AU2008238250B2 - Novel vanilloid receptor ligands and the use thereof for the production of pharmaceuticals - Google Patents

Novel vanilloid receptor ligands and the use thereof for the production of pharmaceuticals Download PDF

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AU2008238250B2
AU2008238250B2 AU2008238250A AU2008238250A AU2008238250B2 AU 2008238250 B2 AU2008238250 B2 AU 2008238250B2 AU 2008238250 A AU2008238250 A AU 2008238250A AU 2008238250 A AU2008238250 A AU 2008238250A AU 2008238250 B2 AU2008238250 B2 AU 2008238250B2
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butyl
group
denotes
case
methyl
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AU2008238250A1 (en
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Gregor Bahrenberg
Thomas Christoph
Jean De Vry
Robert Frank
Jeewoo Lee
Derek John Saunders
Klaus Schiene
Bernd Sundermann
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Gruenenthal GmbH
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Gruenenthal GmbH
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Abstract

The present invention relates to novel vanilloid receptor ligands, a method for the production thereof, pharmaceuticals containing said compounds, and the use of said compounds for the production of pharmaceuticals.

Description

GRA3394-WO-1 Novel vanilloid receptor ligands and the use thereof for the production of pharmaceuticals The present invention relates to novel vanilloid receptor ligands, to methods for producing them, to pharmaceuticals containing these compounds and to the use of these compounds for the production of pharmaceuticals. The treatment of pain, in particular neuropathic pain, is of great medical significance. There is a worldwide need for effective pain treatments. The urgency of the requirement for effective therapeutic methods for providing tailored and targeted treatment of chronic and non-chronic pain, this being taken to mean pain treatment which is effective and satisfactory from the patient's standpoint, is also evident from the large number of scientific papers relating to applied analgesia and to basic nociception research which have appeared in recent times. One suitable approach to the treatment of pain, in particular of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, particularly preferably of neuropathic pain, is the vanilloid receptor subtype 1 (VR1/TRPV1), which is often also known as the capsaicin receptor. This receptor is stimulated inter alia by vanilloids such as for example capsaicin, heat and protons and plays a central role in the genesis of pain. It is furthermore of significance to numerous other physiological and pathophysiological processes, such as for example migraine; depression; neurodegenerative diseases; cognitive disorders; anxiety states; epilepsy; coughing; diarrhoea; pruritus; inflammation; disorders of the cardiovascular system; disorders of food intake; dependency on medicines; abuse of medicines and in particular urinary incontinence. One object of the present invention was accordingly to provide novel compounds which are suitable in particular as pharmacological active ingredients in pharmaceuticals, preferably in pharmaceuticals for the treatment of disorders or diseases which are mediated at least in part by vanilloid receptors 1 (VR1/TRPV1 receptors). 1 -2 It has surprisingly now been found that the substituted compounds of the general formula I stated below display excellent affinity for the vanilloid receptor of the subtype 1 (VR1/TRPV1 receptor) and are therefore suitable in particular for the prevention and/or treatment of disorders or diseases which are mediated 5 at least in part by vanilloid receptors 1 (VR1/TRPV1). Likewise the substituted compounds of the general formula I stated below exhibit anti-inflammatory activity. Disclosed herein are substituted compounds of the general formula I
R
8 UIN R1 7R R H R 6 R7 R VlzW /N R2
(CH
2 )n 0R 5 R 3 10 R4 in which is n denotes 0, 1, 2, 3 or 4;
R
1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; O-C(=O)-NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -O-C(=O)
NR
63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -0-; -NH-C(=O)-NH-; -NH 20 C(=S)-NH-; -NR 66 -C(=0)-NR 65 -; -NR 66
-C(=S)-NR
65 ; -O-CH 2 -C(=0)-NH-; -0
CH
2 -0-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 2 =N-NH-; -CH=N-NR 2 -; -CR 2
=N-NR
2 _ _S 25 C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0
C(=S)-NR
63 -; -S-C(=O)-NR 63 -; -0-C(=O)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR 64 -; -NH-C(=0)-NH-; -NH- GRA3394-WO-1 C(=S)-NH-; -NR 66
-C(=O)-NR
6 1-; -NR 66
-C(=S)-NR
6 5 -; -N=N-NH-; -N=N-NR 67 -; O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; CH 2
-CH
2 -NH-; -CH 2
-CH
2
-CH
2 -NH-; -CH 2 C(=O)-NH, -CH 2
-CH
2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -N=N CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; CH=N-N=CH-, -N=N-CR 68
=CR
69 -; -N=CR 68
-N=CR
69 ; -N=CR 68
-CR
6 9 =N-; CR 68
=CR
69 -CH=N-; -CR 68
=CR
69
-N=CR
7 1-; -CR 68
=N-N=CR
69 - and -0-CH 2 CH 2 -NH- , which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 2 8 =N-NH-; -CH=N-NR 6 2 -; -CR 2 1=N-NR 6 2_; _S_ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -0
C(=S)-NR
63 -; -S-C(=O)-NR 63 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; N=CH-O-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR64-; -NH-C(=0)-NH-; -NH C(=S)-NH-; -NR 6 6
-C(=O)-NR
6 5 -; -NR 6 6
-C(=S)-NR
6 5 -; -N=N-NH-; -N=N-NR 6 7 _; O-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2
-CH
2 -NH, -CH 2 C(=O)-NH, -CH 2
-CH
2 -C(=O)-NH-; -0-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -N=N CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; CH=N-N=CH-, -N=N-CR 68
=CR
69 -; -N=CR 6
"-N=CR
69 ; -N=CR 6 1-CR 69 =N-; CR 68
=CR
6 9 -CH=N-; -CR 68
=CR
69
-N=CR
7 0 -; -CR 68
=N-N=CR
6 9 - and -0-CH 2 CH 2 -NH- , which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0) NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -0-C(=O)-NR 6 3_; __ CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 -O-; -NH-C(=O)-NH-; -NH-C(=S)-NH ; -NR 66 -C(=0)-NR 6 5 -; -NR 66
-C(=S)-NR
6 5 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 - 0-; -0
CH
2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 or R 4 and R 5 together with the carbon atoms joining them together form a 4-, 5-, 6- or 7-membered ring which is saturated, unsaturated or aromatic, has 1, 2 or 3 nitrogen atoms as ring members and is unsubstituted or substituted with 1, 2 or 3 residues mutually independently selected from the group consisting of F, Cl, Br, I, =0, -CN, -CF 3 , -SF 5 , -OH, 3 GRA3394-WO-1 O-C1.
5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C1.
5 -alkyl, -C1.
5 -alkyl, C(=O)-OH, -C(=O)-O-C 1
.
5 -alkyl, -NH-C 1
.
5 -alkyl, -N(C 1
.
5 -alkyl) 2 , -NH-S(=0) 2 -C1. 5 -alkyl, -NH-C(=O)-O-C 1
.
5 -alkyl, -C(=0)-H, -C(=O)-C 1
.
5 -alkyl, -C(=0)-NH 2 , C(=O)-NH-C1.
5 -alkyl, -C(=0)-N-(C 1
.
5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -0 benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, CF 3 , -SF 5 , -CN, -NO 2 , -C1.5 alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -0 benzyl, and the remaining residues R 1 , R 2 , R 3 , R 4 and R 5 , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2
-NH
2 ; C(=O)-NH-OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -C(=NH)-NH 2 ; -C(=NH)
NH-R
9 ; -N=C(NH 2
)
2 ; -N=C(NHR 10
)(NHR
1 ); -O-P(=0) 2 -0-R; -NHR"; NR 14
R
1 ; -NH-C(=O)-R; -ORi 6 ; -SR' 7 ; -C(=O)-NHR' 8 ; -C(=O)-NR 19
R
20 S(=0) 2
-NHR
21 ; -S(=0) 2
-NR
22
R
23 ; -C(=O)-OR 24 ; -C(=O)-R 2 5 ; -S(=O)-R 2 6 ; S(=0) 2
-R
27 or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.1o residue;
R
6 denotes H or a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic CI-o residue;
R
7 denotes hydrogen or -OH; or R 6 and R 7 in each case together with the carbon atom joining them together as a ring member form a saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5- or 6- or 7-membered cycloaliphatic residue;
R
8 denotes -SF 5 ; -0-CF 3 ; -CF 3 ; -O-CFH 2 ; -O-CF 2 H; -CFH 2 ; -CF 2 H; or denotes an unsubstituted or at least monosubstituted tert-butyl residue; T denotes C-R 35 and U denotes C-R 3 6 V denotes N and W denotes C-R 38 or 4 GRA3394-WO-1 T denotes C-R 35 and U denotes N and V denotes C-R 37 and W denotes C-R 38 or T denotes N and U denotes C-R 36 and V denotes C-R 37 and W denotes C-R 38 or T denotes N and U denotes N and V denotes C-R 37 and W denotes C-R 38 or T denotes N and U denotes C-R 3 M and V denotes N and W denotes C-R 8 or T denotes C-R 35 and U denotes N and V denotes N and W denotes C-R 3 8 or T denotes C-R 3 5 and U denotes C-R 3 6 and V denotes C-R 37 and W denotes C-R 38 .
R
9 , R 1 O, R 1 , R 1 , R 1 , R 14 , R 1 , R' 6 , R', R 18 , R 19 , R 20 , R 2 , R 22 , R 23 , R 24 , R 2
R
26 and R 27 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; denote an unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising at least one heteroatom as a ring member, which residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1- alkylene group or 2- to 6 membered heteroalkylene group; or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or 2- to 6-membered heteroalkylene group;
R
28 denotes F; Cl; Br; I; -SF 5 ; -NO 2 ; -CF 3 ; -CN; -NH 2 or denotes a linear or 5 GRA3394-WO-1 branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic Cl.10 residue;
R
29 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 3 1; -NH 2 ; -NH-S(=0) 2
-R
32 ; -NH-C(=O)-O-R 33 ; -S-R 34 or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue;
R
1 , R 32 , R 33 and R 34 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue;
R
35 , R 3 ' and R 37 , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; NO 2 ; -CF 3 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2
-NH
2 ; -C(=O)-NH-OH; C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -NHR 13 ; -NR1 4
R
15 ; -NH-C(=O)-R 13 ; -OR'- SR 17 ; -C(=O)-NHR'"; -C(=O)-NR 19
R
20 ; -S(=0) 2
-NHR
21 ; -S(=0) 2
-NR
22
R
23 _
C(=O)-OR
24 ; -C(=O)-R 2 1; -S(=O)-R 2 6 ; -S(=0) 2
-R
27 ; denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 residue; or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group;
R
38 denotes H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CF 3 ; -CF 2 CI; -CN; -NH 2 ; -OH; -SH; -C(=0)
NH
2 ; -S(=0) 2
-NH
2 ; -C(=O)-NH-OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; NHR 39 ; -NR 40
R
41 ; -OR 42 ; -SR 43 ; -C(=O)-NHR 44 ; -C(=O)-NR 4 5
R
46 ; -S(=0) 2 NHR 47 ; -S(=0) 2
-NR
4 8
R
49 ; -C(=O)-OR 5 0 ; -C(=O)-R 5 1 ; -S(=O)-R 2 ; -S(=0) 2
-R
53 ;
C(=NH)-NH
2 ; -C(=NH)-NH-R 54 ; -N=C(NH 2
)
2 ; -N=C(NHR 55
)(NHR
5 6 ); 6 GRA3394-WO-1 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1 .1 0 residue; denotes an unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising at least one heteroatom as a ring member, which residue is in each case attached to the parent structure via a carbon atom in the ring of the cycloaliphatic residue and may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.
6 alkylene group or C 2
-
6 alkenylene group or C 2
-
6 alkynylene group; or denotes an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.
6 alkylene group or C2-6 alkenylene group or C 2
-
6 alkynylene group;
R
39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , Rs 2 , Rs 3 , R 54 , R 5 and R 56 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1 .1o residue; denote an unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising at least one heteroatom as a ring member, which residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C 1
.
6 alkylene group or 2- to 6 membered heteroalkylene group; 7 GRA3394-WO-1 or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or 2- to 6-membered heteroalkylene group; or
R
4 0 and R 4 1 in each case together with the nitrogen atom joining them together as a ring member form a saturated or unsaturated, unsubstituted 4-, 5-, 6-, 7-, 8- or 9-membered heterocycloaliphatic residue or 4-, 5-, 6-, 7-, 8- or 9-membered heterocycloaliphatic residue substituted with 1, 2, 3, 4 or 5 residues R 57 and optionally comprising at least one further heteroatom as a ring member, which heterocycloaliphatic residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system;
R
57 denotes -NHR 8 , -NR 59
R
6 0 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue;
R
58 , R 59 and R 6 , mutually independently, in each case denote -C(=O)-R 6 1 ; denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group;
R
61 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.1o residue; 8 GRA3394-WO-1 Re 2 , R 63 , R 64 , R 65 , R 6 r and R 6 7 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; Rea, R 69 and R 7 0 , mutually independently, in each case denote F, Cl, Br, I, or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.1o residue; and
R
71 denotes an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or C 2
-
6 alkenylene group or C 2
-
6 alkynylene group; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates; wherein the above-stated aliphatic C1.10 residues and tert-butyl residues may optionally in each case be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, NH 2 , -SH, -O(C1.
5 -alkyl), -S(C1.
5 -alkyl), -NH(C 1
.
5 -alkyl), -N(C1.
5 -alkyl)(C1.
5 -alkyl), C(=O)-O-C 1
.
5 -alkyl, -O-C(=O)-C 1 .s-alkyl, -0-phenyl, phenyl, -OCF 3 and -SCF 3 ; the above-stated 2- to 6-membered heteroalkylene groups, C1.6 alkylene groups and C2-6 alkenylene groups and C2-6 alkynylene groups may optionally in each case be 9 GRA3394-WO-1 substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -O(C1.s-alkyl), S( 1
.
5 -alkyl), -NH(C 1
.
5 -alkyl), -N(C1.
5 -alkyl)(C 1
.
5 -alkyl), -OCF 3 and -SCF 3 ; the above-stated heteroalkylene groups in each case optionally comprise 1, 2 or 3 heteroatom(s) mutually independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain link(s); the above-stated (hetero)cycloaliphatic residues may optionally be substituted in each case with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of -C1.
6 -alkylene-OH, =CH 2 , -O-C1..alkylene-oxetanyl, -C1.5 alkylene-O-C 1
.
5 -alkylene-oxetanyl, -CH 2
-NH-C
1
.
5 -alkyl, -CH 2 -N(C1.s-alkyl),)2, -N[ C(=0)-C1.
5 -alkyl]-phenyl, -CH 2 -0-C 1
.
5 -alkyl, oxo (=0), thioxo (=S), F, Cl, Br, I, -CN, CF 3 , -SF 5 , -OH, -O-C 1
.
5 -alkyl, -O-C(=0)-C1.
5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, S-C 1
.
5 -alkyl, -C1.s-alkyl, -C(=0)-C 1 .s-alkyl, -C(=O)-OH, -C(=0)-0-C1.
5 -alkyl, -NH-C 1
.
5 alkyl, -N(C1.s-alkyl) 2 , -NH-phenyl, -N(-C 1 .s-alkyl)-phenyl, cyclohexyl, cyclopentyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues oxetanyl, (4,5) dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, -N[-C(=O)-C 1 . s-alkyl]-phenyl, -NH-phenyl, -N(-C 1
.
5 -alkyl)-phenyl, -(CH 2 )-pyridinyl, pyridinyl, -0 phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, OH, -CF 3 , -SF 5 , -CN, -NO 2 , -C1.s alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -0 benzyl, and unless otherwise stated the above-stated (hetero)cycloaliphatic residues may in each case optionally comprise 1, 2 or 3 (further) heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur; the rings of the above-stated mono- or polycyclic ring systems may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of oxo (=0), thioxo (=S), F, Cl, Br, I, -CN, -CF 3 , SF 5 , -OH, -O-C1.s-alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 1
.
5 -alkyl, -C 1
.
5 -alkyl, 10
C(=O)-C
1
.
5 -alkyl, -C(=O)-OH, -C(=O)-O-C 1
.
5 -alkyl, -NH-C 1
.
5 -alkyl, -N(C 1
.
5 -alkyl) 2 , -0 phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , -CN, -NO 2 , -C1.
5 -alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -0-benzyl, and the rings of the above-stated mono- or polycyclic ring systems are in each case 5-, 6- or 7-membered and may in each case optionally comprise 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s), which are mutually independently selected from the group consisting of oxygen, nitrogen and sulfur; and the above-stated aryl or heteroaryl residues may optionally be substituted in each case with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-C 1
.
5 -alkyl, -NH 2 , -NO 2 , -0
CF
3 , -S-CF 3 , -SH, -S-C 1 .. s-alkyl, -C 1
.
5 -alkyl, -C(=O)-OH, -C(=O)-C 1
.
5 -alkyl, -NH-C 1 . salkyl, -N(C 1 .s-alkyl) 2 , -NH-S(=0) 2
-C
1 .s-alkyl, -NH-C(=O)-O-C 1 .s-alkyl, -C(=O)-H, C(=O)-C 1
.
5 -alkyl, -C(=O)-NH 2 , -C(=O)-NH-C 1
.
5 -alkyl, -C(=O)-N-(C 1
.
5 -alkyl) 2 , -0 phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 - -or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , -CN, -NO 2 , -C 1 .s-alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl, and the above-stated heteroaryl residues in each case optionally comprise 1, 2, 3, 4 or 5 heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s). 11 - 12 The present invention in a first aspect provides substituted compounds of the general formula I
R
8 R6 R7 RR l HR R7R
(CH
2 )n R5 R 3 R 4 5 I, in which n denotes 0, 1, 2, 3 or 4; la R 1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NRI-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 63 -; -0-C(=O)-NR 63 _; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -; -NH-C(=0)-NH-; -NH-C(=S) NH-; -NR 66 -C(=0)-NR 6 5 -; -NR 66
-C(=S)-NR
6 5 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; is O-CH 2
-CH
2 -0-, -O-CH 2
-CH
2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2_; _S_ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0 20 C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR 6 4 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; NR 66
-C(=O)-NR
65 -; -NR 6 6
-C(=S)-NR
6 5 -; -N=N-NH-; -N=N-NR 67 -; -O-CH 2 -C(=0) NH-; -O-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2
-CH
2 -NH, -CH 2 -C(=0)-NH, -CH 2 CH 2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -N=N-CH=CH-; -N=CH 25 N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH-, N=N-CR 6 1=CR 6 9 -; -N=CR 6 1-N=CR 6 9 ; -N=CR 6 8
-CR
69 =N-; -CR 6 1=CR 6 9 -CH=N-; CR 68
=CR
69
-N=CR
7 0 -; -CR 6 8
=N-N=CR
69 - and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group 30 consisting of -CH=N-NH-; -CR 2 8 =N-NH-; -CH=N-NR 6 2 -; -CR 2 a=N-NR 6 2_; __ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=O)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 _. -0 - 13 C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 0-; -N=CR 3 0 -0-; -N=CH-NH-; -N=CH-NR 6 4 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; NR 66 -C(=O)-N R 6 1-; -NR 66
-C(=S)-NR
6 5 -; -N=N-NH-; -N=N-NR 67 -; -O-CH 2
-C(=O)
NH-; -O-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2
-CH
2 -NH, -CH 2 -C(=0)-NH, -CH 2 5 CH 2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -N=N-CH=CH-; -N=CH N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH-, N=N-CR 6
=CR
69 -; -N=CRea-N=CR 69 ; -N=CRea-CR 69 =N-; -CR 68
CR
69 -CH=N-; CR 6
=CR
6 9
-N=CR
70 -; -CR 68
=N-N=CR
6 9 - and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, 10 or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR- 7 1 ; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 C(=O)-NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 63 -; -O-C(=O)-NR 3 -. -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -0-; -NH-C(=O)-NH-; -NH-C(=S) NH-; -NR 66
-C(=O)-NR
6 1-; -NR 66
-C(=S)-NR
6 1-; -O-CH 2 -C(=O)-NH-; -0-CH 2 -0-; is O-CH 2
-CH
2 -0-, -O-CH 2
-CH
2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R' and R 2 or R 2 and R 3 or R 3 and R 4 or R 4 and R 5 together with the carbon atoms joining them together form a 4-, 5-, 6- or 7-membered ring which is saturated, unsaturated or aromatic, has 1, 2 or 3 nitrogen atoms as ring 20 members and is unsubstituted or substituted with 1, 2 or 3 residues mutually independently selected from the group consisting of F, Cl, Br, I, =0, -CN, -CF 3 , SF 5 , -OH, -O-C 1
.
5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 5 -alkyl, -C1.
alkyl, -C(=O)-OH, -C(=O)-O-C 1
.
5 -alkyl, -NH-C 1
.
5 -alkyl, -N(C 1
.
5 -alkyl) 2 , -NH S(=0) 2
-C
1
.
5 -alkyl, -NH-C(=O)-O-C 1
.
5 -alkyl, -C(=O)-H, -C(=O)-C 1
.
5 -alkyl, -C(=O) 25 NH 2 , -C(=O)-NH-C 1
.
5 -alkyl, -C(=O)-N-(C 1
.
5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, CI, Br, -OH, CF 3 , -SF 5 , -CN, -NO 2 , -C1.5 alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -0 30 benzyl, and the remaining residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=0)-NH 2 ; -S(=0) 2
-NH
2 ; -C(=O)-NH-OH; -C(=0)-OH; -C(=0)-H; -S(=0) 2 -OH; -C(=NH)-NH 2 ; -C(=NH)- - 14 NH-R 9 : -N=C(NH 2
)
2 ; -N=C(NHR 10 )(NHR1); -O-P(=0) 2 -O-R"; -NHR; -NR 1 4
R
15 ; -NH-C(=O)-R"; -OR 16 ; -SR 17 ; -C(=O)-NHR 1 8 ; -C(=O)-NR 19
R
2 0 ; -S(=0) 2 -NHR; S(=0) 2
-NR
22
R
23 ; -C(=O)-OR 24 ; -C(=O)-R 2 5; -S(=O)-R 2 6 ; -S(=0) 2
-R
27 or denote a linear or branched, saturated or unsaturated, unsubstituted or at least 5 monosubstituted aliphatic C1.10 residue;
R
6 denotes H or denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue;
R
7 denotes hydrogen or -OH; or R 6 and R 7 in each case together with the carbon atom joining them io together as a ring member form a saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6- or 7-membered cycloaliphatic residue;
R
8 denotes CF 3 or tert-butyl; T denotes C-R 35 and U denotes C-R 36 and V denotes N and W denotes C
R
38 15 or T denotes C-R 35 and U denotes N and V denotes C-R 37 and W denotes C
R
3 8 or T denotes N and U denotes C-R 3 6 and V denotes C-R 37 and W denotes C 20 Ra3 or T denotes N and U denotes N and V denotes C-R 37 and W denotes C-R 3 8 or T denotes N and U denotes C-R 36 and V denotes N and W denotes C-R 3 8 25 or T denotes C-R 35 and U denotes N and V denotes N and W denotes C-R 3 8 or T denotes C-R 35 and U denotes C-R 36 and V denotes C-R 37 and W denotes C-R 38 ; 30 R 9 , R 10 , R", R , R , R 14 , R , R 16 , R 17 , R , R 19 , R 20 , R , R 22 , R 23 , R ,
R
2 5
R
2 e and R 27 , mutually independently, in each case - 15 denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1
.
10 residue; denote an unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue s optionally comprising at least one heteroatom as a ring member, which residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or 2 to 6-membered heteroalkylene group; 1o or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.
6 alkylene group or 2- to 6-membered heteroalkylene group; 1is R 28 denotes F; Cl; Br; I; -SF 5 ; -NO 2 ; -CF 3 ; -CN; -NH 2 or denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue;
R
29 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 31 ;
-NH
2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=O)-O-R 3 3 ; -S-R 34 or denote a linear or branched, 20 saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1. 10 residue;
R
1 , R 32 , R 33 and R 34 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; 25 R 35 , R 3 e and R , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5
;-NO
2 ; -CF 3 ; -CN; -NH 2 ; -OH; -SH; -C(=0)-NH 2 ; -S(=0) 2
-NH
2 ; -C(=0)-NH OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -NHR 13 ; -NR 14
R
1 5 ; -NH-C(=O)-R 13 ; OR 1 6 ; -SR 17 ; -C(=O)-NHR; -C(=O)-NR' 9
R
2 0 ; -S(=0) 2
-NHR
2 1 ; -S(=0) 2
-NR
22
R
2 3 ;
-C(=O)-OR
24 ; -C(=O)-R 2 5 ; -S(=O)-R 2 6 ; -S(=0) 2
-R
2 7 . 30 denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system - 16 and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group;
R
38 is selected from the group consisting of -NR 40
R
41 , OR 42 and SR 43 5 R 3 9 , R 40 , R 4 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 4 , R 49 , R 0 , R 51 , R 2 , R 3 , R 5 4 ,
R
55 and R 56 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.1o residue; denote an unsaturated or saturated, unsubstituted or at least to monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising at least one heteroatom as a ring member, which residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C 1
.
6 alkylene group or 2 is to 6-membered heteroalkylene group; or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least 20 monosubstituted C1.6 alkylene group or 2- to 6-membered heteroalkylene group; or
R
40 and R 4 1 in each case together with the nitrogen atom joining them together as a ring member form a saturated or unsaturated, unsubstituted 4-, 5-, 6-, 7-, 8- or 9-membered heterocycloaliphatic residue or 4-, 5-, 6-, 7-, 8- or 9 25 membered heterocycloaliphatic residue substituted with 1, 2, 3, 4 or 5 residues
R
57 and optionally comprising at least one further heteroatom as a ring member, which heterocycloaliphatic residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system; 30 R 57 denotes -NHR 8 , -NR 59
R
6 0 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.1o residue;
R
58 , R 5 ' and R 0 , mutually independently, in each case denote -C(=O)-R 6 1 ; denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue - 17 or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least 5 monosubstituted C1.6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group;
R
61 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 residue;
R
62 , Rea, R 64 , R 65 , R 6 and R 67 , mutually independently, in each case 10 denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1
.
10 residue;
R
68 , R ' and R 70 , mutually independently, in each case denote F, Cl, Br, I, or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; and is R 71 denotes an unsubstituted or at least monosubstituted 5- to 14 membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene 20 group, in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of 25 corresponding salts or in each case in the form of corresponding solvates; wherein the above-stated aliphatic C1.10 residues and tert-butyl residues may optionally in each case be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, 30 NO 2 , -OH, -NH 2 , -SH, -O(C 1
.
5 -alkyl), -S(C 1
.
5 -alkyl), -NH(C 1
.
5 -alkyl), -N(C 1
.
5 alkyl)(C 1
.
5 -alkyl), -C(=O)-O-C 1
.
5 -alkyl, -O-C(=O)-C 1
.
5 -alkyl, -0-phenyl, phenyl, OCF 3 and -SCF 3 ; the above-stated 2- to 6-membered heteroalkylene groups, C1.6 alkylene groups and C2-6 alkenylene groups and C2-6 alkynylene groups may optionally in - 18 each case be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, CI, Br, I, -CN, -NO 2 , -OH,
-NH
2 , -SH, -O(C 1
.
5 -alkyl), -S( 1
.
5 -alkyl), -NH(C 1
.
5 -alkyl), -N(C 1
.
5 -alkyl)(C 1
.
5 -alkyl),
-OCF
3 and -SCF 3 ; 5 the above-stated heteroalkylene groups may in each case optionally comprise 1, 2 or 3 heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur (NH) as chain link(s); the above-stated (hetero)cycloaliphatic residues may optionally be substituted in each case with 1, 2, 3, 4 or 5 substituents mutually independently 1o selected from the group consisting of -C 1
.
6 -alkylene-OH, =CH 2 , -O-C 1 .s5alkylene oxetanyl, -C 1
.
5 -alkylene-O-C 1
.
5 -alkylene-oxetanyl, -CH 2
-NH-C
1
.
5 -alkyl, -CH 2 N(C 1
.
5 -alkyl) 2 , -N[-C(=0)-C1.
5 -alkyl]-phenyl, -CH 2 -0-C 1
.
5 -alkyl, oxo (=0), thioxo (=S), F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-C 1
.
5 -alkyl, -O-C(=0)-C 1
.
5 -alkyl, -NH 2 ,
-NO
2 , -O-CF 3 , -S-CF 3 , -SH, -S-C 1
.
5 -alkyl, -C 1
.
5 -alkyl, -C(=0)-C1.
5 -alkyl, -C(=0) 15 OH, -C(=0)-O-C 1
.
5 -alkyl, -NH-C 1
.
5 -alkyl, -N(C 1
.
5 -alkyl) 2 , -NH-phenyl, -N(-C 1
.
5 alkyl)-phenyl, cyclohexyl, cyclopentyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5) thiadiazolyl, thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5) 20 thiadiazolyl, thiophenyl, phenethyl, -N[-C(=0)-C 1
.
5 -alkyl]-phenyl, -NH-phenyl, N(-C 1
.
5 -alkyl)-phenyl, -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , CN, -NO 2 , -C1.5 alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl, 25 and unless otherwise stated the above-stated (hetero)cycloaliphatic residues may in each case optionally comprise 1, 2 or 3 (further) heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur; the rings of the above-stated mono- or polycyclic ring systems may in 30 each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of oxo (=0), thioxo (=S),), F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-C 1
.
5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, S-C 1
.
5 -alkyl, -C 1
.
5 -alkyl, -C(=0)-C 1 .- alkyl, -C(=O)-OH, -C(=0)-O-C 1
.
5 -alkyl, -NH
C
1
.
5 -alkyl, -N(C 1
-
5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in - 19 each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , CN, -N02, -C1-5 alkyl, -0-C1-5 alkyl, -O-CF3, -S-CF3, phenyl and -O-benzyl, 5 and the rings of the above-stated mono- or polycyclic ring systems are in each case 5-, 6- or 7-membered and may in each case optionally comprise 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s), which are mutually independently selected from the group consisting of oxygen, nitrogen and sulfur; and the above-stated aryl or heteroaryl residues may optionally be io substituted in each case with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-C1.
alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 1
.
5 -alkyl, -C 1
.
5 -alkyl, -C(=O)-OH, C(=O)-C 1
.
5 -alkyl, -NH-C 1
.
5 -alkyl, -N(C 1
.
5 -alkyl) 2 , -NH-S(=0) 2
-C
1
.
5 -alkyl, -NH C(=O)-O-C 1
.
5 -alkyl, -C(=O)-H, -C(=O)-C 1
-
5 -alkyl, -C(=O)-NH 2 , -C(=O)-NH-C 1
.
5 is alkyl, -C(=O)-N-(C 1
.
5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , CN, -NO 2 , -C1-5 alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl, 20 and the above-stated heteroaryl residues may in each case optionally comprise 1, 2, 3, 4 or 5 heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s).
