; Is as defined above)
Of isoquinoline compounds. These compounds are proposed not only as isolated factor Xa but also as inhibitors of blood clotting and are therefore proposed as antithrombotic and thrombolytic active substances.
DE 197 18 181 A1 (Boehringer Ingelheim) is the formula
R _a -A-Het-Ar-E
(Wherein R _a is a group of R ₄ —SO ₂ —NR ₅ or R ₄ —SO ₂ groups having several strictly defined amino groups or optionally also having the meanings indicated for R ₄ and R ₅ . One may represent one and A is a phenylene-C _1-3 -alkylene group, nC _2-6 -alkylene group or C _5-7 -cycloalkylene-C _1-3 -alkylene group (these are as specified Het represents an optionally substituted benzimidazole group, indole group, tetrahydroquinolinone group or quinazolinone group, and Ar represents an optionally substituted phenylene group , Naphthylene group, thienylene group, thiazylene group, pyridinylene group, pyrimidinylene group, pyrazinylene group, or pyridazinylene group, and E represents a cyano group or an R _b NH—C (═NH) group (wherein R _b represents H, OH , C _1-3 -alkyl or can be cleaved in vivo Represents a group)
A disubstituted bicyclic heterocycle is proposed. These compounds have been proposed as thrombin inhibitors and thrombin time prolonging actives.

  The object of the present invention is to provide novel carboxamide compounds, in particular compounds which are effective as MCH antagonists. The present invention also seeks to provide novel carboxamide compounds that affect the dietary habits of mammals, and in particular can be used to obtain and / or prevent weight loss in mammals. Furthermore, the present invention attempts to provide new pharmaceutical compositions suitable for the prevention and / or treatment of symptoms and / or diseases caused by MCH or otherwise causally associated with MCH. In particular, it is an object of the present invention to provide a pharmaceutical composition for the treatment of metabolic disorders such as obesity and / or diabetes as well as diseases and / or disorders associated with obesity and diabetes. Another object of the invention relates to demonstrating the advantageous use of the compounds of the invention. The present invention also attempts to provide a method for preparing the carboxamide compounds of the present invention. Other objects of the present invention will be readily apparent to those skilled in the art from the foregoing and following remarks.

  The first subject of the present invention is the general formula I

Carboxamide compounds, their tautomers, diastereomers, enantiomers, mixtures and salts thereof.
Where
R ¹ and R ² are each independently H, C _1-8 -alkyl group or C _3-7 -cycloalkyl group optionally substituted by group R ¹¹ or optionally mono-substituted or poly-substituted by group R ¹² Represents a phenyl group which may be substituted and / or monosubstituted by nitro, or
R ¹ and R ² form a C _2-8 -alkylene bridge;
-1 or 2 -CH ₂ -groups may be independently substituted by -CH = N- or -CH = CH- and / or -1 or 2 -CH ₂ -groups -O is independently from each other -, - S -, - CO -, - C (= CH 2) - or -NR ¹³ - it may be substituted by, as a result, is not connected heteroatom is directly to one another,
In the alkylene bridge as defined above, one or more H atoms may be substituted by R ¹⁴ and / or the alkylene bridge as defined above has a bond between the alkylene bridge and the group Cy- Through a bond or double bond,
-Through a common C atom forming a spirocyclic ring system,
Via two common, adjacent C and / or N atoms forming a fused bicyclic ring system, or three or more C and / or N atoms forming a bridged ring system Optionally substituted by one or two identical or different carbocyclic or heterocyclic groups in a manner as formed via

R ³ is H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-4 -alkyl-} , C _3-7 -cycloalkenyl, C _3-7 -cyclo Alkenyl-C _{1-4 -alkyl-} , phenyl, phenyl-C _{1-4 -alkyl-} , C _1-3 -alkoxy-C _{2-6 -alkyl-} , amino-C _{2-6 -alkyl-} , C _1- Represents ₃ -alkyl-amino-C _{2-6 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _2-6 -alkyl-,
X represents a single bond or a C _1-8 -alkylene bridge;
−1 or 2 —CH ₂ — groups may be independently substituted with —CH═CH— or —C≡C— and / or −1 or 2 —CH ₂ — groups. Are independently of each other in a manner such that two O atoms, S atoms or N atoms or one O atom and S atom are not directly linked to each other -O-, -S-,-(SO)- _{, - (SO 2) -,} - CO- or -NR ⁴ - may be substituted by,
One or two C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl-, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or C _1-3 -alkoxy groups and / or in each case may be substituted by one or two identical or different C _1-6 -alkyl groups and / or their alkylene bridges are R ¹ and X Linked to R ¹ so as to contain an N atom linked to a heterocyclic group,
Z is C _1-4 - represents alkylene bridge, additional C _1-4 - 2 contiguous C atoms with alkylene bridge may be connected to each other, in a group Z, -CH ₂ - group Optionally substituted by —O— or —NR ⁵ —, and one or two C atoms of the alkylene bridge are independently of each other a hydroxy group, an ω-hydroxy-C _1-3 -alkyl- group, an ω -(C _1-3 -alkoxy) -C _1-3 -alkyl-group, C _1-3 -alkoxy group, amino-C _1-3 -alkyl-group, C _1-3 -alkyl-amino-C _1- Substituted by ₃ -alkyl-groups or di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-groups and / or one or two identical or different C _1-6 -alkyl groups And / or
R ³ may be linked to Z to include an N atom linked to R ³ to form a heterocyclic group;
A and Y have one of the meanings indicated for Cy independently of each other;
R ¹ may be linked to Y to include a group X and an N atom linked to R ¹ and X to form a heterocyclic group fused to Y and / or
R ³ may be linked to Y to include a group Z and an N atom linked to R ³ and Z to form a saturated or partially unsaturated heterocyclic group fused to Y, or A and R ³ is a group of formula I

Is sub-formula II

And Q is a partial formula IIIa-IIIg
−CR ⁶ R ⁷ −IIIa
−CR ⁶ = CR ⁷ − IIIb
-N = CR ⁸ - IIIc
-N = N-IIId
-CO-NR ⁹ -IIIe
-CR ⁸ = N- IIIf
-CO- IIIg
Represents a group selected from
L ¹ , L ² , L ³ may be linked together in a manner such that they independently of one another represent one of the meanings given for R ²⁰
B is C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _3-7 -cycloalkenyl-C _{1- Represents 3} -alkyl-, C _3-7 -cycloalkyl-C _1-3 -alkenyl- or C _3-7 -cycloalkyl-C _1-3 -alkynyl- (one or more C atoms are monosubstituted by halogen) Or may be polysubstituted and / or monosubstituted by hydroxy or cyano and / or the cyclic group may be monosubstituted or polysubstituted by R ²⁰ ), or
Having one of the meanings given for Cy, the bond to the group W or optionally the direct bond to the group A is a C atom of a carbocyclic moiety or optionally condensed phenyl or pyridine ring Or through the N or C atom of the heterocyclic moiety,
When k is 0, the group B and the group A may be linked to each other through a common C atom to form a spirocyclic ring system, or linked through two common adjacent atoms. A fused bicyclic ring system may be formed,

W is a single bond, -O-, C _1-4 -alkylene group, C _2-4 -alkenylene group, C _2-4 -alkynylene group, C _1-4 -alkyleneoxy- group, oxy-C _1-4- Alkylene group, C _1-3 -alkylene-oxy-C _1-3 -alkylene group, imino group, N- (C _1-3 -alkyl) -imino group, imino-C _1-4 -alkylene group, N- (C _1-3 -alkyl) -imino-C _1-4 -alkylene-group, C _1-4 -alkylene-imino-group or C _1-4 -alkylene-N- (C _1-3 -alkyl) -Represents an imino-group,
One or two C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl-, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or W optionally having a C _1-3 -alkoxy group and / or one or two identical or different C _1-6 -alkyl groups and / or the definition alkylene, oxyalkylene and alkyleneoxyalkylene May also be linked to B via a double bond,
k represents 0 or 1,
Cy has the following meanings-saturated 3-7 membered carbocyclic group,
An unsaturated 5-7 membered carbocyclic group,
A phenyl group,
A saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having N atom, O atom or S atom as a hetero atom,
A saturated or unsaturated 5- to 7-membered heterocyclic group having 2 or more N atoms or 1 or 2 N atoms and an O atom or S atom as a hetero atom,
-Represents a carbocyclic group or heterocyclic group selected from one or more of aromatic 5 or 6-membered heterocyclic groups having one or more same or different heteroatoms selected from N, O and / or S ,

Said 4, 5, 6 or 7 membered group may be linked via two common adjacent C atoms fused with a phenyl ring or a pyridine ring, and in said 5, 6 or 7 membered group, One or two non-adjacent —CH ₂ — groups may be substituted by a —CO— group, a —C (═CH ₂ ) — group, a — (SO) — group or a — (SO ₂ ) — group. And the saturated 6- or 7-membered group may also be an imino bridge, N- (C _1-4 -alkyl) -imino bridge, methylene bridge, C _1-4 -alkyl-methylene bridge or di- (C _1-4 -alkyl). ) -Methylene bridged ring system, and the cyclic group may be mono- or polysubstituted with R ²⁰ at one or more C atom positions, May further be monosubstituted by nitro and / or may be substituted by R ²¹ at one or more N atom positions,
R ⁴ and R ⁵ independently of one another have one of the meanings indicated for R ^{16
R 6, R 7, R 8} , R 9 is H independently of each other, C _1-6 - alkyl group, omega-C _1-3 - alkoxy -C _1-3 - alkyl - group or ω- hydroxy -C _1- Represents a ₃ -alkyl- group, and R ⁶ , R ⁷ and R ⁸ independently represent halogen,
R ¹¹ represents R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁶ R ¹⁷ N-, R ¹⁸ R ¹⁹ N-CO- or Cy-
R ¹² has one of the meanings given for R ²⁰
R ¹³ has one of the meanings given for R ¹⁷
R ¹⁴ is halogen, C _1-6 - ^{alkyl, R 15 -O-, R 15 -O} -CO-, R 16 R 17 N-, R 18 R 19 N-CO-, R 15 -OC 1-3 - Alkyl-, R ¹⁵ -O-CO-C _1-3 -alkyl-, R ¹⁶ R ¹⁷ NC _{1-3 -alkyl-} , R ¹⁸ R ¹⁹ N-CO-C _1-3 -alkyl- or Cy-C _{1 Represents -3} -alkyl-
R ¹⁵ represents H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , phenyl, phenyl-C _1-3 -alkyl- or pyridinyl. Represent,
R ¹⁶ is H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _4-7 -cycloalkenyl, C _4-7 -cyclo Alkenyl-C _1-3 -alkyl-, ω-hydroxy-C _2-3 -alkyl-, ω- (C _1-3 -alkoxy) -C _{2-3 -alkyl-} , amino-C _{1-6 -alkyl-} , C _1-3 -alkyl-amino-C _{1-6 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _1-6 -alkyl-,

R ¹⁷ has one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl-, pyridinyl, dioxolan-2-yl, C _1-3 -alkylcarbonyl, hydroxycarbonyl-C _{1-3 -alkyl-} , C _1-4 -alkoxycarbonyl, C _1-3 -alkylcarbonylamino-C _{2-3 -alkyl-} , C _1-3 -alkylsulfonyl- or C _1-3 -alkylsulfonylamino- C _{2-3 -alkyl-} represents
R ¹⁸ and R ¹⁹ each independently represent H or C _1-6 -alkyl,
R ²⁰ represents halogen, hydroxy, cyano, C _1-4 -alkyl, C _3-7 -cycloalkyl, hydroxy-C _1-3 -alkyl, R ²² -C _1-3 -alkyl-, or about R ²² Has one of the indicated meanings,
R ²¹ is C _1-3 -alkyl, ω-hydroxy-C _2-3 -alkyl, phenyl, phenyl-C _{1-3 -alkyl-} , C _1-3 -alkyl-carbonyl, carboxy, C _1-4 -alkoxy Represents -carbonyl, C _1-3 -alkylsulfonyl, phenylcarbonyl or phenyl-C _1-3 -alkyl-carbonyl,
R ²² is pyridinyl, phenyl, phenyl-C _1-3 -alkoxy-, C _1-3 -alkoxy, C _1-3 -alkylthio-, carboxy, H-CO-, C _1-3 -alkylcarbonyl, C _{1- 4} -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, C _1-3 -alkyl-sulfonyl-, C _1-3 -alkyl-sulfinyl, C _1-3 -alkyl-sulfonylamino-, amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C _1-3 -alkylamino- or N- (C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenylcarbonylamino-, phenylcarbonylmethylamino-, hydroxyalkylaminocarbonyl, (4- Morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl , (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino- or alkylaminocarbonylamino-
In the radicals and residues A, B, W, X, Y, Z, R ^{1 to} R ⁹ and R ^{11 to} R ²² , in each case one or more C atoms are mono- or polysubstituted by F And / or in each case one or two C atoms may be monosubstituted independently of each other by Cl or Br and / or in each case one or two phenyl rings Are independently of each other the groups F, Cl, Br, I, C _1-4 -alkyl, C _1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C _1-3 -alkylamino-, di- ( C _1-3 -alkyl) -amino-, acetylamino-, aminocarbonyl, CN, difluoromethoxy, trifluoromethoxy, amino-C _{1-3 -alkyl-} , C _1-3 -alkylamino-C _1-3- Further having one, two or three substituents selected from alkyl- and di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl- And / or may be monosubstituted by nitro and the H atom of the carboxy group present or the H atom bonded to the N atom may be substituted in each case by a group that can be cleaved in vivo. Good.

The present invention also relates to compounds in the form of individual optical isomers, individual enantiomers or racemic mixtures, tautomeric forms and corresponding acid addition salts with free bases or pharmacologically acceptable acids. About. The subject of the invention also includes the compounds of the invention (including their salts) in which one or more hydrogen atoms have been replaced by deuterium.
Furthermore, the present invention provides compounds of formula I

(Wherein A, B, W, X, Y, Z, R ¹ , R ² , R ³ and k have one of the previously indicated meanings)
The preparation of a carboxamide compound of
When A represents a group R ³ that is not linked to the group A ,
a) a nitrogen heterocyclic group in which A is linked to a carboxamide group via a nitrogen atom (which may also have one or more heteroatoms selected from N, O and S in addition to the nitrogen atom) Represents the formula I-1

(Wherein R ¹ , R ² , R ³ , X, Y and Z have the meanings indicated above)
In the presence of at least one base in a solvent or mixture of solvents, CDT (1,1′-carbonyldi- (1,2,4-triazole)) and formula I-2

(Wherein A, B, W and k have the meanings indicated above and the group A has a secondary amine function)
Reacting with at least one secondary amine compound of
b) For other cases, formula I-3

(Wherein A, B, W and k have the meanings indicated above)
TBTU (2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium in the presence of at least one base in a solvent or mixture of solvents -Tetrafluoroborate) and formula I-1

(Wherein R ¹ , R ² , R ³ , X, Y and Z have the meanings indicated above)
Reacting with at least one amine compound of
When B is a group R ³ linked to a group A ,
a) means ^{-CR 6 R 7 - (IIIa)} (R 6 and R ⁷ in the case of group Q having the is) as hereinbefore defined, the formula Ia.1

(Wherein R ¹ , R ² , X, Y and Z have the specified meaning)
The amine compound of formula Ia.2

(Wherein R ⁶ , R ⁷ , W, B and k have the specified meaning)
Reaction with o-bromomethyl-benzoic acid ester derivatives of
b) means ^{-CR 6 = CR 7 - (IIIb} ) ( wherein, when R ⁶ and R ⁷ groups Q having a are as previously defined), the formula Ib.2

(Wherein R ⁶ , R ⁷ , W, B and k have the specified meaning)
Isoquinolinone derivatives of formula Ib.3

Wherein Y and Z have the specified meanings and OMs represents a suitable leaving group, preferably mesylate
With an electrophile of formula Ib.4

(Wherein R ⁶ , R ⁷ , W, B, Y, Z and k have the specified meaning)
An isoquinoline derivative of formula Ib.4 is further derivatized by known methods to produce a compound of formula I;
c) means ^{-N = CR 8 - (IIIc)} ( wherein, R ⁸ in the case of group Q having the is) as hereinbefore defined, the formula Ic.4

(Wherein R ⁸ , W, B and k have the specified meaning)
A phthalazinone derivative of formula Ic.5

In which Y and Z have the specified meaning and OMs represents a leaving group, preferably mesylate.
With an electrophilic compound of formula Ic.6

(Wherein R ⁸ , W, B, Y, Z and k have the specified meaning)
Of generating a phthalazinone derivative, a compound of formula I thus obtained phthalazinone derivative of formula Ic.6 further derivatized by known methods (In formula (I), Q is -N = CR ⁸ - (representative of IIIc)) and Generate
d) in the case of the group Q having the meaning -N = N- (IIId), the formula Id.1

(Wherein R ¹ , R ² , W, B, X, Y, Z and k have the specified meanings)
An o-amino-benzamide derivative of is reacted in the presence of a suitable nitrile compound and an acid to produce a compound of formula I wherein Q represents -N = N-
e) in the case of a group Q having the meaning —CO—NR ⁹ — (IIIe), wherein R ⁹ is as defined above, the formula Ie.1

(Wherein R ¹ , R ² , R ⁹ , W, B, X, Y, Z and k have the specified meanings)
Bruno o- amino - benzamide derivative is reacted in the presence of CDI (carbonyldiimidazole) compounds of formula I (wherein, Q is -CO-NR ⁹ - represents a) generating a
f) in the case of a group Q having the meaning -CR ⁸ = N- (IIIf), where R ⁸ is as defined above, the formula If.1

(Wherein R ¹ , R ² , W, B, X, Y, Z and k have the specified meanings)
Bruno o- amino - benzamide derivative is reacted with a carboxylic acid R ⁸ COOH and / or the corresponding activated carboxylic acid derivatives have the meanings specified for R ⁸ in quinazolinone derivative (of the formula I, Q is -CR ⁸ = N-)
g) In the case of the group Q having the meaning —CO— (IIIg), the formula Ig.2

Where W, B and k have the specified meanings.
Isobenzofurandione derivatives of formula Ig.1

(Wherein R ¹ , R ² , X, Y and Z have the specified meaning)
To produce a compound of formula I where Q represents -CO-.
The present invention also includes physiologically acceptable salts of the carboxamide compounds of the present invention described above and described below.
Further, according to the present invention, a composition comprising at least one carboxamide compound of the present invention and / or a salt of the present invention together with one or more physiologically acceptable excipients as necessary is included.
Further, according to the present invention, there is included a pharmaceutical composition characterized in that it contains at least one carboxamide compound of the present invention and / or a salt of the present invention together with one or more inert carriers and / or diluents as necessary. .
The invention also relates to the use of at least one carboxamide compound according to the invention and / or a salt according to the invention for influencing the dietary behavior of mammals.
The invention also relates to the use of at least one carboxamide compound of the invention and / or a salt of the invention for 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 carboxamide compound of the invention and / or a salt of the invention for preparing a pharmaceutical composition having MCH-receptor antagonist activity.
Furthermore, the present invention provides at least one of the present invention for preparing a pharmaceutical composition suitable for the prevention and / or treatment of symptoms and / or diseases caused by MCH or otherwise causally associated with MCH. Of the carboxamide compounds and / or the salts of the invention.
The present invention is also suitable for the prevention and / or treatment of metabolic disorders and / or dietary disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and bulimia. It relates to the use of at least one carboxamide compound according to the invention and / or a salt according to the invention for the preparation of a pharmaceutical composition.
The present invention also relates to diseases and / or disorders associated with obesity, particularly diabetes, particularly type II diabetes, diabetic complications (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance. And / or at least one carboxamide compound of the invention for preparing a pharmaceutical composition suitable for the prevention and / or treatment of cerebral hemorrhage, heart failure, cardiovascular disease, in particular arteriosclerosis and hypertension, arthritis and knee arthritis It relates to the use of the salts according to the invention.
Furthermore, the present invention includes hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorder, emotional disorder, depression, anxiety, sleep disorder, reproductive disorder, sexual disorder, memory disorder, It relates to the use of at least one carboxamide compound according to the invention and / or a salt according to the invention for preparing a pharmaceutical composition suitable for the prevention and / or treatment of epilepsy, dementia forms and hormonal disorders.

Another subject of the present invention is the preparation of a pharmaceutical composition suitable for the prevention and / or treatment of dysuria, for example urinary incontinence, hyperactive bladder, imminent urination, nocturia and enuresis. Use of at least one carboxamide compound and / or a salt according to the invention.
Furthermore, the present invention provides the pharmaceutical of the present invention, characterized in that at least one carboxamide compound of the present invention and / or a salt of the present invention is mixed with one or more inert carriers and / or diluents by non-chemical methods. The present invention relates to a method for preparing a composition.
Furthermore, the present invention provides for the treatment of diabetes as well as the first active substance selected from the carboxamide compounds and / or the corresponding salts of the present invention, optionally together with one or more inert carriers and / or diluents. Active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of hypertension, including arteriosclerosis A pharmaceutical composition comprising a second active substance selected from the group consisting of an active substance for treatment, an active substance for the treatment of arthritis, an active substance for the treatment of anxiety and an active substance for the treatment of depression About.

Unless otherwise specified, groups, residues, substituents and indices, in particular A, B, W, X, Y, Z, R ^{1 to} R ⁹ , R ^{11 to} R ²² , L ¹ , L ² , L ³ and k Has one of the meanings indicated above or indicated below.
A preferred embodiment of the present invention is
R ³ is H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-4 -alkyl-} , C _1-3 -alkoxy-C _{2-6 -alkyl-} , Amino-C _{2-6 -alkyl-} , C _1-3 -alkyl-amino-C _{2-6 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _2-6 -alkyl- ,
B has one of the meanings given for Cy, and the bond to the group W or optionally the direct bond to the group A may be a carbocyclic moiety or optionally a phenyl or pyridine ring C Formed through an atom or an N or C atom of a heterocyclic moiety;
When k is 0, the group B and the group A may be linked together through a common C atom to form a spirocyclic ring system, or linked through two common adjacent atoms. A condensed, bicyclic ring system may be formed,
Cy represents the following-saturated 3-7 membered carbocyclic group,
An unsaturated 5-7 membered carbocyclic group,
A phenyl group,
A saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having N atom, O atom or S atom as a hetero atom,
A saturated or unsaturated 5- to 7-membered heterocyclic group having 2 or more N atoms or 1 or 2 N atoms and an O atom or S atom as a hetero atom,
-Represents a carbocyclic group or heterocyclic group selected from one or more of aromatic 5 or 6-membered heterocyclic groups having one or more same or different heteroatoms selected from N, O and / or S ,

The 5-, 6- or 7-membered group may be linked via two common adjacent C atoms fused with a phenyl ring or a pyridine ring, and in the 5-, 6- or 7-membered group, ₂ -group may be substituted by -CO- group, -C (= CH ₂ )-group,-(SO)-group or-(SO ₂ )-group, and the saturated 6- or 7-membered group is Bridged rings also having imino bridges, N- (C _1-3 -alkyl) -imino bridges, methylene bridges, C _1-3 -alkyl-methylene bridges or di- (C _1-3 -alkyl) -methylene bridges And the cyclic group may be mono- or polysubstituted with R ²⁰ at one or more C atom positions, and in the case of a phenyl group it is also mono-substituted with nitro. And / or may be substituted by R ²¹ at one or more N atom positions,
R ¹⁵ represents H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , phenyl or phenyl-C _1-3 -alkyl-;
R ¹⁷ has one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl-, dioxolan-2-yl, C _1-3 -alkylcarbonyl-, hydroxycarbonyl-C _{1 -3} -alkyl, C _1-3 -alkylcarbonylamino-C _{2-3 -alkyl-} , C _1-3 -alkylsulfonyl- or C _1-3 -alkylsulfonylamino-C _2-3 -alkyl-
R ²² is phenyl, phenyl-C _1-3 -alkoxy-, C _1-3 -alkoxy, C _1-3 -alkylthio, carboxy, C _1-3 -alkylcarbonyl, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, C _1-3 -alkyl-sulfonyl, C _1-3 -alkyl-sulfinyl, C _1-3 -alkyl-sulfonylamino Amino, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C _1-3 -alkyl-amino- or N- (C _1-3 -alkyl) -phenyl -C _1-3 -alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenylcarbonylamino-, phenylcarbonylmethylamino-, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) carbonyl , (1-piperidinyl) Represents, - carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino - or alkylaminocarbonylamino
In the radicals and residues A, B, W, X, Y, Z, R ^{1 to} R ⁹ and R ^{11 to} R ²² , in each case one or more C atoms are mono- or polysubstituted by F And / or in each case one or two C atoms may be monosubstituted independently of each other by Cl or Br and bonded to the H or N atom of the carboxy group present Compounds of formula I, their tautomers, diastereomers, enantiomers, mixtures and salts thereof, in which the H atom is in each case substituted by groups which can be substituted in vivo, are included.
According to a first group of preferred embodiments, the group A and the group R ³ are not directly bonded to each other. The group A therefore has one of the meanings given for Cy.
According to a second group of preferred embodiments, the group A and the group R ³ are groups of the formula I

Is sub-formula II

And Q is a partial formula IIIa-IIIg
−CR ⁶ R ⁷ −IIIa
−CR ⁶ = CR ⁷ − IIIb
-N = CR ⁸ - IIIc
-N = N-IIId
-CO-NR ⁹ -IIIe
-CR ⁸ = N- IIIf
-CO- IIIg
Are linked together in a manner that represents a group selected from
Preferred meanings for the group Q are selected from the partial formulas IIIb, IIId, IIIe, IIIf and IIIg, in particular IIId, IIIe, IIIf and IIIg.
Preferred meanings for the substituents R ⁶ , R ⁷ , R ⁸ and R ⁹ are, independently of one another, H and C _1-4 -alkyl, in particular H, methyl or ethyl.
The substituents L ¹ , L ² , and L ³ have the following meanings independently of each other: H, F, Cl, Br, CH ₃ , CHF ₂ , CF ₃ , C ₂ H ₅ , C ₃ H ₇ , CH (CH ₃ ) ₂ , OCH ₃ , OCHF ₂ , OCF ₃ , OC ₂ H ₅ , OC ₃ H ₇ and OCH (CH ₃ ) ₂ .
It is preferred that only one of the substituents L ¹ , L ² , L ³ has a meaning other than H, particularly one of the above meanings. It is particularly preferred that all three substituents L ¹ , L ² , L ³ represent H.

The radicals R ¹ and R ² are independently of each other H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, ω-hydroxy-C _{2- 3} -alkyl-, ω- (C _1-3 -alkoxy) -C _{2-3 -alkyl-} , C _1-4 -alkoxy-carbonyl-C _{1-3 -alkyl-} , amino-C _{2-4 -alkyl-} , C _1-3 -alkyl-amino-C _{2-4 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _{2-4 -alkyl-} , phenyl or phenyl-C _1-3 -alkyl- In the above groups and residues, one or more C atoms may be mono- or polysubstituted by F, and / or one or two C atoms are independently of each other Cl or monosubstituted even well, and the group R ¹² in which the phenyl group as defined above may be mono- or polysubstituted, and / or may be monosubstituted by nitro by Br.
The groups R ¹ and R ² are independently of each other C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, ω-hydroxy-C _2-3- Most preferably it represents alkyl-, ω- (C _1-3 -alkoxy) -C _{2-3 -alkyl-} , C _1-4 -alkoxy-carbonyl-C _{1-3 -alkyl-} , the groups R ¹ , R One of ² may also represent H.
R ¹ and R ² are R ¹ R ² N- is azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4 , 7-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, preferably forms an alkylene bridge in such a manner as to represent a group selected from piperazine, and the free imine functional group is R ¹³ , optionally substituted by morpholine and thiomorpholine, and according to the general definition of R ¹ and R ² , one or more H atoms may be substituted by R ¹⁴ and / or the above groups are It may be substituted by one or two identical or different carbocyclic or heterocyclic groups Cy in the manner specified in the general definition of R ¹ and R ² .
Base

Is the following sub-expression

Is particularly preferably defined according to one of the following:
One or more H atoms of the heterocycle formed by the group R ¹ R ² N— may be substituted by R ¹⁴ and a ring connected to the heterocycle formed by the group R ¹ R ² N It may be monosubstituted or polysubstituted by R ²⁰ at one or more C atom positions, and in the case of a phenyl ring, it may be further monosubstituted by nitro.
R ¹ and R ² together with the N atom of the group R ¹ R ² N— form a pyrrolidine ring, a piperidine ring or a 2,5-dihydro-1H-pyrrole ring, which may be substituted as specified The above group R ¹ R ² N is most particularly preferred.
Preferred meanings for the group R ¹⁴ are C _1-4 -alkyl, C _1-4 -cycloalkyl, hydroxy, C _1-4 -alkoxy, C _1-4 -alkoxy-C _1-3 -alkyl-, hydroxy-C _{1 -3} -alkyl, C _1-4 -alkyl-carbonyl, C _1-4 -alkoxy-carbonyl, C _1-4 -alkoxy-carbonyl-C _{1-3 -alkyl-} , C _1-4 -alkoxy-carbonylamino- , C _1-4 -alkoxy-carbonylamino-C _{1-3 -alkyl-} , amino, (C _1-4 -alkyl) -amino-, di- (C _1-4 -alkyl) -amino-, phenyl, phenyl Oxy, pyridinyl and pyridinyloxy.
Preferred piperidine groups substituted by the group Cy are structural

(Wherein Cy preferably represents phenyl, which may be substituted as specified)
Have
The alkylene bridge X preferably has no —NR ⁴ — groups or at most one —NR ⁴ — group. The position of the NR ⁴ group in the alkylene bridge X is preferably selected such that no amine function is formed with the amino group NR ¹ R ² or another adjacent amino group, or two N atoms are adjacent to each other. . Therefore, when the —CH ₂ — group is substituted by —NR ⁴ —, the alkylene bridge preferably represents C _2-7 -alkylene-NR ⁴ -C _0-5 -alkylene, and the bridge X is N In addition to the atoms, it has a maximum of 7 bridged C atoms, which may be substituted in the manner specified.

X is a single bond or C _1-6 -alkylene, C _2-6 -alkenylene, C _2-6 -alkynylene, C _1-6 -alkyleneoxy, carbonyl, carbonyl-C _1-6 -alkylene or C _1-6- Preferably represents an unbranched bridge selected from alkylene-amino-, in which the amino group may be substituted by R ⁴ , wherein one or two C atoms are specified in the general definition of X And / or the alkylene bridge may be linked to R ¹ in the manner specified.
X particularly preferably represents an alkylene bridge selected from a single bond, carbonyl or methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, wherein one or two C atoms are independent of each other. Substituted with a hydroxy group, ω-hydroxy-C _1-3 -alkyl group, ω- (C _1-3 -alkoxy) -C _1-3 -alkyl-group and / or C _1-3 -alkoxy group And / or in each case may be substituted by one or two identical or different C _1-4 -alkyl groups, and in each case one or more C atoms are replaced by F It may be substituted or polysubstituted and / or in each case 1 or 2 C atoms may be monosubstituted independently of each other by Cl or Br.
In group X, when one or two C atoms are substituted by a hydroxy group and / or a C _1-3 -alkoxy group, the substituted C atom is an amino group, in particular —NR ¹ R ² or — it is preferably not directly adjacent to - NR ^4.
Most preferably, the bridge X is a single bond, —CH ₂ — or —CH (CH ₃ ) —.
When the —CH ₂ — group is substituted in the bridge Z by —NR ⁵ —, the position of the NR ⁵ group in the group Z is an amine function together with the amino group —NR ³ — or another adjacent amino group Is preferably not formed or selected such that two N atoms are adjacent to each other.

Preferred meanings of bridge Z are methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy and 1,4-butyleneoxy. In which one or two C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or Or may be substituted by a C _1-3 -alkoxy group and / or in each case by one or two identical or different C _1-4 -alkyl groups and In which one or more C atoms may be monosubstituted or polysubstituted by F and / or in each case one or two C atoms are independently monosubstituted by Cl or Br. at best, and it is connected to Z to form a heterocyclic group to include the N atom to which R ³ is bonded to R ³ and It may be.
In the group Z, when one or two C atoms are substituted by a hydroxy group and / or a C _1-3 -alkoxy group, the substituted C atom is an amino group, in particular —NR ³ — or —NR ^5- preferably not directly adjacent to-.
Z is a group _{-CH 2 -, - CH 2 -CH} 2 -, - CH 2 -CH (CH 3) -, - CH 2 -C (CH 3) 2 -, - CH (CH 3) -CH 2 -, Particular preference is given to being selected from —C (CH ₃ ) ₂ —CH ₂ — and —CH ₂ —O—, in particular —CH ₂ —CH ₂ — or —CH (CH ₃ ) —CH ₂ —.
Furthermore, according to a particularly preferred definition, Z is a partial formula

The group of which has a meaning selected from 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,2,5,6-tetrahydropyridine-1,3-ylene and 3-hydroxy-1,3-piperidinylene It is connected to R ^3.
Preferably, the group R ³ is selected from methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or 2-hydroxy-1-methyl-ethyl In the radicals 1, 2 or 3 H atoms may be substituted by F, or R ³ is group H, amino-C _{2-3 -alkyl-} , C _1-3 -alkyl-amino -C _2-3 - alkyl - or di - (C _1-3 - alkyl) - amino -C _2-3 - alkyl - selected from among.
Particularly preferred meanings of the group R ³ are H, methyl or ethyl, especially H or methyl.
Preferred meanings of the radicals R ⁴ and / or R ⁵ are H, C _1-4 -alkyl, C _3-6 -cycloalkyl and C _3-6 -cycloalkyl-C _1-3 -alkyl-, especially H and C _{1 -4} -alkyl.

Preferred meanings of the group R ¹¹ are C _1-6 -cycloalkyl, hydroxy, C _1-4 -alkoxy, amino, C _1-4 -alkyl-amino- and di- (C _1-4 -alkyl) -amino- is there.
Preferred meanings of the group R ²⁰ are halogen, hydroxy, cyano, C _1-4 -alkyl, C _3-7 -cycloalkyl and hydroxy-C _1-3 -alkyl. R ²⁰ is F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso It is particularly preferred to represent -propoxy.
The group Y is a divalent cyclic group 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohex. Silene, 1,3-phenylene, 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1, 3-pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene or 1,4-piperazinylene Preferably, the 5-, 6- or 7-membered group may be linked by two common adjacent C atoms fused with a phenyl ring or a pyridine ring, and the cyclic group is one They may be mono- or polysubstituted with R ²⁰ at the above C atom positions, and in the case of phenyl groups they are also monosubstituted with nitro. And / or may be substituted with R ²¹ at one or more N atom positions, R ¹ may be linked to Y in the manner specified in the general definition, and / or Or R ³ may be linked to Y.
The most particularly preferred meaning of the group Y is

Selected from groups of the cyclic structure consisting, by the cyclic group R ^20, preferably halogen, CF _3, C _1-4 - alkyl and / or C _1-4 - mono- or disubstituted by alkoxy, preferably single May be substituted.
In addition, the group Y is also a partial formula

Is based on the following partial formula

It may be bound to the group R ¹ in such a way as to have a meaning selected from
Preferred meanings for group A are the divalent cyclic groups 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1, 4-cyclohexylene, 1,3- and 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1,3-pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene, 1,4 Selected from among -piperazinylene, 7-aza-bicyclo [2.2.1] heptane-2,7-diyl and 8-aza-bicyclo [3.2.1] octane-3,8-diyl; The member group may be linked by two common, adjacent C atoms fused with a phenyl ring or a pyridine ring, and the cyclic group may be monosubstituted or polysubstituted with R ²⁰ at one or more C atom positions. Replaced Even well, in the case of the phenyl ring may be monosubstituted by them also further nitro, and / or at the location of one or more N atoms may be substituted by R ^21.
The most particularly preferred meaning for group A is

Selected from groups of the cyclic structure consisting, by the cyclic group R ^20, preferably halogen, CF _3, C _1-4 - alkyl and / or C _1-4 - mono- or disubstituted by alkoxy, preferably single May be substituted.
The divalent cyclic groups specified for Y and / or A are in each case in the mirror-symmetric form, ie the adjacent groups, the bonds X and Z in the case of Y and CO and W in the case of A. Including a form that can be replaced. Thus, for example, 1,4-cyclohexenylene is

Represents both. The divalent cyclic groups shown above for groups Y and A include all possible isomers. Some preferred above meanings will be explained more fully below.
Definitions Tetrahydropyridinylene means 1,2,3,4-tetrahydropyridine-1,4- and -3,6-ylene, 1,2,3,6-tetrahydropyridine-1,4, -2,5- And -3,6-ylene, 2,3,4,5-tetrahydropyridine-2,5- and -3,6-ylene. A preferred meaning is 1,2,3,6-tetrahydropyridine-1,4-ylene.
Definitions Dihydropyridinylene means not only 1,4- and 1,2-dihydropyridine-1,4-ylene, but also 1,2-, 1,4-, 1,6-, 2,3-, 2,5 -, 3,4-, 4,5- and 5,6-dihydropyridine-2,5-ylene. A preferred meaning is 1,2-dihydropyridine-1,4-ylene.
Or groups A and / or B is unsubstituted, or preferably which is monosubstituted or disubstituted by R ^20, or unsubstituted, or most preferably which is monosubstituted by R ^20.
Preferred meanings for the group B of the first embodiment are the groups C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _3-7 - cycloalkenyl -C _1-3 - alkyl -, C _3-7 - cycloalkyl -C _1-3 - alkenyl - or C _3-7 - cycloalkyl -C _1-3 - alkynyl - selected from, One or more C atoms may be monosubstituted or polysubstituted by halogen and / or monosubstituted by hydroxy or cyano and / or the cyclic group may be monosubstituted or polysubstituted by R ²⁰ W may be a single bond, -O-, C _1-4 -alkylene group, C _2-4 -alkenylene group, C _2-4 -alkynylene group, C _1-4 -alkyleneoxy group, oxy -C _1-4 -alkylene group, C _1-3 -alkylene-oxy-C _1-3 -alkylene group, imino group, N- (C _1-3 -alkyl) -imino group, imino-C _1-4 -Archile N- (C _1-3 -alkyl) -imino-C _1-4 -alkylene-group, C _1-4 -alkylene-imino-group or C _1-4 -alkylene-N- (C _{1- 3} -alkyl) -imino-group, wherein one or two C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _It may be substituted with a _1-3 -alkyl group and / or a C _1-3 -alkoxy group and / or one or two same or different C _1-4 -alkyl groups, and k is 0 or 1 , Especially 1 and
R ²⁰ has one of the meanings indicated above.
In the preferred meanings described above for B, k preferably has the value 1 and W preferably represents a single bond, imino or N- (C _1-3 -alkyl) -imino, in particular a single bond.
It is particularly preferred that the group B represents C _3-6 -alkynyl, in particular C _3-6 -alkynyl-1, and / or the group W represents a single bond and k is 1.

Preferred meanings for group B in the second embodiment are the cyclic groups cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, Selected from among piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl and thienyl A phenyl ring optionally bonded to the group W or optionally to a direct bond to the group A is a carbocyclic moiety or Or the group cyclopentylidene-methyl together with a group W formed through the C atom of the pyridine ring or through the N or C atom of the heterocyclic moiety, or B linked by a double bond , Cyclohexylidene-methyl and cyclohexanone-4-ylidene-methyl, and the cyclic group may be mono- or polysubstituted with R ²⁰ at one or more C atom positions, In some cases, they may also be further monosubstituted by nitro and / or substituted by R ²¹ at one or more N atom positions.

Most particularly preferably the group B represents phenyl, which is monosubstituted, disubstituted or trisubstituted, preferably monosubstituted or disubstituted by R ²⁰ .
The definition of B given above includes all possible isomers of the group. Thus, in particular, the following isomers are included: cyclopenten-1-, 3- and 4-yl, cyclohexanone-4-yl, cyclohexen-1-, 3- and 4-yl, cyclohepten-1-, 3-, 4- and 5-yl, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, piperidin-1- and 4-yl, pyridine-2, -3- and -4-yl, azepan-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, quinolin-2-, 3 -, 4-, 5-, 6-, 7- and 8-yl, isoquinolin-1-, 3-, 4-, 5-, 6-, 7- and 8-yl, 1H-benzimidazol-1- 2-, 4-, 5-, 6- and 7-yl.
The definition pyrazole includes the isomers 1H-, 3H- and 4H-pyrazole. Pyrazolyl preferably represents 1H-pyrazol-1-yl.
The definition imidazole includes the isomers 1H-, 2H- and 4H-imidazole. A preferred meaning of imidazolyl is 1H-imidazol-1-yl.
The definition tetrahydropyridine includes the isomers 1,2,3,4-, 1,2,3,6- and 2,3,4,5-tetrahydropyridine. Tetrahydropyridinyl preferably represents 1,2,3,4- and 1,2,3,6-tetrahydropyridin-1-yl.
The definition dihydropyridine includes the isomers 1,2-, 1,4-, 2,3-, 2,5- and 4,5-dihydropyridine. Dihydropyridinyl preferably represents 1,2- and 1,4-dihydropyridin-1-yl.

The definition triazole includes not only the isomers 1H, 3H- and 4H- [1,2,4] -triazole, but also 1H, 2H- and 4H- [1,2,3] -triazole. Therefore, the definition triazolyl is 1H- [1,2,4] -triazol-1-, 3- and 5-yl, 3H- [1,2,4] -triazol-3- and 5-yl, 4H- [ 1,2,4] -triazol-3,4- and 5-yl, 1H- [1,2,3] -triazol-1,4- and 5-yl, 2H- [1,2,3] -triazole -2, 4- and 5-yl and 4H- [1,2,3] -triazol-4- and 5-yl.
The term tetrazole includes the isomers 1H-, 2H- and 5H-tetrazole. Hence, the definition tetrazolyl includes 5H-tetrazol-5-yl as well as 1H-tetrazol-1- and 5-yl, 2H-tetrazol-2- and 5-yl.
The definition indole includes the isomers 1H- and 3H-indole. The term indolyl preferably represents 1H-indol-1-yl.
The definition isoindole includes the isomers 1H- and 2H-isoindole. The term isoindolyl preferably represents 2H-isoindol-2-yl.
In general, the bond to one of the above heterocyclic groups, in particular pyrazolyl, imidazolyl, tetrahydropyridinyl, dihydropyridinyl, triazolyl, tetrazolyl, indolyl or isoindolyl, is a C atom or optionally It may be formed through the N atom of the imine functional group.
The group B is not substituted by R ^{20 and} is preferably mono-, di- or tri-substituted. B is particularly preferably mono- or disubstituted by R ²⁰ . When B is a substituted 6-membered ring,

It is preferred that there is a substituent at the para position with respect to the bond of
The index k may take the value 0 or 1. In the preferred case k is 1 and the bridge W has the specified meaning, preferably a single bond, the meaning of —CH ₂ — or —CH═. The preferred meaning of the partial formula -AWB is selected from the structures listed in the list below, in which V represents a C or N atom, preferably a C atom, and the cyclic group described is one or more C It may be monosubstituted or disubstituted with R ²⁰ at the atom position, and in the case of a phenyl group or a phenylene group, it may be further monosubstituted with nitro.

Most particularly preferred are compounds of formula I, wherein k is 1 and W represents a single bond.
The index k may take the value 0. According to the first subvariant, the group A is connected to the group B by a common C atom to form a spirocyclic ring system, the group A represents a saturated 5-7 membered carbocyclic group or heterocyclic group, And the group B represents a saturated 4- to 7-membered carbocyclic group or heterocyclic group, and each of the heterocyclic groups has an N atom, an O atom or an S atom, and two phenyl or pyridine rings. May be condensed to a 5- to 7-membered group B by adjacent C atoms, and the cyclic group may be mono- or polysubstituted by R ²⁰ at the position of one or more C atoms, and may be condensed. In the case of a phenyl ring, it may also be monosubstituted by nitro and / or may be substituted by R ²¹ at one or more N atom positions.
The preferred meaning of the sub-form AWB of this second subvariant is selected from the structures listed in the table below, the listed cyclic groups being mono- or polysubstituted by R ²⁰ at one or more C atom positions. In the case of a phenyl ring, it may be further monosubstituted by nitro.

According to the second subvariant, when k is 0, the group B is fused to the group A by two common, adjacent atoms and fused, bicyclic saturated, unsaturated or aromatic, Forming an 8-12 membered ring system, the ring system may contain one or more of the same or different heteroatoms selected from N, O and / or S, and the bicyclic ring system is 1 It may be mono- or polysubstituted with R ²⁰ at more than one C atom position, and in the case of a fused phenyl ring it may also be further mono-substituted with nitro and / or one or more R ²¹ may be substituted at the N atom position.
The preferred meaning of the sub-form AWB of this first subvariant is selected from the structures listed in the table below, the listed cyclic groups being mono- or polysubstituted by R ²⁰ at one or more C atom positions. In the case of a phenyl ring, it may be further monosubstituted by nitro.

Preferred compounds of the invention are compounds having one of the meanings given above when one or more of groups, residues, substituents and / or indices are preferred.
The preferred meaning of the substituent R ²⁰ is selected from fluorine, chlorine, bromine, CF ₃ , C _1-4 -alkyl and C _1-4 -alkoxy.
Particularly preferred compounds of the present invention are those wherein Y and A are independently of each other divalent cyclic groups 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2 , 3,6-tetrahydro-pyridine-1,4-ylene, 2,5-pyridinylene and 1,4-piperazinylene, A may also be linked to R ³ according to claim 3 and Cyclic groups may be mono- or polysubstituted by R ²⁰ at one or more C atom positions, in the case of phenyl groups they may also be further mono-substituted by nitro and / or Optionally substituted by R ²¹ at one or more N atom positions,
B represents phenyl or cyclohexyl, the group may be mono- or polysubstituted by R ²⁰ and / or the phenyl ring may be further mono-substituted by nitro, R ²⁰ being defined in claim 1 Has the meaning indicated, and k has the value 1,
W is a single bond, —CH ₂ — or —CH═, and Z is —CH ₂ —CH ₂ —, —CH ₂ —CH (CH ₃ ) —, —CH ₂ —C (CH ₃ ) ₂ —, Represents —CH (CH ₃ ) —CH ₂ —, —C (CH ₃ ) ₂ —CH ₂ — or —CH ₂ —O—, or a sub-formula of formula I

In which the group is bound to R ³ in such a way that it has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene.
Particularly preferred compounds of the invention are




Formulas I.1-I.14

(Where
U and V each independently represent C or N;
R ²³ and R ²⁴ each independently represent H, F, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl;
In formulas I.1 to I.6, R ²⁴ is a partial formula

May be bound to R ³ in such a way that it has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene,
R ²⁵ , R ²⁶ , R ²⁷ independently of one another have one of the meanings indicated for R ²⁰ or, in the case of a phenyl group, also simply represents nitro, a residue R ²⁵ , R which appears several times ²⁶ and R ²⁷ may have the same or different meanings, and j is 0, 1, 2, 3 or 4, and m and n each independently represents 0, 1 or 2)
Are listed in the following groups:
Most particularly preferred are compounds of the above formulas I.1, I.2, I.8, I.10 and I.12. Particularly preferred compounds can be described by the following formula:

(Wherein the groups and substituents are as defined above and are defined below)
Further, according to the present invention, the following partial formula

(Where
B is C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _1-3 -alkyl, C _3-7 -cycloalkenyl-C _1-3 Selected from -alkyl, C _3-7 -cycloalkyl-C _1-3 -alkenyl or C _3-7 -cycloalkyl-C _1-3 -alkynyl, wherein one or more C atoms are monosubstituted by halogen or May be polysubstituted and / or monosubstituted by hydroxy or cyano and / or the cyclic group may be monosubstituted or polysubstituted by R ²⁰ and W is a single bond, -O-, C _1-4 -alkylene group, C _2-4 -alkenylene group, C _2-4 -alkynylene group, C _1-4 -alkyleneoxy-group, oxy-C _1-4 -alkylene group, C _{1 -3} -alkylene-oxy-C _1-3 -alkylene group, imino group, N- (C _1-3 -alkyl) -imino-group, imino-C _1-4 -alkylene-group, N- (C _{1- 3} -alkyl) -imino-C _{Represents a 1-4} -alkylene- group, a C _1-4 -alkylene-imino-group or a C _1-4 -alkylene-N- (C _1-3 -alkyl) -imino group, one or two C atoms Are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _1-3 -alkyl and / or C _1-3 -alkoxy and / or _Optionally substituted by one or two identical or different C _1-4 -alkyl groups and k represents 0 or 1)
Are preferred.
Furthermore, according to this embodiment, the group B is C _1-6 -alkyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} or C _3-7 -cycloalkyl- _Represents C _1-3 -alkynyl-, wherein one or more C atoms may be mono- or polysubstituted by halogen and / or monosubstituted by hydroxy or cyano and / or cyclic The radical may be mono- or polysubstituted by R ²⁰ and / or W represents a single bond, —O—, imino or N— (C _1-3 -alkyl) -imino-, one or two C atoms independently of one another are hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _1-3 -alkyl and / or C _1-3 -alkoxy Preference is given to compounds which are substituted by the radicals and / or one or two identical or different C _1-4 -alkyl groups and k is 1. .
Most particularly preferred meanings for the group -WB of this embodiment are C _1-8 -alkyl, -C≡CC _1-6 -alkyl, -CH = CH-C _1-6 -alkyl, -OC _1-6 -alkyl, Selected from —NH (C _1-6 -alkyl) and —N (C _1-6 -alkyl) (C _1-3 -alkyl), especially C _3-8 -alkyl, —C≡CC _3-6 -Alkyl, -CH = CH-C _3-6 -alkyl, -OC _3-6 -alkyl, -NH (C _3-6 -alkyl) and -N (C _3-6 -alkyl) (C _1-3- Alkyl).

Among the compounds of the invention which have already been described as preferred, in particular of the partial formulas I.1 to I.15, the radicals R ¹ , R ² , R ³ , L ¹ , L ² , L ³ and / or the radical X are Particular preference is given to compounds having one of the meanings described as being preferred in each case.
Particularly preferred compounds of the invention are those compounds wherein X is selected from —CH ₂ —, —CH (CH ₃ ) — or —C (CH ₃ ) ₂ —.
Also,
a) the group U represents an N atom and the group V represents a C atom, or
b) the group U represents a C atom and the group V represents an N atom, or
c) Particularly preferred are those compounds of the partial formulas I.1 to I.15 in which the two groups U and V each represent a C atom.
In particularly preferred compounds of the invention, the substituents R ²⁵ , R ²⁶ , R ²⁷ are independently of each other F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso -Propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy, and also in the case of substitution of the phenyl group, simply has a meaning selected from nitro and appears several times The radicals R ²⁵ , R ²⁶ , R ²⁷ may have the same or different meanings, j is 0, 1 or 2 and m and n independently represent 0 or 1.
The preferred meanings of the groups R ⁶ , R ⁷ , R ⁸ and / or R ⁹ in the compounds described as preferred according to the invention are, independently of one another, H, methyl, trifluoromethyl, ethyl, iso-propyl or n- Propyl and also F in the case of R ⁶ , R ⁷ .

Particularly preferred individual compounds are groups
(1) 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(2) 3- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one
(3) 3- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3H-quinazolin-4-one
(4) 7- (4-Methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(5) 7- (3,4-Dichloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(6) 7- (4-Fluoro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(7) 7- (4-Ethyl-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(8) 2-Methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3H-quinazolin-4-one
(9) 2-Methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one
(10) 7- (4-Chloro-phenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

(11) 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -1H-quinazoline-2,4-dione
(12) 7- (4-Chloro-phenyl) -3- {2- [4-((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazoline-4- on
(13) 7- (4-Chloro-phenyl) -3- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(14) 7- (4-Chloro-phenyl) -3- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(15) 7- (4-Chloro-phenyl) -3- [2- (4-morpholin-4-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(16) 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-benzo [d] [1,2,3] triazine-4- on
(17) 5- (4-Fluoro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -isoindole-1,3-dione
(18) 4'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(19) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide
(20) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide

(21) 4'-Methoxy-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide
(22) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amide
(23) 4- (4-Chloro-phenyl) -cyclohexanecarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(24) 4-Methylphenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(25) 4- (4-Chloro-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(26) 4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(27) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide
(28) 4'-Chloro-biphenyl-4-carboxylic acid- (4-pyrrolidin-1-ylmethyl-benzyloxy) -amide
(29) 4-Cyclohexyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(30) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

(31) 7- (4-Chloro-phenyl) -3- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -3H-quinazolin-4-one
(32) 4'-Chloro-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide
(33) 7- (3-Methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(34) 4- (4-Oxo-cyclohexyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(35) 4-Cyclohexyl-1-cyclohexylcarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(36) 4-Benzyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(37) 4-Cyclohexyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(38) 4- (4-Chloro-phenyl) -piperazine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(39) 4- (4-Fluoro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(40) 4- (4-Methoxy-phenyl) -piperazine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

(41) 4-Phenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(42) (4'-Chloro-biphenyl-4-yl)-[3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidin-1-yl] -methanone
(43) 4'-Chloro-biphenyl-4-carboxylic acid- [2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide
(44) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethyl] -amide
(45) 4-Benzyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(46) 4- (4-Oxo-cyclohexylidenemethyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(47) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(48) 5- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one
(49) 4-Piperidin-1-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(50) 7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one

(51) 7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one
(52) 7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one
(53) 7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one
(54) 7- (4-Chloro-phenyl) -3- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -3H-quinazoline-4 -on
(55) 6- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2H-isoquinolin-1-one
(56) 4'-chloro-biphenyl-4-carboxylic acid [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(57) 4'-chloro-biphenyl-4-carboxylic acid [2- (3-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(58) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (1-ethyl-piperidin-2-yl) -phenyl] -ethyl} -amide
(59) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (4-acetyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide
(60) 4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-aza-bicyclo [2.2.1] hept-5-en-2-ylmethyl) -phenyl] -ethyl} -amide

(61) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (1,3-dihydro-isoindol-2-ylmethyl) -phenyl] -ethyl} -amide
(62) 4'-Chloro-biphenyl-4-carboxylic acid (2- {4-[(diisopropylamino) -methyl] -phenyl} -ethyl) -amide
(63) 4'-Chloro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(64) 4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-dimethylaminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(65) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3-dimethylamino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(66) 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(67) 4-Pent-1-inyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(68) 4'-Chloro-biphenyl-4-carboxylic acid [2- (6-pyrrolidin-1-ylmethyl-pyridin-3-yl) -ethyl] -amide
(69) 4'-Chloro-biphenyl-4-carboxylic acid [2- (1-pyrrolidin-1-yl-indan-5-yl) -ethyl] -amide
(70) 4'-chloro-biphenyl-4-carboxylic acid [2- (2-nitro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

(71) 2 ', 4'-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(72) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3-amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(73) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(74) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-2,6-diaza-spiro [3.4] oct-6-ylmethyl) -phenyl] -ethyl} -amide
(75) 4'-Chloro-biphenyl-4-carboxylic acid [2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -amide
(76) 4'-Chloro-biphenyl-4-carboxylic acid [2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(77) 4'-Bromo-biphenyl-4-carboxylic acid {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(78) 4- (5-Chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(79) 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(80) 4'-Bromo-3-fluoro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide

(81) 4'-Chloro-2-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(82) 4'-Ethyl-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(83) tert.butyl [1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-2-ylmethyl] -carbamate
(84) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide
(85) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(86) 4'-Chloro-biphenyl-4-carboxylic acid (2- {4-[(cyclopropylmethyl-amino) -methyl] -phenyl} -ethyl) -amide
(87) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) -phenyl] -ethyl} -amide
(88) 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-{[(2-hydroxy-ethyl) -methyl-amino] -methyl} -phenyl) -ethyl] -amide
(89) tert.butyl [1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-3-yl] -carbamate
(90) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide

(91) 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-azetidin-1-ylmethyl-phenyl) -ethyl] -amide
(92) 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(93) 4'-Fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(94) 4'-Chloro-3-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(95) 2'-Fluoro-4'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(96) 5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(97) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(98) 4'-Bromo-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(99) 4'-chloro-biphenyl-4-carboxylic acid {2- [4- (1-pyrrolidin-1-ylethyl) -phenyl] -ethyl} -amide.

Formula (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), ( (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25) (26), (27), (28), (29), (30), (47) as well as the individual compounds (50) to (99) are most particularly preferred.
Several expressions used earlier to describe the compounds of this invention and used below are now more fully defined.
The term halogen represents an atom selected from F, Cl, Br and I.
The term C _1-n -alkyl (n has a value of 3 to 8) represents a saturated, branched or unbranched hydrocarbon group having 1 to n C atoms. Examples of such groups are methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, Examples include n-hexyl and iso-hexyl.
The term C _1-n -alkylene (n may have a value of 1 to 8) represents a saturated, branched or unbranched hydrocarbon bridge having 1 to n C atoms. Examples of such groups are methylene (—CH ₂ —), ethylene (—CH ₂ —CH ₂ —), 1-methyl-ethylene (—CH (CH ₃ ) —CH ₂ —), 1,1-dimethyl. -Ethylene (-C (CH ₃ ) ₂ -CH _2- ), n-prop-1,3-ylene (-CH ₂ -CH ₂ -CH _2- ), 1-methylprop-1,3-ylene (-CH (CH ₃ ) —CH ₂ —CH ₂ —), 2-methylprop-1,3-ylene (—CH ₂ —CH (CH ₃ ) —CH ₂ —), etc., as well as the corresponding mirror-symmetric forms .

The term C _2-n -alkenyl (n has a value of 3 to 6) represents a branched or unbranched hydrocarbon group having _{2 to n} C atoms and at least one C═C-double bond. . Examples of such groups are vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1- Examples include pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.
The term C _1-n -alkoxy represents an —OC _1-n -alkyl group, where C _1-n -alkyl is as previously defined. Examples of such groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert- Examples include pentoxy, n-hexoxy, iso-hexoxy and the like.
The term C _1-n -alkylthio represents a —SC _1-n -alkyl group, where C _1-n -alkyl is as previously defined. Examples of such groups are methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert- Examples include pentylthio, n-hexylthio, iso-hexylthio and the like.
The term C _1-n -alkylcarbonyl represents a —C (═O) —C _1-n -alkyl group, wherein C _1-n -alkyl is as defined above. Examples of such groups are methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso -Pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl and the like.

The term C _3-n -cycloalkyl represents a saturated mono-, bi-, tri- or spirocarbocyclic group having _{3 to n} C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcalyl, adamantyl and the like Is mentioned.
The term C _3-n -cycloalkylcarbonyl represents a —C (═O) —C _3-n -cycloalkyl group, where C _3-n -cycloalkyl is as previously defined.
The term aryl represents carbocyclic, aromatic ring systems such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentarenyl, azulenyl, biphenylenyl and the like.
The term heteroaryl as used in this application denotes a heterocyclic, aromatic ring system comprising at least one C atom plus one or more heteroatoms selected from N, O and / or S. Examples of such groups are furanyl, thiophenyl (thienyl), pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, Pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, Benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzo Isoxazolyl, it is a purinyl, quinazolinyl, Kinojiriniru, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. The term heteroaryl also includes partially hydrogenated heterocyclic, aromatic ring systems, particularly those listed above. Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

Terms such as aryl-C _1-n -alkyl, heteroaryl-C _1-n -alkyl and the like are substituted with an aryl or heteroaryl group, as defined above, for C _1-n -alkyl. To express. Many of the previously indicated terms may be used repeatedly in defining a formula or group and, in each case, independently of one another, have one of the previously indicated meanings.
The term “unsaturated carbocyclic group” or “unsaturated heterocyclic group”, particularly used in the definition of the group Cy, refers to a fully unsaturated group, as well as the corresponding, only partially saturated group. In particular mono- and diunsaturated groups.
The term “optionally substituted” as used in this application indicates that the group so indicated is unsubstituted or mono- or polysubstituted by the specified substituents. When the group is polysubstituted, the substituents may be the same or different.
The residues and substituents may be mono- or polysubstituted with fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.

The compounds of the general formula I according to the invention may have acid groups, mainly carboxyl groups, and / or basic groups, for example amino functional groups. Therefore, the compounds of general formula I can be used as internal salts as pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acids or organic acids (eg maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid). As a salt with or pharmaceutically usable bases such as alkali metal or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as especially diethylamine, triethylamine, triethanolamine It may exist as a salt with
The compounds of the invention may be obtained using methods of synthesis known in principle. These compounds are preferably obtained by methods of preparation described above and more fully described below.
The first group of preferred embodiments, ie the process according to the invention for obtaining these compounds in which the group A and the group R ³ are not directly linked to one another, basically distinguishes between the two cases. .
In the first case, a nitrogen heterocyclic group in which the group A is linked to the carboxamide group via a nitrogen atom (this may contain one or more heteroatoms selected from N, O and S in addition to the nitrogen atom) And those compounds of the formula I representing The reaction of an amine of formula I-1 with a secondary amine of formula I-2 is shown in the general reaction plan below.


















Reaction plan 1:

The amine compound of formula I-1 is first reacted with CDT (1,1′-carbonyldi- (1,2,4-triazole)) in a solvent or mixture of solvents, and then the reaction mixture is converted to formula I— It is preferred to react further with the two amine compounds, during which a minimum amount of some base is added to the reaction mixture before and / or after the reaction of the amine compound with CDT. Advantageously, the amine compound of formula I-2 is reacted with CDT in the temperature range of −20 ° C. to 20 ° C., and then the reaction mixture is of the formula 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 3 ± 1.5 Amine compound of formula I-2: Amine compound of formula I-2: CDT: The base compound is reacted with an amine compound of formula I-2 in a temperature range of 40 ° C to 100 ° C in a molar ratio. Nitrogen bases, in particular tert. Amines such as triethylamine, are preferably used as bases.
The amine compound of formula I-2 may be a saturated N-heterocyclic compound, such as a piperazine derivative, according to Reaction Plan 2 below.











Reaction plan 2

The second case of the preparation method involves other compounds of the formula I which are not covered by the case 1, in which the group A is not directly bonded to R ³ . TBTU (2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium-tetrafluoroborate) and formula I in a solvent or mixture of solvents in the presence of at least one base Reaction of the carboxylic acid compound of formula I-3 with the amine compound of -1 is shown in Reaction Plan 3.
Reaction plan 3:

  The carboxylic acid compound of formula I-3 is reacted with TBTU in a solvent or mixture of solvents, and then the reaction mixture is further reacted with an amine compound of formula I-1, during which a minimum amount of some base is TBTU. It is preferred to be added to the reaction mixture before and / or after the reaction of the carboxylic acid compound. Instead of carboxylic acids it is also possible to use the corresponding activated carboxylic acid derivatives, such as esters, ortho-esters, carboxylic acid chlorides or acid anhydrides. The base used is preferably a nitrogen base, in particular a tert.-amine, for example triethylamine. Advantageously, the carboxylic acid compound of formula I-3 is reacted with TBTU and the reaction mixture is then converted to 1 ± 0.25: 1 ± 0.25: 1 ± 0.25: 1-4 carboxylic acid compound of formula I-3: formula Used in conjunction with amine compounds of formula I-1 in a temperature range of 0 ° C. to 60 ° C. in an amine compound of I-1: TBTU: base ratio.

The starting compounds of formula I-3 may be obtained by methods known to those skilled in the art. Thus, biaryl compounds are obtained using Suzuki coupling starting from, for example, p-bromoarylcarboxylic acid derivatives and arylboric acid derivatives in the presence of Pd [0] catalyst.
The second group of preferred embodiments, namely the process of the preparation of the invention for these compounds in which the group A and the group R ³ are bonded together, depends on the meaning IIIa-IIIg of the group Q in seven cases. Distinguish between
Q is -CR ⁶ R ⁷ - represents a (IIIa), according to the first case, as an amine compound of formula Ia.1 is shown in reaction plan 4 below, the formula Ia.2 o-bromomethyl - benzoic In this case, the phenyl ring substituents L ¹ , L ² , L ³ were omitted for clarity.





























Reaction plan 4:

It is preferred that the o-bromomethyl-benzoic acid ester derivative of formula Ia.2 is reacted with an amine compound of formula Ia.1 in a solvent or mixture of solvents, during which at least one base is added. Instead of the o-bromomethyl-benzoic acid ester derivative of formula Ia.2, other corresponding o-benzyl-benzoic acid ester derivatives (iodine or mesylate instead of bromine) may also be used. Preferably potassium carbonate or cesium carbonate is used as the base, but tert. Amine bases such as triethylamine are also common. Advantageously, the o-bromomethyl-benzoic acid ester derivative of formula Ia.2 is 1 ± 0.25: 1 ± 0.25: 3 ± 0.50 of acetonitrile in acetonitrile with the formula Ia.2: o-bromomethyl-benzoic acid ester derivative: Used in conjunction with an amine of formula Ia.1 and potassium carbonate as base in a temperature range of 40-80 ° C. in an amine: potassium carbonate molar ratio.
Second case (Q is -CR ⁶ = R ⁷ - (representative of IIIb)) According to the isoquinolinone derivative of formula IB.3 is reacted with an electrophilic compound of formula Ib.4 of formula Ib.5 An isoquinoline derivative is produced, which is further derivatized by known methods to give a compound of formula I. Isoquinolinone derivatives of formula Ib.3 are obtained from cinnamic acid derivatives of formula Ib.1 by reaction with (EtO) ₂ P (O) N ₃ . The synthesis of the basic material was described by M. Becker et al., Bioorganic & Medicinal Chemistry Letters 9 (1999), 2753-2758. The reaction is shown in Reaction Plan 5 below, in which case the phenyl ring substituents L ¹ , L ² , L ³ were omitted for clarity.


Reaction plan 5:

  The compound of formula Ib.2 is advantageously obtained by the reaction sequence described below. The acrylic acid derivative Ib.1 is first reacted by the action of a chlorinating agent such as thionyl chloride, phosphorus pentachloride or oxalyl chloride without using an inert solvent such as dichloromethane or optionally in an inert solvent. The acid chloride is obtained at a temperature between 0 ° C and 80 ° C. This is converted to an acrylic acid azide derivative by the action of sodium azide in a solvent or mixture of solvents. The solvent used may be, for example, dioxane, tetrahydrofuran or water. Isocyanate derivative Ib.2 is preferably synthesized directly by the action of phosphoric acid diphenyl ester azide on acrylic acid derivative Ib.1 at a temperature of 0 ° C. to 150 ° C. in a solvent in the presence of a base. Suitable solvents include, for example, toluene or dioxane. Tertiary amines such as triethylamine may be used as the base. The reaction has a reaction time of 1 to 12 hours. Advantageously, the reaction of acrylic acid derivative Ib.1 in a molar ratio of 1 ± 0.25: 1 ± 0.25: 1 ± 0.25 with phosphoric acid diphenyl ester azide and triethylamine takes place in toluene as solvent. Isocyanate derivative Ib.2 is optionally heated in the presence of a base, for example tributylamine, in a solvent to produce an isoquinolone derivative of formula Ib.3. The reaction preferably occurs in the vicinity of the melting point in diphenyl ether. Heat sources that can be used are oils, metal baths or microwaves.

The reaction of the ioquinolone derivative of formula Ib.3 with the mesylate derivative of formula Ib.4 to produce the isoquinolone derivative of formula Ib.5 is carried out in a solvent in the presence of a base at a temperature between 0 ° C. and 150 ° C. Advantageously, the reaction of isoquinolone derivative Ib.3 with a mesylate derivative of formula Ib.4 and sodium hydride in a molar ratio of 1 ± 0.25: 1 ± 0.25: 1 ± 0.25 takes place in DMF as solvent.
In order to convert the acetal into the corresponding aldehyde, the isoquinolone derivative of formula Ib.5 is first reacted in the presence of an acid in a solvent. This is converted to a compound of formula Ib in a solvent in the presence of a hybrid converter, an amine and an acid. Examples of hybrid converters include, for example, sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. Advantageously, the reaction of aldehyde with amine and sodium cyanoborohydride released from isoquinolone derivative Ib.5 in a molar ratio of 1 ± 0.25: 1 ± 0.25: 0.8 ± 0.25 is carried out in methanol and acetic acid at around 20 ° C. Happens at temperature.
Synthesis of the isoquinoline of formula Ib, including the starting compound, and subsequent derivatization to produce the amine is illustrated by the following plan of synthesis of the specific compound, while free to prepare phthalazinone (Diagram 8) The synthesis of body 1 can be deduced from diagram 6 below.

















Reaction plan 6:

Q is -N = CR ⁸ - According to the case of the third representative of the (IIIc), phthalazinone derivatives of formula Ic.4 is reacted with an electrophilic compound of formula Ic.5 phthalazinone derivative of formula Ic.6 Which is further derivatized by known methods to produce compounds of formula Ic. The phthalazinone derivative of formula Ic.4 with respect to R ⁸ = hydrogen is acylated to produce the o-oxazolyl-benzaldehyde derivative of formula Ic.2 starting from the phenyloxazole derivative of formula Ic.1 and 3 of formula Ic.3 Obtained by subsequent cyclization to produce a -hydroxy-3H-isobenzofuran-1-one derivative. The synthesis of the basic material was described by M. Napoletano et al., Bioorganic & Medicinal Chemistry Letters 12 (2002), 5-8. The reaction to produce the compound of general formula Ic is shown in Reaction Plan 7 below, in which the phenyl ring substituents L ¹ , L ² , L ³ have been omitted for clarity.

The reaction sequence is described in more detail below. The oxazoline derivative Ic.1 is metallated using a suitable organometallic reagent and then formaldehyde equivalents such as dimethylformamide or ortho at temperatures between -70 ° C and 20 ° C, preferably between -20 ° C and 0 ° C. Reacted with formate to produce a compound of formula Ic.2. Suitable solvents include, for example, dioxane, tetrahydrofuran or diethyl ether. The action of aqueous sulfuric acid in a solvent, for example ethanol, at a temperature close to the boiling point of the solvent or mixture of solvents over a period of 1 to 24 hours may give compounds of general formula Ic.3. The phthalazinone derivative of formula Ic.4 may be obtained by reacting the compound of formula Ic.3 with hydrazine in acetic acid and optionally in a solvent at a temperature ranging from 20 ° C to 120 ° C. The synthesis to obtain the phthalazinone derivative of formula Ic is carried out analogously to the reaction described for the synthesis of compounds of general formula Ib.
Synthesis of phthalazinone derivatives of formula Ic, in particular starting compounds and subsequent derivatization, is now illustrated with reference to the synthesis plan 8 of the specific compounds, where the abbreviations have the following meanings: LAH is lithium aluminum hydride BuLi represents n-butyllithium, DMF represents dimethylformamide, MeOH is methanol, and Ms-Cl is methanesulfonic acid chloride.




































Reaction plan 8

According to a fourth case where Q represents -N = N- (IIId), the o-amino-benzamide derivative of formula Id.1 is reacted in the presence of a suitable nitrito compound and an acid to give a diazonium intermediate. To produce a benzotriazinone derivative of formula Id. The reaction is shown in Reaction Plan 9 below, in which case the phenyl ring substituents L ¹ , L ² , L ³ were omitted for clarity.
Reaction plan 9:

The compound of the general formula Id.1 is preferably reacted in a solvent such as methanol in the presence of an inorganic acid such as hydrochloric acid and a salt containing nitrite ions at a temperature of −10 ° C. to 30 ° C. Advantageously, the reaction of the amino compound Id.1 in a molar ratio of 1 ± 0.25: 1.5 ± 0.25 with sodium nitrite takes place in the presence of hydrochloric acid in methanol as solvent.
According to a fifth case, where Q represents —CO—NR ⁹ — (IIIe), an o-amino-benzamide derivative of formula Ie.1 is reacted in the presence of CDI to give a quinazolinedione derivative of formula Ie. Generate. CDI is added to the benzamide derivative of formula Ie.1 in a molar ratio of 1 or more and the reaction is carried out at least partly in the temperature range of 35 ° C. to 100 ° C., preferably near the boiling temperature of the reaction mixture. The reaction is shown in Reaction Plan 10 below, in which case the phenyl ring substituents L ¹ , L ² , L ³ were omitted for clarity.






Reaction plan 10:

According to a sixth case where Q represents —CR ⁸ ═N— (IIIf), the o-amino-benzamide derivative of formula If.1 reacts with the carboxylic acid R ⁸ COOH and / or the corresponding activated carboxylic acid derivative. To produce a quinazolinone derivative of formula If. Suitable activated carboxylic acid derivatives are, for example, esters, ortho-esters, carboxylic acid chlorides and acid anhydrides. A carboxylic acid, which may be activated if necessary, is added to the carboxamide compound of formula If.1 in a molar ratio of 1 or more, and the reaction is at least in the temperature range of 35 ° C. to 100 ° C., preferably near the boiling temperature of the reaction mixture. Partly done. The reaction is shown in Reaction Plan 11 below, where the phenyl ring substituents L ¹ , L ² , and L ³ were omitted for clarity.










Reaction plan 11:

The synthesis of quinazolinone derivatives of formula If, in particular the starting compounds, is shown with reference to the synthesis plan 12 of the specific compounds, in which case the following abbreviations are used: CDI for carbonyldiimidazole, 2- (1H-benzotriazole- TBTU for 1-yl) -1,1,3,3-tetramethyluronium-tetrafluoroborate and NEt _{3 for} triethylamine. Initially, synthetic plans for the two starting compounds 1 and 2 are shown.
















Reaction plan 12

Starting compounds 1 and 2 are coupled together via an amide bond using TBTU. The nitro group ortho to the resulting amide bond is reduced in the presence of PtO ₂ to produce an amine. Cyclization to produce quinazolinone is performed using a carboxylic acid, in this case formic acid.
According to the seventh case where Q represents —CO— (IIIg), an isobenzofurandione derivative of formula Ig.2 is reacted with an amine compound of formula Ig.1 to produce an isoindoledione derivative of formula Ig. . The reaction is shown in Reaction Plan 13 below, in which case the phenyl ring substituents L ¹ , L ² , L ³ were omitted for clarity.













Reaction plan 13:

The isobenzofurandione derivative Ig.2 is reacted with an amine of the general formula Ig.1 in a solvent, for example acetic acid, in a molar ratio of 1 ± 0.25: 1.5 ± 0.25. The temperature during the reaction is preferably the boiling temperature of the solvent.
However, isoindoledione derivatives of formula Ig may also be obtained according to the synthetic plan 14 below. The synthesis of the individual compounds shown is readily applicable to other compounds of formula Ig and may be modified by those skilled in the art as needed. First, an isoindoledione functional group is obtained from an isobenzofurandione derivative by coupling an amine, and then further aryl groups are added by Suzuki coupling in the presence of Pd [0].













Reaction plan 14

The possible methods described above for synthesizing the compounds of the present invention are known to those skilled in the art using known methods for the individual compounds to be synthesized, for example as described in Methoden der organischen Chemie by Houben-Weyl. May be easily improved and / or supplemented at least in their broad outline.
In the above reaction, the reactive groups present, for example hydroxy groups, carboxy groups, amino groups or imino groups, by means of conventional protecting groups (these are cleaved again after the reaction) by methods known from the literature during the reaction. It may be protected. Protecting groups commonly used in peptide chemistry may be used in particular. Information on this can be found, for example, in WO 98/11128.
The stereoisomeric compounds of formula (I) may in principle be separated by the usual methods. Diastereomers are separated on the basis of their different physicochemical properties, for example by fractional crystallization from a suitable solvent and by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases. May be.
As already mentioned, the compounds of formula (I) may be converted into their salts, in particular their physiologically and pharmacologically acceptable salts for pharmaceutical use. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, in the case of hydrogen bonded by an acid, the compound of formula (I) is a physiologically and pharmacologically acceptable salt with an alkali or alkaline earth metal cation as a counter ion by reaction with an inorganic base. May be converted to Acid addition salts can be prepared, for example, using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, tartaric acid or maleic acid. In addition, mixtures of the above acids may be used. Alkali metal and alkaline earth metal hydroxides and hydrides are used to prepare alkali metal and alkaline earth metal salts of compounds of formula (I) having hydrogen bonded by an acid. Preferred are alkali metals, especially sodium and potassium hydroxides and hydrides, most preferably sodium hydroxide and potassium hydroxide.

The compounds of the present invention, including physiologically acceptable salts, are effective as antagonists of MCH receptors, particularly MCH-1 receptor, and show good affinity in MCH receptor binding studies. A pharmacological test system for MCH antagonistic properties is described in the experimental part below.
As antagonists of the MCH receptor, the compounds of the invention are pharmaceutically active for the prevention and / or treatment of symptoms and / or diseases caused by MCH or in some other manner causally associated with MCH. Advantageously suitable as material. In general, the compounds of the present invention have low toxicity, they are well absorbed by the oral route and have transitivity in the brain, in particular brain accessibility. Therefore, an MCH antagonist comprising at least one compound of the invention is a mammal, such as a rat, for the prevention and / or treatment of symptoms and / or diseases caused by or causally associated with MCH. Particularly suitable for mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs, cows, monkeys and also humans.
Diseases caused by, or causally associated with MCH are bulimia, particularly including metabolic disorders such as obesity and dietary disorders such as bulimia nervosa. Indicated obesity, especially exogenous obesity, hyperinsulinic obesity, plasma proliferative obesity, hyperphyseal steatosis, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infanthood Examples include obesity, upper body obesity, dietary obesity, hypogonadal obesity, and central obesity. This range of instructions also includes cachexia, anorexia nervosa and bulimia. The compounds of the present invention may be particularly suitable for reducing hunger, suppressing appetite, controlling dietary behavior and / or inducing satiety.

In addition, diseases caused by MCH or otherwise related to MCH also include hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorder, emotional disorder, Depression, anxiety, reproductive disorders, memory disorders, forms of dementia and hormonal disorders.
The compounds of the present invention may also be used in other diseases and / or disorders, particularly those associated with obesity, such as diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia, diabetic complications (diabetic retinopathy, (Including diabetic neuropathies, diabetic nephropathy, etc.), insulin resistance, pathological glucose tolerance, cardiovascular diseases, in particular arteriosclerosis and hypertension, and knee arthritis.
The MCH antagonists and formulations of the present invention may be advantageously used in combination with diet therapy, such as diet diabetes treatment, and exercise.
Another range of indications for which the compounds of the invention are advantageously suitable are the prevention and / or treatment of dysuria, eg urinary incontinence, hyperactive bladder, nocturia, nocturia, hyperactive bladder and urine Incontinence may or may not be associated with benign prostatic hyperplasia.
The dose required to obtain such an effect is conveniently 1 to 3 times daily in each case, 0.001 to 30 mg per kg body weight, preferably 0.01 to 1 kg body weight, by intravenous or subcutaneous route. -5 mg, by oral or intranasal route or by inhalation, 0.01-50 mg / kg body weight, preferably 0.1-30 mg / kg body weight.
For this purpose, the compounds of the formula I prepared according to the invention can be prepared with one or more physiologically acceptable excipients, customary inert carriers and / or diluents such as corn starch, lactose, glucose, microcrystals Cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard Formulated with fat or a suitable mixture thereof, optionally together with other active substances as described below, to obtain conventional gallen formulations, such as simple or coated tablets, capsules, powders, granules , Solution, emulsion, syrup, inhalation Aerosol may be prepared ointments or suppositories.
In addition to pharmaceutical compositions, the present invention also includes compositions comprising at least one carboxamide compound of the present invention and / or a salt of the present invention, optionally together with one or more physiologically acceptable excipients. Such a composition may also be, for example, a food product (which may be solid or liquid) into which the compound of the invention is incorporated.

The above combinations make it possible to increase the therapeutic effect of the MCH antagonists of the invention and / or reduce the dose of the MCH antagonists of the invention, particularly as additional active substances, for example with respect to one of the above instructions Can be used. One or more additional active substances-active substances for the treatment of diabetes,
-Active substances for the treatment of complications of diabetes,
Active substances for the treatment of obesity, preferably active substances other than MCH antagonists,
-Active substances for the treatment of hypertension,
-Active substances for the treatment of hyperlipidemia, including arteriosclerosis,
-Active substances for the treatment of arthritis,
-Active substances for the treatment of anxiety conditions,
-Preferably selected from active substances for the treatment of depression.
The above categories of active substances are now explained in more detail by way of examples.
Examples of active substances for the treatment of diabetes are insulin sensitizers, insulin secretagogues, biguanides, insulin, α-glucosidase inhibitors, β3 adreno-receptor agonists.
As an insulin sensitizer, pioglitazone and a salt thereof (preferably hydrochloride), troglitazone, rosiglitazone and a salt thereof (preferably maleate), JTT-501, GI-262570, MCC-555, YM-440, Examples include DRF-2593, BM-13-1258, KRP-297, R-119702, and GW-1929.

Examples of the insulin secretagogue include sulfonylureas such as tolbutamide, chloropropamide, tolazamide, acetohexamide, glidopyramide and its ammonium salt, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretagogues are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.
Biguanides include metformin, buformin and phenformin.
Examples of insulin include those obtained from animals, particularly cattle or pigs, semi-synthetic human insulin synthesized enzymatically from insulin obtained from animals, such as human insulin obtained by genetic engineering from Escherichia coli or yeast. It is done. In addition, the term insulin also includes insulin-zinc (containing 0.45-0.9 wt% zinc) and protamine-insulin-zinc obtained from zinc chloride, protamine sulfate and insulin. Insulation may also be obtained from insulin fragments or derivatives (eg INS-1 etc.).
Insulin may also include, for example, different types (“super immediate action”, “immediate action”, “two-stage”, “intermediate”, “prolonged action”, etc.) with respect to the onset time and duration of effect. Often these are chosen according to the patient's condition.
Examples of α-glucosidase inhibitors include acarbose, voglibose, miglitol, and emiglitate.
Examples of β ₃ adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, and AZ40140.
Other active substances for the treatment of diabetes include ergoset, pramlintide, leptin, BAY-27-9955, but also glycogen phosphorylase inhibitor, sorbitol dehydrogenase inhibitor, protein tyrosine phosphatase 1B inhibitor, dipeptidyl protease inhibitor, glipazide, Glyburide is mentioned.

Active substances for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors and protein kinase C inhibitors.
The aldose reductase inhibitor is, for example, tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.
An example of a glycation inhibitor is pimagedin.
An example of a protein kinase C inhibitor is NGF, LY-333531.
Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, thiopride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedin (ALT-711).
Active substances for the treatment of obesity, preferably other than MCH antagonists, include lipase inhibitors and appetite suppressants.
A preferred example of a lipase inhibitor is orlistat.
Examples of preferred appetite suppressants are phentermine, mazindol, dexfenfuramin, fluoxetine, sibutramine, biamine, (S) -sibutramine, SR-141716, NGD-95-1.
An active substance other than those described above for the treatment of obesity includes lipstatin.
Furthermore, for the purposes of this application, the active substance group of anti-obesity active substances also includes appetite suppressants, of which β ₃ agonists, thyromimetic active substances and NPY antagonists should be emphasized . The range of preferred anti-obesity / appetite-suppressing actives here is illustrated by the following additional list by way of example: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, cholecystokinin-A (hereinafter CCK-A) Agonists, monoamine reuptake inhibitors (eg sibutramine), sympathomimetic active substances, serotonergic active substances (eg dexfenfluramine or fenfluramine), dopamine antagonists (eg bromocriptine), melanocyte stimulation Hormone receptor agonist or mimetic, melanocyte stimulating hormone analog, cannabinoid receptor antagonist, MCH antagonist, OB protein (hereinafter referred to as leptin), leptin analog, leptin receptor agonist, galanin Tagonisuto, GI lipase inhibitor or reducer (such as orlistat). Other appetite suppressants include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists such as exendin As well as ciliary neurotrophic factors such as axoquine.

Active substances for the treatment of hypertension include angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers and angiotensin II antagonists.
Examples of inhibitors of angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, and manidipine (hydrochloride).
Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.
Examples of potassium channel openers include lebucromakalim, L-27152, AL0671, and NIP-121.
Angiotensin II antagonists include telmisartan, losartan, candesartan, cilexetil, valsartan, irbeartan, CS-866, E4177.
Examples of active substances for the treatment of hyperlipidemia including arteriosclerosis include HMG-CoA reductase inhibitors and fibrate compounds.
HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripanstat, cerivastatin, itavastatin, ZD-4522 and salts thereof.
Examples of fibrate compounds include bezafibrate, clinofibrate, clofibrate and simfibrate.

An active substance for the treatment of arthritis includes ibuprofen.
Active substances for the treatment of anxiety include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
Conveniently, the dose for these active substances is from 1/5 of the lowest normally recommended dose to 1/1 of the normally recommended dose.
In another embodiment, the present invention also relates to the use of at least one carboxamide compound of the invention and / or a salt of the invention for influencing the dietary behavior of a mammal. This use is particularly based on the fact that the compounds of the invention may be suitable for reducing hunger, limiting appetite, controlling dietary behavior and / or inducing satiety. Advantageously, dietary behavior is affected to reduce food intake. Therefore, the compounds of the present invention are advantageously used to reduce weight. Another use of the present invention is, for example, prevention of weight gain in people who have already taken steps to lose weight and are interested in maintaining their lower weight. According to this embodiment, it is preferably a non-therapeutic use. Such non-therapeutic use may be, for example, a cosmetic use to change the appearance, or an application to improve general health. The compounds of the invention do not suffer from the dietary disorder being diagnosed and are used non-therapeutically in mammals, especially humans, who are diagnosed obese, bulimia, diabetes and / or dysuria, especially urinary incontinence It is preferred that Preferably, the compounds of the invention are defined as their body weight (in kilograms) divided by their height (in meters) squared, people whose BMI (Biomass Index) is below 30 levels, in particular 25 or less Suitable for non-therapeutic use.
The following examples are intended to illustrate the present invention.

Remarks In principle, ¹ H-NMR and / or mass spectra were obtained for the prepared compounds. Unless otherwise stated, R _f values were measured using ready-made silica gel 60 TLC plates F ₂₅₄ (E. Merck, Darmstadt, Item No. 1.05714) without chamber saturation. R _f values obtained under the heading Alox were measured using ready-made aluminum oxide 60 TLC plates F ₂₅₄ (E. Merck, Darmstadt, Item No. 1.05713) without chamber saturation.
Specified HPLC data was measured under the following parameters: Solvax column (Agilent Technologies), SB (Stable Bond) -C18; 3.5 μm; 4.6 x 75 mm; Column temperature: 30 ° C .; : 0.8 mL / min; injection volume: 5 μL; detection at 254 nm.
Method A: Water: acetonitrile: formic acid 9: 1: 0.01 → 1: 9: 0.01 over 9 minutes
Method B: Water: acetonitrile: formic acid 9: 1: 0.01 → 1: 9: 0.01 over 4 minutes, then 1: 9: 0.01 over 6 minutes
In the absence of special information about the arrangement, it is not clear whether there is a pure enantiomer or whether partial or complete racemization has occurred.

The following abbreviations are used first and below.
BOC-acid anhydride tert.-butyloxycarbonyl-acid anhydride
CDI Carbonyldiimidazole
CDT 1,1'-carbonyldi- (1,2,4-triazole)
DMF dimethylformamide ethyl acetate / EtOAc ethyl acetate diethyl ether
HOBt 1-hydroxybenzotriazole hydrate Hunig base N, N-diisopropyl-ethylamine
conc.
Me methyl
MeOH methanol
RT Room temperature (approximately 20 ℃)
TBTU 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium-tetrafluoroborate
THF tetrahydrofuran
eq. equivalent
calc. Calculated value
fnd. Measured value

General implementation method I (TBTU coupling):
Triethylamine (1.5 eq) and TBTU (1.0 eq) are added sequentially to a solution of carboxylic acid (1.0 eq) in THF or DMF. Depending on the carboxylic acid, the mixture is stirred at ambient temperature to 40 ° C. for 10 minutes to 12 hours before adding the amine (1.0 eq). The reaction is stirred at ambient temperature to 40 ° C. for 30 minutes to 2 hours, after which half-saturated NaHCO ₃ solution is added. After extraction of the aqueous phase with a suitable solvent (eg ethyl acetate), the organic phase is dried over magnesium sulfate. Using a rotary evaporator, the solvent is removed and further purification is carried out by column chromatography or HPLC. The reaction may also be performed in a Chemspeed automatic synthesizer.
General implementation method II (CDT coupling):
CDT (1 eq) is added to a solution of primary amine (1.0 eq) in DMF at 0 ° C. (1 mmol / mL) and the mixture is stirred at 0 ° C. for a further 30 min. The reaction is heated to 25 ° C. and triethylamine (3 eq) is added. Then secondary amine (1.0 eq) in DMF (0.25 mmol / mL) is added and the reaction solution is heated to 60-80 ° C. for 30 min to 3 h. The DMF is removed in vacuo and the residue is taken up with dichloromethane and 5% Na ₂ CO ₃ solution or water and tert-butyl methyl ether. The organic phase is extracted with water and, if necessary after drying with magnesium sulfate, the solvent is removed using a rotary evaporator. Further purification is carried out by column chromatography or crystallization. The reaction may also be performed in a Chemspeed automatic synthesizer.
Example 1.1:
7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl-3H-quinazolin-4-one

1.1.a.4-Bromo-2-nitro-benzoic acid To a reaction mixture of 82 g (0.379 mol) 4-bromo-2-nitro-toluene in 700 ml pyridine and 500 ml water, 174.5 g (1.104 mol) potassium permanganate In a batch within 8 hours. The reaction mixture is stirred at 60 ° C. for 12 hours. Then another 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are added alternately. The reaction mixture is stirred at 60 ° C. for 12 hours, combined with 200 ml of ethanol and refluxed for 30 minutes. The reaction mixture is then filtered hot and the filtrate is evaporated in a rotary evaporator. The remaining residue is made alkaline with 10% sodium hydroxide solution and extracted with diethyl ether. The aqueous phase is separated and acidified with dilute hydrochloric acid. The crystals formed are filtered off, washed with water, dried azeotropically with tetrahydrofuran and stirred with diisopropyl ether.
Yield: 37 g (32.8% of theory)
C ₇ H ₄ BrNO ₄ (M = 246.018)
calc .: Mole peak (M + Na) ⁺ : 268/270 fnd .: Mole peak (M + Na) ⁺ : 268/270
R _f value: 0.46 (silica gel, dichloromethane / methanol / acetic acid 8: 2: 0.1)
1.1.b.4'-Chloro-3-nitro-biphenyl-4-carboxylic acid 0.288 g (0.25 mmol) tetrakis- (triphenylphosphine) -palladium, 1.25 g 4-chloro-phenyl-boric acid in 30 ml methanol ( 7.99 mmol) and 2.31 g (21.7 mmol) sodium carbonate in 14 ml water are alternately added to a solution of 1.92 g (7.81 mmol) 4-bromo-2-nitro-benzoic acid in 30 ml dioxane. The reaction mixture is heated to 110 ° C. in the microwave at 300 watts for 1 hour. The reaction mixture is then evaporated in a rotary evaporator, the residue is taken up in water and adjusted to pH 3 with 1M hydrochloric acid. The aqueous solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off using a rotary evaporator and the residue is stirred with diisopropyl ether.
Yield: 2.04 g (93.9% of theory)
C ₁₃ H ₈ ClNO ₄ (M = 277.666)
calc .: molar peak (MH) ^- : 276 fnd .: molar peak (MH) ^- : 276
R _f value: 0.5 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)

1.1.c. Ethyl 4-cyanomethyl-benzoate To a solution of 147.5 g (2.263 mol) of potassium cyanide in 250 ml of hot water is added dropwise a solution of 500 g (2.057 mol) of ethyl 4-bromomethyl-benzoate in 1000 ml of ethanol. The reaction mixture is refluxed for 1 hour and stirred at ambient temperature for 12 hours. An additional 73.7 g (0.5 mol) of potassium cyanide is added and the mixture is refluxed for 2 hours. The solid in the reaction mixture is filtered off, and the filtrate is filtered through a mixture of silica gel and activated carbon. The filtrate obtained is evaporated and the residue is poured into 1000 ml of water. The aqueous solution is extracted with tert-butyl methyl ether and the organic phase is extracted three times with water. The organic phase is then dried over magnesium sulphate and the solvent is distilled off using a rotary evaporator. Purification is carried out by column chromatography on silica gel (petroleum ether / ethyl acetate 8: 2).
Yield: 164.46 g (42.2% of theory)
C ₁₁ H ₁₁ NO ₂ (M = 189.216)
calc .: Mole peak (M + H) ⁺ : 190 fnd .: Mole peak (M + H) ⁺ : 190
R _f value: 0.3 (silica gel, petroleum ether / ethyl acetate 8: 2)
1.1.d. 4-Cyanomethyl-benzoic acid A solution of 10 g (53 mmol) of ethyl 4-cyanomethyl-benzoate and 2.02 ml of 1M sodium hydroxide solution in 100 ml of ethanol is refluxed for 1 hour. The reaction solution is then evaporated and the residue is combined with ice water. Concentrated hydrochloric acid is added dropwise to the reaction solution until no precipitate is formed. The precipitate is filtered off, washed twice with water and dried.
Yield: 4.7 g (55% of theory)
C ₉ H ₇ NO ₂ (M = 161.162)
calc .: molar peak (MH) ^- : 160 fnd .: molar peak (MH) ^- : 160

1.1.e. (4-Hydroxymethyl-phenyl) -acetonitrile
5.17 g (32 mmol) CDI is added to a solution of 4.7 g (29 mmol) 4-cyanomethyl-benzoic acid in 250 ml tetrahydrofuran and stirred until gas evolution ceases. The reaction mixture is added dropwise to a solution of 3.29 g (87 mmol) sodium borohydride in 200 ml water so that the temperature does not exceed 30 ° C. It is stirred for 2 hours and the reaction mixture is adjusted to pH 3-4 with potassium hydrogen sulfate solution. It is then extracted with ethyl acetate, the organic phase is dried over magnesium sulphate and the solvent is separated off using a rotary evaporator.
Yield: 2.6 g (60.9% of theory)
C ₉ H ₉ NO (M = 147.178)
calc .: molar peak (MH) ^- : 146
fnd .: molar peak (MH) ^- : 146
1.1.f. (4-Bromomethyl-phenyl) -acetonitrile 0.86 ml (9 mmol) phosphorus tribromide at 0 ° C. 2.6 g (17.66 mmol) (4-hydroxymethyl-phenyl) -acetonitrile in 25 ml tert-butyl methyl ether ) Added dropwise to the solution. After completion of the reaction, the reaction mixture is combined with water at ambient temperature, the organic phase is separated and extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulfate and the solvent is distilled off using a rotary evaporator.
Yield: 2.9 g (78.1% of theory)
C ₉ H ₈ BrN (M = 210.075)
calc .: Mole peak (M + H) ⁺ : 209/211 fnd .: Mole peak (M + H) ⁺ : 209/211

1.1 g. (4-Pyrrolidin-1-ylmethyl-phenyl) -acetonitrile 0.446 ml (5.44 mmol) pyrrolidine and 1.366 g (9.882 mmol) potassium carbonate are added to 20 ml dimethylformamide. While stirring, 1.038 g (4.941 mmol) of (4-bromomethyl-phenyl) -acetonitrile is added and the mixture is stirred at ambient temperature for 12 hours. The reaction mixture is evaporated in a rotary evaporator and the residue is extracted with ethyl acetate and water. The organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator.
Yield: 0.732 g (74% of theory)
C ₁₃ H ₁₆ N ₂ (M = 200.286)
calc .: Mole peak (M + H) ⁺ : 201 fnd .: Mole peak (M + H) ⁺ : 201
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.1.h.2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethylamine 0.73 g (3.66 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile and 0.1 g of Raney nickel in 25 ml of methanolic ammonia solution The reaction mixture is hydrogenated at 50 ° C. with 3 bar hydrogen for 9 hours.
Yield: 0.72 g (96.4% of theory)
C ₁₃ H ₂₀ N ₂ (M = 204.31)
calc .: Mole peak (M + H) ⁺ : 205 fnd .: Mole peak (M + H) ⁺ : 205
R _f value: 0.23 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

1.1.i.4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro-3- in 30 ml of tetrahydrofuran Nitro-biphenyl-4-carboxylic acid 0.4 g (1.44 mmol), 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine 0.29 g (1.44 mmol), TBTU 0.46 g (1.44 mmol), HOBT 0.19 g (1.44 Mmol) and 0.42 ml (3 mmol) of triethylamine are stirred for 14 hours at ambient temperature. The reaction mixture is evaporated in a rotary evaporator, extracted with water and ethyl acetate and dried over magnesium sulfate. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / methanol / ammonia = 90: 10: 1).
Yield: 0.47 g (70.3% of theory)
C ₂₆ H ₂₆ ClN ₃ O ₃ (M = 463.96)
calc .: Mole peak (M + H) ⁺ : 464/466 fnd .: Mole peak (M + H) ⁺ : 464/466
R _f value: 0.36 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.1.j.4'-Chloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-chloro in 50 ml methanolic ammonia solution A reaction mixture of 0.47 g (1.01 mmol) of -3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide and 0.1 g of Raney nickel at 3 ° C. at 20 ° C. Hydrogenate for 24 hours. The crude product is further reacted without purification.
Crude yield: 0.46 g
C ₂₆ H ₂₈ ClN ₃ O (M = 433.98)
calc .: Mole peak (M + H) ⁺ : 434/436 fnd .: Mole peak (M + H) ⁺ : 434/436
R _f value: 0.34 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

1.1.k.7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
4'-Chloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 0.46 g (1.06 mmol) and 5 ml formic acid at ambient temperature for 3 hours The mixture is stirred at 100 ° C. for 2 hours. The reaction mixture is combined with water, made alkaline with 6N sodium hydroxide solution and the precipitate is filtered off with suction. The precipitate is taken up in dichloromethane and dried over magnesium sulfate. The solvent is distilled off using a rotary evaporator and the residue is triturated with diisopropyl ether.
Yield: 0.3 g (64.6% of theory)
Melting point: 178-179 ℃
C ₂₇ H ₂₆ ClN ₃ O (M = 443.98)
calc .: Mole peak (M + H) ⁺ : 444 fnd .: Mole peak (M + H) ⁺ : 444
R _f value: 0.35 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.2: 3- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one

1.2.a.4'-Methyl-3-nitro-biphenyl-4-carboxylic acid Prepared from 4-bromo-2-nitro-benzoic acid and 4-methyl-phenyl-boric acid as in Example 1.1.b .
Yield: 1.48 g (70.8% of theory)
C ₁₄ H ₁₁ NO ₄ (M = 257.24)
calc .: molar peak (MH) ^- : 256 fnd .: molar peak (MH) ^- : 256
R _f value: 0.54 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.2.b. 4′-Methyl-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 ′ as in Example 1.1.i Prepared from -methyl-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.51 g (78.3% of theory)
C ₂₇ H ₂₉ N ₃ O ₃ (M = 443.55)
calc .: Mole peak (M + H) ⁺ : 444 fnd .: Mole peak (M + H) ⁺ : 444
R _f value: 0.35 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.2.c.4'-Methyl-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'in the same manner as Example 1.1.j Prepared from -methyl-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.2 g (69.2% of theory)
C ₂₈ H ₃₁ N ₃ O (M = 413.56)
calc .: Mole peak (M + H) ⁺ : 414 fnd .: Mole peak (M + H) ⁺ : 414
R _f value: 0.36 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.3: 3- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3H-quinazolin-4-one

1.3.a.4'-Trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid 4-bromo-2-nitro-benzoic acid and 4-trifluoromethyl-phenyl-boro in the same manner as in Example 1.1.b Prepared from acid.
Yield: 1.24 g (49% of theory)
C ₁₄ H ₈ F ₃ NO ₄ (M = 311.21)
calc .: molar peak (MH) ^- : 310 fnd .: molar peak (MH) ^- : 310
R _f value: 0.3 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.3.b. 4'-Trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide As in Example 1.1.i Prepared from 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.36 g (49.3% of theory)
C ₂₇ H ₂₆ F ₃ N ₃ O ₃ (M = 497.52)
calc .: Mole peak (M + H) ⁺ : 498 fnd .: Mole peak (M + H) ⁺ : 498
R _f value: 0.3 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

1.3.c.4'-Trifluoromethyl-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-tri in 50 ml of ethyl acetate A reaction mixture of 0.1 g (0.2 mmol) of fluoromethyl-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide and 0.08 g of platinum oxide at 20 ° C. Hydrogenate for 2.5 hours. The catalyst is filtered off. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / methanol / ammonia = 90: 10: 1).
Yield: 0.06 g (63.8% of theory)
C ₂₇ H ₂₈ N ₃ N ₃ O (M = 467.53)
calc .: Mole peak (M + H) ⁺ : 468 fnd .: Mole peak (M + H) ⁺ : 468
R _f value: 0.46 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.4: 7- (4-Methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.4.a.4'-Methoxy-3-nitro-biphenyl-4-carboxylic acid Prepared from 4-bromo-2-nitro-benzoic acid and 4-methoxy-phenyl-boric acid as in Example 1.1.b .
Yield: 0.38 g (48.9% of theory)
C ₁₄ H ₁₁ NO ₅ (M = 273.24)
calc .: Mole peak (MH) ^- : 272 fnd .: Mole peak (MH) ^- : 272
R _f value: 0.39 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.4.b. 4'-Methoxy-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'as in Example 1.1.j Prepared from -methoxy-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.23 g (57% of theory)
C ₂₇ H ₂₉ N ₃ O ₄ (M = 459.55)
calc .: Mole peak (M + H) ⁺ : 460 fnd .: Mole peak (M + H) ⁺ : 460
R _f value: 0.48 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.4.c.4'-Methoxy-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'in the same manner as in Example 1.3.c Prepared from -methoxy-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.09 g (42% of theory)
C ₂₇ H ₃₁ N ₃ O ₂ (M = 429.56)
calc .: Mole peak (M + H) ⁺ : 430 fnd .: Mole peak (M + H) ⁺ : 430
R _f value: 0.44 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.5:
7- (3,4-Dichloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.5.a.3 ′, 4′-Dichloro-3-nitro-biphenyl-4-carboxylic acid 4-Bromo-2-nitro-benzoic acid and 3,4-dichloro-phenyl-similar to Example 1.1.b Prepared from boric acid.
Yield: 0.72 g (28.4% of theory)
C ₁₃ H ₇ Cl ₂ NO ₄ (M = 312.11)
calc .: Mole peak (MH) ^- : 310/312/314 fnd .: Mole peak (MH) ^- : 310/312/314
R _f value: 0.39 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.5.b. 3 ', 4'-Dichloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide As in Example 1.1.i 3 ′, 4′-dichloro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.47 g (64.2% of theory)
C ₂₆ H ₂₅ Cl ₂ N ₃ O ₃ (M = 498.41)
calc .: Mole peak (M + H) ⁺ : 498/500/502 fnd .: Mole peak (M + H) ⁺ : 498/500/502
R _f value: 0.24 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.5.c. 3 ', 4'-Dichloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide As in Example 1.3.c 3 ′, 4′-dichloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.11 g (25% of theory)
C ₂₆ H ₂₇ Cl ₂ N ₃ O (M = 468.43)
calc .: Mole peak (M + H) ⁺ : 468/470/472 fnd .: Mole peak (M + H) ⁺ : 468/470/472
R _f value: 0.46 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.6:
7- (3-Methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.6.a.3'-Methoxy-3-nitro-biphenyl-4-carboxylic acid Prepared from 4-bromo-2-nitro-benzoic acid and 3-methoxy-phenyl-boric acid as in Example 1.1.b .
Yield: 0.39 g (73.6% of theory)
C ₁₄ H ₁₁ NO ₅ (M = 273.24)
calc .: Mole peak (M + H) ⁺ : 274 fnd .: Mole peak (M + H) ⁺ : 274
R _f value: 0.35 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.6.b. 3'-Methoxy-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3 'as in Example 1.1.i Prepared from -methoxy-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.39 g (57% of theory)
C ₂₇ H ₂₉ N ₃ O ₄ (M = 459.55)
calc .: Mole peak (M + H) ⁺ : 460 fnd .: Mole peak (M + H) ⁺ : 460
R _f value: 0.23 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.6.c.3'-Methoxy-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3 'as in Example 1.1.j Prepared from -methoxy-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.11 g (30.6% of theory)
C ₂₇ H ₃₁ N ₃ O ₂ (M = 429.56)
calc .: Mole peak (M + H) ⁺ : 430 fnd .: Mole peak (M + H) ⁺ : 430
R _f value: 0.36 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.7:
7- (4-Fluoro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.7.a.4'-Fluoro-3-nitro-biphenyl-4-carboxylic acid Prepared from 4-bromo-2-nitro-benzoic acid and 4-fluoro-phenyl-boric acid as in Example 1.1.b .
Yield: 1.3 g (61.2% of theory)
C ₁₃ H ₈ FNO ₄ (M = 261.21)
calc .: Mole peak (MH) ^- : 260 fnd .: Mole peak (MH) ^- : 260
R _f value: 0.34 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.7.b. 4'-Fluoro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'as in Example 1.1.i Prepared from -fluoro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.38 g (57.8% of theory)
C ₂₆ H ₂₆ FN ₃ O ₃ (M = 447.51)
calc .: Mole peak (M + H) ⁺ : 448 fnd .: Mole peak (M + H) ⁺ : 448
R _f value: 0.24 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.7.c.4'-Fluoro-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'in the same manner as in Example 1.3.c Prepared from -fluoro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.06 g (32% of theory)
C ₂₆ H ₂₈ FN ₃ O (M = 417.53)
calc .: Mole peak (M + H) ⁺ : 418 fnd .: Mole peak (M + H) ⁺ : 418
R _f value: 0.63 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.8:
7- (4-Ethyl-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.8.a.4'-Vinyl-3-nitro-biphenyl-4-carboxylic acid Prepared from 4-bromo-2-nitro-benzoic acid and 4-vinyl-phenyl-boric acid as in Example 1.1.b .
Yield: 0.58 g (53% of theory)
C ₁₅ H ₁₁ NO ₄ (M = 269.25)
calc .: Mole peak (MH) ^- : 268 fnd .: Mole peak (MH) ^- : 268
R _f value: 0.39 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.8.b. 4'-Vinyl-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'as in Example 1.1.i Prepared from -vinyl-3-nitro-biphenyl-4-carboxylic acid and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.38 g (56.8% of theory)
C ₂₈ H ₂₉ N ₃ O ₃ (M = 455.56)
calc .: Mole peak (M + H) ⁺ : 456 fnd .: Mole peak (M + H) ⁺ : 456
R _f value: 0.21 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.8.c.4'-Ethyl-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4 'as in Example 1.3.c Prepared from -vinyl-3-nitro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.15 g (63.9% of theory)
C ₂₈ H ₃₃ N ₃ O (M = 427.59)
calc .: Mole peak (M + H) ⁺ : 428 fnd .: Mole peak (M + H) ⁺ : 428
R _f value: 0.47 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
The following compounds were prepared in the same manner as Example 1.1.k.