-20 THIS PAGE HAS BEEN 5 LEFT BLANK
INTENTIONALLY
-21 The term "heteroalkylene" denotes an alkylene chain in which one or more C atoms have in each case been replaced by a heteroatom mutually independently selected from the group consisting of oxygen, sulfur and nitrogen (NH). Heteroalkylene groups may preferably comprise 1, 2 or 3 heteroatom(s), 5 particularly preferably one heteroatom, mutually independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain link(s). Heteroalkylene groups may preferably be 2- to 6-membered, particularly preferably 2- or 3-membered. Mention may be made by way of example of heteroalkylene groups such 10 as -CH 2
-CH
2 -0-CH 2 -, -CH 2
-CH(CH
3
)-O-CH
2 -, -(CH 2 )-O-, -(CH 2
)
2 -0-, -(CH 2
)
3 -0-,
-(CH
2
)
4 -0-, -O-(CH 2 )-, -O-(CH 2
)
2 -, -O-(CH 2
)
3 -, -O-(CH 2
)
4 -, -C(C 2
H
5 )(H)-O-, -0
C(C
2
H
5 )(H)-, -CH 2 -0-CH 2 -, -CH 2
-S-CH
2 -, -CH 2
-NH-CH
2 -, -CH 2 -NH- and -CH 2 CH 2
-NH-CH
2
-CH
2 . If one or more of the above-stated substituents comprise a linear or 15 branched C1.6 alkylene group, this may preferably be selected from the group consisting of -(CH 2 )-, -(CH 2
)
2 -, -C(H)(CH 3 )-, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -, C(H)(C(H)(CH 3
)
2 )- and -C(C 2
H
5 )(H)-. Saturated or unsaturated C1.10 aliphatic residues may denote a -C1.1o alkyl, C2-10 alkenyl or C2.10 alkynyl residue. C2-10 alkenyl residues comprise at least 20 one, preferably 1, 2, 3 or 4 C-C double bonds and C2-10 alkynyl residues comprise at least one, preferably 1, 2, 3 or 4 C-C triple bonds. Preference is given to -C1.10 alkyl residues selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert butyl, n-pentyl, 3- GRA3394-WO-1 methyl-but-1-yl, 2-pentyl, 3-pentyl, sec-pentyl, neopentyl, 4-methyl-penta-1-yl, (3,3) dimethyl-but-1-yl, n-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, n-nonyl, 2 nonyl, 3-nonyl, 4-nonyl, 5-nonyl and (2,6)-dimethyl-hept-4-yl, which may optionally be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of -0-phenyl, -O-C(=O)-CH 3 , -O-C(=O)-C 2
H
5 , -0-C(=0)
CH(CH
3
)
2 , -O-C(=O)-C(CH 3
)
3 , -C(=O)-O-CH 3 , -C(=O)-O-C 2
H
5 , -C(=O)-O-CH(CH 3
)
2 , C(=O)-O-C(CH 3
)
3 , F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -S-CH 3 , -S-C 2
H
5 , -S-CH(CH 3
)
2 , -S-C(CH 3
)
3 , -NH-CH 3 , -NH
C
2
H
5 , -NH-C(CH 3
)
3 , -N(CH 3
)
2 , -N(C 2
H
5
)
2 , -N(CH 3
)(C
2
H
5 ), -OCF 3 and -SCF 3 . Likewise preferred are C2-10 alkenyl residues selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-propen-1-yl, 3 methyl-but-2-en-1-yl, (3,3)-dimethyl-but-1-enyl, 2-methyl-buten-2-y, 1-pentenyl, 2 pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 1-heptenyl and 1-octenyl, which may optionally be substituted with 1, 2 or 3 substituents mutually independently selected from the group consisting of F, C, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -0-CH 3 , -0
C
2
H
5 , -O-CH(CH 3
)
2 , -O-C(CH 3
)
3 , -S-CH 3 , -S-C 2
H
5 , -S-CH(CH 3
)
2 , -S-C(CH 3
)
3 , -NH
CH
3 , -NH-C 2
H
5 , -NH-C(CH 3
)
3 , -N(CH 3
)
2 , -N(C 2
H
5
)
2 , -N(CH 3
)(C
2
H
5 ), -OCF 3 and -SCF 3 . Preference is further given to C2-10 alkynyl residues selected from the group consisting of (3,3)-dimethyl-but-1 -ynyl, 4-methyl-pent-1 -ynyl, 1 -hexynyl, ethynyl, 1 propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3 pentynyl and 4-pentynyl, which may optionally be substituted with 1, 2 or 3 substituents mutually independently selected from the group consisting of F, C, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -0-CH 3 , -O-C 2
H
5 , -O-CH(CH 3
)
2 , -O-C(CH 3
)
3 , -S-CH 3 , -S
C
2
H
5 , -S-CH(CH 3
)
2 , -S-C(CH 3
)
3 , -NH-CH 3 , -NH-C 2
H
5 , -NH-C(CH 3
)
3 , -N(CH 3
)
2 , N(C 2
H
5
)
2 , -N(CH 3
)(C
2
H
5 ), -OCF 3 and -SCF 3 . Particularly preferred optionally substituted C1io aliphatic residues are selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CI, -CC1 2 F, -CC13, -CBr 3 , CH 2 -CN, -CH 2 -0-CH 3 , -CH 2 -0-CF 3 , -CH 2
-SF
3 , -CH 2
-NH
2 , -CH 2 -OH, -CH 2 -SH, -CH 2 NH-CH 3 , -CH 2
-N(CH
3
)
2 , -CH 2
-N(C
2
H
5
)
2 , -CH 2
-N(CH
3
)(C
2
H
5 ), ethyl, -CF 2
-CH
3 , -CHF
CF
2 CI, -CF 2 -CFC1 2 , -CFCI-CF 2 CI, -CFCI-CFC1 2 , -CH 2
-CH
2
-NH
2 , -CH 2
-CH
2 -OH, -CH 2 CH 2 -SH, -CH 2
-CH
2
-NH-CH
3 , -CH 2
-CH
2
-N(CH
3
)
2 , -CH 2
-CH
2
-N(C
2
H
5
)
2 , -CH 2
-CH
2 22 GRA3394-WO-1
N(CH
3
)(C
2
H
5 ), -CH 2
-CF
3 , -C 2
F
5 , -CH 2
-CC
3 , -CH 2 -CBr 3 , -CH 2
-CH
2 -CN, n-propyl, -CH 2 CH 2
-CH
2 -OH, -CH 2
-CH
2
-CH
2 -SH, -CH 2
-CH
2
-CH
2
-NH
2 , -CH 2
-CH
2
-CH
2
-NH-CH
3 , -CH 2 CH 2
-CH
2
-N(CH
3
)
2 , -CH 2
-CH
2
-CH
2
-N(C
2
H
5
)
2 , -CH 2
-CH
2
-CH
2
-N(CH
3
)(C
2
H
5 ), -CH 2
-CH
2 O-CH 3 , -CF 2
-CF
2
-CF
3 , -CF(CF 3
)
2 , isopropyl, -CH 2
-CH
2
-CH
2 -CN, -CH 2 -0-CH 2
-CH
3 , CH 2
-CH
2
-SF
3 , -CH 2
-CH
2
-OCF
3 , -CH(CH 3
)(O-CH
3 ), -CH(CH 3
)(S-CH
3 ), n-butyl, -CF 2 CF 2
-CF
2
-CF
3 , -CH 2
-CH
2
-CH
2
-CH
2 -CN, -CH 2
-CH
2
-CH
2
-CF
3 , -CH 2
-CH
2
-CH
2
-CH
2
-CF
3 ,
-CH
2 -0-C(=O)-CH 3 , -CH 2 -0-C(=O)-C 2
H
5 , -CH 2 -0-C(=O)-CH(CH 3
)
2 , -CH 2 -0-C(=0)
C(CH
3
)
3 , -CH 2 -C(=0)-O-CH 3 , -CH 2 -C(=O)-0-C 2
H
5 , -CH 2
-C(=O)-O-C(CH
3
)
3 , -CH 2 CH 2
-O-CH
3 , -CH 2
-CH
2 -0-C 2
H
5 , -CH 2
-CH
2 -0-phenyl, -CH 2
-CH
2
-CH
2 -0-CH 3 , sec butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neo-pentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-buten-2-yl, (1,1,2)-trifluoro-1 butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, -CF=CF 2 , -CCl=CC12, -CH 2 CF=CF 2 , -CH 2 -CCl=CC1 2 , -CEC-1, -CEC-F and -CEC-Cl. If one or more of the above-stated substituents denote a (hetero)cycloaliphatic residue, which may optionally be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system, the latter may preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, (1,2,3,6)-tetrahydropyridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, (1,3,4,5)-tetrahydropyrido[4,3-b]indolyl, (3,4)-dihydro-1 H-isoquinolinyl, (1,3,4,9)-tetrahydro-[b]-carbolinyl and (1,3) thiazolidinyl. Examples which may be mentioned of suitable (hetero)cycloaliphatic residues which may be unsubstituted or mono- or polysubstituted and are fused with a mono- or bicyclic ring system are (4,5,6,7)-tetrahydroisoxazolo[5,4-c]pyridinyl, (2,3)-dihydro 1 H-indenyl, 3-aza-bicyclo[3. 1.1 ]heptyl, 3-aza-bicyclo[3.2.1 ]octyl, 6-aza bicyclo[3.3.1]heptyl, 8-aza-bicyclo[3.2.1]octyl, isoindolyl, indolyl, (1,2,3,4) tetrahydroquinolinyl, (1,2,3,4)-tetrahydroisoquinolinyl, (2,3)-dihydro-1H-isoindolyl, (1,2,3,4)-tetrahydronaphthyl, (2,3)-dihydro-benzo[l.4]dioxinyl, benzo[1.3]dioxolyl, (1,4)-benzodioxanyl, (2,3)-dihydrothieno[3,4-b][1.4]dioxinyl, (3,4)-dihydro-2H benzo[1.4]oxazinyl, octahydro-1 H-isoindolyl and octahydro-pyrrolo[3,4c]pyrrolyl. 23 GRA3394-WO-1 For the purposes of the present invention, (hetero)cycloaliphatic residues may, together with a further (hetero)cycloaliphatic residue, form a spirocyclic residue by way of a common carbon atom in the two rings. Suitable spirocyclic residues which may be mentioned are, for example, a 6-aza spiro[2.5]octyl residue, 8-azaspiro[4.5]decyl residue and a 1-oxa-2,8-diaza spiro[4.5]dec-2-enyl residue. Particularly preferably, the (hetero)cycloaliphatic residues may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents selected mutually independently from the group consisting of oxo (=0), thioxo (=S), F, Cl, Br, I, -CN, CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -O-CH(CH 3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S
CF
3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S-CH(CH 3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, -C(=O)-CH 3 , -C(=O)-C 2
H
5 , C(=O)-CH(CH 3
)
2 , -C(=O)-C(CH 3
)
3 , -C(=O)-OH, -C(=O)-O-CH 3 , -C(=O)-O-C 2
H
5 , C(=O)-O-CH(CH 3
)
2 , -C(=O)-O-C(CH 3
)
3 , -NH-CH 3 , -NH-C 2
H
5 , -NH-C(CH 3
)
3 , -N(CH 3
)
2 ,
-N(C
2
H
5
)
2 , -N(CH 3
)(C
2
H
5 ), -CH 2 -OH, -CH 2
-CH
2 -OH, =CH 2 , -CH 2 -0-CH 2 -oxetanyl, -0
CH
2 -oxetanyl, -CH 2
-N(CH
3
)
2 , -CH 2
-N(C
2
H
5
)
2 , -CH 2
-NH-CH
3 , -CH 2
-NH-C
2
H
5 , -N
[C(=O)-C
2
H
5 ]-phenyl, -N-[C(=O)-CH 3 ]-phenyl, -CH 2 -0-CH 3 , -CH 2 -0-CH 2
-CH
3 , -NH phenyl, -N(CH 3 )-phenyl, -N(C 2
H
5 )-phenyl, -N(C 2
H
5 )-phenyl, -0-CH 2
-CH
2
-CH
2
-CH
3 , (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, cyclohexyl, cyclopentyl, piperidinyl, pyrrolidinyl, -0-C(=O)-CH 3 , -0-C(=O)-C 2
H
5 , -0
C(=O)-C(CH
3
)
3 , -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each the cyclic moiety of the residues oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5)-thiadiazolyl, thiophenyl, phenethyl, -N-[C(=O)-C 2
H
5 ]-phenyl, -N
[C(=O)-CH
3 ]-phenyl, -NH-phenyl, -N(CH 3 )-phenyl, -N(C 2
H
5 )-phenyl, -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group comprising F, C, Br, -OH, -CF 3 , -SF 5 , -CN, -NO 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-CH 3 , -O-C 2
H
5 , -O-CH(CH 3
)
2 , -O-C(CH 3
)
3 , -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl. 24 GRA3394-WO-1 If one or more of the above-stated substituents denote an aryl residue, the latter may preferably be selected from the group consisting of phenyl and naphthyl (1-naphthyl and 2-naphthyl). If one or more of the above-stated substituents denote a heteroaryl residue, the latter may preferably be selected from the group consisting of tetrazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, benzoxazolyl, benzisoxazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl and isoquinolinyl. Examples which may be mentioned of suitable aryl- and heteroaryl residues which may be unsubstituted or mono- or polysubstituted and are fused with a mono- or bicyclic ring system are isoindolyl, indolyl, (1,2,3,4)-tetrahydroquinolinyl, (1,2,3,4) tetrahydroisoquinolinyl, (2,3)-dihydro-1 H-isoindolyl, (1,2,3,4)-tetrahydronaphthyl, (2,3)-dihydro-benzo[1.4]dioxinyl, (2,3)-dihydrothieno[3,4-b][1,4]dioxinyl, benzo[1.3]dioxolanyl and (1,4)-benzodioxanyl. The aryl or heteroaryl residues may particularly preferably in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -O-CH(CH 3
)
2 ,
-O-C(CH
3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S-CH(CH 3
)
2 , -5
C(CH
3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n pentyl, -C(=O)-OH, -C(=O)-O-CH 3 , -C(=O)-O-C 2
H
5 , -C(=O)-O-CH(CH 3
)
2 , -C(=O)-O
C(CH
3
)
3 , -NH-CH 3 , -NH-C 2
H
5 , -NH-C(CH 3
)
3 , -N(CH 3
)
2 , -N(C 2
H
5
)
2 , -N(CH 3
)(C
2
H
5 ), NH-S(=0) 2
-CH
3 , -NH-S(=0 2
)-C
2
H
5 , -NH-S(=0) 2
-CH(CH
3
)
2 , -NH-C(=O)-O-CH 3 , -NH
C(=O)-O-C
2
H
5 , -NH-C(=O)-O-C(CH 3
)
3 , -C(=O)-H, -C(=O)-CH 3 , -C(=O)-C 2
H
5 , -C(=O)
CH(CH
3
)
2 , -C(=O)-C(CH 3
)
3 , -C(=O)-NH 2 , -C(=O)-NH-CH 3 , -C(=O)-NH-C 2
H
5 , -C(=O)
N(CH
3
)
2 , -C(=O)-N(C 2
H
5
)
2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, C, Br, -OH, -CF 3 , -SF 5 , -CN, -NO 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-CH 3 , -O-C 2
H
5 , -O-CH(CH 3
)
2 , -0
C(CH
3
)
3 , -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl. 25 GRA3394-WO-1 If a polycyclic ring system, such as for example a bicyclic ring system, is present, the various rings may in each case mutually independently be of a different degree of saturation, i.e. be saturated or unsaturated. A polycyclic ring system is preferably a bicyclic ring system. Examples of aryl residues which are fused with a mono- or polycyclic ring system and may be mentioned are (1,3)-benzodioxolyl and (1,4)-benzodioxanyl. If one or more of the above-stated substituents comprise a mono- or polycyclic ring system, the latter may preferably be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of oxo (=0), thioxo (=S), F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -O-CH(CH 3
)
2 , -O-C(CH 3
)
3 , -NH 2 ,
-NO
2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S-CH(CH 3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, -C(=O)-OH, C(=O)-O-CH 3 , -C(=O)-O-C 2
H
5 , -C(=O)-O-CH(CH 3
)
2 , -C(=O)-O-C(CH 3
)
3 , -NH-CH 3 , NH-C 2
H
5 , -NH-C(CH 3
)
3 , -N(CH 3
)
2 , -N(C 2
H
5
)
2 , -N(CH 3
)(C
2
H
5 ), -NH-C(=O)-O-CH 3 , -NH
C(=O)-O-C
2
H
5 , -NH-C(=O)-O-C(CH 3
)
3 , -C(=O)-H, -C(=O)-CH 3 , -C(=O)-C 2
H
5 , -C(=O)
CH(CH
3
)
2 , -C(=O)-C(CH 3
)
3 , -C(=O)-NH 2 , -C(=O)-NH-CH 3 , -C(=O)-NH-C 2
H
5 , -C(=O)
N(CH
3
)
2 , -C(=O)-N(C 2
H
5
)
2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, C, Br, -OH, -CF 3 , -SF 5 , -CN, -NO 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-CH 3 , -O-C 2
H
5 , -0-CH(CH 3
)
2 , -0
C(CH
3
)
3 , -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl. Preferred compounds are those of the general formula la,
R
8 RR 0 / R 4 la, 26 GRA3394-WO-1 in which D denotes N or CH;
R
1 and R 2 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 -; -O-C(=O)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
NR
65 -; -NR 6 6
-C(=S)-NR
6 5 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 62 -; -CR 2 1=N-NR 6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 6 3 -; -0
C(=O)-NR
6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH
NR
64 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 1-; -NR 66
-C(=S)-NR
6 1-; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=O)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 2 8 =N-NH-; -CH=N-NR 62 -; -CR 2 8
=N-NR
62 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 63 -; -0
C(=O)-NR
6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 1-; -NR 66
-C(=S)-NR
6 1-; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH ; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, 27 - 28 or R 4 and R 5 together denote a residue selected from the group consisting of CH=N-NH-; -CH=N-NR"-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=0)-NH-; -O C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 63 -; -0-C(=O)-NR 6 3 ; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S) s NH-; -NR 66 -C(=0)-NR 6 1-; -NR 66
-C(=S)-NR
65 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; 0-CH 2
-CH
2 -0-, -O-CH 2
-CH
2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; F; Cl; Br; I; -CF 3 ; -CN; -OR 16 ; -SR 17 ; or denote a residue io selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl;
R
8 denotes -CF 3 or tert-butyl;
R
16 and R , mutually independently, in each case denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 IS CH 3 , -CH 2
-CF
3 , -C 2
F
5 , n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl hept-4-yl, 3-methyl-butyl, n-hexyl and (3,3)-dimethylbutyl;
R
2 8 denotes F; Cl; Br; I; -CF 3 ; -CN; -NH 2 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 20 sec-butyl, isobutyl, tert-butyl and n-pentyl;
R
29 and R 30 , mutually independently, in each case denote -NH-C(=0)-R 31 ;
-NH
2 ; -NH-S(=0) 2
-R
32 ; -NH-C(=O)-O-R 3 3 ; -S-R 34 or denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; 25 R , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; GRA3394-WO-1
R
62 , Rea, R64, R 65 , R 6 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;
R
71 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue can in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Particularly preferred compounds are those of the general formula la, R8 R R 0 / DN RN R 4 la, in which D denotes N or CH; 29 GRA3394-WO-1
R
1 and R 2 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 63 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
NR
6 5 -; -NR 66
-C(=S)-NR
6 1-; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -O-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -0 C(=0)-NR 63 -; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH
NR
6 4 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 6 6
-C(=O)-NR
6 1-; -NR 6 6
-C(=S)-NR
6 1_; N=N-NH-; -N=N-NR 6 7 -; -O-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=O)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 28
=N-NR
6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 63 -; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 3 0 -- ; -N=CH-NH-; -N=CH NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 5 -; -NR 66
-C(=S)-NR
6 1-; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S
C(=S)-NR
6 3 -; -0-C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -0-C(=O)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0) 30 GRA3394-WO-1
NR
65 -; -NR 6
-C(=S)-NR
6 5 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; Ri 6 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert butyl, and n-pentyl;
R
2 8 denotes F; Cl; Br or 1;
R
2 9 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 3 1 ; -NH 2 ; -NH-S(=0) 2
-R
32 ; -NH-C(=O)-O-R 33 or -S-R 3 4 ;
R
31 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, and n-pentyl; and R 2 , Rea, R64, R 5 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; and
R
7 1 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue can in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; 31 GRA3394-WO-1 in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Very particularly preferred compounds are those of the general formula la, R8 R R N 0R 5 R3 R4 la, in which D denotes N or CH; R' and R 2 together denote a residue selected from the group consisting of -S-CH=N-; -S-CR 2 9 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH ; -O-C(=O)-NH-; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -0-; -N=CH-NH-; -NH C(=O)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -O-CH2-C(=O)-NH-; -O-CH 2
-CH
2 -0-; -0
CH
2
-CH
2
-CH
2 -0-; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group 32 - 33 consisting of -CH=N-NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-O-; -N=CR 3 0 -O- N=CH-NH-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -O-; -N=CH-CH=N-; -CH=CH-CH=N-; 5 CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -S-CH=N-; -S-CR 29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, 10 and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl;
R
8 denotes -CF 3 or tert-butyl; 15 R' 6 and R , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
2 8 denotes F; Cl; Br or I;
R
29 denotes -NH-C(=O)-R 31 ; -NH 2 ; -NH-S(=0) 2
-R
32 ; -NH-C(=O)-O-R 33 or 20 -S-R I
R
30 denotes -NH 2 ;
R
31 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 25 sec-butyl, isobutyl, tert-butyl, and n-pentyl; and GRA3394-WO-1
R
71 denotes a phenyl residue which may be attached via a -(CH 2 )-, -(CH 2
)
2 - or (CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Preferred compounds are those of the general formula Ib, RI H2 D N R R42 R5 R3 R4 lb, in which D denotes N or CH;
R
1 and R 2 together denote a residue selected from the group consisting of CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
6 3 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
NR
65 -; -NR 66
-C(=S)-NR
65 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, 34 GRA3394-WO-1 or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -0
C(=O)-NR
6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)-NR
6 5 -; -NR 66
-C(=S)-NR
6 5 -; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 6 3 -; -S-C(=0)-NR 6 3 -; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)-NR
6 5 -; -NR 66
-C(=S)-NR
6 5 _; N=N-NH-; -N=N-NR 6 7 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH ; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S
C(=S)-NR
63 -; -0-C(=S)-NR 63 -; -S-C(=0)-NR 1-; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-0-; -N=CR 3 0 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)
NR
65 -; -NR 66
-C(=S)-NR
65 -; -O-CH 2 -C(=O)-NH-; -0-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; F; Cl; Br; I; -CF 3 ; -CN; -OR 6 ; -SRi 7 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl; 35 - 36 R 8 denotes -CF 3 or tert-butyl;
R'
6 and R4, mutually independently, in each case denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 CH 3 , -CH 2
-CF
3 , -C 2
F
5 , n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 5 n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl hept-4-yl, 3-methyl-butyl, n-hexyl and (3,3)-dimethylbutyl;
R
28 denotes F; Cl; Br; I; -CF 3 ; -CN; -NH 2 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl; 10 R 29 and R 3 0 , mutually independently, in each case denote -NH-C(=O)-R 3 1 ;
-NH
2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=O)-O-R 3 3 ; -S-R 3 4 or denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; is R 31 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
42 denotes a residue selected from the group consisting of methyl, CH 2 -0-CH 3 , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n 20 pentyl, 3-pentyl, n-hexyl, (3,3)-dimethylbutyl, -CH 2
-CH
2 -0-CH 3 , -CH 2
-CH
2 -0
C
2
H
5 and -CH 2
-CH
2
-CH
2 -0-CH 3 ; or denotes a residue selected from the group consisting of 2,3-dihydro-1 H indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, 25 piperazinyl, azepanyl, diazepanyl, azocanyl and thiomorpholinyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl; GRA3394-WO-1 Re 2 , R 63 , R4, R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2
-CF
3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;
R
71 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, CI, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Particularly preferred compounds are those of the general formula Ib, R8 D N R R42 R 5 R3 R4 lb, in which D denotes N or CH; 37 GRA3394-WO-1
R
1 and R 2 together denote a residue selected from the group consisting of CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
NR
65 -; -NR 66
-C(=S)-NR
65 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -O-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 2 -; -CR 2 8
=N-NR
2 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 _; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 -; -NR 66
-C(=S)-NR
6 1_; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2
"=N-NR
6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 6 3 -; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH
NR
6 4 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 1-C(=0)-NR 6 -; -NR 66
-C(=S)-NR
65 _; N=N-NH-; -N=N-NR 6 7 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR 6 3 -; -S-C(=0)-NR 63 -; -0-C(=O)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
38 - 39 NR 6 5 -; -NR 66
-C(=S)-NR
6 1-; -O-CH 2 -C(=0)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0
CH
2
-CH
2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, 5 in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl;
R
8 denotes -CF 3 or tert-butyl;
R
16 and R 17 , mutually independently, in each case denote a residue io selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
2 8 denotes F; Cl; Br or 1;
R
2 9 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 31 ;
-NH
2 ; -NH-S(=0) 2
-R
32 ; -NH-C(=O)-O-R 33 or -S-R is R , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
4 2 denotes a residue selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl 20 and (3,3)-dimethylbutyl; or denotes a residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 25 sec-butyl, isobutyl, tert-butyl, n-pentyl; GRA3394-WO-1
R
62 , Rea, R 64 , R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; and
R
71 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Very particularly preferred compounds are those of the general formula Ib, DN N R OsR42 0 R5 R3 R4 lb, in which D denotes N or CH;
R
1 and R 2 together denote a residue selected from the group consisting of 40 -41 S-CH=N-; -S-CR 29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S 5 C(=0)-NH-; -O-C(=0)-NH-; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -0-; N=CH-NH-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -N=CH-CH=N-; -CH=CH-CH=N-; CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, 10 or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 2 8 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -0-; N=CH-NH-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; O-CH 2
-CH
2 -0-; O-CH 2
-CH
2
-CH
2 -0-; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH 1s N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -S-CH=N-; -S-CR 29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, 20 and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl; R8 denotes -CF 3 or tert-butyl; 25 R 16 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
2 8 denotes F; Cl; Br or 1; GRA3394-WO-1
R
2 9 denotes -NH-C(=O)-R 3 1 ; -NH 2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=O)-O-R 3 3 or -S-R34
R
3 0 denotes -NH 2 ;
R
1 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, and n-pentyl;
R
42 denotes a residue selected from the group consisting of methyl, ethyl, n propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3) dimethylbutyl; or denotes a residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert butyl, n-pentyl;
R
7 1 denotes a phenyl residue which may be attached via a -(CH 2 )-, -(CH 2
)
2 - or (CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Preferred compounds are those of the general formula Ic, 42 GRA3394-WO-1 R8 R H D N R2 R4 R5 * R3 R4 Ic, in which D denotes N or CH;
R
1 and R 2 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 6 3 -; -S-CH=N-; -S
CR
2 9 =N-; -N=CH-O-; -N=CR 3 0 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)
NR
65 -; -NR 66 -C(=S)-NR 6 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -O-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2
"=N-NR
6 2 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 63 -; -0
C(=O)-NR
6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 -; -NR 66 -C(=S)-NR 65 -; N=N-NH-; -N=N-NR 6 7 -; -0-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -O-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 a=N-NR 6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -0
C(=O)-NR
6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 3 -0-; -N=CH-NH-; -N=CH 43 - 44 NR 64 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)-NR
65 -; -NR 66
-C(=S)-NR
6 1 ; -N=N-NH-; -N=N-NR 6 7-; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2 CH 2
-CH
2 -NH, -CH 2 -C(=O)-NH, -CH 2
-CH
2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; -0-CH 2 CH 2
-CH
2 -0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; s CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -O-C(=0)-NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; io O-C(=0)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0) NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 -; -N R 66
-C(=S)-NR
6 5 -; -O-CH 2
-C(=O)
NH-; -0-CH 2 -0-; -0-CH 2
-CH
2 -0-, -0-CH 2
-CH
2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and CH=CH-N=CH-, which is attached in any desired direction to the parent structure, 15 and the remaining residues R', R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; F; Cl; Br; I; -CF 3 ; -CN; -OR 1 6 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; Ra denotes -CF 3 or tert-butyl; 20 R 16 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 CH 3 , -CH 2
-CF
3 , -C 2
F
5 , n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl hept-4-yl, 3-methyl-butyl, n-hexyl and (3,3)-dimethylbutyl; 25 R 28 denotes F; Cl; Br; 1; -CF 3 ; -CN; -NH 2 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl;
R
29 and R 3 0 , mutually independently, in each case denote -NH-C(=0)-R 3 1 ;
-NH
2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=0)-O-R 33 ; -S-R 3 4 or denote an alkyl residue 30 selected from the GRA3394-WO-1 group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert butyl, and n-pentyl;
R
1 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, and n-pentyl;
R
4 3 denotes a residue selected from the group consisting of methyl, -CH 2 -0-CH 3 , ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3) dimethylbutyl, -CH 2
-CH
2 -0-CH 3 , -CH 2
-CH
2 -0-C 2
H
5 and -CH 2
-CH
2
-CH
2 -0-CH 3 ; or denotes a residue selected from the group consisting of 2,3-dihydro-1 H-indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl and thiomorpholinyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, n-pentyl;
R
62 , Rea, RS4, R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2
-CF
3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;
R
71 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a 45 GRA3394-WO-1 mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Particularly preferred compounds are those of the general formula Ic,
R
8 R H2 D N R NIR4 R5 R3 R4 Ic, in which D denotes N or CH; R' and R 2 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR1 3 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
NR
65 -; -NR 6 -C(=S)-NR 6 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 2 8 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 63 -; -S-C(=0)-NR 6 3 -; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-0-; -N=CR 3 a0O; -N=CH-NH-; -N=CH NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 65 -; -NR 66
-C(=S)-NR
65 -; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2
-CH
2 -C(=O)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; 46 - 47 -CH=N-N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 28
=N-NR
6 2 -; -S-C(=S)-NH-; -0 5 C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 6 3 -; -S
C(=O)-NR
6 3 -; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR 64 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)
NR
65 -; -NR 66
-C(=S)-NR
6 -; -N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=O)-NH-; -0-CH 2 0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2
-CH
2 -NH, -CH 2 -C(=O)-NH, -CH 2
-CH
2 -C(=O)-NH-; I0 0-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR-; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0 is C(=O)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 63 -; -S-C(=0)-N R 63 -; -0-C(=O)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S) NH-; -NR 6 -C(=0)-NR 6 -; -NR 66
-C(=S)-NR
6 5 -; -0-CH 2 -C(=O)-NH-; -O-CH 2 -0-; 0-CH 2
-CH
2 -0-, -O-CH 2
-CH
2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, 20 and the remaining residues R 1 , R 2 , R , R 4 and R , mutually independently, in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl;
R
6 denotes -CF 3 or tert-butyl; 25 R 16 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
28 denotes F; Cl; Br or I; GRA3394-WO-1
R
29 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 31 ; -NH 2 ; -NH S(=0) 2
-R
32 ; -NH-C(=O)-O-R 33 or -S-R34
R
1 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, and n-pentyl;
R
43 denotes a residue selected from the group consisting of methyl, ethyl, n propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3) dimethylbutyl; or denotes a residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert butyl, n-pentyl;
R
62 , R 63 , R64, R 65 , R 6 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert butyl, n-butyl, sec-butyl, and isobutyl; and
R
71 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -O-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any 48 GRA-3394-WO-1 desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Very particularly preferred compounds are those of the general formula Ic, R8 R D N R R 43 R 5 R 3 R4 Ic, in which D denotes N or CH;
R
1 and R 2 together denote a residue selected from the group consisting of S-CH=N-;
-S-CR
29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S CH=N-; -S-CR 2 9 =N-; -N=CH-O-; -N=CR 30 -0-; -N=CH-NH-; -NH-C(=O)-NH-; -NH C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 2 8 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -0-; -N=CH-NH-; -NH-C(=O)-NH-; -NH C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 -0-; N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2
-CH
2 NH-, which is attached in any desired direction to the parent structure, 49 -50 or R 4 and R 5 together denote a residue selected from the group consisting of S CH=N-; -S-CR 29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R 5 , mutually independently, s in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl;
R
8 denotes -CF 3 or tert-butyl;
R'
6 and R , mutually independently, in each case denote a residue io selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
2 8 denotes F; Cl; Br or 1;
R
29 denotes -NH-C(=O)-R 31 ; -NH 2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=O)-O-R 33 or -S-R 4; 15 R 30 denotes -NH 2 ;
R
31 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
43 denotes a residue selected from the group consisting of methyl, 20 ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3)-dimethylbutyl; or denotes a residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently 25 selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl; GRA3394-WO-1 and
R
71 denotes a phenyl residue which may be attached via a -(CH 2 )-, -(CH 2
)
2 - or (CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Preferred compounds are those of the general formula Id, Ra Ri D N R2 N O /
R
4 0
R
4 1 R4 Id, in which D denotes N or CH; R' and R 2 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S
C(=S)-NR
63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 3 0 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)
NR
65 -; -NR 66
-C(=S)-NR
65 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 51 GRA3394-WO-1
CH
2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)-NR
6 1-; -NR 66
-C(=S)-NR
6 5 -; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2
-CH
2 -C(=O)-NH-; -0-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 28
=N-NR
6 2 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 63 -; -S-C(=0)-NR 6 3 -; -0 C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 3 -0-; -N=CH-NH-; -N=CH NR6-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 5 -; -NR 6 6
-C(=S)-NR
6 1-; N=N-NH-; -N=N-NR 67 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=0)-NH-; -0-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH ; -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S
C(=S)-NR
6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 6 3 -; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-0-; -N=CR 3 0 -0-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66
-C(=O)
N R 6 5-; -NR 6 6 -C(=S)-N R 6 5-; -O-CH 2 -C(=O)-NH-; -0-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -0-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, 52 - 53 and the remaining residues R', R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; F; Cl; Br; I; -CF 3 ; -CN; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; s R 8 denotes -CF 3 or tert-butyl;
R
16 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 CH 3 , -CH 2
-CF
3 , -C 2
F
5 , n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl io hept-4-yl, 3-methyl-butyl, n-hexyl and (3,3)-dimethylbutyl;
R
28 denotes F; Cl; Br; I; -CF 3 ; -CN; -NH 2 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl;
R
29 and R 30 , mutually independently, in each case denote -NH-C(=0)-R 3 1 ; 15 -NH 2 ; -NH-S(=0) 2
-R
32 ; -NH-C(=O)-O-R 33 ; -S-R 3 4 or denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
1 , R 32 , R 3 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, 20 isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
40 and R 4 , mutually independently, in each case denote a residue selected from the group consisting of methyl, -CH 2 -0
CH
3 , ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n hexyl, (3,3)-dimethylbutyl, -CH 2
-CH
2 -0-CH 3 , -CH 2
-CH
2 -0-C 2
H
5 and -CH 2
-CH
2 25 CH 2 -0-CH 3 ; denote a residue selected from the group consisting of 2,3-dihydro-1 H indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, GRA3394-WO-1 tetrahydrofuranyl, tetrahyd rothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl and thiomorpholinyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, n-pentyl; or
R
4 0 and R 41 in each case together with the nitrogen atom joining them together as a ring member form a residue selected from the group consisting of 3-aza bicyclo[3.1.1]heptyl, 6-aza-spiro[2.5]octyl, 3-aza-bicyclo[3.2.1]octyl, 6-aza bicyclo[3.3.1]heptyl, 8-aza-bicyclo[3.2.1Joctyl, 1-oxa-2,8-diaza-spiro[4.5]dec-2-enyl, azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl, (4,5,6,7) tetrahyd roisoxazolo[5,4-c]pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and thiomorpholinyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 or 5 residues R 57 ;
R
57 denotes -NHR 8 , -NR 9 R 0 or denotes an alkyl residue selected from the group consisting of -CF 3 , -CH 2
-CF
3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl and isobutyl;
R
58 , R' 9 and R 6 , mutually independently, in each case denote -C(=O)-R 61 ; denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2
-CF
3 , methyl, ethyl, n propyl, isopropyl, tert-butyl, n-butyl, sec-butyl and isobutyl; or denote a residue selected from the group consisting of phenyl and naphthyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -0-CH 3 , -0-C 2
H
5 , -O-CH(CH 3
)
2 , -0-C(CH 3
)
3 , methyl, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl;
R
61 denotes an alkyl residue selected from the group consisting of -CF 3 , -CH 2
-CF
3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; 54 GRA3394-WO-1
R
62 , Rea, R4, R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2
-CF
3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; and
R
7 1 denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Particularly preferred compounds are those of the general formula Id, 8N RSR H2 DN N R2 N 0 53
R
40
R
4 1 R* R R 4 Id, in which D denotes N or CH; 55 GRA3394-WO-1
R
1 and R 2 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR71-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -O-C(=0)-NH-; -S
C(=S)-NR
6 3 -; -O-C(=S)-NR 6 3 -; -S-C(=O)-NR 6 3 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S
CR
29 =N-; -N=CH-O-; -N=CR 30 -0-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)
NR
65 -; -NR 66 -C(=S)-NR 6 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -0-CH 2 CH 2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8
=N-NR
6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 63 -; -S-C(=0)-NR 6 3 -; -0 C(=0)-NR 3 -; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR6-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 6 -; -NR 66
-C(=S)-NR
65 ; N=N-NH-; -N=N-NR 6 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2
-CH
2 -C(=O)-NH-; -0-CH 2
-CH
2 -0-; -O-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 28
=N-NR
6 2 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S C(=0)-NH-; -0-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 6 3 -; -0
C(=O)-NR
6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH NR64-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0)-NR 65 -; -NR 66 -C(=S)-NR 6-; N=N-NH-; -N=N-NR 6 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; -CH 2
-CH
2 -NH-, -CH 2
-CH
2 CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2
-CH
2 -C(=0)-NH-; -O-CH 2
-CH
2 -0-; -0-CH 2
-CH
2
-CH
2 0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH ; -CH=N-N=CH- and -0-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S
C(=S)-NR
6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=O)-NR 63 -; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S
CR
2 9 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0) 56 -57
NR
65 -; -NR 66
-C(=S)-NR
6 5 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; -O-CH 2
-CH
2 -0-, -o
CH
2
-CH
2
-CH
2 -0-; -O-CH 2
-CH
2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R , R 4 and R , mutually independently, 5 in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl;
R
8 denotes -CF 3 of tert-butyl;
R
16 and R 17 , mutually independently, in each case denote a residue io selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
28 denotes F; Cl; Br or 1;
R
29 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 3 1 ;
-NH
2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=O)-O-R 3 3 or -S-R34; is R 3 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
4 0 and R 4 ' in each case together with the nitrogen atom joining them together as a ring member form a residue selected from the group consisting of 20 pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azepanyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 or 5 residues R 57 ;
R
57 denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; GRA3394-WO-1 Re 2 , Rea, R , R 6 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert butyl, n-butyl, sec-butyl, and isobutyl; and R ' denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2
)
2 - or -(CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , -0
CH(CH
3
)
2 , -O-C(CH 3
)
3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2
H
5 , -S
CH(CH
3
)
2 , -S-C(CH 3
)
3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Very particularly preferred compounds are those of the general formula Id,
R
8 R D N R2 N O0/
R
40
R
4 1 R R R4 Id, in which D denotes N or CH; 58 - 59 R 1 and R 2 together denote a residue selected from the group consisting of S CH=N-; -S-CR 29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting 5 of -CH=N-NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 C(=0)-NH-; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -NH C(=0)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -0-CH 2 -C(=O)-NH-; -O-CH 2
-CH
2 -0-; 0-CH 2
-CH
2
-CH
2 -0-; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the 10 parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 2 =N-NH-; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0 C(=0)-NH-; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-O-; -N=CR 3 0 -; -N=CH-NH-; -NH C(=O)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; -O-CH 2
-CH
2 -O-; is O-CH 2
-CH
2
-CH
2 -0-; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N N=CH- and -O-CH 2
-CH
2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of S-CH=N-; -S-CR 29 =N-; -N=CH-0- and -N=CR 30 -0-, which is attached in any 20 desired direction to the parent structure, and the remaining residues R', R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; -OR1 6 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n butyl, sec-butyl, isobutyl and tert-butyl; 25 R 8 denotes -CF 3 or tert-butyl;
R
16 and R' 7 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl;
R
28 denotes F; Cl; Br or 1; GRA3394-WO-1
R
29 denotes -NH-C(=O)-R 3 1 ; -NH 2 ; -NH-S(=0) 2
-R
3 2 ; -NH-C(=O)-O-R 3 3 or -S-R34;
R
30 denotes -NH 2 ;
R
31 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, and n-pentyl;
R
40 and R 41 in each case together with the nitrogen atom joining them together as a ring member form a residue selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azepanyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 or 5 residues R 57.;
R
57 denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl;
R
7 1 denotes a phenyl residue which may be attached via a -(CH 2 )-, -(CH 2
)
2 - or (CH 2
)
3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2
H
5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Further preferred substituted compounds according to the invention are those of the general formulae 1, la, Ib, Ic and Id, in which 60 GRA3394-WO-1
R
1 and R 2 or R 2 and R 3 or R 3 and R 4 or R 4 and R 5 together with the carbon atoms joining them together form a 4-, 5-, 6- or 7-membered ring which is saturated, unsaturated or aromatic, has 1, 2 or 3 nitrogen atoms as ring members and is unsubstituted or substituted with 1, 2 or 3 residues mutually independently selected from the group consisting of F, Cl, Br, I, =0, -CN, -CF 3 , -SF 5 , -OH, O-C 1
.
5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 1
.
5 -alkyl, -C 1
.
5 -alkyl, C(=O)-OH, -C(=O)-O-C1.
5 -alkyl, -NH-C1.
5 -alkyl, -N(C 1
.
5 -alkyl) 2 , -NH-S(=0) 2 -C1. 5 -alkyl, -NH-C(=O)-O-C1.
5 -alkyl, -C(=O)-H, -C(=O)-C 1
.
5 -alkyl, -C(=O)-NH 2 , C(=O)-NH-C1.
5 -alkyl, -C(=O)-N-(C 1
.
5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -0 benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, CF 3 , -SF 5 , -CN, -NO 2 , -C 1
.
5 alkyl, -O-C 1 .s-alkyl, -O-CF 3 , -S-CF 3 , phenyl and -0 benzyl, and the remaining residues R 1 , R 2 , R 3 , R 4 and R 5 , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2
-NH
2 ; C(=O)-NH-OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -C(=NH)-NH 2 ; -C(=NH) NH-R; -N=C(NH 2
)
2 ; -N=C(NHR")(NHRl); -O-P(=0) 2 -0-R 2 ; -NHR ; NR 14
R
15 ; -NH-C(=O)-R 13 ; -OR 16 ; -SR 17 ; -C(=O)-NHR 1 8 ; -C(=O)-NR 19
R
2 0 S(=0) 2
-NHR
2 1 ; -S(=0) 2
-NR
2 2
R
2 3 ; -C(=O)-OR 24 ; -C(=O)-R 2 5 ; -S(=O)-R 2 6 ; S(=0)2-R27 or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; and the other variables and substituents in each case have one of the meanings cited in the context of their definition, in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Further preferred substituted compounds according to the invention are those of the general formulae 1, la, Ib, Ic and Id, 61 GRA3394-WO-1 in which
R
1 and R 2 or R 2 and R 3 or R 3 and R 4 or R 4 and R 5 together with the carbon atoms joining them together form a 4-, 5-, 6- or 7-membered ring which is saturated, unsaturated or aromatic, has 1, 2 or 3 nitrogen atoms as ring members and is unsubstituted or substituted with 1, 2 or 3 residues mutually independently selected from the group consisting of F, Cl, Br, I, OH, =0, CF 3 , OCF 3 , SCF 3 ,
SF
5 , O-C 1
.
4 -alkyl and C1.
4 -alkyl, and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2
-NH
2 ; C(=O)-NH-OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -C(=NH)-NH 2 ; -C(=NH)
NH-R
9 ; -N=C(NH 2
)
2 ; -N=C(NHR'")(NHR 1 '); -O-P(=0) 2 -0-R; -NHR ; NR 14
R
1 5 ; -NH-C(=O)-R; -OR 16 ; -SR 1 7 ; -C(=O)-NHR 18 ; -C(=O)-NR1 9
R
20 _ S(=0) 2
-NHR
2 1 ; -S(=0) 2
-NR
2 2
R
23 ; -C(=O)-OR 24 ; -C(=0)-R 2 5 ; -S(=O)-R 2 6 ; _ S(=0)2-R27 or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1
.
1 0 residue; and the other variables and substituents in each case have one of the meanings cited in the context of their definition, in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. Further preferred substituted compounds according to the invention are those of the general formulae 1, la, Ib, Ic and Id, in which the partial structure
R
6 R7 R R2 R5 R3 R4 denotes one of the following partial structures S-1 to S-4: 62 GRA3394-WO-1
R
6
R
7 2 R 6
R
7 R' R 6
R
7 R R 6
R
7 R' 3 R2 R2 Rs R3 R5 A R5',A A3- R3 R4 R4 A 3 zA2 A2W.ZAl S-1 S-2 S-3 S-4 in which one, two or three of the residues A', A 2 and A 3 in each case mutually independently denote an optionally substituted nitrogen atom and the other residues in each case mutually independently denote an optionally substituted carbon atom. Preferred meanings a) to g) for A', A 2 and A 3 are summarised in the following table, wherein N and C, depending on the position of any double bonds present, may be substituted, e.g. with -H: A' A 2 A3 a) N C C b) C N C c) C C N d) N N C e) N C N f) C N N g) N N N Further preferred substituted compounds according to the invention are those of the general formulae I; la, Ib, Ic and Id, in which the partial structure
R
6 R7 R R 2
R
5
R
3 R 4 denotes one of the following partial structures S-5 to S-8: 63 GRA3394-WO-1
A
2 Rr, 1 'A A3 R
R
6 R, A R6 Ry R 1 R6 R 7
R
1 R6 R 7
R
1 A' R2 R2 A2A RR3 R5 4 R5 'A A R3 R 4 R 4 A A k 2 A3 A' S-5 S-6 S-7 S-8 in which one, two or three of the residues A', A 2 , A 3 and A 4 in each case mutually independently denote an optionally substituted nitrogen atom and the other residues in each case mutually independently denote an optionally substituted carbon atom. Preferred meanings a) to n) for A', A 2 , A 3 and A 4 are summarised in the following table, wherein N and C, depending on the position of any double bonds present, may be substituted, e.g. with -H: A' A 2 A3 A4 a) N C C C b) C N C C c) C C N C d) C C C N e) N N C C f) N C N C g) N C C N h) C N N C i) C N C N j) C C N N k) N N N C 1) N N C N m) N C N N n) C N N N 64 GRA3394-WO-1 Further preferred substituted compounds according to the invention are those of the general formulae 1, la, Ib, Ic and Id, in which the partial structure
R
6 R7 R
R
5 R3
R
4 denotes one of the following partial structures S-9 to S-1 2:
A
2 -ZA3
R
6
R
7 A A4 Re R 7 R, Re R 7
R
1 R6 R 7
R
1 A A- R2R
R
5
R
3
R
5 A'-' R 5 A' R 3
A
5 4A R4R4 A5, A2 ;/A1 A4
A
3 A S-9 S-10 S-11 S-12 in which one, two or three of the residues A', A 2 , A 3 , A 4 and A 5 in each case mutually independently denote an optionally substituted nitrogen atom and the other residues in each case mutually independently denote an optionally substituted carbon atom. Preferred meanings a) to o) for A', A 2 , A 3 , A 4 and A 5 are summarised in the following table, wherein N and C, depending on the position of any double bonds present, may be substituted, e.g. with -H: 65 GRA3394-WO-1 A' A A A A a) N C C C C b) C N C C C c) C C N C C d) C C C N C e) C C C C N f) N N C C C g) N C N C C h) N C C N C i) N C C C N j) C N N C C k) C N C N C 1) C N C C N m) C C N N C n) C C N C N a) C C C N N In the case of partial structures S-1 to S-12, " -"in each case denotes a single of a double bond. It will be apparent to the person skilled in the art that, as a function of the position of any double bonds present, the number of any hydrogen atoms present or possible substituents varies and that no double bonds follow directly after another within the ring structure. Partial structures S-1 to S-12 may have hydrogen atoms or other substituents at the nitrogen atoms or at the carbon atoms in positions A 1 , A 2 , A 3 , A 4 or A 5 due to the position of the single bonds or the position of any double bonds present. In one preferred embodiment, partial structures S-1 to S-12 have a total of at most two, preferably a total of at most one substituents which are different from hydrogen at the carbon or at the nitrogen atoms in positions A', A 2 , A 3 , A 4 or A 5 , which substituents are in each case mutually independently selected from the group consisting of F, Cl, Br, I, -CN, =0, -CF 3 , -SF 5 , -OH, -O-C 1
.
5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , 66 GRA3394-WO-1
-S-CF
3 , -SH, -S-C1.
5 -alkyl, -C 1
.
5 -alkyl, -C(=O)-OH, -C(=O)-O-C 1
.
5 -alkyl, -NH-C 1
.
5 -alkyl,
-N(C
1
.
5 -alkyl) 2 , -NH-S(=0) 2 -C1.
5 -alky, -NH-C(=O)-O-C1.
5 -alkyl, -C(=O)-H, -C(=O)-C1.5 alkyl, -C(=O)-NH 2 , -C(=O)-NH-C 1 .- alkyl, -C(=O)-N-(C 1 .s-alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , SF 5 , -CN, -NO 2 , -C1.s alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl; preferably from the group consisting of F, Cl, Br, I, OH, =0, CF 3 , OCF 3 , SCF 3 , SF 5 , O-C 1
.
4 -alkyl and C 1
.
4 -alkyl, particularly preferably from the group consisting of F, C, Br, I, OH, =0, CF 3 , OCF 3 ,
SCF
3 , SF 5 , methoxy, ethoxy, methyl, ethyl, n-propyl and iso-propyl. In one preferred embodiment of partial structures S-1 to S-12, the ring formed by A',
A
2 , A 3 and ring members A 4 or A 5 which may be present is saturated, up to the double bond of the anellated phenyl ring, which bears substituents R 1 to R . In another preferred embodiment of partial structures S-1 to S-12, the ring formed by A', A 2 , A 3 and ring members A 4 or A 5 which may be present is at least monounsaturated, in addition to the double bond of the anellated phenyl ring, which bears substituents R 1 to R 5 . In a further preferred embodiment of partial structures S-1 to S-12, the ring formed by A', A 2 , A 3 and ring members A 4 or A 5 which may be present is aromatic. 67 GRA3394-WO-1 Further preferred substituted compounds according to the invention are those of the general formula I, in which the partial structure
R
6 R7 R R5 R3 R4 denotes a residue selected from the group consisting of 0 6 R Ra 6 R7HN N R 6 R
RR
6 RR7R Ra 3 R R b e RR R 3 Rb Rb Rb a N N RbH R R5 R3 R5 R R5 jR3 N5 R3 0 R b R4 NR4 R 4 R5 R4 6 R
N
5
R
3 R Re N 5 Rb R 5 b 3 R RbI/ Rb Rb
R
6 _a R R 7 N'1 N 6 7 N N \6 R7 N N RbR e N
R
6 R R 7 R R5 5 3 3 b Rb RR5 4 R3 R5 4 R
R
6 R 6 7 ,N
R
6
R
7 N I5 R Rb R R5 NHR 5 R R 4 R Re 66$8 G RA3394-WO-1 Do R7 R Re R7 R Re
R
7 R Re R7 R' N R7 R' R~R I N Rb . R4R 4 R4 R R, 4 R R 4 R. Rb R e R 7 R lR R 7 R ' R R 7 N N~NR R e R 7 R R 8
R
7 R b R '
X
1 N NH R RbI-R R'R R' N R ~
R
5 N 0 R R 4RR 7 R4 RR R R " R R b RbR
.