R _f value: A = (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.9

1.9.a7- (4-Trifluoromethyl-phenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one 4 ml acetic acid and acetic anhydride 4'-Trifluoromethyl-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide in 0.028 ml (0.3 mmol) (Example 1.3. c)) 0.07 g (0.15 mmol) of the solution is refluxed for 12 hours. The reaction solution is diluted with water, adjusted to pH 8 with dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried with magnesium sulfate. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / methanol / ammonia 90: 10: 1).
Yield: 0.008 g (11% of theory)
C ₂₉ H ₂₈ F ₃ N ₃ O (M = 491.56)
calc .: Mole peak (M + H) ⁺ : 492 fnd .: Mole peak (M + H) ⁺ : 492
R _f value: 0.36 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
The following compounds were prepared in the same manner as Example 1.9a.

R _f value: A = (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.10: 2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one Example 1.11: 7- (4- Chloro-phenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one Example 1.12.

1,12.a 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -1H-quinazoline-2,4-dione 4 'in 50 ml of tetrahydrofuran -Chloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (see Example 1.1.j) 0.3 g (0.69 mmol) And 0.1 g (0.65 mmol) of CDI is refluxed for 24 hours. An additional 0.1 g of CDI is then added and the reaction mixture is refluxed for an additional 24 hours. The reaction mixture is evaporated in a rotary evaporator. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / methanol / ammonia 60: 1: 0.1).
Yield: 0.2 g (62.9% of theory)
Melting point: 274-276 ℃
C ₂₇ H ₂₆ ClN ₃ O ₂ (M = 459.98)
calc .: Mole peak (M + H) ⁺ : 460/462 fnd .: Mole peak (M + H) ⁺ : 460/462
R _f value: 0.1 (silica gel, dichloromethane / methanol / ammonia 50: 1: 0.1)
Example 1.13:
7- (4-Chloro-phenyl) -3- {2- [4-((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one

1.13.a [4- (2- (S) -Methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -acetonitrile Similar to Example 1.1.g, 2- (S) -methoxymethyl-pyrrolidine and (4- Prepared from bromomethyl-phenyl) -acetonitrile.
Yield: 0.9 g (51.6% of theory)
C ₁₅ H ₂₀ N ₂ O (M = 244.33)
calc .: Mole peak (M + H) ⁺ : 245 fnd .: Mole peak (M + H) ⁺ : 245
R _f value: 0.3 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.13.b 2- [4- (2- (S) -Methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethylamine [4- (2- (S) -methoxymethyl as in Example 1.1.h] -Pyrrolidin-1-ylmethyl) -phenyl] -acetonitrile.
Yield: 0.5 g (54.7% of theory)
C ₁₅ H ₂₄ N ₂ O (M = 248.37)
calc .: Mole peak (M + H) ⁺ : 249 fnd .: Mole peak (M + H) ⁺ : 249
R _f value: 0.3 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
1.13.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide Implementation 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethylamine as in Example 1.1.i Prepared from
Yield: 0.5 g (54.7% of theory)
C ₂₈ H ₃₀ ClN ₃ O ₄ (M = 508.02)
calc .: Mole peak (M + H) ⁺ : 508/510 fnd .: Mole peak (M + H) ⁺ : 508/510
R _f value: 0.6 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
1.13.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (2- (S) -methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl]-as in Example 1.3.c Prepared from ethyl} -amide.
Yield: 0.24 g (51% of theory)
C ₂₈ H ₃₂ ClN ₃ O ₂ (M = 478.03)
calc .: Mole peak (M + H) ⁺ : 478/480 fnd .: Mole peak (M + H) ⁺ : 478/480
R _f value: 0.2 (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1)
Example 1.14:
7- (4-Chloro-phenyl) -3- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.14.a (4-Dimethylaminomethyl-phenyl) -acetonitrile Prepared as in Example 1.1.g from dimethylamine and (4-bromomethyl-phenyl) -acetonitrile.
Yield: 1.0 g (30% of theory)
C ₁₁ H ₁₄ N ₂ (M = 174.24)
calc .: Mole peak (M + H) ⁺ : 175 fnd .: Mole peak (M + H) ⁺ : 175
R _f value: 0.2 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.14.b 2- (4-Dimethylaminomethyl-phenyl) -ethylamine Prepared from (4-dimethylaminomethyl-phenyl) -acetonitrile as in Example 1.1.h.
Crude yield: 1.0 g
C ₁₁ H ₁₈ N ₂ (M = 178.28)
calc .: Mole peak (M + H) ⁺ : 179 fnd .: Mole peak (M + H) ⁺ : 179
R _f value: 0.2 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
1.14.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -amide 4'-Chloro- similar to example 1.1.i Prepared from 3-nitro-biphenyl-4-carboxylic acid and 2- (4-dimethylaminomethyl-phenyl) -ethylamine.
Yield: 0.5 g (63.4% of theory)
C ₂₄ H ₂₄ ClN ₃ O ₃ (M = 437.93)
calc .: Mole peak (M + H) ⁺ : 438/440 fnd .: Mole peak (M + H) ⁺ : 438/440
R _f value: 0.35 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
1.14.d 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -amide 4'-Chloro- similar to Example 1.3.c Prepared from 3-nitro-biphenyl-4-carboxylic acid- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -amide.
Yield: 0.2 g (43% of theory)
C ₂₄ H ₂₆ ClN ₃ O (M = 407.94)
calc .: Mole peak (M + H) ⁺ : 408/410 fnd .: Mole peak (M + H) ⁺ : 408/410
R _f value: 0.2 (silica gel, dichloromethane / methanol / ammonia 20: 1: 0.1)
Example 1.15:
7- (4-Chloro-phenyl) -3- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.15.a (4-Piperidin-1-ylmethyl-phenyl) -acetonitrile Prepared from piperidine and (4-bromomethyl-phenyl) -acetonitrile as in Example 1.1.g.
Yield: 1.6 g (39% of theory)
C ₁₄ H ₁₈ N ₂ (M = 214.31)
calc .: Mole peak (M + H) ⁺ : 215 fnd .: Mole peak (M + H) ⁺ : 215
R _f value: 0.4 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.15.b 2- (4-Piperidin-1-ylmethyl-phenyl) -ethylamine Prepared from (4-piperidin-1-ylmethyl-phenyl) -acetonitrile as in Example 1.1.h.
Yield: 1.4 g (85.9% of theory)
C ₁₄ H ₂₂ N ₂ (M = 218.34)
calc .: Mole peak (M + H) ⁺ : 219 fnd .: Mole peak (M + H) ⁺ : 219
R _f value: 0.2 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
1.15.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide 4'- in the same manner as in Example 1.1.i Prepared from chloro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-piperidin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.07 g (40.7% of theory)
C ₂₇ H ₂₈ ClN ₃ O ₃ (M = 477.99)
calc .: Mole peak (M + H) ⁺ : 478/480 fnd .: Mole peak (M + H) ⁺ : 478/480
R _f value: 0.5 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
1.15.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide 4'- in the same manner as in Example 1.3.c Prepared from chloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.05 g (76.4% of theory)
C ₂₇ H ₃₀ ClN ₃ O (M = 448.01)
Example 1.16:
7- (4-Chloro-phenyl) -3- [2- (4-morpholin-4-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one

1.16.a (4-morpholin-4-ylmethyl-phenyl) -acetonitrile Prepared from morpholine and (4-bromomethyl-phenyl) -acetonitrile as in Example 1.1.g.
Yield: 1.63 g (98.9% of theory)
C ₁₃ H ₁₆ N ₂ O (M = 216.28)
calc .: Mole peak (M + H) ⁺ : 217 fnd .: Mole peak (M + H) ⁺ : 217
R _f value: 0.33 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.16.b 2- (4-Morpholin-1-ylmethyl-phenyl) -ethylamine Prepared from (4-morpholin-1-ylmethyl-phenyl) -acetonitrile as in Example 1.1.h.
Yield: 1.65 g (99.4% of theory)
C ₁₃ H ₂₀ N ₂ O (M = 220.31)
calc .: Mole peak (M + H) ⁺ : 221 fnd .: Mole peak (M + H) ⁺ : 221
R _f value: 0.54 (silica gel, dichloromethane / ethanol / ammonia 9: 1: 0.1)
1.16.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-morpholin-1-ylmethyl-phenyl) -ethyl] -amide 4'- in the same manner as in Example 1.1.i Prepared from chloro-3-nitro-biphenyl-4-carboxylic acid and 2- (4-morpholin-1-ylmethyl-phenyl) -ethylamine.
Yield: 0.53 g (76.6% of theory)
C ₂₆ H ₂₆ ClN ₃ O ₄ (M = 479.97)
calc .: Mole peak (M + H) ⁺ : 480/482 fnd .: Mole peak (M + H) ⁺ : 480/482
R _f value: 0.5 (silica gel, dichloromethane / ethanol / ammonia 90: 1: 0.1)
1.16.d 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- [2- (4-morpholin-1-ylmethyl-phenyl) -ethyl] -amide 4'- in the same manner as in Example 1.3.c Prepared from chloro-3-nitro-biphenyl-4-carboxylic acid- [2- (4-morpholin-1-ylmethyl-phenyl) -ethyl] -amide.
Yield: 0.45 g (90.6% of theory)
C ₂₆ H ₂₈ ClN ₃ O ₂ (M = 449.98)
calc .: Mole peak (M + H) ⁺ : 450/452 fnd .: Mole peak (M + H) ⁺ : 450/452
R _f value: 0.67 (silica gel, dichloromethane / ethanol / ammonia 90: 1: 0.1)
The following compounds were prepared in the same manner as Example 1.1.k.

R _f value: A = (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
C = (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1)
D = (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1)
Example 1.17 7- (4-Chloro-phenyl) -3- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -3H-quinazolin-4-one

1.17.a (6-Chloro-pyridin-3-yl) -acetonitrile A solution of 7.5 g (41.66 mmol) of 2-chloro-5-chloromethyl-pyridine dissolved in 100 ml of ethanol was added to an ethanol / water mixture (9: 1 ) Add dropwise to a solution of 6.91 g (41.66 mmol) potassium iodide and 2.24 g (49.01 mmol) sodium cyanide in 400 ml. The reaction mixture is then heated to 85 ° C. for 5 hours. The solvent is substantially distilled off in vacuo and the residue is extracted with water and ethyl acetate. The organic phase is washed 3 times with water and dried over sodium sulfate. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / ethanol).
Yield: 2.9 g (45.6% of theory)
C ₇ H ₅ ClN ₂ (M = 152.58)
calc .: Mole peak (M + H) ⁺ : 151/153 fnd .: Mole peak (M + H) ⁺ : 151/153.
1.17.b [6- (4-Methyl-piperazin-1-yl) -pyridin-3-yl] -acetonitrile
A solution of 2.9 g (19 mmol) (6-chloro-pyridin-3-yl) -acetonitrile, 5.27 ml (38 mmol) triethylamine and 2.1 ml (19 mmol) N-methylpiperazine in 50 ml n-butanol in a microwave. To 180 ° C. for 2 hours. The solvent is distilled off in vacuo and the residue is suspended in water and then extracted with ethyl acetate. The combined organic phases are extracted 3 times with water and dried over sodium sulphate. Purification is carried out by column chromatography on Alox (eluent: petroleum ether / ethyl acetate 1: 1).
Yield: 1 g (24.6% of theory)
Melting point: 58-59 ℃
C ₁₂ H ₁₆ N ₄ (M = 216.28)
calc .: Mole peak (M + H) ⁺ : 217 fnd .: Mole peak (M + H) ⁺ : 217
R _f value: 0.35 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1).

1.17.c 2- [6- (4-Methyl-piperazin-1-yl) -pyridin-3-yl] -ethylamine In the same manner as in Example 1.1.i, [6- (4-methyl-piperazin-1-yl ) -Pyridin-3-yl] -acetonitrile.
Yield: 0.94 g (96% of theory)
C ₁₂ H ₂₀ N ₄ (M = 220.32)
calc .: Mole peak (M + H) ⁺ : 221 fnd .: Mole peak (M + H) ⁺ : 221.
1.17.d 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide Examples Prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethylamine as in 1.1.j did.
Yield: 0.48 g (36.7% of theory)
Melting point: 158-159 ℃
C ₂₅ H ₂₆ ClN ₅ O ₃ (M = 479.97)
calc .: Mole peak (M + H) ⁺ : 480/482 fnd .: Mole peak (M + H) ⁺ : 480/482.
1.17.e 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide Examples 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} as in 1.1.i -Prepared from amide.
Yield: 0.12 g (64% of theory)
Melting point: 198-199 ℃
C ₂₅ H ₂₈ ClN ₅ O (M = 449.98)
calc .: Mole peak (M + H) ⁺ : 450/452 fnd .: Mole peak (M + H) ⁺ : 450/452.
1.17.f 7- (4-Chloro-phenyl) -3- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -3H-quinazolin-4-one 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl]-in the same manner as in Example 1.1.l Prepared from ethyl} -amide and formic acid.
Yield: 0.06 g (53.5% of theory)
Melting point: 263-264 ℃
C ₂₆ H ₂₆ ClN ₅ O (M = 459.98)
calc .: Mole peak (M + H) ⁺ : 460/462 fnd .: Mole peak (M + H) ⁺ : 460/462.
Example 1.18 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-benzo [d] [1,2,3] triazine-4- on

1.18.a 7- (4-Chloro-phenyl) -3- {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -3H-benzo [d] [1,2, 3] Triazin-4-one A solution of 0.09 g (0.93 mmol) of sodium nitrite in 2 ml of water was added to 4'-chloro-3-amino-biphenyl-4 in 10 ml of methanol and 1N hydrochloric acid at a temperature between 0 ° C and 5 ° C. -Carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide (see Example 1.1.j) is slowly added dropwise to a solution of 0.27 g (0.62 mmol). . The reaction mixture is then stirred for 3 hours at ambient temperature, then diluted with 30 ml of water and made alkaline with ammonia solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed 3 times with water, dried over sodium sulphate and filtered through activated charcoal. The solvent is removed and the residue is washed with diisopropyl ether.
Yield: 0.09 g (32.5% of theory)
Melting point: 151-152 ℃
C ₂₆ H ₂₅ ClN ₄ O (M = 444.96)
calc .: Mole peak (M + H) ⁺ : 445/447 fnd .: Mole peak (M + H) ⁺ : 445/447
R _f value: 0.35 (silica gel, dichloromethane / ethanol = 10: 1).
Example 1.19 7- (4-Chloro-phenyl) -3- (4-pyrrolidin-1-ylmethyl-benzyl) -3H-benzo [d] [1,2,3] triazin-4-one

1.19.a 4- (1-Pyrrolidin-1-yl-ethyl) -benzonitrile Prepared from piperidine and 4-bromomethyl-benzonitrile as in Example 1.1.g.
Yield: 2.4 g (85.9% of theory)
C ₁₂ H ₁₄ N ₂ (M = 186.25)
calc .: Mole peak (M + H) ⁺ : 187 fnd .: Mole peak (M + H) ⁺ : 187
R _f value: 0.63 (silica gel, dichloromethane / methanol / ammonia = 8: 2: 1).
1.19.b 4- (1-Pyrrolidin-1-yl-ethyl) -benzylamine Prepared from 4- (1-pyrrolidin-1-yl-ethyl) -benzonitrile as in Example 1.1.h.
Yield: 2.42 g (98.7% of theory)
C ₁₂ H ₁₈ N ₂ (M = 190.29)
calc .: Mole peak (M + H) ⁺ : 191 fnd .: Mole peak (M + H) ⁺ : 191
R _f value: 0.26 (silica gel, dichloromethane / methanol / ammonia = 90: 10: 1).
1.19.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid-4- (1-pyrrolidin-1-yl-ethyl) -benzylamide 4'-Chloro-3 as in Example 1.1.i Prepared from -nitro-biphenyl-4-carboxylic acid and 2- (4-4- (1-pyrrolidin-1-yl-ethyl) -benzylamine.
Yield: 0.28 g (28.8% of theory)
C ₂₅ H ₂₄ ClN ₃ O ₃ (M = 449.94)
calc .: Mole peak (M + H) ⁺ : 450/452 fnd .: Mole peak (M + H) ⁺ : 450/452.

1.19.d. 3-Amino-4'-chloro-biphenyl-4-carboxylic acid-4- (1-pyrrolidin-1-yl-ethyl) -benzylamide 4'-Chloro- similar to Example 1.3.c Prepared from 3-nitro-biphenyl-4-carboxylic acid-4- (1-pyrrolidin-1-yl-ethyl) -benzylamide.
Yield: 0.19 g (72.7% of theory)
C ₂₅ H ₂₆ ClN ₃ O (M = 419.95)
calc .: Mole peak (M + H) ⁺ : 420/422 fnd .: Mole peak (M + H) ⁺ : 420/422.
1.19.e 7- (4-Chloro-phenyl) -3- [4- (1-pyrrolidin-1-yl-ethyl) -benzyl] -3H-benzo [d] [1,2,3] triazine-4- On Prepared as in Example 1.18.a from 3-amino-4′-chloro-biphenyl-4-carboxylic acid-4- (1-pyrrolidin-1-yl-ethyl) -benzylamide.
Yield: 0.045 g (31.4% of theory)
Melting point: 147-148 ℃
C ₂₅ H ₂₃ ClN ₄ O (M = 430.94)
calc .: Mole peak (M + H) ⁺ : 431/433 fnd .: Mole peak (M + H) ⁺ : 431/433
R _f value: 0.3 (silica gel, dichloromethane / ethanol = 10: 1).
Example 1.20 5- (4-fluoro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -isoindole-1,3-dione

1.20.a 5-Bromo-2- {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -isoindole-1,3-dione 5-bromo-iso in 10 ml acetic acid A solution of 0.8 g (3.52 mmol) benzofuran-1,3-dione and 0.72 g (3.52 mmol) 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (see Example 1.1.h) Heat to 110 ° C. over time. The reaction mixture is then poured into water, made alkaline with 2N sodium hydroxide solution and the precipitate is filtered off. The precipitate is washed several times with water and dried.
Yield: 0.5 g (34.3% of theory)
C ₂₁ H ₂₁ BrN ₂ O ₂ (M = 413.31)
calc .: Mole peak (M + H) ⁺ : 413/415 fnd .: Mole peak (M + H) ⁺ : 413/415.
1.20.b. 5- (4-Fluoro-phenyl) -2- {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -isoindole-1,3-dione Examples Similar to 1.1.b 5-bromo-2- {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -isoindole-1,3-dione and 4-fluoro- Prepared from phenylboric acid.
Yield: 0.01 g (4.8% of theory)
C ₂₇ H ₂₅ FN ₂ O ₂ (M = 428.51)
calc .: Mole peak (M + H) ⁺ : 429 fnd .: Mole peak (M + H) ⁺ : 429.
Example 1.21:
7- (4-Chloro-phenyl) -3- {2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one

1.21.a [4- (4-Phenyl-piperidin-1-ylmethyl) -phenyl] -acetonitrile Prepared from 4-phenylpiperidine and (4-bromomethyl-phenyl) -acetonitrile as in Example 1.1.g.
Yield: 3.8 g (98% of theory)
C ₂₀ H ₂₂ N ₂ (M = 290.41)
calc .: Mole peak (M + H) ⁺ : 291 fnd .: Mole peak (M + H) ⁺ : 291
R _f value: 0.5 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.21.b 2- [4- (4-Phenyl-piperidin-1-ylmethyl) -phenyl] -ethylamine In the same manner as in Example 1.1.h, [4- (4-Phenyl-piperidin-1-ylmethyl) -phenyl] -Prepared from acetonitrile.
Crude yield: 3.6 g
C ₂₀ H ₂₆ N ₂ (M = 294.44)
calc .: Mole peak (M + H) ⁺ : 295 fnd .: Mole peak (M + H) ⁺ : 295
R _f value: 0.49 (silica gel, dichloromethane / ethanol 20: 1)
1.21.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide Example 1.1.i and Similarly prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethylamine.
Yield: 1.33 g (70.7% of theory)
C ₃₃ H ₃₂ ClN ₃ O ₃ (M = 554.09)
calc .: Mole peak (M + H) ⁺ : 554/556 fnd .: Mole peak (M + H) ⁺ : 554/556
R _f value: 0.58 (silica gel, dichloromethane / ethanol / ammonia 10: 1: 0.1)
1.21.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide Example 1.3.c and Similarly prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide.
Yield: 0.82 g (65.2% of theory)
C ₃₃ H ₃₄ ClN ₃ O (M = 524.11)
calc .: Mole peak (M + H) ⁺ : 524/526/528 fnd .: Mole peak (M + H) ⁺ : 524/526/528
R _f value: 0.65 (silica gel, dichloromethane / methanol 10: 1)
Example 1.22:
7- (4-Chloro-phenyl) -3- {2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one

1.22.a [4- (4-Phenyl-piperazin-1-ylmethyl) -phenyl] -acetonitrile Prepared from 4-phenylpiperazine and (4-bromomethyl-phenyl) -acetonitrile as in Example 1.1.g.
Yield: 3.7 g (97% of theory)
C ₁₉ H ₂₁ N ₃ (M = 291.39)
calc .: Mole peak (M + H) ⁺ : 292 fnd .: Mole peak (M + H) ⁺ : 292
R _f value: 0.6 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.22.b 2- [4- (4-Phenyl-piperazin-1-ylmethyl) -phenyl] -ethylamine [4- (4-Phenyl-piperazin-1-ylmethyl) -phenyl] as in Example 1.1.h -Prepared from acetonitrile.
Yield: 1.1 g (28.6% of theory)
C ₁₉ H ₂₅ N ₃ (M = 295.43)
calc .: Mole peak (M + H) ⁺ : 296 fnd .: Mole peak (M + H) ⁺ : 296
1.22.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide Example 1.1.i and Similarly prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethylamine.
Yield: 0.32 g (18.2% of theory)
C ₃₂ H ₃₁ ClN ₄ O ₃ (M = 555.08)
calc .: Mole peak (M + H) ⁺ : 555/557 fnd .: Mole peak (M + H) ⁺ : 555/557

1.22.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide Example 1.3.c and Similarly prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide.
Yield: 0.11 g (38.8% of theory)
C ₃₂ H ₃₃ ClN ₄ O (M = 525.09)
calc .: Mole peak (M + H) ⁺ : 525/527 fnd .: Mole peak (M + H) ⁺ : 525/527
Example 1.23:
7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one

1.23.a [4- (4-Hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -acetonitrile 4-hydroxy-4-phenylpiperidine and (4-bromomethyl-phenyl as in Example 1.1.g ) -Acetonitrile.
Yield: 3.8 g (98% of theory)
C ₂₀ H ₂₂ N ₂ O (M = 306.41)
calc .: Mole peak (M + H) ⁺ : 307 fnd .: Mole peak (M + H) ⁺ : 307
R _f value: 0.1 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.23.b 2- [4- (4-Hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethylamine In the same manner as in Example 1.1.h, [4- (4-hydroxy-4-phenyl-piperidine Prepared from 1-ylmethyl) -phenyl] -acetonitrile.
Yield: 3.36 g (92.1% of theory)
C ₂₀ H ₂₆ N ₂ O (M = 310.44)
calc .: Mole peak (M + H) ⁺ : 311 fnd .: Mole peak (M + H) ⁺ : 311
R _f value: 0.1 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1)
1.23.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide Examples Prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethylamine as in 1.1.i did.
Yield: 1.2 g (65.3% of theory)
C ₃₃ H ₃₂ ClN ₃ O ₄ (M = 570.09)
calc .: Mole peak (M + H) ⁺ : 570/572 fnd .: Mole peak (M + H) ⁺ : 570/572
R _f value: 0.35 (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1)

1.23.d 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide Examples 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} as in 1.3.c -Prepared from amide.
Yield: 1.04 g (91.5% of theory)
C ₃₃ H ₃₄ ClN ₃ O ₂ (M = 540.11)
Melting point: 175-180 ℃
calc .: Mole peak (M + H) ⁺ : 540/542/544 fnd .: Mole peak (M + H) ⁺ : 540/542/544
R _f value: 0.34 (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1)
1.23.e. 7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazoline-4- ON 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl as in Example 1.1.k. Prepared from] -ethyl} -amide.
Yield: 0.025 g (8.2% of theory)
Melting point: 204-205 ℃
C ₃₄ H ₃₂ ClN ₃ O ₂ (M = 550.10)
calc .: Mole peak (M + H) ⁺ : 550/552 fnd .: Mole peak (M + H) ⁺ : 550/552
R _f value: 0.46 (silica gel, dichloromethane / ethanol / ammonia 10: 1: 0.1)
Example 1.24:
7- (4-Chloro-phenyl) -3- {2- [4- (4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazoline-4- on

1.24.a. 7- (4-Chloro-phenyl) -3- {2- [4- (4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H- Quinazolin-4-one 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-hydroxy-4-phenyl-piperidine-1- (Ilmethyl) -phenyl] -ethyl} -amide was prepared as a by-product in Example 123.e.
Yield: 0.08 g (27.1% of theory)
Melting point: 166-167 ℃
C ₃₄ H ₃₀ ClN ₃ O (M = 532.09)
calc .: Mole peak (M + H) ⁺ : 532/534 fnd .: Mole peak (M + H) ⁺ : 532/534
R _f value: 0.57 (silica gel, dichloromethane / ethanol / ammonia 10: 1)
Example 1.25:
7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one

1.25.a [4- (3-Aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -acetonitrile Similar to Example 1.1.g, 3-aza-spiro [5.5] undecane and (4-bromomethyl- Prepared from (phenyl) -acetonitrile.
Yield: 3.38 g (98% of theory)
C ₁₉ H ₂₆ N ₂ (M = 282.43)
calc .: Mole peak (M + H) ⁺ : 283 fnd .: Mole peak (M + H) ⁺ : 283
R _f value: 0.56 (silica gel, cyclohexane / ethyl acetate 1: 1)
1.25.b 2- [4- (3-Aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethylamine [4- (3-Aza-spiro [5.5] undeca) as in Example 1.1.h. Prepared from -3-ylmethyl) -phenyl] -acetonitrile.
Yield: 3.33 g (96.6% of theory)
C ₁₉ H ₃₀ N ₂ (M = 286.46)
calc .: Mole peak (M + H) ⁺ : 287 fnd .: Mole peak (M + H) ⁺ : 287
R _f value: 0.18 (silica gel, dichloromethane / ethanol 20: 1)

1.25.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -amide Examples Prepared from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethylamine as in 1.1.i did.
Yield: 1 g (52.5% of theory)
C ₃₂ H ₃₆ ClN ₃ O ₃ (M = 546.11)
calc .: Mole peak (M + H) ⁺ : 546/548 fnd .: Mole peak (M + H) ⁺ : 546/548
R _f value: 0.3 (silica gel, dichloromethane / ethanol 20: 1)
1.25.d 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -amide Examples 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} as in 1.3.c -Prepared from amide.
Yield: 0.8 g (84.7% of theory)
C ₃₂ H ₃₈ ClN ₃ O (M = 516.13)
calc .: Mole peak (M + H) ⁺ : 516/518 fnd .: Mole peak (M + H) ⁺ : 516/518
R _f value: 0.38 (silica gel, dichloromethane / methanol 10: 1)
Example 1.26:
7- (4-Chloro-phenyl) -3- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -3H-quinazolin-4-one

1.26.a {4- [4- (Pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -acetonitrile Similar to Example 1.1.g, 2- (piperidin-4-yloxy) -pyridine and ( Prepared from 4-bromomethyl-phenyl) -acetonitrile.
Yield: 0.91 g (49.8% of theory)
C ₁₉ H ₂₁ N ₃ O (M = 307.39)
calc .: Mole peak (M + H) ⁺ : 308 fnd .: Mole peak (M + H) ⁺ : 308
R _f value: 0.49 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.26.b 2- {4- [4- (Pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethylamine {4- [4- (Pyridin-2- Prepared from (yloxy) -piperidin-1-ylmethyl] -phenyl} -acetonitrile.
Yield: 0.92 g (99.8% of theory)
C ₁₉ H ₂₅ N ₃ O (M = 311.43)
calc .: Mole peak (M + H) ⁺ : 312 fnd .: Mole peak (M + H) ⁺ : 312
R _f value: 0.16 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.26.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid and 2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} as in Example 1.1.i -Prepared from ethylamine.
Yield: 0.8 g (97.2% of theory)
C ₃₂ H ₃₁ ClN ₄ O ₄ (M = 571.08)
calc .: Mole peak (M + H) ⁺ : 571/573 fnd .: Mole peak (M + H) ⁺ : 571/573
R _f value: 0.52 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)

1.26.d 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl as in Example 1.3.c } -Ethyl) -amide.
Yield: 0.38 g (50% of theory)
C ₃₂ H ₃₃ ClN ₄ O ₂ (M = 541.09)
calc .: Mole peak (M + H) ⁺ : 541/543 fnd .: Mole peak (M + H) ⁺ : 541/543
R _f value: 0.5 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
Example 1.27:
7- (4-Chloro-phenyl) -3- (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethyl) -3H-quinazolin-4-one

1.27.a {4- [4- (Pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -acetonitrile Similar to Example 1.1.g, 2- (piperidin-4-ylamino) -pyridine and ( Prepared from 4-bromomethyl-phenyl) -acetonitrile.
Yield: 1.57 g (86.1% of theory)
C ₁₉ H ₂₂ N ₄ (M = 306.41)
calc .: Mole peak (M + H) ⁺ : 307 fnd .: Mole peak (M + H) ⁺ : 307
R _f value: 0.43 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.27.b 2- {4- [4- (Pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethylamine {4- [4- (pyridin-2- Prepared from (Ilamino) -piperidin-1-ylmethyl] -phenyl} -acetonitrile.
Yield: 1.62 g (99.8% of theory)
C ₁₉ H ₂₆ N ₄ (M = 310.44)
calc .: Mole peak (M + H) ⁺ : 311 fnd .: Mole peak (M + H) ⁺ : 311
R _f value: 0.1 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.27.c 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid and 2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} as in Example 1.1.i -Prepared from ethylamine.
Yield: 0.36 g (43.8% of theory)
C ₃₂ H ₃₂ ClN ₅ O ₃ (M = 570.09)
calc .: Mole peak (M + H) ⁺ : 570/572 fnd .: Mole peak (M + H) ⁺ : 570/572
R _f value: 0.28 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
1.27.d 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl} -ethyl) -amide 4'-Chloro-3-nitro-biphenyl-4-carboxylic acid- (2- {4- [4- (pyridin-2-ylamino) -piperidin-1-ylmethyl] -phenyl as in Example 1.3.c } -Ethyl) -amide.
Yield: 0.29g (85.7% of theory)
C ₃₂ H ₃₄ ClN ₅ O (M = 540.11)
calc .: Mole peak (M + H) ⁺ : 540/542 fnd .: Mole peak (M + H) ⁺ : 540/542
R _f value: 0.27 (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
The following compounds were prepared in the same manner as Example 1.1.k.

R _f value: A = (silica gel, dichloromethane / methanol / ammonia 9: 1: 0.1)
E = (silica gel, dichloromethane / ethanol 10: 1)
F = (silica gel, dichloromethane / ethanol / ammonia 10: 1: 0.1)
Example 1.28 7- (4-chloro-phenyl) -3- {2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [1,2, 3) Triazin-4-one

1.28.a 7- (4-Chloro-phenyl) -3- {2- [4- (4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [1,2, 3] Triazin-4-one 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-phenyl-piperidin-1-ylmethyl)-in the same manner as in Example 1.18.a Prepared from phenyl] -ethyl} -amide.
Yield: 0.13 g (50.9% of theory)
Melting point: 183-184 ° C
C ₃₃ H ₃₁ ClN ₄ O (M = 535.09)
calc .: Mole peak (M + H) ⁺ : 535/537 fnd .: Mole peak (M + H) ⁺ : 535/537
R _f value: 0.66 (silica gel, dichloromethane / ethanol 10: 1)
Example 1.29 7- (4-chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one

1.29.a 7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one 4'-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (4-hydroxy-4-phenyl) as in Example 1.18.a Prepared from -piperidin-1-ylmethyl) -phenyl] -ethyl} -amide.
Yield: 0.21 g (68.7% of theory)
Melting point: 265-266 ℃
C ₃₃ H ₃₁ ClN ₄ O ₂ (M = 551.09)
calc .: Mole peak (M + H) ⁺ : 551/553 fnd .: Mole peak (M + H) ⁺ : 551/553
R _f value: 0.53 (silica gel, dichloromethane / ethanol 10: 1)
Example 1.30 7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one

1.30.a 7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one 4′-Chloro-3-amino-biphenyl-4-carboxylic acid- {2- [4- (3-aza-spiro [5.5] as in Example 1.18.a. ] Prepared from undec-3-ylmethyl) -phenyl] -ethyl} -amide.
Yield: 0.14 g (54.9% of theory)
Melting point: 165-166 ℃
C ₃₂ H ₃₅ ClN ₄ O (M = 527.11)
calc .: Mole peak (M + H) ⁺ : 527 fnd .: Mole peak (M + H) ⁺ : 527
R _f value: 0.56 (silica gel, dichloromethane / ethanol 10: 1)
Example 1.31:
6- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2H-isoquinolin-1-one

1.31.a.2- [2- (4-Bromo-phenyl) -ethoxy] -tetrahydro-pyran
0.025 g of p-toluenesulfonic acid and 2.575 ml (28.22 mmol) of dihydropyran are added successively to a solution of 4.83 g (24.02 mmol) of 2- (4-bromo-phenyl) -ethanol in 12 ml of dichloromethane at 0 ° C. The reaction mixture is then stirred at ambient temperature for 3 hours. The reaction mixture is extracted with sodium hydrogen carbonate solution and the organic phase is dried over sodium sulfate. Purification is carried out by column chromatography on Alox (eluent: cyclohexane / ethyl acetate = 8: 2).
Yield: 37 g (32.8% of theory)
C ₁₃ H ₁₇ BrO ₂ (M = 285.18)
calc .: Mole peak (M) ⁺ : 284/286 fnd .: Mole peak (M) ⁺ : 284/286
1.31.b 4- [2- (Tetrahydro-pyran-2-yloxy) -ethyl] -benzaldehyde
11.5 ml (18.41 mmol) of 1.6M n-butyllithium solution was added to a solution of 5 g (17.53 mmol) of 2- [2- (4-bromo-phenyl) -ethoxy] -tetrahydro-pyran in 80 ml of tetrahydrofuran at -70 ° C. Add dropwise and stir at this temperature for 1 hour. Then 2.8 ml (36.46 mmol) of dimethylformamide are added dropwise and the reaction mixture is stirred at -70 ° C. for a further 2 hours. The reaction mixture is combined with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are extracted three times with saturated sodium chloride solution and dried over sodium sulfate. Purification is carried out by column chromatography over silica gel (eluent: cyclohexane / ethyl acetate = 6: 4).
Yield: 2.8 g (68.2% of theory)
C ₁₄ H ₁₈ O ₃ (M = 234.29)
calc .: Mole peak (M + H) ⁺ : 235 fnd .: Mole peak (M + H) ⁺ : 235
R _f value: 0.57 (silica gel, petroleum ether / ethyl acetate 3: 1)

1.31.c 4- (2-Hydroxy-ethyl) -benzaldehyde
A solution of 2.8 g (11.95 mmol) of 4- [2- (tetrahydro-pyran-2-yloxy) -ethyl] -benzaldehyde in a mixture of 48 ml of 1M hydrochloric acid and 60 ml of acetone is stirred at 5 ° C. for 5 hours. The reaction mixture is combined with 140 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed three times with water and dried over sodium sulfate. Purification is carried out by column chromatography over silica gel (eluent: cyclohexane / ethyl acetate = 1: 1).
Yield: 1.3 g (72.4% of theory)
C ₉ H ₁₀ O ₂ (M = 150.17)
calc .: Mole peak (M + H) ⁺ : 151 fnd .: Mole peak (M + H) ⁺ : 151
R _f value: 0.52 (silica gel, petroleum ether / ethyl acetate 1: 1)
1.31.d 2- (4- [1.3] Dioxane-2-yl-phenyl) -ethanol
A suspension of 9.4 g (62.59 mmol) 4- (2-hydroxy-ethyl) -benzaldehyde, 15.83 ml (219.07 mmol) 1,3-propanediol, 0.3 g p-toluenesulfonic acid and 150 ml toluene is refluxed for 3 hours. . The reaction mixture is extracted three times with saturated sodium bicarbonate solution and the organic phase is dried over sodium sulfate.
Yield: 8 g (61.4% of theory)
C ₁₂ H ₁₆ O ₃ (M = 208.26)
calc .: Mole peak (M + H) ⁺ : 209 fnd .: Mole peak (M + H) ⁺ : 209
1.31.e Methanesulfonic acid-2- (4- [1.3] dioxan-2-yl-phenyl) -ethyl ester
8 g (38.41 mmol) 2- (4- [1.3] dioxan-2-yl-phenyl) -ethanol and 10.65 ml (42.25 mmol) triethylamine were dissolved in 300 ml dichloromethane and dissolved in 50 ml dichloromethane at 0 ° C. Combine with 3.27 ml of acid chloride. The reaction mixture is stirred for 1 hour at ambient temperature, extracted three times with water and the organic phase is dried over sodium sulfate. Purification is carried out by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate = 1: 1).
Yield: 7.7 g (70% of theory)
C ₁₃ H ₁₈ O ₅ S (M = 286.34)
calc .: Mole peak (M + H) ⁺ : 287 fnd .: Mole peak (M + H) ⁺ : 287
R _f value: 0.49 (silica gel, petroleum ether / ethyl acetate 1: 1)

1.31.f (E) -3- (3-Bromo-phenyl) -acryloyl azide 25 g (111.1 mmol) of (E) -3- (3-bromo-phenyl) -acrylic acid and 15.26 ml of triethylamine (110.10) in 800 ml of acetone 11.5 ml (121.11 mmol) of ethyl chloroformate are added dropwise at 0 ° C. to the solution. After 1 hour, 11.45 g (176.16 mmol) of sodium azide, dissolved in 88 ml of distilled water, is also added dropwise at 0 ° C. The reaction mixture is warmed to ambient temperature and then poured into 1.3 liters of ice water. The formed precipitate is filtered off, washed with water and dried at 30 ° C. in a circulating air dryer.
Yield: 21.1 g (76.1% of theory)
C ₉ H ₆ BrN ₃ O (M = 252.07)
calc .: Mole peak (M + H) ⁺ : 256/258 fnd .: Mole peak (M + H) ⁺ : 256/258
R _f value: 0.85 (silica gel, petroleum ether / ethyl acetate 1: 1)

1.31 g 6-bromo-2H-isoquinolin-1-one 150 g of biphenyl ether and 7.08 ml (29.75 mmol) of tributylamine are heated to 100 ° C. At this temperature, 5 g (19.83 mmol) of (E) -3- (3-bromo-phenyl) -acryloyl azide is added and then heated to 195-205 ° C. for 2 hours. The reaction mixture is then cooled and poured into chilled n-hexane. The precipitate is filtered off and washed with a cooled mixture of n-hexane and diethyl ether. The solid is then dried at 50 ° C. in a circulating air dryer. The solid is stirred with a mixture of diisopropyl ether and ethyl acetate and the drying process is repeated.
Yield: 0.6 g (13.5% of theory)
C ₉ H ₆ BrN ₃ O (M = 224.05)
calc .: Mole peak (M + H) ⁺ : 224/226 fnd .: Mole peak (M + H) ⁺ : 224/226
1.31.h 6- (4-Chloro-phenyl) -2H-isoquinolin-1-one 0.57 g (2.54 mmol) 6-bromo-2H-isoquinolin-1-one in 20 ml dioxane and 5 ml methanol, 4-chlorophenylboronic acid A reaction mixture of 0.398 g (2.54 mmol), 2.6 ml of 2M sodium carbonate solution is heated to 110 ° C. in a microwave for 2 hours. The reaction mixture is then poured into water, the precipitate is filtered off and dried at 40 ° C. in a circulating air dryer.
Yield: 0.42 g (64.6% of theory)
C ₁₅ H ₁₀ ClNO (M = 255.70)
calc .: Mole peak (M + H) ⁺ : 256/258 fnd .: Mole peak (M + H) ⁺ : 256/258
R _f value: 0.6 (silica gel, dichloromethane / ethanol 10: 1)

1.31.i 2- [2- (4-Formyl-phenyl) -ethyl] -6- (4-chloro-phenyl) -2H-isoquinolin-1-one 6- (4-chloro-phenyl) in 10 ml of dimethylformamide A solution of 0.41 g (1.6 mmol) of -2H-isoquinolin-1-one is combined with 0.18 g (1.6 mmol) of potassium tert.butoxide and stirred at 50 ° C. for 30 minutes. Then 0.46 g (1.6 mmol) of methanesulfonic acid-2- (4- [1.3] dioxan-2-yl-phenyl) -ethyl ester is added. The reaction mixture is heated in a microwave at 180 ° C. for 5 hours and then poured into a 10% citric acid solution. It is extracted with ethyl acetate. The organic phase is extracted 3 times with water and dried over sodium sulfate. Purification is carried out by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate = 3: 1 to 1: 1).
Yield: 0.15 g (24.1% of theory)
C ₂₄ H ₁₈ ClNO ₂ (M = 387.87)
calc .: Mole peak (M + H) ⁺ : 388/390 fnd .: Mole peak (M + H) ⁺ : 388/390
R _f value: 0.7 (silica gel, petroleum ether / ethyl acetate 1: 1)
1.31.j 6- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2H-isoquinolin-1-one
2- [2- (4-formyl-phenyl) -ethyl] -6- (4-chloro-phenyl) -2H-isoquinolin-1-one 0.14 g (0.36 mmol) and pyrrolidine 0.03 ml (0.36 mmol) in 40 ml dichloromethane Dissolve in The pH is adjusted to 3 with glacial acetic acid. Then 0.076 g (0.36 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred for 48 hours at ambient temperature. The reaction mixture is then extracted with 2M sodium carbonate solution and dried over sodium sulfate. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / ethanol 10: 1 to 1: 1).
Yield: 0.04 g (25% of theory)
Melting point: 136-137 ℃
C ₂₈ H ₂₇ ClN ₂ O (M = 442.99)
calc .: Mole peak (M + H) ⁺ : 443 fnd .: Mole peak (M + H) ⁺ : 443
R _f value: 0.5 (silica gel, dichloromethane / methanol 10: 1)
The following compounds are prepared analogously to Examples 1.1 to 1.31.

Example 2.1:
4'-Chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.1.a 4'-chloro-biphenyl-4-carboxylic acid
Dissolve 5.83 g (29.0 mmol) 4-bromo-benzoic acid in 50 ml dioxane and 29 ml 2M sodium carbonate solution. 4.5 g (29.0 mmol) 4-chlorophenylboric acid and 1.68 g (1.45 mmol) tetrakis- (triphenylphosphine) -palladium are added in succession and the reaction is refluxed for 6 hours. The hot reaction solution is suction filtered through a glass fiber filter. The filtrate is extracted with ethyl acetate. The aqueous phase is acidified with citric acid and stirred at 0 ° C. for 1 hour. The formed precipitate is filtered off, washed with water and dried in vacuo.
Yield: 5.1 g (75.6% of theory)
C ₁₃ H ₉ ClO ₂ (M = 232.668)
calc .: Mole peak (MH) ^- : 231/233 fnd .: Mole peak (MH) ^- : 231/233.
2.1.b.4'-Chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
471 mg (1.47 mmol) of TBTU and 0.26 ml (1.47 mmol) of Hunig's base are added to a suspension of 251 mg (1.08 mmol) of 4'-chloro-biphenyl-4-carboxylic acid in 5 ml of THF at ambient temperature. The reaction mixture is stirred for 10 minutes and then 200 mg (0.98 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (see Example 1.1.h) is added. The mixture is stirred overnight. The reaction solution is combined with saturated NaHCO ₃ solution, the aqueous phase is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate. The solvent is distilled off using a rotary evaporator and the residue is stirred with tert-butyl methyl ether while heating. The solid formed is filtered off, washed with a small amount of tert-butyl methyl ether and dried in air.
Yield: 210 mg (51.2% of theory)
C ₂₆ H ₂₇ ClN ₂ O (M = 418.971)
calc .: Mole peak (M + H) ⁺ : 419/421 fnd .: Mole peak (M + H) ⁺ : 419/421
R _f value: 0.57 (silica gel, dichloromethane / methanol / acetic acid 9: 1: 0.1).
Example 2.2:
4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide

2.2.a (4-Diethylaminomethyl-phenyl) -acetonitrile 0.88 ml (8.38 mmol) of diethylamine was dissolved in 30 ml of acetone, 2.1 g (15.2 mmol) of potassium carbonate and 1.6 g (7.62 mmol) of (4-bromomethyl-phenyl) -acetonitrile. ) Is added continuously (see 1.1.f). The reaction mixture is stirred for 2 hours at ambient temperature, filtered through a glass frit and washed with ethyl acetate. The filtrate is evaporated in a rotary evaporator and extracted with water and ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator. Further purification is carried out by column chromatography over silica gel (eluent: dichloromethane / methanol 9: 1).
Yield: 900 mg (58.4% of theory)
C ₁₃ H ₁₈ N ₂ (M = 202.30)
calc .: Mole peak (M + H) ⁺ : 203 fnd .: Mole peak (M + H) ⁺ : 203
R _f value: 0.65 (silica gel, dichloromethane / methanol 9: 1).
2.2.b. 2- (4-Diethylaminomethyl-phenyl) -ethylamine A solution of 900 mg (4.45 mmol) of (4-diethylaminomethyl-phenyl) -acetonitrile in 20 ml of methanolic ammonia solution was combined with 100 mg of Raney nickel and autoclaved at 50 ° C. Shake at 5 bar. After removing the catalyst by suction filtration, the solvent is removed using a rotary evaporator.
Yield: 900 mg (98.0% of theory)
C ₁₃ H ₂₂ N ₂ (M = 206.334)
calc .: Mole peak (M + H) ⁺ : 207 fnd .: Mole peak (M + H) ⁺ : 207
R _f value: 0.12 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
2.2.c. 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide 4'-Chloro-biphenyl-4-amide as in Example 2.1.b Prepared from carboxylic acid (248 mg, 1.07 mmol) and 2- (4-diethylaminomethyl-phenyl) -ethylamine (200 mg, 0.97 mmol).
Yield: 280 mg (68.6% of theory)
C ₂₆ H ₂₉ ClN ₂ O (M = 420.987)
calc .: Mole peak (M + H) ⁺ : 421/423 fnd .: Mole peak (M + H) ⁺ : 421/423
R _f value: 0.49 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
Example 2.3:
4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide

2.3.a. 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-Chloro-biphenyl analogously to Example 2.1.b Prepared from 4-carboxylic acid (234 mg, 1.01 mmol) and 2- (4-piperidin-1-ylmethyl-phenyl) -ethylamine (see 1.15.b, 200 mg, 0.92 mmol).
Yield: 260 mg (65.6% of theory)
C ₂₇ H ₂₉ ClN ₂ O (M = 432.998)
calc .: Mole peak (M + H) ⁺ : 433/435 fnd .: Mole peak (M + H) ⁺ : 433/435
R _f value: 0.57 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
Example 2.4:
4'-Methoxy-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide

2.4.a 1- (4'-Methoxy-biphenyl-4-yl) -ethanone
4-Methoxybiphenyl is added to a solution of 11.3 g (85.0 mmol) of aluminum chloride in 100 ml of carbon disulfide. The mixture is heated to 40 ° C. and then 6.07 ml (81.4 mmol) of acetyl chloride is added very slowly. The reaction is refluxed for 1 hour. After cooling, the reaction solution is added to 100 g of ice and 25 ml of concentrated hydrochloric acid. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate. The solvent is removed using a rotary evaporator and the residue is recrystallized from isopropanol.
Yield: 8.8 g (48.0% of theory)
C ₁₅ H ₁₄ O ₂ (M = 226.278)
calc .: Mole peak (M + H) ⁺ : 227 fnd .: Mole peak (M + H) ⁺ : 227
2.4.b 4'-methoxy-biphenyl-4-carboxylic acid 6.0 ml (117 mmol) bromine are slowly added dropwise at 0 ° C. to a solution of 15.6 g (390.9 mmol) NaOH in 70 ml water. Then 8.8 g (39.1 mmol) of 1- (4′-methoxy-biphenyl-4-yl) -ethanone in 50 ml of dioxane are slowly added. After 3 hours, the solid formed is filtered off, taken up in dichloromethane and filtered again. Remove the solvent from the filtrate using a rotary evaporator.
Yield: 9.0 g (100.0% of theory)
C ₁₅ H ₁₄ O ₂ (M = 228.250)
calc .: Mole peak (MH) ^- : 227 fnd .: Mole peak (MH) ^- : 227

2.4.c 4'-Methoxy-biphenyl-4-carboxylic acid chloride A solution of 3.0 g (0.013 mol) of 4'-methoxy-biphenyl-4-carboxylic acid in 47.4 ml (0.65 mmol) of thionyl chloride at 50 ° C for 3 hours Stir. After removal of thionyl chloride using a rotary evaporator, the product is obtained as a yellow solid, which is stored in a refrigerator.
Yield: 3.2 g (99.8% of theory)
C ₁₅ H ₁₄ O ₂ (M = 246.696)
calc .: Mole peak (M + H) ⁺ : 246/248 fnd .: Mole peak (M + H) ⁺ : 246/248.
2.4.d 4'-Methoxy-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide acid chloride 287 mg (1.16 mmol) at 0 ° C. in 2- (4 -Diethylaminomethyl-phenyl) -ethylamine is added to a solution of 200 mg (0.97 mmol) and Hunig's base 0.25 ml (1.45 mmol). The reaction is stirred overnight and then combined with half-saturated NaHCO ₃ solution. The aqueous phase is washed with dichloromethane and the combined organic phases are dried over magnesium sulfate. After removing the solvent using a rotary evaporator, the residue is triturated with tert-butyl methyl ether and the resulting solid is filtered off with suction.
Yield: 90 mg (22.3% of theory)
C ₂₇ H ₃₂ N ₂ O ₂ (M = 416.568)
calc .: Mole peak (M + H) ⁺ : 417 fnd .: Mole peak (M + H) ⁺ : 417.
R _f value: 0.46 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.5
4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amide

2.5.a Tert-butyl [2- (4-diethylaminomethyl-phenyl) -ethyl] -carbamate
Add 815 mg (3.73 mmol) of BOC-anhydride to a solution of 700 mg (3.93 mmol) of 2- (4-diethylaminomethyl-phenyl) -ethylamine in 5.0 ml of dichloromethane and 0.52 ml (3.73 mmol) of triethylamine at ambient temperature. Stir overnight. The mixture is combined with saturated NaHCO ₃ solution. The aqueous phase is washed with dichloromethane and the organic phase is dried over magnesium sulfate. After removing the solvent using a rotary evaporator, the residue is purified by column chromatography over silica gel (eluent: dichloromethane / methanol / NH ₃ = 9: 1: 0.1).
Yield: 600 mg (57.7% of theory)
C ₁₈ H ₃₀ N ₂ O ₂ (M = 306.452)
calc .: Mole peak (M + H) ⁺ : 307 fnd .: Mole peak (M + H) ⁺ : 307.
2.5.b [2- (4-Diethylaminomethyl-phenyl) -ethyl] -methyl-amine
600 mg (1.96 mmol) of tert-butyl [2- (4-diethylaminomethyl-phenyl) -ethyl] -carbamate in THF is slowly added dropwise to a suspension of 250 mg (6.59 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran. Add. The reaction is stirred overnight and heated to 50 ° C. for an additional hour. The treatment is carried out by successive additions of 0.25 ml water, 0.25 ml 15% NaOH solution and 0.75 ml water. After filtration, the organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator.
Yield: 350 mg (81.1% of theory)
C ₁₄ H ₂₄ N ₂ (M = 220.361)
calc .: Mole peak (M + H) ⁺ : 221 fnd .: Mole peak (M + H) ⁺ : 221.
2.5.c 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amide 4'-Chloro-biphenyl-4 as in Example 2.1.b Prepared from -carboxylic acid (222 mg, 0.95 mmol) and [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amine (175 mg, 0.79 mmol).
Yield: 60 mg (17.4% of theory)
C ₂₇ H ₃₁ ClN ₂ O (M = 435.014)
calc .: Mole peak (M + H) ⁺ : 435/437 fnd .: Mole peak (M + H) ⁺ : 435/437
R _f value: 0.39 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.6:

2.6.a. 4- (4-Chloro-phenyl) -cyclohexanecarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro-phenyl) according to general procedure I ) -Cyclohexanecarboxylic acid (239 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1.0 mmol).
Yield: 65 mg (15.3% of theory)
C ₂₆ H ₃₃ ClN ₂ O (M = 425.019)
calc .: Mole peak (M + H) ⁺ : 425/427 fnd .: Mole peak (M + H) ⁺ : 425/427
R _f value: 0.3 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.7:
4-Piperidin-1-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.7.a Ethyl 4-piperidin-1-yl-benzoate 0.41 ml piperidine is added to a suspension of 0.5 ml (4.13 mmol) ethyl 4-fluoro-benzoate and 571 mg (4.13 mmol) potassium carbonate in 20 ml DMSO. The reaction mixture is stirred at 70 ° C. overnight, an additional 1 ml (2.44 mmol) of piperidine is added and stirring is continued at 70 ° C. for a further 6 hours. After filtration, water is added, the mixture is extracted with ethyl acetate, the organic phase is separated and the solvent is removed using a rotary evaporator. The product is reacted further without purification.
Yield: 706 mg (73.2% of theory)
C ₁₄ H ₁₉ NO ₂ (M = 233.313)
calc .: Mole peak (M + H) ⁺ : 234 fnd .: Mole peak (M + H) ⁺ : 234
Retention time HPLC: 6.2 minutes (Method A)
2.7.b 4-Piperidin-1-yl-benzoic acid
0.78 ml (0.74 mmol) of 2N NaOH is added to a solution of 350 mg (1.50 mmol) of ethyl 4-piperidin-1-yl-benzoate in 10 ml of ethanol. The reaction solution is stirred at 60 ° C. for 2 hours, then the pH is adjusted to 6-7 with 1N HCl. The precipitate formed is filtered and dried overnight under high vacuum.
Yield: 158 mg (51.3% of theory)
C ₁₂ H ₁₅ NO ₂ (M = 205.259)
calc .: Mole peak (M + H) ⁺ : 206 fnd .: Mole peak (M + H) ⁺ : 206
Retention time HPLC: 6.2 minutes (Method A)
2.7.c 4-Piperidin-1-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-Pyrrolidin-1-ylmethyl-phenyl) according to general procedure I Prepared from -ethylamine (157 mg, 0.77 mmol) and 4-piperidin-1-yl-benzoic acid (158 mg, 0.77 mmol).
Yield: 102 mg (33.8% of theory)
C ₂₅ H ₃₃ N ₃ O (M = 391.561)
calc .: Mole peak (M + H) ⁺ : 392 fnd .: Mole peak (M + H) ⁺ : 392
Retention time HPLC: 4.4 minutes (Method A)
Example 2.8:

2.8.a 4-Benzyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide Diphenylmethane-4-carboxylic acid (104 mg, 0.49 mmol) and 2- Prepared from (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (100 mg, 0.49 mmol).
Yield: 66 mg (33.9% of theory)
C ₂₇ H ₃₀ N ₂ O (M = 398.553)
calc .: Mole peak (M + H) ⁺ : 399 fnd .: Mole peak (M + H) ⁺ : 399
R _f value: 0.46 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.9:
4- (4-Oxo-cyclohexylidenemethyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.9.a Ethyl 4- (1,4-dioxa-spiro [4.5] dec-8-ylidenemethyl) -benzoate
350 ml of n-BuLi solution (0.56 mol, 1.6 M in hexane) was added dropwise at −20 ° C. to a solution of 90.0 ml (0.63 mol) of diisopropylamine in 100 ml of THF, and the reaction solution was stirred at −20 ° C. for 30 minutes. To do. 112 g (0.37 mol) of ethyl 4- (diethoxy-phosphorylmethyl) -benzoate in 100 ml of THF are slowly added dropwise. The reaction solution is stirred for 1 hour at −20 ° C. and then 58 g (0.37 mol) of 1,4-dioxa-spiro [4.5] decan-8-one in 200 ml of THF are added dropwise. The reaction solution is stirred at −12 ° C. for 30 minutes and then heated to ambient temperature for 2 hours. Water is added and the aqueous phase is extracted with ether, ethyl acetate and dichloromethane. The organic phase is filtered through silica gel. After removing the solvent using a rotary evaporator, the residue is purified by chromatography (silica gel, petroleum ether / ethyl acetate 9: 1).
Yield: 80g (72.0% of theory)
2.9.b 4- (1,4-Dioxa-spiro [4.5] dec-8-ylidenemethyl) -benzoic acid 20 g NaOH in 130 ml water with ethyl 4- (1,4-dioxa-spiro [4.5] deca in 150 ml ethanol -8-ylidenemethyl) -benzoate is added to a solution of 35 g (0.12 mol) and the mixture is refluxed for 2 hours. The reaction solution is added to 400 g of ice and 60 ml of concentrated hydrochloric acid, the aqueous phase is extracted with ethyl acetate, and the solvent is removed using a rotary evaporator.
Yield: 32g (91.4% of theory)
Melting point: 164-165 ° C
2.9.c 4- (4-Oxo-cyclohexylidenemethyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide According to general procedure I 4- (1,4-dioxa Prepared from -spiro [4.5] dec-8-ylidenemethyl) -benzoic acid (134 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (100 mg, 0.49 mmol).
Yield: 57 mg (28.0% of theory)
C ₂₇ H ₃₂ N ₂ O ₂ (M = 416.568)
calc .: Mole peak (M + H) ⁺ : 417 fnd .: Mole peak (M + H) ⁺ : 417
R _f value: 0.36 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.10:

2.10.a 4- (4-Oxo-cyclohexyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 4- (4-Oxo-cyclohexyl) -benzoic acid according to general procedure I Prepared from acid (128 mg, 0.49 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (100 mg, 0.49 mmol).
Yield: 26 mg (13.1% of theory)
C ₂₆ H ₃₂ N ₂ O ₂ (M = 404.557)
calc .: Mole peak (M + H) ⁺ : 405 fnd .: Mole peak (M + H) ⁺ : 405
R _f value: 0.31 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.11:
4-Cyclohexyl-1-cyclohexylcarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.11.a 4-Cyclohexyl-1-cyclohexylcarboxylic acid 0.44 ml of concentrated hydrochloric acid and 100 mg of platinum oxide are added to a solution of 500 mg (2.10 mmol) of 4- (4-chlorophenyl) -cyclohexanecarboxylic acid in 10 ml of methanol. The reaction mixture is stirred at 50 ° C. with 5 bar hydrogen for 3 hours. After separation of the catalyst, the solvent is removed using a rotary evaporator.
Yield: 440 mg (99.9% of theory)
C ₁₃ H ₂₂ O ₂ (M = 210.319)
calc .: Mole peak (MH) ^- : 209 fnd .: Mole peak (MH) ^- : 209
2.11.b 4-Cyclohexyl-1-cyclohexylcarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide Bicyclohexyl-4-carboxylic acid (103 mg, 0.49 mmol) according to General Procedure I ) And 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (100 mg, 0.49 mmol).
Yield: 2.0 mg (1.0% of theory)
C ₂₆ H ₄₀ N ₂ O (M = 396.622)
calc .: Mole peak (M + H) ⁺ : 397 fnd .: Mole peak (M + H) ⁺ : 397
R _f value: 0.46 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.12:

2.12.a 4-Methylphenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-methylphenyl-piperidine (175 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1.0 mmol).
Yield: 90.0 mg (22.2% of theory)
C ₂₆ H ₃₅ N ₃ O (M = 405.558)
calc .: Mole peak (M + H) ⁺ : 406 fnd .: Mole peak (M + H) ⁺ : 406
R _f value: 0.30 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.13:
4- (4-Chloro-phenyl) -3,6-dichloro-2H-pyridine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.13.a 4- (4-Chloro-phenyl) -1,2,3,6-tetrahydro-pyridine
4-Chloro-methylstyrene is added dropwise at 60 ° C. to 100 ml (1.2 mol) of formalin solution (37% in water) and 32.1 g (0.6 mol) of ammonium chloride. The reaction mixture is stirred at 60 ° C. for 3 hours and then cooled to ambient temperature. 100 ml of methanol are added and the mixture is stirred overnight. After evaporating the solvent using a rotary evaporator, the residue is combined with 150 ml of concentrated hydrochloric acid and stirred at 100 ° C. for 4 hours. After cooling to ambient temperature, it is added to ice and made alkaline with NaOH chips. After repeated extraction with ether, the organic phase is dried over sodium sulfate. After removing the solvent using a rotary evaporator, the residue is purified by column chromatography over silica gel (eluent: ethyl acetate: methanol: NH ₃ 9: 1: 0.1).
Yield: 17.0 g (29.3% of theory)
C ₁₁ H ₁₂ ClN (M = 193.678)
calc .: Mole peak (M + H) ⁺ : 194 fnd .: Mole peak (M + H) ⁺ : 194
R _f value: 0.26 (silica gel, ethyl acetate / methanol / NH ₃ 6: 4: 0.4).
2.13.b 4- (4-Chloro-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide General procedure 4- (4-Chloro-phenyl) -1,2,3,6-tetrahydro-pyridine (193 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1.0 mmol).
Yield: 40.0 mg (9.4% of theory)
C ₂₅ H ₃₀ ClN ₃ O (M = 423.990)
calc .: Mole peak (M + H) ⁺ : 424/426 fnd .: Mole peak (M + H) ⁺ : 424/426
R _f value: 0.30 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.14:

2.14.a 3,4,5,6-Tetrahydro-2H- [4.4 '] bipyridinyl-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide according to General Procedure II From 1,2,3,4,5,6-hexahydro- [4.4 '] bipyridinyl (81 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol) Prepared.
Yield: 43.8 mg (22.3% of theory)
C ₂₄ H ₃₂ N ₄ O (M = 392.549)
calc .: Mole peak (M + H) ⁺ : 393 fnd .: Mole peak (M + H) ⁺ : 393
R _f value: 0.14 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.15:

2.15.a 4-Benzyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure II 4-benzyl-piperidine (87.7 mg, 0.50 mmol) And 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 33.5 mg (16.5% of theory)
C ₂₆ H ₃₅ N ₃ O (M = 405.6)
calc .: Mole peak (M + H) ⁺ : 406 fnd .: Mole peak (M + H) ⁺ : 406
R _f value: 0.36 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.16:

2.16.a 4- (1H-Indol-3-yl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3-piperidine-in accordance with general procedure II Prepared from 4-yl-1H-indole (100 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 56.5 mg (26.2% of theory)
C ₂₇ H ₃₄ N ₄ O (M = 430.6)
calc .: Mole peak (M + H) ⁺ : 431 fnd .: Mole peak (M + H) ⁺ : 431
R _f value: 0.36 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.17:

2.17.a tert-Butyl 1 '-[2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethylcarbamoyl]-[4.4'] bipiperidinyl-1-carboxylate tert-Butyl according to General Procedure II [4.4 '] Prepared from -bipiperidinyl-1-carboxylate (134 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 51.0 mg (20.5% of theory)
C ₂₉ H ₄₆ N ₄ O ₃ (M = 498.7)
calc .: Mole peak (M + H) ⁺ : 499 fnd .: Mole peak (M + H) ⁺ : 499
R _f value: 0.40 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.18:
4-Cyclohexyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.18.a 4-cyclohexyl-piperidine To a solution of 1.0 g (6.4 mmol) 4-phenylpyridine in 20 ml methanol is added 1.35 ml concentrated hydrochloric acid and 200 mg platinum oxide. The reaction mixture is stirred at 50 ° C. with 3 bar hydrogen for 2.5 hours. After separation of the catalyst, the solvent is removed using a rotary evaporator, during which the product is precipitated as the hydrochloride salt.
Yield: 1.2 (91.4% of theory)
C ₁₁ H ₂₁ N * HCl (M = 203.758)
calc .: Mole peak (M + H) ⁺ : 168 fnd .: Mole peak (M + H) ⁺ : 168.
2.18.b 4-Cyclohexyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure II 4-cyclohexyl-piperidine (83.7 mg, 0.50 mmol) And 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 38.0 mg (19.1% of theory)
C ₂₅ H ₃₉ N ₃ O (M = 397.6)
calc .: Mole peak (M + H) ⁺ : 398 fnd .: Mole peak (M + H) ⁺ : 398
R _f value: 0.54 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.19:
4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.19.a 4- (4-Chloro-phenyl) -piperidine 4- (4-Chloro-phenyl) -1,2,3,6-tetrahydro-pyridine (see 2.13.a) in 20 ml methanol 5.0 g To a solution of (21.7 mmol), 500 mg of Pd / C is added. The reaction mixture is stirred for 7 hours at ambient temperature with hydrogen at 0.70kg / cm ² (10psi). After separation of the catalyst, the solvent is removed using a rotary evaporator. Further purification is carried out by column chromatography over silica gel (eluent: dichloromethane / methanol / ammonia = 5: 4.9: 0.1).
Yield: 3.2 (75.3% of theory)
C ₁₁ H ₁₄ ClN (M = 195.694)
calc .: Mole peak (M + H) ⁺ : 196/198 fnd .: Mole peak (M + H) ⁺ : 196/198.
R _f value: 0.37 (silica gel, dichloromethane / methanol / NH ₃ 5: 4.9: 0.1).
2.19.b 4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro Prepared from -phenyl) -piperidine (97.9 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 9.0 mg (4.2% of theory)
C ₂₅ H ₃₂ ClN ₃ O (M = 426.0)
calc .: Mole peak (M + H) ⁺ : 426/428 fnd .: Mole peak (M + H) ⁺ : 426/428
R _f value: 0.49 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.20:

2.20.a 4-hydroxy-4- (4-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide according to general procedure II Prepared from 4-hydroxy-4- (4-trifluoromethyl-phenyl) -piperidine (123 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol) .
Yield: 35.0 mg (14.7% of theory)
C ₂₆ H ₃₂ F ₃ N ₃ O ₂ (M = 475.6)
calc .: Mole peak (M + H) ⁺ : 476 fnd .: Mole peak (M + H) ⁺ : 476
R _f value: 0.45 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.21:

2.21.a 3-Phenyl-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3- Prepared from phenyl-8-aza-bicyclo [3.2.1] octane (93.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 26.0 mg (12.5% of theory)
C ₂₇ H ₃₅ N ₃ O (M = 417.6)
calc .: Mole peak (M + H) ⁺ : 418 fnd .: Mole peak (M + H) ⁺ : 418
R _f value: 0.51 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.22:

2.22.a 4- (4-Chloro-phenyl) -piperazine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- (4-chloro Prepared from -phenyl) -piperazine (117 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 13.0 mg (6.1% of theory)
C ₂₄ H ₃₁ ClN ₄ O (M = 427.0)
calc .: Mole peak (M + H) ⁺ : 427/429 fnd .: Mole peak (M + H) ⁺ : 427/429
R _f value: 0.42 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.23:

2.23.a 4-cyano-4-phenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-cyano-4-phenyl- according to general procedure II Prepared from piperidine (111 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 27.0 mg (13.0% of theory)
C ₂₆ H ₃₂ N ₄ O (M = 416.6)
calc .: Mole peak (M + H) ⁺ : 417 fnd .: Mole peak (M + H) ⁺ : 417
R _f value: 0.46 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.24:

2.24.a 3-Aza-spiro [5.5] undecane-3-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 3-aza-spiro [5.5] according to general procedure II Prepared from undecane (76.7 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 24.0 mg (12.5% of theory)
C ₂₄ H ₃₇ N ₃ O (M = 383.6)
calc .: Mole peak (M + H) ⁺ : 384 fnd .: Mole peak (M + H) ⁺ : 384
R _f value: 0.49 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.25:

2.25.a 4- (4-Fluoro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure II 4- (4-Fluoro Prepared from -phenyl) -piperidine (108 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 32.0 mg (15.6% of theory)
C ₂₅ H ₃₂ FN ₃ O (M = 409.6)
calc .: Mole peak (M + H) ⁺ : 410 fnd .: Mole peak (M + H) ⁺ : 410
R _f value: 0.50 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.26

2.26.a 1.2-Dihydro-1- (methylsulfonyl) -spiro [3H-indole-3,4'-piperidine] -1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -Amide 1,2-dihydro-1- (methylsulfonyl) -spiro [3H-indole-3,4'-piperidine] (133.2 mg, 0.50 mmol) and 2- (4-pyrrolidine-1- Prepared from ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 28.0 mg (11.3% of theory)
C ₂₇ H ₃₆ N ₄ O ₃ S (M = 496.7)
calc .: Mole peak (M + H) ⁺ : 497 fnd .: Mole peak (M + H) ⁺ : 497
R _f value: 0.42 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.27:

2.27.a 4- (4-Chloro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide according to general procedure II Prepared from (4-chloro-phenyl) -4-hydroxy-piperidine (106 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 32.0 mg (14.5% of theory)
C ₂₅ H ₃₂ ClN ₃ O ₂ (M = 442.0)
calc .: Mole peak (M + H) ⁺ : 442/444 fnd .: Mole peak (M + H) ⁺ : 442/444
R _f value: 0.44 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.28:

2.28.a 4- (4-Methoxy-phenyl) -piperazine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- (4-methoxy according to general procedure II Prepared from -phenyl) -piperazine (133 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 35.0 mg (16.6% of theory)
C ₂₅ H ₃₄ N ₄ O ₂ (M = 422.6)
calc .: Mole peak (M + H) ⁺ : 423 fnd .: Mole peak (M + H) ⁺ : 423
R _f value: 0.47 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.29:

2.29. 4- (2-Methoxy-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure II, 4- (2-methoxy- Prepared from (phenyl) -piperidine (114 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 20.0 mg (9.5% of theory)
C ₂₆ H ₃₅ N ₃ O ₂ (M = 421.6)
calc .: Mole peak (M + H) ⁺ : 422 fnd .: Mole peak (M + H) ⁺ : 422
R _f value: 0.55 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.30:

2.30.a 1,3-Dihydro-isoindole-2-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 1,3-dihydro-isoindole according to general procedure II 77.8 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 13.0 mg (7.4% of theory)
C ₂₂ H ₂₇ N ₃ O (M = 349.48)
calc .: Mole peak (M + H) ⁺ : 350 fnd .: Mole peak (M + H) ⁺ : 350
R _f value: 0.30 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
Example 2.31:

2.31.a 1,2,4,5-Tetrahydro-benzo [d] azepine-3-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 1, according to general procedure II Prepared from 2,4,5-tetrahydro-benzo [d] azepine (73.6 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 12.0 mg (6.4% of theory)
C ₂₄ H ₃₁ N ₃ O (M = 377.534)
calc .: Mole peak (M + H) ⁺ : 378 fnd .: Mole peak (M + H) ⁺ : 378
R _f value: 0.33 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
Example 2.32:

2.32.a 4-Phenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure II 4-phenyl-piperidine (80.6 mg, 0.50 mmol) And 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 24.0 mg (12.3% of theory)
C ₂₅ H ₃₃ N ₃ O (M = 391.561)
calc .: Mole peak (M + H) ⁺ : 392 fnd .: Mole peak (M + H) ⁺ : 392
R _f value: 0.35 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
Example 2.33:
4- (4-Dimethylaminomethyl-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.33.a tert.Butyl 4- (4-dimethylaminomethyl-phenyl) -4-hydroxy-piperidine-1-carboxylate
236 ml of n-BuLi (0.38 mol, 1.6 M in hexane) is added dropwise at −65 ° C. over 35 minutes to a solution of 81 g (0.38 mol) 4-bromodimethylbenzylamine in 450 ml THF. 75 g (0.38 mol) of tert.butyl 4-oxo-piperidine-1-carboxylate in 150 ml of THF are added dropwise over 60 minutes so that the temperature does not exceed -60 ° C. The reaction solution is stirred at −65 ° C. for 2 hours and at ambient temperature for a further 17 hours. The reaction mixture is combined with 300 ml of ether, cooled to 5 ° C. and the precipitate formed is filtered off with suction. The precipitate is combined with 200 ml water and 700 ml ether and stirred for 10 minutes. The organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator. The product obtained is dried in vacuo.
Yield: 45g (35.7% of theory)
2.33.b Dimethyl- [4- (1,2,3,6-tetrahydro-pyridin-4-yl) -benzyl] -amine 70 ml of trifluoroacetic acid in tert.butyl 4- (4 -Dimethylaminomethyl-phenyl) -4-hydroxy-piperidine-1-carboxylate is added dropwise to a solution of 45 g (0.14 mol). The solution is stirred for 1.5 hours at ambient temperature, cooled to −10 ° C. and 30 ml of concentrated sulfuric acid are added. After 0.5 hours, add another 10 ml of sulfuric acid. After 1 hour, remove the solvent using a rotary evaporator and add to 300 g of ice. The pH is adjusted to 14 with 6N NaOH solution. The aqueous phase is saturated with potassium carbonate and extracted twice with ether. The combined organic phases are concentrated and dried using a rotary evaporator.
Yield: 25.2g (86.9%)

2.33.c Dimethyl- (4-piperidin-4-yl-benzyl) -amine
6 g of Pd / BaSO ₄ is added to a solution of 16 g (74 mmol) of dimethyl- [4- (1,2,3,6-tetrahydro-pyridin-4-yl) -benzyl] -amine in 200 ml of methanol. The solution is stirred for 1 hour at ambient temperature in a hydrogen atmosphere, the catalyst is filtered off and the solvent is removed using a rotary evaporator. Dissolve the residue in methanol, add methanolic hydrochloric acid, and then add ether until the mixture becomes cloudy. After storage at −20 ° C., the obtained hydrochloride is filtered off with suction.
Yield: 16g (84.9%)
2.33.d 4- (4-Dimethylaminomethyl-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4- (4 Prepared from -dimethylaminomethyl-phenyl) -piperidine (127 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 37.0 mg (16.5% of theory)
C ₂₈ H ₄₀ N ₄ O (M = 448.657)
calc .: Mole peak (M + H) ⁺ : 449 fnd .: Mole peak (M + H) ⁺ : 449
R _f value: 0.37 (silica gel, dichloromethane / methanol / NH ₃ 9: 1: 0.1).
Example 2.34:
4'-Chloro-biphenyl-4-yl)-[3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidin-1-yl] -methanone

2.34.a 1- (4-Bromo-benzyl) -pyrrolidine
20.0 g (0.080 mol) of 4-bromobenzyl bromide in THF is slowly added dropwise to a solution of 13.1 ml (0.16 mmol) of pyrrolidine and 200 ml of tetrahydrofuran so that the temperature does not exceed 20 ° C. The reaction solution is stirred overnight, mixed with ice and acidified with concentrated hydrochloric acid. After extraction with ether, the aqueous phase is made alkaline with sodium hydroxide solution and saturated with potassium carbonate. After extraction with ether, the organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator.
Yield: 18.1 g (94.2% of theory)
C ₁₁ H ₁₄ BrN (M = 240.145)
calc .: Mole peak (M + H) ⁺ : 240/242 fnd .: Mole peak (M + H) ⁺ : 240/242
R _f value: 0.19 (silica gel, petroleum ether / ethyl acetate 8: 2).
2.34.b 3- (4-Pyrrolidin-1-ylmethyl-phenyl) -pyridine
1.11 g (4.64 mmol) of 1- (4-bromo-benzyl) -pyrrolidine is dissolved in 10 ml of dioxane and 5 ml of 2M sodium carbonate solution. 570 mg (4.64 mmol) pyridine-3-boric acid and 270 mg (0.23 mmol) tetrakis- (triphenylphosphine) -palladium are added in succession and the reaction is refluxed for 6 hours. The reaction solution is suction filtered through a glass fiber filter. The filtrate is extracted several times with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator. Further purification is carried out by column chromatography over silica gel (eluent: ethyl acetate / methanol / NH ₃ = 8: 2: 0.1).
Yield: 500 mg (45.2% of theory)
C ₁₆ H ₁₈ N ₂ (M = 238.335)
calc .: Mole peak (M + H) ⁺ : 239 fnd .: Mole peak (M + H) ⁺ : 239

2.34.c 3- (4-Pyrrolidin-1-ylmethyl-phenyl) -piperidine
4 ml of 1M hydrochloric acid and 200 mg of platinum oxide are added to a solution of 500 mg (2.10 mmol) of 3- (4-pyrrolidin-1-ylmethyl-phenyl) -pyridine in 10 ml of ethanol. The reaction mixture is stirred at ambient temperature with 3 bar hydrogen for 4.5 hours. After separation of the catalyst, the solvent is removed using a rotary evaporator, during which the product is precipitated as the hydrochloride salt.
Yield: 600 mg (100% of theory)
C ₁₆ H ₂₄ N ₂ * HCl (M = 280.844)
calc .: Mole peak (M + H) ⁺ : 245 fnd .: Mole peak (M + H) ⁺ : 245.
2.34.d (4'-Chloro-biphenyl-4-yl)-[3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidin-1-yl] -methanone 4'-Chloro-biphenyl according to General Procedure I Prepared from 4-carboxylic acid (183 mg, 0.78 mmol) and 3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidine (200 mg, 0.71 mmol).
Yield: 20.0 mg (6.1% of theory)
C ₂₉ H ₃₁ ClN ₂ O (M = 459.036)
calc .: Mole peak (M + H) ⁺ : 459/461 fnd .: Mole peak (M + H) ⁺ : 459/461
R _f value: 0.58 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.35:
4'-Chloro-biphenyl-4-carboxylic acid- [2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide

2.35.a 2-Methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propionitrile Potassium-tert-butoxide 3.4 g (30 mmol) in (4-pyrrolidine-1- Add to a solution of 2.0 g (10.0 mmol) of ylmethyl-phenyl) -acetonitrile (see 1.1. G). The reaction solution is stirred rapidly, combined with 1.9 ml (30 mmol) of methyl iodide, stirred for a further 2 hours at ambient temperature and then evaporated to dryness using a rotary evaporator. The residue is partitioned between water and ethyl acetate, the organic phase is washed with water and dried over magnesium sulfate. The solvent is removed using a rotary evaporator and the crude product is further reacted without purification.
Yield: 1.4 g (61.3% of theory)
C ₁₅ H ₂₀ N ₂ (M = 228.340)
calc .: Mole peak (M + H) ⁺ : 229 fnd .: Mole peak (M + H) ⁺ : 229
R _f value: 0.40 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
2.35.b 2-Methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propylamine Raney nickel 150 mg in 20 ml methanolic ammonia solution 2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -Add to a solution of 1.4 g (6.13 mmol) propionitrile. The reaction mixture is stirred at 50 ° C. under a 5 bar hydrogen atmosphere overnight. After the catalyst has been filtered off, the solvent is removed using a rotary evaporator.
Yield: 1.4 g (98.3% of theory)
C ₁₅ H ₂₄ N ₂ (M = 232.372)
calc .: Mole peak (M + H) ⁺ : 233 fnd .: Mole peak (M + H) ⁺ : 233
R _f value: 0.30 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
2.35.c. 4'-Chloro-biphenyl-4-carboxylic acid- [2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide 4'-Chloro-biphenyl according to general procedure I Prepared from 4-carboxylic acid (233 mg, 1.0 mmol) and 2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propylamine (232 mg, 1.0 mmol).
Yield: 400 mg (89.5% of theory)
C ₂₈ H ₃₁ ClN ₂ O (M = 447.025)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
R _f value: 0.35 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.36:
4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide

2.36.a 2- (4-Pyrrolidin-1-ylmethyl-phenyl) -propionitrile Potassium-tert-butoxide 1.12 g (10 mmol) in (4-Pyrrolidin-1-ylmethyl-phenyl) in 50 ml of tetrahydrofuran at ambient temperature Add to a solution of 2.0 g (10.0 mmol) of acetonitrile (see 1.1. G). The reaction solution is stirred for 30 minutes and then combined with 0.63 ml (10 mmol) of methyl iodide. The reaction is stirred at 50 ° C. for 1 hour and then concentrated to dryness using a rotary evaporator. The residue is partitioned between water and ethyl acetate, the organic phase is washed twice with water and dried over magnesium sulfate. The solvent is removed using a rotary evaporator and the crude product (which contains about 20% of the dimethylated compound) is reacted further without purification.
Yield: 0.5 g (23.3% of theory)
C ₁₄ H ₁₈ N ₂ (M = 214.313)
calc .: Mole peak (M + H) ⁺ : 215 fnd .: Mole peak (M + H) ⁺ : 215
R _f value: 0.40 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
2.36.b 2- (4-Pyrrolidin-1-ylmethyl-phenyl) -propylamine 100 mg of Raney Nickel 400 mg (1.87 mmol) of 2- (4-Pyrrolidin-1-ylmethyl-phenyl) -propionitrile in 20 ml of methanolic ammonia solution ) To the solution. The reaction mixture is stirred overnight at 50 ° C. in a 5 bar hydrogen atmosphere. After the catalyst has been filtered off, the solvent is removed using a rotary evaporator. The amine (which contains about 20% of the dimethylated compound) is reacted further without further purification.
Yield: 0.4 g (98.6% of theory)
C ₁₅ H ₂₂ N ₂ (M = 218.345)
calc .: Mole peak (M + H) ⁺ : 219 fnd .: Mole peak (M + H) ⁺ : 219
R _f value: 0.30 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
2.36.c 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide 4'-Chloro-biphenyl-4-carboxylic acid according to General Procedure I Prepared from (233 mg, 1.0 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -propylamine (218 mg, 1.0 mmol).
Yield: 10 mg (2.3% of theory)
C ₂₈ H ₃₁ ClN ₂ O (M = 447.025)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
R _f value: 0.35 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.37:
4'-Chloro-biphenyl-4-carboxylic acid- (4-pyrrolidin-1-ylmethyl-benzyloxy) -amide

2.37.a 2- (4-Pyrrolidin-1-ylmethyl-benzyloxy) -isoindole-1,3-dione 8.2 g (50 mmol) N-hydroxy-phthalimide in 125 ml acetonitrile and 8.7 ml (50 mmol) Hunig's base To a solution of 13.2 g (50 mmol) of α, α′-dibromo-p-xylene in 125 ml of acetonitrile at ambient temperature. The reaction solution is stirred for 10 minutes, then 4.1 ml (50 mmol) of pyrrolidine are added and stirring is continued for 1 hour. After filtration, the mother liquor is evaporated and dried using a rotary evaporator. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia). The material is further reacted immediately after purification.
Yield: 1.0 g (5.9% of theory)
R _f value: 0.60 (Alox, ethyl acetate / petroleum ether 1: 1).
2.37.b O- (4-Pyrrolidin-1-ylmethyl-benzyl) -hydroxylamine 50 ml of a 40% methylamine solution in water and 2- (4-pyrrolidin-1-ylmethyl-benzyloxy) -isoindole- in 50 ml of toluene A solution of 1.0 g (2.97 mmol) of 1,3-dione is added and the mixture is stirred at ambient temperature for 2.5 days. After separation of the organic phase, the aqueous phase is extracted twice with tert-butyl methyl ether. The combined organic phases are washed with water and dried over magnesium sulfate. The solvent is removed using a rotary evaporator and the resulting product is further reacted without purification.
Yield: 260 mg (42.4% of theory)
C ₁₂ H ₁₈ N ₂ O (M = 206.290)
calc .: Mole peak (M + H) ⁺ : 207 fnd .: Mole peak (M + H) ⁺ : 207.
2.37.c 4′-Chloro-biphenyl-4-carboxylic acid- (4-pyrrolidin-1-ylmethyl-benzyloxy) -amide 4′-chloro-biphenyl-4-carboxylic acid (116 mg, 0.5 Mmol) and O- (4-pyrrolidin-1-ylmethyl-benzyl) -hydroxylamine (103 mg, 0.5 mmol).
Yield: 10.0 mg (4.8% of theory)
C ₂₀ H ₂₅ ClN ₂ O ₂ (M = 420.943)
calc .: Mole peak (M + H) ⁺ : 421/423 fnd .: Mole peak (M + H) ⁺ : 421/423
R _f value: 0.38 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.38:
4'-Chloro-biphenyl-4-carboxylic acid- [1,1-dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.38.a Ethyl (4-pyrrolidin-1-ylmethyl-phenyl) -acetate
3.0 g (15 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (see 1.1. G) is dissolved in ethanolic hydrochloric acid (saturated) and refluxed for 4 hours. The solvent is removed using a rotary evaporator and the residue is taken up with dilute NaHCO ₃ solution and tert-butyl methyl ether. The organic phase is dried over sodium sulfate, filtered with suction through activated carbon, and then the solvent is removed using a rotary evaporator.
Yield: 3.4 g (91.6% of theory)
C ₁₅ H ₂₁ NO ₂ (M = 247.340)
calc .: Mole peak (M + H) ⁺ : 248 fnd .: Mole peak (M + H) ⁺ : 248
R _f value: 0.25 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
2.38.b 2-Methyl-1- (4-pyrrolidin-1-ylmethyl-phenyl) -propan-2-ol 3.4 g (13.8 mmol) of ethyl (4-pyrrolidin-1-ylmethyl-phenyl) -acetate in 20 ml of tetrahydrofuran Is added dropwise at ambient temperature to 13.3 ml (40 mmol) of a 3.0 M solution of methylmagnesium chloride in tetrahydrofuran. The temperature rises to 40 ° C. The reaction mixture is stirred for 1 hour and then poured into 100 ml of ammonium chloride solution. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with saturated brine solution and dried over magnesium sulfate. The solvent is removed using a rotary evaporator and the residue is purified by column chromatography over Alox (activity 2-3) (eluent: cyclohexane: ethyl acetate 4: 1).
Yield: 800 mg (24.9% of theory)
C ₁₅ H ₂₃ NO (M = 233.357)
calc .: Mole peak (M + H) ⁺ : 234 fnd .: Mole peak (M + H) ⁺ : 234
R _f value: 0.50 (Alox, petroleum ether / ethyl acetate 6: 4).

2.38.c N- [1,1-dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -formamide A mixture of 2 ml of sulfuric acid and 1 ml of glacial acetic acid, the temperature of the reaction mixture does not exceed 20 ° C To a solution of 250 mg (5.0 mmol) of sodium cyanide in 2 ml of glacial acetic acid. Then 800 mg (3.43 mmol) of 2-methyl-1- (4-pyrrolidin-1-ylmethyl-phenyl) -propan-2-ol in 2 ml of glacial acetic acid are added dropwise. Keep temperature below 20 ° C. The reaction solution is stirred for 1 hour at ambient temperature, then poured onto ice and neutralized with sodium carbonate solution. The aqueous phase is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed using a rotary evaporator and the product is further reacted without purification.
Yield: 520 mg (58.2% of theory)
C ₁₆ H ₂₄ N ₂ O (M = 260.382)
calc .: Mole peak (M + H) ⁺ : 261 fnd .: Mole peak (M + H) ⁺ : 261.
2.38.d 1,1-Dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine 25 ml of concentrated hydrochloric acid in 10 ml of ethanol with N- [1,1-dimethyl-2- (4-pyrrolidine-1- A solution of 520 mg (2 mmol) of (ylmethyl-phenyl) -ethyl] -formamide is added and the mixture is refluxed overnight. After cooling, the reaction solution is made alkaline with 25% aqueous sodium hydroxide solution and the aqueous phase is extracted several times with tert-butyl methyl ether. The combined organic phases are washed with water, dried over magnesium sulphate and filtered through activated charcoal. Remove the solvent using a rotary evaporator.
Yield: 380 mg (81.8% of theory)
C ₁₅ H ₂₄ N ₂ (M = 232.372)
calc .: Mole peak (M + H) ⁺ : 233 fnd .: Mole peak (M + H) ⁺ : 233
R _f value: 0.10 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
2.38.e 4'-Chloro-biphenyl-4-carboxylic acid- [1,1-dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'-Chloro- according to General Procedure I Prepared from biphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and 1,1-dimethyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (116 mg, 0.5 mmol).
Yield: 73.0 mg (32.7% of theory)
C ₂₈ H ₃₁ ClN ₂ O ₂ (M = 447.025)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
R _f value: 0.48 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.39:
4'-chloro-biphenyl-4-carboxylic acid-4- (2-pyrrolidin-1-yl-ethyl) -benzylamide

2.39.a 4- (2-Pyrrolidin-1-yl-ethyl) -benzonitrile Potassium iodide 91 mg (0.56 mmol), potassium carbonate 453 mg (3.28 mmol) and 1,4-dibromobutane 0.33 ml (2.74 mmol) in acetonitrile It is added successively to a solution of 500 mg (2.74 mmol) of 4- (2-amino-ethyl) -benzonitrile in 50 ml. The reaction is stirred at 78 ° C. for 6 hours. An additional 0.08 ml (0.66 mmol) of 1,4-dibromobutane is added and the reaction is stirred at 78 ° C. overnight. After filtration, the filtrate is evaporated to dryness. Further purification is carried out by column chromatography on silica gel (dichloromethane / methanol 8: 2).
Yield: 183.0 mg (33.4% of theory)
C ₁₃ H ₁₆ N ₂ (M = 200.286)
calc .: Mole peak (M + H) ⁺ : 201 fnd .: Mole peak (M + H) ⁺ : 201.
2.39.b 4- (2-Pyrrolidin-1-yl-ethyl) -benzylamine Raney nickel 75 mg 4- (2-pyrrolidin-1-yl-ethyl) -benzonitrile 183 mg (0.91 mmol) in 20 ml ethanolic ammonia solution Add to the solution. The reaction solution is stirred at 50 ° C. with 3 bar hydrogen overnight. An additional 75 mg of Raney nickel is added and the mixture is stirred at 50 ° C. with 3 bar of hydrogen for a further 6 hours.
The catalyst is filtered off and the solvent is removed using a rotary evaporator. The crude product may be used without further purification.
Yield: 114.0 mg (61.0% of theory)
C ₁₃ H ₂₀ N ₂ (M = 204.318)
calc .: Mole peak (M + H) ⁺ : 205 fnd .: Mole peak (M + H) ⁺ : 205.
2.39.c 4'-Chloro-biphenyl-4-carboxylic acid-4- (2-pyrrolidin-1-yl-ethyl) -benzylamide 4'-Chloro-biphenyl-4-carboxylic acid (130 mg according to General Procedure I) , 0.56 mmol) and 4- (2-pyrrolidin-1-yl-ethyl) -benzylamine (114 mg, 0.56 mmol).
Yield: 75.0 mg (32.1% of theory)
C ₂₆ H ₂₇ ClN ₂ O (M = 418.971)
calc .: Mole peak (M + H) ⁺ : 419/421 fnd .: Mole peak (M + H) ⁺ : 419/421
R _f value: 0.38 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.40:

2.40.a [1,4 ′] bipiperidinyl-1′-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-piperidinopiperidine (84.1 mg) according to general procedure II , 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Yield: 3.0 mg (1.5% of theory)
C ₂₄ H ₃₈ N ₄ O (M = 398.597)
calc .: Mole peak (0.5M + H) ⁺ : 200 fnd .: Mole peak (0.5M + H) ⁺ : 200
Retention time HPLC: 1.59 minutes (Method A)
Example 2.41:

2.41.a 4-Cyclohexyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide According to general procedure I 4-cyclohexylbenzoic acid (102 mg, 0.50 mmol) and 4- (2 Prepared from -pyrrolidin-1-yl-ethyl) -benzylamine (102 mg, 0.50 mmol).
Yield: 2.0 mg (1.0% of theory)
C ₂₆ H ₃₄ N ₂ O (M = 390.574)
calc .: Mole peak (M + H) ⁺ : 391 fnd .: Mole peak (M + H) ⁺ : 391
R _f value: 0.38 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.42:
4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethyl] -amide

2.42.a 2- (4-Pyrrolidin-1-ylmethyl-cyclohexyl) -ethylamine 1.52 ml concentrated hydrochloric acid and 300 mg platinum oxide in 2-ml (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (Example 1.1) in 10 ml methanol Add to a 500 mg (2.45 mmol) solution. The reaction mixture is stirred at 50 ° C. with 5 bar hydrogen for 50 hours. After separation of the catalyst, the solvent is removed using a rotary evaporator. Further purification is carried out by column chromatography on silica gel (dichloromethane / methanol / ammonia 8: 2: 0.2).
Yield: 130 mg (25.3% of theory)
C ₁₃ H ₂₆ N ₂ (M = 210.366)
calc .: Mole peak (M + H) ⁺ : 211 fnd .: Mole peak (M + H) ⁺ : 211
R _f value: 0.14 (silica gel, dichloromethane / methanol / NH ₃ 8: 2: 0.2).
2.42.b 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethyl] -amide 4'-Chloro-biphenyl-4-carboxylic acid according to General Procedure I (116 mg, 0.50 mmol) and 2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethylamine (105 mg, 0.50 mmol).
Yield: 53.0 mg (24.9% of theory)
C ₂₆ H ₃₃ ClN ₂ O (M = 425.019)
calc .: Mole peak (M + H) ⁺ : 425/427 fnd .: Mole peak (M + H) ⁺ : 425/427
R _f value: 0.16 (silica gel, ethyl acetate / methanol / NH ₃ 9: 1: 0.1).
Example 2.43: 4′-chloro-biphenyl-4-carboxylic acid- [2- (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.43.a 4-Cyanomethyl-2-methoxy-benzoic acid Prepared from methyl 4-cyanomethyl-2-methoxy-benzoate as in Example 1.1.d.
Yield: 6.5 g (69.8% of theory)
C ₁₀ H ₉ NO ₃ (M = 191.18)
calc .: Mole peak (M + H) ⁺ : 192 fnd .: Mole peak (M + H) ⁺ : 192
R _f value: 0.64 (silica gel, dichloromethane / ethanol 10: 1).
2.43.b (4-Hydroxymethyl-3-methoxy-phenyl) -acetonitrile Prepared from 4-cyanomethyl-2-methoxy-benzoic acid as in Example 1.1.e.
Yield: 4.81 g (81% of theory)
C ₁₀ H ₁₁ NO ₂ (M = 177.20)
calc .: Mole peak (M) ⁺ : 177 fnd .: Mole peak (M) ⁺ : 177.
2.43.c (4-Bromomethyl-3-methoxy-phenyl) -acetonitrile Prepared from (4-hydroxymethyl-3-methoxy-phenyl) -acetonitrile as in Example 1.1.f.
Yield: 4.2 g (64.6% of theory)
C ₁₀ H ₁₀ BrNO (M = 240.10)
calc .: Mole peak (M) ⁺ : 239/241 fnd .: Mole peak (M) ⁺ : 239/241
R _f value: 0.84 (silica gel, dichloromethane / ethanol 50: 1).

2.43.d (3-Methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile Prepared as in Example 1.1.g from (4-bromomethyl-3-methoxy-phenyl) -acetonitrile and piperidine.
Yield: 0.95 g (24.2% of theory)
C ₁₄ H ₁₈ N ₂ O (M = 230.31)
calc .: Mole peak (M + H) ⁺ : 231 fnd .: Mole peak (M + H) ⁺ : 231.
2.43.e (3-Methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine Prepared from (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile as in Example 1.1.h. The crude product is further reacted immediately without purification.
2.43.f 4′-Chloro-biphenyl-4-carboxylic acid- [2- (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (3-methoxy- Prepared from 4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 4'-chloro-biphenyl-4-carboxylic acid.
Yield: 0.5 g (86.2% of theory)
Melting point: 162-163 ℃
C ₂₇ H ₂₉ ClN ₂ O ₂ (M = 448.99)
calc .: Mole peak (M + H) ⁺ : 449/451 fnd .: Mole peak (M + H) ⁺ : 449/451
R _f value: 0.85 (silica gel, dichloromethane / ethanol / ammonia 5: 1: 0.1).
Example 2.44:
4'-chloro-biphenyl-4-carboxylic acid- [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.44.a (E) -3- (4-Cyano-2-fluoro-phenyl) -acrylic acid 2.75 g (10 mmol) of palladium acetate and 7.0 g (25 mmol) of tri-o-tolylphosphate in 4-mL DMF Add to a solution of 20.0 g (100 mmol) of bromo-3-fluoro-benzonitrile. Then 50 ml of triethylamine and 30 ml (30 mmol) of ethyl acrylate are added. The reaction mixture is stirred at 100 ° C. for 3 hours, after cooling, diluted with 400 ml of dichloromethane and washed twice with water. The solvent is removed using a rotary evaporator and the residue is taken up in 250 ml of methanol with heating. Insoluble components are removed by suction filtration through diatomaceous earth and the filtrate is half evaporated in a rotary evaporator. After filtration again, it is combined with 150 ml THF, 100 ml MeOH and 43 ml 2N NaOH and stirred at ambient temperature for 2 hours. The solvent is removed using a rotary evaporator and the residue is combined with 100 ml of water. After extraction with ether, the aqueous phase is acidified with concentrated hydrochloric acid. The precipitated crystals are dissolved in 300 ml of warm ethyl acetate and the aqueous phase is separated. The ethyl acetate is distilled off and the crystals obtained are suspended in ether and filtered with suction.
Yield: 11.5g (60.2% of theory)
Melting point: 214-218 ° C
2.44.b 3- (4-Cyano-2-fluoro-phenyl) -propionic acid 11.5 g (60 mmol) of (E) -3- (4-cyano-2-fluoro-phenyl) -acrylic acid in 200 ml of water The solution is combined with 4.0 g of 5% Pd / C and 24.4 g of potassium carbonate. The mixture is shaken in an autoclave for 6 hours at ambient temperature and normal hydrogen pressure. After suction filtration of the catalyst, the mother liquor is acidified with concentrated hydrochloric acid. The precipitated crystals are dissolved in 250 ml of warm ethyl acetate, dried and the ethyl acetate is distilled off. The crystals obtained are stirred with ether / hexane and filtered off with suction.
Yield: 900 mg (98.0% of theory)
Melting point: 102-106 ℃

2.44.c tert.butyl [2- (4-cyano-2-fluoro-phenyl) -ethyl] -carbamate 1.25 ml of triethylamine and 0.61 ml (2.8 mmol) of diphenylphosphoryl azide in 3 ml of 3- (4- Add to a solution of 500 mg (2.6 mmol) of cyano-2-fluoro-phenyl) -propionic acid. The reaction mixture is refluxed overnight and then the solvent is removed using a rotary evaporator. Purification is carried out by column chromatography on silica gel (dichloromethane / methanol 9: 1).
Yield: 138 mg (20.2% of theory)
C ₁₄ H ₁₇ FN ₂ O ₂ (M = 264.302)
calc .: Mole peak (M + H) ⁺ : 265 fnd .: Mole peak (M + H) ⁺ : 265
2.44.d tert.butyl [2- (4-aminomethyl-2-fluoro-phenyl) -ethyl] -carbamate tert.butyl [2- (4-cyano-2-fluoro-phenyl) in 15 ml of ethanolic ammonia solution A solution of 138 mg (0.52 mmol) of -ethyl] -carbamate is combined with 75 mg of Raney nickel and the mixture is shaken overnight in an autoclave with 3 bar of hydrogen at 50 ° C. After the catalyst is filtered off with suction, the solvent is removed using a rotary evaporator.
Yield: 137 mg (97.8% of theory)
C ₁₄ H ₂₁ FN ₂ O ₂ (M = 268.334)
calc .: Mole peak (M + H) ⁺ : 269 fnd .: Mole peak (M + H) ⁺ : 269.

2.44.e tert.butyl [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -carbamate tert.butyl [2- (4-aminomethyl-2-fluoro-phenyl) in 15 ml of acetonitrile To a solution of 300 mg (1.12 mmol) of) -ethyl] -carbamate, 42 mg (0.25 mmol) of potassium iodide, 180 mg (1.30 mmol) of potassium carbonate and 0.13 ml (1.11 mmol) of 1,4-dibromobutane are added successively. . The reaction is stirred at 78 ° C. for 6 hours. An additional 0.08 ml (0.66 mmol) of 1,4-dibromobutane is added and the reaction is stirred at 78 ° C. overnight. The solvent is removed using a rotary evaporator and the product is further reacted without purification.
Yield: 320 mg (88.8% of theory)
C ₁₈ H ₂₇ FN ₂ O ₂ (M = 322.426)
calc .: Mole peak (M + H) ⁺ : 323 fnd .: Mole peak (M + H) ⁺ : 323.
2.44.f 2- (2-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine tert.butyl [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] in 5 ml of dichloromethane -To a solution of 232 mg (0.72 mmol) of carbamate, 1.5 ml of trifluoroacetic acid is added. The reaction mixture is stirred at ambient temperature for 2 hours. The solvent is removed using a rotary evaporator and the crude product is further reacted without purification.
Yield: 160 mg (100% of theory)
C ₁₃ H ₁₉ FN ₂ (M = 222.308)
calc .: Mole peak (M + H) ⁺ : 223 fnd .: Mole peak (M + H) ⁺ : 223.
2.44.g 4′-Chloro-biphenyl-4-carboxylic acid- [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (2-Fluoro- Prepared from 4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (160 mg, 0.72 mmol) and 4′-chloro-biphenyl-4-carboxylic acid (168 mg, 0.72 mmol).
Yield: 49 mg (15.6% of theory)
C ₂₆ H ₂₆ ClFN ₂ O (M = 436.961)
calc .: Mole peak (M + H) ⁺ : 437/439 fnd .: Mole peak (M + H) ⁺ : 437/439
Retention time HPLC: 6.6 minutes (Method A)
Example 2.45:
4-Pyridin-4-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.45a. Methyl 4-pyridin-4-yl-benzoate
Dissolve 3.0 g (15 mmol) 4-bromo-pyridine in 50 ml dioxane and 15 ml 2M sodium carbonate solution. 2.7 g (15 mmol) 4-methoxycarbonylphenyl-boric acid and 1.73 g (2 mmol) tetrakis- (triphenylphosphine) -palladium are added in succession and the reaction is refluxed for 6 hours. The hot reaction solution is suction filtered through a glass fiber filter. The solvent is removed using a rotary evaporator and purification is carried out by column chromatography on silica gel (dichloromethane / methanol 9: 1).
Yield: 845 mg (26.4% of theory)
C ₁₃ H ₁₁ NO ₂ (M = 213.238)
calc .: Mole peak (M + H) ⁺ : 214 fnd .: Mole peak (M + H) ⁺ : 214
Retention time HPLC: 4.1 minutes (Method A)
2.45b. 4-Pyridin-4-yl-benzoic acid
0.37 ml (0.74 mmol) of 2N NaOH is added to a solution of 150 mg (0.70 mmol) of methyl 4-pyridin-4-yl-benzoate in 10 ml of ethanol. The reaction solution is stirred at 60 ° C. for 2 hours, then the pH is adjusted to 6-7 with 1N HCl. After filtration, the resulting precipitate is dried overnight under high vacuum.
Yield: 84 mg (60.0% of theory)
C ₁₂ H ₉ NO ₂ (M = 199.211)
calc .: Mole peak (M + H) ⁺ : 200 fnd .: Mole peak (M + H) ⁺ : 200
Retention time HPLC: 2.5 minutes (Method A)
2.45c. 4-Pyridin-4-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-Pyrrolidin-1-ylmethyl-phenyl) according to General Procedure I Prepared from -ethylamine (86 mg, 0.42 mmol) and 4-pyridin-4-yl-benzoic acid (84 mg, 0.42 mmol).
Yield: 65 mg (40.0% of theory)
C ₂₅ H ₂₇ N ₃ O (M = 385.513)
calc .: Mole peak (M + H) ⁺ : 386 fnd .: Mole peak (M + H) ⁺ : 386
Retention time HPLC: 4.7 minutes (stable bond C18; 3.5 μm; water: acetonitrile: formic acid 91: 9: 0.01).
Example 2.46:
5- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one

2.46.a Ethyl 4-bromo-2-methyl-benzoate A solution of 5.0 g (23.3 mmol) 4-bromo-2-methyl-benzoic acid in 50 ml ethanolic hydrochloric acid is stirred at 45 ° C. for 8 hours. The reaction solution is cooled to ambient temperature overnight and then the solvent is removed using a rotary evaporator. The residue is taken up in ether, filtered and freed from the solvent using a rotary evaporator. The residue is reacted further without purification.
R _f value: 0.88 (silica gel, dichloromethane / ethanol 95: 5)
2.46.b Ethyl 4′-chloro-3-methyl-biphenyl-4-carboxylate 1.66 g (6.83 mmol) of ethyl 4-bromo-2-methyl-benzoate are dissolved in 70 ml of dioxane and 7 ml of 2M sodium carbonate solution. 1.07 g (6.83 mmol) 4-chloro-phenyl-boric acid and 0.40 g (0.34 mmol) tetrakis- (triphenylphosphine) -palladium are added in succession and the reaction is refluxed for 6 hours, further at ambient temperature. Stir for 60 hours. The hot reaction solution is suction filtered through a glass fiber filter. Remove the solvent using a rotary evaporator. The residue is combined with water and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is removed using a rotary evaporator. Purification is carried out by column chromatography on silica gel (petroleum ether / ethyl acetate 8: 2).
Yield: 1.3 g (69.3% of theory)
C ₁₆ H ₁₅ ClO ₂ (M = 274.750)
calc .: Mole peak (M + H) ⁺ : 275/277 fnd .: Mole peak (M + H) ⁺ : 275/277
R _f value: 0.67 (silica gel, petroleum ether / ethyl acetate 8: 2).