R eR R. N& ' N' R b N RbRb
R'R
5 N R 5
N
5 NH Re R' R R Re R 7 R FI RaN Rb R~i~ NRb N- 6R7H- b\ 6 R7 R
R
6 RHN Re R 7 NNR R H R 6 R7R Rb 'N R Ra \X N R RR R5 4R 3 R
R
5 R4 R/S I Re b 4 RaR 4 Re Re R7 HN-\ Re R 7 N-(Re R7 Rl Re R 7 R N N H ' N N I Re Ij \ I N>R K /> - Re R5R.
R
3
R
5 5 R4 R4 R 4 R Re R 7 HN-N Re 7R 6 "N H
I
5 I N 0
R
8 RH b Re R 7 HN Rb HN RR
H
6 R7 N N Re R'1N R5 R R 3
R
5 4 R3R R R RbR R R 7 Ra Rb Rb Re 0 Re R7 R Re R7 R R 8 N 6 DReR HN NH I N Rb 1 'N IR 5 N R5b H5 R3 H N R5 R3 R7R 4 R 4R RbD6 .7R Re R7R H Re R 7 \LR N Rb N NH NH R 5 N NHRH
R
5 N R5 I 'N
R
4 R
R
5 R5 R3 69 GRA3394-WO-1 Ra R\ Rb
R
6 R7H R RR R 6
R
7
R
1 7
R
1 WH N.~~~R RbRbeN.NN R5 R 3
R
5
R
3 /5 R R5R R4 R4 R 4 Rb R 4 Re Rb Re Rc Rb
R
6
R
7
R
1 Re R 6
R
7
R
1 RC R RR RR R 7
R
1 RR RH eR 7 N R3 bHN RRRbe 7 1R R 'R RH RIe R N Ra b HRb RR R 3 R5 R 3 4RR R R H R NH NH RN R 5 R 4 R R 3 R 5 R a R 3 N H H4 R a R RN N RR 7 RR H R e R7 R Re R7 HN R R7HN 1' R R NH. RbR 5 R NRR Rb R 3
R
5
R
3 R4 R3 HReR7 R' R R 0 R7 0
N
6 Re Rb Rb NH N Rb R Rb H H 4 H in w Ra R, a ia R 7 R' R he R g R R b R 3 Rb R 4
R
3 Re H R Rb - ( .a Rly) Rb -a R 5 N H R b R7 N R 4 R b
R.
7 NH) 2 6 R-NHHC.-lyC( R( 1 . \ 4 R' \ N F . HN
R
5 A R3 Rb R 3 Rb R7 R Ne R b 7 R' R R4R 4
R
4 4 phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -O-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, 70 GRA3394-WO-1 Br, -OH, -CF 3 , -SF 5 , -CN, -NO 2 , -C1-5 alkyl, -O-C 1
.
5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl; preferably from the group consisting of H, F, CI, Br, I, OH, =0, CF 3 , OCF 3 , SCF 3 , SF 5 ,
-O-C
1
.
4 -alkyl and C 1
.
4 -alkyl, and particularly preferably from the group consisting of F, CI, Br, I, OH, =0, CF 3 ,
OCF
3 , SCF 3 , SF 5 , methoxy, ethoxy, methyl, ethyl, n-propyl and iso-propyl. Further preferred substituted compounds according to the invention are those of the general formulae 1, Ia, Ib, Ic, Id, in which the partial structure
R
6 R7 R R R2~ bzw. R 2
R
5 R3 R5 R3 R4 R4 [Key: bzw. = or] denotes a residue selected from the group consisting of 0 R N HN 3HN R e R4 e R e RHR
R
5
R
3
R
5
R
3
R
5
R
3
R
5
R
3
R
5 N Rb Rb H -~~
R
8 I ~ R -Rb3 R Rb R\ N Re b
R
5 R. Rb R 4
R
4 R5 R 55 3 R b b N Rb71 ReN 3 1 RbN R54R3 71 GRA3394-WO-1 Ne R' b/ Rs N R 5
R
5 Rb R 5 .. R lR1Rb 5 R R R ~ NNRN. NH\ Rb Re \ Ra \ ~~ b NH
R
5 Rb R 5 Rb NR 5 N 5 5 N 1 Rb R RH5 R~ 4 R4 R4R R 4R Rb R R. R R b N)R eR Rb N
R
5 b RbN 4N ReN-* N R NR N HRR \N N N R5 R3-
R
5 N 4 5 R R 5
R
3 R 4 Re R 5 / Rb R e HN- RN\<. R 1 Rb N H N. N NN
R
5 3R R5 H N- N R H N N.N Rb N
R
5
R
3 R 72 GPRA3394-WO-1 0 MN Rb HN Rb R H H
'R
8 Re \ - NRb N N \R35 3
R
5 R5 Re R44R 4
R
4 Rb ReRb Re 0
R
1 R' Re RbRe Rb NH NH 'N \* HRjR
R
5 N R 5
R
3
R
5
R
3
R
4
HR
4 H Rb Re ~Re H HN\ HN-'IN -Rb 0 NH* NH N 5 N> HHR R* N
R
5
R
3
R
5 R Re Re\ Rb R HN N RcN ReN Rb RR4R 4 Rb R 4 Rc Rb Re Rc Rb R' Re 0 R \ NH N-R8 ' Rb \ ~ '" Rb
'NR
5 ~ N 5 N H H
R
5
R
3
R
5
R
3
R
4
R
4 Re 73 GRA3394-WO-1 ReOR R4 R HN RH HNR R N R N R NH b R 5 )R R R5 R RR RNR R 3N ~ 4 R H H NHHRH R R RR RR R 4 R4 R4 R' R'0 N ReK Re N Rb H bNHN id in Rb R h rb cnisi f H F N NH ,R C - C 3 R R5 R R3 R 5
R
3 iR 0 ~ N N~ NRR b -RN -2NCa = H aNH - NH2 N Re R 5 Rb R 5 N R R 4 R4 H inwhc 5Rsbsttundtsb mutually independentlyaeiechas selected from the group cnitn fF I crostn -CF3, -F, CNBr, -N, ,-C1.Faky, -SF-OHal, -O-CF3 5 al, -NHCF, -hnyl -0 -OF-enzyl; -reerbl from theagroup consisting, -of)-H, FC(,OBr,-C, OHk=0, CFNOF, SCF3,)O 1 Sly, -- 1.4-nHd C.4 -- 1 -alkyl, dpriual preferabCi.lyym -0-gou -Obny;peeal rmtegopconsisting of H F, Cl, Br, I, OH, =0, F, OCF 3 , SCF 3 ,Ssmtoyehxmty, ethyl, n-propyl and iso-propyl. 74 GRA3394-WO-1 Still more preferred are compounds of the general formulae 1, la, Ib, Ic, and Id selected from the group consisting of [1] 2-(benzo[d]oxazol-5-yl)-N-(4-tert-butylbenzyl)propanamide, [2] 2-(benzo[d]oxazol-6-yl)-N-(4-tert-butylbenzyl)propanamide, [3] 2-(benzo[d]oxazol-7-yl)-N-(4-tert-butylbenzyl)propanamide, [4] N-(4-tert-butylbenzyl)-2-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5 yl)propanamide, [5] N-(4-tert-butylbenzyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7 yl)propanamide, [6] N-(4-tert-butylbenzyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6 yl)propanamide, [7] N-(4-tert-butylbenzyl)-2-(7-methoxybenzo[d]oxazol-5-yl)propanamide, [8] 2-(benzo[d]oxazol-4-yl)-N-(4-tert-butylbenzyl)propanamide, [9] N-(4-tert-butylbenzyl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanamide, [10] N-(4-tert-butylbenzyl)-2-(2-thioxo-2,3-dihydro-1 H-benzo[d]imidazol-5 yl)propanamide, [11] N-(4-tert-butylbenzyl)-2-(quinoxalin-6-yl)propanamide, [12] 2-(1 H-benzo[d][1,2,3]triazol-5-yl)-N-(4-tert-butylbenzyl)propanamide, [13] 2-(1 H-benzo[d]imidazol-5-yl)-N-((2-(4-methylpiperid in-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide, [14] 2-(1 H-benzo[d]imidazol-5-yl)-N-(4-tert-butylbenzyl)propanamide, [15] 2-(1 H-benzo[d][1,2,3]triazol-5-yl)-N-((2-(4-methylpiperid in-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide, [16] N-(4-tert-butylbenzyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propanamide, [17] N-(4-tert-butylbenzyl)-2-(2-thioxo-2,3-dihydrobenzo[d]oxazol-5 yl)propanamide, [18] 2-(2-aminobenzo[d]oxazol-6-yl)-N-(4-tert-butylbenzyl)propanamide, [19] N-(4-tert-butylbenzyl)-2-(2-thioxo-2,3-dihydrobenzo[d]oxazol-6 yl)propanamide, [20] N-(4-tert-butylbenzyl)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7 yl)propanamide, 75 GRA3394-WO-1 [21] N-(4-tert-butylbenzyl)-2-(quinolin-6-yI)propanamide, [22] 2-(l1 H-benzo[d][1 ,2 ,3]triazol-5-yI)-N-((2-butoxy-6-tert-butylpyridin-3 yI)methyl)propanamide, [23] 2-(lI H-benzo[d]imidazol-5-yI)-N-((2-butoxy-6-tert-butylpyrid in-3 yI)methyl)propanamide, [24] 2-( 1 H-benzo [d] [1, ,2,3]triazol-5-yI)-N-((6-te rt- butyl-2-(4-methyl pipe rid in- 1 yI)pyrid in-3-yI)methyl)propanamide, [25] 2-(l1 H-be nzo [d] imid azol1-5-yI)- N-((6-te rt-b utyl-2-(4-methyl pipe rid in- 1 -yI)pyridin 3-yI)methyl)propanamide, [26] 2-(lI H-benzo[d][1 ,2 ,3]triazol-5-yI)-N-((6-tert-butyl-2-(cyclohexylthio)pyridin-3 yI)methyl)propanamide, [27] 2-(l1 H-benzo[dlimidazol-5-yI)-N-((6-tert-butyl-2-(cyclohexylthio)pyridin-3 yI)methyl)propanamide, [28] N-((2-butoxy-6-tert-butylpyrid in-3-yI )methyl)-2-(2-oxo-2 ,3 dihyd robenzo[d]thiazol-6-yl)propanamide, [29] N-(2-butoxy-6-tert-butyl-pyridin-3-ylmethyl)-2-(2-ethylsulfanyl-benzothiazol-6 yI)-propionamide, [30] N-((2-(4-methyl pipe rid in- 1 -yI)-6-(trifluoromethyl)pyridin-3-yI)methyl)-2-(2 (methylthio)benzo[d]thiazol-6-yI)propanamide, [31] N-((2-butoxy-6-tert-butyl pyrid in-3-yI )methyl )-2-hyd roxy-2-(2 (methylthio)benzo[d]thiazol-6-yI)propanamide, [32] N-((2-(4-methylpiperid in-I -yI)-6-(trifluoromethyl)pyridin-3-yI)methyl)-2-(2 thioxo-2, 3-dihydrobenzo[d]thiazol-6-yI)propanamide, [33] N-((6-tert-butyl-2-(4-methyipiperid in-i -yI)pyrid in-3-yI)methyl)-2-(2-thioxo-2 ,3 dihyd robenzo[dlthiazol-6-y )propanamide, [34] N-((6-tert-butyl-2-(4-methylpiperid in-I -yI)pyrid in-3-yI)methyl)-2-(2 (methylthio)benzo[d]thiazol-6-yI)propanamide, [35] 2-(2-aminobenzo[d]oxazol-5-y)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, [36] 2-(2-a cetamrnido be nzo [d]th iazol-6-yI)-N-(4-te rt-butyl be nzyl) pro pan amid e, [37] 2-(2-a cetamrnido be nzo [d]th iazol-6-y)-N-((2-(4- methyl p ipe rid i n-I1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, [38] 2-(2-a m inobe nzo[d]th iazo1-6-yI)- N-((2-(4-methyl pipe rid in-I1 -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, 76 GRA3394-WO-1 [39] N-((2-(4-methylpiperid in-I -yI)-6-(trifluoromethyl)pyrid in-3-yI)methyl)-2-(2 (methylsulfonamido)benzo[d]thiazol-6-yI)propanamide, [40] tert-butyl 6-(lI-((2-(4-methylpiperid in-i -yI)-6-(trifluoromethyl)pyridin-3 yI )methylamino)-1 -oxo pro pa n-2-yI)be nzo [d]th iazol1-2-ylca rba mate, [41] 2-(2-acetamidobenzo[d]thiazol-6-y)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, [42] 2-(2-acetamidobenzo[d]thiazol-5-yI)-N-((2-(4-methylpiperid in-I -yl)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, [43] 2-(2-aceta mido benzo [d]th iazo-4-y)- N-((2-(4- methyl p ipe rid i n-i1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, [44] 2-( 1 H-i nd azol1-5-yI)-N -((2-(4-methyl p ipe rid in-I1 -yI)-6-(trifluoromethyl)pyridin-3 yI)methyl)propanamide, [45] 2-(3-fluoro-1 H- ind azol-5-yI)-N-((2-(4-methyl p ipe rid i n-I1 -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, [46] N-((2-butoxy-6-tert-butylpyridin-3-yI)methyl)-2-(I H-indazol-5-yI)propanamide, [48] N-((6-tert-butyl-2-(cyclohexylthio)pyrid in-3-yI)methyl)-2-( 1 H-indazol-5 yI)propanamide [49] N-(2-butoxy-6-tert-butyl-pyrid in-3-ylmethyl)-2-(2-thioxo-2 ,3-d ihydro benzothiazol-6-yI)-propionamide; [50] tert-butyl 6-(lI-(4-tert-butylbenzylamino)-I -oxopropan-2-yI)benzo[d]thiazol-2 ylcarbamate, [51] 2-(2-aminobenzo[d]thiazol-6-yI)-N-(4-tert-butylbenzyl)propanamide, [52] 2-(2-aminobenzo[d]thiazol-6-yI)-N-((2-(4-methylpiperidin-I -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl )propanamide, [53] 2-(2-acetamidobenzo[d]thiazol-6-y)-N-((6-tert-butyl-2-(4-methylpiperidin-I yI)pyrid in-3-yI)methyl)propanamide and [54] tert-butyl 6-(lI-((2-(4-methylpiperid in-I -yI)-6-(trifluoromethyl)pyridin-3 yI)methylamino)-I -oxopropan-2-yI)benzo[d]th iazol-2-ylca rba mate; [54] tert-butyl 6-(l1-((2-(4-methylpiperid in-I -yI)-6-(trifluoromethyl)pyrid in-3 yI )methylamino)-1 -oxopropan-2-yI)benzo[d]thiazol-2-ylca rba mate; [55] tert-butyl 6-(1I -((6-te rt-butyl-2-(4-m ethyl pipe rid i n-I -yI)pyrid in-3-yI )methylamino) 1 -oxo pro pa n-2-yl)be nzo [d]th iazol1-2-yl ca rba mate; [56] 2-(2-amni no benzo [d]th iazo 1-6-y)-N-((6-tert-b utyl-2-(4-methyl p ipe rid i n-I1 yI)pyridin-3-yI)methyl)propanamide; 77 GRA3394-WO-1 [57] N-(4-tert-butylbenzyl)-2-(2-(methylsulfonamide)benzo[d]thiazol-6 yl)propanamide; [58] 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((2-(4-methylpiperid in-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)acetamide; [59] N-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(2,3 dihydrobenzo[b][1,4]dioxin-6-yl)acetamide; [60] 2-(benzo[d][1,3]dioxol-5-yl)-N-((2-(4-methylpiperidin-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide; [61] 2-(benzo[d][1 ,3]dioxol-4-yl)-N-((2-(4-methylpiperid in-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide; [62] 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((2-(4-methylpiperidin-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide; [63] 2-(2,3-dihydrobenzo[b][1,4]d ioxin-5-yl)-N-((2-(4-methylpiperid in-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [64] 2-(isoquinolin-7-yl)-N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3 yl)methyl)propanamide [65] 2-(isoquinolin-6-yl)-N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3 yl)methyl)propanamide [66] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(quinolin 6-yl)propanamide [67] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2 (quinoxalin-6-yl)propanamide [68] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2 (quinazolin-6-yl)propanamide [69] 2-(1 H-indazol-5-yl)-N-(2-(4-methylpiperidin-1 -yl)-4 (trifluoromethyl)benzyl)propanamide [70] 2-(1 H-indazol-4-yl)-N-((2-(4-methylpiperidin-1-yI)-6-(trifluoromethyl)pyridin-3 yl)methyl)propanamide [71] 2-(1 H-indazol-6-yl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3 yl)methyl)propanamide [72] 2-(1 H-indazol-7-yI)-N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3 yl)methyl)propanamide [73] 2-(1-(2-fluorophenyl)-1 H-indazol-4-yl)-N-((2-(4-methylpiperidin-1 -yl)-6 (trifluoromethyl)pyrid in-3-yl)methyl)propanamide 78 GRA3394-WO-1 [74] 2-(indolin-5-yl)-N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3 yl)methyl)propanamide [75] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(1,2,3,4 tetrahydroquinolin-6-yl)propanamide [76] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(2 oxoindolin-5-yl)propanamide and [77] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-(2-oxo 1,2,3,4-tetrahydroquinolin-6-yl)propanamide in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates; In addition, compounds according to the invention of the general formulae 1, la, Ib, Ic, and Id, may be preferred which in the FLIPR assay with CHO K1 cells, which have been transfected with the human VR1 gene, in a concentration of less than 2000 nM, preferably of less than 1000 nM, particularly preferably of less than 300 nM, very particularly preferably of less than 100 nM, still more preferably of less than 75 nM, further preferably of less than 50 nM and most preferably of less than 10 nM, bring about a 50 percent displacement of capsaicin, which is present in a concentration of 100 nM. In this FLIPR assay, the influx of Ca 2 + is quantified with the assistance of a Ca sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, Netherlands) in a Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA) as described below. The present invention also provides a method for producing compounds of the above-stated general formula 1, in accordance with which at least one compound of the general formula 11, 79 GRA3394-WO-1 W (CH 2 )m OR ll, in which R 8 , U, T, V, and W have the above-stated meanings, m denotes 0, 1, 2 or 3 and R denotes hydrogen or denotes a linear or branched C 1
.
6 alkyl residue, is reacted in a reaction medium, in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, sodium, potassium hydride, lithium aluminium hydride, sodium borohydride and di(isobutyl)aluminium hydride to yield at least one compound of the general formula 111, W (CH 2 )m OH in which R3, U, T, V and W have the above-stated meaning and m denotes 0, 1, 2 or 3 and said compound is optionally purified and/or isolated, and at least one compound of the general formula Ill is reacted in a reaction medium in the presence of diphenylphosphoryl azide or in the presence of HN 3 to yield at least one compound of the general formula IV, RyU W
(CH
2 )m
N
3 IV, in which R 8 , U, T, V and W have the above-stated meaning and m denotes 0, 1, 2 or 3 and said compound is optionally purified and/or isolated, 80 GRA3394-WO-1 and at least one compound of the general formula IV is reacted in a reaction medium in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, potassium hydride, lithium aluminium hydride, sodium borohydride and di(isobutyl)aluminium hydride or in a reaction medium in the presence of a catalyst, preferably in the presence of a catalyst based on platinum or palladium, particularly preferably in the presence of palladium on carbon, and in the presence of hydrogen or in the presence of hydrazine or in a reaction medium in the presence of triphenylphosphine to yield at least one compound of the general formula V, 8 R YU W (CH 2 )m
NH
2 V, in which R 8 , U, T, V and W have the above-stated meaning and m denotes 0, 1, 2 or 3 and said compound is optionally purified and/or isolated, or at least one compound of the general formula VI, VlzW 'j ,CN W
(CH
2 )m VI, in which R 8 , U, T, V, and W have the above-stated meanings and m denotes 0, 1, 2 or 3, is reacted in a reaction medium in the presence of at least one catalyst, preferably in the presence of at least one catalyst based on palladium or platinum, particularly preferably in the presence of 81 GRA3394-WO-1 palladium on carbon, under a hydrogen atmosphere, optionally in the presence of at least one acid, preferably in the presence of hydrochloric acid, or in the presence of at least one reducing agent selected from the group consisting of BH 3
-S(CH
3
)
2 , lithium aluminium hydride and sodium borohydride, optionally in the presence of NiCl 2 , to yield at least one compound of the general formula V, optionally in the form of a corresponding salt, preferably in the form of a corresponding hydrochloride, and said compound is optionally purified and/or isolated, and at least one compound of the general formula V is reacted with at least one compound of the general formula VII,
R
6 R7 R HO R2 i R R3 R4 VIl, in which R', R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the above-stated meanings, in a reaction medium, optionally in the presence of at least one suitable coupling agent, optionally in the presence of at least one base, or with at least one compound of the general formula Vill,
R
6 R7 R LG R2
R
5 R3 R4 Vill, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the above-stated meanings and LG denotes a leaving group, preferably a chlorine or bromine atom, in a reaction 82 GRA3394-WO-1 medium, optionally in the presence of at least one base, to yield at least one compound of the general formula 1, R8 Us| H
R
6 7 R 1 W N R
(CH
2 )n 0R 5 R 3 R4 I, in which T, U, V, W, R 1 , R 2 , R 3 , R 4 , R', R 6 , R 7 and R 8 have the above-stated meanings and n denotes 1, 2, 3 or 4 and said compound is optionally purified and/or isolated. The present invention also provides a method for producing compounds of the above-stated general formula 1, in accordance with which at least one compound of the general formula X, W
NH
2 X, in which R 8 , U, T, V, and W have the above-stated meanings, is reacted with at least one compound of the general formula VII,
R
6 R7 RI HO R2 0 / R5#R3 R4 Vil, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the above-stated meanings, in a reaction medium, optionally in the presence of at least one suitable coupling agent, optionally in the presence of at least one base, 83 GRA3394-WO-1 or with at least one compound of the general formula Vill,
R
6 R7 R LG R2 R5 R3 R4 Vill, in which R1, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the above-stated meanings and LG denotes a leaving group, preferably a chlorine or bromine atom, in a reaction medium, optionally in the presence of at least one base, to yield at least one compound of the general formula Im, R8 U
R
6 7 R W NH R2 o / 0R5 R R4 Im, in which T, U, V, W, R1, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the above-stated meanings, and said compound is optionally purified and/or isolated. The reaction of compounds of the above-stated general formulae V or X with carboxylic acids of the above-stated general formula Vil to yield compounds of the above-stated general formulae I or Im preferably proceeds in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1,2)-dichloroethane, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxy-tris (dimethylamino)-phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), N-[(dimethylamino)-1 H 1,2,3-triazolo[4, 5-b]pyridino-1-ylmethylene]-N-methylmethanaminium 84 GRA3394-WO-1 hexafluorophosphate N-oxide (HATU), 0-(benzotriazol-1-yl)-N,N,N',N' tetramethyluronium hexafluorophosphate (HBTU), 0-(benzotriazol-1-yl)-N,N,N',N' tetramethyluronium tetrafluoroborate (TBTU), N-hydroxybenzotriazole (HOBt) and 1 hydroxy-7-azabenzotriazole (HOAt), optionally in the presence of at least one organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and diisopropylethylamine, preferably at temperatures of -70 C to 100 0 C. Alternatively, the reaction of compounds of the above-stated general formulae V or X with carboxylic acid derivatives of the above-stated general formula VIII, in which LG denotes a leaving group, preferably a chlorine or bromine atom, to yield compounds of the above-stated general formulae lh or Im proceeds in a reaction medium preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of an organic base or inorganic base, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine, at temperatures of -70*C to 100C. The compounds of the above-stated formulae 11, 111, IV, V, X, VI, VII and VIII are in each case commercially obtainable and may also be produced using conventional methods known to the person skilled in the art. The synthesis method for compounds of the general formula VII may be found in the document "4-(Methylsulfonylamino)phenyl analogues as vanilloid antagonist showing excellent analgesic activity and the pharmaceutical compositions comprising the same" by J.W. Lee et al. (WO 2005/003084-Al]. The corresponding parts of the reference are hereby deemed to be part of the disclosure. The above-described reactions may in each case be performed under conventional conditions familiar to a person skilled in the art, for example with regard to pressure or the sequence of addition of the components. Optimum control of the process under the respective conditions may optionally be established by the person skilled in the art by simple preliminary testing. The intermediate and final products obtained 85 GRA3394-WO-1 from the above-described reactions may in each case, if desired and/or necessary, be purified and/or isolated using conventional methods known to the person skilled in the art. Suitable purification methods are, for example, extraction methods and chromatographic methods such as column chromatography or preparative chromatography. All the above-described method steps and in each case also the purification and/or isolation of intermediate or final products may be performed in part or entirely under an inert gas atmosphere, preferably under a nitrogen atmosphere. The substituted compounds according to the invention of the above-stated general formulae 1, la, Ib, Ic and Id, hereinafter designated only as compounds of the general formula 1, and corresponding stereoisomers may be isolated both in the form of the free bases thereof, the free acids thereof and in the form of corresponding salts, in particular physiologically acceptable salts. The free bases of the particular substituted compounds according to the invention of the above-stated general formula I and corresponding stereoisomers may, for example, be converted into the corresponding salts, preferably physiologically acceptable salts by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. The free bases of the respective substituted compounds of the above-stated general formula I and corresponding stereoisomers may likewise be converted into the corresponding physiologically acceptable salts with the free acid or a salt of a sugar substitute, such as for example saccharin, cyclamate or acesulfame. The free acids of the substituted compounds of the above-stated general formula I and corresponding stereoisomers may correspondingly be converted into the corresponding physiologically acceptable salts by reaction with a suitable base. Examples which may be mentioned are alkali metal salts, alkaline earth metal salts or ammonium salts NHxR 4 .j 4 , in which x = 0, 1, 2, 3 or 4 is and R denotes a linear or branched C 1 4 alkyl residue. 86 GRA3394-WO-1 The substituted compounds according to the invention of the above-stated general formula I and corresponding stereoisomers may optionally, like the corresponding acids, the corresponding bases or salts of these compounds, also be obtained in the form of the solvates thereof, preferably in the form of the hydrates thereof, by conventional methods known to a person skilled in the art. If the substituted compounds according to the invention of the above-stated general formula I are obtained after the production thereof in the form of a mixture of the stereoisomers thereof, preferably in the form of the racemates thereof or other mixtures of their various enantiomers and/or diastereomers, these may be separated and optionally isolated by conventional methods known to a person skilled in the art. Examples are chromatographic separation methods, in particular liquid chromatography methods at standard pressure or at elevated pressure, preferably MPLC and HPLC methods, and fractional crystallisation methods. Individual enantiomers, for example diastereomeric salts formed by means of HPLC on a chiral stationary phase or by means of crystallisation with chiral acids, such as (+)-tartaric acid, (-)-tartaric acid or (+)-10-camphorsulfonic acid, may here in particular be separated from one another. The substituted compounds according to the invention of the above-stated general formula I and corresponding stereoisomers as well as in each case the corresponding acids, bases, salts and solvates are toxicologically safe and are therefore suitable as pharmaceutical active ingredients in pharmaceuticals. The present invention accordingly also provides a pharmaceutical containing at least one compound according to the invention of the above-stated general formula 1, in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable auxiliary substances. 87 GRA3394-WO-1 These pharmaceuticals according to the invention are suitable in particular for vanilloid receptor 1-(VR1/TRPV1) regulation, preferably for vanilloid receptor 1 (VR1 /TRPV1) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1) stimulation. The pharmaceuticals according to the invention are likewise preferably suitable for the prevention and/or treatment of disorders or diseases, which are mediated at least in part by vanilloid receptors 1. The pharmaceutical according to the invention is preferably suitable for the treatment and/or prevention of one or more diseases selected from the group consisting of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; neuropathy; nerve injury; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea; cognitive dysfunction, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; airways diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughing; urinary incontinence; an overactive bladder (OAB); diseases and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritation; skin irritation; neurotic skin conditions; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammation, preferably inflammation of the intestines, the eyes, the bladder, the skin or the nasal mucosa; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; disorders of food intake, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; dependency on medicines; abuse of medicines; withdrawal symptoms associated with dependency on medicines; development of tolerance towards medicines, preferably towards natural or synthetic opioids; dependency on drugs; drug abuse; withdrawal symptoms associated with dependency on drugs; dependency on alcohol; alcohol abuse and withdrawal symptoms associated with dependency on alcohol; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating locomotor activity; for anxiolysis; for local anaesthesia; and/or for 88 GRA3394-WO-1 inhibiting undesired side-effects, preferably selected from the group consisting of hyperthermia, high blood pressure and constriction of bronchial tubes, triggered by the administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ 249665, SDZ-249482, nuvanil and capsavanil. The pharmaceutical according to the invention is particularly preferably suitable for the treatment and/or prevention of one or more diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; joint pain; migraine; depression; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea; cognitive dysfunction, preferably cognitive deficiency states, particularly preferably memory disorders; inflammation, preferably inflammation of the intestines, the eyes, the bladder, the skin or the nasal mucosa; urinary incontinence; an overactive bladder (OAB); dependency on medicines; abuse of medicines; withdrawal symptoms associated with dependency on medicines; development of tolerance towards medicines, preferably development of tolerance towards natural or synthetic opioids; dependency on drugs; drug abuse; withdrawal symptoms associated with dependency on drugs; dependency on alcohol; alcohol abuse and withdrawal symptoms associated with dependency on alcohol. The pharmaceutical according to the invention is very particularly preferably suitable for the treatment and/or prevention of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and/or urinary incontinence. The present invention also provides the use of at least one compound according to the invention and optionally one or more pharmaceutically acceptable auxiliary substances for the production of a pharmaceutical for vanilloid receptor 1 (VR1/TRPV1) regulation, preferably for vanilloid receptor 1-(VR1/TRPV1) inhibition and/or for vanilloid receptor 1-(VR1/TRPV1) stimulation. 89 GRA3394-WO-1 It is preferred to use at least one substituted compound according to the invention and optionally one or more pharmaceutically acceptable auxiliary substances for the production of a pharmaceutical for the prevention and/or treatment of disorders or diseases which are mediated at least in part by vanilloid receptors 1. It is particularly preferred to use at least one compound according to the invention and optionally one or more pharmaceutically acceptable auxiliary substances for the production of a pharmaceutical for the treatment and/or prevention of one or more diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain and joint pain. It is particularly preferred to use at least one compound according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the production of a pharmaceutical for the treatment and/or prevention of one or more diseases selected from the group consisting of hyperalgesia; allodynia; causalgia; migraine; depression; neuropathy; nerve injury; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea; cognitive dysfunction, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; airways diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughing; urinary incontinence; an overactive bladder (OAB); diseases and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritation; skin irritation; neurotic skin conditions; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammation, preferably inflammation of the intestines, the eyes, the bladder, the skin or the nasal mucosa; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; disorders of food intake, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; dependency on medicines; abuse of medicines; withdrawal symptoms associated with dependency on medicines; development of tolerance towards medicines, preferably towards natural or synthetic opioids; dependency on drugs; drug abuse; withdrawal symptoms associated with dependency on drugs; dependency on alcohol; alcohol abuse and withdrawal symptoms associated with dependency on alcohol; for diuresis; for 90 GRA3394-WO-1 antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating locomotor activity; for anxiolysis; for local anaesthesia; and/or for inhibiting undesired side-effects, preferably selected from the group consisting of hyperthermia, high blood pressure and constriction of bronchial tubes, triggered by the administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil. It is very particularly preferred to use at least one substituted compound according to the invention and optionally one or more pharmaceutically acceptable auxiliary substances for the production of a pharmaceutical for the treatment and/or prevention of one or more diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; joint pain; migraine; depression; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea; cognitive dysfunction, preferably cognitive deficiency states, particularly preferably memory disorders; inflammation, preferably inflammation of the intestines, the eyes, the bladder, the skin or the nasal mucosa; urinary incontinence; an overactive bladder (OAB); dependency on medicines; abuse of medicines; withdrawal symptoms associated with dependency on medicines; development of tolerance towards medicines, preferably development of tolerance towards natural or synthetic opioids; dependency on drugs; drug abuse; withdrawal symptoms associated with dependency on drugs; dependency on alcohol; alcohol abuse and withdrawal symptoms associated with dependency on alcohol. It is still further preferred to use at least one substituted compound according to the invention and optionally one or more pharmaceutically acceptable auxiliary substances for the production of a pharmaceutical for the treatment and/or prevention of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and/or urinary incontinence. 91 GRA3394-WO-1 The pharmaceutical according to the invention is suitable for administration to adults and children including small children and babies. The pharmaceutical according to the invention may be formulated as a liquid, semisolid or solid dosage form, for example in the form of solutions for injection, drops, succi, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally pressed into tablets, packaged in capsules or suspended in a liquid, and may also be administered as such. In addition to at least one substituted compound of the above-stated general formula 1, optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemate thereof or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio, or optionally in the form of a corresponding salt or in each case in the form of a corresponding solvate, the pharmaceutical according to the invention conventionally contains further physiologically acceptable pharmaceutical auxiliary substances, which may for example be selected from the group consisting of matrix materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, slip agents, lubricants, aromas and binders. Selection of the physiologically acceptable auxiliary substances and the quantities thereof which are to be used depends upon whether the pharmaceutical is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example onto infections of the skin, mucous membranes and eyes. Preparations in the form of tablets, coated tablets, capsules, granules, pellets, drops, succi and syrups are preferred for oral administration, while solutions, suspensions, readily reconstitutible dried preparations and sprays are preferred for parenteral, topical and inhalatory administration. The substituted compounds according to the invention used in the pharmaceutical according to the invention in a depot in dissolved form or in a dressing, optionally with the addition of skin penetration promoters, are suitable percutaneous administration preparations. Orally or percutaneously administrable 92 GRA3394-WO-1 formulations may also release the particular substituted compound according to the invention in a delayed manner. Production of the pharmaceuticals according to the invention proceeds with the assistance of conventional means, devices, methods and processes known from the prior art, as are described for example in "Remington's Pharmaceutical Sciences", ed. A.R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93. The corresponding description is hereby introduced as a reference and is deemed to be part of the disclosure. The quantity of the particular substituted compounds according to the invention of the above-stated general formula I to be administered to the patient may vary and is for example dependent on the weight or age of the patient and on the mode of administration, the indication and the severity of the complaint. Conventionally, 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg/kg of patient body weight of at least one such compound according to the invention are administered. 93 GRA3394-WO-1 Pharmacological methods I. Functional investigation on vanilloid receptor 1 (VRI/TRPV1 receptor) The agonistic or antagonistic action of the substances to be investigated on the vanilloid receptor 1 (VR1/TRPV1) of the rat species may be determined with the following assay. According to this assay, the influx of Ca2+ through the receptor channel is quantified with the assistance of a Ca 2 +-sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, Netherlands) in a Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA). Method: Complete medium: 50 mL HAMS F12 Nutrient Mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) with 10 vol.% FCS (foetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heat inactivated); 2 mM L-glutamine (Sigma, Munich, Germany); 1 wt.% AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria) and 25 ng/ml NGF medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany) Cell culture plate: poly-D-lysine-coated, black 96-hole plates with clear base (96 well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Karlsruhe, Germany), by diluting laminin to a concentration of 100 pg/mL with PBS (Ca-Mg-free PBS, Gibco Invitrogen GmbH, Karlsruhe, Germany). Aliquots with a concentration of 100 pg/mL of laminin are taken and stored at -20 0 C. The aliquots are diluted with PBS in the ratio of 1:10 to 10 pg/mL of laminin and 50 pL of the solution is pipetted into each well of the cell culture plate. The cell culture plates are incubated for at least two hours at 37 0 C, the supernatant solution is aspirated and the wells are each washed twice with PBS. The coated cell culture plates are stored with supernatant PBS and this is only removed directly prior to introduction of the cells. 94 GRA3394-WO-1 Preparation of the cells: The spinal column is removed from decapitated rats and this is placed directly in cold HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany), i.e. located in an ice bath, combined with 1 vol.% (percent by volume) of an AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria). The spinal column is severed lengthwise and removed from the spinal canal together with fasciae. The dorsal root ganglia (DRGs) are then removed and in turn stored in cold HBSS buffer combined with 1 vol.% of an AA solution. The DRGs, from which blood residues and spinal nerves have been completely removed, are in each case transferred into 500 pL cold collagenase type 2 (PAA, Pasching, Austria) and incubated for 35 minutes at 37*C. After the addition of 2.5 vol.% trypsin (PAA, Pasching, Austria) incubation at 370C is continued for a further 10 minutes. After complete incubation, the enzyme solution is carefully pipetted off and the remaining DRGs are combined in each case with 500 pL of complete medium. The DRGs are in each case repeatedly suspended, drawn through cannulas no. 1, no. 12 and no. 16 by means of a syringe and transferred into 50 mL Falcon microtubes, these being filled to 15 mL with complete medium. The content of each Falcon microtube is in each case filtered through a 70 pm Falcon filter insert and centrifuged for 10 minutes at 1200 revolutions and RT. The resultant pellet is in each case redissolved in 250 pL of complete medium and the cell count is determined. The number of cells in the suspension is adjusted to 3 x 105 per mL and a 150 pL portion of this suspension is in each case placed in a well of the cell culture plates which have been coated as described above. The plates are left to stand in the incubator for two to three days at 37*C, 5 vol.% C02 and 95% relative atmospheric humidity. The cells are then loaded with 2 pM Fluo-4 and 0.01 vol.% Pluronic F127 (Molecular Probes Europe BV, Leiden, Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) for 30 mins at 370C, washed 3 x with HBSS buffer and, after a further 15 minutes' incubation at room temperature, used for Ca2+ measurement in the FLIPR assay. Ca2+-dependent fluorescence is here measured before and after the addition of substances (Xex = 95 GRA3394-WO-1 488 nm, Xem = 540 nm). Quantification proceeds by measuring the highest fluorescence intensity (FC, fluorescence counts) over time. FLIPR assay: The FLIPR protocol consists of 2 additions of substance. First of all, the compounds to be tested (10 pM) are pipetted onto the cells and Ca2+ influx is compared with the control (capsaicin 10 pM). This gives rise to a % activation value relative to the Ca2+ signal after addition of 10 pM capsaicin (CP). After 5 minutes' incubation, 100 nM of capsaicin are added and the influx of Ca2+ is likewise determined. Desensitising agonists and antagonists result in suppression of Ca2+ influx. The percentage inhibition in comparison with the maximum achievable inhibition with 10 pM capsaicin is calculated. Three-fold determinations (n=3) are performed and these are repeated in at least 3 independent experiments (N=4). On the basis of the percentage displacement by different concentrations of the compounds to be tested of the general formula 1, IC50 inhibition concentrations which bring about 50% displacement of capsaicin were calculated. Ki values for the test substances were obtained by conversion using the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973). II. Functional investigations on vanilloid receptor (VR1) The agonistic or antagonistic action of the substances to be investigated on the vanilloid receptor (VR1) may also be determined with the following assay. According to this assay, the influx of Ca2+ through the channel is quantified with the assistance of a Ca2+-sensitive dye (type Fluo-4, Molecular Probes, Europe BV, Leiden, Netherlands) in a Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA). 96 GRA3394-WO-1 Method: Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC), Great Britain) are stably transfected with the VR1 gene. For functional investigations, these cells are plated out onto poly-D-lysine-coated, black 96-hole plates with a clear base (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells/hole. The cells are incubated overnight at 37"C and 5% CO 2 in a culture medium (Ham's Nutrient Mixture F12, 10 vol.% FCS (foetal calf serum), 18 pg/mL L proline). On the following day, the cells are incubated with Fluo-4 (Fluo-4 2 pM, Pluronic F127 0.01 vol.%, Molecular Probes in HBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH, Karlsruhe, Germany) for 30 minutes at 37 0 C. The plates are then washed 3 times with HBSS buffer and, after a further 15 minutes' incubation at room temperature, used for Ca2+ measurement in the FLIPR. Ca2+_ dependent fluorescence is here measured before and after the addition of the substances to be investigated (wavelength Xex = 488 nm, Xem = 540 nm). Quantification proceeds by measuring the highest fluorescence intensity (FC, fluorescence counts) over time. FLIPR assay: The FLIPR protocol consists of 2 additions of substance. The substances to be tested (10 pM) are firstly pipetted onto the cells and Ca2+ influx is compared with the control (capsaicin 10 pM) (% activation relative to the Ca2+ signal after addition of 10 pM of capsaicin). After 5 minutes' incubation, 100 nM of capsaicin are administered and the influx of Ca2+ is likewise determined. Desensitising agonists and antagonists resulted in suppression of Ca2+ influx. The percentage inhibition in comparison with the maximum achievable inhibition with 10 pM capsaicin is calculated. On the basis of the percentage displacement by different concentrations of the compounds to be tested of the general formula I, IC 50 inhibition concentrations which bring about 50% displacement of capsaicin were calculated. Ki values for the test 97 GRA3394-WO-1 substances were obtained by conversion using the Cheng-Prusoff equation (Cheng, Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973). IL. b. Formalin test in mice The investigation for determining the antinociceptive action of the compounds according to the invention is performed using the formalin test on male mice (NMRI, 20 to 30 g body weight, Iffa, Credo, Belgium). In the formalin test, according to D. Dubuisson et al., Pain 1977, 4, 161-174 a distinction is drawn between the first (early) phase (0 to 15 minutes after the formalin injection) and the second (late) phase (15 to 60 minutes after the formalin injection). The early phase, being a direct response to the formalin injection, is considered to be a model for acute pain, while the late phase is considered to be a model for persistent (chronic) pain (T.J. Coderre, et al., Pain 1993, 52, 259-285). The corresponding literature descriptions are hereby introduced as a reference and are deemed to be part of the disclosure. The compounds according to the invention are investigated in the second phase of the formalin test in order to obtain information concerning the effects of the substances on chronic/inflammatory pain. The administration time of the compounds according to the invention prior to the formalin injection is selected as a function of the mode of administration of the compounds according to the invention. Intravenous administration of 10 mg/kg body weight of the test substances proceeds 5 minutes prior to the formalin injection. This is effected by a one-off subcutaneous formalin injection (20 pL, 1% aqueous solution) into the dorsal side of the right hand hind paw, such that, in the case of freely mobile test animals, a nociceptive reaction is induced, which manifests itself in marked licking and biting of the relevant paw. Then, the nociceptive behaviour of the animals is observed and recorded continuously for an investigation period of three minutes in the second (late) phase of the formalin test (21 to 24 minutes after the formalin injection). Quantification of the 98 GRA3394-WO-1 pain behaviour proceeds by summation of the seconds in which the animals licked and bit the relevant paw during the investigation period. The comparison is made in each case with control animals, which, instead of compounds according to the invention, received vehicle (0.9% aqueous sodium chloride soln.) before administration of the formalin. On the basis of the quantification of the pain behaviour, the substance effect in the formalin test is determined in percent as a change compared with the corresponding control. After the injection of substances which have an antinociceptive action in the formalin test, the described behaviours of the animals, i.e. licking and biting, are reduced or eliminated. IV. Investigation of analgesic efficacy in the writhing test Investigation of the compounds according to the invention of the general formula I for analgesic efficacy was performed by phenylquinone-induced writhing in mice, modified in accordance with 1.C. Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. There. 125, 237-240. The corresponding literature description is hereby introduced as a reference and is deemed to be part of the disclosure. Male NMRI mice weighing from 25 to 30 g were used for this purpose. Groups of 10 animals per compound dose received, 10 minutes after intravenous administration of the compounds to be tested, 0.3 mL/mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, Germany; solution prepared with addition of 5% by weight of ethanol and stored in a water bath at 450C) administered intraperitoneally. The animals were placed individually in observation cages. A push button counter was used to record the number of pain-induced stretching movements ('writhing reactions' = straightening of the torso with stretching of the rear extremities) for 5-20 minutes after phenylquinone administration. The control was provided by animals which had received only physiological saline solution. All the compounds were tested at the standard dosage of 10 mg/kg. 99 GRA3394-WO-1 V. Hypothermia assay in mice Description of method: The hypothermia assay is carried out on male NMRI mice (weight 25-35 grams, breeder IFFA CREDO, Brussels, Belgium). The animals were kept under standardised conditions: light/dark cycle (06:00 to 18:00 light phase; 18:00 to 06:00 dark phase), RT 19-22"C, relative humidity 35-70%, 15 air exchanges per hour, air movement < 0.2 m/sec. The animals received standard feed (ssniff R/M maintenance, ssniff Spezialdisten GmbH, Soest, Germany) and tap water. Water and feed were withdrawn during the test. All the animals were used only once in the test. The animals had a habituation phase of at least 5 days. Acute administration of capsaicin (VR-1 agonist) leads to a drop in core body temperature in rats and mice by stimulation of heat sensors. Only specifically acting VR-1-receptor antagonists are capable of antagonising capsaicin-induced hypothermia. Morphine-induced hypothermia, in contrast, is not antagonised by VR-1 antagonists. This model is therefore suitable for identifying substances with VR-1 antagonistic properties from their action on body temperature. Core body temperature was measured using a digital thermometer (Thermalert TH-5, physitemp, Clifton NJ, USA). The sensor is here inserted into the animal's rectum. Body temperature is measured twice for each animal at an interval of approx. half an hour as an individual baseline value. One group of animals (n= 6 to 10) then receives intraperitoneal (i.p.) administration of capsaicin 3 mg/kg and vehicle (control group). Another group of animals receives the substance to be tested (i.v. or per os) and additionally capsaicin (3 mg/kg) i.p. The test substance is administered i.v. 10 minutes or per os 15 minutes before the capsaicin. Body temperature is then measured 7.5 / 15 and 30 min after capsaicin (i.v. + i.p.) or 15 / 30 / 60 /90 /120 min (per os + i.p.) after capsaicin. In addition, one group of animals is treated only with the test substance and one group only with vehicle. The measured values are evaluated and presented as a mean +/- SEM of the absolute values on a graph. The antagonistic action is calculated as a percentage reduction in capsaicin-induced hypothermia. 100 GRA3394-WO-1 VI. Neuropathic pain in mice Efficacy against neuropathic pain was investigated in the Bennett model (chronic constriction injury; Bennett and Xie, 1988, Pain 33: 87-107). NMRI mice weighing 16-18 g are provided under Ketavet-Rompun anaesthesia with three loose ligatures of the right ischial nerve. On the paw innervated by the damaged nerve, the animals develop hypersensitivity which, after one week's convalescence, is quantified over a period of approx. three weeks by means of a cold metal plate at 4 0 C (cold allodynia). The animals are observed on this plate for a period of 2 min. and the number of withdrawal responses by the damaged paw is measured. Relative to the preliminary value prior to administration of the substance, the action of the substance is determined at different occasions over a given period (for example 15, 30, 45, 60 min. after administration) and the resultant area under the curve (AUC) and/or the inhibition of cold allodynia at the individual measuring points is stated as a percentage action relative to the vehicle control (AUC) or to the initial value (individual measurement points). The size of the group is n=10, the significance of an antiallodynic action (*=p<0.05) is determined with reference to an analysis of variance with repeated measurement and post hoc Bonferroni analysis. The invention will be explained below with reference to a number of examples. These explanations are given merely by way of example and do not restrict the general concept of the invention. 101 GRA3394-WO-1 Examples: The yields of the compounds produced have not been optimised. All temperatures are uncorrected. The term "equivalents" means molar equivalents, "RT" means room temperature, "M" and "N" are concentrations stated in mol/l, "aq." means aqueous, "sat." means saturated, "soln." means solution, Other abbreviations: AcOH acetic acid DCM dichloromethane DMF N,N-dimethylformamide EDCI N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride EA ethyl acetate
H
2 0 water HOBt N-hydroxybenzotriazole MeOH methanol TEA triethylamine THF tetrahydrofuran The chemicals and solvents used were purchased from conventional suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood etc.) or synthesised by conventional methods known to a person skilled in the art. Silica gel 60 (0.0-0-0.063 mm) from E. Merck, Darmstadt, was used as the stationary phase for the column chromatography. Thin-layer chromatography was performed with pre-coated silica gel 60 F 254 HPTLC plates from E. Merck, Darmstadt. 102 GRA3394-WO-1 The mixture ratios for solvents, mobile solvents or for chromatographic investigations are always stated in volume/volume. Analysis was performed by mass spectroscopy and NMR. 1. General method of preparing amines of the general formula V-A Amines of the general formula V-A are prepared as illustrated in the following Scheme 1. Rk, U RK, U, RT u, RCH2) CN 1 (CH 2 ) CN 2 (CH 2 ) NH 2 CI ci R 40 -N R 41
R
40 NR41 VI-A VI-B V-A Scheme 1. Stage 1: Preparation of nitriles of the general formula VI-B Method A: Compounds of the general formula VI-A (1 equivalent), in which R , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are stirred with an amine of the general formula HNR 40
R
41 (6 equivalents) for 48 hours at RT. The reaction mixture is combined with 1 N hydrochloric acid and extracted repeatedly with EA. The aqueous phase is saturated with NaCl and then extracted again with EA. The combined organic phases are washed with 1 N hydrochloric acid and with a sat. aq. NaCl soln., dried over MgSO 4 and the solvent was removed under a vacuum. The following compound was produced using Method A. 103 GRA3394-WO-1 6'-tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-carbonitrile H N N / N CN N CI 1 H-NMR (CDC13) 8 7.65 (d, 1 H, J=7.9 Hz, Ar), 6.70 (d, 1 H, J=8.0 Hz, Ar), 4.45 (m, 2H, piperidine), 2.98 (m, 2H, piperidine), 1.75-1.24 (m, 5H, piperidine), 1.29 (s, 9H,
C(CH
3
)
3 ), 0.98 (d, 3H, J=5.9 Hz, CHCH 3 ) IR 2956, 2213, 1583, 1550, 1452, 1230, 965 cm-1 Method B: Compounds of the general formula VI-A (1 equivalent), in which R 8 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are stirred with an amine of the general formula HNR 40
R
41 (2 equivalents) and DBU [1,8-diaza bicyclo[5.4.0]undec-7-ene] (2 equivalents) in acetonitrile (7 mL per mmol of the compound of formula VI-A) for 12 hours at RT. The reaction mixture is extracted repeatedly with EA. The combined organic phases are washed with sat. aq. NaCl solution, dried over MgSO 4 and the solvent was removed under a vacuum. The residue is purified in each case by column chromatography (SiO 2 , different mixtures of hexane/EA). The following compounds were produced using Method B. 6-(trifluoromethyl)-2-(4-methylpiperidin-1 -yl)pyridine-3-carbonitrile CN
F
3 C N N 'H NMR (300 MHz, CDC13) 6 7.87 (d, 1H, J = 7.8 Hz), 6.95 (d, 1H, J = 7.8 Hz), 4.53 (m, 2H), 3.05 (m, 2 H), 1.78 (m, 2 H), 1.64 (m, 1 H), 1.29 (m, 2 H), 1.00 (d, 3 H, J = 6.6 Hz); IR (pur) 2926, 2852, 2218, 1590, 1497, 1456, 1324, 1237, 1186, 1147, 1082, 963 cm- 1 ; MS (FAB) m/z 270 (M+H) 104 GRA3394-WO-1 Stage 2: Method 1 Compounds of the general formula VI-B (5 mmol), in which R , R 40 , R 4 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, palladium on carbon (10%, 500 mg) and concentrated hydrochloric acid (3 mL) are dissolved in MeOH (30 mL) and exposed to a hydrogen atmosphere for 6 hours at RT. The reaction mixture is filtered through Celite and the filtrate is evaporated under a vacuum. The residue is purified by means of flash chromatography (SiO 2 , EA). Method 2: Compounds of the general formula VI-B (2 mmol), in which R', R 40 , R 4 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are dissolved in THF (10 mL, 10 mL) and BH 3
-S(CH
3
)
2 [2.0 M in THF, 3 mL, 3 equivalents] is added thereto. The reaction mixture is heated to reflux for 8 hours, aq. HCI (2 N) is added thereto and the reaction mixture is again heated to reflux for 30 minutes. The reaction mixture is combined with aq. sodium hydroxide solution (2N) and washed with EA. The combined organic phases are washed with a sat. aq. NaCl solution and dried over magnesium sulfate. The solvent is removed under a vacuum and the residue is purified by column chromatography (SiO 2 , different mixture of dichloromethane and MeOH as mobile solvent). The following compounds were obtained using Method 2. (6-(trifluoromethyl)-2-(4-methylpiperidin-1 -yI)pyridin-3-yl)methanamine
NH
2
F
3 C N N 'H NMR (300 MHz, CDCl 3 ) 6 7.89 (d, 1 H, J = 7.8 Hz), 7.33 (d, 1H, J = 7.8 Hz), 3.88 (s, 2H), 3.39 (m, 2 H), 2.83 (m, 2 H), 1.75 (m, 2 H), 1.55 (m, 1 H), 1.38 (m, 2 H), 1.00 (d, 3 H, J = 6.6 Hz); MS (FAB) m/z 274 (M+H) 105 GRA3394-WO-1 C-(6'-tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-yl) methylamine N CN BH 3 SMe 2 in THF(2.OM) N / NH 2 N THF N 'H-NMR (CDCl 3 ) 5 7.48 (d, 1H, J=7.7Hz, Ar), 6.90 (d, 1H, J=7.7Hz, Ar), 3.82 (s, 2H,
CH
2
NH
2 ), 3.38 (m, 2H, piperidine), 2.81 (m, 2H, piperidine), 1.73-1.28 (m, 5H, piperidine), 1.31 (s, 9H, C(CH 3
)
3 ), 0.98 (d, 3H, J=6.4Hz, CHCH 3 ) IR 3363, 2954, 1571, 1451, 1400, 1372, 1234, 960 cm 1 2. General method of preparing amines of the general formula V-E Amines of the general formula V-E are prepared as illustrated in the following Scheme 2. R8Uj R UT
R
8 U T )CN C) mCN 2 V-" (CH 2 )m NH 2 CI
(CH
2 )6(H) Cl S'R43 SIR43 VI-A VI-F V-E Scheme 2. Stage 1: Synthesis of 2-(cyclohexylthio)-6-(trifluoromethyl)nicotinonitrile CN
F
3 C N S 1.3 equivalents of NaH (4.9 g, 0.124 mol) were dissolved in 50 mL DMF under a nitrogen atmosphere. After the addition of 1.2 equivalents of cyclohexanethiol (14.2 mL, 0.116 mol) stirring was performed at RT for 1.5 h. The resultant suspension was cooled to 100C and 1 equivalent of 2-chloro-6-(trifluoromethyl)nicotinonitrile (20 g, 106 GRA3394-WO-1 0.096 mol) in 50 mL DMF was added dropwise and stirred for 2 h at RT. The reaction mixture was combined with sat. aq. NH 4 CI soln., diluted with 1 L of water and extracted repeatedly with EA (3 x 200 mL). The combined organic phases were washed with a sat. aq. NaCl soin., dried over MgSO 4 and concentrated under a vacuum. Purification performed by column chromatography (silica gel, 100-200 mesh, eluent: 2% EA in hexane) resulted in 26 g (93.8%) of product. 1 H NMR (300 MHz, CDCl 3 ) 8 7.94 (d ,1 H, J = 7.9 Hz), 7.34 (d, 1 H, J = 7.9 Hz), 4.00 (m, 1 H),1.90-2.14 (m, 2 H), 1.42-1.88 (m, 8 H) IR (neat) 2930, 2854, 2232, 1643, 1573,1447, 1334,1245, 1186, 1149,1107, 851 cm MS (FAB ) m/z 287 (M+H) Stage 2: Synthesis of (2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yI)methanamine dihydrochloride The nitrile (26 g, 0.091 mol) was dissolved under a nitrogen atmosphere in 600 mL of THF and cooled to 5 0 C. BH 3 dimethyl sulfide (13.78 g, 0.182 mol) was added dropwise and refluxed for 20 h. After cooling to 50C, the reaction batch was combined with 100 mL of MeOH and stirred for 15 minutes at RT. Then di-tert-butyl dicarbonate (29.7 g, 0.136 mol) was added and stirring was performed for 30 min at RT. After removal of the solvent under a vacuum, the crude product was purified by column chromatography (silica gel, 100-200, mesh, eluent: 10% EA in hexane) and 23.4 g (66%) of product was obtained. The crude product was dissolved in 120 mL sat. HCI-dioxane soln. and stirred for 6 h at RT. After removal of the solvent under a vacuum, the solid was washed with 10% EA in hexane (2 x 100 mL) and filtered out. Yield: 17 g (88.8%) 'H NMR (DMSO-d 6 , 400 MHz): 6 8.8 (s,2H), 8.05 (d,1 H), 7.76 (d,1 H), 4.01 (s, 1 H), 3.86-3.93 (m,1H), 2.02-2.08 (m,2H), 1.71-1.74 (m,2H), 1.40-1.60 (m,6H). 107 GRA3394-WO-1 3. General method of preparing amines of the general formula V-B Amines of the general formula V-B are prepared as illustrated in the following Scheme 3.
R
8 , R 8 U~ R 8 U~ )-CN 1 CN 2 R (OH 2 ' mNH 2 CI (CH (CH 2 )m C1 0 ,R42 0 ,R42 VI-A VI-C V-B Scheme 3. Stage 1: Preparation of nitriles of the general formula VI-C Compounds of the general formula VI-A (1 equivalent), in which R , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are stirred with an alcohol of the general formula HO-R 42 (3.5 equivalents) and DBU [1,8-diaza bicyclo[5.4.0]undec-7-ene] (3.5 equivalents) in acetonitrile (7 mL per mmol of the compound of formula VI-A) for 12 hours at RT. The reaction mixture is extracted repeatedly with EA. The combined organic phases are washed with sat. aq. NaCl solution, dried over MgSO 4 and the solvent was removed under a vacuum. The residue is purified in each case by column chromatography (SiO2, different mixtures of hexane/EA). Method 2: Compounds of the general formula VI-C (2 mmol), in which R", R 42 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are dissolved in THF (10 mL, 10 mL) and BH 3
-S(CH
3
)
2 [2.0 M in THF, 3 mL, 3 equivalents] is added thereto. The reaction mixture is heated to reflux for 8 hours, aq. HCl (2 N) is added thereto and the reaction mixture is again heated to reflux for 30 minutes. The reaction mixture is combined with aq. sodium hydroxide solution (2N) and washed with EA. The combined organic phases are washed with a sat. aq. NaCl solution and dried over magnesium sulfate. The solvent is removed under a vacuum and the residue is purified by column chromatography (SiO 2 , different mixture of dichloromethane and methanol as mobile solvent). 108 GRA3394-WO-1 Method 3: Compounds of the general formula VI-C (1.5 mmol), in which R", R 4 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are dissolved in diethyl ether (3 ml) and a suspension of lithium aluminium hydride (3 mmol) in ether (5 ml) is added slowly dropwise at 0*C. The reaction mixture is heated to reflux for 4 hours and methanol and then 1 N aq. NaOH solution are added slowly dropwise at 0*C. The reaction mixture is diluted with methanol and filtered through Celite. The solvent is removed under a vacuum and the residue is purified by column chromatography (SiO 2 , different mixture of dichloromethane and methanol as mobile solvent). 4. General method of preparing amines of the general formula V-C Amines of the general formula V-C are prepared as illustrated in the following Scheme 4.
R
8 U R 8 U1 R 8 U, R)CN .CN 2 Ra U (CH 2 )m NH 2 CI
(CH
2 )m 'C C2 (CH 2 )m NH2C1*~ C1 I I VI-A Vl-D V-C Scheme 4. Stage 1: Preparation of nitriles of the general formula VI-D Compounds of the general formula VI-A (1 equivalent), in which R , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are dissolved with bis(triphenylphosphine)palladium dichloride (7 mol%) and copper(l) iodide (14 mol%) in 1-methyl-2-pyrrolidinone (7 ml per mmol of compound of the general formula VI-A). After 10 minutes the alkyne of the general formula HCaC-R 3 8 (3.5 equivalents) and N, N-diisopropylethylamine (2 equivalents) are added and the reaction mixture is stirred for 12 h at a temperature of between 90 and 110*C. The reaction mixture is filtered through Celite and extracted repeatedly with EA. The combined organic 109 GRA3394-WO-1 phases are washed with sat. aq. NaCl solution, dried over MgSO 4 and the solvent was removed under a vacuum. The residue is purified in each case by column chromatography (SiO 2 , different mixtures of hexane/EA). 5. General method of preparing amines of the general formula V-D Amines of the general formula V-D are prepared as illustrated in the following Scheme 5. R8 R 8 U "TR 8 U '' a ?'-
-
(CH2) CN (CH 2 )m NH 2 CI CI R38 R38
R
3 8= Ary, Heteroaryl, Cycloalkenyl VI-A VI-E V-D Scheme 5. Stage 1: Preparation of nitriles of the general formula VI-E Compounds of the general formula VI-A (1 equivalent), in which R , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are stirred with palladium dichloride (5 mol%) and a compound of the general formula R 38
-B(OH)
2 (2 equivalents), in which R 38 denotes aryl, heteroaryl or cycloalkenyl, in a solvent mixture of toluene/dioxane/2 N aq. sodium carbonate solution (20 mL per 1 mmol compounds of the general formula VI-A). The reaction mixture is heated to reflux for 12 h and filtered through Celite. The combined organic phases are dried over magnesium sulfate and the solvent is removed under a vacuum. The residue is purified by column chromatography (SiO 2 , different solvent mixtures of hexane and EA). Stage 2: Method 1 Compounds of the general formula VI-E (5 mmol), in which R , R 38 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, palladium on carbon (10%, 500 mg) and concentrated hydrochloric acid (3 mL) are dissolved in MeOH (30 mL) 110 GRA3394-WO-1 and exposed to a hydrogen atmosphere for 6 hours at RT. The reaction mixture is filtered through Celite and the filtrate is concentrated under a vacuum. The residue is purified by means of flash chromatography (SiO 2 , EA). Method 2: Compounds of the general formula VI-E (2 mmol), in which R 8 , R 38 , U, T and V have the above-stated meanings and m denotes 0, 1, 2 or 3, are dissolved in THF (10 mL, 10 mL) and BH 3
-S(CH
3
)
2 [2.0 M in THF, 3 mL, 3 equivalents] is added. The reaction mixture is heated to reflux for 8 hours, aq. HCI (2 N) is added thereto and the reaction mixture is again heated to reflux for 30 minutes. The reaction mixture is combined with aq. sodium hydroxide solution (2N) and washed with EA. The combined organic phases are washed with a sat. aq. NaCl solution and dried over magnesium sulfate. The solvent is removed under a vacuum and the residue is purified by column chromatography (SiO 2 , different mixture of dichloromethane and methanol as mobile solvent). 6. Method of preparing carboxylic acids of the general formula VII 6.1 Preparation of 2-(benzo[d]oxazol-5-yl)propanoic acid oO 1 o NO 2 2 o NH2 0Y OH O 0H O 0H 3 -o 4 5 HO N I 01 Stage 1: Synthesis of methyl-2-(4-hydroxy-3-nitrophenyl) acetate Methyl-2-(4-hydroxyphenyl) acetate (2.0 g, 12.0 mmol) was dissolved in acetic acid (15 ml) and nitric acid (60-62%, 1.27g, 12.1 mmol) was added at RT. The reaction mixture was stirred for 30 minutes at RT, poured into ice water (100 ml) and extracted with EA. The organic phase was dried over MgSO 4 , the solvent removed under a vacuum and the residue purified by means of column chromatography (n hexane/EA = 4:1). 111 GRA3394-WO-1 Stage 2: Synthesis of methyl-2-(3-amino-4-hydroxyphenyl) acetate Methyl-2-(4-hydroxy-3-nitrophenyl) acetate (2.31 g, 10.9 mmol) was dissolved in THF (20 mL) and MeOH (20 mL) and 10% palladium on carbon (210 mg) was added slowly at RT. The reaction mixture was hydrogenated for 2 h at 39 psi hydrogen pressure, filtered through Celite and washed with MeOH. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n hexane/EA = 2:1). Stage 3: Synthesis of methyl-2-(benzo[d]oxazol-5-yl) acetate Methyl-2-(3-amino-4-hydroxyphenyl) acetate (1.39 g, 7.67 mmol) was combined at RT with triethyl orthoformate (10 ml). The reaction mixture was heated to reflux for 12 h and then cooled to RT. Water (70 mL) was added thereto and the reaction mixture was extracted with EA. The combined organic phases were dried over MgSO 4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA = 2:1). Stage 4: Synthesis of methyl-2-(benzo[d]oxazol-5-yl) propanoate Methyl-2-(benzo[d]oxazol-5-yl) acetate (0.90 g, 4.71 mmol) was dissolved in DMF (5 ml) and combined at 0*C with sodium hydride (198 mg, 4.95 mmol) and methyl iodide (661 mg, 4.65 mmol). The reaction mixture was stirred for 30 min at 0*C and then for 1 h at RT. The reaction mixture was combined with water (70 ml) and extracted with EA. The combined organic phases were dried over MgSO 4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA = 4/1). 1 H-NMR(CDC1 3 ) 8 8.10 (s, 1H, Ar), 7.74 (d, 1H, J=1.7Hz, Ar), 7.54 (d, 1H, 8.4Hz, Ar), 7.35 (dd, 1H, J=8.6, 1.8Hz, Ar), 3.87 (q, 1H, J=7.3Hz, CHCH 3 ), 3.67 (s, 3H, OCH 3 ), 1.57 (d, 3H, J=7.1Hz, CHCH 3 ) IR 2982, 1735, 1517, 1437,1248, 1201, 1170, 1067 cm 1 Stage 5: Synthesis of 2-(benzo[d]oxazol-5-yl)propanoic acid Methyl-2-(benzo[d]oxazol-5-yl) propanoate (425 mg, 2.07 mmol) was dissolved in THF (8 ml) and water (8 ml). LiOH*H 2 0 (93 mg, 2.21 mmol) was added thereto at RT. The reaction mixture was stirred for 40 h at RT, combined with water (25 ml) and adjusted with acetic acid to a pH value of 3. The reaction mixture was extracted with 112 GRA3394-WO-1 DCM and the combined organic phases were dried over MgSO 4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (DCM/MeOH = 15:1). 1H-NMR (CD 3 0D) 6 8.46 (s, 1H, Ar), 7.70 (d, 1H, J=1.7Hz, Ar), 7.61 (d, 1H, 8.0Hz, Ar), 7.42 (dd, 1H, J=8.6, 1.8Hz, Ar), 3.87 (q, 1H, J=7.1Hz, CHCH 3 ), 1.51 (d, 3H, J=7.lHz, CHCH 3 ) 6.2 Preparation of 2-(benzo[d]oxazol-6-yl)propanoic acid The compound 2-(benzo[d]oxazol-6-yl)propanoic acid was produced in a similar manner to the synthesis of 2-(benzo[d]oxazol-5-yl)propanoic acid (see 6.1) starting from 2-(3-hydroxyphenyl)acetic acid. 1 H-NMR (CD 3 0D) 6 8.44 (s, 1H, Ar), 7.67 (m, 2H, Ar), 7.38 (dd, 1H, J=8.3, 1.5Hz, Ar), 3.88 (q, 1H, J=7.1Hz, CHCH 3 ), 1.51 (d, 3H, J=7.1Hz, CHCH 3 ) HO OH a EtO OH b EtO OH c O O NO 2
NH
2 EtO O d EtO lO e HO 0 0 />NI/> Ii-1 > O N N N 0 NN a. HNO 3 , AcOH, H 2 S0 4 (kat.), EtOH, 26%; b. 10% Pd/C, H 2 , THF/EtOH, 85%; c. CH(OEt) 3 , 99%; d. NaH, CH 3 1, DMF, 56%; e. LiOH H 2 0, THF/H 2 0, 97% [Key: kat. = cat.] 6.3 Preparation of 2-(benzo[d]oxazol-7-yl)propanoic acid The compound 2-(benzo[d]oxazol-7-yl)propanoic acid was produced in a similar manner to the synthesis of 2-(benzo[d]oxazol-5-yl)propanoic acid (see 6.1) starting from 2-(2-hydroxyphenyl)acetic acid. 113 GRA3394-WO-1 H H H HO a EtO b EtO NO2 C O0 0 EtO _ - NH 2 d EtO N e EtO N 0 _ HO N 0 a. H 2
SO
4 (kat.), EtOH, 94%; b. HNO 3 , AcOH, 35%; c. 10%Pd/C, H 2 , THF/EtOH, 88%; d. CH(OEt) 3 , 96%; e. NaH, CH 3 1, DMF, 80%; f. LiOH H 2 0, THF/H 2 0, 98% [Key: kat. = cat.] 6.4 Preparation of 2-(7-methoxybenzo[d]oxazol-5-yl)propanoic acid The compound 2-(7-methoxybenzo[d]oxazol-5-yl)propanoic acid was produced in a similar manner to the synthesis of 2-(benzo[d]oxazol-5-yl)propanoic acid (see 6.1) starting from ethyl-2-(4-hydroxy-3-methoxyphenyl) acetate. EtOt a O
NO
2 b EtO
NH
2 C 0OH 0OH 0 OH
OCH
3
OCH
3
OCH
3 EtO d EtO N HO o* 0 0
OCH
3
OCH
3
OCH
3 a. HNO 3 , AcOH, 48%; b. 10% Pd/C, H 2 , THF/EtOH, quantitativ; c. Triethylorthoformiat, 99%; d. NaH, CH 3 1, DMF, 52%; e. LiOH H 2 0, THF/H 2 0, 74% [Key: quantitativ = quantitative; Triethylorthoformiat = triethyl orthoformiate] 114 GRA3394-WO-1 6.5 Preparation of 2-(benzo[d]oxazol-4-yl)propanoic acid The compound 2-(benzo[d]oxazol-4-yl)propanoic acid was produced in a similar manner to the synthesis of 2-(benzo[d]oxazol-5-yl)propanoic acid (see 6.1) starting from 2-(3-hydroxyphenyl)acetic acid. 1
H-NMR(CD
3 0D) 8.42 (s, 1 H, Ar), 7.55 (dd, 1 H, J=7.9, 1.1Hz, Ar), 7.37 (m, 2H, Ar), 4.38 (q, 1H, J=7.1Hz, CHCH 3 ), 1.57 (d, 3H, J=7.4Hz, CHCH 3 )
NO
2
NH
2 HO OH a EtO OH b EtO OH c O 0 0 Yo0 . N:-\ ,_N \ N-= EtO d EtO e HO O O 0 . 0 a. HNO 3 , AcOH, H 2
SO
4 (kat.), EtOH, 14%; b. 10% Pd/C, H 2 , THF/EtOH, 90%; c. CH(OEt) 3 , 90%; d. NaH, CH 3 1, DMF, 69%; e. LiOH H 2 0, THF/H 2 0, 67% [Key: kat. = cat.] 6.6a. General method of preparing (iso)quinolinpropanoic acids (cf. Examples 49, 64-68) 0 0
NH
2 o 1 2 3 N NN N O 0 0 o~'N 4 HO N N N 115 GRA3394-WO-1 Step 1: A solution of the starting compound (10.6 mmol) in hydrochloric acid (6 N, 20 mL) is cooled to 0 *C and solution of sodium nitrite (730 mg, 10.6 mmol) in water (10 mL) is added dropwise. The resultant solution is added at a constant temperature of 0*C to a solution of potassium iodide (7.3 g, 44 mmol) in water (15 mL). The reaction mixture is heated to room temperature, stirred for three hours and then extracted with ethyl acetate. The combined organic phases are washed consecutively with a 10% strength sodium thiosulphate solution and a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure in order to thus obtain the iodised isoquinolin as a solid which can be used directly in the next step without further purification. Step 2: Distilled diethyl malonate (304 pL, 2.00 mmol) and aryl iodide (1.00 mmol) are added to a mixture of copper(l) iodide (9.5 mg, 5.0 mol%), 2-picolinic acid (12.3 mg, 10.0 mol%), caesium carbonate (0.98 g, 3.0 mmol) and 1,4-dioxan (10 ml) and the reaction mixture is stirred for 7 hours at 70 0C. The reaction mixture is then heated to room temperature and extracted with ethyl acetate (20 mL x 3) and saturated ammonium chloride solution (10 mL). The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The oil obtained in this manner can be purified by means of flash chromatography on silica gel in order to obtain the desired a-aryl malonate. Step 3: Sodium hydride (1.1 mmol) and methyl iodide (1 mmol) are added to a solution, which is cooled to 0 OC, of a-aryl malonate (1 mmol) in DMF (10 mL) and the reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture can then be concentrated under reduced pressure and the residue purified using a mixture of hexane and ethyl acetate (4:1) as an eluent by means of flash chromatography on silica gel. Step 4: A mixture of a-arylmethyl malonate (1 mmol) and sodium hydroxide (2 mmol) in 80% strength aqueous ethanol is heated under reflux for 6 hours. The reaction mixture is neutralised with hydrochloric acid (1 N) and subsequently extracted with ethyl acetate (20 mL x 3). The combined organic phases are concentrated under reduced pressure. The residue obtained in this manner can be purified using a 116 GRA3394-WO-1 mixture of hexane and ethyl acetate (1:1) by means of flash chromatography on silica gel in order thus to obtain the desired (iso)quinolinpropanoic acids. 117 GRA3394-WO-1 6.6b. General method of preparing (iso)quinolinpropanoic acids Br a b N HO 0 a. Kalium-allyltrifluorboran, Pd(OAc) 2 , D-t-BPD, K 2