2.46.c Ethyl 3-bromomethyl-4'-chloro-biphenyl-4-carboxylate
78 mg (0.47 mmol) of 2,2′-azobis (isobutyronitrile) are added to 1.3 g (4.73 mmol) of ethyl 4′-chloro-3-methyl-biphenyl-4-carboxylate and N-bromo in 10 ml of carbon tetrachloride. Add to a solution of 0.84 g (4.73 mmol) succinimide. The reaction mixture is refluxed overnight. After filtration, the solvent is evaporated in a rotary evaporator. Purification is carried out by column chromatography on silica gel (petroleum ether / ethyl acetate 8: 2).
Yield: 1.6 g (62.1% of theory)
C ₁₆ H ₁₄ BrClO ₂ (M = 353.646)
calc .: Mole peak (M + H) ⁺ : 353/355/357 fnd .: Mole peak (M + H) ⁺ : 353/355/357
R _f value: 0.57 (silica gel, petroleum ether / ethyl acetate 8: 2).
2.46.d 5- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one
375 mg (1.47 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 800 mg (1.47 mmol) of ethyl 3-bromomethyl-4′-chloro-biphenyl-4-carboxylate and potassium carbonate in 7.5 ml of acetonitrile Slowly add dropwise to 508 mg (3.68 mmol) suspension at ambient temperature. The reaction mixture is refluxed for 5 hours. After removing the solvent using a rotary evaporator, the residue is taken up in water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. After removing the solvent using a rotary evaporator, the residue was dissolved in DMF and HPLC chromatography (stable bond C18; 3.5 μm; water: acetonitrile: formic acid 9: 1: 0.01 → 1: 9: over 9 minutes) 0.01).
Yield: 82 mg (12.9% of theory)
C ₂₇ H ₂₇ ClN ₂ O ₂ (M = 430.982)
calc .: Mole peak (M + H) ⁺ : 431/433 fnd .: Mole peak (M + H) ⁺ : 431/433
Retention time HPLC: 6.13 min (Method A)
Example 2.47:
4-Piperidin-1-ylmethyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.47.a 4-piperidin-1-ylmethyl-pyridine 242 ml (2.44 mmol) piperidine are added dropwise to a solution of 100 g (0.61 mol) 4-chloromethyl-pyridine in 600 ml dry methanol and the reaction mixture is added at 50 ° C. For 1 hour. Remove the solvent using a rotary evaporator. The residue is made alkaline with 40% sodium hydroxide solution and the aqueous phase is extracted with ether. The organic phase is dried over sodium sulfate, and after filtration through activated carbon, the solvent is removed using a rotary evaporator. The crude product is further reacted without purification.
Yield: 106g (98% of theory)
2.47.b 4-piperidin-1-ylmethyl-piperidine A solution of 106 g (0.6 mol) 4-piperidin-1-ylmethyl-pyridine in 1.0 liter glacial acetic acid was combined with 7 g platinum dioxide and 3 bar at ambient temperature in an autoclave. Shake with hydrogen. After the catalyst is filtered off with suction, the solvent is removed using a rotary evaporator. The crude product is further reacted without purification.
Yield: 48g (43.9% of theory)
2.47.c 4-Piperidin-1-ylmethyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4-piperidin-1-ylmethyl- according to general procedure II Prepared from piperidine (182 mg, 1.00 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1.00 mmol).
Yield: 160.0 mg (38.8% of theory)
C ₂₅ H ₄₀ N ₄ O (M = 412.624)
calc .: Mole peak (M + H) ⁺ : 413 fnd .: Mole peak (M + H) ⁺ : 413
Retention time HPLC: 1.75 min (Stable Bond C18; 3.5 μm; water: acetonitrile: formic acid 9: 1: 0.01 → 4: 6: 0.01 over 8 min).






Example 2.48:

2.48.a 4- (1H-Benzimidazol-2-yl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2-piperidine according to General Procedure II Prepared from 4-yl-1H-benzimidazole (164 mg, 1.00 mmol) and 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1.00 mmol).
Yield: 80.0 mg (18.5% of theory)
C ₂₆ H ₃₃ N ₅ O (M = 431.586)
calc .: Mole peak (M + H) ⁺ : 432 fnd .: Mole peak (M + H) ⁺ : 432
Retention time HPLC: 2.80 min (Stable Bond C18; 3.5 μm; water: acetonitrile: formic acid 9: 1: 0.01 → 4: 6: 0.01 over 8 min).
Example 2.49:
4- (1-Methyl-piperidin-4-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.49.a Methyl 4-piperidin-4-yl-benzoate
4.0 ml of 1M hydrochloric acid and 200 mg of platinum oxide are added to a solution of 695 mg (3.26 mmol) of methyl 4-pyridin-4-yl-benzoate (see Example 2.45.a) in 10 ml of ethanol. The reaction mixture is stirred at ambient temperature with 3 bar hydrogen for 2 hours. After adding an additional 300 mg of platinum oxide and 6.0 ml of 1M hydrochloric acid, the mixture is stirred at ambient temperature with 3 bar of hydrogen for a further 16 hours. After separation of the catalyst, the solvent is removed using a rotary evaporator. The crude product is further reacted without purification.
Yield: 589 mg (82.4% of theory)
C ₁₃ H ₁₇ NO ₂ (M = 219.286)
calc .: Mole peak (M + H) ⁺ : 220 fnd .: Mole peak (M + H) ⁺ : 220
Retention time HPLC: 3.5 minutes (Method A)
2.49.b Methyl 4- (1-methyl-piperidin-4-yl) -benzoate 48 mg (2.00 mmol) of sodium hydride in nitrogen atmosphere at 0 ° C. with 429 mg of methyl 4-piperidin-4-yl-benzoate in 10 ml of DMF 1.96 mmol) solution is added batchwise. The reaction mixture is stirred at ambient temperature for 1 hour. 0.13 ml (2.10 mmol) methyl iodide is added dropwise and the solution is stirred for 2 hours at ambient temperature. The reaction solution is combined with water, the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over magnesium sulfate and the solvent is removed using a rotary evaporator. Purification is carried out by column chromatography (silica gel; dichloromethane / methanol 8: 2).
Yield: 70 mg (15.3% of theory)
C ₁₄ H ₁₉ NO ₂ (M = 233.313)
calc .: Mole peak (M + H) ⁺ : 234 fnd .: Mole peak (M + H) ⁺ : 234
Retention time HPLC: 2.7 minutes (Method A)

2.49.c 4- (1-Methyl-piperidin-4-yl) -benzoic acid
0.37 ml (0.74 mmol) of 2N NaOH is added to a solution of 70 mg (0.30 mmol) of methyl 4- (1-methyl-piperidin-4-yl) -benzoate in 10 ml of ethanol. The reaction solution is stirred at 60 ° C. for 2 hours and then adjusted to pH 6-7 using 1N HCl. After filtration, the resulting precipitate is dried overnight under high vacuum.
Yield: 50 mg (76.0% of theory)
C ₁₃ H ₁₇ NO ₂ (M = 219.286)
calc .: Mole peak (M + H) ⁺ : 220 fnd .: Mole peak (M + H) ⁺ : 220
Retention time HPLC: 1.5 minutes (Method A)
2.49.d 4- (1-Methyl-piperidin-4-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-pyrrolidin- Prepared from 1-ylmethyl-phenyl) -ethylamine (47 mg, 0.23 mmol) and 4- (1-methyl-piperidin-4-yl) -benzoic acid (50 mg, 0.23 mmol).
Yield: 22 mg (23.8% of theory)
C ₂₆ H ₃₅ N ₃ O (M = 405.588)
calc .: Mole peak (M + H) ⁺ : 406 fnd .: Mole peak (M + H) ⁺ : 406
Retention time HPLC: 2.4 minutes (Method A)
Example 2.50:

1.21.a 4'-chloro-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide Example 1.1.i and Similarly prepared from 2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethylamine and 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 0.94 g (96% of theory)
Melting point: 211-213 ℃
C ₂₅ H ₂₇ ClN ₄ O (M = 434.97)
calc .: Mole peak (M + H) ⁺ : 435/437 fnd .: Mole peak (M + H) ⁺ : 435/437.
Example 2.51: 4′-chloro-biphenyl-4-carboxylic acid- {2- [4- (4-methyl-piperazine-1-carbonyl) -phenyl] -ethyl} -amide

2.51.a [4- (4-Methyl-piperazine-1-carbonyl) -phenyl] -acetonitrile
Stir a solution of 2 g (12.41 mmol) 4-cyanomethyl-benzoic acid, 1.25 g (12.5 mmol) N-methylpiperazine, 4.01 g (12.5 mmol) TBTU and 3.48 ml (25 mmol) triethylamine in 40 ml DMF at ambient temperature for 12 hours. To do. The reaction mixture is then evaporated to some extent and combined with water. The mixture is extracted with ethyl acetate and the solvent is distilled off using a rotary evaporator. Also, the aqueous phase is evaporated and the organic phase is combined with the residue. Purification is carried out by column chromatography over silica gel (eluent: dichloromethane / ethanol / ammonia 30: 1: 0.1).
Yield: 2.6 g (86% of theory)
C ₁₄ H ₁₇ N ₃ O (M = 243.31)
calc .: Mole peak (M + H) ⁺ : 244 fnd .: Mole peak (M + H) ⁺ : 244
R _f value: 0.35 (silica gel, dichloromethane / ethanol / ammonia 20: 1: 0.1).
2.51.b [4- (2-Amino-ethyl) -phenyl]-(4-methyl-piperazin-1-yl) -methanone In the same manner as in Example 1.1.i, [4- (4-methyl-piperazine-1 Prepared from -carbonyl) -phenyl] -acetonitrile.
Yield: 2.9 g (90% of theory)
C ₁₄ H ₂₁ N ₃ O x HCl (M = 283.80)
R _f value: 0.25 (silica gel, dichloromethane / ethanol / ammonia 10: 1: 0.1).
2.51.c 4′-chloro-biphenyl-4-carboxylic acid- {2- [4- (4-methyl-piperazine-1-carbonyl) -phenyl] -ethyl} -amide [4- (2 Prepared from -amino-ethyl) -phenyl]-(4-methyl-piperazin-1-yl) -methanone and 4'-chloro-biphenyl-4-carboxylic acid.
Yield: 0.18 g (48.4% of theory)
Melting point: 217-218 ℃
C ₂₇ H ₂₈ ClN ₃ O ₂ (M = 461.99)
calc .: Mole peak (M + H) ⁺ : 462/464 fnd .: Mole peak (M + H) ⁺ : 462/464
R _f value: 0.25 (silica gel, dichloromethane / methanol / ammonia 10: 1: 0.1).
Example 2.52:
4'-Bromo-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.52a. Methyl 4′-bromo-biphenyl-4-carboxylate 0.54 g (2.5 mmol) of methyl 4-bromo-benzoate is dissolved in 10 ml of dioxane and 2.5 ml of 2M sodium carbonate solution. 0.6 g (3 mmol) 4-bromophenyl-boric acid and 0.12 g (0.1 mmol) tetrakis- (triphenylphosphine) -palladium are added in succession and the reaction is refluxed for 5 hours. The reaction mixture is combined with water and EtOAc, filtered and the phases are separated. The aqueous phase is extracted with EtOAc and the combined organic phases are dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is triturated with acetonitrile, suction filtered and dried in air.
Yield: 100 mg (13.7% of theory)
C ₁₄ H ₁₁ BrO ₂ (M = 291.15)
calc .: Mole peak (M + H) ⁺ : 291/293 fnd .: Mole peak (M + H) ⁺ : 291/293
R _f value: 0.68 (silica gel, petroleum ether / EtOAc 8: 2).
2.52b. 4'-Bromo-biphenyl-4-carboxylic acid
A solution of 100 mg (0.34 mmol) of methyl 4′-bromo-biphenyl-4-carboxylate in 3 ml of THF is combined with 3 ml of 1M NaOH solution in water and refluxed for 3 hours. The reaction mixture is evaporated in vacuo, the aqueous residue is acidified with 1M HCl, the precipitated product is filtered off and dried in air.
Yield: 60 mg (63.1% of theory)
C ₁₃ H ₉ BrO ₂ (M = 277.19)
calc .: Mole peak (MH) ^- : 275/277 fnd .: Mole peak (MH) ^- : 275/277
Retention time HPLC: 8.48 min (Method A)
2.52.c 4'-Bromo-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (4-Pyrrolidin-1-ylmethyl-phenyl) ) -Ethylamine 45 mg (0.22 mmol) and 4'-bromo-biphenyl-4-carboxylic acid 60 mg (0.22 mmol).
Yield: 28 mg (27.5% of theory)
C ₂₆ H ₂₇ BrN ₂ O (M = 463.42)
calc .: Mole peak (M + H) ⁺ : 463/465 fnd .: Mole peak (M + H) ⁺ : 463/465
Retention time HPLC: 6.46 min (Method A)
Example 2.53:
4'-Ethyl-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

Prepared from 102 mg (0.5 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 113 mg (0.5 mmol) of 4′-ethyl-biphenyl-4-carboxylic acid (Lancaster) according to General Procedure I.
Yield: 65 mg (31.5% of theory)
C ₂₈ H ₃₂ N ₂ O (M = 412.58)
calc .: Mole peak (M + H) ⁺ : 463 fnd .: Mole peak (M + H) ⁺ : 463
Retention time HPLC: 6.64 min (Method A)
Example 2.54:
Biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

Prepared from 102 mg (0.5 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 99 mg (0.5 mmol) of biphenyl-4-carboxylic acid according to General Procedure I.
Yield: 46 mg (23.9% of theory)
C ₂₆ H ₂₈ N ₂ O (M = 384.53)
calc .: Mole peak (M + H) ⁺ : 385 fnd .: Mole peak (M + H) ⁺ : 385
Retention time HPLC: 5.70 minutes (Method A)
Example 2.55:
4'-Fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.55a. 4'-Fluoro-biphenyl-4-carboxylic acid
14.27 g (71 mmol) of 4-bromo-benzoic acid is dissolved in 120 ml of dioxane and 70 ml of 2M Na ₂ CO ₃ solution. 10 g (71 mmol) 4-fluorophenyl-boric acid and 4.1 g (4 mmol) tetrakis- (triphenylphosphine) -palladium are added in succession and the reaction is refluxed for 6 hours. The catalyst is filtered off with suction and washed with hot water. The reaction mixture is combined with EtOAc, the phases are separated and the aqueous phase is acidified with citric acid. The precipitate formed is filtered off with suction, washed with water and dried at 45 ° C. in vacuo.
Yield: 4.9 g (31.9% of theory)
C ₁₃ H ₉ FO ₂ (M = 216.21)
calc .: molar peak (MH) ^- : 215 fnd .: molar peak (MH) ^- : 215
2.55b. 4′-Fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (4-pyrrolidin-1-ylmethyl-phenyl) ) -Ethylamine prepared from 102 mg (0.5 mmol) and 4′-fluoro-biphenyl-4-carboxylic acid 108 mg (0.5 mmol).
Yield: 12 mg (6.0% of theory)
C ₂₆ H ₂₇ FN ₂ O (M = 402.52)
calc .: Mole peak (M + H) ⁺ : 403 fnd .: Mole peak (M + H) ⁺ : 403
Retention time HPLC: 5.83 min (Method A)
Example 2.56:
4'-hydroxy-3'-nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

Prepared from 102 mg (0.5 mmol) of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 130 mg (0.5 mmol) of 4′-fluoro-3′-nitrobiphenyl-4-carboxylic acid according to General Procedure I.
Yield: 9 mg (4.0% of theory)
C ₂₆ H ₂₇ N ₃ O ₄ (M = 445.52)
calc .: Mole peak (M + H) ⁺ : 446 fnd .: Mole peak (M + H) ⁺ : 446
Retention time HPLC: 5.83 min (Method A)
Example 2.57:
3'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.57a. 3'-Chloro-biphenyl-4-carboxylic acid Prepared analogously to Example 2.55a from 9.64 g (47.96 mmol) 4-bromo-benzoic acid and 7.5 g (47.96 mmol) 3-chlorophenyl-boric acid .
Yield: 6.2 g (55.6% of theory)
C ₁₃ H ₉ ClO ₂ (M = 232.67)
calc .: Mole peak (MH) ^- : 231/233 fnd .: Mole peak (MH) ^- : 231/233
2.57b. 3′-Chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2- (4-pyrrolidin-1-ylmethyl-phenyl) according to General Procedure I ) -Ethylamine prepared from 102 mg (0.5 mmol) and 3′-chloro-biphenyl-4-carboxylic acid 116 mg (0.5 mmol).
Yield: 63 mg (30.1% of theory)
C ₂₆ H ₂₇ ClN ₂ O (M = 418.97)
calc .: Mole peak (M + H) ⁺ : 419/421 fnd .: Mole peak (M + H) ⁺ : 419/421
Retention time HPLC: 6.20 minutes (Method A)
Example 2.58:
3 ', 4'-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.58a. 3 ′, 4′-Dichloro-biphenyl-4-carboxylic acid 5.27 g (26.20 mmol) 4-bromo-benzoic acid and 5.0 g 3 ′, 4′-dichloro-phenylboric acid as in Example 2.55a (26.20 mmol).
Yield: 4.05 g (57.9% of theory)
C ₁₃ H ₈ Cl ₂ O ₂ (M = 267.11)
calc .: Mole peak (MH) ^- : 265/267/269 fnd .: Mole peak (MH) ^- : 265/267/269
2.58b. 3 ′, 4′-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (4-pyrrolidine-1- Prepared from 102 mg (0.5 mmol) of ylmethyl-phenyl) -ethylamine and 134 mg (0.5 mmol) of 3 ′, 4′-dichloro-biphenyl-4-carboxylic acid.
Yield: 45 mg (19.8% of theory)
C ₂₆ H ₂₆ Cl ₂ N ₂ O (M = 453.42)
calc .: Mole peak (M + H) ⁺ : 453/455/457 fnd .: Mole peak (M + H) ⁺ : 453/455/457
Retention time HPLC: 6.45 min (Method A)
Example 2.59:
2 ', 4'-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.59a. 2 ', 4'-Dichloro-biphenyl-4-carboxylic acid 5.23 g (26.0 mmol) 4-bromo-benzoic acid and 10.0 g 2,4-dichlorophenyl-boric acid (52.0 The reaction mixture was prepared by refluxing for 48 hours.
Yield: 1.5 g (21.6% of theory)
C ₁₃ H ₈ Cl ₂ O ₂ (M = 267.11)
calc .: Mole peak (MH) ^- : 265/267/269 fnd .: Mole peak (MH) ^- : 265/267/269
2.59b. 2 ', 4'-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2- (4-pyrrolidin-1- Prepared from 102 mg (0.5 mmol) of ylmethyl-phenyl) -ethylamine and 134 mg (0.5 mmol) of 2 ′, 4′-dichloro-biphenyl-4-carboxylic acid.
Yield: 72 mg (31.8% of theory)
C ₂₆ H ₂₆ Cl ₂ N ₂ O (M = 453.42)
calc .: Mole peak (M + H) ⁺ : 453/455/457 fnd .: Mole peak (M + H) ⁺ : 453/455/457
Retention time HPLC: 6.84 min (Method A)
Example 2.60:
2'-Fluoro-4'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.60a. 2'-Fluoro-4'-chloro-biphenyl-4-carboxylic acid 0.52 g (2.5 mmol) of 1-bromo-4-chloro-2-fluorobenzene and 4-carboxyphenyl as in Example 2.55a -Prepared from 0.5 g (3.0 mmol) of boric acid.
Yield: 0.5 g (79.8% of theory)
C ₁₃ H ₈ ClFO ₂ (M = 250.66)
calc .: Mole peak (MH) ^- : 249/251 fnd .: Mole peak (MH) ^- : 249/251
Retention time HPLC: 8.39 min (Method A)
2.60b. 2′-Fluoro-4′-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (4-pyrrolidine- Prepared from 102 mg (0.5 mmol) of 1-ylmethyl-phenyl) -ethylamine and 125 mg (0.5 mmol) of 2′-fluoro-4′-chloro-biphenyl-4-carboxylic acid.
Yield: 36 mg (16.5% of theory)
C ₂₆ H ₂₆ ClFN ₂ O (M = 436.96)
calc .: Mole peak (M + H) ⁺ : 437/439 fnd .: Mole peak (M + H) ⁺ : 437/439
Retention time HPLC: 6.32 min (Method A)
Example 2.61:
3,4'-dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.61a. 3,4'-Dichloro-biphenyl-4-carboxylic acid 0.59 g (2.5 mmol) 4-bromo-2-chloro-benzoic acid and 0.47 g 4-chlorophenyl-boric acid (as in Example 2.55a) 3.0 mmol).
Yield: 0.55 g (82.4% of theory)
C ₁₃ H ₈ Cl ₂ O ₂ (M = 267.11)
calc .: Mole peak (MH) ^- : 265/267/269 fnd .: Mole peak (MH) ^- : 265/267/269
Retention time HPLC: 8.83 min (Method A)
2.61b. 3,4'-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure I 2- (4-pyrrolidin-1-ylmethyl) Prepared from 102 mg (0.5 mmol) of -phenyl) -ethylamine and 134 mg (0.5 mmol) of 3,4'-dichloro-biphenyl-4-carboxylic acid.
Yield: 24 mg (10.6% of theory)
C ₂₆ H ₂₆ Cl ₂ N ₂ O (M = 453.42)
calc .: Mole peak (M + H) ⁺ : 453/455/457 fnd .: Mole peak (M + H) ⁺ : 453/455/457
Retention time HPLC: 6.41 min (Method A)
Example 2.62:
4'-Chloro-3-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.62a. 4'-Chloro-3-fluoro-biphenyl-4-carboxylic acid 0.55 g (2.5 mmol) 4-bromo-2-fluoro-benzoic acid and 0.47 4-chlorophenyl-boric acid as in Example 2.55a Prepared from g (3.0 mmol).
Yield: 0.60 g (95.7% of theory)
C ₁₃ H ₈ ClFO ₂ (M = 250.66)
calc .: Mole peak (MH) ^- : 249/251 fnd .: Mole peak (MH) ^- : 249/251
Retention time HPLC: 8.22 minutes (Method A)
2.62b. 4′-Chloro-3-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (4-pyrrolidine-1 Prepared from 102 mg (0.5 mmol) of -ylmethyl-phenyl) -ethylamine and 125 mg (0.5 mmol) of 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid.
Yield: 37 mg (16.9% of theory)
C ₂₆ H ₂₆ ClFN ₂ O (M = 436.96)
calc .: Mole peak (M + H) ⁺ : 437/439 fnd .: Mole peak (M + H) ⁺ : 437/439
Retention time HPLC: 6.45 min (Method A)
Example 2.63:
4'-Chloro-2-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.63a. 4'-Chloro-2-fluoro-biphenyl-4-carboxylic acid 0.66 g (3.0 mmol) 4-bromo-3-fluoro-benzoic acid and 0.47 4-chlorophenyl-boric acid as in Example 2.55a Prepared from g (3.0 mmol).
Yield: 0.60 g (79.8% of theory)
C ₁₃ H ₈ ClFO ₂ (M = 250.66)
calc .: Mole peak (MH) ^- : 249/251 fnd .: Mole peak (MH) ^- : 249/251
Retention time HPLC: 8.50 min (Method A)
2.63b. 4′-Chloro-2-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure I 2- (4-pyrrolidine-1 Prepared from 163 mg (0.8 mmol) of -ylmethyl-phenyl) -ethylamine and 201 mg (0.8 mmol) of 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid.
Yield: 74 mg (21.2% of theory)
C ₂₆ H ₂₆ ClFN ₂ O (M = 436.96)
calc .: Mole peak (M + H) ⁺ : 437/439 fnd .: Mole peak (M + H) ⁺ : 437/439
Retention time HPLC: 6.61 min (Method A)
Example 2.64:
3-Nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.64a. 3-Nitro-biphenyl-4-carboxylic acid tetrakis- (triphenylphosphine) -palladium 150 mg (0.13 mmol) in 4-bromo-2-nitro-benzoic acid 1.0 g (4.07 mmol) in 20 ml toluene And stir at room temperature for 10 minutes. Then a solution of 0.5 g (4.10 mmol) of phenylboric acid in 10 ml of MeOH and a solution of 1.0 g of Na ₂ CO _{3 in} 10 ml of water are added. The reaction mixture is refluxed for 5 hours and stirred at room temperature over the end. The solvent is removed in vacuo, the residue is combined with water, acidified with concentrated HCl, extracted with EtOAc, the organic phase is dried over Na ₂ SO ₄ and then the solvent is removed.
Yield: 0.87 g (87.5% of theory)
R _f value: 0.40 (silica gel, dichloromethane / ethanol 3: 1).
2.64b. 3-Nitro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure I 2- (4-pyrrolidin-1-ylmethyl-phenyl) Prepared from 102 mg (0.5 mmol) of ethylamine and 122 mg (0.5 mmol) of 3-nitro-biphenyl-4-carboxylic acid.
Yield: 100 mg (46.6% of theory)
C ₂₆ H ₂₇ N ₃ O ₃ (M = 429.52)
calc .: Mole peak (M + H) ⁺ : 430 fnd .: Mole peak (M + H) ⁺ : 430
Retention time HPLC: 5.83 min (Method A)
Example 2.65:
5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.65a. 5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid 0.51 g (2.5 mmol) of 5-bromo-pyridine-2-carboxylic acid and 4-chlorophenyl-boric acid as in Example 2.55a Prepared from 0.47 g (3.0 mmol).
Yield: 0.23 g (39.4% of theory)
C ₁₂ H ₈ ClNO ₂ (M = 233.66)
calc .: Mole peak (MH) ^- : 232/234 fnd .: Mole peak (MH) ^- : 232/234
Retention time HPLC: 5.89 min (Method A)
2.65b. 5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to general procedure I 2- (4-Pyrrolidine- Prepared from 102 mg (0.5 mmol) of 1-ylmethyl-phenyl) -ethylamine and 116 mg (0.5 mmol) of 5- (4-chloro-phenyl) -pyridine-2-carboxylic acid. .
Yield: 7 mg (3.3% of theory)
C ₂₅ H ₂₆ ClN ₃ O (M = 419.96)
calc .: Mole peak (M + H) ⁺ : 420/422 fnd .: Mole peak (M + H) ⁺ : 420/422
Retention time HPLC: 6.40 minutes (Method A)
Example 2.66:
N- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4-thiophen-3-yl-benzamide

2.66a. Ethyl 4-thiophen-3-yl-benzoate Prepared as in Example 2.46b from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophen-3-borate.
Yield: 348 mg (100% of theory)
C ₁₃ H ₁₂ O ₂ S (M = 232.30)
calc .: Mole peak (M + H) ⁺ : 233 fnd .: Mole peak (M + H) ⁺ : 233
Retention time HPLC: 6.20 minutes (Method B)
2.66b. 4-Thiophen-3-yl-benzoic acid Prepared from 280 mg (1.5 mmol) of ethyl 4-thiophen-3-yl-benzoate as in Example 2.7b.
Yield: 146 mg (59.3% of theory)
C ₁₁ H ₈ O ₂ S (M = 204.25)
calc .: molar peak (MH) ^- : 203 fnd .: molar peak (MH) ^- : 203
Retention time HPLC: 7.60 minutes (Method A)
2.66c. N- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4-thiophen-3-yl-benzamide 2- (4-Pyrrolidin-1-ylmethyl-phenyl) according to General Procedure I Prepared from 102 mg (0.5 mmol) of ethylamine and 102 mg (0.5 mmol) of 4-thiophen-3-yl-benzoic acid.
Yield: 103 mg (53.0% of theory)
C ₂₄ H ₂₆ N ₂ OS (M = 390.55)
calc .: Mole peak (M + H) ⁺ : 391 fnd .: Mole peak (M + H) ⁺ : 391
Retention time HPLC: 6.10 minutes (Method A)
Example 2.67:
N- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4-thiophen-2-yl-benzamide

2.67a. Ethyl 4-thiophen-2-yl-benzoate Prepared as in Example 2.46b from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophen-2-boric acid.
Yield: 348 mg (100% of theory)
C ₁₃ H ₁₂ O ₂ S (M = 232.30)
calc .: Mole peak (M + H) ⁺ : 233 fnd .: Mole peak (M + H) ⁺ : 233
Retention time HPLC: 6.29 min (Method B)
2.67b. 4-Thiophen-2-yl-benzoic acid Prepared from 280 mg (1.5 mmol) of ethyl 4-thiophen-2-yl-benzoate as in Example 2.7b.
Yield: 126 mg (51.2% of theory)
C ₁₁ H ₈ O ₂ S (M = 204.25)
calc .: molar peak (MH) ^- : 203 fnd .: molar peak (MH) ^- : 203
Retention time HPLC: 7.60 minutes (Method A)
2.67c. N- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4-thiophen-2-yl-benzamide 2- (4-Pyrrolidin-1-ylmethyl-phenyl) according to General Procedure I -Prepared from 102 mg (0.5 mmol) of ethylamine and 102 mg (0.5 mmol) of 4-thiophen-2-yl-benzoic acid.
Yield: 112 mg (57.5% of theory)
C ₂₄ H ₂₆ N ₂ OS (M = 390.55)
calc .: Mole peak (M + H) ⁺ : 391 fnd .: Mole peak (M + H) ⁺ : 391
Retention time HPLC: 6.05 min (Method A)
Example 2.68:
4- (5-Chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.68a. 4- (5-Chloro-thiophen-2-yl) -benzoic acid 300 mg (1.52 mmol) 2-bromo-5-chlorothiophene and 277 mg 4-carboxyphenyl-boric acid (as in Example 2.55a) 1.67 mmol) was prepared by acidifying the treated reaction mixture using KHSO ₄ solution.
Yield: 76 mg (21.0% of theory)
C ₁₁ H ₇ ClO ₂ S (M = 238.69)
calc .: Mole peak (MH) ^- : 237/239 fnd .: Mole peak (MH) ^- : 237/239
Retention time HPLC: 8.75 minutes (Method A)
2.68b. 4- (5-Chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide According to general procedure I 2- (4-pyrrolidin- Prepared from 61 mg (0.3 mmol) of 1-ylmethyl-phenyl) -ethylamine and 71 mg (0.3 mmol) of 4- (5-chloro-thiophen-2-yl) -benzoic acid.
Yield: 29 mg (22.9% of theory)
C ₂₄ H ₂₅ ClN ₂ OS (M = 425.0)
calc .: Mole peak (M + H) ⁺ : 425/427 fnd .: Mole peak (M + H) ⁺ : 425/427
Retention time HPLC: 6.65 minutes (Method A)
Example 2.69:
4-furan-2-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.69a. 4-furan-2-yl-benzoic acid Prepared as in Example 2.68a from 302 mg (1.5 mmol) 4-bromo-benzoic acid and 201 mg (1.8 mmol) furan-2-borate.
Yield: 166 mg (58.8% of theory)
C ₁₁ H ₈ O ₃ (M = 188.19)
calc .: molar peak (MH) ^- : 187 fnd .: molar peak (MH) ^- : 187
Retention time HPLC: 6.82 min (Method A)
2.69b. 4-Furan-2-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-Pyrrolidin-1-ylmethyl-phenyl) according to General Procedure I -Prepared from 102 mg (0.5 mmol) of ethylamine and 94 mg (0.5 mmol) of 4-furan-2-yl-benzoic acid.
Yield: 91 mg (48.4% of theory)
C ₂₄ H ₂₆ N ₂ O ₂ (M = 374.49)
calc .: Mole peak (M + H) ⁺ : 375 fnd .: Mole peak (M + H) ⁺ : 375
Retention time HPLC: 6.48 min (Method A)
Example 2.70:
4- (5-Methyl-pyridin-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.70a. 4- (5-Methyl-pyridin-2-yl) -benzoic acid 430 mg (2.50 mmol) 2-bromo-5-methylpyridine and 498 mg 4-carboxyphenyl-boric acid (as in Example 2.55a) 3.00 mmol).
Yield: 300 mg (56.3% of theory)
C ₁₃ H ₁₁ NO ₂ (M = 213.24)
calc .: Mole peak (M + H) ⁺ : 214 fnd .: Mole peak (M + H) ⁺ : 214
Retention time HPLC: 4.55 minutes (Method A)
2.70b. 4- (5-Methyl-pyridin-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-Pyrrolidine- Prepared from 102 mg (0.5 mmol) of 1-ylmethyl-phenyl) -ethylamine and 107 mg (0.5 mmol) of 4- (5-methyl-pyridin-2-yl) -benzoic acid.
Yield: 53 mg (26.5% of theory)
C ₂₆ H ₂₉ N ₃ O (M = 399.54)
calc .: Mole peak (M + H) ⁺ : 400 fnd .: Mole peak (M + H) ⁺ : 400
Retention time HPLC: 3.98 min (Method A)
Example 2.71:
4- (6-Methyl-pyridin-3-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.71a. 4- (6-Methyl-pyridin-3-yl) -benzoic acid As in Example 2.55a, 430 mg (2.50 mmol) of 5-bromo-2-methylpyridine and 498 mg of 4-carboxyphenyl-boric acid ( 3.00 mmol).
Yield: 300 mg (56.3% of theory)
C ₁₃ H ₁₁ NO ₂ (M = 213.24)
calc .: Mole peak (M + H) ⁺ : 214 fnd .: Mole peak (M + H) ⁺ : 214
Retention time HPLC: 2.66 minutes (Method A)
2.71b. 4- (6-Methyl-pyridin-3-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-Pyrrolidine- Prepared from 102 mg (0.5 mmol) of 1-ylmethyl-phenyl) -ethylamine and 107 mg (0.5 mmol) of 4- (6-methyl-pyridin-3-yl) -benzoic acid.
Yield: 48 mg (24.0% of theory)
C ₂₆ H ₂₉ N ₃ O (M = 399.54)
calc .: Mole peak (M + H) ⁺ : 400 fnd .: Mole peak (M + H) ⁺ : 400
Retention time HPLC: 3.06 minutes (Method A)
Example 2.72:
4- (4-Chloro-phenyl) -thiophene-2-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.72a. Methyl 4- (4-chloro-phenyl) -thiophene-2-carboxylate 420 mg (1.25 mmol) of methyl 4-bromo-thiophene-2-carboxylate is dissolved in 10 ml of dioxane and 5 ml of 2M Na ₂ CO ₃ solution. . 196 mg (0.06 mmol) 4-chloro-phenyl-boric acid and 72 mg (0.06 mmol) tetrakis- (triphenylphosphine) -palladium were added in succession and the reaction was refluxed for 6 hours and stirred at room temperature for a further 60 hours. To do. After heating again, the hot reaction solution is suction filtered through a glass fiber filter, washed with dioxane, combined with half-saturated NaHCO ₃ solution and extracted with EtOAc. The combined organic phases are dried with MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by column chromatography on silica gel (petroleum ether / ethyl acetate 9: 1).
Yield: 150 mg (47.3% of theory)
C ₁₂ H ₉ ClO ₂ S (M = 252.72)
calc .: Mole peak (M + H) ⁺ : 253/255 fnd .: Mole peak (M + H) ⁺ : 253/255
Retention time HPLC: 6.21 minutes (Method B)
2.72b. 4- (4-Chloro-phenyl) -thiophene-2-carboxylic acid
2 ml of 1M NaOH solution is added to a solution of 150 mg of methyl 4- (4-chloro-phenyl) -thiophene-2-carboxylate in 10 ml of EtOH and the reaction solution is stirred at room temperature over the end. The solvent is evaporated in vacuo and the residue is combined with 2 ml of 1N hydrochloric acid and cooled to 0 ° C. The precipitated product is filtered off with suction, washed with water and dried at 50 ° C.
Yield: 140 mg (98.7% of theory)
C ₁₁ H ₇ ClO ₂ S (M = 238.69)
calc .: Mole peak (M + H) ⁺ : 239/241 fnd .: Mole peak (M + H) ⁺ : 239/241
Retention time HPLC: 8.31 min (Method A)
2.72c. 4- (4-Chloro-phenyl) -thiophene-2-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure I, 2- (4-pyrrolidine- Prepared from 144 mg (0.70 mmol) of 1-ylmethyl-phenyl) -ethylamine and 140 mg (0.59 mmol) of 4- (4-chloro-phenyl) -thiophene-2-carboxylic acid.
Yield: 78 mg (31.3% of theory)
C ₂₆ H ₂₉ N ₃ O (M = 425.00)
calc .: Mole peak (M + H) ⁺ : 425/427 fnd .: Mole peak (M + H) ⁺ : 425/427
Retention time HPLC: 3.90 minutes (Method A)
Example 2.73:
4- (5-Acetyl-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.73a. 4-Iodo-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2.04 g 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine according to General Procedure I (10.0 mmol) and 4.48 g (10.0 mmol) of 4-iodo-benzoic acid.
Yield: 1.91 g (44.0% of theory)
C ₂₀ H ₂₃ IN ₂ O (M = 434.32)
calc .: Mole peak (M + H) ⁺ : 435 fnd .: Mole peak (M + H) ⁺ : 435
Retention time HPLC: 5.40 minutes (Method A)
2.73b. 4- (5-Acetyl-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 4-iodo--similar to Example 2.46b From 250 mg (0.58 mmol) of N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide and 118 mg (0.69 mmol) of 5-acetyl-2-thiophene-boric acid, the reaction mixture is refluxed for 15 hours. Prepared.
Yield: 50 mg (20.2% of theory)
C ₂₆ H ₂₈ N ₂ O ₂ S (M = 432.59)
calc .: Mole peak (M + H) ⁺ : 433 fnd .: Mole peak (M + H) ⁺ : 433
Retention time HPLC: 3.91 min (Method B)
Example 2.74:
4- (5-Formyl-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

Analogously to Example 2.46b 4-iodo-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 250 mg (0.58 mmol) and 5-formyl-2-thiophene-boric acid 107 mg (0.69 mmol) was prepared by refluxing the reaction mixture for 15 hours.
Yield: 22 mg (9.1% of theory)
C ₂₅ H ₂₆ N ₂ O ₂ S (M = 418.56)
calc .: Mole peak (M + H) ⁺ : 419 fnd .: Mole peak (M + H) ⁺ : 419
Retention time HPLC: 3.82 min (Method B)
Example 2.75:
4'-Chloro-biphenyl-4-carboxylic acid [2- (4-aminomethyl-phenyl) -ethyl] -amide

2.75a. Ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate 20 ml of thionyl chloride and 1 ml of DMF were added to 9.31 g of 4'-chloro-biphenyl-4-carboxylic acid (2. 40 mmol) is added dropwise. The reaction mixture is heated to 60 ° C. for 2 hours. The excess thionyl chloride is then removed in vacuo at 50 ° C. and the residue is taken up in 200 ml of CH ₂ Cl ₂ . This solution was added dropwise to 9.19 g (40 mmol) of ethyl 4- (2-amino-ethyl) -benzoate used as the hydrochloride salt in 100 ml of 10% aqueous Na ₂ CO ₃ solution and the reaction mixture was added. Stir for another hour at room temperature. After the addition of water and CH ₂ Cl ₂ , the organic phase is separated, the aqueous phase is extracted with CH ₂ Cl ₂ and the combined organic phases are washed with half-saturated NaHCO ₃ solution and water and dried over MgSO ₄ . After removal of the desiccant, the solution is filtered through activated carbon, evaporated in vacuo and the residue is recrystallized from tert-butyl methyl ether.
Yield: 11.93 g (73.1% of theory)
C ₂₄ H ₂₂ ClNO ₃ (M = 407.90)
calc .: Mole peak (M + H) ⁺ : 408 fnd .: Mole peak (M + H) ⁺ : 408
Retention time HPLC: 9.8 minutes (Method A)
2.75b. 4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid
50 ml of 2M NaOH solution is added to a solution of 11.93 g (29.25 mmol) of ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate in 150 ml of EtOH and 2 at room temperature. Stir for hours. The reaction solution is adjusted to pH 6-7 with 1N HCl solution, the precipitated product is filtered off and dried in a vacuum oven.
Yield: 10.74 g (96.7% of theory)
C ₂₂ H ₁₈ ClNO ₃ (M = 379.85)
calc .: Mole peak (M + H) ⁺ : 380/382 fnd .: Mole peak (M + H) ⁺ : 380/382
Retention time HPLC: 8.0 minutes (Method A)

2.75c. 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-hydroxymethyl-phenyl) -ethyl] -amide
4.82 g (29.69 mmol) CDI was added to a solution of 10.74 g (28.28 mmol) 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid in 150 ml dry THF. The reaction mixture is heated to 50 ° C. for 2 hours. This solution is added to a suspension of 2.14 g (56.56 mmol) NaBH4 in 5 ml water and stirred vigorously for another hour at room temperature. Adjust the pH of the solution to 6 using 1N HCl, then combine it with EtOAc and filter. The filtrate is washed with half-saturated NaHCO ₃ solution and water and dried over MgSO ₄ . Since the residue still contains unreacted 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid after removal of the desiccant and solvent, the above reduction step is repeated. The product obtained is dried at 40 ° C.
Yield: 9.3 g (89.9% of theory)
C ₂₂ H ₂₀ ClNO ₂ (M = 365.86)
calc .: Mole peak (M + H) ⁺ : 366/368 fnd .: Mole peak (M + H) ⁺ : 366/368
Retention time HPLC: 8.11 min (Method A)
2.75d. 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide
1.22 ml of PBr _{3 was} added dropwise to a solution of 7.9 g (21.59 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (4-hydroxymethyl-phenyl) -ethyl] -amide in 300 ml of CH ₂ Cl _2. Add. The reaction mixture is stirred overnight at room temperature. The precipitate formed is filtered off with suction and the filtrate is evaporated. The residue is triturated with a small amount of acetonitrile and CH ₂ Cl ₂ , filtered off with suction, combined with the precipitate obtained initially and dried in air.
Yield: 8.6 g (92.9% of theory)
C ₂₂ H ₁₉ BrClNO (M = 428.76)
calc .: Mole peak (M + H) ⁺ : 428/430/432 fnd .: Mole peak (M + H) ⁺ : 428/430/432
R _f value: 0.40 (silica gel, CH ₂ Cl ₂ ).

2.75e. 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-aminomethyl-phenyl) -ethyl] -amide ₃ ml of 0.5 M NH ₃ solution in dioxane was added to 4'-chloro-biphenyl in 10 ml of acetonitrile. 4-Carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide is added to a solution of 150 mg (0.35 mmol) and stirred at room temperature for 3 days. The reaction mixture is evaporated and the residue is purified by column chromatography (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Yield: 8 mg (6.3% of theory)
C ₂₂ H ₂₁ ClN ₂ O (M = 364.88)
calc .: Mole peak (M + H) ⁺ : 365/367 fnd .: Mole peak (M + H) ⁺ : 365/367
Retention time HPLC: 5.97 min (Method A)
Example 2.76:
4'-Chloro-biphenyl-4-carboxylic acid (2- {4-[(diisopropylamino) -methyl] -phenyl} -ethyl) -amide

47 μL (0.33 mmol) of diisopropylamine was added to 129 mg (0.3 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide and 55 mg of K ₂ CO _{3 in} 20 ml of acetonitrile ( 0.4 mmol) and the reaction mixture is stirred overnight at room temperature. It is diluted with CH ₂ Cl ₂ and filtered to remove insoluble inorganic salts and the filtrate is evaporated. The residue is triturated with acetonitrile, filtered off with suction and dried in air.
Yield: 75 mg (55.7% of theory)
C ₂₈ H ₃₃ ClN ₂ O (M = 449.04)
calc .: Mole peak (M + H) ⁺ : 449/451 fnd .: Mole peak (M + H) ⁺ : 449/451
R _f value: 0.35 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.77:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (3-oxo-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide

From 129 mg (0.3 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide and 33 mg (0.33 mmol) of piperazin-2-one as in Example 2.76 Prepared.
Yield: 23 mg (17.1% of theory)
C ₂₆ H ₂₆ ClN ₃ O ₂ (M = 447.97)
calc .: Mole peak (M + H) ⁺ : 448/450 fnd .: Mole peak (M + H) ⁺ : 448/450
R _f value: 0.10 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.78:
Ethyl [(4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -methyl-amino] -acetate

4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 257 mg (0.6 mmol), K ₂ CO ₃ 193 mg and ethylmethylamino-acetate as in Example 2.76 Prepared from 101 mg (0.66 mmol) (used as the hydrochloride salt).
Yield: 152 mg (54.5% of theory)
C ₂₇ H ₂₉ ClN ₂ O ₃ (M = 465.0)
calc .: Mole peak (M + H) ⁺ : 465/467 fnd .: Mole peak (M + H) ⁺ : 465/467
R _f value: 0.40 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.79:
[(4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -methyl-amino] -acetic acid

0.3 ml of 1M NaOH solution was added 80 mg (0.17 mmol) of ethyl [(4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -methyl-amino] -acetate in 3 ml of EtOH. ) And reflux for 1 hour. The solvent is evaporated in vacuo and the residue is combined with water and 0.3 ml of 1M HCl. The precipitate is filtered off with suction and dried at 40 ° C.
Yield: 76 mg (100% of theory)
C ₂₅ H ₂₅ ClN ₂ O ₃ (M = 436.94)
calc .: Mole peak (M + H) ⁺ : 437/439 fnd .: Mole peak (M + H) ⁺ : 437/439
Retention time HPLC: 6.35 minutes (Method A)
Example 2.80:
4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (4-acetyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide

In the same manner as in Example 2.76, 129 mg (0.3 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide and 42 mg of 1-piperazin-1-yl-ethanone ( 0.33 mmol).
Yield: 60 mg (42.0% of theory)
C ₂₈ H ₃₀ ClN ₃ O ₂ (M = 476.02)
calc .: Mole peak (M + H) ⁺ : 476/478 fnd .: Mole peak (M + H) ⁺ : 476/478
R _f value: 0.15 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.81:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-aza-bicyclo [2.2.1] hept-5-en-2-ylmethyl) -phenyl] -ethyl} -amide

4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 129 mg (0.3 mmol) and 2-aza-bicyclo [2.2.1] hept as in Example 2.76 Prepared from 31 mg (0.33 mmol) of -5-ene.
Yield: 100 mg (75.2% of theory)
C ₂₈ H ₂₇ ClN ₂ O (M = 442.99)
calc .: Mole peak (M + H) ⁺ : 443/445 fnd .: Mole peak (M + H) ⁺ : 443/445
R _f value: 0.08 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.82:
4'-Chloro-biphenyl-4-carboxylic acid- {2- [4- (1,3-dihydro-isoindol-2-ylmethyl) -phenyl] -ethyl} -amide

4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 129 mg (0.3 mmol), K ₂ CO ₃ 97 mg and 2,3-dihydro as in Example 2.76 Prepared from 51 mg (0.33 mmol) of -1H-isoindole (used as hydrochloride).
Yield: 80 mg (57.1% of theory)
C ₃₀ H ₂₇ ClN ₂ O (M = 467.02)
calc .: Mole peak (M + H) ⁺ : 467/469 fnd .: Mole peak (M + H) ⁺ : 467/469
R _f value: 0.40 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.83:
4'-Chloro-biphenyl-4-carboxylic acid- {2- [4- (7-methyl-2,7-diaza-spiro [4.4] non-2-ylmethyl) -phenyl] -ethyl} -amide

Analogously to Example 2.76 4'-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 129 mg (0.3 mmol) and 2-methyl-2.7-diaza-spiro [4.4 It was prepared from 46 mg (0.33 mmol) of nonane.
Yield: 42 mg (28.7% of theory)
C ₃₀ H ₃₄ ClN ₃ O (M = 488.08)
calc .: Mole peak (M + H) ⁺ : 488/490 fnd .: Mole peak (M + H) ⁺ : 488/490
R _f value: 0.05 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.84:
4'-chloro-biphenyl-4-carboxylic acid- {2- [4- (3-diethylamino-azetidin-1-ylmethyl) -phenyl] -ethyl} -amide

4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 129 mg (0.3 mmol), K ₂ CO ₃ 138 mg and azetidin-3-yl as in Example 2.76 Prepared from 66 mg (0.33 mmol) of diethyl-amine (used as dihydrochloride) and the product is purified by column chromatography.
Yield: 15 mg (10.5% of theory)
C ₂₉ H ₃₄ ClN ₃ O (M = 476.07)
calc .: Mole peak (M + H) ⁺ : 476/478 fnd .: Mole peak (M + H) ⁺ : 476/478
R _f value: 0.10 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.1).
Example 2.85:
Ethyl (S) -1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-2-carboxylate

In the same manner as in Example 2.76, 4'-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 257 mg (0.6 mmol), K ₂ CO ₃ 193 mg and ethyl (S)- Prepared from 119 mg (0.66 mmol) of pyrrolidine-2-carboxylate (used as the hydrochloride) and the product is purified by column chromatography.
Yield: 160 mg (54.3% of theory)
C ₂₉ H ₃₁ ClN ₂ O ₃ (M = 491.04)
calc .: Mole peak (M + H) ⁺ : 491/493 fnd .: Mole peak (M + H) ⁺ : 491/493
R _f value: 0.60 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.86:
(S) -1- (4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-2-carboxylic acid

Ethyl (S) -1- (4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-2-carboxylate 130 mg as in Example 2.79 (0.27 mmol).
Yield: 120 mg (97.8% of theory)
C ₂₇ H ₂₇ ClN ₂ O ₃ (M = 462.98)
calc .: Mole peak (M + H) ⁺ : 463/465 fnd .: Mole peak (M + H) ⁺ : 463/465
Retention time HPLC: 6.20 minutes (Method A)
Example 2.87:
tert.butyl [1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-3-yl] -carbamate

4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 429 mg (1.0 mmol) and tert.butyl pyrrolidin-3-yl-carbamate 205 mg as in Example 2.76 (1.10 mmol).
Yield: 500 mg (93.6% of theory)
C ₃₁ H ₃₆ ClN ₃ O ₃ (M = 534.10)
calc .: Mole peak (M + H) ⁺ : 534/536 fnd .: Mole peak (M + H) ⁺ : 534/536
R _f value: 0.33 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.88:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (3-amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide

1 ml of trifluoroacetic acid in tert.butyl [1- (4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-3 in 15 ml of CH ₂ Cl ₂ -Yl] -carbamate is added to a solution of 500 mg (0.94 mmol) and the reaction mixture is stirred overnight. It is then evaporated and the residue is taken up in a small amount of CH ₂ Cl ₂ and combined with half-saturated NaHCO ₃ solution. The precipitated product is filtered off with suction, triturated with acetonitrile and dried at 40 ° C.
Yield: 240 mg (59.1% of theory)
C ₂₆ H ₂₈ ClN ₃ O (M = 433.99)
calc .: Mole peak (M + H) ⁺ : 434/436 fnd .: Mole peak (M + H) ⁺ : 434/436
R _f value: 0.22 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Example 2.89:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (3-dimethylamino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide

37% aqueous formaldehyde solution 0.12 ml, NaBH ₃ CN 28 mg (0.45 mmol) and 1 drop of glacial acetic acid in 4 ml of 4′-chloro-biphenyl-4-carboxylic acid {2- [4- (3-amino-pyrrolidine-1- Add to a solution of 60 mg (0.14 mmol) of (Ilmethyl) -phenyl] -ethyl} -amide. The reaction mixture is stirred at room temperature overnight and then combined with dilute NaOH solution and EtOAc. The phases are separated and the organic phase is dried over MgSO ₄ and then the desiccant and solvent are removed. The residue is purified by column chromatography.
Yield: 10 mg (15.7% of theory)
C ₂₈ H ₃₂ ClN ₃ O (M = 462.04)
calc .: Mole peak (M + H) ⁺ : 462/464 fnd .: Mole peak (M + H) ⁺ : 462/464
Retention time HPLC: 5.16 minutes (Method A)
Example 2.90:
tert.butyl [1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-2-ylmethyl] -carbamate

Analogously to Example 2.76 4'-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 230 mg (0.54 mmol) and tert.butyl pyrrolidin-2-ylmethyl-carbamate 116 mg (1.10 mmol).
Yield: 230 mg (78.3% of theory)
C ₃₂ H ₃₈ ClN ₃ O ₃ (M = 548.13)
calc .: Mole peak (M + H) ⁺ : 548/550 fnd .: Mole peak (M + H) ⁺ : 548/550
R _f value: 0.35 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
Example 2.91:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide

Tert.butyl [1- (4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-2-ylmethyl] -carbamate as in Example 2.88 Prepared from 230 mg (0.42 mmol).
Yield: 188 mg (100% of theory)
C ₂₇ H ₃₀ ClN ₃ O (M = 448.01)
calc .: Mole peak (M + H) ⁺ : 448/450 fnd .: Mole peak (M + H) ⁺ : 448/450
R _f value: 0.35 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Example 2.92:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-dimethylaminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide

40 '(0.09 mmol) of 4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide as in Example 2.89 Prepared from 0.08 ml of 37% aqueous formaldehyde and 19 mg (0.30 mmol) NaBH ₃ CN.
Yield: 10 mg (23.6% of theory)
C ₂₉ H ₃₄ ClN ₃ O (M = 476.07)
calc .: Mole peak (M + H) ⁺ : 476/478 fnd .: Mole peak (M + H) ⁺ : 476/478
R _f value: 0.12 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Example 2.93:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-2,6-diaza-spiro [3.4] oct-6-ylmethyl) -phenyl] -ethyl} -amide

4'-Chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide 250 mg (0.58 mmol), K ₂ CO ₃ 97 mg and 2-methyl-2 in the same manner as in Example 2.76 , 6-Diaza-spiro [3.4] octane is prepared from 81 mg (0.64 mmol) and the product is purified by HPLC.
Yield: 20 mg (7.2% of theory)
C ₂₉ H ₃₂ ClN ₃ O (M = 474.05)
calc .: Mole peak (M + H) ⁺ : 474/476 fnd .: Mole peak (M + H) ⁺ : 474/476
R _f value: 0.20 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Example 2.94:
3-[(4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -ethyl-amino] -propionic acid

257 mg (0.6 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (4-bromomethyl-phenyl) -ethyl] -amide, 166 mg (1.2 mmol) of K ₂ CO ₃ and 3-ethylamino in 20 ml of acetonitrile A suspension of 138 mg propionic acid (0.9 mmol, used as hydrochloride) is stirred at room temperature for 3 days. 5 ml of DMF is added and the mixture is heated to 50 ° C. for 3 hours. The reaction mixture is filtered, the filtrate is evaporated and the residue is purified by HPLC.
Yield: 50 mg (17.9% of theory)
C ₂₇ H ₂₉ ClN ₂ O ₃ (M = 465.0)
calc .: Mole peak (M + H) ⁺ : 465/467 fnd .: Mole peak (M + H) ⁺ : 465/467
Retention time HPLC: 5.85 min (Method A)
Example 2.95:
Methyl (S) -1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-2-carboxylate

2.95a. Ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate According to General Procedure I 10.0 g of 4'-chloro-biphenyl-4-carboxylic acid (42.98 Mmol) and ethyl 4- (2-amino-ethyl) -benzoate 9.87 g (42.98 mmol).
Yield: 10.64 g (60.7% of theory)
C ₂₄ H ₂₂ ClNO ₃ (M = 407.90)
calc .: Mole peak (M + H) ⁺ : 408/410 fnd .: Mole peak (M + H) ⁺ : 408/410
R _f value: 0.87 (silica gel, CH ₂ Cl ₂ / MeOH 95: 5).
2.95b. 4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid
14 ml of 2M NaOH solution is added to a solution of 10.64 g (26.08 mmol) of ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate in 100 ml of EtOH and the reaction mixture Is heated to 60 ° C. overnight. Then another 30 ml NaOH solution is added and the mixture is kept at this temperature for a further 3 hours. The reaction mixture is adjusted to pH 6-7 with 1M HCl solution and the precipitated product is filtered and dried in vacuo.
Yield: 7.65 g (77.2% of theory)
C ₂₂ H ₁₈ ClNO ₃ (M = 379.85)
calc .: Mole peak (M + H) ⁺ : 380/382 fnd .: Mole peak (M + H) ⁺ : 380/382
Retention time HPLC: 8.1 minutes (Method A)
2.95c. 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-hydroxymethyl-phenyl) -ethyl] -amide
3.24 g (20 mmol) CDI was added to a solution of 7.2 g (18.97 mmol) 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid in 150 ml dry THF. The reaction mixture is heated to 50 ° C. for 2 hours. This solution is added to a suspension of 1.44 g (38 mmol) of NaBH _{4 in} 5 ml of water and stirred for another hour. The reaction mixture is adjusted to pH 6-7 with 1M HCl solution and exhaustively extracted with EtOAc. The organic phase is washed with NaHCO ₃ solution, washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography (silica gel, CH ₂ Cl ₂ / MeOH 9: 1). Since there are still educts in the product, the above procedure is repeated using 50% of the reagents.
Yield: 2.85 g (41.0% of theory)
C ₂₂ H ₂₀ ClNO ₂ (M = 365.86)
calc .: Mole peak (M + H) ⁺ : 366/368 fnd .: Mole peak (M + H) ⁺ : 366/368
Retention time HPLC: 8.0 minutes (Method A)

2.95d. 4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 1.25 ml (9 mmol) of triethylamine in 4 ml of 4'-chloro-biphenyl- in 100 ml of dry THF 4-Carboxylic acid [2- (4-hydroxymethyl-phenyl) -ethyl] -amide is added to a solution of 1.0 g (2.73 mmol) and the mixture is cooled to -20 ° C. Then 0.64 ml (8.2 mmol) of methanesulfonic acid chloride are added dropwise and the mixture is stirred at this temperature for a further 2 hours. 5% NaHCO ₃ solution is added and the mixture is exhaustively extracted with EtOAc. The organic phase is dried over Na ₂ SO ₄ , the desiccant and solvent are removed and the residue is dried at 30 ° C. in vacuo.
Yield: 1.21 g (99.7% of theory)
C ₂₃ H ₂₂ ClNO ₄ S (M = 443.95)
calc .: Mole peak (M + H) ⁺ : 444/446 fnd .: Mole peak (M + H) ⁺ : 444/446
Retention time HPLC: 8.8 minutes (Method A)
2.95e. Methyl (S) -1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidine-2-carboxylate
Under N ₂ atmosphere, a solution of 50 mg (0.3 mmol) methyl (2S) -pyrrolidine-2-carboxylate (used as hydrochloride) and 0.7 ml (0.5 mmol) triethylamine in 4 ml DMF is stirred at room temperature for 20 minutes. Then 111 mg (0.25 mmol) of 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate is added and the mixture is heated to 60 ° C. for 2 hours. The reaction mixture is evaporated in vacuo and the residue is purified by HPLC.
Yield: 4 mg (3.4% of theory)
C ₂₈ H ₂₉ ClN ₂ O ₃ (M = 477.01)
calc .: Mole peak (M + H) ⁺ : 477/479 fnd .: Mole peak (M + H) ⁺ : 477/479
Retention time HPLC: 6.51 min (Method A)
Example 2.96:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide

Analogously to Example 2.95e 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and 2-methylpiperidine 35 μL (0.3 mmol) ) Without using triethylamine.
Yield: 7 mg (6.3% of theory)
C ₂₈ H ₃₁ ClN ₂ O (M = 447.03)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
Retention time HPLC: 6.4 min (Method A)
Example 2.97:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide

Analogously to Example 2.95e 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and 2-methyl-pyrrolidine 32 μL (0.3 Millimoles) without using triethylamine.
Yield: 2 mg (1.8% of theory)
C ₂₇ H ₂₉ ClN ₂ O (M = 433.0)
calc .: Mole peak (M + H) ⁺ : 433/435 fnd .: Mole peak (M + H) ⁺ : 433/435
Retention time HPLC: 6.3 minutes (Method A)
Example 2.98:
4'-Chloro-biphenyl-4-carboxylic acid (2- {4-[(cyclopropylmethyl-amino) -methyl] -phenyl} -ethyl) -amide

Analogously to Example 2.95e 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and cyclopropylmethylamine 26 μL (0.3 mmol) ) From triethylamine.
Yield: 4 mg (3.8% of theory)
C ₂₆ H ₂₇ ClN ₂ O (M = 418.97)
calc .: Mole peak (M + H) ⁺ : 418/420 fnd .: Mole peak (M + H) ⁺ : 418/420
Retention time HPLC: 6.4 min (Method A)
Example 2.99:
4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) -phenyl] -ethyl} -amide

4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and 1,2,3.4-tetrahydroisoquinoline as in Example 2.95e Prepared from 40 mg (0.3 mmol) without using triethylamine.
Yield: 21 mg (17.5% of theory)
C ₂₆ H ₂₇ ClN ₂ O (M = 481.04)
calc .: Mole peak (M + H) ⁺ : 481/483 fnd .: Mole peak (M + H) ⁺ : 481/483
Retention time HPLC: 6.8 minutes (Method A)
Example 2.100:
4'-Chloro-biphenyl-4-carboxylic acid [2- (4-{[(2-hydroxy-ethyl) -methyl-amino] -methyl} -phenyl) -ethyl] -amide

Analogously to Example 2.95e 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and 2-methylamino-ethanol 24 μL ( From 0.3 mmol) without using triethylamine.
Yield: 13 mg (12.3% of theory)
C ₂₅ H ₂₇ ClN ₂ O ₂ (M = 422.96)
calc .: Mole peak (M + H) ⁺ : 423/425 fnd .: Mole peak (M + H) ⁺ : 423/425
Retention time HPLC: 5.8 minutes (Method A)
Example 2.101:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide

Analogously to Example 2.95e 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and 2,6-dimethylpiperidine 41 μL ( From 0.3 mmol) without using triethylamine.
Yield: 8 mg (6.9% of theory)
C ₂₉ H ₃₃ ClN ₂ O (M = 461.05)
calc .: Mole peak (M + H) ⁺ : 461/463 fnd .: Mole peak (M + H) ⁺ : 461/463
Retention time HPLC: 6.6 minutes (Method A)
Example 2.102:
4'-Chloro-biphenyl-4-carboxylic acid [2- (4-azetidin-1-ylmethyl-phenyl) -ethyl] -amide

In the same manner as in Example 2.95e, from 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 111 mg (0.42 mmol) and azetidine 20 μL (0.3 mmol), Prepared without using triethylamine.
Yield: 3 mg (3.0% of theory)
C ₂₅ H ₂₅ ClN ₂ O (M = 404.94)
calc .: Mole peak (M + H) ⁺ : 405/407 fnd .: Mole peak (M + H) ⁺ : 405/407
Retention time HPLC: 5.9 minutes (Method A)
Example 2.103:
4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide

Analogously to Example 2.95e 4- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzylmethanesulfonate 50 mg (0.11 mmol) and 2,5-dihydro-1H— Prepared from 11 μL (0.14 mmol) of pyrrole without using triethylamine.
Yield: 18 mg (38.2% of theory)
C ₂₆ H ₂₅ ClN ₂ O (M = 416.95)
calc .: Mole peak (M + H) ⁺ : 417/419 fnd .: Mole peak (M + H) ⁺ : 417/419
Retention time HPLC: 6.2 minutes (Method A)
Example 2.104:
4'-Bromo-biphenyl-4-carboxylic acid {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide

2.104a. Ethyl 4'-bromo-biphenyl-4-carboxylate From 1.22 ml (7.47 mmol) of ethyl 4-bromo-benzoate and 1.8 g (8.96 mmol) of 4-bromophenyl-boric acid as in Example 2.46b. And refluxed for 72 hours. The product is crystallized from acetonitrile.
Yield: 293 mg (12.8% of theory)
C ₁₅ H ₁₃ BrO ₂ (M = 305.17)
calc .: Mole peak (M + H) ⁺ : 304/306 fnd .: Mole peak (M + H) ⁺ : 304/306
R _f value: 0.9 (silica gel, petroleum ether / EtOAc 6: 4).
2.104b. 4'-Bromo-biphenyl-4-carboxylic acid
1.24 ml of 2M NaOH solution is added to a solution of 270 mg (0.89 mmol) of ethyl 4′-bromo-biphenyl-4-carboxylate in 10 ml of EtOH and the reaction mixture is stirred at room temperature for 2 hours. The pH is adjusted to 6-7 with 1M HCl and the precipitated product is filtered and dried.
Yield: 205 mg (83.6% of theory)
C ₁₃ H ₉ BrO ₂ (M = 277.12)
calc .: Mole peak (MH) ^- : 275/277 fnd .: Mole peak (MH) ^- : 275/277
Retention time HPLC: 8.5 minutes (Method A)
2.104c. [4- (2-Amino-ethyl) -phenyl] -methanol 580 mg of Raney nickel in (4-hydroxymethyl-phenyl) -acetonitrile in 116 ml of methanolic NH ₃ solution (see Example 1.1e.) was added to 5.8 g (39.41 mmol), its hydrogenated with H ₂ in the reaction mixture 3.5kg / cm ² (50psi). At the end of the reaction, the catalyst is filtered off, the solvent is removed and the residue is purified by chromatography (silica gel, EtOAc / MeOH / NH ₃ 7: 3: 0.3).
Yield: 3.9 g (65.4% of theory)
C ₉ H ₁₃ NO (M = 151.21)
calc .: Mole peak (M + H) ⁺ : 152 fnd .: Mole peak (M + H) ⁺ : 152
R _f value: 0.18 (silica gel, EtOAc / MeOH / NH ₃ 8: 2: 0.2).

2.104d tert.butyl [2- (4-hydroxymethyl-phenyl) -ethyl] -carbamate
CH ₂ and 1M BOC anhydride 17.36ml in Cl ₂ in CH ₂ Cl ₂ 50 ml [4- (2-amino - ethyl) - phenyl] - was added at room temperature to a solution of methanol 2.5 g (16.53 mmol), The reaction mixture is stirred overnight at room temperature. 100 ml of KHSO ₄ solution are added, the organic phase is separated, washed with dilute NaHCO ₃ solution and water and dried over MgSO ₄ . After removal of the desiccant and solvent, the desired product is obtained.
Yield: 4.06 g (97.7% of theory)
C ₁₄ H ₂₁ NO ₃ (M = 251.33)
calc .: Mole peak (M + H) ⁺ : 252 fnd .: Mole peak (M + H) ⁺ : 252
Retention time HPLC: 6.4 min (Method A)
2.104e. Tert.butyl [2- (4-chloromethyl-phenyl) -ethyl] -carbamate 1 ml of pyridine in tert.butyl [2- (4-hydroxymethyl-phenyl) -ethyl]-in 50 ml of CH ₂ Cl ₂ Add to a solution of 2.6 g (10.35 mmol) carbamate, cool to 0 ° C. and add 1.03 ml (12.41 mmol) thionyl chloride. The mixture is kept at 0 ° C. for 1 hour and then heated to room temperature. The reaction mixture is washed with water, dilute KHSO ₄ solution and again with water, dried over MgSO ₄ and filtered through activated charcoal. After removal of the solvent, the product is obtained as an oil, which is reacted without further purification.
Yield: 1.8 g (64.5% of theory)
C ₁₄ H ₂₀ ClNO ₂ (M = 269.77)
calc .: Mole peak (MH) ^- : 268/270 fnd .: Mole peak (MH) ^- : 268/270
R _f value: 0.62 (silica gel, petroleum ether / EtOAc 7: 3).

2.104f. Tert-Butyl {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -carbamate
2.37 g (17.13 mmol) of K ₂ CO ₃ and 0.8 ml (10.38 mmol) of 2,5-dihydro-1H-pyrrole in tert.butyl [2- (4-chloromethyl-phenyl) -ethyl] -carbamate in 50 ml of acetonitrile 1.4 g (5.19 mmol) of solution are added and the mixture is stirred overnight at room temperature. The reaction mixture is diluted with CH ₂ Cl ₂ , washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the desired product is obtained.
Yield: 1.46 g (93.0% of theory)
C ₁₈ H ₂₆ N ₂ O ₂ (M = 302.42)
calc .: Mole peak (M + H) ⁺ : 303 fnd .: Mole peak (M + H) ⁺ : 303
R _f value: 0.15 (silica gel, petroleum ether / EtOAc 7: 3).
2.104 g. 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethylamine 5 ml of trifluoroacetic acid in 50 ml of CH ₂ Cl ₂ tert.butyl {2- [4- (2, Add to a solution of 1.21 g (4 mmol) of 5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -carbamate and stir at room temperature for 2 hours. The reaction mixture is evaporated in vacuo and the residue is combined with water and CH ₂ Cl ₂ and made alkaline with K ₂ CO ₃ solution. The organic phase is separated, washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the desired product is obtained.
Yield: 0.35 g (43.3% of theory)
C ₁₃ H ₁₈ N ₂ (M = 202.30)
calc .: Mole peak (M + H) ⁺ : 203 fnd .: Mole peak (M + H) ⁺ : 203
R _f value: 0.05 (silica gel, EtOAc / MeOH / NH ₃ 9: 1: 0.1).
2.104h. 4'-Bromo-biphenyl-4-carboxylic acid- {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide 4'- according to General Procedure I Prepared from 139 mg (0.50 mmol) bromo-biphenyl-4-carboxylic acid and 101 mg (0.50 mmol) 2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethylamine.
Yield: 21 mg (9.1% of theory)
C ₂₆ H ₂₅ BrN ₂ O (M = 461.41)
calc .: Mole peak (M + H) ⁺ : 461/463 fnd .: Mole peak (M + H) ⁺ : 461/463
Retention time HPLC: 6.46 min (Method A)
Example 2.105:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (1-ethyl-piperidin-2-yl) -phenyl] -ethyl} -amide

2.105a. (4-Pyridin-2-yl-phenyl) -acetonitrile 0.52 ml (5.40 mmol) 2-bromo-pyridine and 1.0 g (5.96 mmol) 4-cyanomethylphenyl-boric acid as in Example 2.46b Prepared from After removal of the desiccant and solvent, the residue is triturated with diisopropyl ether and dried in air.
Yield: 0.76 g (72.5% of theory)
C ₁₃ H ₁₀ N ₂ (M = 194.24)
calc .: Mole peak (M + H) ⁺ : 195 fnd .: Mole peak (M + H) ⁺ : 195
Retention time HPLC: 3.56 minutes (Method B)
2.105b. 2- (4-Cyanomethyl-phenyl) -1-ethyl-pyridinium iodide 0.38 ml (4.7 mmol) of ethyl iodide in 760 mg (3.91 mmol) of (4-pyridin-2-yl-phenyl) -acetonitrile in 5 ml of DMF ) And stirred overnight at room temperature. To complete the reaction, the solution is treated in a microwave at 120 ° C. for 20 minutes. The solvent is evaporated in vacuo and the residue is combined with water and extracted with EtOAc. The aqueous phase is evaporated, the residue is triturated with THF and the suspension is cooled to 0 ° C. The product is filtered off with suction and dried at 50 ° C.
Yield: 800 mg (58.4% of theory)
C ₁₅ H ₁₅ IN ₂ (M = 350.21)
calc .: Mole peak (M) ⁺ : 223 fnd .: Mole peak (M) ⁺ : 223
Retention time HPLC: 1.76 minutes (Method A)

2.105c. 2- [4- (1-Ethyl-piperidin-2-yl) -phenyl] -ethylamine 100 mg of Raney nickel in 2- (4-cyanomethyl-phenyl) -1-ethyl-pyridinium iodide in 10 ml of methanolic NH ₃ The reaction mixture is hydrogenated in an autoclave at 1.4 kg / cm ² (20 psi) at room temperature for 24 hours. The catalyst is filtered off with suction and the reaction solution is combined with 100 mg of PtO ₂ and again hydrogenated at 1.4 kg / cm ² (20 psi) for 30 hours at room temperature. After removal of the catalyst, the product is obtained (as hydroiodide), which is further reacted without purification.
Yield: 700 mg (85.1% of theory)
C ₁₅ H ₂₄ IN ₂ (M = 360.28)
calc .: Mole peak (M) ⁺ : 233 fnd .: Mole peak (M) ⁺ : 233
Retention time HPLC: 0.93 min (isoclatio water: acetonitrile: formic acid 95: 5: 0.01 over 8 min).
2.105d. 4′-Chloro-biphenyl-4-carboxylic acid {2- [4- (1-ethyl-piperidin-2-yl) -phenyl] -ethyl} -amide 2- [4- ( Prepared from 480 mg (1.33 mmol) 1-ethyl-piperidin-2-yl) -phenyl] -ethylamine (used as hydroiodide) and 310 mg (1.33 mmol) 4'-chloro-biphenyl-4-carboxylic acid .
Yield: 20 mg (3.4% of theory)
C ₂₈ H ₃₁ ClN ₂ O (M = 447.03)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
Retention time HPLC: 6.68 min (Method A)
Example 2.106:
4'-Chloro-biphenyl-4-carboxylic acid [2- (1-pyrrolidin-1-yl-indan-5-yl) -ethyl] -amide

2.106a. Ethyl (E) -3- (1-oxo-indan-5-yl) -acrylate 5.96 ml (55 mmol) ethyl acrylate, 275 mg (1.21 mmol) Pd (OAc) ₂ and 704 mg tri-o-tolylphosphine (2.31 mmol) is added to a solution of 4.64 g (21.99 mmol) of 5-bromo-indan-1-one in 110 ml of triethylamine under a nitrogen atmosphere and the reaction mixture is heated to 100 ° C. for 4 hours. The solvent is distilled off, the residue is combined with 150 ml EtOAc and 100 ml ice water, acidified with concentrated HCl, the organic phase is washed with 100 ml water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography (silica gel, hexane / EtOAc 9: 1 → 8: 2).
Yield: 4.0g (79.0% of theory)
Melting point: 100-102 ℃
2.106b. (E) -3- (1-Oxo-indan-5-yl) -acrylic acid
10 ml of 2N NaOH is added to a solution of 4.0 g (17.0 mmol) of ethyl (E) -3- (1-oxo-indan-5-yl) -acrylate in 50 ml of MeOH and the reaction mixture is refluxed for 30 minutes. It is then combined with 11 ml of 2N HCl solution, the MeOH is distilled off and the crystals are filtered off with suction and dried.
Yield: 3.0 g (87.3% of the theoretical value)
Melting point: 240-244 ° C
2.106c. 3- (1-Oxo-indan-5-yl) -propionic acid
150 mg of 10% Pd / C is added to a solution of 1.6 g (7.91 mmol) of (E) -3- (1-oxo-indan-5-yl) -acrylic acid in 50 ml of MeOH, giving a theoretical absorption of hydrogen The reaction mixture is shaken with 3 bar hydrogen at room temperature in a pearl autoclave. Add 10 ml of 1N NaOH and remove the solvent. The residue is acidified with dilute hydrochloric acid, exhaustively extracted with EtOAc, and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is triturated with tert.-butyl methyl ether and the precipitate is filtered off with suction and dried.
Yield: 500 mg (31.0% of theory)
C ₁₂ H ₁₂ O ₃ (M = 204.23)
calc .: molar peak (MH) ^- : 203 fnd .: molar peak (MH) ^- : 203
R _f value: 0.45 (silica gel, CH ₂ Cl ₂ / MeOH 9: 1).

2.106d.tert.Butyl [2- (1-oxo-indan-5-yl) -ethyl] -carbamate
1.6 g (7.83 mmol) of 3- (1-oxo-indan-5-yl) -propionic acid are added to 25 ml of tert. Butanol and 2.5 ml of triethylamine under an argon atmosphere. Add 2.22 ml (10.0 mmol) of diphenylazide-phosphate to this solution and heat to 80 ° C. for 3 hours. The reaction mixture is evaporated in vacuo and the residue is purified by chromatography on silica gel.
Yield: 750 mg (34.8% of theory)
C ₁₆ H ₂₁ NO ₃ (M = 275.35)
calc .: Mole peak (M) ⁺ : 275 fnd .: Mole peak (M) ⁺ : 275
R _f value: 0.65 (silica gel, CH ₂ Cl ₂ / MeOH 95: 5).
2.106e.tert.Butyl [2- (1-hydroxy-indan-5-yl) -ethyl] -carbamate
700 mg (18.5 mmol) NaBH ₄ is added dropwise to a solution of 700 mg (2.54 mmol) tert.butyl [2- (1-oxo-indan-5-yl) -ethyl] -carbamate in 70 ml MeOH and overnight at room temperature. Stir. The reaction solution is carefully combined with a 10% KHSO ₄ solution, diluted with water and extracted thoroughly with tert.-butylmethyl-ether. The organic phase is washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography on silica gel.
Yield: 350 mg (49.7% of theory)
C ₁₆ H ₂₃ NO ₃ (M = 277.37)
calc .: Mole peak (M) ⁺ : 277 fnd .: Mole peak (M) ⁺ : 277
R _f value: 0.30 (silica gel, petroleum ether / EtOAc 6: 4).
2.106f. [2- (1-Pyrrolidin-1-yl-indan-5-yl) -ethyl] -carbamate tert.butyl Thionyl chloride (dissolved in a small amount of CH ₂ Cl ₂ ) 109 μL (1.5 mmol) Is slowly added dropwise to a solution of 350 mg (1.26 mmol) of tert.butyl [2- (1-hydroxy-indan-5-yl) -ethyl] -carbamate in 7.5 ml of cooled CH ₂ Cl ₂ . Stirring is continued at 10 ° C. for a further 30 minutes, the reaction solution is combined with ice-cold NaHCO ₃ solution, the organic phase is separated, washed with cold water and dried over MgSO ₄ . After removal of the desiccant, the filtrate is cooled to 0 ° C., 417 μL (5.0 mmol) of pyrrolidine is added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is evaporated and the residue is purified by chromatography on silica gel.
Yield: 120 mg (28.8% of theory)
C ₂₀ H ₃₀ N ₂ O ₂ (M = 330.47)
calc .: Mole peak (M + H) ⁺ : 331 fnd .: Mole peak (M + H) ⁺ : 331
Retention time HPLC: 5.6 minutes (Method A)

2.106 g. 2- (1-pyrrolidin-1-yl-indan-5-yl) -ethylamine tert.butyl [2- (1-pyrrolidin-- in 100 ml of CH ₂ Cl ₂ with gentle cooling of 100 μL of trifluoroacetic acid 1-yl-indan-5-yl) -ethyl] -carbamate is added to a solution of 100 mg (0.3 mmol) and stirred at room temperature for 1 hour. To complete the reaction, an additional 500 μL of trifluoroacetic acid is added with cooling and the mixture is stirred at room temperature for 2 hours. The reaction mixture is evaporated in vacuo and the product (as bis-trifluoroacetate) is further reacted without purification.
Yield: 100 mg (72.7% of theory)
C ₁₉ H ₂₄ F ₆ N ₂ O ₄ (M = 458.51)
calc .: Mole peak (M + H) ⁺ : 231 fnd .: Mole peak (M + H) ⁺ : 231
R _f value: 0.3 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
2.106h. 4'-Chloro-biphenyl-4-carboxylic acid [2- (1-pyrrolidin-1-yl-indan-5-yl) -ethyl] -amide 2- (1-pyrrolidine-1 according to General Procedure I Prepared from 100 mg (0.29 mmol) of 4-yl-indan-5-yl) -ethylamine (used as ditrifluoroacetate salt) and 70 mg (0.3 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 40 mg (30.0% of theory)
C ₂₈ H ₂₉ ClN ₂ O (M = 445.01)
calc .: Mole peak (M + H) ⁺ : 445/447 fnd .: Mole peak (M + H) ⁺ : 445/447
Retention time HPLC: 6.65 minutes (Method A)
Example 2.107:
4'-Chloro-biphenyl-4-carboxylic acid [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.107a. Methyl 2-bromo-4-cyanomethyl-benzoate
A solution of 98.55 g (0.32 mol) of methyl 2-bromo-4-bromomethyl-benzoate in 60 ml of EtOH is added to a solution of 24.51 g (0.5 mol) of NaCN in 40 ml of water and the reaction mixture is refluxed for 5 hours. 1 liter of tert.-butyl methyl ether and 500 ml of water are added, the organic phase is separated off, washed several times with water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography on silica gel (petroleum ether / EtOAc 8: 2).
Yield: 15.0 g (16.6% of theory)
C ₁₀ H ₈ BrNO ₂ (M = 254.09)
calc .: molar peak (MH) ^- : 252/254
fnd .: Mole peak (MH) ^- : 252/254
2.107b. 2-Bromo-4-cyanomethyl-benzoic acid
35 ml of 1M NaOH solution is added to a solution of 7.9 g (31.0 mmol) methyl 2-bromo-4-cyanomethyl-benzoate in 100 ml EtOH and the reaction mixture is refluxed for 1 hour and then stirred overnight at room temperature. Ice water is added and the mixture is acidified with dilute KHSO ₄ solution. The precipitate is filtered off with suction, washed with water and dried at 50 ° C.
Yield: 6.2 g (83.3% of theory)
C ₉ H ₆ BrNO ₂ (M = 240.06)
calc .: Mole peak (MH) ^- : 238/240 fnd .: Mole peak (MH) ^- : 238/240
Retention time HPLC: 3.99 min (Method B)
2.107c. (3-Bromo-4-hydroxymethyl-phenyl) -acetonitrile
1.78 g (11 mmol) CDI is added to a solution of 2.4 g (10 mmol) 2-bromo-4-cyanomethyl-benzoic acid in 50 ml THF and the water bath is heated until gas evolution ceases. This is then added to a solution of 0.76 g (20 mmol) NaBH _{4 in} 50 ml water while the temperature should not exceed 30 ° C. Stirring is continued for a further 2 hours at room temperature, the reaction mixture is carefully acidified with dilute KHSO ₄ solution, exhaustively extracted with tert.-butyl methyl ether, the organic phase is washed with water and dried over MgSO ₄ . It is filtered through activated charcoal and the solvent is removed in vacuo.
Yield: 2.2 g (97.3% of theory)
C ₉ H ₈ BrNO (M = 226.07)
calc .: Mole peak (MH) ^- : 224/226 fnd .: Mole peak (MH) ^- : 224/226
R _f value: 0.6 (silica gel, CH ₂ Cl ₂ / MeOH 9: 1).

2.107d. (3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile 1.25 ml (9 mmol) of triethylamine in 1.9 g of (3-bromo-4-hydroxymethyl-phenyl) -acetonitrile (8.4 g) in 50 ml of CH2Cl2. The solution is cooled to 0 ° C. and a solution of 0.66 ml (8.5 mmol) of methanesulfonic acid chloride in 10 ml of CH ₂ Cl ₂ is added dropwise. The mixture is stirred for 1 hour at 0 ° C. and then a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH ₂ Cl ₂ is added dropwise with cooling with ice. The reaction mixture is heated to room temperature overnight, combined with water, the organic phase is separated, washed twice with water, filtered through activated carbon and evaporated in vacuo. The residue is coevaporated twice with toluene and the resulting product is further reacted without purification.
Yield: 2.25 g (95.9% of theory)
C ₁₃ H ₁₅ BrN ₂ (M = 279.18)
calc .: Mole peak (M + H) ⁺ : 279/281 fnd .: Mole peak (M + H) ⁺ : 279/281
R _f value: 0.5 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
2.107e. 2- (3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine 20 mg of Raney nickel in (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-in 5 ml of methanolic NH _{3 and} 5 ml of EtOAc Add to a solution of 225 mg (0.81 mmol) of acetonitrile and shake in a Parr autoclave for 1 hour at room temperature with 5 psi H ₂ at 0.35 kg / cm ² . The catalyst is filtered off, the solvent is evaporated in vacuo and the product is reacted further without purification.
Yield: 225 mg (98.1% of theory)
C ₁₃ H ₁₉ BrN ₂ (M = 283.21)
calc .: Mole peak (M + H) ⁺ : 283/285 fnd .: Mole peak (M + H) ⁺ : 283/285
R _f value: 0.08 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
2.107f. 4′-Chloro-biphenyl-4-carboxylic acid [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide hydrochloride According to General Procedure I, 2- (3-bromo Prepared from 220 mg (0.78 mmol) of 4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 186 mg (0.8 mmol) of 4′-chloro-biphenyl-4-carboxylic acid. After removal of the desiccant and solvent, the residue is taken up in isopropanol / tert.-butyl methyl ether, combined with ethereal HCl and evaporated in vacuo. The residue is taken up again in 20 ml of isopropanol, ground, filtered off with suction, washed with a little isopropanol and dried at 50 ° C.
Yield: 165 mg (39.6% of theory)
C ₂₆ H ₂₇ BrCl ₂ N ₂ O (M = 534.33)
calc .: Mole peak (M + H) ⁺ : 497/499/501 fnd .: Mole peak (M + H) ⁺ : 497/499/501
R _f value: 0.35 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Example 2.108:
4'-Chloro-biphenyl-4-carboxylic acid [2- (3-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

17.3 mg (0.28 mmol) of methylboric acid, 2.5 ml of 2M Na ₂ CO ₃ solution and 32 mg (0.03 mmol) of tetrakis- (triphenylphosphine) -palladium in 4 ml of 4′-chloro-biphenyl-4-carboxylic acid [2 -(3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide hydrochloride is added to a suspension of 150 mg (0.28 mmol) and the reaction mixture is refluxed for 5 hours. The hot suspension is suction filtered through a glass fiber filter and the filtrate is combined with half-saturated NaHCO ₃ solution, exhaustively extracted with EtOAc and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH 8: 2).
Yield: 20 mg (16.4% of theory)
C ₂₇ H ₂₉ ClN ₂ O (M = 433.0)
calc .: Mole peak (M + H) ⁺ : 433/435 fnd .: Mole peak (M + H) ⁺ : 433/435
Retention time HPLC: 6.47 min (Method A)
Example 2.109:
4'-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.109a. Ethyl 4- (2-amino-ethyl) -3-nitro-benzoate
5.78 g (57 mmol) of KNO ₃ was added batchwise to a solution of 12.0 g (52 mmol) of ethyl 4- (2-amino-ethyl) -benzoate in 80 ml of concentrated H ₂ SO ₄ cooled to −5 ° C. For 1 hour. The reaction solution is slowly added dropwise to ice water (temperature should not exceed 0 ° C.) and stirred for 1 hour. The precipitate is filtered off with suction, washed with water and dried at 50 ° C.
Yield: 8.2 g (66.2% of theory)
C ₁₁ H ₁₄ N ₂ O ₄ (M = 238.25)
calc .: Mole peak (M + H) ⁺ : 239 fnd .: Mole peak (M + H) ⁺ : 239
Retention time HPLC: 3.64 min (Method A)
2.109b. Ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoate Ethyl 4- (2-amino-ethyl)-according to General Procedure I Prepared from 8.2 g (34 mmol) of 3-nitro-benzoate and 7.91 g (34 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 7.7 g (50.0% of theory)
C ₂₄ H ₂₁ ClN ₂ O ₅ (M = 452.90)
calc .: Mole peak (M + H) ⁺ : 452/454 fnd .: Mole peak (M + H) ⁺ : 452/454
Retention time HPLC: 6.14 min (Method B)
2.109c. Ethyl 3-amino-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate 0.5 g of Raney nickel was added to ethyl 4- {2-[( 4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoate is added to a solution of 7.7 g (17 mmol) and the reaction mixture is placed in an autoclave at room temperature at 0.7 kg / cm ² ( Shake overnight with 10 psi) H ₂ . In order to complete the reaction, 50 ml of THF are added and the mixture is shaken for a further 2 hours. The catalyst is filtered off with suction, washed thoroughly with THF, the solvent is evaporated in vacuo, the residue is triturated with EtOAc, suction filtered again and dried in air.
Yield: 5.0 g (69.5% of theory)
C ₂₄ H ₂₃ ClN ₂ O ₃ (M = 422.92)
calc .: Mole peak (M + H) ⁺ : 423/425 fnd .: Mole peak (M + H) ⁺ : 423/425
Retention time HPLC: 5.71 minutes (Method B)

2.109d. Ethyl 3-bromo-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate
Add 20 ml of 48% HBr to a solution of 5.0 g (7.69 mmol) of ethyl 3-amino-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate in 20 ml of water And cool to 0 ° C. A solution of 0.9 g NaNO ₂ (13 mmol) in 5.2 ml water is then added dropwise such that the temperature does not exceed 5 ° C. and the mixture is stirred at 0 ° C. for a further 10 minutes. A solution of 1.87 g (13 mmol) of CuBr in 6.65 ml of 48% HBr is then immediately added dropwise at this temperature. The reaction mixture is then heated to 60 ° C. for 1 hour. Water is added and the mixture is exhaustively extracted with EtOAc. The organic phase is washed with water and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue is purified by chromatography on silica gel (petroleum ether / EtOAc 6: 4).
Yield: 1.3 g (34.7% of theory)
C ₂₄ H ₂₁ BrClNO ₃ (M = 486.80)
calc .: Mole peak (M + H) ⁺ : 486/488/490 fnd .: Mole peak (M + H) ⁺ : 486/488/490
R _f value: 0.55 (silica gel, petroleum ether / EtOAc 6: 4).
2.109e. 3-Bromo-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid
Suspension of 1.3 g (2.67 mmol) of ethyl 3-bromo-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate in 6 ml of 1N NaOH solution in 20 ml EtOH and 5 ml THF Add to the liquor and stir the reaction mixture at room temperature overnight. It is evaporated in vacuo, the residue is combined with water and neutralized with 1N HCl, after which the product is precipitated. Stirring is continued for another hour while cooling with ice, the mixture is filtered with suction, washed with water and the product is dried at 50 ° C.
Yield: 1.2 g (97.9% of theory)
C ₂₂ H ₁₇ BrClNO ₃ (M = 458.74)
calc .: Mole peak (M + H) ⁺ : 456/458/460 fnd .: Mole peak (M + H) ⁺ : 456/458/460
Retention time HPLC: 5.51 min (Method B)
2.109f. 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-hydroxymethyl-phenyl) -ethyl] -amide
A solution of 1.2 g (2.62 mmol) of 3-bromo-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoic acid in 0.6 ml of DMF in 0.64 g (3.92 mmol) of CDI And the mixture is heated to 50 ° C. until gas evolution ceases. The reaction mixture is added to a solution of 0.3 g (7.85 mmol) NaBH _{4 in} 10 ml water, stirred at room temperature for 1 hour, acidified with dilute KHSO ₄ solution and exhaustively extracted with EtOAc. The organic phase is washed with half-saturated NaHCO ₃ solution and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 0.87 g (74.8% of theory)
C ₂₂ H ₁₉ BrClNO ₂ (M = 444.76)
calc .: Mole peak (M + H) ⁺ : 444/446/448 fnd .: Mole peak (M + H) ⁺ : 444/446/448
Retention time HPLC: 8.07 minutes (Method A)

2.109 g. 4′-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-chloromethyl-phenyl) -ethyl] -amide 0.24 ml (2.93 mmol) of pyridine in 4 ml of CH ₂ Cl ₂ Add to a solution of 0.87 g (1.96 mmol) of '-chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-hydroxymethyl-phenyl) -ethyl] -amide and cool to 0 ° C. 0.21 ml (2.93 mmol) thionyl chloride is added and the mixture is stirred at this temperature for 1 hour and then warmed to room temperature. Water is added, the mixture is filtered through celite, the aqueous phase is extracted with CH ₂ Cl ₂ and the combined organic phases are dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 0.66 g (72.8% of theory)
C ₂₂ H ₁₈ BrCl ₂ NO (M = 463.21)
calc .: Mole peak (M + H) ⁺ : 462/464/466 fnd .: Mole peak (M + H) ⁺ : 462/464/466
Retention time HPLC: 6.37 min (Method B)
2.109h. 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
0.59 g (4.28 mmol) of K ₂ CO ₃ and 0.24 ml (2.85 mmol) of pyrrolidine were added to 4′-chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-chloromethyl-phenyl) in 20 ml of acetonitrile and 6 ml of DMF. ) -Ethyl] -amide is added to a solution of 0.66 g (1.43 mmol) and stirred at room temperature for 5 hours. Water is added, the mixture is exhaustively extracted with EtOAc, the organic phase is washed several times with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1).
Yield: 0.2 g (28.2% of theory)
C ₂₆ H ₂₆ BrClN ₂ O (M = 497.87)
calc .: Mole peak (M + H) ⁺ : 497/499/501 fnd .: Mole peak (M + H) ⁺ : 497/499/501
Retention time HPLC: 4.39 min (Method B)
Example 2.110:
4'-Chloro-biphenyl-4-carboxylic acid [2- (2-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

4'-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 200 mg (0.40 mmol) and methylboric acid 27.3 as in Example 2.108 Prepared from mg (0.44 mmol) by refluxing for only 2 hours and purifying the product by HPLC.
Yield: 62 mg (35.6% of theory)
C ₂₇ H ₂₉ ClN ₂ O (M = 433.0)
calc .: Mole peak (M + H) ⁺ : 433/435 fnd .: Mole peak (M + H) ⁺ : 433/435
Retention time HPLC: 6.15 min (Method A)
Example 2.111:
4'-Chloro-biphenyl-4-carboxylic acid [2- (2-nitro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.111a. 4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoic acid
200 ml (0.44 mmol) 200 ml (0.44 mmol) ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoate (Example 2.109b) in 10 ml EtOH And the reaction mixture is stirred at room temperature for 1 hour. The mixture is evaporated in vacuo, water and 2 ml of 1N HCl solution are added to the residue and the suspension is stirred in an ice bath for 30 minutes. The product is filtered off with suction, washed with water and dried at 50 ° C.
Yield: 180 mg (95.9% of theory)
C ₂₂ H ₁₇ ClN ₂ O ₅ (M = 424.84)
calc .: Mole peak (M + H) ⁺ : 425/427 fnd .: Mole peak (M + H) ⁺ : 425/427
R _f values: 0.07 (silica _{gel, EtOAc / MeOH / NH 3 9} : 1: 0.1).
2.111b. 4′-Chloro-biphenyl-4-carboxylic acid- [2- (4-hydroxymethyl-2-nitro-phenyl) -ethyl] -amide 4- {2-[( Prepared from 180 mg (0.42 mmol) of 4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-nitro-benzoic acid.
Yield: 110 mg (63.1% of theory)
C ₂₂ H ₁₉ ClN ₂ O ₄ (M = 410.86)
calc .: Mole peak (M + H) ⁺ : 411/413 fnd .: Mole peak (M + H) ⁺ : 411/413
Retention time HPLC: 8.27 min (Method A)
2.111c. 4′-chloro-biphenyl-4-carboxylic acid [2- (2-nitro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide CH ₂ cooled to 5 ° C. with 23 μL of methanesulfonic acid chloride Gradually add a solution of 110 mg (0.27 mmol) of 4′-chloro-biphenyl-4-carboxylic acid- [2- (4-hydroxymethyl-2-nitro-phenyl) -ethyl] -amide and 48 μL of triethylamine in 5 ml of Cl _2. Add dropwise. The solution is heated to 40 ° C. for 1 hour, 5 ml of DMF and 115 μL (1.34 mmol) of pyrrolidine are added, the mixture is heated to 80 ° C. for a further hour, during which time CH ₂ Cl ₂ is evaporated. The reaction mixture is evaporated in vacuo, the residue is combined with water, extracted exhaustively with EtOAc and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by HPLC.
Yield: 11 mg (8.8% of theory)
C ₂₆ H ₂₆ ClN ₃ O ₃ (M = 463.97)
calc .: Mole peak (M + H) ⁺ : 464/466 fnd .: Mole peak (M + H) ⁺ : 464/466
Retention time HPLC: 6.44 min (Method A)
Example 2.112:
4'-Chloro-biphenyl-4-carboxylic acid [2- (2-methanesulfonylamino-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.112a. Ethyl 4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-methanesulfonylamino-benzoate 44 μL (0.57 mmol) of methanesulfonic acid chloride cooled to 0 ° C. To a solution of 200 mg (0.47 mmol) of ethyl 3-amino-4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzoate (Example 2.109c) in 5 ml of pyridine Gradually add dropwise and the reaction mixture is stirred at room temperature for 1 hour. It is combined with ice water, extracted thoroughly with EtOAc, the organic phase is washed several times with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 230 mg (97.1% of theory)
C ₂₅ H ₂₅ ClN ₂ O ₅ S (M = 501.01)
calc .: Mole peak (M + H) ⁺ : 501/503 fnd .: Mole peak (M + H) ⁺ : 501/503
Retention time HPLC: 5.66 min (Method B)
2.112b. 4- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-methanesulfonylamino-benzoic acid Ethyl 4- {2- Prepared from 230 mg (0.46 mmol) of [(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-methanesulfonylamino-benzoate.
Yield: 180 mg (theoretical 82.9)
C ₂₃ H ₂₁ ClN ₂ O ₅ S (M = 472.95)
calc .: Mole peak (MH) ^- : 471/473 fnd .: Mole peak (MH) ^- : 471/473
Retention time HPLC: 7.67 min (Method A)

2.112c. 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-hydroxymethyl-2-methanesulfonylamino-phenyl) -ethyl] -amide 4- {2- [ Prepared from 180 mg (0.38 mmol) of (4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -3-methanesulfonylamino-benzoic acid.
Yield: 150 mg (85.8% of theory)
C ₂₃ H ₂₃ ClN ₂ O ₄ S (M = 458.97)
calc .: Mole peak (M + H) ⁺ : 459/461 fnd .: Mole peak (M + H) ⁺ : 459/461
Retention time HPLC: 7.53 min (Method A)
2.112d. 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-methanesulfonylamino-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 4'- in the same manner as Example 2.111c Prepared from 150 mg (0.33 mmol) of chloro-biphenyl-4-carboxylic acid [2- (4-hydroxymethyl-2-methanesulfonylamino-phenyl) -ethyl] -amide and 140 μL (1.64 mmol) of pyrrolidine.
The product is obtained as formate after purification by HPLC.
Yield: 18 mg (9.9% of theory)
C ₂₇ H ₃₀ ClN ₃ O ₃ S * CH ₂ O ₂ (M = 558.10)
calc .: Mole peak (M + H) ⁺ : 512/514 fnd .: Mole peak (M + H) ⁺ : 512/514
Retention time HPLC: 6.13 min (Method A)
Example 2.113:
4'-chloro-biphenyl-4-carboxylic acid [2- (3-pyridin-4-yl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

4'-Chloro-biphenyl-4-carboxylic acid [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 200 mg (0.40 mmol) and pyridine-4 as in Example 2.108 -Prepared from 74 mg (0.60 mmol) of boric acid and the product is purified by HPLC.
Yield: 13 mg (6.5% of theory)
C ₃₁ H ₃₀ ClN ₃ O (M = 496.06)
calc .: Mole peak (M + H) ⁺ : 496/498 fnd .: Mole peak (M + H) ⁺ : 496/498
Retention time HPLC: 6.37 min (Method A)
Example 2.114:
Methyl 5- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-benzoate

2.114a. Methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl-benzoate 0.5 ml (3.58 mmol) of triethylamine, 40 mg (0.18 mmol) of Pd (OAc) ₂ and 99 mg of 1,1′-diphenylphosphino-ferrocene (0.18 mmol) Is added to a solution of 500 mg (1.79 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (Example 2.107d) in 10 ml of MeOH and 10 ml of DMF. The reaction mixture is stirred for 15 hours at 50 ° C. with 2 bar of CO in an autoclave. In order to complete the reaction, another 0.5 ml of triethylamine, 40 mg of Pd (OAc) ₂ and 99 mg of 1,1′-diphenylphosphino-ferrocene are added, and the mixture is added at 50 ° C. with 2 bar of CO for another 10 hours and 4 Stir overnight at bar CO and 70 ° C. The solvent is evaporated in vacuo and the residue is combined with EtOAc and extracted twice with water. The aqueous phase is saturated with K ₂ CO ₃ , extracted exhaustively with EtOAc and dried over MgSO ₄ . After removal of the desiccant and solvent, the product remains as a black oil that is further reacted without purification.
Yield: 380 mg (82.1% of theory).
C ₁₅ H ₁₈ N ₂ O ₂ (M = 258.32)
calc .: Mole peak (M + H) ⁺ : 259 fnd .: Mole peak (M + H) ⁺ : 259
Retention time HPLC: 2.49 min (Method B)
2.114b. Methyl 5- (2-amino-ethyl) -2-pyrrolidin-1-ylmethyl-benzoate 100 mg of Raney nickel in 380 mg (1.47 of methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl-benzoate in 20 ml of methanolic NH ₃ The reaction mixture is hydrogenated with 1.4 kg / cm ² (20 psi) H ₂ at room temperature for 27 hours. The catalyst is filtered off with suction, the solvent is removed and the residue is reacted further without purification.
Yield: 330 mg (85.5% of theory).
C ₁₅ H ₂₂ N ₂ O ₂ (M = 262.36)
calc .: Mole peak (M + H) ⁺ : 263 fnd .: Mole peak (M + H) ⁺ : 263
Retention time HPLC: 1.40 minutes (Method A)
2.114c. Methyl 5- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-benzoate Methyl 5- (2-amino according to General Procedure I Prepared from 330 mg (1.26 mmol) of 4-ethyl) -2-pyrrolidin-1-ylmethyl-benzoate and 293 mg (1.26 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 315 mg (52.5% of theory)
C ₂₈ H ₂₉ ClN ₂ O ₃ (M = 477.01)
calc .: Mole peak (M + H) ⁺ : 477/479 fnd .: Mole peak (M + H) ⁺ : 477/479
Retention time HPLC: 6.82 min (Method A)
Example 2.115:
5- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-benzoic acid

Prepared from 310 mg (0.65 mmol) of methyl 5- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-benzoate as in Example 2.111a did.
Yield: 85 mg (28.2% of theory)
C ₂₇ H ₂₇ ClN ₂ O ₃ (M = 462.98)
calc .: Mole peak (M + H) ⁺ : 463/465 fnd .: Mole peak (M + H) ⁺ : 463/465
Retention time HPLC: 6.30 minutes (Method A)
Example 2.116:
tert.butyl (5- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl-phenyl) -carbamate

0.27 ml (1.92 mmol) of triethylamine and 0.41 ml (1.92 mmol) of diphenyl azide-phosphate in 5- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl}-in 10 ml of tert. Butanol A solution of 740 mg (1.6 mmol) of 2-pyrrolidin-1-ylmethyl-benzoic acid is added and the reaction mixture is refluxed for 5 hours. It is evaporated in vacuo, the residue is combined with CH ₂ Cl ₂ and extracted with 1N NaOH solution and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography on silica gel.
Yield: 85 mg (28.2% of theory)
C ₃₁ H ₃₆ ClN ₃ O ₃ (M = 534.10)
calc .: Mole peak (M + H) ⁺ : 534/536 fnd .: Mole peak (M + H) ⁺ : 534/536
Retention time HPLC: 4.82 min (Method B)
Example 2.117:
4'-chloro-biphenyl-4-carboxylic acid [2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.117a. (4-Pyrrolidin-1-ylmethyl-3-trimethylsilanylethynyl-phenyl) -acetonitrile
(3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl) -acetonitrile (Example 2.107d) 0.36 g (1.29 mmol), trimethylsilylacetylene 0.36 ml (2.58 mmol), triethylamine 0.36 ml (2.58 mmol) in 3 ml of DMF, A suspension of 25 mg (0.13 mmol) CuI and 0.15 g (0.13 mmol) tetrakis- (triphenylphosphine) -palladium is stirred in a microwave (CEM) for 15 minutes at 100 ° C. and 200 watts. After cooling the reaction mixture, saturated NaCl solution is added, the mixture is exhaustively extracted with EtOAc and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography on silica gel (EtOAc).
Yield: 50 mg (13.1% of theory)
C ₁₈ H ₂₄ N ₂ Si (M = 296.49)
calc .: Mole peak (M + H) ⁺ : 297 fnd .: Mole peak (M + H) ⁺ : 297
Retention time HPLC: 6.39 min (Method A)

2.117b. 2- (3-Ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine 20 mg of Raney nickel in (4-pyrrolidin-1-ylmethyl-3-trimethylsilanylethynyl-phenyl) in 5 ml of methanolic NH ₃ - added to a solution of acetonitrile 50 mg (0.17 mmol), the reaction mixture is shaken at room temperature for 3 bar H ₂ for 22 hours. The catalyst is filtered off with suction and the solvent is removed in vacuo. The crude product is further reacted without purification.
Yield: 39 mg (100% of theory)
C ₁₅ H ₂₄ N ₂ (M = 232.37)
calc .: Mole peak (M + H) ⁺ : 233 fnd .: Mole peak (M + H) ⁺ : 233
2.117c. 4'-Chloro-biphenyl-4-carboxylic acid [2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide 2- (3-ethyl-4 Prepared from 40 mg (0.17 mmol) of -pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 48 mg (0.21 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 2 mg (2.6% of theory)
C ₂₈ H ₃₁ ClN ₂ O (M = 447.03)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
Retention time HPLC: 6.87 min (Method A)
Example 2.118:
4'-Chloro-biphenyl-4-carboxylic acid [2- (6-pyrrolidin-1-ylmethyl-pyridin-3-yl) -ethyl] -amide

2.118a. Methyl 6-dibromomethyl-nicotinate
53.4 g (0.3 mol) NBS and 2 g dibenzoyl peroxide are added to a solution of 38.96 g (0.25 mol) methyl 6-methyl-nicotinate in 1 liter CCl ₄ and the reaction mixture is refluxed overnight. Then 26.7 g (0.15 mol) of NBS and 1 g of dibenzoyl peroxide are added and the mixture is refluxed again for 24 hours. After cooling the reaction mixture, the precipitate is filtered off with suction, the solvent is removed and the residue is purified by chromatography.
Yield: 15.0 g (19.4% of theory)
C ₈ H ₇ Br ₂ NO ₂ (M = 308.96)
calc .: Mole peak (M + H) ⁺ : 308/310/312 fnd .: Mole peak (M + H) ⁺ : 308/310/312
R _f value: 0.6 (silica gel, petroleum ether / EtOAc 8: 2).
2.118b. Methyl 6-dimethoxymethyl-nicotinate
13.9 ml NaOMe (30% in MeOH, 75 mmol) in 100 ml MeOH is heated to boiling. A solution of 11.0 g (34.1 mmol) methyl 6-dibromomethyl-nicotinate in 10 ml MeOH is added dropwise to the boiling solution and refluxed overnight. To complete the reaction, an additional 1.5 ml (8.1 mmol) of NaOMe solution is added and the mixture is refluxed again for 24 hours. The reaction mixture is evaporated in vacuo, the residue is combined with dilute KHSO ₄ solution, neutralized with dilute NaHCO ₃ solution, exhaustively extracted with EtOAc, the organic phase is washed with water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 5.0 g (69.5% of theory)
C ₁₀ H ₁₃ NO ₄ (M = 211.22)
calc .: Mole peak (M + H) ⁺ : 212 fnd .: Mole peak (M + H) ⁺ : 212
R _f value: 0.44 (silica gel, petroleum ether / EtOAc 6: 4).