CO
3 , THF/H 2 0; b. KMnO 4 , NalO 4 [Key: Kalium-allyltrfluorboran = Potassium-allyltrifluoroborane] General method for reaction catalysed by a Pd(OAc) 2 /D-t-BPF complex of aryl halides with potassium-allyltrifluoroborane In an analogous manner to Yamamoto, Y. et al., Chem. Lett. (2006), 35, 7, 704-705, potassium-allyltrifluoroborane (2.5 mmol), Pd(OAc) 2 (0.03 mmol, 3 mol%), D-t-BPF (0.036 mmol) and K 2
CO
3 (3 mmol) are provided in a flask under a protective gas atmosphere. After addition of THF (5 mL) and of the corresponding aryl-bromide (1 mmol), the reaction mixture is boiled for 22 h under reflux. After removal of the solvent, the obtained residue is purified by means of column chromatography (a). As described in Kawatsura M. et al., Tetrahedron (2000), 56, 15, 2247-2258, the alkene obtained can now be boiled to produce propanoic acid. For this purpose, the obtained residue (1 mmol) is dissolved in t-BuOH (18 mL) and water (45 mL), KMnO 4 (2.5 mmol), NalO 4 (16 mmol) and K 2
CO
3 (6.5 mmol) are added and the reaction mixture is adjusted to pH 8 with 3 N aq NaOH. After 2 hours of stirring at room temperature, the mixture is acidifed with conc. HCI to pH 1 and the MnO 2 is reduced with sodium hydrogen sulphite. The reaction mixture is now combined with ether, the phases separated and the organic phase extracted with 3 N aq NaOH. The aqueous phase is acidified with conc. HCI and likewise extracted with ether. The combined organic phases are dried over MgSO4 and concentrated in a vacuum (b). 118 GRA3394-WO-1 6.7 Preparation of benzooxocyclic propionic and acetic acids (cf. Examples 9, 58-63) Method for benzenedioxol-propionic acid (Example 60) O I C1 Br 0> a O O b HO0> a. NBu 4
BF
4 , NiBr 2 bipy, DMF, 25*C, 9% b. LiOH, THF/H 2 0, reflux, 12 h, 97% 4-bromo-1,2-(methylenedioxy)benzene (2 g, 10 mmol) was stirred together witrh ethylchloropropionate (1.6 mL, 13 mmol) under a nitrogen atmosphere at room temperature in 15 ml DMF. For the purpose of activation, (1.1 g, 20 mmol) Mn, followed by 2,2'-bipyridin)nickel-(II)-dibromide (0.26 g, 0.7 mmol) and TFA (20 mL) were then added. The reaction mixture was stirred for 1.5 h at 50 *C. After cooling of the reaction mixture, hydrolysis was carried out with 25 mL 1 N HCI, the mixture extracted 3 x with 25 mL diethyl ether, the combined organic phases washed with 25 mL water and 25 mL sat. NaCl solution, dried over MgSO 4 and concentrated in a vacuum. The resultant precipitate was removed by suction and washed with diethyl ether. After purification by means of column chromatography (n hexane/tert-BME = 9/1), it was possible to obtain 0.198 g of product (9% of theory) as a white solid. The propionate (180 mg, 0.81 mmol) was dissolved in a mixture of THF (1.6 mL, 20 mmol) and water (0.8 mL, 45 mmol). After addition of LiOH (0.058 g, 2.43 mmol), the reaction mixture was refluxed overnight. For processing, 25 mL water and 25 mL diethyl ether were added to the mixture and the resultant phases separated. The aqueous phase was acidified with HCI and extracted 3x with in each case 25 mL dichloromethane. After purification of the organic phases, drying over MgSO 4 and concentration in a vacuum, it was possible to obtain the propionic acid in a 97% yield (0.150 g). 119 GRA3394-WO-1 In an analogous manner to the procedures described here, further benzooxocyclic propanoic acids can be prepared: 2-(benzo[d][1,3]dioxol)propanoic acids (i), 2-(2,3-dihydrobenzo[b][1,4]dioxin)propanoic acids (ii), 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin)propanoic acids (iii) and HO HO HO 0 0 0 The corresponding benzooxocyclic acetic acids can also be made accessible by means of this method: 2-(benzo[d][1,3]dioxol)acetic acids (i), 2-(2,3-dihydrobenzo[b][1,4]dioxin)acetic acids (ii), 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin)acetic acids (iii) and >N 0 0 HO 0 HO 0 HO 0 0 0 120 GRA3394-WO-1 6.8. Alternative possibilities for the preparation of aryl propionic acids from aryl bromides Br a b HO R Q1 1!5-K R I R a. THF, reflux, 6 h b. LiOH, THF/H 2 0, reflux, 12 h Preparation of the catalyst In order to prepare the palladium(0) catalyst, Pd(dppf)C1 2 (110 mg, 0.15 mmol), dppf (83 mg, 0.15 mmol) and butyl lithium in hexane (0.3 mmol) are added to a dry THF solution (10 ml). The reaction mixture is stirred for 1 min at room temperature and used directly in the next reaction as a palladium catalyst. General method for palladium-catalysed reaction of aryl halides with (E)-1-methoxy 1 -trimethylsiloxypropane The freshly prepared palladium(0) catalyst in dry THF (10 mL) is added under an argon atmosphere to 90% TIOAc (1.78 g, 6 mmol) in dry THF (20 mL). After 5 minutes of stirring the reaction mixture at room temperature, the aryl halide (3 mmol) in dry THF (10 mL) and (E)-1-methoxy-1-trimethylsiloxypropane (0.96g, 6 mmol) are added and refluxed for 4 - 24 h. After removal of the solvent in a vacuum, the residue is absorbed and filtered off in diethyl ether and water. The filtrate is extracted with diethyl ether, the combined organic phases dried over MgSO 4 , the diethyl ether removed in a vacuum and the obtained residue is separated by column chromatography. 121 GRA3394-WO-1 6.9 Alternative method for the preparation of 2-(1 H-indazol)propanoic acids (cf. Examples 44-46, 48, 69-72) a, b C r-~ d Br N ,. Br N2*BF4- c Br N NH N -BF HN Br HON \\N N N f N N N HON Ts 0 Ts 0 a. HBF 4 aq 50%; b. NaNO 2 aq, 0 *C; c. AcOK, 18-crown-6, CHCl3. rt; d. TsCI, TEA, CH 2 Cl 2 ; e. Ethylchlorpropionat, NBu 4
BF
4 , NiBr 2 bipy DMF, rt; f. TMSCI, Nal, CH 3 CN, reflux [Key: Ethylchlorpropionat = Ethylchloropropionate] Indazol derivatives can be prepared as explained in the above scheme. On the basis of the corresponding bromo-methylaniline, the desired bromo-1-H-indazol can be obtained in accordance with Boulouard M. et. al., Bloorganic Medicinal Chemistry Letters (2007), 17, 3177-3180 (a, b und c). The 1 H-indazol of the compound can be protected (d) with a tosyl group in accordance with a method known to the person skilled in the art. Below, this tosyl-protected bromo-indazol can be reacted in accordance with Durandetti M. et al., Tetrahedron (2007), 63, 1146-1153 with ethylchloropropionate to yield indazol-propanoic acid ester (e). In order to obtain the desired indazol-propanoic acid, the removal of protection from the propanoic acid function and from the 1-H-indazol is carried out as described in Sabitha G. et al., Tetrahedron Letters (1999), 40, 1569-1570 (f). 0 H N.a N NN bN Br a Br NO Br F F H a. NH 2 0CH 3 *HCI, K 2
CO
3 ; b. NH 2
NH
2 Starting from bromo-fluorophenylethanons, Lukin K. et al. J. Org. Chem. (2006), 71, 21, 8166-8172 describe an alternative procedure for the preliminary stage of the bromo-1-H-indazols (a, b). 122 GRA3394-WO-1 6.10. General method for preparing 2-(1-phenyl-1H-indazol)propanoic acids (cf. Example 73) N 0I 0 N O H 2 N H a b N R C N R d HO N R O 0 a. HOAc, H 2 0, 2 min, 200 *C, pwave; b. 2-Brompropanssure, Zn, I, HgCl2, Benzen; c.S, 190 *C, 1 h, Raney-Nickel; d. aq NaOH, reflux, 4 h [Key: 2-Brompropansaure = 2-bromopropanoic acid, Benzen = benzene] Phenylindazol-propanoic acids can be prepared in an analogous manner to US3657270 (b-d). The educts required for this, correspondingly substituted 6,7 dihydro-1-phenyl-indazol-4(5H)-one, can be obtained as described in Molteni V. et al., Synthesis (2002), 12, 1669-1674 in a three-component reaction with microwave support (a). 123 GRA3394-WO-1 6.11. General method for preparing 2-(indolin)propanoic acids (cf. Examples 74-77) Br a Br b s c HO 0 HH Ts 0" Ts 0 a. TsCI, TEA, CH 2 Cl 2 ; b. Ethylchlorpropionat, NBu 4
BF
4 , NiBr 2 bipy, DMF, rt; c. TMSCI, Nal, CH 3 CN, reflux [Key: Ethylchlorpropionat = Ethylchloropropionate ] Starting from the corresponding bromo-indolin, according to the method known to the person skilled in the art, a tosyl protective group is introduced (a). In an analogous manner to that described in Durandetti M. et al., Tetrahedron (2007), 63, 1146-1153, reaction is carried out with ethylchloropropionate to yield indolin-propanoic acid ester (b). In order to obtain the desired 2-(indolin)-propanoic acid, protection is removed from the compound as described in Sabitha G. et al., Tetrahedron Letters (1999), 40, 1569-1570 (c). In an analogous manner to the procedure described here, corresponding 2-(1 H-indol)propanoic acids (i), 2-(2-oxoindolin)propanoic acids (ii), 2-(1,2,3,4-tetrahydroquinolin) propanoic acids (iii) and 2-(2-oxo-1,2,3,4-tetrahydroquinolin)propanoic acids (iv) can be obtained. HO N HO N HO N HO N 0 0 H o H ii iii iv 7. General method of reacting amines of the general formulae V or X with carboxylic acids of the general formula VII Method A: The acid of the general formula VII (1 equivalent), the amine of the general formulae V or X (1.2 equivalents) and EDCI (1.2 equivalents) are stirred in DMF (10 mmol acid 124 GRA3394-WO-1 in 20 mL) for 12 hours at RT and then water is added thereto. The reaction mixture is extracted repeatedly with EA, the aqueous phase is saturated with NaCl and then re extracted with EA. The combined organic phases are washed with 1 N hydrochloric acid and a sat. aq. NaCl soln., dried over MgSO 4 and the solvent is removed under a vacuum. The residue is purified by means of flash chromatography (SiO 2 , EA/hexane 1:2). Method B: The acid of the general formula VII (1 equivalent) and the amine of the general formulae V or X (1.1 equivalents) are dissolved in DCM (1 mmol acid in 6 mL) and combined at 00C with EDCI (1.5 equivalents), HOBt (1.4 equivalents) and triethylamine (3 equivalents). The reaction mixture is stirred for 20 h at RT and purified by means of column chromatography (n-hexane/EA = 2:1). The following exemplary compounds were obtained according to the above-stated Method B. Exemplary compound 1: 2-benzooxazol-5-yl-N-(4-tert-butyl-benzyl)-propionamide H 0 1 H-NMR(CDCl 3 ) 8 8.10 (s, 1H, Ar), 7.74 (d, 1H, J=1.7Hz, Ar), 7.56 (d, 1H, J=8.4Hz, Ar), 7.38 (dd, 1 H, J=8.6, 1.8Hz, Ar), 7.30 (d, 2H, J=8.4Hz, Ar), 7.09 (d, 2H, J=8.4Hz, Ar), 5.64 (bs, NH), 4.37 (m, 2H, NHCH 2 Ar), 3.72 (q, 1H, J=7.1Hz, COCH), 1.61 (d, 3H, J=7.1Hz, CHCH 3 ), 1.28 (s, 9H, C(CH 3
)
3 ) Synthesis of exemplary compound 2: 2-benzooxazol-6-yl-N-(4-tert-butyl-benzyl)-propionamide 125 GRA3394-WO-1 NN 'H-NMR(CDCl 3 ) 68.02 (d, 1H, J=2.OHz, Ar), 7.07 (dd, 1H, J=8.3, 1.7Hz, Ar), 7.54 (s, 1 H, Ar), 7.25 (m, 3H, Ar), 7.04 (d, 2H, J=7.0Hz, Ar), 5.79 (bs, NH), 4.32 (m, 2H,
NHCH
2 Ar), 3.67 (q, 1H, J=7.1Hz, COCH), 1.55 (d, 3H, J=7.1Hz, CHCH 3 ), 1.23 (s, 9H, C(CH 3
)
3 ) IR 3296, 2963, 1649,1518, 1479, 1434,1247, 1067 cm-1 Mass (FAB) m/z 337 [M+H]* Synthesis of exemplary compound 3: 2-benzooxazol-7-yI-N-(4-tert-butyl-benzyl)-propionamide NN H S N N N H-NMR(CDCl 3 ) 6 8.07 (s, 1H, Ar), 7.71 (m, 1H, Ar), 7.39-7.28 (m, 4H, Ar), 7.06 (d, 2H, J=8.4Hz, Ar), 5.74 (bs, NH), 4.38 (m, 2H, CH 2 NH), 4.06 (q, 1 H, J=7.1 Hz,
CHCH
3 ), 1.68 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.29 (s, 9H, C(CH 3
)
3 ) Mass (FAB) m/z 337 [M+H]* Synthesis of exemplary compound 4: a) 2-(4-aminophenyl)propanoic acid HO N 10% Pd/C, H 2 HO 0 NO2 THF:EtOH=1:1 0
NH
2 2-(4-nitrophenyl)propans ure im Handel erh~ltlich [Key: propansaure = propanoic acid, im Handel erhaitlich = commercially available] THF/EtOH (1:1, 100 ml) and subsequently 2-(4-nitrophenyl)propanoic acid (10 g, 51.2 mmol) and 10% palladium on carbon (0.87 g) were added into the flask at room 126 GRA3394-WO-1 temperature. The reaction mixture was hydrogenated and stirred for 1 h at 45 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. White or light black solid, yield: quantitative. b) 2-(4-amino-3-nitrophenyl)propanoic acid HO HNO 3 HO : NO 2 O
NH
2 AcOH 0
NH
2
HNO
3 (60%, 5.66 g) was added to a solution of 2-(4-aminophenyl)propanoic acid (8.45 g, 51.2 mmol) in AcOH (70 ml) at room temperature. The reaction mixture was boiled for 4 h under reflux and subsequently cooled to room temperature. The mixture was poured into ice water (200 ml) and extracted with CH 2
C
2 .The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. c) Ethyl 2-(4-amino-3-nitrophenyl)propanoate HO N02 H 2
S
4 EtO NO 2 0
NH
2 EO H EtOH (200 ml) and sulphuric acid in a catalyst quantity (1 ml) were added into the flask with 2-(4-amino-3-nitrophenyl)propanoic acid residue at room temperature. The reaction mixture was boiled for 6 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. Light yellow oil, yield: 17.4% (two steps) d) Ethyl 2-(3,4-diaminophenyl)propanoate EtO NO 2 10% Pd/C, H 2 EtO s NH 2 SNH2 THF:EtOH=1:1 0 NH 2 127 GRA3394-WO-1 THF/EtOH (1:1, 50 ml) and subsequently ethyl 2-(4-amino-3-nitrophenyl)propanoate (2.12 g, 8.90 mmol) and 10% palladium on carbon (220 mg) were added into the flask at room temperature. The reaction mixture was hydrogenated and stirred for 3 h at 45 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4-1:2) as the eluent on silica gel. Yellow oil, yield: 74.5% e) 2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-5-yl)propanoate H EtO N NH 2 CDI, DBU EtO N
CH
2
CI
2 I- N
NH
2 0H 1,1'-carbonydiimidazol (189 mg) and DBU (330 mg, in CH 2
CI
2 (4 ml)) were added at room temperature to a solution of ethyl 2-(3,4-diaminophenyl)propanoate (217 mg, 1.04 mmol) in CH 2
CI
2 (4 ml). The reaction mixture was stirred for 1 h at room temperature. The mixture was diluted with H 2 0 (20 ml) and extracted with CH 2
CI
2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4-1:2) as the eluent on silica gel. Light yellow solid, yield: 72.7% f) 2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-5-yl)propanoic acid EOH H Eto N NaOH HO N YI C N 90% aq. EtOH N H H 90% aqueous EtOH (5 ml) at room temperature and additionally NaOH (70 mg) were added into the flask with 2-(2,3-dihydro-2-oxo-1 H-benzo[d]imidazol-5-yl)propanoate (175 mg, 0.747 mmol). The reaction mixture was stirred for 10 h at 40 *C and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (25 ml) 128 GRA3394-WO-1 and acidified with AcOH (4 ml, pH=4) and then extracted with CH 2 Cl 2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with CH 2
CI
2 :MeOH (10:1) as the eluent on silica gel . Light brown solid, yield: 63.6% Example 4: N-(4-tert-butyl-benzyl)-2-(2-oxo-2,3-dihydro-1 H-benzoimidazol-5-yl) propionamide I Hy _C H IN N H H NMR (300 MHz, DMSO) 5 10.6-10.5 (bs, 2 H), 8.33 (bt, 1 H), 7.34-7.22 (m, 2 H), 7.09-7.06 (m, 2 H), 6.93-6.81 (m, 3 H), 4.21-4.17 (m, 2 H), 3.60 (q, 1 H, J= 7.1 Hz), 1.34-1.24 (m, 12 H) MS (El) m/z 451 (M+H) Synthesis of exemplary compound 5: a) Ethyl 2-(3-hydroxyphenyl)acetate HO OH Et~-r 2 o 4 EO OH 5: -'EtSO4 O -N EtOH im Handel erhaltlich [Key: Im Handel erhaltlich = Commercially available] EtOH (100 ml) and subsequently 2-(3-hydroxyphenyl)acetic acid (9.83 g, 64.6 mmol) and sulphuric acid (catalyst quantity) were added into the flask. The mixture was boiled for 3 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (100 ml) and extracted with EtOAc (100 ml). The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The 129 GRA3394-WO-1 residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4) as the eluent on silica gel. Light yellow oil, yield: 94.5%. b) Ethyl 2-(3-methoxymethoxy)phenyl)acetate EtO OH EtO OMOM NaH, MOM-CI O ' THF Reference: JACS,100,8031(1978) NaH (2.93 g, 73.3 mmol) and MOM-CI (5.94 g, 73.3 mmol) were added at 0 *C to a solution of ethyl 2-(3-hydroxyphenyl)acetate (11 g, 61 mmol) in THF (100 ml). The reaction mixture was stirred for 16 h at 0 0C and subsequently heated to room temperature. The reaction mixture was diluted with H 2 0 (200 ml) and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:10) as the eluent on silica gel. Colourless oil, yield: 79.7%. c) Ethyl 2-(3-methoxymethoxy)phenyl)propanoate EtO OMOM EtO OMOM NaH, Mel NaH (1.74 g, 43.5 mmol) and iodomethane (6.37 g, 44.9 mmol) were added at 0 *C to a solution of ethyl 2-(3-methoxymethoxy)phenyl)acetate (8.06 g, 35.9 mmol) in DMF (50 ml). The reaction mixture was stirred for 1 h at 0 0C and subsequently diluted with H 2 0 (250 ml) and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:10) as the eluent on silica gel. Colourless oil, yield: 49.1%. 130 GRA3394-WO-1 d) Ethyl 2-(3-hydroxyphenyl)propanoate EtO OMOM EtO OH 0 0
CH
2
CI
2 Trifluoroacetic acid (40 ml) was added at 0 *C to a solution of ethyl 2-(3 methoxymethoxy)phenyl)propanoate (4.17 g, 17.5 mmol) in CH 2
C
2 (80 ml). The reaction mixture was stirred for 1 h at 0 *C and alkalified with NaHCO 3 (60 g). The mixture was gradually diluted with H 2 0 (250 ml) and extracted with CH 2 Cl 2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4) as the eluent on silica gel. Colourless oil, yield: 74.1% e) Ethyl 2-(3-hydroxy-4-nitrophenyl)propanoate Eto OH EtO OH I HN0 3 ylaAcOH 0 N0 2 Nitric acid (1.45 g, 13.8 mmol) in acetic acid (2 ml) was added at room temperature to a solution of ethyl 2-(3-hydroxyphenyl)propanoate (2.51 g, 12.9 mmol) in acetic acid (20 ml). After 1-2 minutes of stirring, the colourless oil turned into the dark brown oil. The reaction mixture was stirred for 15 minutes at room temperature and subsequently poured into ice water (100 ml) and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:6) as the eluent on silica gel. Yellow solid (melting point 45-47 *C), yield: 30.8% 131 GRA3394-WO-1 f) Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate DO OH 10% Pd/C, H 2 EtO OH 0 N N2 THF:EtOH=1:1 0 N NH 2 THF/EtOH (1:1, 30 ml) and subsequently ethyl 2-(3-hydroxy-4 nitrophenyl)propanoate (900 mg, 3.76 mmol) and 10% palladium on carbon (93 mg) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 1 h at 46 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. White solid (melting point 119-121 *C), yield: 80.1% g) Ethyl 2-(4-(2-chloroacetamido)-3-hydroxyphenyl)propanoate 0 EtO OH CIAC 1 EtO OH O NH2 4-Methyl-2-pentanon O N CI Y, NH 2 N"C H [Key: 4-Methyl-2-pentanon = 4-methyl-2-pentanone] Chloroacetylchloride (58 mg, 0.514 mmol) in 4-methyl-2-pentanone (2 ml) was added at room temperature to a solution of ethyl 2-(4-amino-3-hydroxyphenyl)propanoate (101 mg, 0.483 mmol) in 4-methyl-2-pentanone (4 ml). The reaction mixture was stirred for 12 h at 80 *C and subsequently cooled to room temperature. The mixture was diluted with H 2 0 and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. Light pink solid (melting point 118-120 *C), yield: 90.6% 132 GRA3394-WO-1 h) Ethyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)propanoate EtO OH K 2
CO
3 EtO 0. O N N CI Aceton O N 0 H H [Key: Aceton = Acetone] Potassium carbonate (61 mg) was added to a solution of ethyl 2-(4-(2 chloroacetamido)-3-hydroxyphenyl)propanoate (110 mg, 0.385 mmol) in acetone (10 ml). The reaction mixture was boiled for 3 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. White solid (melting point 101 OC), yield: 91.7% i) 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)propanoic acid EtO 0 NaOH HO 0 O O NO 90% aq. EtOH O N O H H NaOH (64 mg, 1.60 mmol) was added at room temperature to a solution of ethyl 2 (3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-7-yl)propanoate (80 mg, 0.321 mmol) in 90% aqueous EtOH (5 ml). The reaction mixture was stirred for 12 h at 50 *C and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (20 ml) and acidified with AcOH and subsequently extracted with CH 2
CI
2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. White solid (melting point 199-201 C), yield: 98.4% 133 GRA3394-WO-1 Example 5 - N-(4-tert-butyl-benzyl)-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7 yl)propionamide NN H N N 0
NI
2 X H 'H-NMR(CDCl 3 ) 8 9.15 (bs, NH), 7.32 (d, 2H, J=8.2Hz, Ar), 7.12 (d, 2H, J=8.2Hz, Ar), 6.93-6.78 (m, 3H, Ar), 5.79 (bs, NH), 4.58 (s, 2H, OCH 2 ), 4.38 (m, 2H, NHCH 2 ), 3.50 (q, 1 H, J=7.1 Hz, COCH), 1.51 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.29 (s, 9H, C(CH 3
)
3 ) IR 3284, 2962, 1700, 1645, 1517, 1417 cm- 1 Mass (FAB) m/z 367 [M+H]*, 389 [M+Na]* Synthesis of exemplary compound 6: a) Ethyl 2-(4-methoxymethoxy)phenyl acetate EtOlr, EtO NaH, MOM-Cl O ~ OH TE0 N OMOM Ethyl 2-(4-hydroxyphenyl)acetat im Handel erhsltlich [Ethyl 2-(4-hydroxyphenyl)acetat = Ethyl 2-(4-hydroxyphenyl) acetate; im Handel erhaltlich = commercially available] Sodium hydride (0.50 g, 12.5 mmol) and chloromethylmethylether (1.00 g, 12.4 mmol) were added slowly at 0 0C to ethyl 2-(4-hydroxyphenyl) acetate (2.14 g, 11.8 mmol) in THF (20 ml). The reaction mixture was stirred for 16 h at room temperature. Water (50 ml) was added to the mixture and it was extracted with EtOAc. The organic layer was dried over MgSO 4 . The organic layer was filtered and the filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (6:1). Colourless oil, yield: 67% 134 GRA3394-WO-1 b) Ethyl 2-(4-methoxymethoxy)phenyl)propanoate EtO NaH, Mel, EtO 0 N OMOM DMF O OMOM Sodium hydride (330 mg, 8.25 mmol) and iodomethane (1.13 g, 7.96 mmol) were gradually added at 0 OC to ethyl 2-(4-methoxymethoxy)phenyl acetate (1.75 g, 7.80 mmol) in DMF (50 ml). The reaction mixture was stirred for 1 h at 0 *C. Water (50 ml) was added to the mixture and it was extracted with EtOAc. The organic layer was dried over MgSO 4 . The organic layer was filtered and the filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (15:1). Colourless oil, yield: 57% c) Ethyl 2-(4-hydroxyphenyl)propanoate EtO TFA EtO o OMOM CH 2
CI
2 0Et OH Trifluoroacetic acid (5 ml) was added at 0 *C to a solution of ethyl 2-(4 methoxymethoxy)phenyl)propanoate (485 mg, 2.04 mmol) in methylene chloride (10 ml). The mixture was stirred for 40 minutes at 0 *C and subsequently solid sodium bicarbonate (7.14 g) and water (100 ml) were added slowly at 0 *C. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO 4 . The organic layer was filtered and the filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (4:1). Colourless oil, yield: 67% 135 GRA3394-WO-1 d) Ethyl 2-(4-hydroxy-3-nitrophenyl)propanoate EtO HNO, EtO : NO 2 O OH AcOH 0 OH Nitric acid (60-62%, 300 mg, 2.86 mmol) was added at room temperature to a solution of ethyl 2-(4-hydroxyphenyl)propanoate (275 mg, 1.42 mmol) in acetic acid (2 ml). The reaction mixture was stirred for 1 h at 50 *C and subsequently cooled to room temperature. The reaction mixture was poured into ice water (20 ml) and extracted with EtOAc. The organic layer was dried with MgSO 4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (6:1). Yellow oil, yield: 87% e) Ethyl 2-(3-amino-4-hydroxyphenyl)propanoate EtO .NO 2 EtO H E 10% Pd/C, H 2 E NH 2 OH THF:EtOH=1:1 10% Pd/C (29 mg) was gradually added at room temperature to ethyl 2-(4-hydroxy-3 nitrophenyl)propanoate (260 mg, 1.09 mmol) in THF (6 ml) and ethanol (6 ml). The mixture was hydrogenated for 2 h at 43 psi and subsequently filtered with diatomite and washed with EtOAc. The filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n hexane/EtOAc (1:1). Yellow oil, yield: 86% f) Ethyl 2-(3-(2-chloroacetamido)-4-hydroxyphenyl)propanoate 136 GRA3394-WO-1 0 H EtO
NH
2 CI Cl EtO N C I, 0 OH 4-Methyl-2-pentanon OH [Key: 4-Methyl-2-pentanon = 4-methyl-2-pentanone] Chloroacetychloride (56 mg, 0.496 mmol) was added at room temperature to ethyl 2 (3-amino-4-hydroxyphenyl)propanoate (104 mg, 0.497 mmol) in 4-methyl-2 pentanone (4 ml) and the mixture was stirred for 20 h at 80 *C. The reaction mixture was cooled to room temperature and water (30 ml) was added. The mixture was extracted with EtOAc. The organic layer was dried with MgSO 4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (2:1). White solid (melting point 126-128 0 C), yield: 78% g) Ethyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-6-yl)propanoate H H EtO H. CI EtO N 0 O -a H AcetonQ [Key: Aceton = Acetone] Potassium carbonate (59 mg) was added at room temperature to ethyl 2-(3-(2 chloroacetamido)-4-hydroxyphenyl)propanoate (100 mg, 0.350 mmol) in acetone (10 ml) and the mixture was boiled for 3 h under reflux. The reaction mixture was cooled to room temperature and water (15 ml) was added thereto. The mixture was extracted with EtOAc. The organic layer was dried with MgSO 4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (2:1). White solid (melting point 116-118 *C), yield: 92% h) 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-6-yl)propanoic acid 137 GRA3394-WO-1 O, N O 90% aq. EtOH OT Sodium hydroxide (50 mg, 1.25 mmol) was added at room temperature to ethyl 2 (3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-6-yl)propanoate (63 mg, 0.253 mmol) in 90% aqueous EtOH (4.5 ml). The reaction mixture was stirred for 12 h at 50 *C and subsequently cooled to room temperature. Water (20 ml) was added to the mixture and it was acidified with acetic acid. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO 4 and filtered. The filtrate was concentrated under a vacuum. White solid (melting point 191-193 0C), yield: 95%, Exemplary compound 6 - N-(4-tert-butyl-benzyl)-2-(3-oxo-3,4-dihydro-2H benzo[1,4]oxazin-6-yl)propionamide H H N NO 00 1 H-NMR(CDCl 3 ) 8 8.76 (bs, NH), 7.32 (d, 2H, J=8.4Hz, Ar), 7.12 (d, 2H, J=8.3Hz, Ar), 6.93-6.85 (m, 3H, Ar), 5.73 (bs, NH), 4.58 (s, 2H, OCH 2 ), 4.38 (m, 2H, NHCH 2 ), 3.48 (q, 1H, J=7.1Hz, COCH), 1.51 (d, 3H, J=7.1Hz, CHCH 3 ), 1.29 (s, 9H, C(CH 3 )3) IR 2925, 2855, 1648, 1540,1459 cm- 1 Mass (FAB) m/z 367 [M+H]* Synthesis of exemplary compound 7: N-(4-tert-butyl-benzyl)-2-(7-methoxy-benzooxazolyl-5-yI)-propionamide H N N 0 O
OCH
3 138 GRA3394-WO-1 'H-NMR (CDCl 3 ) 6 8.06 (s, 1H, Ar), 7.29 (m, 3H, Ar), 7.10 (d, 2H, J=8.lHz, Ar), 6.87 (s, 1H, Ar), 5.70 (bs, NH), 4.37 (m, 2H, NHCH 2 Ar), 4.00 (s, 3H, OCH 3 ), 3.69 (q, 1H, J=7.1Hz, COCH), 1.60 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.28 (s, 9H, C(CH 3
)
3 ) IR 3297, 2963, 1647, 1519, 1316, 1110cm-1 Mass (FAB) m/z 367 [M+H]* Exemplary compound 8: 2-benzooxazol-4-yl-N-(4-tert-butyl-benzyl)-propionamide H := - N 0 0 1H-NMR(CDCl 3 ) 8 8.04 (s, 1H, Ar), 7.51 (m, 1H, Ar), 7.41 (m, 2H, Ar), 7.26 (d, 2H, J=8.2Hz, Ar), 7.03 (d, 2H, J=8.3Hz, Ar), 6.65 (bs, NH), 4.35 (m, 3H, NHCH 2 Ar & COCH), 1.68 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.29 (s, 9H, C(CH 3
)
3 ) IR 3304, 2962, 1658, 1519, 1428,1242,1076 cm- 1 Mass (FAB) m/z 337 [M+H]* Synthesis of exemplary compound 9: a) Ethyl 2-(3,4-dihydroxyphenyl)acetate HOOH H 2
SO
4 EtO OH 0 I--, OH EIOH 0 N OH im Handel erhaltlich [Key: im Handel erhaltlich = commercially available] EtOH (15 ml) and subsequently 2-(3,4-dihydroxyphenyl)acetic acid (1.07 g, 6.36 mmol) and sulphuric acid (catalyst quantity) were added into the flask. The mixture was boiled for 3 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (30 ml) and extracted with EtOAc (30 ml). The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:1) as the eluent on silica gel. Colourless oil, yield: 89.8%. 139 GRA3394-WO-1 b) Ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)acetate EtO OH B Br ,CS 2
CO
3 EtO o OH DMF Caesium carbonate (3.71 g, 11.4 mmol) was added to a mixture of ethyl 2-(3,4 dihydroxyphenyl)acetate (1.11 g, 5.66 mmol) and 1,2-dibromoethane (1.07, 5.69 mmol) in DMF (5 ml). The reaction mixture was stirred for 2 h at 80 0C and subsequently cooled to room temperature. The mixture was diluted with H 2 0 and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4-1:2) as the eluent on silica gel. Colourless oil, yield: 21.5%. c) Ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)propanoate EtO O NaH, Mel EtO O0 Q DMF 00 NaH (50 mg, 1.25 mmol) and iodomethane (167 mg, 1.18 mmol) in DMF (0.5 ml) were added at 0 0C to a solution of ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7 yl)acetate (257 mg, 1.16 mmol) in DMF (2 ml). The reaction mixture was stirred for 1 h at 0 0C and subsequently diluted with H 2 0 (20 ml) and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:6) as the eluent on silica gel. Colourless oil, yield: 82.1%. d) 2-(2-3-dihydrobenzo[b][1,4]dioxin-7-yl)propanoic acid 140 GRA3394-WO-1 EtO O NaOH HO O O ) THF:H 2 0 = 1:1 O O
THF/H
2 0 (1:1, 4 ml) and subsequently SM (133 mg, 0.563 mmol) and NaOH (30 mg, 0.750 mmol) were added at room temperature into the flask. The reaction mixture was stirred for 16 h at room temperature. The mixture was diluted with H 2 0 (20 ml) and acidified with acetic acid (4 ml, pH=4) and subsequently extracted with CH 2
CI
2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. Colourless oil, yield: quantitative. Example 9 - N-(4-tert-butyl-benzyl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-yI) propionamide H 00
'H-NMR(CDC
3 ) 6 7.32 (d, 2H, J=8.3Hz, Ar), 7.10 (d, 2H, J=8.3Hz, Ar), 6.84-6.74 (m, 3H, Ar), 5.62 (bs, NH), 4.36 (m, 2H, NHCH 2 ), 4.25 (s, 4H, CH 2
CH
2 ), 3.49 (q, 1H, J=7.1Hz, COCH), 1.51 (d, 3H, J=7.1Hz, CHCH 3 ), 1.30 (s, 9H, C(CH 3
)
3 ) IR 3298, 2963,1648, 1507, 1287,1255, 1068 cm- 1 Mass (FAB) m/z 354 [M+H]* Synthesis of exemplary compound 10: a) 2-(4-aminophenyl)propanoic acid HO N 10% Pd/C, H 2 , HO S /N2 THF:EtOH=1:1 0
NH
2 2-(4-nitrophenyl)propanssure im Handel erhaltlich [Key: 2-(4-nitrophenyl)propansaure = 2-(4-nitrophenyl)propanoic acid; im Handel erhaitlich = commercially available] 141 GRA3394-WO-1 THF/EtOH (1:1, 100 ml) and subsequently commercially available (10 g, 51.2 mmol) and 10% palladium on carbon (0.87 g) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 1 h at 45 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. White or light black solid, yield: quantitative b) 2-(4-amino-3-nitrophenyl)propanoic acid HO NHNO 3 HO NO 2 O ,NH 2 AcOH 0 ~NH 2
HNO
3 (60%, 5.66 g) was added at room temperature to a solution of 2-(4 aminophenyl)propanoic acid (8.45 g, 51.2 mmol) in AcOH (70 ml). The reaction mixture was boiled for 4 h under reflux and subsequently cooled to room temperature. The mixture was poured into ice water (200 ml) and extracted with
CH
2 Cl 2 .The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. c) Ethyl 2-(4-amino-3-nitrophenyl)propanoate HO N NO 2
H
2
S
4 EtO N NO 2 O NH 2 EtOH
~N
2 EtOH (200 ml) and sulphuric acid in a catalyst quantity (1 ml) were added at room temperature into the flask with 2-(4-amino-3-nitrophenyl)propanoic acid residue. The reaction mixture was boiled for 6 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. Light yellow oil, yield: 17.4% (two steps) d) Ethyl 2-(3,4-diaminophenyl)propanoate 142 GRA3394-WO-1 EtO N NO 2 10% Pd/C, H 2 EtO N NH 2 0 / H2THF:EtOH=1:1 NH 2
~NH
2 0 H THF/EtOH (1:1, 50 ml) and subsequently ethyl 2-(4-amino-3-nitrophenyl)propanoate (2.12 g, 8.90 mmol) and 10% palladium on carbon (0.87 g) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 3 h at 45 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4-1:2) as the eluent on silica gel. Yellow oil, yield: 74.5% e) Ethyl 2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-5-yl)propanoate EtO NH 2 TDI, DBU EtO H O H 2
CH
2
CI
2 S N H2 H 1,1'-thiocarbonyldiimidazol (241 mg) and DBU (345 mg, in CH 2
CI
2 (4 ml)) were added at room temperature to a solution of ethyl 2-(3,4-diaminophenyl)propanoate (222 mg, 1.07 mmol) in CH 2
CI
2 (4 ml). The reaction mixture was stirred for 1 h at room temperature. The mixture was diluted with H 2 0 (20 ml) and extracted with CH 2 Cl 2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4-1:2) as the eluent on silica gel. Colourless oil, yield: 35.8% f) 2-(2,3-dihydro-2-thioxo-1 H-benzo[d]imidazol-5-yl)propanoic acid 143 GRA3394-WO-1 H H EtO N NaOH HO N O N S 90% aq. EtOH N H H 90% aqueous EtOH (5 ml) at room temperature and additionally NaOH (30 mg) were added into the flask with ethyl 2-(2,3-dihydro-2-oxo-1 H-benzo[d]imidazol-5 yl)propanoate (93 mg, 0.372 mmol). The reaction mixture was stirred for 10 h at 40 *C and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (25 ml) and acidifed with AcOH (3 ml, pH=4) and subsequently extracted with
CH
2
CI
2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with
CH
2 Cl 2 :MeOH (10:1) as the eluent on silica gel. Brown oil, yield: 94.3% Example 10 - N-(4-tert-butyl-benzyl)-2-(2-thioxo-2,3-dihydro-1 H-benzoimidazol 5-yl)-propionamide Nx N H 1 H NMR (300 MHz, CD 3 0D) 8 7.28-6.95 (m, 7 H), 4.19 (s, 2 H), 3.63 (q, 1 H, J = 7.0 Hz), 1.38 (d, 3 H, J = 7.1 Hz), 1.16 (s, 9 H) MS (El) m/z 367 (M+H) Synthesis of exemplary compound 11: a) 2-(4-aminophenyl)propionitrile NC N 10% Pd/C, H 2 NC NO2 THF:EtOH=1:1 C NH 2 im Handel erhiltlich [Key: im Handel erhiltlich = commercially available] 144 GRA3394-WO-1 THF/EtOH (1:1, 70 ml) and subsequently 2-(4-nitrophenyl)propionitrile (13.2 g, 74.9 mmol) and 10% palladium on carbon (1.07 g) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 30 minutes at 47 psi to 28 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:3) as the eluent on silica gel. Yellow oil, yield: 94.1% b) N-[4-(cyanomethylmethyl)phenyl]-acetamide NC Ac 2 O NC
NH
2 Pyridine NHAc Reference: Eur. J. Med. Chem. (1975), 10, 239 Ac 2 0 (7.49 g, 73.4 mmol) was added at room temperature to a solution of 2-(4 aminophenyl)propionitrile (10.2 g, 69.8 mmol) in pyridine (40 ml). The reaction mixture was boiled for 1 h under reflux and subsequently cooled to room temperature and added under a vacuum. White solid (melting point 75-77 0C), yield: 98.2% c) N-[4-(cyanomethylmethyl)-2-nitrophenyl]acetamide NC NHc HNO 3 NC N 2 NHAc AC 2 0 NHAc Reference: Eur. J. Med. Chem. (1975), 10, 239 145 GRA3394-WO-1 Ac 2 0 (35 ml) was added at 5 0C into the flask with N-[4-(cyanomethylmethyl)phenyl] acetamide (12.9 g, 68.5 mmol). The mixture was stirred and HNO 3 (7.45 g, 70.9 mmol) was added thereto at 0 *C. This reaction was highly exothermal. The reaction mixture was stirred for 1 h at 0 0C and additionally cooled for 3 h at room temperature. The mixture was diluted with H 2 0 and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. Yellow solid (melting point 84-86 *C), yield: 55.7% d) 2-(4-amino-3-nitrophenyl)-propionic acid NCNO2 conc. HCI HO
NO
2 NHAc
NH
2 Reference: Eur. J. Med. Chem. (1975), 10, 239 Conc. HCI (25 ml) was added at room temperature into the flask with N-[4 (cyanomethylmethyl)-2-nitrophenyl]acetamide (8.90 g, 38.2 mmol). The reaction mixture was boiled for 5 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (150 ml) and extracted with CH 2 Cl 2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with
CH
2 Cl 2 :MeOH (20:1-10:1) as the eluent on silica gel. Yellow solid (melting point 118-120 *C), yield: 87.8% e) 2-(3,4-diaminophenyl)propanoic acid HO N NO 2 10% Pd/C, H 2 HO s NH 2 0 EtOH:H 2 0=3.5:1 0
NH
2 NH 2 1 146 GRA3394-WO-1 EtOH / H 2 0 (3.5:1, 45 ml) and subsequently 2-(4-amino-3-nitrophenyl)-propionic acid (5.73 g, 27.3 mmol) and 10% palladium on carbon (117 mg) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 5 h at 64 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with CH 2 Cl 2 :MeOH (10:1) as the eluent on silica gel. Brown solid (melting point 142-144 0C), yield: 50.0% f) N-(4-tert-butylbenzyl)-2-(3,4-diaminophenyl)-propionamide H HO r NH 2
NH
2 , EDC,HOBT N NH 2
NH
2 DMF 0NH 2 4-t-butylbenzyl amine (399 mg, 2.44 mmol), EDC (702 mg, 3.66 mmol), HOBt (496 mg, 3.67 mmol) and triethyl amine (617 mg, 6.10 mmol) were added at 0 0C to 2 (3,4-diaminophenyl)propanoic acid (436 mg, 2.42 mmol) in DMF (5 ml). The reaction mixture was stirred for 16 h at room temperature and subsequently water (50 ml) was added to the mixture and it was extracted with methylene chloride. The organic layer was dried with MgSO 4 and filtered. Methylene chloride was removed by evaporation. The residue was purified by column chromatography, wherein elution was performed with CH 2
CI
2 /MeOH (20:1). Brown oil, yield: 70%, g) N-(4-tert-butylbenzyl)-2-(quinoxalin-6-yl)propanamide HH H1oa k N NH 2 glyoxal N N (40% in water soln.)