2.118c. 6-Dimethoxymethyl-nicotinic acid
15 ml of 1N NaOH solution is added to a solution of 2.8 g (13.26 mmol) methyl 6-dimethoxymethyl-nicotinate in 50 ml MeOH and stirred at room temperature for 24 hours. The reaction mixture is neutralized with 15 ml of 1N HCl, evaporated in vacuo, the residue is triturated with MeOH / THF, the precipitate is filtered off with suction and the filtrate is evaporated. The product obtained is further reacted without purification.
Yield: 2.6 g (99.4% of theory)
C ₉ H ₁₁ NO ₄ (M = 197.19)
calc .: Mole peak (M + H) ⁺ : 198 fnd .: Mole peak (M + H) ⁺ : 198
Retention time HPLC: 3.65 minutes (Method A)
2.118d. (6-Dimethoxymethyl-pyridin-3-yl) -methanol In analogy to example 2.109f, using THF as solvent and tert.butyl methyl ether for extraction, 6-dimethoxymethyl- Prepared from 2.7 g (13.7 mmol) of nicotinic acid.
Yield: 2.1 g (83.7% of theory)
C ₉ H ₁₃ NO ₃ (M = 183.21)
calc .: Mole peak (M + H) ⁺ : 184 fnd .: Mole peak (M + H) ⁺ : 184
Retention time HPLC: 2.85 min (Method A)
2.118e. 5-Chloromethyl-2-dimethoxymethyl-pyridine 0.3 ml (4.14 mmol) thionyl chloride, dissolved in a small amount of CH ₂ Cl ₂ , in (10-dimethoxy) in 10 ml CH ₂ Cl ₂ cooled to 0 ° C. Methyl-pyridin-3-yl) -methanol is slowly added dropwise to a solution of 500 mg (2.73 mmol) and stirred at this temperature for another 30 minutes. The reaction mixture is diluted with CH ₂ Cl ₂ , washed with cold NaHCO ₃ solution and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 500 mg (90.8% of theory)
C ₉ H ₁₂ ClNO ₂ (M = 201.65)
calc .: Mole peak (M + H) ⁺ : 202/204 fnd .: Mole peak (M + H) ⁺ : 202/204
R _f value: 0.3 (silica gel, petroleum ether / EtOAc 6: 4).

2.118f. (6-Dimethoxymethyl-pyridin-3-yl) -acetonitrile
20 ml of DMSO was added to 5.21 g (80 mmol) of KCN in 5.2 ml of water, and a solution of 500 mg (2.48 mmol) of 5-chloromethyl-2-dimethoxymethyl-pyridine in 10 ml of DMSO was added dropwise at 80 ° C. The reaction mixture is kept at 80 ° C. for a further hour. It is poured into 200 ml of water, saturated with NaCl, exhaustively extracted with EtOAc, the organic phase is dried over MgSO ₄ and filtered through activated charcoal. The filtrate is evaporated and the residue is purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1).
Yield: 330 mg (69.2% of theory)
C ₁₀ H ₁₂ N ₂ O ₂ (M = 192.22)
calc .: Mole peak (M + H) ⁺ : 193 fnd .: Mole peak (M + H) ⁺ : 193
R _f value: 0.48 (silica gel, CH ₂ Cl ₂ / MeOH 9: 1).
2.118 g. 2- (6-Dimethoxymethyl-pyridin-3-yl) -ethylamine 50 mg of Raney nickel in 330 ml (1.72 mmol) of (6-dimethoxymethyl-pyridin-3-yl) -acetonitrile in 10 ml of methanolic NH ₃ And the reaction mixture is hydrogenated in a Pearl autoclave at 30 ° C. for 15 hours under 3 bar of H ₂ . The catalyst is filtered off, the solvent is evaporated in vacuo and the residue is reacted further without purification.
Yield: 340 mg (100% of theory)
C ₁₀ H ₁₆ N ₂ O ₂ (M = 196.25)
calc .: Mole peak (M + H) ⁺ : 197 fnd .: Mole peak (M + H) ⁺ : 197
Retention time HPLC: 1.3 minutes (Method A)
2.118h. 4'-Chloro-biphenyl-4-carboxylic acid [2- (6-dimethoxymethyl-pyridin-3-yl) -ethyl] -amide According to general procedure I 2- (6-Dimethoxymethyl-pyridine-3 Prepared from 340 mg (1.73 mmol) -yl) -ethylamine and 419 mg (1.80 mmol) 4'-chloro-biphenyl-4-carboxylic acid.
Yield: 210 mg (28.4% of theory)
C ₂₃ H ₂₃ ClN ₂ O ₃ (M = 410.90)
calc .: Mole peak (M + H) ⁺ : 411/413 fnd .: Mole peak (M + H) ⁺ : 411/413
R _f value: 0.4 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).

2.118i. 4'-Chloro-biphenyl-4-carboxylic acid [2- (6-formyl-pyridin-3-yl) -ethyl] -amide
5 ml of 12% HCl is added to a solution of 205 mg (0.5 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (6-dimethoxymethyl-pyridin-3-yl) -ethyl] -amide in 10 ml of MeOH. The reaction mixture is stirred at room temperature for 4 hours and heated to 80 ° C. overnight. An additional 2.5 ml of 12% HCl is added and the mixture is heated at 80 ° C. for an additional 8 hours and at 100 ° C. overnight. The reaction mixture is combined with 50 ml of water, adjusted to pH 8 with Na ₂ CO ₃ solution, exhaustively extracted with CH ₂ Cl ₂ and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 180 mg (98.7% of theory)
C ₂₁ H ₁₇ ClN ₂ O ₂ (M = 364.84)
calc .: Mole peak (M + H) ⁺ : 365/367 fnd .: Mole peak (M + H) ⁺ : 365/367
Retention time HPLC: 5.25 min (Method A)
2.118k. 4′-chloro-biphenyl-4-carboxylic acid [2- (6-pyrrolidin-1-ylmethyl-pyridin-3-yl) -ethyl] -amide pyrrolidine 50 μL (0.6 mmol), NaBH ₃ CN 37.7 mg ( 0.6 mmol) and 2 ml of MeOH are added to a solution of 180 mg (0.49 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (6-formyl-pyridin-3-yl) -ethyl] -amide in 5 ml of acetonitrile. The pH value is adjusted to 5-6 with glacial acetic acid and the mixture is stirred at room temperature for 5 hours. The reaction mixture is acidified with 1M KHSO ₄ solution, made alkaline with 2M Na ₂ CO ₃ solution, exhaustively extracted with CH ₂ Cl ₂ and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Yield: 25 mg (12.1% of theory)
C ₂₅ H ₂₆ ClN ₃ O (M = 419.96)
calc .: Mole peak (M + H) ⁺ : 420/422 fnd .: Mole peak (M + H) ⁺ : 420/422
R _f value: 0.2 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
Example 2.119:
4'-Chloro-biphenyl-4-carboxylic acid [2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -amide

2.119a. Methyl 6-hydroxymethyl-nicotinate 5-Methylpyridine-2,5-dicarboxylate as in Example 2.109f using THF as solvent and tert-butyl methyl ether for extraction. Prepared from 5.0 g (27.6 mmol).
Yield: 2.0 g (43.3% of theory)
C ₈ H ₉ NO ₃ (M = 167.17)
calc .: Mole peak (M + H) ⁺ : 168 fnd .: Mole peak (M + H) ⁺ : 168
R _f value: 0.2 (silica gel, CH ₂ Cl ₂ / MeOH 95: 5).
2.119b. Methyl 6-chloromethyl-nicotinate 2.0 g (11.96) of methyl 6-hydroxymethyl-nicotinate in 100 ml of CH ₂ Cl ₂ cooled to 0 ° C. with 1.06 ml (13 mmol) of pyridine and 1.08 ml (13 mmol) of thionyl chloride. Is slowly added dropwise to the solution. This is stirred at 0 ° C. for a further hour and then gradually heated to room temperature. To complete the reaction, an additional 1 ml (12 mmol) of thionyl chloride is added and the mixture is stirred at room temperature for 1 hour. The reaction mixture is added to water and the organic phase is separated, washed with dilute NaHCO ₃ solution and water and dried over MgSO ₄ . This is filtered through activated charcoal and the solvent is evaporated in vacuo. The product obtained is further reacted without purification.
Yield: 1.7 g (65.1% of theory)
C ₈ H ₈ ClNO ₂ (M = 185.61)
calc .: Mole peak (M + H) ⁺ : 186/188 fnd .: Mole peak (M + H) ⁺ : 186/188
Retention time HPLC: 6.7 minutes (Method A)
2.119c. Methyl 6-cyanomethyl-nicotinate 1.5 g of methyl 6-chloromethyl-nicotinate as in Example 2.118f, using cyclohexane / EtOAc 8: 2 as eluent for chromatographic purification on silica gel. (8.08 mmol) and KCN 5.2 g (80 mmol).
Yield: 220 mg (15.5% of theory)
C ₉ H ₈ N ₂ O ₂ (M = 176.18)
calc .: Mole peak (M + H) ⁺ : 177 fnd .: Mole peak (M + H) ⁺ : 177
R _f value: 0.6 (silica gel, petroleum ether / EtOAc 1: 1).

2.119d. Methyl 6- (2-amino-ethyl) -nicotinate 20 mg of Raney nickel is added to a solution of 75 mg (0.43 mmol) of methyl 6-cyanomethyl-nicotinate in 5 ml of methanolic NH ₃ and the reaction mixture is placed in a pearl autoclave. Hydrogenate under 3 bar H ₂ at 30 ° C. for 6 hours. The catalyst is filtered off, the solvent is evaporated in vacuo and the residue is reacted further without purification.
Yield: 70 mg (90.3% of theory)
C ₉ H ₁₂ N ₂ O ₂ (M = 180.21)
calc .: Mole peak (M + H) ⁺ : 181 fnd .: Mole peak (M + H) ⁺ : 181
Retention time HPLC: 2.5 minutes (Method A)
2.119e. Methyl 6- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -nicotinate 70 mg (0.39) of methyl 6- (2-amino-ethyl) -nicotinate according to General Procedure I Mmol) and 100 mg (0.43 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 150 mg (88.3% of theory)
C ₂₂ H ₁₉ ClN ₂ O ₃ (M = 394.86)
calc .: Mole peak (M + H) ⁺ : 395/397 fnd .: Mole peak (M + H) ⁺ : 395/397
Retention time HPLC: 8.6 minutes (Method A)
2.119f. 6- {2-[(4'-Chloro-biphenyl-4-carbonyl) -amino] -ethyl} -nicotinic acid
0.8 ml of 1M NaOH solution is added to a solution of 150 mg (0.38 mmol) of methyl 6- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -nicotinate in 25 ml of MeOH and the reaction mixture Is refluxed for 1 hour. It is neutralized with 0.8 ml of 1N HCl, evaporated in vacuo, the residue is stirred with water and the precipitate is removed by suction filtration. It is dissolved in THF and the solution is dried over MgSO ₄ , filtered and evaporated in vacuo. The residue is reacted further without purification.
Yield: 90 mg (62.2% of theory)
C ₂₁ H ₁₇ ClN ₂ O ₃ (M = 380.83)
calc .: Mole peak (M + H) ⁺ : 381/383 fnd .: Mole peak (M + H) ⁺ : 381/383
Retention time HPLC: 6.9 minutes (Method A)

2.119 g. 4′-Chloro-biphenyl-4-carboxylic acid [2- (5-hydroxymethyl-pyridin-2-yl) -ethyl] -amide As in Example 2.109f, THF as solvent and extraction Prepared from 90 mg (0.24 mmol) of 6- {2-[(4′-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -nicotinic acid using tert-butyl methyl ether.
Yield: 50 mg (56.8% of theory)
C ₂₁ H ₁₉ ClN ₂ O ₂ (M = 366.85)
calc .: Mole peak (M + H) ⁺ : 367/369 fnd .: Mole peak (M + H) ⁺ : 367/369
R _f value: 0.5 (silica gel, CH ₂ Cl ₂ / MeOH 9: 1).
2.119h. 4′-Chloro-biphenyl-4-carboxylic acid [2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -amide CH ₂ Cl ₂ cooled to 0 ° C. with 22 μL of thionyl chloride The reaction was added dropwise to a solution of 50 mg (0.14 mmol) of 4′-chloro-biphenyl-4-carboxylic acid [2- (5-hydroxymethyl-pyridin-2-yl) -ethyl] -amide in 5 ml The mixture is gradually warmed to room temperature. After 1 hour at room temperature, an additional 22 μL of thionyl chloride is added dropwise to complete the reaction and stirring is continued for 1 hour. The reaction mixture is diluted with 30 ml of CH ₂ Cl ₂ , combined with ice water, made alkaline with NaHCO ₃ solution, the organic phase is separated, washed with water and dried over MgSO ₄ . After removal of the desiccant, 50 μL (0.6 mmol) of pyrrolidine is added to the solution and the reaction mixture is stirred overnight at room temperature. It is evaporated in vacuo and the residue is purified by HPLC chromatography.
Yield: 2.4 mg (4.1% of theory)
C ₂₅ H ₂₆ ClN ₃ O (M = 419.96)
calc .: Mole peak (M + H) ⁺ : 420/422 fnd .: Mole peak (M + H) ⁺ : 420/422
R _f value: 0.3 (silica gel, CH ₂ Cl ₂ / MeOH 9: 1).
Retention time HPLC: 6.0 minutes (Method A)
Example 2.120:
4'-chloro-biphenyl-4-carboxylic acid {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -amide

2.120a. Tert.butyl [2- (4-acetyl-phenyl) -ethyl] -carbamate
5.46 g (25 mmol) of BOC-anhydride was added to 4.99 g (25 mmol) of 1- [4- (2-amino-ethyl) -phenyl] -ethanone (used as hydrochloride) in 100 ml of CH ₂ Cl ₂ . Add to the solution and slowly add 25 ml of 1N NaOH solution dropwise at room temperature, and after the addition is complete, stir the mixture at room temperature for 2 hours. The reaction mixture is filtered through celite, washed twice with water and dried over MgSO ₄ . It is filtered through activated charcoal, evaporated in vacuo and the product is reacted further without purification.
Yield: 6.4 g (97.2% of theory)
C ₁₅ H ₂₁ NO ₃ (M = 263.34)
calc .: Mole peak (M + H) ⁺ : 262 fnd .: Mole peak (M + H) ⁺ : 262
R _f value: 0.88 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).
2.120b. Tert.butyl {2- [4- (1-hydroxy-ethyl) -phenyl] -ethyl} -carbamate
NaBH ₄ 4.72 g (125 mmol) is added batchwise to a solution of 6.58 g (25 mmol) of tert.butyl [2- (4-acetyl-phenyl) -ethyl] -carbamate in 250 ml of MeOH at room temperature and the reaction mixture is brought to completion Over stirring. It is carefully acidified with KHSO ₄ solution, exhaustively extracted with tert-butyl methyl ether, the organic phase is washed with saturated NaCl solution and dried over MgSO ₄ . After removal of the desiccant and solvent, the product remains as a slightly yellow oil that crystallizes on standing.
Yield: 5.4 g (81.4% of theory)
C ₁₅ H ₂₃ NO ₃ (M = 265.36)
calc .: Mole peak (M + H) ⁺ : 266 fnd .: Mole peak (M + H) ⁺ : 266
R _f value: 0.4 (silica gel, petroleum ether / EtOAc 6: 4).

2.120c. Tert.butyl {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -carbamate
0.66 ml (8.5 mmol) of methanesulfonic acid chloride dissolved in 10 ml of CH ₂ Cl ₂ was added to tert.butyl {2- [4- (1-hydroxyl) in 50 ml of CH ₂ Cl ₂ cooled to 0 ° C. -Ethyl) -phenyl] -ethyl} -carbamate is added dropwise to a solution of 2.89 g (10.89 mmol). Stirring is continued for 1 hour at this temperature and then a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH ₂ Cl ₂ is slowly added dropwise. The reaction mixture is stirred overnight at room temperature, combined with dilute KHSO ₄ solution, the organic phase is separated, washed twice with dilute KHSO ₄ solution, the combined aqueous phase is basified with K ₂ CO ₃ solution, Extract thoroughly with tert-butyl methyl ether. The combined organic phases are washed several times with a small amount of water and dried over MgSO ₄ . After removal of the desiccant and solvent, the product is further reacted without purification.
Yield: 0.3 g (8.7% of theory)
C ₁₉ H ₃₀ N ₂ O ₂ (M = 318.46)
calc .: Mole peak (M + H) ⁺ : 319 fnd .: Mole peak (M + H) ⁺ : 319
R _f value: 0.22 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 9: 1: 0.1).

2.120d. 2- [4- (1-Pyrrolidin-1-yl-ethyl) -phenyl] -ethylamine 0.72 ml of trifluoroacetic acid in tert.butyl {2- [4- (1-pyrrolidine] in 20 ml of CH ₂ Cl ₂ Add to a solution of 300 mg (0.94 mmol) of 1-yl-ethyl) -phenyl] -ethyl} -carbamate and stir at room temperature for 1 hour. To complete the reaction, an additional 0.72 ml of trifluoroacetic acid is added and the reaction mixture is kept at room temperature for 1 hour. The solvent is evaporated in vacuo, the residue is taken up in water, made alkaline with 2N NaOH, exhaustively extracted with EtOAc and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the product is further reacted without purification.
Yield: 150 mg (72.9% of theory)
C ₁₄ H ₂₂ N ₂ (M = 218.35)
calc .: Mole peak (M + H) ⁺ : 219 fnd .: Mole peak (M + H) ⁺ : 219
R _f value: 0.15 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 8: 2: 0.2).
2.120e. 4′-Chloro-biphenyl-4-carboxylic acid {2- [4- (1-pyrrolidin-1-yl-ethyl) -phenyl] -ethyl} -amide 2- [4- ( Prepared from 150 mg (0.69 mmol) of 1-pyrrolidin-1-yl-ethyl) -phenyl] -ethylamine and 176 mg (0.76 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 150 mg (88.3% of theory)
C ₂₇ H ₂₉ ClN ₂ O (M = 433.0)
calc .: Mole peak (M + H) ⁺ : 433/435 fnd .: Mole peak (M + H) ⁺ : 433/435
Retention time HPLC: 6.33 min (Method A)
Example 2.121:
4'-chloro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide

2.121a. [4- (2-Amino-ethyl) -2-bromo-phenyl] -methanol 100 mg of Raney nickel in (3-bromo-4-hydroxymethyl-phenyl) -acetonitrile (Example) in 100 ml of THF and 50 ml of methanolic NH3 (See 2.107c.) 4 g (17.68 mmol) of solution are added and the reaction mixture is shaken in a Parr autoclave for 5 hours at room temperature with 5 psi H ₂ at 0.35 kg / cm ² . The catalyst is filtered off, the solvent is removed and the product is reacted further without purification.
Yield: 3.8 g (93.4% of theory)
C ₉ H ₁₂ BrNO (M = 230.11)
calc .: Mole peak (M + H) ⁺ : 230/232 fnd .: Mole peak (M + H) ⁺ : 230/232
Retention time HPLC: 1.85 min (Method A)
2.121b. Tert.butyl [2- (3-bromo-4-hydroxymethyl-phenyl) -ethyl] -carbamate
CH ₂ and 1M BOC-anhydride solution 17ml in Cl ₂ in CH ₂ Cl ₂ 50 ml [4- (2-amino - ethyl) -2-bromo - phenyl] - To a solution of methanol 3.8 g (16.51 mmol) Add and stir the reaction mixture overnight at room temperature. It is diluted with 100 ml of dilute KHSO ₄ solution and the organic phase is separated, washed with dilute NaHCO ₃ solution and water and dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by chromatography on silica gel.
Yield: 2.3 g (42.2% of theory)
C ₁₄ H ₂₀ BrNO ₃ (M = 330.22)
R _f value: 0.44 (silica gel, petroleum ether / EtOAc 6: 4).

2.121c. Tert.butyl [2- (3-Bromo-4-chloromethyl-phenyl) -ethyl] -carbamate 0.54 ml (6.5 mmol) thionyl chloride cooled to 0 ° C. in 50 ml CH ₂ Cl ₂ and 0.53 ml pyridine Was slowly added dropwise to a solution of 1.98 g (6.0 mmol) of tert.butyl [2- (3-bromo-4-hydroxymethyl-phenyl) -ethyl] -carbamate and stirred at 0 ° C. for an additional hour, It is then heated to room temperature. Water is added to the reaction mixture and the organic phase is washed with dilute KHSO ₄ solution and water and dried over MgSO ₄ . After filtration with activated charcoal and removal of the solvent, the product is further reacted without purification.
Yield: 2.0 g (95.6% of theory)
C ₁₄ H ₁₉ BrClNO ₂ (M = 348.67)
calc .: Mole peak (M + H) ⁺ : 348/350/352 fnd .: Mole peak (M + H) ⁺ : 348/350/352
R _f value: 0.6 (silica gel, petroleum ether / EtOAc 6: 4).
2.121d. Tert.butyl {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -carbamate
0.84 ml (11 mmol) of 2,5-dihydro-1H-pyrrole 1.9 g (5.45 mmol) of tert.butyl [2- (3-bromo-4-chloromethyl-phenyl) -ethyl] -carbamate in 50 ml of acetonitrile and A suspension of 2.5 g (18.1 mmol) of K ₂ CO ₃ is added and the reaction mixture is stirred overnight at room temperature. The suspension is filtered, the filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel.
Yield: 0.5 g (24.1% of theory)
C ₁₈ H ₂₅ BrN ₂ O ₂ (M = 381.32)
calc .: Mole peak (M + H) ⁺ : 381/383 fnd .: Mole peak (M + H) ⁺ : 381/383
R _f value: 0.58 (silica gel, CH ₂ Cl ₂ / MeOH 8: 2).

2.121E 2-. [3-bromo-4- (2,5-dihydro - pyrrol-1-ylmethyl) - phenyl] -. Tert ethylamine trifluoroacetic acid 5ml in CH ₂ Cl ₂ 50 ml butyl {2- [3 -Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -carbamate is added to a solution of 500 mg (1.31 mmol) and the reaction mixture is stirred at room temperature for 2 hours. It is evaporated in vacuo, combined with water and CH ₂ Cl ₂ , adjusted to alkaline pH with K ₂ CO ₃ solution, the organic phase is separated and washed again with water. It is evaporated in vacuo and the product is purified by chromatography on silica gel.
Yield: 350 mg (95.0% of theory)
C ₁₃ H ₁₇ BrN ₂ (M = 281.20)
calc .: Mole peak (M + H) ⁺ : 281/283 fnd .: Mole peak (M + H) ⁺ : 281/283
R _f value: 0.08 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 95: 5: 0.5).
2.121f. 4′-Chloro-biphenyl-4-carboxylic acid {2- [3-Bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide According to General Procedure I From 141 mg (0.5 mmol) of 2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethylamine and 116 mg (0.5 mmol) of 4′-chloro-biphenyl-4-carboxylic acid Prepared.
Yield: 140 mg (56.5% of theory)
C ₂₆ H ₂₄ BrClN ₂ O (M = 495.85)
calc .: Mole peak (M + H) ⁺ : 495/497/499 fnd .: Mole peak (M + H) ⁺ : 495/497/499
Retention time HPLC: 6.6 minutes (Method A)
Example 2.122:
4'-Bromo-3-fluoro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide

2.122a. 4'-Bromo-3-fluoro-biphenyl-4-carboxylic acid
1.04 g (5 mmol) of 4-bromophenylboric acid, 115 mg (0.1 mmol) of tetrakis- (triphenylphosphine) -palladium and 2 ml of 2M Na ₂ CO ₃ solution in 4-bromo-2-fluorobenzoic acid in 5 ml of DMF and 5 ml of dioxane A solution of 1.1 g (5 mmol) of acid is added in succession and the reaction mixture is refluxed for 2 hours. To complete the reaction, an additional 250 mg (1.25 mmol) of 4-bromophenylboric acid is added and the mixture is refluxed for a further 2 hours. The reaction mixture is filtered hot with a glass fiber filter, washed with water, acidified with dilute KHSO ₄ solution, and the precipitate formed is filtered off with suction and washed with water. The residue is triturated with acetonitrile and a small amount of MeOH, filtered to remove insolubles, the filtrate is evaporated, the residue is triturated with MeOH and the product is filtered off with suction.
Yield: 140 mg (9.5% of theory)
C ₁₃ H ₈ BrFO ₂ (M = 295.11)
calc .: Mole peak (M + H) ⁺ : 293/295 fnd .: Mole peak (M + H) ⁺ : 293/295
R _f value: 0.5 (silica gel, CH ₂ Cl ₂ / MeOH 9: 1).
2.122b. 4'-Bromo-3-fluoro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide in general According to method I 2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethylamine 141 mg (0.5 mmol) and 4′-bromo-3-fluoro-biphenyl-4- Prepared from 140 mg (0.47 mmol) of carboxylic acid.
Yield: 10 mg (3.8% of theory)
C ₂₆ H ₂₃ Br ₂ FN ₂ O (M = 558.29)
calc .: Mole peak (M + H) ⁺ : 557/559/561 fnd .: Mole peak (M + H) ⁺ : 557/559/561
Retention time HPLC: 7.0 minutes (Method A)
Example 2.123:
4'-chloro-biphenyl-4-carboxylic acid [2- (3-amino-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

0.12 ml of trifluoroacetic acid was added to tert.butyl (5- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -2-pyrrolidin-1-ylmethyl- in 3 ml of CH ₂ Cl ₂ Phenyl) -carbamate (see Example 2.116) is added to a solution of 40 mg (0.08 mmol) and the reaction mixture is stirred at room temperature throughout. It is evaporated in vacuo, combined with half-saturated NaHCO ₃ solution, extracted with EtOAc, and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is purified by HPLC.
Yield: 3 mg (7.3% of theory)
C ₂₆ H ₂₈ ClN ₃ O * C ₂ HF ₃ O ₂ (M = 548.01)
calc .: Mole peak (M + H) ⁺ : 434/436 fnd .: Mole peak (M + H) ⁺ : 434/436
Retention time HPLC: 5.35 min (Stable Bond C18; 3.5 μM; water: acetonitrile: formic acid 6: 4: 0.015)
Example 2.124:
4'-Chloro-biphenyl-4-carboxylic acid-ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.124a. Ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine
A solution of 89 μL (1.1 mmol) ethyl iodide in 1 ml THF was added dropwise to a solution of 204 mg (1.0 mmol) 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 0.17 ml triethylamine in 5 ml THF, The reaction mixture is stirred at room temperature for 24 hours. It is combined with saturated NaHCO ₃ solution, extracted with EtOAc, and the organic phase is dried over MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 70 mg (30.1% of theory)
2.124b. 4'-Chloro-biphenyl-4-carboxylic acid-ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
Prepared from 70 mg (0.3 mmol) ethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] amine and 81 mg (0.35 mmol) 4'-chloro-biphenyl-4-carboxylic acid according to general procedure I did.
Yield: 20 mg (14.9% of theory)
C ₂₈ H ₃₁ ClN ₂ O (M = 447.03)
calc .: Mole peak (M + H) ⁺ : 447/449 fnd .: Mole peak (M + H) ⁺ : 447/449
Retention time HPLC: 6.92 min (Method A)
Example 2.125:
4'-Chloro-biphenyl-4-carboxylic acid-isobutyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.125a. Isobutyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine
A solution of 204 mg (1.0 mmol) 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine and 91 μL (1.0 mmol) isobutyraldehyde in 20 ml THF was slightly acidified with glacial acetic acid and 253 mg NaBH (OAc) ₃ Mmol) and stir overnight at room temperature. The reaction mixture is combined with half-saturated NaHCO ₃ solution, exhaustively extracted with EtOAc, the aqueous phase is saturated with K ₂ CO ₃ and extracted with EtOAc. The combined organic phases are dried with MgSO ₄ . After removal of the desiccant and solvent, the residue is further reacted without purification.
Yield: 250 mg (96.0% of theory).
C ₁₇ H ₂₈ N ₂ (M = 260.43)
calc .: Mole peak (M + H) ⁺ : 261 fnd .: Mole peak (M + H) ⁺ : 261
R _f value: 0.4 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 8: 2: 0.2).
2.125b. 4′-Chloro-biphenyl-4-carboxylic acid-isobutyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide Isobutyl- [2- (4-pyrrolidine according to General Procedure I Prepared from 250 mg (0.96 mmol) of 1-ylmethyl-phenyl) -ethyl] -amine and 244 mg (1.05 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 67 mg (14.7% of theory)
C ₃₀ H ₃₅ ClN ₂ O (M = 475.08)
calc .: Mole peak (M + H) ⁺ : 475/477 fnd .: Mole peak (M + H) ⁺ : 475/477
Retention time HPLC: 7.67 min (Method A)
Example 2.126:
4'-chloro-biphenyl-4-carboxylic acid-cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.126a. Cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine Example 2.125a. Similar to 2- (4-pyrrolidin-1-ylmethyl-phenyl) -Prepared from 204 mg (1.0 mmol) of ethylamine and 114 μL (1.0 mmol) of 1,2,3,6-tetrahydrobenzaldehyde.
Yield: 100 mg (33.5% of theory).
C ₂₀ H ₃₀ N ₂ (M = 298.48)
R _f value: 0.2 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 8: 2: 0.2).
2.126b. 4′-Chloro-biphenyl-4-carboxylic acid-cyclohex-3-enylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide Cyclohex-3-enylmethyl according to general procedure I Prepared from 100 mg (0.34 mmol) of 4- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine and 86 mg (0.37 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 46 mg (26.8% of theory)
C ₃₃ H ₃₇ ClN ₂ O (M = 513.13)
calc .: Mole peak (M + H) ⁺ : 513/515 fnd .: Mole peak (M + H) ⁺ : 513/515
Retention time HPLC: 8.20 minutes (Method A)
Example 2.127:
4'-Chloro-biphenyl-4-carboxylic acid-benzyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.127a. Benzyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine 204 mg of 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine in the same manner as in Example 2.125a. 1.0 mmol) and 102 μL (1.0 mmol) of benzaldehyde.
Yield: 160 mg (54.3% of theory).
C ₂₀ H ₂₆ N ₂ (M = 294.44)
R _f value: 0.28 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 8: 2: 0.2).
2.127b. 4'-Chloro-biphenyl-4-carboxylic acid-benzyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure I, benzyl- [2- (4-pyrrolidine Prepared from 160 mg (0.54 mmol) of 1-ylmethyl-phenyl) -ethyl] -amine and 140 mg (0.60 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 16 mg (5.8% of theory)
C ₃₃ H ₃₃ ClN ₂ O (M = 509.10)
calc .: Mole peak (M + H) ⁺ : 509/511 fnd .: Mole peak (M + H) ⁺ : 509/511
Retention time HPLC: 7.51 min (Method A)
Example 2.128:
4'-chloro-biphenyl-4-carboxylic acid-cyclohexylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.128a. Cyclohexylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine 204 mg mg 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine as in Example 2.125a. (1.0 mmol) and 121 μL (1.0 mmol) of cyclohexanecarbaldehyde.
Yield: 100 mg (33.3% of theory).
C ₂₀ H ₃₂ N ₂ (M = 300.49)
R _f value: 0.18 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 8: 2: 0.2).
2.128b. 4′-Chloro-biphenyl-4-carboxylic acid-cyclohexylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide According to General Procedure I, cyclohexylmethyl- [2- (4 -Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine 100 mg (0.33 mmol) and 4'-chloro-biphenyl-4-carboxylic acid 86 mg (0.37 mmol).
Yield: 70 mg (40.8% of theory)
C ₃₃ H ₃₃ ClN ₂ O (M = 515.15)
calc .: Mole peak (M + H) ⁺ : 515/517 fnd .: Mole peak (M + H) ⁺ : 515/517
Retention time HPLC: 8.63 min (Method A)
Example 2.129:
4'-Chloro-biphenyl-4-carboxylic acid-cyclopropylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide

2.129a. Cyclopropylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine Example 2.125a. Similar to 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine Prepared from 204 mg (1.0 mmol) and 75 μL (1.0 mmol) of cyclopropanecarbaldehyde.
Yield: 100 mg (38.7% of theory).
C ₁₇ H ₂₆ N ₂ (M = 258.41)
R _f value: 0.30 (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ 8: 2: 0.2).
2.129b. 4'-Chloro-biphenyl-4-carboxylic acid-cyclopropylmethyl- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide Cyclopropylmethyl- [2- Prepared from 100 mg (0.39 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amine and 100 mg (0.43 mmol) of 4′-chloro-biphenyl-4-carboxylic acid.
Yield: 23 mg (12.6% of theory)
C ₃₀ H ₃₃ ClN ₂ O (M = 473.06)
calc .: Mole peak (M + H) ⁺ : 473/475 fnd .: Mole peak (M + H) ⁺ : 473/475
Retention time HPLC: 7.45 min (Method A)
Example 2.130:
4-Pentyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

Prepared from 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol) and 4-pentyl-benzoic acid (96 mg, 0.50 mmol) according to General Procedure I.
Yield: 75 mg (39.6% of theory)
C ₂₅ H ₃₄ N ₂ O (M = 378.56)
calc .: Mole peak (M + H) ⁺ : 379 fnd .: Mole peak (M + H) ⁺ : 379
Retention time HPLC: 6.5 minutes (Method A)
Example 2.131:
4-Butyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

Prepared from 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol) and 4-butyl-benzoic acid (89 mg, 0.50 mmol) according to General Procedure I.
Yield: 60 mg (32.9% of theory)
C ₂₄ H ₃₂ N ₂ O (M = 364.54)
calc .: Mole peak (M + H) ⁺ : 365 fnd .: Mole peak (M + H) ⁺ : 365
Retention time HPLC: 6.0 minutes (Method A)
Example 2.132:
4-Butylamino-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

Prepared from 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (204 mg, 1.0 mmol) and 4-butylamino-benzoic acid (155 mg, 0.80 mmol) according to General Procedure I.
Yield: 30 mg (9.9% of theory)
C ₂₄ H ₃₃ N ₃ O (M = 379.55)
calc .: Mole peak (M + H) ⁺ : 380 fnd .: Mole peak (M + H) ⁺ : 380
Retention time HPLC: 6.0 minutes (Method A)
Example 2.133:
4- (1-Methyl-butyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

Prepared from 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (82 mg, 0.40 mmol) and 4- (1-methyl-butyl) -benzoic acid (75 mg, 0.39 mmol) according to General Procedure I .
Yield: 40 mg (27.1% of theory)
C ₂₄ H ₃₂ N ₂ O (M = 378.56)
calc .: Mole peak (M + H) ⁺ : 379 fnd .: Mole peak (M + H) ⁺ : 379
Retention time HPLC: 4.3 min (Method B)
Example 2.134:
N- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4- (4,4,4-trifluoro-butoxy) -benzamide

2.134a. Methyl 4- (4,4,4-trifluoro-butoxy) -benzoate
608 mg (4.4 mmol) of K ₂ CO ₃ is added to a solution of 304 mg (2.0 mmol) of methyl 4-hydroxybenzoate in 10 ml of DMF, followed by 382 mg (2.0 mmol) of 1-bromo-4,4,4-trifluorobutane To do. The mixture is stirred overnight at room temperature, again combined with 1-bromo-4,4,4-trifluorobutane and stirred for an additional 24 hours at room temperature. The reaction solution is diluted with water and extracted twice thoroughly with EtOAc. The combined organic extracts are dried over MgSO ₄ and dried in vacuo. The crude product is used in the next reaction step without further purification.
Yield: 500 mg (95.3% of theory)
C ₁₂ H ₁₃ F ₃ O ₃ (M = 262.23)
calc .: Mole peak (M + H) ⁺ : 263 fnd .: Mole peak (M + H) ⁺ : 263
R _f value: 0.9 (silica gel, petroleum ether / EtOAc 6: 4).
2.134b. 4- (4,4,4-Trifluoro-butoxy) -benzoic acid
10.0 ml (10.0 mmol) of 1M sodium hydroxide solution is added to a solution of 500 mg (1.9 mmol) of methyl 4- (4,4,4-trifluoro-butoxy) -benzoate in 7 ml of THF. The mixture is stirred at reflux for 8 hours. The THF is removed in vacuo and the residue is acidified with hydrochloric acid. After filtration, the resulting precipitate is dried in air.
Yield: 350 mg (73.9% of theory)
C ₁₁ H ₁₁ F ₃ O ₃ (M = 248.20)
calc .: Mole peak (MH) ^- : 247 fnd .: Mole peak (MH) ^- : 247
Retention time HPLC: 7.5 minutes (Method A)

2.134c. N- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -4- (4,4,4-trifluoro-butoxy) -benzamide 2- (4-Pyrrolidine according to General Procedure I Prepared from 1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol) and 4- (4,4,4-trifluoro-butoxy) -benzoic acid (124 mg, 0.50 mmol).
Yield: 37 mg (17.0% of theory)
C ₂₄ H ₂₉ F ₃ N ₂ O ₂ (M = 434.51)
calc .: Mole peak (M + H) ⁺ : 435 fnd .: Mole peak (M + H) ⁺ : 435
Retention time HPLC: 5.8 minutes (Method A)
Example 2.135:
3-Methyl-4-pent-1-ynyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.135a. Methyl 3-methyl-4-pent-1-ynyl-benzoate 0.39 ml (4.0 mmol) pentyne, 0.56 ml (4.0 mmol) triethylamine, 70 mg bis- (triphenylphosphine) -palladium (II) -chloride (0.1 Mmol) and 19 mg (0.1 mmol) of copper (I) iodide are successively added to a solution of 458 mg (2.0 mmol) of methyl 4-bromo-3-methyl-benzoate in 3.0 ml of DMF. The reaction solution is stirred at 200 watts at 65 ° C. for 10 minutes in the microwave. An additional 0.20 ml (2.0 mmol) of pentine is added and the reaction solution is stirred at 70 ° C. at 200 watts in a microwave for another 20 minutes. The mixture is diluted with 30 ml of EtOAc, filtered through celite and the filtrate is washed 3 times with 50 ml of water. The combined organic extracts are dried over MgSO ₄ , filtered through activated charcoal and the solvent removed in vacuo. Purification is carried out by column chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 followed by cyclohexane).
Yield: 200 mg (46.2% of theory)
C ₁₄ H ₁₆ O ₂ (M = 216.28)
calc .: Mole peak (M + H) ⁺ : 217 fnd .: Mole peak (M + H) ⁺ : 217
Retention time HPLC: 6.8 minutes (Method B)
2.135b. 3-Methyl-4-pent-1-ynyl-benzoic acid
3.0 ml (3.0 mmol) of 1M sodium hydroxide solution is added to a solution of 200 mg (0.93 mmol) of methyl 3-methyl-4-pent-1-ynyl-benzoate in 3 ml of methanol. The mixture is refluxed for 3 hours. The reaction solution is diluted with water and extracted once with 40 ml of EtOAc. The aqueous phase is acidified with 1M KHSO ₄ solution and extracted twice with 40 ml of EtOAc. The combined organic phases are dried with MgSO ₄ . After removal of the desiccant and solvent, the crude product is used in the next reaction step without further purification.
Yield: 50 mg (26.7% of theory)
C ₁₃ H ₁₄ O ₂ (M = 202.26)
calc .: molar peak (MH) ^- : 201 fnd .: molar peak (MH) ^- : 201
Retention time HPLC: 5.6 minutes (Method B)
2.135c. 3-Methyl-4-pent-1-ynyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-pyrrolidin-1- Prepared from ylmethyl-phenyl) -ethylamine (51 mg, 0.25 mmol) and 3-methyl-4-pent-1-ynyl-benzoic acid (50 mg, 0.25 mmol).
Yield: 22 mg (22.9% of theory)
C ₂₆ H ₃₂ N ₂ O (M = 388.558)
calc .: Mole peak (M + H) ⁺ : 389 fnd .: Mole peak (M + H) ⁺ : 389
Retention time HPLC: 6.9 minutes (Method A)
Example 2.136:
4-Pent-1-inyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.136a. Ethyl 4-pent-1-ynyl-benzoate
0.39 ml (4 mmol) of 1-pentyne, 0.56 ml of triethylamine, 70 mg (0.1 mmol) of bis- (triphenylphosphine) -palladium (II) -chloride and 19 mg (0.1 mmol) of CuI in ethyl 4-iodo in 3.0 ml of DMF It is added continuously to a solution of 552 mg (2.0 mmol) of benzoate. The reaction solution is stirred at 80 ° C. for 4 hours. The mixture is diluted with 30 ml of EtOAc and filtered through celite, and the filtrate is washed 3 times with 50 ml of water in each case and dried over MgSO ₄ . After filtration through activated carbon, the solvent is removed in vacuo. Purification is carried out by column chromatography on silica gel (cyclohexane / ethyl acetate 9: 1 followed by cyclohexane).
Yield: 150 mg (34.7% of theory)
C ₁₄ H ₁₆ O ₂ (M = 216.282)
calc .: Mole peak (M + H) ⁺ : 217 fnd .: Mole peak (M + H) ⁺ : 217
Retention time HPLC: 6.8 minutes (Method B)
2.135b. 4-Pent-1-inyl-benzoic acid
5.0 ml (5.0 mmol) of 1M sodium hydroxide solution is added to a solution of 150 mg (0.69 mmol) of ethyl 4-pent-1-inyl-benzoate in 3 ml of methanol. The mixture is stirred at reflux for 3 hours. The reaction solution is diluted with water and extracted once with 40 ml of EtOAc. The aqueous phase is acidified with 1M KHSO ₄ solution and extracted twice with 40 ml of EtOAc. The combined organic extracts are dried over magnesium sulfate and the solvent is removed in vacuo. The crude product is used in the next reaction step without further purification.
Yield: 150 mg (115% of theory)
C ₁₂ H ₁₂ O ₂ (M = 188.23)
calc .: molar peak (MH) ^- : 187 fnd .: molar peak (MH) ^- : 187
R _f value: 0.2 (silica gel, petroleum ether / EtOAc 8: 2).
2.136c. 4-Pent-1-inyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide 2- (4-Pyrrolidin-1-ylmethyl-phenyl) according to General Procedure I Prepared from -ethylamine (163 mg, 0.80 mmol) and 4-pent-1-inyl-benzoic acid (150 mg, 0.80 mmol).
Yield: 122 mg (40.9% of theory)
C ₂₅ H ₃₀ N ₂ O (M = 374.53)
calc .: Mole peak (M + H) ⁺ : 375 fnd .: Mole peak (M + H) ⁺ : 375
R _f value: 0.35 (silica gel, EtOAc / methanol / NH ₃ 9: 1: 0.1).
Example 2.137:
(4-Pent-1-enyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

2.137a. Methyl 4-pent-1-enyl-benzoate Potassium-tert-butoxide 246 mg (2.2 mmol) at 0 ° C. under argon atmosphere in (4-methoxycarbonyl-benzyl) -triphenyl-phosphonium-bromide 1.08 in 20 ml of THF Add to a solution of g (2.2 mmol). The orange solution is stirred for a further 15 minutes at 0 ° C. and then combined with 0.18 ml (2.0 mmol) of butyraldehyde. The reaction solution is refluxed for 3 hours and then diluted with EtOAc. The organic phase is washed twice with water, dried over magnesium sulphate and the solvent is removed in vacuo. The residue is triturated with diisopropyl ether, filtered and the filtrate is evaporated. Further purification is carried out by column chromatography on silica gel (petroleum ether / EtOAc 6: 4). Methyl 4-pent-1-enyl-benzoate is obtained as a 2: 1 mixture of E / Z isomers.
Yield: 350 mg (56.5% of theory)
C ₁₃ H ₁₆ O ₂ (M = 204.27)
calc .: Mole peak (M + H) ⁺ : 204 fnd .: Mole peak (M + H) ⁺ : 204
R _f value: 0.90 (silica gel, petroleum ether / EtOAc 6: 4).
2.137b. 4-Pent-1-enyl-benzoic acid
5.0 ml (5.0 mmol) of 1M sodium hydroxide solution is added to a solution of 350 mg (1.71 mmol) of ethyl 4-pent-1-enyl-benzoate in 4 ml of methanol. The mixture was refluxed for 2 hours. The solvent is removed in vacuo and the residue is combined with 6M hydrochloric acid solution. The precipitate formed is filtered off with suction and dried at 35 ° C. in a circulating air dryer. Further purification is carried out by filtration through a silica gel column (petroleum ether / EtOAc 6: 4).
Yield: 300 mg (92.1% of theory)
C ₁₂ H ₁₄ O ₂ (M = 190.24)
calc .: molar peak (MH) ^- : 189 fnd .: molar peak (MH) ^- : 189
R _f value: 0.4 (silica gel, petroleum ether / EtOAc 6: 4).
2.137c. (4-Pent-1-enyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide According to general procedure I 2- (4-Pyrrolidin-1-ylmethyl- Prepared as a 2: 1 mixture of E / Z isomers from phenyl) -ethylamine (306 mg, 1.50 mmol) and 4-pent-1-enyl-benzoic acid (300 mg, 1.56 mmol).
Yield: 130 mg (23.0% of theory)
C ₂₅ H ₃₂ N ₂ O (M = 376.547)
calc .: Mole peak (M + H) ⁺ : 377 fnd .: Mole peak (M + H) ⁺ : 377
Retention time HPLC: 6.9 minutes (Method A)
Example 2.138:
3-Chloro-4-cyclohexyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide

Prepared from 2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol) and 3-chloro-4-cyclohexyl-benzoic acid (119 mg, 0.50 mmol) according to General Procedure I.
Yield: 46 mg (21.6% of theory)
C ₂₆ H ₃₃ ClN ₂ O (M = 425.019)
calc .: Mole peak (M + H) ⁺ : 425/427 fnd .: Mole peak (M + H) ⁺ : 425/427
Retention time HPLC: 4.7 minutes (Method B)
Certain test methods for measuring MCH-receptor antagonist activity are now described. In addition, for example, described by Hoogduijn M et al., “Melanin-concentrating hormone and its receptor are expressed and functional in human skin”, Biochem. Biophys. Res Commun. 296 (2002) 698-701. By inhibiting MCH-receptor-mediated inhibition of cAMP production, and also by Karlsson OP and Lofas S. “On the flow-mediated surface of G protein-coupled receptors for application in surface plasmon resonance biosensors” Regenerative ”, Anal. Biochem. 300 (2002), 132-138, by one skilled in the art by biosensory measurement of MCH binding to MCH receptors in the presence of antagonists by plasmon resonance. Other test methods known in the art are used. Other test methods for antagonist activity against the MCH receptor are included in the literature and patent documents, and a description of the test method used is included in this application.

MCH-1 receptor binding test method: MCH binding species to hMCH-1R transfected cells: human test cells: hMCH-1R stably transfected into CHO / G alpha 16 cells
Results: IC50 value Using a syringe (needle 0.6x25mm), resuspend the membrane from CHO / G alpha 16 cells stably transfected with human hMCH-1R and test buffer (50mM HEPES, 10mM MgCl ₂ , 2 mM EGTA, pH 7.00; 0.1% bovine serum albumin (protease-free), 0.021% bacitracin, 1 μg / ml aprotinin, 1 μg / ml leupeptin and 1 μM phosphoramidon) to a concentration of 5-15 μg / ml Dilute. 200 microliters of this membrane fraction (containing 1-3 μg of protein) in a final volume of 250 microliters of 100 pM ¹²⁵ I-tyrosylmelamine-concentrating hormone ( ¹²⁵ I-MCH commercially obtained from NEN) and increasing concentrations Incubate with test compound at ambient temperature for 60 minutes. After the incubation, the reaction is filtered through a 0.5% PEI treated glass fiber filter (GF / B, Unifilter Packard) using a cell harvester. The membrane bound radioactivity retained on the filter is then measured after the addition of the scintillator material (Packard Microsint 20) in a measuring device (Packard TopCount).
Non-specific binding is defined as radioactivity bound in the presence of 1 micromolar MCH during the incubation period.
Analysis of the concentration binding curve is performed under the assumption of one receptor binding site.
standard:
Unlabeled MCH competes with labeled ¹²⁵ I-MCH for receptor binding with an IC50 value of 0.06-0.15 nM.
The radioligand has a KD value of 0.156 nM.

MCH-1 receptor binding Ca ²⁺ mobilization test method: Calcium mobilization test type by human MCH (FLIPR ³⁸⁴ ) Species: Human test cell: CHO / G alpha 16 cell stably transfected with hMCH-R1 Result: 1 Second measurement:% stimulation of reference (MCH 10 ^-6 M)
Second measurement: pKB value Reagent: HBSS (10x) (Gibco)
HEPES buffer (1M) (Gibco)
Pluronic F-127 (Molecular Probes)
Fluo-4 (Molecular Probes)
Probenecid (Sigma)
MCH (Beacham)
Bovine serum albumin (Selva)
(Protease-free)
DMSO (Selva)
Ham's F12 (Bio Whittaker)
FCS (Bio Whittaker)
L-Glutamine (Gibco)
Hygromycin B (Gibco)
PENStrep (Bio Whittaker)
Zeocin (Invitrogen)

Clone CHO / G alpha 16hMCH-R1 cells are cultured in Ham's F12 cell medium (L-glutamine; Bio Whitaker; catalog number: BE12-615F included). This includes 10 ml FCS, 1% PENStrep, 5 ml L-glutamine (200 mM stock solution), 3 ml hygromycin B (50 mg / ml in PBS) and 1.25 ml zeocin (100 μg / ml stock solution) per 500 ml. One day prior to the experiment, cells were applied to a 384-well microtiter plate (with a black wall with a transparent base made by Coster) at a density of 2500 cells per cavity and 37 ° C in the above medium. Incubate overnight at 5% CO ₂ and 95% relative humidity. On the day of the experiment, the cells are incubated with cell culture medium (with 2 mM Fluo-4 and 4.6 mM probenecid) at 37 ° C. for 45 minutes. After loading the fluorescent dye, the cells are washed 4 times with Hanks buffer (1 × HBSS, 20 mM HEPES) and combined with 0.07% probenecid. Test substances are diluted in Hanks buffer and combined with 2.5% DMSO. Background fluorescence of unstimulated cells was measured in the 384-well microtiter plate 5 minutes after the last wash step in the FLIPR ³⁸⁴ instrument (molecular instrument; excitation wavelength: 488 nm; emission wavelength: bandpass 510-570 nm). Measure in the presence. To stimulate cells, dilute MCH in Hank's buffer containing 0.1% BSA, pipet it into a 384-well cell culture plate 35 minutes after the last wash step, and then transfer MCH-stimulated fluorescence to FLIPR ³⁸⁴ Measure in the instrument.

Data analysis:
First measurement: Ca ²⁺ mobilization of the cells is measured as relative fluorescence peak-background and expressed as a percentage of the maximum signal of the reference (MCH 10 ^-6 M). This measurement can be used to identify possible antagonism of the test substance.
Second measurement: Cellular Ca ²⁺ mobilization is measured as relative fluorescence peak-background and expressed as a percentage of the maximum signal of the reference (MCH 10 ⁻⁶ M; signal normalized to 100%). EC50 values of MCH dose activity curves with and without test substance (specific concentration) are measured graphically with GraphPad Prism 2.01 curve program. MCH antagonists shift the MCH stimulation curve to the right in the plotted graph.
Express the suppression as a pKB value:
pKB = log (EC _{50 (test substance + MCH)} / EC _{50 (MCH)} -1) -log c _{(test substance)}
The compounds of the present invention (including their salts) show MCH-receptor antagonistic activity in the above test. Using the MCH-1 receptor binding test, antagonistic activity is obtained in a dose range of about 10 ⁻¹⁰ to 10 ⁻⁵ M, especially 10 ⁻⁹ to 10 ⁻⁶ M.
The following IC50 values were measured using the MCH-1 receptor binding test.

Several examples of formulations are described below, and the term “active substance” refers to one or more compounds of the present invention, including their salts. In the case of one of the combinations with one or more active substances described, the term “active substance” also includes additional active substances.
Example 3
Capsule for powder inhalation containing 1 mg of active substance Composition:
One capsule for powder inhalation contains the following ingredients:
Active substance 1.0mg
Lactose 20.0mg
Hard gelatin capsule 50.0mg
71.0mg
Method of preparation:
The active substance is ground to the required particle size for inhalation. The ground active substance is mixed homogeneously with lactose. The mixture is packed into hard gelatin capsules.
Example 4
Inhalable solution for Respimat (R) containing 1 mg of active substance Composition:
A single spray contains the following ingredients:
Active substance 1.0mg
Benzalkonium chloride 0.002mg
Edetate disodium 0.0075mg
Added purified water 15.0μl
Method of preparation:
The active substance and benzalkonium chloride are dissolved in water and packed into a Respimat® cartridge.

Example 5
Inhalable solution for nebulizer containing 1 mg of active substance Composition:
One vial contains the following components:
Active substance 0.1g
Sodium chloride 0.18g
Benzalkonium chloride 0.002g
Added purified water 20.0ml
Method of preparation:
The active substance, sodium chloride and benzalkonium chloride are dissolved in water.
Example 6
Propellant-type metered dose aerosol containing 1 mg of active substance Composition:
A single spray contains the following ingredients:
Active substance 1.0mg
Lecithin 0.1%
Additive propellant gas 50.0μl
Method of preparation:
The finely divided active substance is uniformly suspended in the mixture of lecithin and propellant gas. The suspension is transferred to a pressure vessel equipped with a metering valve.

Example 7
Nasal spray containing 1 mg of active substance Composition:
Active substance 1.0mg
Sodium chloride 0.9mg
Benzalkonium chloride 0.025mg
Edetate disodium 0.05mg
Added purified water 0.1ml
Method of preparation:
The active substance and excipients are dissolved in water and transferred to the corresponding container.
Example 8
Injection solution containing 5 mg of active substance per 5 ml Composition:
Active substance 5mg
Glucose 250mg
Human serum albumin 10mg
Glycoflor 250mg
Water for injection, addition 5ml
Preparation:
Glycofurol and glucose are dissolved in water for injection (WfI), human serum albumin is added, the active ingredient is dissolved with heating, WfI is replenished to a specific volume, and transferred to an ampoule under nitrogen gas.

Example 9
Injection solution containing 100 mg of active substance per 20 ml Composition:
Active substance 100mg
Monopotassium dihydrogen phosphate
= KH ₂ PO ₄ 12mg
Disodium hydrogen phosphate
= Na ₂ HPO ₄・ 2H ₂ O 2mg
Sodium chloride 180mg
Human serum albumin 50mg
Polysorbate 80 20mg
Water for injection, addition 20ml
Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injection (WfI), human serum albumin is added, the active ingredient is dissolved with heating, and the specific volume of WfI is added. Replenish and transfer to an ampoule.
Example 10
Freeze-dried preparation containing 10 mg of active substance Composition:
Active substance 10mg
Mannitol 300mg
Human serum albumin 20mg
Preparation:
Mannitol is dissolved in water for injection (WfI), human serum albumin is added, the active ingredient is dissolved with heating, WfI is replenished to a specified volume, transferred to a vial and lyophilized.
Solvents for lyophilized formulations:
Polysorbate 80 = Tween 80 20mg
Mannitol 200mg
Water for injection, addition 10ml
Preparation:
Polysorbate 80 and mannitol are dissolved in water for injection (WfI) and transferred to an ampoule.

Example 11
Tablet containing 20 mg of active substance Composition:
Active substance 20mg
Lactose 120mg
Corn starch 40mg
Magnesium stearate 2mg
Povidone K25 18mg
Preparation:
The active substance, lactose and corn starch are mixed uniformly, granulated with an aqueous solution of povidone, mixed with magnesium stearate and compressed in a tablet press. Tablet weight 200mg.
Example 12
Capsules containing 20 mg of active substance Composition:
Active substance 20mg
Corn starch 80mg
Highly dispersed silica 5mg
Magnesium stearate 2.5mg
Preparation:
The active substance, corn starch and silica are mixed homogeneously and mixed with magnesium stearate and the mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

Example 13
Suppository containing 50 mg of active substance Composition:
Active substance 50mg
Add enough amount of hard fat (Adeps / Soridus) 1700mg
Preparation:
The hard fat is melted at about 38 ° C. and the ground active substance is uniformly dispersed in the melted hard fat, cooled to about 35 ° C. and then poured into a cooling mold.
Example 14
Injection solution containing 10 mg of active substance per ml Composition:
Active substance 10mg
Mannitol 50mg
Human serum albumin 10mg
Water for injection, addition 1ml
Preparation:
Mannitol is dissolved in water for injection (WfI), human serum albumin is added, the active ingredient is dissolved with heating, WfI is replenished to a specific volume, and transferred to an ampoule under nitrogen gas.

Claims (44)

Formula I

Carboxamide compounds, their tautomers, diastereomers, enantiomers, mixtures and salts thereof.
[Where,
R ¹ and R ² are each independently H, C _1-8 -alkyl group or C _3-7 -cycloalkyl group optionally substituted by group R ¹¹ or optionally mono-substituted or poly-substituted by group R ¹² Represents a phenyl group which may be substituted and / or monosubstituted by nitro, or
R ¹ and R ² form a C _2-8 -alkylene bridge;
-1 or 2 -CH ₂ -groups may be independently substituted by -CH = N- or -CH = CH- and / or -1 or 2 -CH ₂ -groups -O is independently from each other -, - S -, - CO -, - C (= CH 2) - or -NR ¹³ - it may be substituted by, as a result, is not connected heteroatom is directly to one another,
In the alkylene bridge as defined above, one or more H atoms may be substituted by R ¹⁴ and / or the alkylene bridge as defined above has a bond between the alkylene bridge and the group Cy- Through a bond or double bond,
-Through a common C atom forming a spirocyclic ring system,
Via two common, adjacent C and / or N atoms forming a fused bicyclic ring system, or three or more C and / or N atoms forming a bridged ring system Optionally substituted by one or two identical or different carbocyclic or heterocyclic groups in a manner as formed via
R ³ is H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-4 -alkyl-} , C _3-7 -cycloalkenyl, C _3-7 -cyclo Alkenyl-C _{1-4 -alkyl-} , phenyl, phenyl-C _{1-4 -alkyl-} , C _1-3 -alkoxy-C _{2-6 -alkyl-} , amino-C _{2-6 -alkyl-} , C _1- Represents ₃ -alkyl-amino-C _{2-6 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _2-6 -alkyl-,
X represents a single bond or a C _1-8 -alkylene bridge;
−1 or 2 —CH ₂ — groups may be independently substituted with —CH═CH— or —C≡C— and / or −1 or 2 —CH ₂ — groups. Are independently of each other in a manner such that two O atoms, S atoms or N atoms or one O atom and S atom are not directly linked to each other -O-, -S-,-(SO)- _{, - (SO 2) -,} - CO- or -NR ⁴ - may be substituted by,
One or two C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl-, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or C _1-3 -alkoxy groups and / or in each case may be substituted by one or two identical or different C _1-6 -alkyl groups and / or their alkylene bridges are R ¹ and X Linked to R ¹ so as to contain an N atom linked to a heterocyclic group,
Z is C _1-4 - represents alkylene bridge, additional C _1-4 - 2 contiguous C atoms with alkylene bridge may be connected to each other, in a group Z, -CH ₂ - group Optionally substituted by —O— or —NR ⁵ —, and one or two C atoms of the alkylene bridge are independently of each other a hydroxy group, an ω-hydroxy-C _1-3 -alkyl- group, an ω -(C _1-3 -alkoxy) -C _1-3 -alkyl-group, C _1-3 -alkoxy group, amino-C _1-3 -alkyl-group, C _1-3 -alkyl-amino-C _1- Substituted by ₃ -alkyl-groups or di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-groups and / or one or two identical or different C _1-6 -alkyl groups And / or
R ³ may be linked to Z to include an N atom linked to R ³ to form a heterocyclic group;
A and Y have one of the meanings indicated for Cy independently of each other;
R ¹ may be linked to Y to include a group X and an N atom linked to R ¹ and X to form a heterocyclic group fused to Y and / or
R ³ may be linked to Y to include a group Z and an N atom linked to R ³ and Z to form a saturated or partially unsaturated heterocyclic group fused to Y, or A and R ³ is a group of formula I

Is sub-formula II

And Q is a partial formula IIIa-IIIg
−CR ⁶ R ⁷ −IIIa
−CR ⁶ = CR ⁷ − IIIb
-N = CR ⁸ - IIIc
-N = N-IIId
-CO-NR ⁹ -IIIe
-CR ⁸ = N- IIIf
-CO- IIIg
Represents a group selected from
L ¹ , L ² , L ³ may be linked together in a manner such that they independently of one another represent one of the meanings given for R ²⁰
B is C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _3-7 -cycloalkenyl-C _{1- Represents 3} -alkyl-, C _3-7 -cycloalkyl-C _1-3 -alkenyl- or C _3-7 -cycloalkyl-C _1-3 -alkynyl- (one or more C atoms are monosubstituted by halogen) Or may be polysubstituted and / or monosubstituted by hydroxy or cyano and / or the cyclic group may be monosubstituted or polysubstituted by R ²⁰ ), or
Having one of the meanings given for Cy, the bond to the group W or optionally the direct bond to the group A is a C atom of a carbocyclic moiety or optionally condensed phenyl or pyridine ring Or through the N or C atom of the heterocyclic moiety,
When k is 0, the group B and the group A may be linked to each other through a common C atom to form a spirocyclic ring system, or linked through two common adjacent atoms. A fused bicyclic ring system may be formed,
W is a single bond, -O-, C _1-4 -alkylene group, C _2-4 -alkenylene group, C _2-4 -alkynylene group, C _1-4 -alkyleneoxy- group, oxy-C _1-4- Alkylene-group, C _1-3 -alkylene-oxy-C _1-3 -alkylene-group, imino group, N- (C _1-3 -alkyl) -imino-group, imino-C _1-4 -alkylene-group , N- (C _1-3 -alkyl) -imino-C _1-4 -alkylene-group, C _1-4 -alkylene-imino-group or C _1-4 -alkylene-N- (C _1-3 -alkyl ) -Imino-group,
One or two C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or C W which may be substituted by a _1-3 -alkoxy group and / or one or two identical or different C _1-6 -alkyl groups and / or has the definition alkylene, oxyalkylene and alkyleneoxyalkylene It may also be linked to B via a double bond,
k represents 0 or 1,
Cy has the following meanings-saturated 3-7 membered carbocyclic group,
An unsaturated 5-7 membered carbocyclic group,
A phenyl group,
A saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group having N atom, O atom or S atom as a hetero atom,
A saturated or unsaturated 5- to 7-membered heterocyclic group having 2 or more N atoms or 1 or 2 N atoms and an O atom or S atom as a hetero atom,
-Represents a carbocyclic group or heterocyclic group selected from one or more of aromatic 5 or 6-membered heterocyclic groups having one or more same or different heteroatoms selected from N, O and / or S ,
Said 4, 5, 6 or 7 membered group may be linked via two common adjacent C atoms fused with a phenyl ring or a pyridine ring, and in said 5, 6 or 7 membered group, One or two non-adjacent —CH ₂ — groups may be substituted by a —CO— group, a —C (═CH ₂ ) — group, a — (SO) — group or a — (SO ₂ ) — group. And the saturated 6- or 7-membered group may also be an imino bridge, N- (C _1-4 -alkyl) -imino bridge, methylene bridge, C _1-4 -alkyl-methylene bridge or di- (C _1-4 -alkyl). ) -Methylene bridged ring system, and the cyclic group may be mono- or polysubstituted with R ²⁰ at one or more C atom positions, May further be monosubstituted by nitro and / or may be substituted by R ²¹ at one or more N atom positions,
R ⁴ and R ⁵ independently of one another have one of the meanings indicated for R ^{16
R 6, R 7, R 8} , R 9 is H independently of each other, C _1-6 - alkyl group, omega-C _1-3 - alkoxy -C _1-3 - alkyl - group or ω- hydroxy -C _1- Represents a ₃ -alkyl- group, and R ⁶ , R ⁷ and R ⁸ independently represent halogen,
R ¹¹ represents R ¹⁵ -O-, R ¹⁵ -O-CO-, R ¹⁶ R ¹⁷ N-, R ¹⁸ R ¹⁹ N-CO- or Cy-
R ¹² has one of the meanings given for R ²⁰
R ¹³ has one of the meanings given for R ¹⁷
R ¹⁴ is halogen, C _1-6 - ^{alkyl, R 15 -O-, R 15 -O} -CO-, R 16 R 17 N-, R 18 R 19 N-CO-, R 15 -OC 1-3 - Alkyl-, R ¹⁵ -O-CO-C _1-3 -alkyl-, R ¹⁶ R ¹⁷ NC _{1-3 -alkyl-} , R ¹⁸ R ¹⁹ N-CO-C _1-3 -alkyl- or Cy-C _{1 Represents -3} -alkyl-
R ¹⁵ represents H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , phenyl, phenyl-C _1-3 -alkyl- or pyridinyl. Represent,
R ¹⁶ is H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _4-7 -cycloalkenyl, C _4-7 -cyclo Alkenyl-C _1-3 -alkyl-, ω-hydroxy-C _2-3 -alkyl-, ω- (C _1-3 -alkoxy) -C _{2-3 -alkyl-} , amino-C _{1-6 -alkyl-} , C _1-3 -alkyl-amino-C _{1-6 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _1-6 -alkyl-,
R ¹⁷ has one of the meanings given for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl-, pyridinyl, dioxolan-2-yl, C _1-3 -alkylcarbonyl, hydroxycarbonyl-C _{1-3 -alkyl-} , C _1-4 -alkoxycarbonyl, C _1-3 -alkylcarbonylamino-C _{2-3 -alkyl-} , C _1-3 -alkylsulfonyl- or C _1-3 -alkylsulfonylamino- C _{2-3 -alkyl-} represents
R ¹⁸ and R ¹⁹ each independently represent H or C _1-6 -alkyl,
R ²⁰ represents halogen, hydroxy, cyano, C _1-4 -alkyl, C _3-7 -cycloalkyl, hydroxy-C _1-3 -alkyl, R ²² -C _1-3 -alkyl-, or about R ²² Has one of the indicated meanings,
R ²¹ is C _1-3 -alkyl, ω-hydroxy-C _2-3 -alkyl-, phenyl, phenyl-C _{1-3 -alkyl-} , C _1-3 -alkyl-carbonyl, carboxy, C _1-4- Represents alkoxy-carbonyl, C _1-3 -alkylsulfonyl, phenylcarbonyl or phenyl-C _1-3 -alkyl-carbonyl,
R ²² is pyridinyl, phenyl, phenyl-C _1-3 -alkoxy-, C _1-3 -alkoxy, C _1-3 -alkylthio, carboxy, H-CO-, C _1-3 -alkylcarbonyl, C _1-4 -Alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, C _1-3 -alkyl-sulfonyl-, C _1-3 -alkyl-sulfinyl-, C _1-3 -alkyl-sulfonylamino-, amino, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C _1-3 -alkylamino- or N- ( C _1-3 -alkyl) -phenyl-C _1-3 -alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenylcarbonylamino-, phenylcarbonylmethylamino-, hydroxyalkylaminocarbonyl, (4-morpholinyl ) Carbonyl, (1-pyrrolidinyl) carboni , (1-piperidinyl) carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy -, aminocarbonylamino - or alkylaminocarbonylamino - represents,
In the radicals and residues A, B, W, X, Y, Z, R ^{1 to} R ⁹ and R ^{11 to} R ²² , in each case one or more C atoms are mono- or polysubstituted by F And / or in each case one or two C atoms may be monosubstituted independently of each other by Cl or Br and / or in each case one or two phenyl rings Are independently of each other the groups F, Cl, Br, I, C _1-4 -alkyl, C _1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C _1-3 -alkylamino-, di- ( C _1-3 -alkyl) -amino-, acetylamino-, aminocarbonyl, CN, difluoromethoxy, trifluoromethoxy, amino-C _{1-3 -alkyl-} , C _1-3 -alkylamino-C _1-3- Further having one, two or three substituents selected from alkyl- and di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl- And / or may be monosubstituted by nitro, and the H atom of the carboxy group present or the H atom bonded to the N atom may be substituted in each case by a group that can be cleaved in vivo. Good) R ³ is H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-4 -alkyl-} , C _1-3 -alkoxy-C _{2-6 -alkyl-} , Amino-C _{2-6 -alkyl-} , C _1-3 -alkyl-amino-C _{2-6 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _2-6 -alkyl- ,
B has one of the meanings given for Cy, and the bond to the group W or optionally the direct bond to the group A may be a carbocyclic moiety or optionally a phenyl or pyridine ring C Formed through an atom or an N or C atom of a heterocyclic moiety;
When k is 0, the group B and the group A may be linked together through a common C atom to form a spirocyclic ring system, or linked through two common adjacent atoms. A condensed, bicyclic ring system may be formed,
R ¹⁵ represents H, C _1-4 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , phenyl or phenyl-C _1-3 -alkyl-;
R ¹⁷ has one of the meanings indicated for R ¹⁶ or phenyl, phenyl-C _1-3 -alkyl-, dioxolan-2-yl, C _1-3 -alkylcarbonyl, hydroxycarbonyl-C _{1- Represents 3} -alkyl, C _1-3 -alkylcarbonylamino-C _{2-3 -alkyl-} , C _1-3 -alkylsulfonyl- or C _1-3 -alkylsulfonylamino-C _2-3 -alkyl-,
R ²² is phenyl, phenyl-C _1-3 -alkoxy-, C _1-3 -alkoxy, C _1-3 -alkylthio, carboxy, C _1-3 -alkylcarbonyl, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, C _1-3 -alkyl-sulfonyl, C _1-3 -alkyl-sulfinyl, C _1-3 -alkyl-sulfonylamino -, Amino, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, phenyl-C _1-3 -alkyl-amino- or N- (C _1-3 -alkyl)- Phenyl-C _1-3 -alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenylcarbonylamino-, phenylcarbonylmethylamino-, hydroxyalkylaminocarbonyl, (4-morpholinyl) carbonyl, (1-pyrrolidinyl) Carbonyl, (1-piperidinyl) Represents carbonyl, (hexahydro-1-azepinyl) carbonyl, (4-methyl-1-piperazinyl) carbonyl, methylenedioxy, aminocarbonylamino- or alkylaminocarbonylamino-
In the radicals A, B, W, X, Y, Z, R ^{1 to} R ⁹ and R ^{11 to} R ²² , in each case one or more C atoms may be mono- or polysubstituted by F. And / or in each case one or two C atoms may be monosubstituted independently of each other by Cl or Br, and the radicals A, W, X, Y, Z, R ¹ , R ² , R ^{4 to} R ⁹ , R ^{11 to} R ¹⁴ , R ¹⁶ and R ^{18 to} R ^{21 and} k has the meaning according to claim 1 and is an H atom bonded to an H atom or an N atom of a carboxy group present The carboxamide compounds according to claim 1, their tautomers, diastereomers, enantiomers, mixtures and these, characterized in that in each case may be substituted by a group which can be substituted in vivo Salt.   Carboxamide compound according to claim 1 or 2, characterized in that the group A has the meaning indicated for Cy in claim 1. A and R ³ are groups of formula I

Is sub-formula II

And Q is a partial formula IIIa-IIIg
−CR ⁶ R ⁷ −IIIa
−CR ⁶ = CR ⁷ − IIIb
-N = CR ⁸ - IIIc
-N = N-IIId
-CO-NR ⁹ -IIIe
-CR ⁸ = N- IIIf
-CO- IIIg
Represents a group selected from
L ¹ , L ² , L ³ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are connected to one another in a manner having the meaning indicated in claim 1, 4. The carboxamide compound according to any one of 3. R ¹ and R ² are independently of each other H, C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-3 -alkyl-, ω-hydroxy-C _2-3 -Alkyl, ω- (C _1-3 -alkoxy) -C _{2-3 -alkyl-} , C _1-4 -alkoxy-carbonyl-C _1-3 -alkyl, amino-C _{2-4 -alkyl-} , C _{1 -3} -alkyl-amino-C _{2-4 -alkyl-} or di- (C _1-3 -alkyl) -amino-C _{2-4 -alkyl-} , phenyl or phenyl-C _{1-3 -alkyl-}
In the above groups and residues, one or more C atoms may be monosubstituted or polysubstituted by F and / or one or two C atoms are monosubstituted independently of each other by Cl or Br. And the phenyl group may be mono- or polysubstituted by the radical R ¹² as defined in claim 1 and / or monosubstituted by nitro, Item 5. The carboxamide compound according to any one of Items 1 to 4. R ¹ and R ² are R ¹ R ² N- is azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7 The alkylene bridge of claim 1 is formed in such a manner as to form a group selected from -tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, morpholine, thiomorpholine, and piperazine. The free imine functional group may be substituted with R ¹³ ;
According to claim 1, one or more H atoms may be substituted by R ¹⁴ and / or specified in claim 1 with one or two identical or different carbocyclic or heterocyclic groups Cy May be substituted in the manner
Carboxamide compound according to any one of claims 1 to 4, characterized in that R ¹³ , R ¹⁴ and Cy have the meaning indicated in claim 1 or 2. Base

Is the following sub-expression

Meaning to follow one of
One or more H atoms of the heterocycle formed by the group R ¹ R ² N— may be substituted by R ¹⁴ and a ring connected to the heterocycle formed by the group R ¹ R ² N May be mono- or polysubstituted with R ²⁰ at one or more C atom positions, and in the case of the phenyl ring may be further mono-substituted with nitro, and
^{R 13, R 14, R 20} , R 21 and X are characterized by having the meanings indicated in claim 1 or 2, claim 6 carboxamide compound according. X is a single bond or C _1-6 -alkylene, C _2-6 -alkenylene, C _2-6 -alkynylene, C _1-6 -alkyleneoxy, carbonyl, carbonyl-C _1-6 -alkylene or C _1-6- Represents an unbranched bridge selected from alkylene-amino, the amino group of which may be substituted with R ⁴ , or one or two C atoms may be substituted as specified in claim 1 Carboxamide compound according to any one of claims 1 to 7, characterized in that and / or the alkylene bridge may be linked to R ¹ as specified in claim 1. X represents an alkylene bridge selected from a single bond, carbonyl or methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene;
1 or 2 C atoms independently of one another are hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or C _May be substituted with a _1-3 -alkoxy group and / or in each case may be substituted with one or two identical or different C _1-4 -alkyl groups, and in each case One or more C atoms may be mono- or polysubstituted by F and / or in each case one or two C atoms may be mono-substituted by Cl or Br independently of each other Carboxamide compound according to claim 8, characterized in that it is good. Z represents methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy or 1,4-butyleneoxy;
1 or 2 C atoms independently of one another are hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or C _May be substituted with a _1-3 -alkoxy group and / or in each case may be substituted with one or two identical or different C _1-4 -alkyl groups, and in each case One or more C atoms may be monosubstituted or polysubstituted by F and / or in each case one or two C atoms may be monosubstituted by Cl or Br independently of each other Well and
The carboxamide compound according to any one of claims 1 to 9, wherein R ³ may be linked to Z so as to contain an N atom bonded to R ³ to form a heterocyclic group. . Z is a bridge _{-CH 2 -, - CH 2 -CH} 2 -, - CH 2 -CH (CH 3) -, - CH 2 -C (CH 3) 2 -, - CH (CH 3) -CH 2 -, Selected from the group of —C (CH ₃ ) ₂ —CH ₂ — and —CH ₂ —O—, or Z is a partial formula

The group of which has a meaning selected from 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,2,5,6-tetrahydropyridine-1,3-ylene and 3-hydroxy-1,3-piperidinylene Carboxamide compound according to claim 10, characterized in that it is bound to R ³ in a manner. R ³ is selected from methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl and 2-hydroxy-1-methyl-ethyl- (in the above group, 1 , 2 or 3 H atoms may be substituted by F), or H, amino-C _{2-3 -alkyl-} , C _1-3 -alkyl-amino-C _{2-3 -alkyl-} Carboxamide compound according to any one of claims 1 to 11, characterized in that it is selected from: and di- (C _1-3 -alkyl) -amino-C _2-3 -alkyl-. The group Y is a divalent cyclic group 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohex Silene, 1,3-phenylene, 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1, 3-pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene or 1,4-piperazinylene Chosen from
The 5-, 6- or 7-membered group may be linked by two common, adjacent C atoms fused with a phenyl or pyridine ring;
The cyclic groups may be mono- or polysubstituted with R ²⁰ at one or more C atoms, in the case of phenyl groups they may also be further mono-substituted with nitro and / or Or may be substituted with R ²¹ at one or more N atom positions,
R ¹ may be linked to Y as specified in claim 1 and / or R ³ may be linked to Y, and
Carboxamide compound according to any one of claims 1 to 12, characterized in that R ¹ , R ³ , R ²⁰ and R ²¹ have the meaning indicated in claim 1 or 2. R ¹ is a subexpression

Is based on the following partial formula

Carboxamide compound according to claim 13, characterized in that it is bound to Y in a manner having the meaning selected from. Group A is a divalent cyclic group 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohex Silene, 1,3- and 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1,3 -Pyrrolinylene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydropyridinylene, 2,4- and 2,5-pyridinylene, 1,4-piperazinylene, Selected from 7-aza-bicyclo [2.2.1] heptane-2,7-diyl and 8-aza-bicyclo [3.2.1] octane-3,8-diyl;
The 5-, 6- or 7-membered group may be linked by two common, adjacent C atoms fused with a phenyl ring or a pyridine ring;
The cyclic groups may be mono- or polysubstituted with R ²⁰ at one or more C atom positions, and in the case of phenyl rings they may also be further mono-substituted with nitro and / or Or they may be substituted with R ²¹ at one or more N atom positions, and
Carboxamide compound according to any one of claims 1, 2, 3 and 5 to 13, characterized in that R ²⁰ , R ²¹ and Y have the meaning indicated in claim 1 or 2. Group B is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl , Pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzimidazolyl, isoquinolinyl, furanyl and thienyl,
The bond to the group W or optionally the direct bond to the group A is via the C atom of the carbocyclic moiety or optionally condensed phenyl or pyridine ring, or the N atom or C of the heterocyclic moiety. Selected from the groups cyclopentylidene-methyl, cyclohexylidene-methyl and cyclohexanone-4-ylidene-methyl, together with a group W made through an atom, or B linked by a double bond, and the ring The formula group may be mono- or poly-substituted with R ²⁰ at one or more C atoms, and in the case of a phenyl group may also be mono-substituted with nitro and / or one or more. Optionally substituted with R ²¹ at the N atom position of
Carboxamide compound according to any one of claims 1 to 15, characterized in that R ²⁰ and R ²¹ have the meaning indicated in claim 1 or 2. The group B is C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _3-7 -cycloalkenyl-C _{1 -3 -alkyl-} , C _3-7 -cycloalkyl-C _1-3 -alkenyl- or C _3-7 -cycloalkyl-C _1-3 -alkynyl-, wherein one or more C atoms are May be mono- or polysubstituted by halogen and / or monosubstituted by hydroxy or cyano and / or the cyclic group may be monosubstituted or polysubstituted by R ²⁰ and W is a single bond, -O-, C _1-4 -alkylene group, C _2-4 -alkenylene group, C _2-4 -alkynylene group, C _1-4 -alkyleneoxy group, oxy-C _1-4 -alkylene -Group, C _1-3 -alkylene-oxy-C _1-3 -alkylene- group, imino group, N- (C _1-3 -alkyl) -imino-group, imino-C _1-4 -alkylene-group, N- (C _1-3 -alkyl) -imino Represents a -C _1-4 -alkylene- group, a C _1-4 -alkylene-imino- group or a C _1-4 -alkylene-N- (C _1-3 -alkyl) -imino- group, one or two In which the C atoms are independently of one another hydroxy, ω-hydroxy-C _1-3 -alkyl, ω- (C _1-3 -alkoxy) -C _{1-3 -alkyl-} and / or C _1-3 -alkoxy _Optionally substituted with one or two identical or different C _1-4 -alkyl groups, and k represents 0 or 1, and
Carboxamide compound according to any one of claims 1 to 15, characterized in that R ²⁰ has the meaning indicated in claim 1 or 2. k is 0 and the group A is bonded to the group B by a common C atom to form a spirocyclic ring system;
Group A represents a saturated 5- to 7-membered carbocyclic group or heterocyclic group, and group B represents a saturated 4- to 7-membered carbocyclic group or heterocyclic group, and the heterocyclic group is N atom in each case , An O atom or an S atom, and a phenyl ring or a pyridine ring may be condensed to a 5- to 7-membered group B by two adjacent C atoms, and the cyclic group is one or more C atoms It may be mono- or polysubstituted with R ²⁰ at the position, and in the case of fused phenyl rings, they may be further mono-substituted with nitro and / or R at one or more N atoms. Carboxamide compound according to any one of claims 1 to 15, characterized in that it may be substituted with ²¹ and R ²⁰ and R ²¹ have the meaning indicated in claim 1 or 2. a bicyclic saturated, unsaturated or aromatic, 8- to 12-membered carbocyclic ring in which k is 0 and the group B is fused to the group A by two common adjacent atoms Forming a ring or heterocyclic ring system,
The heterocyclic ring system has one or more of the same or different heteroatoms selected from N, O and / or S, and the bicyclic ring system is R ²⁰ at the position of one or more C atoms. In the case of a fused phenyl ring, it may also be further monosubstituted by nitro and / or substituted with R ²¹ at one or more N atoms. Carboxamide compound according to any one of claims 1 to 15, characterized in that R ²⁰ and R ²¹ have the meaning indicated in claim 1 or 2. The carboxamide compound according to any one of claims 1 to 16, wherein W is a single bond, -CH ₂ -or -CH =. Y and A are independently divalent cyclic groups 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2,3,6-tetrahydro- Selected from among pyridine-1,4-ylene, 2,5-pyridinylene and 1,4-piperazinylene, A may also be linked to R ³ according to claim 3 and one or more of said cyclic groups May be mono- or polysubstituted by R ²⁰ at the C atom position, in the case of phenyl groups they may also be further mono-substituted by nitro and / or one or more N atoms Optionally substituted by R ^{21 in} position,
B represents phenyl or cyclohexyl, the group may be mono- or polysubstituted by R ²⁰ , and / or the phenyl ring may be further mono-substituted by nitro, and R ²⁰ is defined in claim 1 or And W is a single bond, —CH ₂ — or —CH═, and Z is —CH ₂ —CH ₂ —, —CH ₂ —CH (CH ₃ ) —, — Represents CH ₂ —C (CH ₃ ) ₂ —, —CH (CH ₃ ) —CH ₂ —, —C (CH ₃ ) ₂ —CH ₂ — or —CH ₂ —O—, or a sub-formula of formula I

Is attached to R ³ in a manner such that the group has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene, and
Carboxamide compound according to any one of claims 1 to 20, characterized in that R ³ , R ²⁰ and R ²¹ have the meanings indicated in claims 1, 2 and / or 12. Formulas I.1-I.14

(Where
U and V each independently represent C or N;
R ²³ and R ²⁴ each independently represent H, F, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl;
In formulas I.1 to I.6, R ²⁴ is a partial formula

May be linked to R ³ in such a way that it has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene,
R ²⁵ , R ²⁶ , R ²⁷ independently of one another have one of the meanings given for R ^{20 according} to claim 1 or 2 or, in the case of a phenyl group, also simply represents nitro and appears repeatedly The radicals R ²⁵ , R ²⁶ , R ²⁷ may have the same or different meanings, and j is 0, 1, 2, 3 or 4 and m and n are independently 0, 1 or 2 And
L ¹ , L ² , L ³ , R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ²⁰ and X are defined in claims 1, 2, 5-9 and / or 12. Has a meaning)
The carboxamide compound according to any one of claims 1 to 21, which is selected from the group consisting of: Formula I.15

(Where
B is C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 -alkynyl, C _3-7 -cycloalkyl-C _{1-3 -alkyl-} , C _3-7 -cycloalkenyl-C _1- Selected from among ₃ -alkyl-, C _3-7 -cycloalkyl-C _1-3 -alkenyl- or C _3-7 -cycloalkyl-C _1-3 -alkynyl-, wherein one or more C atoms are halogen And / or may be monosubstituted by hydroxy or cyano and / or the cyclic group may be monosubstituted or polysubstituted by R ²⁰ and W Is a single bond, -O-, C _1-4 -alkylene group, C _2-4 -alkenylene group, C _2-4 -alkynylene group, C _1-4 -alkyleneoxy-group, oxy-C _1-4 -alkylene -Group, C _1-3 -alkylene-oxy-C _1-3 -alkylene- group, imino group, N- (C _1-3 -alkyl) -imino-group, imino-C _1-4 -alkylene-group, N-(C _1-3 - alkyl) - Lee Bruno -C _1-4 - alkylene - group, C _1-4 - alkylene - imino - group or a C _1-4 - alkylene-N-(C _1-3 - alkyl) - represents an imino group, one or two The C atoms of each independently represent a hydroxy group, a ω-hydroxy-C _1-3 -alkyl group, a ω- (C _1-3 -alkoxy) -C _1-3 -alkyl group and / or a C _1-3 -alkoxy group. And / or may be substituted by one or two identical or different C _1-4 -alkyl groups, and k represents 0 or 1, and U, V, R ²³ , R ²⁴ , R ²⁶ , R ²⁷ , m, n, L ¹ , L ² , L ³ , R ¹ , R ² , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ²⁰ and X are indicated in claim 22 Has meaning)
23. A carboxamide compound according to any one of claims 1 to 22, characterized by:   24. Carboxamide compound according to claim 22 or 23, characterized in that U and V each represent a C atom. R ¹ and R ² have the meaning of claim 5 and / or 6 independently of each other, and
R ³ has the meaning of claim 12 and X has the meaning of claim 8 or 9,
Carboxamide compound according to claim 21, 22, 23 or 24, characterized in that the group R ¹ R ² NX- may also have the meaning according to claim 7. X is _{-CH 2 -, - CH (CH} 3) - or -C (CH _{3) 2} -, characterized in that a carboxamide compound according to any one of claims 21 25. R ²⁵ , R ²⁶ and R ²⁷ are independently of each other F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoro Represents methoxy, ethoxy, n-propoxy or iso-propoxy, in the case of substitution of the phenyl group, they may also represent nitro, the repeated groups R ²⁵ , R ²⁶ , R ²⁷ have the same or different meanings 27. The method according to any one of claims 21 to 26, characterized in that j is 0, 1 or 2, and m and n are 0 or 1 independently of each other. Carboxamide compounds. R ⁶ , R ⁷ , R ⁸ and / or R ⁹ independently of one another represent H, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl, and in the case of R ⁶ , R ⁷ also represents F The carboxamide compound according to any one of claims 1 to 27, wherein formula
(1) 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(2) 3- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one
(3) 3- [2- (4-Pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3H-quinazolin-4-one
(4) 7- (4-Methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(5) 7- (3,4-Dichloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(6) 7- (4-Fluoro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(7) 7- (4-Ethyl-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(8) 2-Methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7- (4-trifluoromethyl-phenyl) -3H-quinazolin-4-one
(9) 2-Methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -7-p-tolyl-3H-quinazolin-4-one
(10) 7- (4-Chloro-phenyl) -2-methyl-3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(11) 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -1H-quinazoline-2,4-dione
(12) 7- (4-Chloro-phenyl) -3- {2- [4-((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazoline-4- on
(13) 7- (4-Chloro-phenyl) -3- [2- (4-dimethylaminomethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(14) 7- (4-Chloro-phenyl) -3- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(15) 7- (4-Chloro-phenyl) -3- [2- (4-morpholin-4-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(16) 7- (4-Chloro-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-benzo [d] [1,2,3] triazine-4- on
(17) 5- (4-Fluoro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -isoindole-1,3-dione
(18) 4'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(19) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide
(20) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-piperidin-1-ylmethyl-phenyl) -ethyl] -amide
(21) 4'-Methoxy-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -amide
(22) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-diethylaminomethyl-phenyl) -ethyl] -methyl-amide
(23) 4- (4-Chloro-phenyl) -cyclohexanecarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(24) 4-Methylphenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(25) 4- (4-Chloro-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(26) 4- (4-Chloro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(27) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide
(28) 4'-Chloro-biphenyl-4-carboxylic acid- (4-pyrrolidin-1-ylmethyl-benzyloxy) -amide
(29) 4-Cyclohexyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(30) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(31) 7- (4-Chloro-phenyl) -3- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -3H-quinazolin-4-one
(32) 4'-Chloro-biphenyl-4-carboxylic acid- {2- [6- (4-methyl-piperazin-1-yl) -pyridin-3-yl] -ethyl} -amide
(33) 7- (3-Methoxy-phenyl) -3- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -3H-quinazolin-4-one
(34) 4- (4-Oxo-cyclohexyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(35) 4-Cyclohexyl-1-cyclohexylcarboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(36) 4-Benzyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(37) 4-Cyclohexyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(38) 4- (4-Chloro-phenyl) -piperazine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(39) 4- (4-Fluoro-phenyl) -piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(40) 4- (4-Methoxy-phenyl) -piperazine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(41) 4-Phenyl-piperidine-1-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(42) (4'-Chloro-biphenyl-4-yl)-[3- (4-pyrrolidin-1-ylmethyl-phenyl) -piperidin-1-yl] -methanone
(43) 4'-Chloro-biphenyl-4-carboxylic acid- [2-methyl-2- (4-pyrrolidin-1-ylmethyl-phenyl) -propyl] -amide
(44) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (4-pyrrolidin-1-ylmethyl-cyclohexyl) -ethyl] -amide
(45) 4-Benzyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(46) 4- (4-Oxo-cyclohexylidenemethyl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(47) 4'-Chloro-biphenyl-4-carboxylic acid- [2- (2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(48) 5- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one
(49) 4-Piperidin-1-yl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(50) 7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one
(51) 7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one
(52) 7- (4-Chloro-phenyl) -3- {2- [4- (3-aza-spiro [5.5] undec-3-ylmethyl) -phenyl] -ethyl} -3H-benzo [d] [ 1,2,3] triazin-4-one
(53) 7- (4-Chloro-phenyl) -3- {2- [4- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -3H-quinazolin-4-one
(54) 7- (4-Chloro-phenyl) -3- (2- {4- [4- (pyridin-2-yloxy) -piperidin-1-ylmethyl] -phenyl} -ethyl) -3H-quinazoline-4 -on
(55) 6- (4-Chloro-phenyl) -2- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -2H-isoquinolin-1-one
(56) 4'-chloro-biphenyl-4-carboxylic acid [2- (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(57) 4'-chloro-biphenyl-4-carboxylic acid [2- (3-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(58) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (1-ethyl-piperidin-2-yl) -phenyl] -ethyl} -amide
(59) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (4-acetyl-piperazin-1-ylmethyl) -phenyl] -ethyl} -amide
(60) 4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-aza-bicyclo [2.2.1] hept-5-en-2-ylmethyl) -phenyl] -ethyl} -amide
(61) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (1,3-dihydro-isoindol-2-ylmethyl) -phenyl] -ethyl} -amide
(62) 4'-Chloro-biphenyl-4-carboxylic acid (2- {4-[(diisopropylamino) -methyl] -phenyl} -ethyl) -amide
(63) 4'-Chloro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(64) 4'-chloro-biphenyl-4-carboxylic acid {2- [4- (2-dimethylaminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(65) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3-dimethylamino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(66) 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-bromo-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(67) 4-Pent-1-inyl-N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(68) 4'-Chloro-biphenyl-4-carboxylic acid [2- (6-pyrrolidin-1-ylmethyl-pyridin-3-yl) -ethyl] -amide
(69) 4'-Chloro-biphenyl-4-carboxylic acid [2- (1-pyrrolidin-1-yl-indan-5-yl) -ethyl] -amide
(70) 4'-chloro-biphenyl-4-carboxylic acid [2- (2-nitro-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(71) 2 ', 4'-Dichloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(72) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3-amino-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(73) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-aminomethyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(74) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-2,6-diaza-spiro [3.4] oct-6-ylmethyl) -phenyl] -ethyl} -amide
(75) 4'-Chloro-biphenyl-4-carboxylic acid [2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -ethyl] -amide
(76) 4'-Chloro-biphenyl-4-carboxylic acid [2- (3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(77) 4'-Bromo-biphenyl-4-carboxylic acid {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(78) 4- (5-Chloro-thiophen-2-yl) -N- [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -benzamide
(79) 4'-Chloro-biphenyl-4-carboxylic acid [2- (2-methyl-4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(80) 4'-Bromo-3-fluoro-biphenyl-4-carboxylic acid {2- [3-bromo-4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(81) 4'-Chloro-2-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(82) 4'-Ethyl-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(83) tert.butyl [1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-2-ylmethyl] -carbamate
(84) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide
(85) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2-methyl-pyrrolidin-1-ylmethyl) -phenyl] -ethyl} -amide
(86) 4'-Chloro-biphenyl-4-carboxylic acid (2- {4-[(cyclopropylmethyl-amino) -methyl] -phenyl} -ethyl) -amide
(87) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (3,4-dihydro-1H-isoquinolin-2-ylmethyl) -phenyl] -ethyl} -amide
(88) 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-{[(2-hydroxy-ethyl) -methyl-amino] -methyl} -phenyl) -ethyl] -amide
(89) tert.butyl [1- (4- {2-[(4'-chloro-biphenyl-4-carbonyl) -amino] -ethyl} -benzyl) -pyrrolidin-3-yl] -carbamate
(90) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -phenyl] -ethyl} -amide
(91) 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-azetidin-1-ylmethyl-phenyl) -ethyl] -amide
(92) 4'-Chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(93) 4'-Fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(94) 4'-Chloro-3-fluoro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(95) 2'-Fluoro-4'-chloro-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(96) 5- (4-Chloro-phenyl) -pyridine-2-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(97) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (2,5-dihydro-pyrrol-1-ylmethyl) -phenyl] -ethyl} -amide
(98) 4'-Bromo-biphenyl-4-carboxylic acid [2- (4-pyrrolidin-1-ylmethyl-phenyl) -ethyl] -amide
(99) 4'-Chloro-biphenyl-4-carboxylic acid {2- [4- (1-pyrrolidin-1-ylethyl) -phenyl] -ethyl} -amide selected from claims 1 or 2 Carboxamide compounds.   Formula (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), ( (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25) 30. The carboxamide compound according to claim 29, selected from among (26), (27), (28), (29), (30), (47) and (50) to (99). Formula I

Wherein A, B, W, X, Y, Z, R ¹ , R ² , R ³ and k have one of the meanings specified in claims 1 to 28.
A method for preparing a carboxamide compound of
When A represents a group R ³ that is not linked to the group A ,
a) a nitrogen heterocyclic group in which A is linked to a carboxamide group via a nitrogen atom (which may also have one or more heteroatoms selected from N, O and S in addition to the nitrogen atom) Represents the formula I-1

(Wherein R ¹ , R ² , R ³ , X, Y and Z have the meanings indicated above)
In the presence of at least one base in a solvent or mixture of solvents, CDT (1,1′-carbonyldi- (1,2,4-triazole)) and formula I-2

(Wherein A, B, W and k have the meanings indicated above and the group A has a secondary amine function)
Reacting with at least one secondary amine compound of
b) For other cases, formula I-3

(Wherein A, B, W and k have the meanings indicated above)
TBTU (2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium in the presence of at least one base in a solvent or mixture of solvents -Tetrafluoroborate) and formula I-1

(Wherein R ¹ , R ² , R ³ , X, Y and Z have the meanings indicated above)
Reacting with at least one amine compound of
When B is a group R ³ linked to a group A ,
a) means ^{-CR 6 R 7 - (IIIa)} (R 6 and R ⁷ in the case of group Q having the is) as hereinbefore defined, the formula Ia.1

(Wherein R ¹ , R ² , X, Y and Z have the specified meaning)
The amine compound of formula Ia.2

(Wherein R ⁶ , R ⁷ , W, B and k have the specified meaning)
Reaction with o-bromomethyl-benzoic acid ester derivatives of
b) means ^{-CR 6 = CR 7 - (IIIb} ) ( wherein, when R ⁶ and R ⁷ groups Q having a are as previously defined), the formula Ib.2

(Wherein R ⁶ , R ⁷ , W, B and k have the specified meaning)
Isoquinolinone derivatives of formula Ib.3

Wherein Y and Z have the specified meanings and OMs represents a suitable leaving group, preferably mesylate
With an electrophile of formula Ib.4

(Wherein R ⁶ , R ⁷ , W, B, Y, Z and k have the specified meaning)
An isoquinoline derivative of formula Ib.4 is further derivatized by known methods to produce a compound of formula I;
c) means ^{-N = CR 8 - (IIIc)} ( wherein, R ⁸ in the case of group Q having the is) as hereinbefore defined, the formula Ic.4

(Wherein R ⁸ , W, B and k have the specified meaning)
A phthalazinone derivative of formula Ic.5

In which Y and Z have the specified meaning and OMs represents a leaving group, preferably mesylate.
With an electrophilic compound of formula Ic.6

(Wherein R ⁸ , W, B, Y, Z and k have the specified meaning)
Of generating a phthalazinone derivative, a compound of formula I thus obtained phthalazinone derivative of formula Ic.6 further derivatized by known methods (In formula (I), Q is -N = CR ⁸ - (representative of IIIc)) and Generate
d) in the case of the group Q having the meaning -N = N- (IIId), the formula Id.1

(Wherein R ¹ , R ² , W, B, X, Y, Z and k have the specified meanings)
An o-amino-benzamide derivative of is reacted in the presence of a suitable nitrile compound and an acid to produce a compound of formula I wherein Q represents -N = N-
e) in the case of a group Q having the meaning —CO—NR ⁹ — (IIIe), wherein R ⁹ is as defined above, the formula Ie.1

(Wherein R ¹ , R ² , R ⁹ , W, B, X, Y, Z and k have the specified meanings)
Bruno o- amino - benzamide derivative is reacted in the presence of CDI (carbonyldiimidazole) compounds of formula I (wherein, Q is -CO-NR ⁹ - represents a) generating a
f) in the case of a group Q having the meaning -CR ⁸ = N- (IIIf), where R ⁸ is as defined above, the formula If.1

(Wherein R ¹ , R ² , W, B, X, Y, Z and k have the specified meanings)
Bruno o- amino - benzamide derivative is reacted with a carboxylic acid R ⁸ COOH and / or the corresponding activated carboxylic acid derivatives have the meanings specified for R ⁸ in quinazolinone derivative (of the formula I, Q is -CR ⁸ = N-)
g) In the case of the group Q having the meaning —CO— (IIIg), the formula Ig.2

Where W, B and k have the specified meanings.
Isobenzofurandione derivatives of formula Ig.1

(Wherein R ¹ , R ² , X, Y and Z have the specified meaning)
A method for preparing a carboxamide compound of the above formula I, characterized in that it is reacted with an amine of the formula to produce a compound of formula I wherein Q represents -CO-.   A physiologically acceptable salt of the carboxamide compound according to any one of claims 1 to 30.   A composition comprising at least one carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32, optionally together with one or more physiologically acceptable excipients. object.   It contains at least one carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32, optionally together with one or more inert carriers and / or diluents. Pharmaceutical composition.   32. Use of at least one carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32 for influencing a mammal's dietary behavior.   33. Use of at least one carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32 for reducing the weight of a mammal and / or preventing an increase in body weight.   Use of at least one carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32 for the preparation of a pharmaceutical composition having MCH-receptor antagonistic activity.   31. A method for preparing a pharmaceutical composition suitable for preventing and / or treating symptoms and / or diseases caused by MCH or otherwise causally associated with MCH. 33. Use of at least one carboxamide compound according to any one of claims 1 and / or a salt according to claim 32.   Suitable for preventing and / or treating metabolic disorders and / or dietary disorders, in particular obesity, bulimia, bulimia nervosa, cachexia, anorexia nervosa, anorexia nervosa and bulimia. Use of at least one carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32 for the preparation of a pharmaceutical composition.   Diseases and / or disorders associated with obesity, especially diabetes, especially type II diabetes, diabetic complications (including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance), cerebral hemorrhage, 31. Any one of claims 1 to 30 for preparing a pharmaceutical composition suitable for preventing and / or treating heart failure, cardiovascular disease, in particular arteriosclerosis and hypertension, arthritis and knee arthritis. 33. Use of at least one carboxamide compound according to claim and / or a salt according to claim 32.   Hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorder, emotional disorder, depression, anxiety, sleep disorder, reproductive disorder, sexual disorder, memory disorder, epilepsy, dementia And / or at least one carboxamide compound and / or claim 32 for the preparation of a pharmaceutical composition suitable for preventing and / or treating hormonal disorders. Use of the described salts.   31 to 30 for preparing a pharmaceutical composition suitable for preventing and / or treating dysuria such as urinary incontinence, hyperactive bladder, imminent urination, nocturia and enuresis 33. Use of at least one carboxamide compound according to any one of claims 1 and / or a salt according to claim 32.   The at least one carboxamide compound according to any one of claims 1 to 30 and / or the salt according to claim 32 is mixed into one or more inert carriers and / or diluents by non-chemical methods. A method for preparing a pharmaceutical composition according to any one of claims 33 to 38. Optionally with one or more inert carriers and / or diluents,
A first active substance selected from a carboxamide compound according to any one of claims 1 to 30 and / or a salt according to claim 32, and an active substance for the treatment of diabetes, for the treatment of complications of diabetes Active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of hypertension, active substances for the treatment of hyperlipidemia, including arteriosclerosis, for the treatment of arthritis And a second active substance selected from the group consisting of an active substance for the treatment of anxiety and an active substance for the treatment of depression.