NH
2 DMF N 147 GRA3394-WO-1 Glyoxal (4 ml, 40% in aqueous solution) was added at room temperature and additionally DMF (4 ml) was added into the flask with N-(4-tert-butylbenzyl)-2-(3,4 diaminophenyl)-propionamide (81 mg, 0.249 mmol) because SM is not sufficiently soluble in glyoxal. The reaction mixture was boiled for 2 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (25 ml) and extracted with CH 2
CI
2 .The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:1) as the eluent on silica gel. Brown solid (melting point 53-55 QC), yield: 55.5% Example 11 - N-(4-tert-butyl-benzyl)-2-quinoxalin-6-yl-propionamide H S N ~ N N 'H NMR (300 MHz, CDC13) 8 8.84 (m, 2 H), 8.10 (d, 1 H, J = 8.8 Hz), 7.81 (dd, 1 H, J = 8.8 Hz, 2.0 Hz), 7.30 (d, 2 H, J = 8.3 Hz), 7.11 (d, 2 H, J = 8.3 Hz), 5.68 (bt, 1 H), 4.40 (m, 2 H), 3.84 (q, 1 H, J = 7.1 Hz), 1.68 (d, 3 H, J = 7.1 Hz), 1.28 (s, 9 H) MS (FAB) m/z 348 (M+H) Synthesis of exemplary compound 15: a) 2-(4-aminophenyl)-propionitrile NC N 10% Pd/C, H 2 NC N N2 THF:EtOH=1:1
NH
2 Im Handel erhaltlich [Key: im Handel erhaltlich = commercially available] THF/EtOH (1:1, 70 ml) and subsequently 2-(4-nitrophenyl)propionitrile (13.2 g, 74.9 mmol) and 10% palladium on carbon (1.07 g) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 30 minutes at 47 psi to 28 psi and subsequently filtered by a silica bed and washed with EtOAc. The 148 GRA3394-WO-1 filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:3) as the eluent on silica gel. Yellow oil, yield: 94.1% b) N-[4-(cyanomethylmethyl)phenyl]acetamide NC Ac 2 0 NC
NH
2 Pyridin NHAc [Key: Pyridin = Pyridine] Reference: Eur. J. Med. Chem. (1975), 10, 239 Ac 2 0 (7.49 g, 73.4 mmol) was added at room temperature to a solution of 2-(4 aminophenyl)-propionitrile (10.2g, 69.8mmol) in pyridine (40 ml). The reaction mixture was boiled for 1 h under reflux, cooled to room temperature and concentrated under a vacuum. White solid (melting point 75-77 *C), yield: 98.2% c) N-[4-(cyanomethylmethyl)-2-nitrophenyl]acetamide NC NH-c HNO 3 NC N 2 SNHAC AC20 NHAc Reference: Eur. J. Med. Chem. (1975), 10, 239 Ac 2 0 (35 ml) was added at 5 *C into the flask with N-[4 (cyanomethylmethyl)phenyl]acetamide (12.9 g, 68.5 mmol). The mixture was stirred and HNO 3 (7.45 g, 70.9 mmol) was added thereto at 0 *C. This reaction was highly exothermal. The reaction mixture was stirred for 1 h at 0 *C and cooled for an additional 3 h at room temperature. The mixture was diluted with H 2 0 and extracted 149 GRA3394-WO-1 with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. Yellow solid (melting point 84-86 *C), yield: 55.7% d) 2-(4-amino-3-nitrophenyl)-propionic acid NC NO 2 conc. HCI HO NO 2 NHAc
NH
2 Reference: Eur. J. Med. Chem. (1975), 10, 239 Conc. HCI (25 ml) was added at room temperature into the flask with N-[4 (cyanomethylmethyl)-2-nitrophenyl]acetamide (8.90 g, 38.2 mmol). The reaction mixture was boiled for 5 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (150 ml) and extracted with CH 2
C
2 . The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with
CH
2 Cl 2 :MeOH (20:1-10:1) as the eluent on silica gel. Yellow solid (melting point 118-120 0C), yield: 87.8% e) 2-(3,4-diaminophenyl)propanoic acid HO s NO 2 10% Pd/C, H 2 HO s NH 2 0 EtOH:H 2 O=3.5:1 0
NH
2 NH 2 H EtOH / H 2 0 (3.5:1, 45 ml) and subsequently 2-(4-amino-3-nitrophenyl)-propionic acid (5.73 g, 27.3 mmol) and 10% palladium on carbon (117 mg) were added at room temperature into the flask. The reaction mixture was hydrogenated and stirred for 5 h at 64 psi and subsequently filtered by a silica bed and washed with EtOH. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography with CH 2
CI
2 :MeOH (10:1) as the eluent on silica gel. 150 GRA3394-WO-1 Brown solid (melting point 142-144 *C), yield: 50.0% f) N-[4-tert-butylbenzyl)-2-(3,4-diaminophenyl)propionamide H| HO NH 2
NH
2 ,EDC,HOBT N NH2
NH
2 DMF
NH
2 4-t-butylbenzyl amine (399 mg, 2.44 mmol), EDC (702 mg, 3.66 mmol), HOBt (496 mg, 3.67 mmol) and triethyl amine (617 mg, 6.10 mmol) were added at 0 *C to 2 (3,4-diaminophenyl)propanoic acid (436 mg, 2.42 mmol) in DMF (5 ml). The reaction mixture was stirred for 16 h at room temperature and subsequently water (50 ml) was added to the mixture and it was extracted with methylene chloride. The organic layer was dried with MgSO 4 and filtered. Methylene chloride was removed by evaporation. The residue was purified by column chromatography, wherein elution was performed with CH 2 Cl 2 /MeOH (20:1). Brown oil, yield: 70% g) N-[4-tert-butylbenzyl)-2-(1H-benzo[d][1,2,3]triazol-5-yl)propanamide H H N NH 2 NaNO 2 N N "N O 5% aq. AcOH N
NH
2 0H Sodium nitrite (30 mg, 0.435 mmol) was added at 0 *C to N-[4-tert-butylbenzyl)-2 (3,4-diaminophenyl)propionamide (110 mg, 0.338 mmol) in 5% aqueous acetic acid (3 ml) and DMF (2.5 ml). The reaction mixture was stirred for 14 h at room temperature. Water (20 ml) was added to the mixture and it was extracted with methylene chloride. The organic layer was dried with MgSO 4 and filtered. Methylene 151 GRA3394-WO-1 chloride was removed by evaporation. The residue was purified by column chromatography, wherein elution was performed with CH 2 Cl 2 /MeOH (10:1). Light brown solid (melting point 126-1280C), yield: quantitative Example 15 - 2-(1 H-benzotriazol-5-yl)-N-(4-methyl-6'-trifluoromethyl-3,4,5,6 tetrahydro-2H-[1,2'] bipyridinyl-3'-ylmethyl)-propionamide
F
3 C N N N ' N H 'H-NMR (CDC1 3 ) 5 7.81 (m, 2H), 7.49 (d, 1H, J=7.7Hz), 7.35 (m, 1H), 7.14 (d, 1H, J=7.5Hz), 6.77 (bs, NH), 4.52 (d, 2H), 3.84 (q, 1 H, J=7.OHz), 3.25 (m, 2H), 2.76 (m, 2H), 1.77 (m, 2H), 1.64 (d, 3H, J=7.OHz), 1.15-1.10 (m, 2H), 0.90 (d, 3H, J=6.4Hz) IR 3295, 2921, 1650, 1539, 1458, 1419,1177,1136 cm Mass (FAB) m/z 447 [M+H]* (base), 469 [M+Na]* Synthesis of exemplary compound 16: a) Ethyl 2-(3-hydroxyphenyl)acetate HO OH EtO OH
H
2
SO
4 0 'N EtOH0 2-(3-Hydroxyphenyl)essigssure im Handel erhaltlich [Key: 2-(3-Hydroxyphenyl)essigssure = 2-(3-hydroxyphenyl)acetic acid; im Handel erhaltlich = commercially available] Sulphuric acid was added in a catalyst quantity to a solution of 2-(3-hydroxyphenyl acetic acid) (9.83 g, 64.6 mmol) in ethanol (100 ml). The mixture was boiled for 3 h under reflux and subsequently cooled to room temperature. The mixture was diluted with H 2 0 (100 ml) and extracted with EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by 152 GRA3394-WO-1 means of flash column chromatography with EtOAc:hexanes (1:4) as the eluent on silica gel. Light yellow oil, yield: 94.5% b) EtO OH EtO OMOM NaH, MOM-Ci zz THF0 Ethyl 2-(3-methoxymethoxy)phenyl)acetate Sodium hydride (2.93 g, 73.3 mmol) and chloromethylmethylether (5.94 g, 73.7 mmol) were added slowly at 0 0C to ethyl 2-(3-hydroxyphenyl)acetate (24 g, 80.51 mmol) in THF (100 ml). The reaction mixture was stirred for 16 h at room temperature. Water (200 ml) was added to the mixture and it was extracted with EtOAc. The organic layer was dried with MgSO 4 .The organic layer was filtered and the filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (10:1). Colourless oil, yield: 79.7% c) EtO OMOM NaH, Mei EtO OMOM o 0 . DMF 0 ' Ethyl 2-(3-methoxymethoxy)phenyl)propanoate Sodium hydride (1.74 mg, 43.5 mmol) and iodomethane (6.37 g, 44.9 mmol) were gradually added at 0 0C to ethyl 2-(3-methoxymethoxy)phenyl)acetate (8.06 g, 35.9 mmol) in DMF (50 ml). The reaction mixture was stirred for 1 h at 00C. Water (250 ml) was added to the mixture and it was extracted with EtOAc. The organic layer was dried with MgSO 4 . The organic layer was filtered and the filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (10:1). 153 GRA3394-WO-1 Colourless oil, yield: 49% d) EtO OMOM C22 EtO OH
CH
2
CI
2 Ethyl 2-(3-hydroxyphenyl)propanoate Trifluoroacetic acid (40 ml) was added at 0 0C to a solution of ethyl 2-(3 methoxymethoxy)phenyl)propanoate (4.17 g, 17.5 mmol) in methylene chloride (80 ml). The mixture was stirred for 1 h at 0 *C and subsequently solid sodium bicarbonate (60 g) and water (250 ml) was added thereto at 0 *C. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO 4 . The organic layer was filtered and the filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (4:1). Colourless oil, yield: 74% e) EtO OH EtO OH O AcOH
NO
2 Ethyl 2-(3-hydroxy-4-nitrophenyl)propanoate Nitric acid (60-62%, 1.45 g, 13.8 mmol) was added at room temperature to ethyl 2-(3 hydroxyphenyl)propanoate (2.51 g, 12.9 mmol) in acetic acid (20 ml). The reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured into ice water (100 ml) and extracted with EtOAc. The organic layer was dried with MgSO 4 and filtered. EtOAc was removed by evaporation. The residue was 154 GRA3394-WO-1 purified by column chromatography, wherein elution was performed with n hexane/EtOAc (6:1). Yellow solid (melting point 44 *C), yield: 30.8% f) EtO OH 10% Pd/C, H 2 EtO OH O N NO 2 THF:EtOH=1:1 O NH 2 Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate 10% Pd/C (93 mg) was gradually added at room temperature to a solution of ethyl 2 (3-hydroxy-4-nitrophenyl)propanoate (900 mg, 3.76 mmol) in THF/ethanol (1:1, 30 ml). The mixture was hydrogenated for 1 h at 46 psi and subsequently filtered with diatomite and washed with EtOAc. The filtrate was concentrated under a vacuum. The residue was purified by column chromatography, wherein elution was performed with n-hexane/EtOAc (2:1). White solid (melting point 119-121 *C), yield: 80.1% g) EtO OH Harnstoff EtO O 0 1 YI-aI>=0 o ~ NH 2 DMF 0 N [Key: Hamstoff = Urea] Reference: Heterocycles, Vol. 51, No. 8, 1929-1943 Ethyl 2-(2,3-dihydro-2-oxobenzo[d]oxazol-6-yl)propanoate Urea (305 mg, 5.19 mmol) was added to a solution of ethyl 2-(4-amino-3 hydroxyphenyl)propanoate (205 mg, 0.978 mmol) in DMF (5 ml) and it was boiled for 5 h under reflux. The reaction mixture was cooled to room temperature and water (30 ml) was added. The mixture was acidified with conc. HCI (1 ml) and extracted with 155 GRA3394-WO-1 EtOAc. The organic layer was dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. Brown oil, yield: 88.2% h) EtO O NHO O N )=o NaOH IIO C N N H 90% aq. EtOH H 90% aqueous EtOH 2-(2,3-dihydro-2-oxobenzo[d]oxazol-6-yl)propanoic acid Sodium hydroxide (82 mg, 2.05 mmol) was added at room temperature to a solution of ethyl 2-(2,3-dihydro-2-oxobenzo[d]oxazol-6-yl)propanoate (95 mg, 0.404 mmol) in 90% aqueous EtOH (5 ml). The reaction mixture was stirred for 24 h at 45 0C and cooled to room temperature. Water (10 ml) was added to the mixture and it was acidified with acetic acid (pH=4). The mixture was extracted with methylene chloride. The organic layer was dried with MgSO 4 and filtered. The filtrate was concentrated under a vacuum. White solid (melting point 169-171 *C), yield: 83.6%, Example 16 - N-(4-tert-butyl-benzyl)-2-(2-oxo-2,3-dihydro-benzooxazol-6-y) propionamide 0 N >=o H 'H-NMR(CDCl 3 ) 6 9.46 (bs, NH), 7.32 (d, 2H, J=8.2Hz, Ar), 7.11 (m, 4H, Ar), 6.90 (d, 1H, J=8.OHz, Ar), 5.99 (bs, NH), 4.40 (m, 2H, NHCH 2 ), 3.61 (q, 1H, J=7.1 Hz, COCH), 1.54 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.28 (s, 9H, C(CH 3
)
3 ) IR 3301, 2963, 1767, 1649, 1501, 1264, 937, 733 cm- 1 Mass (FAB) m/z 353 [M+H]*, 375 [M+Na]* 156 GRA3394-WO-1 Synthesis of exemplary compound 17: a) HO H 2
SO
4 (kat.) EtO O OH EtOH, R(ckfluB, 12 h 0 OH [Key: kat. = cat.; RUckfluB = reflux] 2-(4-hydroxyphenyl)-propionic acid-ethyl ester Sulphuric acid (10 drops) was added to a solution of 2-(4-hydroxyphenyl)propanoic acid (8.60 g) in ethanol (70 ml) and it was boiled for 12 h under reflux. The reaction mixture was cooled to room temperature. Water (50 ml) was added to the mixture and it was extracted with EtOAc. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. (9.0 g, brown oil) b) EtO HN 3 , AcOH EtO NO 2 oOH rt, 30min 0OH 2-(4-hydroxy-3-nitrophenyl)-propionic acid-ethyl ester Nitric acid (60%, 5.24 g in AcOH) was added at room temperature to a solution of 2 (4-hydroxyphenyl)-propionic acid-ethyl ester (9.02 g) in acetic acid (75 ml). The reaction mixture was stirred for 30 minutes at room temperature and water was added. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=10:1) in order to obtain the product as a light yellow oil. (9.71 g) c) 157 GRA3394-WO-1 EtO NO 2 10% Pd/C, H 2 EO NH 2 0 OH THF:EtOH(1:1) OOH 2-(3-amino-4-hydroxyphenyl)-propionic acid-ethyl ester 10% Pd/C (0.89 g) was gradually added at room temperature to a stirred solution of 2-(4-hydroxy-3-nitrophenyl)-propionic acid-ethyl ester (9.71 g) in THF (40 ml) and EtOH (40 ml). After 0.5 h of hydrogenation with H2 round flask, the reaction mixture was filtered off using diatomite and washed with EtOAc. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=2:1) in order to obtain the product as a light yellow oil. d) EtO N NH 2 phenyl thionochloroformiat, DBU EtO N 0 OH DMF, rt, 16 h 0 [Key: thionochloroformiat = thionochloroformiate] 2-(2-thioxo-2,3-dihydrobenzothiazo-5-y)-propionic acid-ethyl ester Phenylchlorothionoformiate (380 mg in DMF) and DBU (540 mg, in DMF) were added at room temperature to a solution of 2-(3-amino-4-hydroxyphenyl)-propionic acid ethyl ester (370 mg) in DMF (2 ml). The reaction mixture was stirred for 16 h at room temperature and water was added to this mixture. The resultant mixture was extracted with ethyl ether. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=4:1) in order to obtain the product as a white solid. (130 mg, 29.2%) e) H H EtO N N NaOH, 90 % aq. EtOH HO N O O C 45 *C, 20 h C 158 GRA3394-WO-1 90% aqueous EtOH 2-(2-thioxo-2,3-dihydrobenzooxazol-5-yl)-propionic acid NaOH (102 mg) was added at room temperature to a stirred solution of 2-(2-thioxo 2,3-dihydrobenzothiazol-5-yI)-propionic acid-ethyl ester (124 mg) in 90% aqueous EtOH. After 20 h of stirring at 45 *C, the reaction mixture was cooled to room temperature and diluted with water. The resultant aqueous layer was acidified with acetic acid and subsequently extracted with dichloromethane. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. (105 mg, 95.4%) Example 17 - N-(4-tert-butyl-benzyl)-2-(2-thioxo-2,3-dihydro-benzooxazol-5-y) propionamide H H N ~. N 00 1 H-NMR(CDC1 3 ) 8 7.34-7.05 (m, 7H, Ar), 5.99 (bt, NH), 4.52 (m, 2H, NHCH 2 ), 3.61 (q, 1 H, J=7.1 Hz, COCH), 1.58 (d, 3H, J=7.OHz, CHCH 3 ), 1.27 (s, 9H, C(CH 3
)
3 ) IR 3297, 2963, 1646, 1534,1460, 1428, 1267, 1105 cm 1 Mass (FAB) m/z 369 [M+H]* Synthesis of exemplary compound 18: a) HO, OH H 2 SO4 (kat.) EtO OH O / EtOH, RUckfluss, 2.5 h O / [Key: kat. = cat.; Rckflul = reflux] (3-hydroxy-phenyl)-acetic acid-ethyl ester Sulphuric acid (1 ml) was added to a solution of 3-hydroxyphenyl acetic acid (15.5 g) in ethanol (200 ml) and it was boiled for 1 h under reflux. The reaction mixture was cooled to room temperature. Water (50 ml) was added to the mixture and it was extracted with EtOAc. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. (18.2 g, brown oil) 159 GRA3394-WO-1 b) EtO OH NaH, MOM-CI EtO OMOM 0 - ~ THE I (3-methoxymethoxy-phenyl)-acetic acid-ethyl ester NaH (7.35 g) and MOM-Cl (14.8 g) was added gradually at 0 *C to a solution of (3 hydroxy-phenyl)-acetic acid-ethyl ester (27.6 g) in THF. After 14 h of stirring at the same temperature, the reaction mixture was heated to room temperature. The resultant mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n hex:EtOAc=15:1 to 10:1) in order to obtain the product as a colourless oil. (31.2 g, 90.9%) c) EtO , OMOM NaH, CH 3 1 EtO OMOM O DMF 0 2-(3-methoxymethoxy-phenyl)-propionic acid-ethyl ester Sodium hydride (6.21 g) and iodomethane were added gradually at 0 *C to a stirred solution of (3-methoxymethoxy-phenyl)-acetic acid-ethyl ester (31.2 g) in DMF (200 ml). After 20 h of stirring at 0 *C, this reaction mixture was quenched with water. This mixture was extracted with EtOAC and the combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=10:1) in order to obtain the product as a colourless oil. d) EtO OMOM TFA EtO OH 0 -CCH 2
CI
2 , 0 0 OC0 2-(3-hydroxy-phenyl)-propionic acid-ethyl ester TFA (150 ml) at 0 *C was added dropwise to a stirred solution of 2-(3 methoxymethoxy-phenyl)-propionic acid-ethyl ester in dichloromethane. The reaction 160 GRA3394-WO-1 mixture was stirred for 1 h at 0 *C and solid sodium bicarbonate (200 g) was added very slowly. The resultant mixture was poured very slowly into ice water and extracted with EtOAc. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=10:1 to 4:1) in order to obtain the product as a colourless oil. (19.0 g, 70.4%, 2 steps) e) EtO OH HNO 3 , AcOH EtO OH O - rt, 1h
-NO
2 2-(3-hydroxy-4-nitro-phenyl)-propionic acid-ethyl ester Nitric acid (11.3 g) was added at room temperature to a solution of 2-(3-hydroxy phenyl)-propionic acid-ethyl ester (19.0 g) in acetic acid (150 ml). The reaction mixture was stirred for 1 h at room temperature and water was added thereto. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=10:1) in order to obtain the product as a yellow solid. (6.08 g, 26.0%) f) EtO OH NaOH, 90 % aq. EtOH HO OH
NO
2 45 C, 20h
NO
2 90% aqueous EtOH 2-(3-hydroxy-4-nitro-phenyl)-propionic acid NaOH (1.24 mg) was added at room temperature to a stirred solution of 2-(3 hydroxy-4-nitro-phenyl)-propionic acid-ethyl ester (1.48 mg) in 90% aqueous EtOH. After 14 h of stirring at 45 *C, the reaction mixture was cooled to room temperature and diluted with water. The resultant aqueous layer was acidifed with acetic acid and subsequently extracted with dichloromethane. The combined organic layer was dried 161 GRA3394-WO-1 over magnesium sulphate, filtered and concentrated under a vacuum. (1.30 mg, 99.5 %, yellow solid) g) HO , OH 10% Pd/C, H 2 HO OH O NO 2 THF:EtOH(1:1) 0 NH 2 2-(4-amino-3-hydroxy-phenyl)-propionic acid 10% Pd/C (0,12 g) was gradually added at room temperature to a stirred solution of 2-(3-hydroxy-4-nitro-phenyl)-propionic acid (1.28 g) in THF (20 ml) and EtOH (20 ml). After 3 h of hydogenation with H 2 round flask, the reaction mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum in order to obtain the product as a yellow solid. (1.08 g, 98.4%) h) HO OH BrCN,hH 2 0 HO 20 O .- rt,40h 0 NH 0
NH
2 2-(2-amino-benzoxazol-6-yl)-propionic acid BrCN (648 mg) was added at room temperature to a stirred solution of 2-(4-amino-3 hydroxy-phenyl)-propionic acid (1.02 g) in H20. After 40 h of stirring at room temperature, the reaction mixture was neutralized with 30% aqueous NaOH to pH 6-7 and stirred for 1 h. The solid was filtered, washed with water and dried under a reduced vacuum in order to obtain the product as a yellow solid. (760 mg, 65.5%) Example 18 - 2-(2-amino-benzooxazol-6-y)-N-(4-tert-butyl-benzyl) propionamide H NH2 162 GRA3394-WO-1
'H-NMR(CDC
3 ) 6 7.32-7.28 (m, 4H, Ar), 7.12-7.07 (m, 3H, Ar), 5.61 (bt, NH), 5.01 (bs, NH 2 ), 4.37 (m, 2H, NHCH 2 ), 3.63 (q, 1H, J=7.1Hz, COCH), 1.57 (d, 3H, J=7.2Hz,
CHCH
3 ), 1.29 (s, 9H, C(CH 3
)
3 ) Synthesis of exemplary compound 19: a) EtO OH 10% Pd/C, H2 EtO OH O NO 2 THF:EtOH(1:1)
NH
2 2-(4-amino-3-hydroxy -phenyl)-propionic acid-ethyl ester 10% Pd/C (0.42 g) was gradually added at room temperature to a stirred solution of the starting material (4.63 g) in THF (50 ml) and EtOH (50 ml). After 2 h of hydogenation with H 2 round flask, the reaction mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=4:1) in order to obtain the product as a white or light pink solid. (3.86 g, 95.1%) b) EtO OH phenyl thionochloroformiat, DBU EtO 0 O N DMF, rt, 16 h 0 -C N 0NH 2 H [Key; thionochloroformiat = thionochloroformiate] 2-(2-thioxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid-ethyl ester Phenylchlorothionoformiate (563 mg in DMF) and DBU (829 mg, in DMF) at room temperature were added to a solution of 2-(4-amino-3-hydroxy -phenyl)-propionic acid-ethyl ester (570 mg) in DMF (5 ml). The reaction mixture was stirred for 14 h at room temperature and water was added to the mixture. The resultant mixture was extracted with ethyl ether. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=10:1 to 4:1) in order to obtain the product as a yellow oil. (90 mg, 13.2%) 163 GRA3394-WO-1 c) EtO NaOH, 90 % aq. EtOH HO 0 0 N 45 0 C, 20 h 0 N H H 2-(2-thioxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid NaOH (48 mg) was added at room temperature to a stirred solution of 2-(2-thioxo 2,3-dihydro-benzooxazol-6-yl)-propionic acid-ethyl ester (76 mg) in 90% aqueous EtOH. After 16 h of stirring at room temperature, the reaction mixture was cooled to room temperature and diluted with water. The resultant aqueous layer was acidified with acetic acid and subsequently extracted with dichloromethane. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. (58 mg, 86.0%, brown solid) Example 19 - N-(4-tert-butyl-benzyl)-2-(2-thioxo-2,3-dihydro-benzooxazol-6-y) propionamide H N 0 o>=s 0 N H 'H-NMR(CDC1 3 ) 8 7.36 (d, 2H, J=8.4Hz, Ar), 7.25 (d, 1H, J=1.5Hz, Ar), 7.20 (d, 2H, J=8.3Hz, Ar), 7.13 (dd, 1H, J=8.3, 1.5Hz, Ar), 6.79 (d, 1H, J=8.1Hz, Ar), 6.09 (bt, NH), 4.47 (m, 2H, NHCH 2 ), 3.68 (q, 1H, J=7.1 Hz, COCH), 1.57 (d, 3H, J=7.1 Hz,
CHCH
3 ), 1.29 (s, 9H, C(CH 3
)
3 ) IR 3300, 2962, 1645, 1496, 1418, 1362, 1150 cm-1 Mass (FAB) m/z 369 [M+H]* Synthesis of exemplary compound 20: a) 164 GRA3394-WO-1 EtO OH 1,2-Dibromoethan, K 2
CO
3 EtO
NH
2 DMF, 140 0 C, 3 h N NH2 H [Dibromoethan dibromoethane] 2-(3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-propionic acid-ethyl ester Potassium carbonate (2.68 g) and 1,2-dibromoethane (1.90 g) were added at room temperature to a stirred solution of the starting material (2.01 g) in DMF (25 ml). After 3 h of stirring at 140 0 C, the reaction mixture was cooled to room temperature and diluted with EtOAc. The resultant mixture was washed with water and the organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=4:1) in order to obtain the product as a brown oil. (265 mg, 11.7%) b) EtO O NaOH HO 0 O O / THF:H20=1:1 0 / H H 2-(3,4-d ihyd ro-2H-benzo[1,4]oxazin-7-yl)-propionic acid NaOH (134 mg) was added at room temperature to a stirred solution of 2-(3,4 dihydro-2H-benzo[1,4]oxazin-7-yl)-propionic acid-ethyl ester (258 mg) in THF (3 ml) and H20 (3 ml). After 20 h of stirring at room temperature, the reaction mixture was acidified with AcOH (pH = 4) and diluted with water. The resultant mixture was extracted with dichloromethane and the combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (CH 2
CI
2 :MeOH=1 5:1) in order to obtain the product as a brown oil. (150 mg, 65.8%) Example 20 - N-(4-tert-butylbenzyl)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7 yl)propionamide 165 GRA3394-WO-1 H N0 0N H 1
H-NMR(CDC
3 ) 6 7.31 (d, 2H, J=8.4Hz, Ar), 7.10 (d, 2H, J=8.2Hz, Ar), 6.70 (m, 2H, Ar), 6.55 (d, 1 H, J=7.9Hz, Ar), 5.68 (bt, NH), 4.44-4.23 (m, 4H, OCH 2 & NHCH 2 ), 3.75 (bt, NH), 3.50-3.39 (m, 3H, NHCH 2 & COCH), 1.50 (d, 3H, J=7.1Hz, CHCH 3 ), 1.30 (s, 9H, C(CH 3
)
3 ) IR 3304, 2963, 1649, 1516, 1357, 1305 cm-1 Mass (FAB) m/z 353 [M+H]* Synthesis of exemplary compound 21: a) HO 10% Pd/C, H 2 HO 0 NO 2 THF:EtOH(1:1) -O NH 2 2-(4-amino-phenyl)-propionic acid 10% Pd/C (0.21 g) was added slowly at room temperature to a stirred solution of 2 (4-nitrophenyl)propionic acid (2.05 g) in THF (20 ml) and EtOH (20 ml). After 2 h of hydrogenation with H 2 round flask, the reaction mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum in order to obtain the product as a light brown solid. (1.75 g, quantitative) b) HO FeSO 4 7H 2 0, Glycerol, Nitrobenzene HO Nz 0 NH 2
H
2
SO
4 , R~ckfluss, 5 h / N [Rickfluss = reflux] 2-quinolin-6-yl-propionic acid The mixture of 2-(4-amino-phenyl)-propionic acid (1.70 g), FeSO 4 7H 2 0 (0.30 g), glycerol (4.04 g) and sulphuric acid (2 ml) was stirred for 5 h under reflux. The reaction mixture was cooled to room temperature and subsequently concentrated 166 GRA3394-WO-1 under a reduced vacuum. The aqueous solution was treated with 12N-NaOH solution. The solid precipitate was filtered and the filtrate was acidified with AcOH. The resultant mixture was extracted and the combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (CH 2 Cl 2 :MeOH=15:1 to 10:1) in order to obtain the product as a brown solid. (0.83 g, 40.0%) Example 21 - N-(4-tert-butyl-benzyl)-2-quinolin-6-yI-propionamide H NN
H-NMR(CDC
3 ) 6 8.89 (dd, 1H, J=4.2, 1.4Hz, Ar), 8.10 (m, 2H, Ar), 7.74 (d, 1H, J=1.8Hz, Ar), 7.67 (dd, 1H, J=8.6, 1.8Hz, Ar), 7.41 (m, 1H, Ar), 7.29 (d, 2H, J=8.3Hz, Ar), 7.09 (d, 2H, J=8.1Hz, Ar), 5.74 (bt, NH), 4.39 (m, 2H, NHCH 2 ), 3.77 (q, 1H, J=7.1Hz, COCH), 1.64 (d, 3H, J=7.1Hz, CHCH 3 ), 1.28 (s, 9H, C(CH 3
)
3 ) IR 3294, 2962, 1651, 1544,1366,1232, 1117 cm~ 1 Synthesis of exemplary compound 22: Example 22 - 2-(1H-benzotriazol-5-yI)-N-(2-butoxy-6-tert-butyl-pyridin-3 ylmethyl)-propionamide N N N 0 0 " H H-NMR(CDCl 3 ) 6 7.80 (m, 2H, Ar), 7.37-7.30 (m, 2H, Ar), 6.75 (d, 1H, J=7.5Hz, Ar), 6.24 (bt, NH), 4.43-4.18 (m, 4H, OCH 2 & CH 2 NH), 3.74 (q, 1H, J=7.1 Hz, CHCH 3 ), 1.61-1.52 (m, 5H, CHCH 3 & OCH 2
CH
2 ), 1.35 (M, 2H, CH 2
CH
3 ), 1.27 (s, 9H, C(CH 3
)
3 ), 0.90 (t, 3H, J=7.4Hz, CH 2
CH
3 ) IR 3300, 2960, 1648, 1543,1457, 1413, 1255 cm 1 167 UKA3394-WU-1 Mass (FAB) m/z 410 [M+H]*, 432 [M+Na]* Exemplary compound 23: 2-(1 H-benzoimidazol-5-yi)-N-(2-butoxy-6-tert-butyl-pyridin-3-ylmethyl) propionamide N NN 0 0 N N H 'H-NMR(CDCl 3 ) 8 8.00 (s, 1H, Ar), 7.59 (m, 2H, Ar), 7.30 (d, 1H, J=7.5Hz, Ar), 7.17 (dd, 1H, J=8.3, 1.5Hz, Ar), 6.73 (d, 1H, J=7.5Hz, Ar), 6.17 (bt, NH), 4.38-4.14 (m, 4H,
OCH
2 & CH 2 NH), 3.70 (q, 1H, J=7.1Hz, CHCH 3 ), 1.58-1.47 (m, 5H, CHCH 3 &
OCH
2
CH
2 ), 1.38-1.25 (M, 11 H, CH 2
CH
3 & C(CH 3
)
3 ), 0.89 (t, 3H, J=7.3Hz, CH 2
CH
3 ) IR 3270, 2961, 1650, 1544, 1456, 1412, 1357, 1254 cm- 1 Mass (FAB) m/z 409 [M+H]*, 431 [M+Na]* Exemplary compound 24: 2-(1 H-benzotriazol-5-yi)-N-(6'-tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-3'-ylmethyl)-propionamide N N N- N -- N N 0 N N H 1 H-NMR (CDCI 3
+CD
3 0D) 8 7.77 (m, 2H, Ar), 7.37-7.26 (m, 2H, Ar), 6.85 (d, 1 H, J=7.7 Hz, Ar), 4.40 (m, 2H, CH 2 NH), 3.75 (q, 1H, J=7.0 Hz, CHCH 3 ), 3.18 (m, 2H, piperidine), 2.72 (m, 2H, piperidine), 1.65-1.00 (m, 5H, piperidine), 1.60 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.27 (s, 9H, C(CH 3
)
3 ), 0.88 (d, 3H, J=6.6 Hz, piperidine CH 3 ) IR 3300, 2956, 1646, 1565, 1450, 1371, 1234 cm-1 Mass (FAB) m/z 435 [M+H]* Exemplary compound 25: 168 GRA3394-WO-1 2-(1 H-benzoimidazol-5-yI)-N-(6'-tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-3'-ylmethyl)-propionamide NN I H H 'H-NMR (CDCl 3 ) 8 8.02 (s, 1H, Ar), 7.60 (bs, 2H, Ar), 7.26-7.19 (m, 2H, Ar), 6.83 (d, 1 H, J=7.7 Hz, Ar), 6.73 (bs, NH), 4.40 (m, 2H, CH 2 NH), 3.71 (q, 1 H, J=6.8 Hz,
CHCH
3 ), 3.18 (m, 2H, piperidine), 2.69 (m, 2H, piperidine), 1.65-1.00 (m, 5H, piperidine), 1.60 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.27 (s, 9H, C(CH 3
)
3 ), 0.88 (d, 3H, J=6.6 Hz, piperidine
CH
3 ) IR 3280, 2955, 1649, 1566, 1451, 1401, 1371, 1252 cm Mass (FAB) m/z 434 [M+H]* Exemplary compound 26: 2-(1 H-benzotriazol-5-yl)-N-(6-tert-butyl-2-cyclohexylsulfany-pyridin-3-ymethyl) propionamide s N H 1H-NMR (CDCl 3 ) 6 7.79 (bs, 2H, Ar), 7.36-7.30 (m, 2H, Ar), 6.88 (d, 1 H, J=7.9 Hz, Ar), 6.29 (bt, NH), 4.36 (m, 2H, CH 2 NH), 3.92 (m, 1H, SCH), 3.78 (q, 1H, J=7.1 Hz,
CHCH
3 ), 2.05-1.20 (m, 1OH, cyclohexyl), 1.60 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.28 (s, 9H,
C(CH
3
)
3 ) IR 3278, 2929, 2854, 1649, 1553, 1450, 1370, 1203, 734 cm Mass (FAB) m/z 452 [M+H]*, 474 [M+Na]* Exemplary compound 27: 2-(1 H-benzoimidazol-5-yI)-N-(6-tert-butyl-2-cyclohexylsulfanyl-pyridin-3 ylmethyl)-propionamide 169 GRA3394-WO-1 IH N- N Y - J, N S-N H 'H-NMR (CDCi 3 ) 6 8.03 (s, 1H, Ar), 7.60 (bs, 2H, Ar), 7.25 (m, 2H, Ar), 6.88 (d, 1H, J=7.7 Hz, Ar), 5.94 (bt, NH), 4.28 (m, 2H, CH 2 NH), 3.92 (m, 1 H, SCH), 3.72 (q, 1 H, J=7.3 Hz, CHCH 3 ), 2.01 (m, 2H, cyclohexyl), 1.77-1.20 (m, 8H, cyclohexyl), 1.59 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.29 (s, 9H, C(CH 3
)
3 ) IR 3270, 2928, 2854, 1652, 1554, 1449, 733 cm-1 Mass (FAB) m/z 451 [M+H]*, 473 [M+Na]* Synthesis of exemplary compound 29: I H IH - N - N SS diethyl chlorophosphat, K 2 Co 3 N N - s 0 N aceton, reflux, 14 h 0 0y -s H H [Key: phosphat = phosphate; aceton = acetone] n-(2-butyloxy-6-tert-butyl-pyridin-3-ylmethyl)-2-(2-ethylsulfanyl-2,3-dihydro benzothiazol-6-yi)-propionamide Diethylchlorophosphate (87 mg) and potassium carbonate (111 mg) were added at room temperature to a stirred solution of dwk-1877 (146 mg) in acetone. After 14 h of reflux, the reaction mixture was cooled to RT. The resultant mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=4:1 to 2:1) in order to obtain the product as a white solid. (122 mg, 78.7%) 170 GRA3394-WO-1 Example 29 - N-(2-butoxy-6-tert-butyl-pyridin-3-ylmethyl)-2-(2-ethylsulfanyl benzothiazol-6-yi)-propionamide N ~ NN N />SEt 1 H-NMR(CDCl 3 ) 8 7.80 (d, 1H, J=8.4Hz, Ar), 7.67 (d, 1H, J=1.7Hz, Ar), 7.34 (d, 1H, J=7.5Hz, Ar), 7.29 (dd, 1H, J=8.4, 1.8Hz, Ar), 6.76 (d, 1H, J=7.3Hz, Ar), 5.98 (bs, NH), 4.35-4.13 (m, 4H, OCH 2 & CH 2 NH), 3.63 (q, 1H, J=7.1Hz, CHCH 3 ), 3.35 (q, 2H, J=7.5Hz, SCH 2
CH
3 ), 1.59-1.47 (m, 8H), 1.32 (m, 2H, CH 2
CH
3 ), 1.28 (s, 9H, C(CH 3
)
3 ), 0.90 (t, 3H, J=7.3Hz, CH 2
CH
3 ) IR 3296, 2960, 1648, 1543, 1450, 1412, 1254,1002 cm- 1 Mass (FAB) m/z 486 [M+H]*, 508 [M+Na]* Synthesis of exemplary compound 30: F FE F H F H N / N N)S dimethyl chlorophosphat, K 2 Co 3 N N S N O N aceton, reflux, 14 h N 0 / N H H [Key: phosphat = phosphate] 2-(2-methylsulfanyl-2,3-dihydrobenzothiazol-6-yl)-N-(4-methyl-6' trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl) propionamide Dimethylchlorophosphate (92 mg) and potassium carbonate (140 mg) were added at room temperature to a stirred solution of dwk-1 891 (188 mg) in acetone. After 14 h of reflux, the reaction mixture was cooled to RT. The resultant mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant 171 GRA3394-WO-1 residue underwent chromatography on silica gel (n-hex:EtOAc=2:1) in order to obtain the product as a white solid. (164 mg, 84.9%) Example 30: 2-(2-methylsulfanyl-benzothiazol-6-y)-N-(4-methyl-6'-trifluoromethyl-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl)-propionamide F3CN-SMe N 0 />-WN 'H-NMR (CDC1 3 ) 6 7.82 (d, 1H, J=8.4 Hz, Ar), 7.71 (d, 1H, J=1.7 Hz, Ar), 7.43 (d, 1H, J=7.9 Hz, Ar), 7.32 (dd, 1H, J=8.4, 1.8 Hz, Ar), 7.16 (d, 1H, J=7.7 Hz, Ar), 6.19 (bt, NH), 4.45 (m, 2H, CH 2 NH), 3.70 (q, 1H, J=7.1 Hz, CHCH 3 ), 3.25 (m, 2H, piperidine), 2.79 (s, 3H, SCH 3 ), 2.76 (m, 2H, piperidine), 1.70-1.05 (m, 5H, piperidine), 1.60 (d, 3H, J=7.1 Hz, CHCH 3 ), 0.92 (d, 3H, J=6.6 Hz, piperidine CH 3 ) IR 3295, 2925, 1651, 1540, 1453,1177,1136 cm- 1 Mass (FAB) m/z 509 [M+H]* Synthesis of exemplary compound 32: a) HO
H
2
SO
4 , EtOH EtO
NO
2 reflux, 16 h
NO
2 (4-nitrophenyl)-acetic acid-ethyl ester Sulphuric acid (0.3 ml) was added at room temperature to the solution of starting material (3.42 g) in ethanol (30 ml). The reaction mixture was stirred for 16 h under reflux and subsequently cooled to room temperature. Ethanol was concentratd under a reduced vacuum and water was added to the residue. The aqueous layer was extracted with EtOAc and the organic layer was subsequently dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent 172 GRA3394-WO-1 chromatography on silica gel (n-hex:EtOAc=4:1) in order to obtain the product as a white solid. b) EtO N NaH,
CH
3 1 EtO o N0 2 DMF 0 N0 2 2-(4-nitrophenyl)-propionic acid-ethyl ester Sodium hydride (0.78 g) and iodomethane (1.21 ml) were added slowly at 0 *C to a stirred solution of (4-nitrophenyl)-acetic acid-ethyl ester (3.88 g) in DMF (15 ml). After 14 h of stirring at room temperature, this reaction mixture was quenched with water. This mixture was extracted with diethyl ether and the combined organic layer was subsequently dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n hex:EtOAc=10:1 to 4:1) in order to obtain the product as a light yellow oil. (89.1%) c) EtO 10% Pd/C, H 2 EtO O / NO THF:EtOH(1:1) NH 2 2-(4-aminophenyl)-propionic acid-ethyl ester 10% Pd/C (405 mg) was slowly added at room temperature to a stirred solution of 2 (4-nitrophenyl)-propionic acid-ethyl ester (3.67 g) in THF (40 ml) and EtOH (40 ml). After 20 h of hydrogenation with H 2 round flask, the reaction mixture was filtered off using diatomite and washed with EtOAc. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=4:1) in order to obtain the product as a light yellow oil. (99.7%) d) 173 GRA3394-WO-1 EtO OXONE, NaBr EtO Br o NH2 acetone/H 2 0 NH 2
NH
2 NH 2-(4-amino-3-bromo-phenyl)-propionic acid-ethyl ester OXONE (10.0 g) and NaBr (6,75 g) were added at room temperature to a stirred solution of 2-(4-aminophenyl)-propionic acid-ethyl ester (3.16 g) in acetone and water. After 2 min of stirring at room temperature, the reaction mixture was diluted with EtOAc and poured into 5% aqueous Na 2
S
2
O
3 solution. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=6:1) in order to obtain the product as a white solid. (49.6%) e) EtO Br Kaliumethylxanthat EtO S o NH2 DMF, reflux, 14h N
NH
2 H [Kaliumethlxanthat = Potassium ethic xanthate ] 2-(2-thioxo-2,3-dihydro-benzothiazol-6-yl)-propionic acid-ethyl ester Potassium ethyl xanthate (1.86 g) was added at room temperature to a stirred solution of 2-(4-amino-3-bromo-phenyl)-propionic acid-ethyl ester (1.58 g) in DMF. After 14 h of stirring under reflux, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and salt water, dried over magnesium sulphate and concentrated under a vacuum. The resultant residue underwent chromatography on silica gel (n-hex:EtOAc=6:1 to 4:1) in order to obtain the product as a yellow oil. (595 mg, 38.3%) f) EtO _ S NaOH HO S 0 N THF:H20=1:1 0 N H H 174 GRA3394-WO-1 2-(2-thioxo-2,3-d ihyd ro-benzothiazol-6-yl)-propionic acid NaOH (229 mg) was added at room temperature to a stirred solution of 2-(2-thioxo 2,3-dihydro-benzothiazol-6-yl)-propionic acid-ethyl ester (587 mg) in THF (4 ml) and
H
2 0 (4 ml). After 14 h of stirring at room temperature, the reaction mixture was acidified with AcOH (pH = 4) and diluted with water. The resultant mixture was extracted with dichloromethane and the combined organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. (511 mg, 97%, light yellow solid) Example 32 - N-(4-methyl-6'-trifluoromethyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-3'-ylmethyl)-2-(2-thioxo-2,3-dihydro-benzothiazol-6-yl) propionamide
F
3 C .S NJ N N 0 " N H 1 H-NMR (CDCl 3 ) 8 7.51 (d, 1H, J=7.9 Hz, Ar), 7.41 (d, 1H, J=1.3 Hz, Ar), 7.25-7.19 (m, 2H, Ar), 7.12 (d, 1H, J=8.4 Hz, Ar), 6.42 (bt, NH), 4.51 (m, 2H, CH 2 NH), 3.64 (q, 1H, J=7.1 Hz, CHCH 3 ), 3.31 (m, 2H, piperidine), 2.81 (m, 2H, piperidine), 1.78-1.10 (m, 5H, piperidine), 1.57 (d, 3H, J=7.1 Hz, CHCH 3 ), 0.96 (d, 3H, J=6.6 Hz, piperidine
CH
3 ) IR 3300, 2924,1650, 1534,1472, 1416, 1332, 1177,1136, 1035 cm' Mass (FAB) m/z 495 [M+H]* Exemplary compound 33: N-(6'-tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl)-2-(2 thioxo-2,3-dihydro-benzothiazol-6-yl)-propionamide N N N N I-aI>=S Y H 175 GRA3394-WO-1 'H-NMR (CDC13) 8 7.40-7.21 (m, 3H, Ar), 7.06 (d, 1 H, J=8.4 Hz, Ar), 7.05 (bs, NH), 6.90 (d, 1H, J=7.7 Hz, Ar), 4.46 (m, 2H, CH 2 NH), 3.61 (q, 1H, J=7.1 Hz, CHCH 3 ), 3.25 (m, 2H, piperidine), 2.83-2.71 (m, 2H, piperidine), 1.75-1.50 (m, 3H, piperidine), 1.55 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.30 (s, 9H, C(CH 3
)
3 ), 1.30-1.10 (m, 2H, piperidine), 0.95 (d, 3H, J=6.4 Hz, piperidine CH 3 ) IR 3295, 2923, 1647, 1536, 1475, 1400, 1034 cm-1 Mass (FAB) m/z 483 [M+H] Exemplary compound 34: N-(6'-tert-butyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl)-2-(2 methylsulfanyl-benzothiazol-6-yI)-propionamide H N N S N~
>-SCH
3 H-NMR (CDC1a) 3 7.80 (d, 1H, J=8.3 Hz, Ar), 7.72 (s, 1H, Ar), 7.34-7.25 (m, 2H, Ar), 6.85 (d, 1H, J=8.0 Hz, Ar), 6.68 (bt, NH), 4.40 (m, 2H, CH 2 NH), 3.66 (q, 1H, J=6.8 Hz, CHCH 3 ), 3.18 (m, 2H, piperidine), 2.79 (s, 3H, SCH 3 ), 2.71 (m, 2H, piperidine), 1.65-1.40 (m, 6H, piperidine & CHCH 3 ), 1.28 (s, 9H, C(CH 3
)
3 ), 1.20-1.00 (m, 2H, piperidine), 0.89 (d, 3H, J=6.4 Hz, piperidine CH 3 ) IR 3293, 2955, 1648, 1543, 1450, 1238, 1013 cm-1 Mass (FAB) m/z 497 [M+H]* Synthesis of exemplary compound 35: a) HO
HNO
3 HO s NO 2 OH H 3 COOH OH 2-(4-hydroxy-3-nitrophenyl)-propionic acid 60% nitric acid (552 mg, 1.11 mmol) was added at room temperature to 2-(4 hydroxyphenyl)-propionic acid (788 mg, 1 mmol) in CH 3 COOH (10 ml). 176 GRA3394-WO-1 The reaction mixture was stirred for 1 h. Ice water (50 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulphate, filtered and concentrated under a vacuum. The residue was purified by flash column chromatography with CH 2
CI
2 :MeOH. Light yellow solid, yield: 86.9%. b) HO s NO 2 10% Pd/C, H 2 HO s NH 2 O OH THF:EtOH=1:1 0 OH 2-(3-amino-4-hydroxyphenyl)-propionic acid 10% Pd/C (90 mg) was added slowly at room temperature to a mixture of 2-(4 hydroxy-3-nitrophenyl)-propionic acid (810 g, 1 mmol) in THF (20 ml) and EtOH (20 ml). The reaction mixture was hydrogenated for 3 h with H2 round flask at 45 psi. The mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum. Light black solid, yield: 99.2% c) HO NH 2 BrCN HO N O H 2 0Y I 0 Reference: DE 2 324 443 2-(2-aminobenzoxazol-5-yl)-propionic acid BrCN (383 mg, 1.04 mmol) was added at room temperature to a mixture of 2-(3 amino-4-hydroxyphenyl)-propionic acid (630 mg, 1 mmol) in H 2 0 (33 ml). The reaction mixture was stirred for 40 h at room temperature. The reaction mixture was neutralised to pH 6.7 with 40% aqueous NaOH and filtered. 177 GRA3394-WO-1 The solid was recrystallised with 50% aqueous MeOH and filtered. The solid was dried in a vacuum. Light brown solid, yield: 48.8%. Example 35 - 2-(2-amino-benzooxazol-5-yl)-N-(4-methyl-6'-trifluoromethyl 3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl)-propionamide
F
3 C Y H N N Y 0 'H-NMR (CDCl 3 ) 8 7.43 (d, 1H, J=7.5 Hz, Ar), 7.28-6.97 (m, 4H, Ar), 6.09 (bt, NH), 5.35 (bs, NH 2 ), 4.43 (d, 2H, J=5.7 Hz, CH 2 NH), 3.68 (q, 1 H, J=7.3 Hz, CHCH 3 ), 3.26 (m, 2H, piperidine), 2.76 (m, 2H, piperidine), 1.72-1.45 (m, 6H, piperidine & CHCH 3 ), 1.14 (m, 2H, piperidine), 0.93 (d, 3H, J=6.4 Hz, CHCH 3 ) IR 3298, 2925, 1660, 1573, 1419, 1178, 1138, 951 cm- 1 Mass (FAB) m/z 462 [M+H]* Synthesis of exemplary compound 36: a) NC N Conc. HCI HO ~N0 2 0 0 2-(4-aminophenyl)-propionic acid (1) Conc. hydrochloric acid (50 ml) was added at room temperature to 2-(4 nitrophenylpropionitrile (6.03 g). The reaction mixture was boiled for 14 h under reflux. The mixture was cooled to room temperature. The mixture was extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulphate, filtered and concentrated under a vacuum. Light yellow solid, yield: quantitative. 178 GRA3394-WO-1 b) HO H 2
SO
4 EtO 0
NO
2 EtOH 0 NO 2 2-(4-nitrophenyl)-propionic acid-ethyl ester (2) A mixture of 1 (6.7 g, 1 mmol) in EtOH (100 ml) was stirred at room temperature. A sulphuric acid (0.5 ml; catalytic quantity) was added slowly to the mixture. The reaction mixture was boiled for 15 h under reflux. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by means of flash column chromatography with (n hexane:EtOAc). Light yellow oil, yield: 88%. c) EtO 10% Pd/C, H 2 EtO ON2 THF:EtOH=1:1 0 / NH 2 2-(4-aminophenyl)-propionic acid-ethyl ester (3) 10% Pd/C (680 mg) was added slowly at room temperature to a solution of 2 (6.7g, 1mmol) in THF (100ml) and EtOH (100ml). The reaction mixture was hydrogenated for 24 h with H2 round flask at room temperature. The mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum. Light yellow oil, yield: 54% d) 179 GRA3394-WO-1 EtO NH2 KSCN, Br 2 EtO HS
NH
2
CH
3 COOH N Reference: Indian Journal of Chemistry, Vol. 16B, S. 605-609 2-(2-aminobenzothiazol-6-y)-propionic acid-ethyl ester (4) A mixture of 3 (3.13g, 1 mmol) in CH 3 COOH (15ml) was cooled in an ice bath to -5. A mixture of KSCN (6.36 g, 4.04 mmol) in CH 3 COOH (15ml) was added to the flask with 4 and CH 3 COOH at -5"C in an ice bath. A solution of bromine (0.80 ml) in CH 3 COOH (10 ml) was added dropwise to a stirred mixture of 4, KSCN and CH 3 COOH at -5 0 C in an ice bath. The reaction mixture was stirred for 1 h at room temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by flash column chromatography (n-hexane:EtOAc). Light yellow solid. e) EtO 2S Ac 2 0 EtO r - s 0 ~~ />-NH 2 />N o N N 2-(2-acethlaminobenzthiazol-6-yl)-propionic acid-ethyl ester (5) A mixture of 4 (278 mg) in acetic acid anhydride (4 ml) was boiled for 3h under reflux. The mixture was cooled to room temperature. Water (30 ml) was added to the mixture and extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. Yield: 88%. f) 180 GRA3394-WO-1 EtO S NaOH HO .- S /NH 0NH O N THF:H 2 0=1:1 O N 2-(2-acetylaminobenzothiazol-6-yl)-propionic acid (6) A mixture of 5 (276 mg, 1 mmol) in THF (10 ml) and H 2 0 (10 ml) was stirred at room temperature. Sodium hydroxide (96 mg) was added to the mixture. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was acidified with acetic acid to pH 3.4. Water was added to the mixture and extracted with dichloromethane. The organic layer was dried over magnesium sulphate, filtered and concentrated in a vacuum. Light yellow solid, yield: 99.8%. Exemplary compound 35: 2-(2-acetylamino-benzothiazol-6-y)-N-(4-tert-butyl-benzyl)-propionamide H N SN >-NHAc 1 H-NMR(CDCl 3 ) 5 11.17 (bs, NH), 7.78-7.68 (m, 2H, Ar), 7.42-7.21 (m, 3H, Ar), 7.11 (d, 2H, J=8.2Hz, Ar), 5.75 (bt, NH), 4.39 (m, 2H, CH 2 NH), 3.71 (q, 1H, J=7.1Hz,
CHCH
3 ), 2.27 (s, 3H, COCH 3 ), 1.61 (d, 3H, J=7.1Hz, CHCH 3 ), 1.28 (s, 9H, C(CH 3
)
3 ) IR 3298, 2963, 1649, 1548, 1462, 1369,1275 cm- 1 Mass (FAB) m/z 410 [M+H]*, 432 [M+Na]* Exemplary compound 37: 2-(2-acetylamino-benzothiazol-6-y)-N-(4-methyl-6'-trifluoromethyl-3,4,5,6 tetrahydro-2H-[1,2']bipyridinyl-3'-ylmethyl)-propionamide 181 GRA3394-WO-1
F
3C NNc N H 1)' IaS/-NHAc 'H-NMR (CDCl 3 ) 67.80-7.63 (m, 2H, Ar), 7.39 (m, 2H, Ar), 7.13 (d, 1H, J=7.5 Hz, Ar), 4.43 (m, 2H, CH 2 NH), 3.78 (m, 1 H, CHCH 3 ), 3.30 (m, 2H, piperidine), 2.79 (m, 2H, piperidine), 2.31 (s, 3H, COCH 3 ), 1.80-1.20 (m, 8H, CHCH 3 & piperidine), 0.94 (d, 3H, J=6.2 Hz, piperidine CH 3 ) IR 3189, 2923, 2455, 1644, 1548, 1458, 1418, 1372, 1335, 1270, 1175, 1135 cm Mass (FAB) m/z 520 [M+H]* Synthesis of exemplary compound 38: a) NC NO2 Conc. HCI HO N ~N0 2 0 I NH 2 2-(4-aminophenyl)-propionic acid (1) 2-(4-nitrophenyl)-propionitrile (6,03g) was added to conc. hydrochloric acid (50 ml) at room temperature. The reaction mixture was boiled for 14 h under reflux. The mixture was cooled to room temperature. The mixture was extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulphate, filtered and concentrated in a vacuum. Bright white solid, yield: 99%. b) HO 10% Pd/C, H 2 HO
NO
2 THF:EtOH=1:1 O NH2 2-(4-aminophenyl)-propionic acid (2) 182 GRA3394-WO-1 10 % Pd/C (680 mg) was added slowly at room temperature to a mixture of 1 (6.7 g, 1 mmol) in THF (100ml) and EtOH (100 ml). The reaction mixture was hydrogenated for 24 h with H2 round flask at room temperature. The mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum. Light yellow solid, yield: 99.8% c) HO NH KSCN, Br 2 HO S
NH
2 C00H0 N Reference: Indian Journal of Chemistry, Vol. 16B, S. 605-609 2-(2-aminobenzthiazol-6-yl)-propionic acid (3) A mixture of 2 (3.13 g, 1 mmol) in CH 3 COOH (15 ml) was cooled in an ice bath to -5. A mixture of KSCN (6.36 g, 4.04 mmol) in CH 3 COOH (15 ml) was added to the flask with 4 and CH 3 COOH at -5 in an ice bath. A solution of bromine (0.80 ml) in CH 3 COOH (10 ml) was added dropwise to a stirred mixture of 4, KSCN and CH 3 COOH at -5 in an ice bath. The reaction mixture was stirred for 1 h at room temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light yellow solid. Synthesis of exemplary compound 39: a) NC NO2 Conc. HCI HO NH2 N 1 8
NO
2 0 NH 2 183 GRA3394-WO-1 2-(4-aminophenyl)-propionic acid (1) 2-(4-nitrophenyl)-propionitrile (6,03 g) was added at room temperature to conc. hydrochloric acid (50 ml). The reaction mixture was boiled for 14 h under reflux. The mixture was cooled to room temperature. The mixture was extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulphate, filtered and concentrated in a vacuum. Light yellow solid, yield: quantitative. b) HO H 2 S0 4 EtO O NO 2 EtOH
NO
2 2-(4-nitrophenyl)-propionic acid-ethyl ester (2) A mixture of 1 (6.7 g, 1 mmol) in EtOH (100 ml) was stirred at room temperature. A sulphuric acid (0.5 ml; catalytic quantity) was added slowly to the mixture. The reaction mixture was boiled for 15 h under reflux. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light yellow oil, yield: 88%. c) EtO 10% Pd/C, H 2 EtO O NO 2 THF:EtOH=1:1 0 NH 2 2-(4-aminophenyl)-propionic acid-ethyl ester (3) 184 GRA3394-WO-1 10% Pd/C (680 mg) was added slowly at room temperature to a mixture of 2 (6.7 g, 1 mmol) in THF (100 ml) and EtOH (100 ml). The reaction mixture was hydrogenated for 24 h with H2 round flask at room temperature. The mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum. Light yellow oil, yield: 54% d) EtO KSCN, Br 2 EtO Hs
NH
2
CH
3 COOH N N Reference: Indian Journal of Chemistry, Vol. 16B, S 605-609 2-(2-aminobenzothiazol-6-y)-propionic acid-ethyl ester (4) A mixture of 3 (3.13 g, 1 mmol) in CH 3 COOH (15 ml) was cooled in an ice bath to -5. A mixture of KSCN (6.36 g, 4.04 mmol) in CH 3 COOH (15 ml) was added to the flask with 4 and CH 3 COOH at -5 in an ice bath. A solution of bromine (0.80 ml) in CH 3 COOH (10 ml) was added dropwise to a stirred mixture of 4, KSCN and CH 3 COOH at -5 in an ice bath. The reaction mixture was stirred for 1 h at room temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light yellow solid. e) 185 GRA3394-WO-1 EtO S MSCI EtO O S ,S.. 0 />NH Pyridin 0 > N/W0 [Pyridin = Pyridine] 2-(2-methansulfonylamino-benzothiazol-6-yl)-propionic acid-ethyl ester (5) A mixture of 4 (347 mg, 1 mmol) in pyridine (3 ml) was added to MsCI (0.13 ml, 1.21 mmol) at room temperature. The reaction mixture was stirred for 14 h at room temperature. 1 N HCI (30 ml) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulphate. The filtrate was concentrated under a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light yellow oil, yield: 35%. f) Et 1 0 NaOH HO .. s S, I />-_NH' 1 I >-NW E O N THF:H 2 0=1:1 H N 2-(2-methansulfonylamino-benzothiazol-6-yl)-propionic acid (6) A mixture of 5 (156 mg, 1 mmol) in THF (10ml) and H 2 0 (10 ml) was stirred at room temperature. Sodium hydroxide (50 mg, 2.5 mmol) was added to the mixture. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was acidified to pH 3-4 with acetic acid. Water was added to the mixture and extracted with dichloromethane. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. Yield: quantitative. Synthesis of exemplary compound 40: 186 GRA3394-WO-1 a) NC-NO2 Conc. HCI HO ~N0 2 0 I NH 2 2-(4-aminophenyl)-propionic acid (1) 2-(4-nitrophenyl)-propionitrile (6.03 g) was added to conc. hydrochloric acid (50 ml) at room temperature. The reaction mixture was boiled for 14 h under reflux. The mixture was cooled to room temperature. The mixture was extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulphate, filtered and concentrated in a vacuum. Light yellow solid, yield: quantitative. b) HO H 2
SO
4 EtO O ~N0 2 EtOH 0 ~N0 2 2-(4-nitrophenyl)-propionic acid-ethyl ester (2) A mixture of 1 (6.7 g, 1 mmol) in EtOH (100 ml) was stirred at room temperature. A sulphuric acid (0.5 ml; catalytic quantity) was added slowly to the mixture. The reaction mixture was boiled for 15 h under reflux. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light yellow oil, yield: 88%. c) EtO 10% Pd/C, H 2 EtO 0 NO 2 THF:EtOH=1:1 0 NH 2 187 GRA3394-WO-1 2-(4-aminophenyl)-propionic acid-ethyl ester (3) 10% Pd/C (680 mg) was added slowly at room temperature to a mixture of 2 (6.7 g, 1 mmol) in THF (100 ml) and EtOH (100 ml). The reaction mixture was hydrogenated for 24 h with H2 round flask at room temperature. The mixture was filtered off using diatomite and washed with EtOH. The filtrate was concentrated under a vacuum. Light yellow oil, yield: 54% d) EtO NH KSCN, Br 2 EtO Hs
NH
2
CH
3 COOH ~ N Reference: Indian Journal of Chemistry, Vol. 16B, S. 605-609 2-(2-aminobenzothiazol-6-yl)-propionic acid-ethyl ester (4) A mixture of 4 (3.13 g, 1 mmol) in CH 3 COOH (15 ml) was cooled in an ice bath to -5. A mixture of KSCN (6.36 g, 4.04 mmol) in CH 3 COOH (15 ml) was added to the flask with 4 and CH 3 COOH at -5 in an ice bath. A solution of bromine (0.80 ml) in CH 3 COOH (10 ml) was added dropwise to a stirred mixture of 4, KSCN and CH 3 COOH at -5 in an ice bath. The reaction mixture was stirred for 1 h at room temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water and salt water, dried over magnesium sulphate, filtered and concentrated in a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light yellow solid. e) 188 GRA3394-WO-1 EtO H2S Boc 2 O, TEA EtO os I>NH I,-ia />-NHBoc SN 1,-ixn [Key: Dioxan = dioxane] 2-(2-tert-butoxycarbonylamino-benzthiazol-6-y)-propionic acid-ethyl ester (5) A mixture of 4 (793 mg, 1 mmol) in 1,4-dioxane was added to Boc 2 0 (3.5 g, 5 mmol) and TEA (2.21 ml, 5 mmol) at room temperature. The reaction mixture was boiled for 14 h under reflux. The mixture was cooled to room temperature. Water was added to the mixture und extracted with dichloromethane. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography (n hexane:EtOAc). Light white solid, yield: 22%. f) EtO r S NaOH HO S SNHBoc -NHBoc >N THF:H 2 0=1:1 O N 2-(2-tert-butoxycarbonylamino-benzothiazol-6-yl)-propionic acid (6) A mixture of 5 (239 mg, 1 mmol) in THF (10 ml) and H 2 0 (10 ml) was stirred at room temperature. Sodium hydroxide (68.2 mg, 2.5 mmol) was added to the mixture. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was acidified to pH 3-4 with acetic acid. Water was added to the mixture und extracted with dichloromethane. The organic layer was dried over magnesium sulphate, filtered and concentrated under a vacuum. Yield: quantitative. 189 GRA3394-WO-1 Synthesis of exemplary compound 44 a)
H
2 N s 1. NaNO 2 , HCI, 0*C 1 N' 2. aq KI, rt, 3h / N H H 1 H-indazol-5-ylamine 5-iodo-1 H-indazole A solution of NaNO 2 (730 mg, 10.6 mmol) in water (10 ml) was added dropwise to a solution cooled to 0O0C of 1H-indazol-5-amine (1.41 g, 10.6 mmol) in 6 N HCI (20 ml). The resultant solution was added to a solution of KI (7.3 g, 44 mmol) in water (15 ml) and the temperature was kept at 0 *C. The reaction mixture was allowed to heat to room temperature and stirred for 3 h and subsequently extracted with ethyl acetate. The combined layers were consecutively washed with 10% Na 2
S
2 0 3 and salt water, subsequently dried over Na 2
SO
4 and concentrated under a vacuum in order to obtain a light brown solid (1.90 g, 75%) which was used in the next step without further purification. b) 0 OEt Cs 2
CO
3 , Cul (5 mol%), N 2-picolinic acid(10 mol%) E N H 1,4-dioxane, 70*C, 7h H 5-Iodo-1 H-indazole 2-(1H-Indazol-5-yl)-malonic acid diethyl ester Distilled diethyl malonate (304 pL, 2.00 mmol) and 5-iodo-1H-indazole (1.00 mmol) were added to Cul (9.5 mg, 5.0 mol%), 2-picolinic acid (12.3 mg, 10.0 mol%), Cs 2 C0 3 (0.98 g, 3.0 mmol), and aryl iodide (1.0 mmol) in 1,4-dioxane (10 ml). After 7 hours of stirring at 70 *C, the reaction mixture was cooled to room temperature. The mixture was extracted/washed with ethyl acetate (20 mL x 3) and with saturated aqueous NH 4 CI (10 mL). The combined organic phases were filtered via Na 2
SO
4 and concentrated in a vacuum. The oily residue was purified by flash chromatography on silica gel and the desired product obtained as a colourless oil (60%). c) 190 GRA3394-WO-1 OEt 0 0 0 NaH, Mel O OEt IN DMF, 0 0 C ON H H 2-(1 H-indazol-5-yl)-malonic acid diethyl ester 2-(IH-indazol-5-yl)-2-methyl malonic acid diethyl ester A cooled solution of diethyl-2-(1H-indazol-5-yl)malonate (1 mmol) in DMF (10 ml) was treated at 0 0C with NaH (1.1 mmol) and Mel (1.2 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated under a vacuum and the residue was purified by means of flash column chromatography with EtOAc:hexanes (1:4) as the eluent on silica gel. (65%) d) NaOH HO O ~ N N aq EtOH, reflux, 6h H 2-(1 H-indazol-5-yl)-2-methyl-malonic acid diethyl ester 2-(1H-indazol-5-yl) 2-propionic acid A mixture of diethyl-2-(1 H-indazol-5-yl)-2-methyl malonate (1 mmol) and NaOH (2 mmol) in 80% aqueous EtOH (10 ml) was boiled for 6 h under reflux. The mixture was neutralized with 1 N HCI. The reaction mixture was extracted with ethyl acetate (20 ml x 3) and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:1) as the eluent on silica gel. 53% e) 191 GRA3394-WO-1
F
3 C ,,
F
3 CH HO N + N NH 2 HOBT, EDC N NN N AN'aXN 0 N H H A mixture of acid (10 mmol), amine (12 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidhydrochloride (12 mmol) in DMF (20 ml) was stirred for 12 h at room temperature. The reaction mixture was extracted with EtOAc (50 ml). The aqueous phase was saturated with NaCl and once again extracted with EtOAc (25 ml). The combined organic extracts were washed with 1 N HCI (25 ml) and salt water (25 ml), dried over MgSO 4 , filtered and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:2) as the eluent on silica gel. 75%, white solid, melting point = 113-115 *C Synthesis of exemplary compound 45:
H
2 N F 1. NaNO 2 , HCI, O 0 C F N I \N 2. aq KI, rt, 3h / N H H 3-fluoro-1 H-indazol-5-ylamine 3-fluoro-5-iodo 1 H-indazole In accordance with general method 56% colourless oil O OEt F F Cs 2
CO
3 , Cui (5 mol%), N 2-Picolinssure(10 mol%) N N OEt N' H 1,4-Dioxan, 70 0 C, 7h H [2-Picolinsaure = 2-picolinic acid; Dioxan = dioxane] 192 GRA3394-WO-1 3-fluoro-5-iodo- IH-indazole 2-(3-fluoro-1 H-indazol-5-yl)-malonic acid diethyl ester In accordance with general method Colourless oil (60%) o OEt 0 O - F 0 NaH, Mel O OEt NN DMF, 0C ,N H H 2-(3-fluoro-1 H-indazol-5-yl)-malonic acid diethyl ester 2-(3-fluoro-1 H-indazol-5 yl)-2- methyl-malonic acid diethyl ester In accordance with general method Colourless oil (70%) F H O N NaOH HO N o0 N' aq EtOH, reflux, 6h H H 2-(3-fluoro-1 H-indazol-5-yl)-2- 2-(3-fluoro-1 H-indazol-5-yl) propionic acid methyl-malonic acid diethyl ester In accordance with general method Colourless oil (53%) F H3 F3 HO N F3C NH 2 HOBT, EDC N- N 0N AN, rt N 0 H H 193 GRA3394-WO-1 2-(3-fluoro-1 H-indazol-5-yi)-propionic acid 2-(3-fluoro-1 H-indazol-5-yl)-N-((2-(4 methylpiperidin-1 -yl)-6 In accordance with general method 70%, white solid, melting point = 123-127 *C Synthesis of exemplary compound 46: a)
H
2 N 1. NaNO 2 , HCI, 0*C ' N 2. aq KI, rt, 3h / N H H 1 H-indazol-5-ylamine 5-iodo-1 H-indazole A solution of NaNO 2 (730 mg, 10.6 mmol) in water (10 ml) was added dropwise to a solution cooled to 0 *C of 1 H-indazol-5-amine (1.41 g, 10.6 mmol) in 6 N HCI (20 ml). The resultant solution was added to a solution of KI (7.3 g, 44 mmol) in water (15 ml) and the temperature was kept at 0 *C. The reaction mixture was allowed to heat to room temperature and stirred for 3 h and subsequently extracted with ethyl acetate. The combined layers were consecutively washed with 10% Na 2
S
2
O
3 and salt water, subsequently dried over Na 2
SO
4 and concentrated under a vacuum in order to obtain a light brown solid (1.90 g, 75%) which was used in the next step without further purification. b) 0 OEt Cs 2
CO
3 , Cul (5 mol%), 2-Picolinssure(10 mol%) \N SN H 1,4-dioxan, 704C, 7h H [Key: 2-Picolinssure = 2-picolinic acid; Dioxan = dioxane] 5-iodo-1 H-indazole 2-(1H-indazol-5-yl)-malonic acid diethyl ester 194 GRA3394-WO-1 Distilled diethylmalonate (304 pL, 2.00 mmol) and 5-iodo-1 H-indazole (1.00 mmol) were added to Cul (9.5 mg, 5.0 mol%), 2-picolinic acid (12.3 mg, 10.0 mol%), Cs2CO3 (0.98 g, 3.0 mmol), and aryl iodide (1.0 mmol) in 1,4-dioxane (10 ml). After 7 hours of stirring at 70 0C, the reaction mixture was cooled to RT. The reaction mixtures were extracted with ethyl acetate (20 mL x 3) and saturated aqueous NH 4 CI (10 mL). The combined organic layer was dried over Na 2
SO
4 , filtered and concentrated under a vacuum. The oily residue was purified by flash chromatography on silica gel in order to obtain the desired product in the form of a colourless oil (60%). c) o OEt 0 O, 0 NaH, Mel O I N IN OEt NN DMF, 0 0 C 0 N H H 2-(1H-indazol-5-yl)-malonic acid diethyl ester 2-(1 H-indazol-5-yl)-2 methyl-malonic acid diethyl ester A cooled solution of diethyl-2-(1 H-indazol-5-yl)malonate (1 mmol) in DMF (10 ml) was treated at 0 0C with NaH (1.1 mmol) and Mel (1.2 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated under a vacuum and the residue was purified by means of flash column chromatography on silica gel with EtOAc:hexanes (1:4) as the eluent. (65%) d) O 0HO O N NaOH HON 0 N' aq EtOH, reflux, 6h H H aqueous EtOH, reflux, 6h 2-(1 H-Indazol-5-yl)-2-methyl- 2-(1 H-indazol-5-yl)-propionic acid malonic acid diethyl ester 195 GRA3394-WO-1 A mixture of diethyl-2-(1 H-indazol-5-yl)-2-methyl malonate (1 mmol) and NaOH (2 mmol) in 80% aqueous EtOH (10 ml) was boiled for 6 h under reflux. The reaction mixture was neutralized with 1 N HCI. The reaction mixture was extracted with ethyl acetate (20 ml x 3) and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:1) as the eluent on silica gel. 53% e) HO F 3 c H Ho N F N- NH 2 HOBT, EDC NN N H 0 AN, rt 0 0 2-(1H-Indazol-5-yl)-propionic acid 2-(1H-indazol-5-yl)-2-propionic acid N-(2-butoxy-6-tert-butyl-pridin 3-ylmethyl)-2- (1H-indazol-5-yl)- propionamide In accordance with general method 60%, white solid, melting point = 103-107 0C 196 GRA3394-WO-1 Synthesis of exemplary compound 48 a)
H
2 N 1. NaNO 2 , HCI, 0 0 C IN N N 2. aq KI, rt, 3h - N H H 1 H-indazol-5-ylamine 5-iodo-1 H-indazole A solution of NaNO 2 (730 mg, 10.6 mmol) in water (10 ml) was added dropwise to a solution cooled to 0 OC of 1 H-Indazol-5-amine (1.41 g, 10.6 mmol) in 6 N HCI (20 ml). The resultant solution was added to a solution of KI (7.3 g, 44 mmol) in water (15 ml) and the temperature was kept at 0 *C. The reaction mixture was allowed to heat to room temperature and stirred for 3 h and subsequently extracted with ethyl acetate. The combined layers were consecutively washed with 10% Na 2
S
2 0 3 and salt water, subsequently dried over Na 2
SO
4 and concentrated under a vacuum in order to obtain the product as a light brown solid (1.90 g, 75%) which was used in the next step without further purification. b) 0 OEt Cs 2
CO
3 , Cul (5 mol%), 0 N 2-Picolinsaure(10 mol%) O N -~ N' Et t N H 1,4-dioxan, 70 0 C, 7h H [Key: 2-Picolinsaure = 2-picolinic acid; Dioxan = dioxane] 1,4-dioxane 5-iodo-1 H-indazole 2-(1H-indazol-5-yl)-malonic acid diethyl ester Distilled diethyl malonate (304 pL, 2.00 mmol) and 5-iodo-1 H-indazole (1.00 mmol) were added to Cul (9.5 mg, 5.0 mol%), 2-picolinic acid (12.3 mg, 10.0 mol%), Cs 2
CO
3 (0.98 g, 3.0 mmol), and aryl iodide (1.0 mmol) in 1,4-dioxane (10 ml). After 7 hours of stirring at 70 *C, the reaction mixture was cooled to RT. The reaction mixtures were extracted with ethyl acetate (20 mL x 3) and saturated aqueous NH 4 CI (10 mL). The combined organic layer was dried over Na 2
SO
4 , filtered and concentrated under a vacuum. The oily residue was purified by flash chromatography 197 GRA3394-WO-1 on silica gel in order to obtain the desired product in the form of a colourless oil (60%). c) OQEt 0 O, NaH, Mel O OEt N DMF, 0*C O N H H 2-(1H-indazol-5-yl)-malonic acid diethyl ester 2-(1 H-indazol-5-yl)-2-methyl malonic acid diethyl ester A cooled solution of diethyl-2-(1 H-indazol-5-yl)malonate (1 mmol) in DMF (10 ml) was treated at 0 0C with NaH (1.1 mmol) and Mel (1.2 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated under a vacuum and the residue was purified by means of flash column chromatography on silica gel with EtOAc:hexanes (1:4) as the eluent.(65%) d) O NNaOH HO N 01 N ON aq EtOH, reflux, 6h H H 2-(1 H-indazol-5-yl)-2-methyl- 2-(1 H-indazol-5-yl)-propionic acid malonic acid diethyl ester A mixture of diethyl-2-(1 H-indazol-5-yl)-2-methyl malonate (1 mmol) and NaOH (2 mmol) in 80% aqueous EtOH (10 ml) was boiled for 6 h under reflux. The mixture was neutralized with 1 N HCI. The reaction mixture was extracted with ethyl acetate (20 ml x 3) and concentrated under a vacuum. The residue was purified by means of flash column chromatography with EtOAc:hexanes (1:1) as the eluent on silica gel. 53% 198 GRA3394-WO-1 e) HO N + NH 2 HOBT, EDC NN 0 ~ N + s N N AN, rt Y' :N' H H 2-(1H-indazol-5-yl)-propionic acid N-(6-tert-butyl-2 cyclohexylsulfanyl-pyridin- 3-ylmethyl)-2-1 H-indazol-5-yl) propionamide In accordance with general method 76%, white solid, melting point = 105-108 0C Exemplary compound 49: N-(2-butoxy-6-tert-butyl-pyridin-3-ylmethyl)-2-(2-thioxo-2,3-dihydro benzothiazol-6-yl)-propionamide N N S 0 0 I-C N= H 1 H-NMR(CDCl 3 ) S 7.38 (m, 2H, Ar), 7.21-7.03 (m, 2H, Ar), 6.79 (d, 1H, J=7.5Hz, Ar), 6.16 (bs, NH), 4.33 (m, 4H, OCH 2 & CH 2 NH), 3.58 (q, 1H, J=7.1Hz, CHCH 3 ), 1.65 (m, 2H, OCH 2
CH
2 ), 1.52 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.40 (m, 2H, CH 2
CH
3 ), 1.30 (s, 9H, C(CH 3
)
3 ), 0.95 (t, 3H, J=7.3Hz, CH 2
CH
3 ) IR 2958, 1648, 1537, 1475, 1405,1254,1033 cm-1 Mass (FAB) m/z 458 [M+H]* Synthesis of further exemplary compounds Exemplary compound 12: 2-(1 H-benzotriazol-5-yl)-N-(4-tert-butyl-benzyl)-propionamide 199 GRA3394-WO-1
'H-NMR(CDC
3 ) 5 7.82 (m, 2H, Ar), 7.48 (dd, 1H, Ar), 7.26 (d, 2H, J=8.4Hz, Ar), 7.08 (d, 2H, J=8.4Hz, Ar), 4.30 (s, 2H, NHCH 2 ), 3.87 (q, 1 H, J=7.1 Hz, CHCH 3 ), 1.54 (d, 3H, J=7.1 Hz, CHCH 3 ), 1.26 (s, 9H, C(CH 3
)
3 ) Mass (FAB) m/z 338 [M+H]* NC - N2 a NC - NH2 b NC NHAc C NC ,a NO 2 d HO r - NO 2 e HO y - NH 2 NHAc NH2 0 NH2 NzN I H H H ' N NH 2 g N . 0 N0 N N
NH
2 H a. 10% Pd/C, H 2 , THF/EtOH, 94%; b. Ac 2 0, Pyridin, 98%; c. Ac 2 0, HNO 3 56%; d. konz. HCl, 88%; e. 10% Pd/C, H 2 , H 2 0/EtOH, 50%; f. 4-t-Butylbenzylamin, EDCI, HOBt, TEA, DMF, 70%; g. NaNO 2 , 5% aq. AcOH, quantitativ [Key: Pyridin = pyridine; konz. = conc.; 4-t-Butylbenzylamin = "4-t-butylbenzylamine; aq. = aq.; quantitativ = quantitative] Exemplary compound 13: 2-(1 H-benzoimidazol-5-yl)-N-(4-methyl-6'-trifluoromethyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-3'-ylmethyl)-propionamide
F
3 C
F
3 C IH IH N- N .- NH 2 Nd- N N N 0 N NH 2 N 0 NN H 2-(3,4-diaminophenyl)-N-(4-methyl-6'-trifluoromethyl-3,4,5,6-tetrahydro-2H [1,2']bipyridinyl-3'-ylmethyl)-propionamide (48 mg, 0.110 mmol) was combined at RT with triethyl orthoformate (2 ml). The reaction mixture was heated to reflux for 2 h and cooled to RT. The reaction mixture was combined with water and repeatedly 200 GRA3394-WO-1 extracted with DCM. The combined organic phases were dried over MgSO 4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (DCM/MeOH = 10:1). 1
H-NMR(CD
3 0D) 6 8.16 (s, 1H), 7.61-7.56 (m, 2H), 7.39 (d, 1H, J=7.3Hz), 7.28 (dd, 1 H, J=8.3, 1.7Hz), 7.08 (d, 1 H, J=7.7Hz), 4.46-4.27 (m, 2H), 3.84 (q, 1 H, J=7.OHz), 3.37-3.30 (m, 2H), 2.81-2.70 (m, 2H), 1.65 (m, 2H), 1.54 (d, 3H, J=7.OHz), 1.52-1.45 (m, 1H), 1.32-1.21 (m, 2H), 0.94 (d, 3H, J=6.6Hz) IR 3310, 2921, 1650, 1539, 1457, 1418, 1134, 759 cm-1 Mass (FAB) m/z 447 [M+H]* Exemplary compound 14: 2-(1 H-benzoimidazol-5-yl)-N-(4-tert-butyl-benzyl)-propionamide H N .- N H The compound was obtained by reacting N-(4-tert-butylbenzyl)-2-(3,4 diaminophenyl)propanamide with triethyl orthoformate in a similar manner to exemplary compound 13. 1
H-NMR(CD
3 0D) 5 8.13 (s, 1H), 7.61-7.53 (m, 2H), 7.29-7.24 (m, 3H), 7.06 (d, 1H, J=8.6Hz), 4.29 (s, 2H), 3.78 (q, 1H, J=7.1Hz), 1.52 (d, 3H, J=7.1Hz), 1.25 (s, 9H) IR 3272, 2965, 1649, 1515, 1266, 1113, 756 cm 1 Mass (FAB) m/z 337 [M+H]* Exemplary compounds 61-77 and 43-49 can likewise be obtained in accordance with the methods described herein. Pharmacological data The affinity of the compounds according to the invention for the vanilloid receptor 1 (VR1/TRPV1 receptor) was determined as described above (Pharmacological methods I or II). 201 GRA3394-WO-1 The compounds according to the invention of the above-stated formula I exhibit excellent affinity for the VR1/TRPV1 receptor (Table 1). Table 1. Compound Ki (Rat) Ki (Human) IC 50 (Human) according to Capsaicin [nM] Capsaicin [nM] [nM] Example after pH stimulus 1 579 ne 7 2173 ne 9 1075 ne 11 ne 13 7 ne 14 ne 20 9% @ 5 pM; ne 0% @ 1 pM 23 15.3 ne 34 38% @ 5 pM; ne 3%@ 1pM 38 28.4 ne 39 15% @ 1 PM; ne 0% @ 0.1 pM 40 34% @ 5 pM; 37% @ 10 pM; 14%@1pM 21%@5pM 0% @0.1 PM 0% @ 1 PM 41 18% @ 1 pM ne 5% @ 0.1 pM 50 10% @ 5 pM 53% @ 10 pM 6% @ 1 pM 25% @ 5 pM 0% @ 0.1 PM 10% @ 1 PM 51 27% @ 1 pM 39% @ 5 pM 3% @ 0.1 pM 27% @ 1 pM 10% @ 0,1 PM 52 18% @ 1 pM ne 5% @ 0.1 pM 55 12% @ 5 pM 27% @ 5 pM 0%@1pM 5%@1pM 56 18.7 12% @ 10 pM 2%@5pM 57 32.8 32% @ 10 pM 3% @ 5 pM 58 60 27.8 ne 59 5.7 3.5 ne 60 45.8 26 ne 202 GRA3394-WO-1 ne means in each case "no effect", i.e. no response was observed. The value after the sign "@" indicates the concentration at which inhibition (in percent) was determined in each case. The action of the compound according to the invention was likewise determined using the formalin test (Pharmacological methods 1ll) in mice. Compound according Inhibition to Example Formalin test 13 0.3 per os 25% 23 0.3 per os 13% per os (perorally) 203

Claims (16)

1. Substituted compounds of the general formula I, R 8 U | R 7 Ri V IR N R2 (CH 2 )n R6 R3 R 4 5 in which n denotes 0, 1, 2, 3 or 4; 10 R 1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 6 3 -; -S-C(=0)-NR 63 -; -0-C(=0)-NR 6 3_; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -0-; -NH-C(=0)-NH-; -NH-C(=S) NH-: -NR 66 -C(=0)-NR 6 5 -; -NR 66 -C(=S)-NR 6 1-; -O-CH 2 -C(=0)-NH-; -O-CH 2 -0-; is O-CH 2 -CH 2 -0-, -0-CH 2 -CH 2 -CH 2 -0-; -0-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8 =N-NR 6 2_; _S_ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 63 -; -0 20 C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 2 9 =N-; -N=CH 0-; -N=CR 3 0 -0-; -N=CH-NH-; -N=CH-NR 64 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; NR 66 -C(=O)-NR 6 1-; -NR 66 -C(=S)-NR 6 5 -; -N=N-NH-; -N=N-NR 6 7 -; -0-CH 2 -C(=0) NH-; -0-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2 CH 2 -C(=0)-NH-; -0-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH 25 N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH-, N=N-CR 6 5 =CR 69 -; -N=CR 6 6 -N=CR 69 ; -N=CR 68 -CR 69 =N-; -CR 66 =CR 69 -CH=N-; CR 6 1=CR 6 9 -N=CR 70 -; -CR 68 =N-N=CR 6 9 - and -O-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group 30 consisting of -CH=N-NH-; -CR 2 8 =N-NH-; -CH=N-NR 6 2 -; -CR 2 1=N-NR 6 2_; __ C(=S)-NH-; -O-C(=S)-NH-; -S-C(=0)-NH-; -O-C(=0)-NH-; -S-C(=S)-NR 63-; -O- - 205 C(=S)-NR 63 -; -S-C(=O)-NR 63 -; -0-C(=O)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 0-; -N=CR 3
6-O-; -N=CH-NH-; -N=CH-NR 64 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; NR 66 -C(=O)-NR 6 1-; -NR 66 -C(=S)-NR 6 5 -; -N=N-NH-; -N=N-NR 6 7 -; -O-CH 2 -C(=0) NH-; -O-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2 5 CH 2 -C(=O)-NH-; -O-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH-, N=N-CR 6 1=CR 6 9 -; -N=CR 6 -N=CR 69 ; -N=CRea-CR 69 =N-; -CRes=CR 69 -CH=N-; CR 6 1=CR 6 9 -N=CR 70 -; -CRes=N-N=CR 6 9 - and -O-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent structure, I or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=0)-NH-; -0 C(=O)-NH-: -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 63 -; -O-C(=O)-NR 6 3 _; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -- ; -NH-C(=O)-NH-; -NH-C(=S) NH-; -NR 66 -C(=0)-NR 6 5 -; -NR 66 -C(=S)-NR 6 5 -; -O-CH 2 -C(=O)-NH-; -0-CH 2 -0-; is O-CH 2 -CH 2 -0-, -O-CH 2 -CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 or R 4 and R 5 together with the carbon atoms joining them together form a 4-, 5-, 6- or 7-membered ring which is saturated, unsaturated or aromatic, has 1, 2 or 3 nitrogen atoms as ring 20 members and is unsubstituted or substituted with 1, 2 or 3 residues mutually independently selected from the group consisting of F, Cl, Br, I, =0, -CN, -CF 3 , SF 5 , -OH, -O-C 1 . 5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 1 . 5 -alkyl, -C 1 - 5 alkyl, -C(=O)-OH, -C(=O)-O-C 1 . 5 -alkyl, -NH-C 1 . 5 -alkyl, -N(C 1 . 5 -alkyl) 2 , -NH S(=0) 2 -C 1 . 5 -alkyl, -NH-C(=O)-O-C1. 5 -alkyl, -C(=O)-H, -C(=O)-C 1 . 5 -alkyl, -C(=O) 25 NH 2 , -C(=O)-NH-C 1 . 5 -alkyl, -C(=O)-N-(C 1 . 5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, CF 3 , -SF 5 , -CN, -NO 2 , -C1.5 alkyl, -O-C 1 . 5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -0 30 benzyl, and the remaining residues R 1 , R 2 , R , R 4 and R , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2 -NH 2 ; -C(=O)-NH-OH; -C(=0)-OH; -C(=O)-H; -S(=0) 2 -OH; -C(=NH)-NH 2 ; -C(=NH)- -206 NH-R 9 ; -N=C(NH 2 ) 2 ; -N=C(NHR")(NHR"); -O-P(=0) 2 -0-R 12 ; -NHR"; -NR 14 R 15 -NH-C(=O)-R; -OR 16 ; -SR"; -C(=O)-NHR; -C(=O)-NR 19 R 2 0 ; -S(=0) 2 -NHR 21 ; S(=0) 2 -NR 22 R 2 3 ; -C(=O)-OR 24 ; -C(=O)-R 2 5 ; -S(=O)-R 2 6 ; -S(=0) 2 -R 2 7 or denote a linear or branched, saturated or unsaturated, unsubstituted or at least 5 monosubstituted aliphatic C1.10 residue; R 6 denotes H or denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; R 7 denotes hydrogen or -OH; or R 6 and R 7 in each case together with the carbon atom joining them io together as a ring member form a saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6- or 7-membered cycloaliphatic residue; R 8 denotes CF 3 or tert-butyl; T denotes C-R 35 and U denotes C-R 36 and V denotes N and W denotes C R 38 is or T denotes C-R 35 and U denotes N and V denotes C-R 37 and W denotes C R 3 8 or T denotes N and U denotes C-R 3 6 and V denotes C-R 37 and W denotes C 20 R 38 or T denotes N and U denotes N and V denotes C-R 37 and W denotes C-R 3 " or T denotes N and U denotes C-R 3 6 and V denotes N and W denotes C-R 3 25 or T denotes C-R 35 and U denotes N and V denotes N and W denotes C-R 3 or T denotes C-R 35 and U denotes C-R 36 and V denotes C-R 37 and W denotes C-R 3 8; 30 R 9 , R 10 , R", R , R , R 4 , Ri 5 , Ri 6 , R , R 18 , R 19 , R 20 , R , R 22 , R 23 , R 24 R 25 R and R , mutually independently, in each case - 207 denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.1o residue; denote an unsaturated or saturated, unsubstituted or at least monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue 5 optionally comprising at least one heteroatom as a ring member, which residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1-6 alkylene group or 2 to 6-membered heteroalkylene group; 1o or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or 2- to 6-membered heteroalkylene group; 1s R 2 denotes F; Cl; Br; I; -SF 5 ; -NO 2 ; -CF 3 ; -CN; -NH 2 or denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; R 29 and R 3 0 , mutually independently, in each case denote -NH-C(=O)-R 3 1 ; -NH 2 ; -NH-S(=0) 2 -R 3 2 ; -NH-C(=O)-O-R 3 ; -S-R 3 4 or denote a linear or branched, 20 saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1. 10 residue; R 31 , R 32 , R 3 and R 34 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; 25 R , R 36 and R , mutually independently, in each case denote H; F; Cl; Br; 1; -SF 5 ;-NO 2 ; -CF 3 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2 -NH 2 ; -C(=0)-NH OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -NHR"; -NR' 4 R"; -NH-C(=O)-R ; OR 16 ; -SR 17 ; -C(=O)-NHR; -C(=O)-NR"R 20 ; -S(=0) 2 -NHR 2 1 ; -S(=0) 2 -NR 22 R 23 ; -C(=O)-OR 24 ; -C(=O)-R 25 ; -S(=O)-R 2 6 ; -S(=0) 2 -R 27 ; 30 denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system - 208 and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C 1 . 6 alkylene group or C 2 - 6 alkenylene group or C 2 - 6 alkynylene group; R 38 is selected from the group consisting of -NR 40 R 4 1, OR 4 2 and SR 43 ; 5 R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 4 , R 47 , R 4 , R 49 , R 50 , R 51 , Rs 2 , R 53 , R 54 , R 55 and R 56 , mutually independently, in each case denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1 . 1 0 residue; denote an unsaturated or saturated, unsubstituted or at least 10 monosubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic residue optionally comprising at least one heteroatom as a ring member, which residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C 1 . 6 alkylene group or 2 is to 6-membered heteroalkylene group; or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least 20 monosubstituted C1.6 alkylene group or 2- to 6-membered heteroalkylene group; or R 4 0 and R 41 in each case together with the nitrogen atom joining them together as a ring member form a saturated or unsaturated, unsubstituted 4-, 5-, 6-, 7-, 8- or 9-membered heterocycloaliphatic residue or 4-, 5-, 6-, 7-, 8- or 9 25 membered heterocycloaliphatic residue substituted with 1, 2, 3, 4 or 5 residues R 57 and optionally comprising at least one further heteroatom as a ring member, which heterocycloaliphatic residue may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system; 30 R 57 denotes -NHR 5 , -NR 5 9 R 6 0 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1 . 10 residue; R" 8 , R 5 ' and R 60 , mutually independently, in each case denote -C(=O)-R 6 1 ; denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue - 209 or denote an unsubstituted or at least monosubstituted 5- to 14-membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least s monosubstituted C1-6 alkylene group or C2-6 alkenylene group or C2-6 alkynylene group; R 61 denotes a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1-10 residue; R 62 , R 63 , R 64 , R 65 , R 66 and R 67 , mutually independently, in each case to denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; Rea, R 69 and R 70 , mutually independently, in each case denote F, Cl, Br, I, or denote a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C1.10 residue; and is R 71 denotes an unsubstituted or at least monosubstituted 5- to 14 membered aryl or heteroaryl residue, which may be fused with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system and/or be attached via a linear or branched, unsubstituted or at least monosubstituted C1.6 alkylene group or C2.6 alkenylene group or C2.6 alkynylene 20 group, in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of 25 corresponding salts or in each case in the form of corresponding solvates; wherein the above-stated aliphatic C1.10 residues and tert-butyl residues may optionally in each case be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, 30 NO 2 , -OH, -NH 2 , -SH, -O(C 1 . 5 -alkyl), -S(C 1 . 5 -alkyl), -NH(C 1 . 5 -alkyl), -N(C 1 . 5 alkyl)(C 1 . 5 -alkyl), -C(=0)-O-C1. 5 -alkyl, -O-C(=O)-C 1 . 5 -alkyl, -0-phenyl, phenyl, OCF 3 and -SCF 3 ; the above-stated 2- to 6-membered heteroalkylene groups, C1.6 alkylene groups and C2.6 alkenylene groups and C2-6 alkynylene groups may optionally in -210 each case be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -O(C 1 . 5 -alkyl), -S(C 5 -alkyl), -NH(C 1 . 5 -alkyl), -N(C 1 . 5 -alkyl)(Cl. 5 -alkyl), -OCF 3 and -SCF 3 ; 5 the above-stated heteroalkylene groups may in each case optionally comprise 1, 2 or 3 heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur (NH) as chain link(s); the above-stated (hetero)cycloaliphatic residues may optionally be substituted in each case with 1, 2, 3, 4 or 5 substituents mutually independently 10 selected from the group consisting of -C 1 . 6 -alkylene-OH, =CH 2 , -O-C 1 .s5alkylene oxetanyl, -C 1 . 5 -alkylene-O-Cl 5 -alkylene-oxetanyl, -CH 2 -NH-C 1 . 5 -alkyl, -CH 2 N(C 1 . 5 -alkyl) 2 , -N[-C(=0)-C 1 . 5 -alkyl]-phenyl, -CH 2 -0-C1. 5 -alkyl, oxo (=0), thioxo (=S), F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-Cl. 5 -alkyl, -O-C(=0)-C 15 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 1 .s-alkyl, -C 5 -alkyl, -C(=0)-C1.s-alkyl, -C(=O) is OH, -C(=0)-0-C 1 . 5 -alkyl, -NH-C 1 . 5 -alkyl, -N(C 5 -alkyl) 2 , -NH-phenyl, -N(-C 5 alkyl)-phenyl, cyclohexyl, cyclopentyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5) thiadiazolyl, thiophenyl, phenethyl, piperidinyl, pyrrolidinyl, -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues oxetanyl, (4,5)-dihydroisoxazolyl, thiazolyl, (1,2,5) 20 thiadiazolyl, thiophenyl, phenethyl, -N[-C(=0)-C 1 . 5 -alkylj-phenyl, -NH-phenyl, N(-C 1 5 -alkyl)-phenyl, -(CH 2 )-pyridinyl, pyridinyl, -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , CN, -NO 2 , -C1-5 alkyl, -O-C 1 . 5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl, 25 and unless otherwise stated the above-stated (hetero)cycloaliphatic residues may in each case optionally comprise 1, 2 or 3 (further) heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur; the rings of the above-stated mono- or polycyclic ring systems may in 30 each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of oxo (=0), thioxo (=S),), F, C, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-C 1 . 5 -alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, S-C 1 . 5 -alkyl, -C 1 5 -alkyl, -C(=0)-C1. 5 -alkyl, -C(=O)-OH, -C(=0)-0-C 1 . 5 -alkyl, -NH C 1 .s-alkyl, -N(C 1 . 5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in - 211 each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, -OH, -CF 3 , -SF 5 , CN, -N02, -C1-5 alkyl, -0-C1-5 alkyl, -O-CF3, -S-CF3, phenyl and -O-benzyl, 5 and the rings of the above-stated mono- or polycyclic ring systems are in each case 5-, 6- or 7-membered and may in each case optionally comprise 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s), which are mutually independently selected from the group consisting of oxygen, nitrogen and sulfur; and the above-stated aryl or heteroaryl residues may optionally be io substituted in each case with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-C1.5 alkyl, -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-C 1 . 5 -alkyl, -C 1 .s-alkyl, -C(=O)-OH, C(=O)-C 1 . 5 -alkyl, -NH-C 1 . 5 -alkyl, -N(C 1 . 5 -alkyl) 2 , -NH-S(=0) 2 -C1. 5 -alkyl, -NH C(=O)-0-C 1 . 5 -alkyl, -C(=O)-H, -C(=O)-C 1 .s-alkyl, -C(=O)-NH 2 , -C(=O)-NH-C 1 . 5 is alkyl, -C(=O)-N-(C 1 . 5 -alkyl) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl, wherein in each case the cyclic moiety of the residues -0-phenyl, -O-benzyl, phenyl and benzyl may be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, C, Br, -OH, -CF 3 , -SF 5 , CN, -NO 2 , -C.s alkyl, -O-C 1 . 5 -alkyl, -0-CF 3 , -S-CF 3 , phenyl and -O-benzyl, 20 and the above-stated heteroaryl residues may in each case optionally comprise 1, 2, 3, 4 or 5 heteroatom(s) mutually independently selected from the group consisting of oxygen, nitrogen and sulfur as ring member(s). 2. A compound according to claim 1, characterised in that 25 n denotes 0, 1, 2, 3 or 4; R 1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 C(=O)-NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=O)-NR 63 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 3 0 -- ; -NH-C(=O)-NH-; -NH-C(=S) 30 NH-; -NR 66 -C(=O)-NR 6 5 -; -NR 66 -C(=S)-NR 6-; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; O-CH 2 -CH 2 -0-, -O-CH 2 -CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, -212 or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR1 2 -; -CR 28 =N-NR 6 2 -; -S-C(=S)-NH-; -0 C(=S)-NH-; -S-C(=O)-NH-; -O-C(=O)-NH-; -S-C(=S)-NR 6 3 -; -O-C(=S)-NR 63 -; -S C(=O)-NR 6 3 -; -O-C(=O)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -0-; 5 -N=CH-NH-; -N=CH-NR 64 -; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=O) NR 65 -; -NR 66 -C(=S)-NR 6 5 -; -N=N-NH-; -N=N-NR 6 7 -; -O-CH 2 -C(=O)-NH-; -0-CH 2 0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2 -CH 2 -C(=O)-NH-; 0-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -O-CH 2 -CH 2 10 NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 28 =N-NR 6 2_; _S_ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -O-C(=0)-NH-; -S-C(=S)-NR 63 -; -0 C(=S)-NR 63 -; -S-C(=O)-NR 6 -; -O-C(=O)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 1s 0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR64-; -NH-C(=0)-NH-; -NH-C(=S)-NH-; NR 66 -C(=O)-N R 65 -; -NR 66 -C(=S)-NR 6 5 -; -N=N-NH-; -N=N-N R 67 -; -O-CH 2 -C(=O) NH-; -O-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2 CH 2 -C(=O)-NH-; -O-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and 20 O-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 63 -; -S-C(=O)-NR 63 -; -O-C(=0)-NR 63 -; 25 -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -- ; -NH-C(=O)-NH-; -NH-C(=S) NH-; -NR 66 -C(=O)-NRe1-; -NR 66 -C(=S)-NR 6 5 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; O-CH 2 -CH 2 -0-, -0-CH 2 -CH 2 -CH 2 -O-; -O-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R 5 , mutually independently, 30 in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; S(=0) 2 -NH 2 ; -C(=O)-NH-OH; -C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -NHR"; NR 14 R 15 ; -NH-C(=O)-R 13 ; -OR 16 ; -SR 17 ; -S(=O)-R 2 6 ; -S(=0) 2 -R 27 or denote a residue selected from the group consisting of methyl, -CF 3 , -CC13, -CBr 3 , -CHF 2 , -213 -CH 2 F, -CF 2 CI, -CCl 2 F, ethyl, -CF 2 -CH 3 , -CH 2 -CF 3 , -C 2 F 5 , -CH 2 -CCl 3 , -CH 2 -CBr 3 , -CHF-CF 2 CI, -CF 2 -CF 2 CI, -CFCI-CF 2 CI, n-propyl, -CF 2 -CF 2 -CF 3 , -CF(CF 3 ) 2 , isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; R 6 denotes H or denotes an alkyl residue selected from the group 5 consisting of -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -CH 2 OH, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, methyl, ethyl and n-propyl; R 7 denotes hydrogen or -OH; or R 6 and R , in each case together with the carbon atom joining them together as a ring member, form a residue selected from the group consisting of 10 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; R 8 denotes -CF 3 or tert-butyl; T denotes C-R 3 5 and U denotes C-R 3 6 and V denotes N and W denotes C R 38 or is T denotes C-R 3 5 and U denotes N and V denotes C-R 37 and W denotes C Ras8 or T denotes N and U denotes C-R 36 and V denotes C-R 37 and W denotes C R 3 8 20 or T denotes N and U denotes N and V denotes C-R 37 and W denotes C-R 38 or T denotes N and U denotes C-R 36 and V denotes N and W denotes C-R 3 1 or 25 T denotes C-R 35 and U denotes N and V denotes N and W denotes C-R 3 8 or T denotes C-R 35 and U denotes C-R 36 and V denotes C-R 37 and W denotes C-R 38 ; R 1 , R", R 1 , R 16 , R 17 , R 26 and R , mutually independently, in each case 30 denote a residue selected from the group consisting of methyl, -CF 3 , CC1 3 , -CBr 3 , -CHF 2 , -CH 2 F, -CF 2 CI, -CCl 2 F, -CH 2 -CN, -CH 2 -0-CH 3 , -CH 2 -0-CF 3 , -CH 2 -SF 3 , ethyl, -CF 2 -CH 3 , -CH 2 -CF 3 , -C 2 F 5 , -CH 2 -CC1 3 , -CH 2 -CBr 3 , -CHF CF 2 Cl, -CF 2 -CF 2 Cl, -CFCI-CF 2 CI, -CH 2 -CH 2 -CN, n-propyl, -CF 2 -CF 2 -CF 3 , CF(CF 3 ) 2 , isopropyl, -CH 2 -CH 2 -CH 2 -CN, -CH 2 -0-CH 2 -CH 3 , -CH 2 -CH 2 -SF 3 , -CH 2 - -214 CH 2 -OCF 3 , -CH(CH 3 )(0-CH 3 ), -CH(CH 3 )(S-CH 3 ), n-butyl, -CF 2 -CF 2 -CF 2 -CF 3 , CH 2 -CH 2 -CH 2 -CH 2 -CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl-hept-4-yl, 3-methyl butyl, n-hexyl, (3,3)-dimethylbutyl, -CH 2 -CH 2 -0-CH 3 , -CH 2 -CH 2 -0-C 2 H 5 , -CH 2 5 CH 2 -CH 2 -0-CH 3 , ethenyl, propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and 3 pentenyl; denote a residue selected from the group consisting of 2,3-dihydro-1 H indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, 1a piperazinyl, azepanyl, diazepanyl, azocanyl and thiomorpholinyl, which may in each case be attached via a -CH 2 -0, -CH 2 -CH 2 -0, -CH 2 -CH 2 -0-CH 2 , -CH 2 CH(CH 3 )-O-CH 2 , -(CH 2 ), -(CH 2 ) 2 or -(CH 2 ) 3 group and/or in each case be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of oxo (=0), thioxo (=S), -OH, is -0-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, n-pentyl, -C(=0)-CH 3 , -C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 , -C(=O)-C(CH 3 ) 3 , -C(=O)-OH, -C(=O)-O-CH 3 , -C(=0)-O-C 2 H 5 , -C(=0)-0 CH(CH 3 ) 2 and -C(=0)-O-C(CH 3 ) 3 ; 20 or denote a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl and isoxazolyl, the residue in each case being capable of being attached via a -(CH 2 ), -(CH 2 ) 2 or -(CH 2 ) 3 group and/or in each case unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents 25 mutually independently selected from the group consisting of F, Cl, Br, I, -CN, CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -NH 2 , -NO 2 , -0 CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, -C(=0)-OH, C(=O)-O-CH 3 , -C(=O)-O-C 2 H 5 , -C(=O)-O-CH(CH 3 ) 2 , -C(=O)-0-C(CH 3 ) 3 , -NH 30 CH 3 , -NH-C 2 H 5 , -NH-C(CH 3 ) 3 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , -N(CH 3 )(C 2 H 5 ), -NH-C(=O) O-CH 3 , -NH-C(=O)-O-C 2 H 5 , -NH-C(=0)-O-C(CH 3 ) 3 , -C(=O)-H, -C(=O)-CH 3 , C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 , -C(=O)-C(CH 3 ) 3 , -C(=O)-NH 2 , -C(=O)-NH-CH 3 , C(=O)-NH-C 2 H 5 , -C(=0)-N(CH 3 ) 2 , -C(=O)-N(C 2 H 5 ) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl; -215 R 2 8 denotes F; Cl; I; -SF 5 ; -NO 2 ; -CF 3 ; -CN; -NH 2 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl, which may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents s mutually independently selected from the group consisting of F, Cl, Br, I, -CN, NO 2 , -OH, -NH 2 and -SH; R 29 and R 30 , mutually independently, in each case denote -NH-C(=O)-R 31 ; -NH 2 ;.-NH-S(=0) 2 -R 3 2 ; -NH-C(=O)-O-R 33 ; -S-R 3 4 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, io sec-butyl, isobutyl, tert-butyl, and n-pentyl, which may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, NO 2 , -OH, -NH 2 and -SH; R 31 , R 32 , R 3 3 and R 34 , mutually independently, in each case denote an is alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl, which may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 and -SH; 20 R 35 , R ' and R 3 7 , mutually independently, in each case denote H; F; Cl; Br; I; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -C(=O)-NH 2 ; -S(=0) 2 -NH 2 ; -C(=O)-NH-OH; C(=O)-OH; -C(=O)-H; -S(=0) 2 -OH; -NHR 13 ; -NR 1 4 R 15 ; -OR"; -SR 17 ; -S(=O)-R 25 ; -S(=0) 2 -R 2 6 ; denote a residue selected from the group consisting of -CH 2 -OH, methyl, -CF 3 , -CC13, -CBr 3 , -CHF 2 , -CH 2 F, -CF 2 CI, -CCl 2 F, ethyl, -CF 2 -CH 3 , 25 CH 2 -CF 3 , -C 2 F 5 , -CH 2 -CC1 3 , -CH 2 -CBr 3 , -CHF-CF 2 CI, -CF 2 -CF 2 CI, -CFCI-CF 2 C1, n-propyl, -CF 2 -CF 2 -CF 3 , -CF(CF 3 ) 2 , isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl or denote a phenyl residue, which may be unsubstituted or optionally substituted with 1, 2, 3; 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-CH 3 , -O-C 2 H 5 , 30 -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2 H 5 , S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl. R 38 is selected from the group consisting of NR 40 R 41 , OR 42 and SR 43 -216 R 39 , R 40 , R 4 , R 42 , R 43 , R 50 , R 52 , R 53 , R 54 , R 55 and R 5 , mutually independently, in each case denote a residue selected from the group consisting of methyl, -CF 3 , CC13, -CBr 3 , -CHF 2 , -CH 2 F, -CF 2 Cl, -CCl 2 F, -CH 2 -CN, -CH 2 -0-CH 3 , -CH 2 -0-CF 3 , s -CH 2 -SF 3 , ethyl, -CF 2 -CH 3 , -CH 2 -CF 3 , -C 2 F 5 , -CH 2 -CC1 3 , -CH 2 -CBr 3 , -CHF CF 2 CI, -CF 2 -CF 2 CI, -CFCI-CF 2 CI, -CH 2 -CH 2 -CN, n-propyl, -CF 2 -CF 2 -CF 3 , CF(CF 3 ) 2 , isopropyl, -CH 2 -CH 2 -CH 2 -CN, -CH 2 -0-CH 2 -CH 3 , -CH 2 -CH 2 -SF 3 , -CH 2 CH 2 -OCF 3 , -CH(CH 3 )(0-CH 3 ), -CH(CH 3 )(S-CH 3 ), n-butyl, -CF 2 -CF 2 -CF 2 -CF 3 , CH 2 -CH 2 -CH 2 -CH 2 -CN, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n io heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl-hept-4-yl, 3-methyl butyl, n-hexyl, (3,3)-dimethylbutyl, -CH 2 -CH 2 -0-CH 3 , -CH 2 -CH 2 -0-C 2 H 5 , -CH 2 CH 2 -CH 2 -0-CH 3 , ethenyl, propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and 3 pentenyl; denote a residue selected from the group consisting of 2,3-dihydro-1 H is indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl and thiomorpholinyl, which may in each case be attached via a -CH 2 -0-, -CH 2 -CH 2 -0-, -CH 2 -CH 2 -0-CH 2 -, -CH 2 CH(CH 3 )-O-CH 2 -, -(CH 2 )-, -(CH 2 ) 2 - or -(CH 2 ) 3 - group and/or in each case 20 unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of oxo (=0), thioxo (=S), -OH, -0-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -0-C(CH 3 ) 3 , -0-CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, isobutyl, tert-butyl, n-pentyl, -C(=O)-CH 3 , -C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 , 25 -C(=O)-C(CH 3 ) 3 , -C(=O)-OH, -C(=O)-O-CH 3 , -C(=O)-O-C 2 H 5 , -C(=O)-O CH(CH 3 ) 2 and -C(=O)-O-C(CH 3 ) 3 ; or denote a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl and isoxazolyl, the residue in each case 30 being capable of being attached via a -(CH 2 ), -(CH 2 ) 2 or -(CH 2 ) 3 group and/or in each case unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -NH 2 , -NO 2 , -0 CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n- -217 propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, -C(=O)-OH, C(=O)-O-CH 3 , -C(=O)-O-C 2 H 5 , -C(=O)-O-CH(CH 3 ) 2 , -C(=O)-O-C(CH 3 ) 3 , -NH CH 3 , -NH-C 2 H 5 , -NH-C(CH 3 ) 3 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , -N(CH 3 )(C 2 H 5 ), -NH-C(=O) O-CH 3 , -NH-C(=O)-O-C 2 H 5 , -NH-C(=O)-O-C(CH 3 ) 3 , -C(=O)-H, -C(=O)-CH 3 , s C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 , -C(=O)-C(CH 3 ) 3 , -C(=O)-NH 2 , -C(=O)-NH-CH 3 , C(=O)-NH-C 2 H 5 , -C(=O)-N(CH 3 ) 2 , -C(=O)-N(C 2 H 5 ) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl; or R 40 and R 41 in each case together with the nitrogen atom joining them 10 together as a ring member form a residue selected from the group consisting of 3-aza-bicyclo[3.1.1]heptyl, 6-aza-spiro[2.5]octyl, 3-aza-bicyclo[3.2.1]octyl, 6 aza-bicyclo[3.3.1]heptyl, 8-aza-bicyclo[3.2.1]octyl, 1-oxa-2,8-diaza spiro[4.5]dec-2-enyl, azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl, (4,5,6,7)-tetrahydroisoxazolo[5,4-c]pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, 15 morpholinyl, azepanyl, diazepanyl and thiomorpholinyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 or 5 residues R 57 ; R1 7 denotes -NHR 5 a, -NR 59 R 60 or denotes an alkyl residue selected from the group consisting of -CF 3 , -CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert 20 butyl, n-butyl, sec-butyl, and isobutyl; R1 8 , R 59 and R 60 , mutually independently, in each case denote -C(=O)-R 61 ; denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or denote a residue selected from the group consisting of phenyl, 25 naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl and isoxazolyl, the residue in each case being capable of being attached via a -(CH 2 ), -(CH 2 ) 2 or -(CH 2 ) 3 group and/or in each case unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, 30 CF 3 , -SF 5 , - OH, -0-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -NH 2 , -NO 2 , -0 CF 3 , -S-CF 3 , -SH, -S-CH 3 , -S-C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, -C(=O)-OH, C(=O)-O-CH 3 , -C(=O)-O-C 2 H 5 , -C(=O)-O-CH(CH 3 ) 2 , -C(=O)-O-C(CH 3 ) 3 , -NH CH 3 , -NH-C 2 H 5 , -NH-C(CH 3 ) 3 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , -N(CH 3 )(C 2 H 5 ), -NH-C(=O)- -218 O-CH 3 , -NH-C(=O)-O-C 2 H 5 , -NH-C(=O)-O-C(CH 3 ) 3 , -C(=O)-H, -C(=O)-CH 3 , C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 , -C(=O)-C(CH 3 ) 3 , -C(=O)-NH 2 , -C(=O)-NH-CH 3 , C(=O)-NH-C 2 H 5 , -C(=O)-N(CH 3 ) 2 , -C(=O)-N(C 2 H 5 ) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl; 5 R 6 ' denotes an alkyl residue selected from the group consisting of -CF 3 , CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl and isobutyl; Re 2 , R 63 , R 64 , R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n io propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl, which may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 and -SH; and R 1 denotes a residue selected from the group consisting of phenyl, is naphthyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, wherein the residue may in each case be attached via a -(CH 2 )-, -(CH 2 ) 2 - or -(CH 2 ) 3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, 20 Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -NH 2 , NO 2 , -0-CF 3 , S-CF 3 , -SH, -S-CH 3 , -S-C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, C(=O)-OH, -C(=O)-O-CH 3 , -C(=O)-O-C 2 H 5 , -C(=O)-O-CH(CH 3 ) 2 , -C(=O)-O C(CH 3 ) 3 , -NH-CH 3 , -NH-C 2 H 5 , -NH-C(CH 3 ) 3 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , 25 N(CH 3 )(C 2 H 5 ), -NH-C(=O)-O-CH 3 , -NH-C(=O)-O-C 2 H 5 , -NH-C(=O)-O-C(CH 3 ) 3 , C(=O)-H, -C(=O)-CH 3 , -C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 , -C(=O)-C(CH 3 ) 3 , C(=O)-NH 2 , -C(=O)-NH-CH 3 , -C(=O)-NH-C 2 H 5 , -C(=O)-N(CH 3 ) 2 , -C(=O) N(C 2 H 5 ) 2 , -0-phenyl, -O-benzyl, phenyl and benzyl; in each case optionally in the form of one of the pure stereoisomers 30 thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. -219 3. A compound according to claim 1 or claim 2, characterised in that n denotes 0, 1 or 2; R 1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=O)-NH-; -0 5 C(=0)-NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 3 -; -S-C(=0)-NR 6 3 -; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S) NH-; -NR 66 -C(=0)-NR 6 1-; -NR 66 -C(=S)-NR 6 1-; -0-CH 2 -C(=O)-NH-; -O-CH 2 -0-; 0-CH 2 -CH 2 -0-, -0-CH 2 -CH 2 -CH 2 -0-; -0-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, 10 or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 28 =N-NR 6 2 -; -S-C(=S)-NH-; -0 C(=S)-NH-; -S-C(=0)-NH-; -0-C(=O)-NH-; -S-C(=S)-NR 6 3 -; --OC(=S)-NR 6 3 -; -S C(=0)-NR 6 3 -; -0-C(=O)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR 64 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=0) is NR 65 -; -NR 66 -C(=S)-NR 6 5 -; -N=N-NH-; -N=N-NR 67 -; -O-CH 2 -C(=O)-NH-; -0-CH 2 0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2 -CH 2 -C(=0)-NH-; O-CH 2 -CH 2 -0-; -0-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -0-CH 2 -CH 2 NH-, which is attached in any desired direction to the parent structure, 20 or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8 =N-NR 6 2_; __ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0 C(=S)-NR 63 -; -S-C(=O)-NR 6 3 -; -O-C(=0)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 0-; -N=CR 3 6-0-; -N=CH-NH-; -N=CH-NR 6 4 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; 25 NR 66 -C(=0)-NR 6 5 -; -NR 66 -C(=S)-NR 65 -; -N=N-NH-; -N=N-NR 67 -; -O-CH 2 -C(=O) NH-; -O-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2 CH 2 -C(=0)-NH-; -0-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and 0-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent 30 structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 7 1 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0 C(=0)-NH-; -S-C(=S)-NR 63 -; -O-C(=S)-NR 63 -; -S-C(=0)-NR 63 -; -0-C(=O)-NR 63 _; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 3 0 -; -NH-C(=0)-NH-; -NH-C(=S)- -220 NH-; -NR 66 -C(=O)-NR 6 5 -; -NR 66 -C(=S)-NR 6 5 -; -O-CH 2 -C(=O)-NH-; -O-CH 2 -0-; O-CH 2 -CH 2 -0-, -O-CH 2 -CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, 5 in each case denote H; F; Cl; Br; I; -CF 3 ; -CN; -OR 1 6 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; R 6 denotes H or denotes an alkyl residue selected from the group io consisting of isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, methyl, ethyl and n-propyl; R 7 denotes hydrogen or -OH; or R 6 and R , in each case together with the carbon atom joining them together as a ring member, form a residue selected from the group consisting of 15 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; R 8 denotes -CF 3 or tert-butyl; T denotes C-R 3 5 and U denotes C-R 36 and V denotes N and W denotes C R 38 or 20 T denotes C-R 35 and U denotes C-R 36 and V denotes C-R 37 and W denotes C-R 38 R 16 and R , mutually independently, in each case denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 CH 3 , -CH 2 -CF 3 , -C 2 F 5 , n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 25 n-pentyl, 3-pentyl, n-heptyl, 4-heptyl, n-octyl, n-nonyl, 5-nonyl, (2,6)-dimethyl hept-4-yl, 3-methyl-butyl, n-hexyl and (3,3)-dimethylbutyl; R 28 denotes F; Cl; Br; I; -CF 3 ; -CN; -NH 2 or denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl; 30 R 29 and R 3 0 , mutually independently, in each case denote -NH-C(=O)-R 31 ; -NH 2 ; -NH-S(=O) 2 -R 3 2 ; -NH-C(=O)-O-R 33 ; -S-R 34 or denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; -221 R 3 ', R 32 , R 33 and R 3 4, mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R 35 , Ras and R 37 , mutually independently, in each case denote H; F; Cl; Br; sI; -SF 5 ; -NO 2 ; -CN; -NH 2 ; -OH; -SH; -OR' 1 ; -SR 17 ; or denote a residue selected from the group consisting of -CH 2 -OH, methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; R 38 is selected from the group consisting of NR 40 R 4 , -OR 42 and -SR 43 R 39 , R 4 0 , R 41 , R 42 and R 43 , mutually independently, in each case 1o denote a residue selected from the group consisting of methyl, -CH 2 -0 CH 3 , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3 pentyl, n-hexyl, (3,3)-dimethylbutyl, -CH 2 -CH 2 -0-CH 3 , -CH 2 -CH 2 -O-C 2 H 5 and CH 2 -CH 2 -CH 2 -O-CH 3 ; denote a residue selected from the group consisting of 2,3-dihydro-1 H 1s indenyl, cyclopropyl, oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, diazepanyl, azocanyl and thiomorpholinyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, 20 isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl; or R 40 and R 4 1 in each case together with the nitrogen atom joining them together as a ring member form a residue selected from the group consisting of 3-aza-bicyclo[3.1.1]heptyl, 6-aza-spiro[2.5]octyl, 3-aza-bicyclo[3.2.1]octyl, 6 25 aza-bicyclo[3.3.1]heptyl, 8-aza-bicyclo[3.2.1]octyl, 1-oxa-2,8-diaza spiro[4.5]dec-2-enyl, azocanyl, isoindolyl, indolyl, (1,2,3,6)-tetrahydropyridinyl, (4,5,6,7)-tetrahydroisoxazolo[5,4-c]pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and thiomorpholinyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 30 or 5 residues R 57 R 57 denotes -NHR 5 , -NR 59 R 0 or denotes an alkyl residue selected from the group consisting of -CF 3 , -CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert butyl, n-butyl, sec-butyl, and isobutyl; R" 8 , R 9 and R" 0 , mutually independently, in each case denote -C(=O)-R 61 ; - 222 denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; or denote a residue selected from the group consisting of phenyl and naphthyl, wherein the residue may in each case be attached via a -(CH 2 )-, s (CH 2 ) 2 - or -(CH 2 ) 3 group and/or may in each case be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, 1, -CN, -CF 3 , -0-CH 3 , -O-C 2 H 5 , -0 CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl; 10 R 61 denotes an alkyl residue selected from the group consisting of -CF 3 , CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl and isobutyl; R 62 , R 63 , R 4 , R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of -CF 3 , -CH 2 -CF 3 , is methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl and isobutyl; and R 7 ' denotes a residue selected from the group consisting of phenyl, naphthyl, thiophenyl, furanyl and pyridinyl, wherein the residue can in each case be attached via a -(CH 2 )-, -(CH 2 ) 2 - or -(CH 2 ) 3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually 20 independently selected from the group consisting of F, C, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2 H 5 , -O-CH(CH 3 ) 2 , -O-C(CH 3 ) 3 , -NH 2 , -NO 2 , -0-CF 3 , -S-CF 3 , SH, -S-CH 3 , -S-C 2 H 5 , -S-CH(CH 3 ) 2 , -S-C(CH 3 ) 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -0-phenyl, -O-benzyl, phenyl and benzyl; 25 in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. 30 4. A compound according to one or more of claims 1 to 3, characterised in that n denotes 0, 1 or 2; R 1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S-C(=0)-NH-; -0- -223 C(=0)-NH-; -S-C(=S)-NR 6 3 -; -0-C(=S)-NR 63 -; -S-C(=0)-NR 63 -; -0-C(=0)-NR 63 -; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-0-; -N=CR 3 a-O-; -NH-C(=0)-NH-; -NH-C(=S) NH-; -NR 66 -C(=0)-NR 6 5 -; -NR 66 -C(=S)-NR 6 5 -; -0-CH 2 -C(=0)-NH-; -O-CH 2 -0-; 0-CH 2 -CH 2 -0-, -0-CH 2 -CH 2 -CH 2 -0-; -0-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, 5 which is attached in any desired direction to the parent structure, or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR, 2 -; -CR 2 1=N-NR 6 2 -; -S-C(=S)-NH-; -0 C(=S)-NH-; -S-C(=0)-NH-; -0-C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR13_; -S C(=O)-NR 63 -; -O-C(=0)-NR 63 -; -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 3 6-0 1o -N=CH-NH-; -N=CH-NR 6 4 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; -NR 66 -C(=O) NR 65 -; -NR 66 -C(=S)-NR 65 -; -N=N-NH-; -N=N-NR 6 7 -; -O-CH 2 -C(=0)-NH-; -O-CH 2 0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2 -CH 2 -C(=0)-NH-; O-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH-N=CH; -N=CH CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and -0-CH 2 -CH 2 is NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -CH=N-NR 6 2 -; -CR 2 8 =N-NR 6 2_; _S_ C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0-C(=O)-NH-; -S-C(=S)-NR 63 _; -0 C(=S)-NR 63 -; -S-C(=0)-NR 6 3 -; -0-C(=0)-NR 6 3 -; -S-CH=N-; -S-CR 29 =N-; -N=CH 20 0-; -N=CR 30 -0-; -N=CH-NH-; -N=CH-NR 6 4 -; -NH-C(=0)-NH-; -NH-C(=S)-NH-; NR 66 -C(=0)-NR 65 -; -NR 66 -C(=S)-NR 65 -; -N=N-NH-; -N=N-NR 6 7 -; -0-CH 2 -C(=0) NH-; -0-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=0)-NH, -CH 2 CH 2 -C(=0)-NH-; -0-CH 2 -CH 2 -0-; -0-CH 2 -CH 2 -CH 2 -0-; -N=N-CH=CH-; -N=CH N=CH; -N=CH-CH=N-; -CH=CH-CH=N-; -CH=CH-N=CH-; -CH=N-N=CH- and 25 0-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -; -S-C(=S)-NH-; -0-C(=S)-NH-; -S-C(=0)-NH-; -0 C(=0)-NH-; -S-C(=S)-NR 63 -; -0-C(=S)-NR 63 -; -S-C(=0)-NR 63 -; -0-C(=0)-NR 63 -; 30 -S-CH=N-; -S-CR 29 =N-; -N=CH-0-; -N=CR 30 -0-; -NH-C(=0)-NH-; -NH-C(=S) NH-; -NR 66 -C(=0)-NR 6 5 -; -NR 66 -C(=S)-NR 6 5 -; -0-CH 2 -C(=0)-NH-; -0-CH 2 -0-; 0-CH 2 -CH 2 -0-, -0-CH 2 -CH 2 -CH 2 -0-; -0-CH 2 -CH 2 -NH- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, - 224 and the remaining residues R 1 , R 2 , R 3 , R 4 and R , mutually independently, in each case denote H; -OR 1 6 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec 5 butyl, isobutyl and tert-butyl; R 6 denotes H or denotes an alkyl residue selected from the group consisting of isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methyl, ethyl and n-propyl; R 7 denotes hydrogen or -OH; 10 R 8 denotes -CF 3 or tert-butyl; T denotes C-R 35 and U denotes C-R 3 and V denotes N and W denotes C R 38 or T denotes C-R 35 and U denotes C-R 3 and V denotes C-R 37 and W Is denotes C-R 3 8 ; R 16 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R 2 8 denotes F; Cl; Br or 1; 20 R 29 and R 30 , mutually independently, in each case denote -NH-C(=0)-R 31 ; -NH 2 ; -NH-S(=0) 2 -R 3 2 ; -NH-C(=O)-O-R 33 or -S-R 34 R 3 , R 32 , R 33 and R 34 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; 25 R 35 , R 3 ' and R 3 7 in each case denote H; R 38 is selected from the group consisting or NR 40 R 4 , -OR 42 and -SR 43 R 39 , R 42 and R 43 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n 30 hexyl, and (3,3)-dimethylbutyl; or denote a residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may in each case optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently -225 selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl; R 40 and R 4 1 in each case together with the nitrogen atom joining them together as a ring member form a residue selected from the group consisting of 5 pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azepanyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 or 5 residues R 57 ; R 57 denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; 10 R 2 , R 63 , R 64 , R 65 , R 66 and R 67 , mutually independently, in each case denote an alkyl residue selected from the group consisting of methyl, ethyl, n propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; and R 71 denotes a phenyl residue which may be attached via a -(CH 2 )-, (CH 2 ) 2 - or -(CH 2 ) 3 group and/or in each case may be unsubstituted or optionally is substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -0-CH 3 , -O-C 2 H 5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in 20 the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. 5. A compound according to one or more of claims 1 to 4, characterised in that 25 n denotes 1; R 1 and R 2 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -;-S-CH=N-; -S-CR 2 9 =N-; -N=CH-O-; -N=CR 30 -0-; -0 CH 2 -0-; -O-CH 2 -CH 2 -0- and -CH=CH-N=CH-, which is attached in any desired direction to the parent structure, 30 or R 2 and R 3 together denote a residue selected from the group consisting of -CH=N-NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=0)-NH-; -S-CH=N-; -S-CR 29 =N-; -N=CH-O-; -N=CR 30 -0-; N=CH-NH-; -NH-C(=O)-NH-; -NH-C(=S)-NH-; -N=N-NH-; -O-CH 2 -C(=O)-NH-; O-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2 -CH 2 - - 226 C(=O)-NH-; -O-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -O-; -N=CH-CH=N-; -CH=CH CH=N-; -CH=CH-N=CH-; -CH=N-N=CH-; -CH=N-CH=N- and -O-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent structure, or R 3 and R 4 together denote a residue selected from the group 5 consisting of -CH=N-NH-; -CR 28 =N-NH-; -S-C(=S)-NH-; -O-C(=S)-NH-; -S C(=O)-NH-; -O-C(=O)-NH-; -S-CH=N-; -S-CR 2 9 =N-; -N=CH-O-; -N=CR 3 0 -0-; N=CH-NH-; -NH-C(=O)-NH-: -NH-C(=S)-NH-: -N=N-NH-; -O-CH 2 -C(=O)-NH-; O-CH 2 -0-; -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 -NH, -CH 2 -C(=O)-NH, -CH 2 -CH 2 C(=O)-NH-; -O-CH 2 -CH 2 -0-; -O-CH 2 -CH 2 -CH 2 -O-; -N=CH-CH=N-; -CH=CH 10 CH=N-; -CH=CH-N=CH-; -CH=N-N=CH-; -CH=N-CH=N- and -O-CH 2 -CH 2 -NH-, which is attached in any desired direction to the parent structure, or R 4 and R 5 together denote a residue selected from the group consisting of -CH=N-NH-; -CH=N-NR 71 -;-S-CH=N-; -S-CR 29 =N-; -N=CH-O-; N=CR 30 -0-; -O-CH 2 -0-; -O-CH 2 -CH 2 -0- and -CH=CH-N=CH-, which is is attached in any desired direction to the parent structure, and the remaining residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; -OR 16 ; -SR 17 ; or denote a residue selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, 20 isobutyl and tert-butyl; R 6 denotes H or denotes an alkyl residue selected from the group consisting of isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, methyl, ethyl and n-propyl; R 7 denotes hydrogen or -OH; 25 R 8 denotes -CF 3 or tert-butyl; T denotes C-R 35 and U denotes C-R 36 and V denotes N and W denotes C R 38 or T denotes C-R 35 and U denotes C-R 36 and V denotes C-R 37 and W 30 denotes C-R 38 ; R' 6 and R 17 , mutually independently, in each case denote a residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R 28 denotes F; Cl; Br or I; -227 R 2 9 denotes -NH-C(=O)-R 3 1 ; -NH 2 ; -NH-S(=0) 2 -R1 2 ; -NH-C(=O)-O-R 33 or -S-R 34; R 30 denotes -NH 2 ; R 3 , R 3 , R 33 and R 34 , mutually independently, in each case denote an 5 alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and n-pentyl; R 35 , R 3 ' and R" in each case denote H; R 38 is selected from the group consisting of -NR 40 R 41 , -OR 42 and -SR 43 ; R 39 , R 42 and R 43 , mutually independently, in each case 10 denote a residue selected from the group consisting of methyl, ethyl, n propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n hexyl, and (3,3)-dimethylbutyl; or denote a residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may in each case is optionally be substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl; R 40 and R 41 in each case together with the nitrogen atom joining them together as a ring member form a residue selected from the group consisting of 20 pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azepanyl, the heterocycloaliphatic moiety of which may in each case be unsubstituted or substituted with 1, 2, 3, 4 or 5 residues R 57 ; R 57 denotes an alkyl residue selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, sec-butyl, and isobutyl; 25 R 71 denotes a phenyl residue which may be attached via a -(CH 2 )-, (CH 2 ) 2 - or -(CH 2 ) 3 group and/or in each case may be unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents mutually independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -SF 5 , -OH, -O-CH 3 , -O-C 2 H 5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; 30 in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates. - 228 6. A compound of the general formula la, according to one or more of the preceding claims, R 8 R HI D R R 2 YR5 R3 R4 5 la, in which D denotes N or CH; and 10 R 1 , R 2 , R 3 , R 4 , R 5 and R 8 have the meanings according to claim 3; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of is corresponding salts or in each case in the form of corresponding solvates.
7. A compound of the general formula la, according to one or more of the preceding claims, H R 2 NR 00/ R4 20 la, in which D denotes N or CH; and 25 R 1 , R 2 , R 3 , R 4 , R 5 and R 8 have the meanings according to claim 4; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in - 229 the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
8. A compound of the general formula lb, according to one or more of 5 the preceding claims, R 8 H D N R2 OR42 0 R R3 R4 lb, io in which D denotes N or CH; and R', R 2 , R 3 , R 4 , R 5 , R 8 and R 4 2 have the meanings according to claim 3; in each case optionally in the form of one of the pure stereoisomers is thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
9. A compound of the general formula Ib, according to one or more of 20 the preceding claims, R 8 HR H D N R O R 42 O R5 R3 R4 lb, 25 in which D denotes N or CH; -230 and R', R 2 , R 3 , R 4 , R 5 , R 8 and R 4 2 have the meanings according to claim 4; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in 5 the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
10. A compound of the general formula Ic, according to one or more of the preceding claims, 10 R 8 H D -N )R s'R 43 0R R3 R4 Ic, in which is D denotes N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 43 have the meanings according to claim 3; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in 20 the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
11. A compound of the general formula Ic, according to one or more of the preceding claims, 25 -231 R8,, H D N R2 SsR 43 0 5 R3 R4 Ic, in which 5 D denotes N or CH; and R 1 , R 2 , R 3 , R 4 , R', R 8 and R 43 have the meanings according to claim 4; in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in 1o the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
12. A compound of the general formula Id, according to one or more of the preceding claims, 15 R8R H D N R /N 0 R 4 0 R 4 1 R4 Id, in which 20 D denotes N or CH; and R', R 2 , R 3 , R 4 , R 5 , R", R 42 and R 41 have the meanings according to claim 3; in each case optionally in the form of one of the pure stereoisomers 25 thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or - 232 diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
13. A compound of the general formula Id, according to one or more of the preceding claims, 5 R R H D N R 2 N 0 / R 40 R 4 1 R 4 Id, in which to D denotes N or CH; and R 1 , R 2 , R 3 , R 4 , R', R 8 , R 42 and R 4 ' have the meanings according to claim 4; in each case optionally in the form of one of the pure stereoisomers is thereof, in particular enantiomers or diastereomers, the racemates thereof or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates.
14. A compound according to one or more of claims 1 to 13 selected 20 from the group consisting of [1] 2-(benzo[d]oxazol-5-yl)-N-(4-tert-butylbenzyl)propanamide, [2] 2-(benzo[d]oxazol-6-yl)-N-(4-tert-butylbenzyl)propanamide, [3] 2-(benzo[d]oxazol-7-yl)-N-(4-tert-butylbenzyl)propanamide, [4] N-(4-tert-butylbenzyl)-2-(2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5 25 yl)propanamide, [5] N-(4-tert-butylbenzyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7 yl)propanamide, [6] N-(4-tert-butylbenzyl)-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6 yl)propanamide, - 233 [7] N-(4-tert-butylbenzyl)-2-(7-methoxybenzo[d]oxazol-5 yI) propa nam ide, [8] 2-(be nzo [d]oxazol-4-yI) -N -(4-te rt-b utylbe nzyl) pro pan amid e, [9] N-(4-tert-butylbenzyl)-2-(2,3-d ihyd robenzo[b][ 1,4]d ioxi n-6 5 yI)propanamide, [10] N-(4-te rt-b utyl ben zyl)-2-(2-th ioxo-2,3-d ihyd ro- 1 H-be nzo [d] imid azol1-5 yI) propa nam ide, [11] N-(4-tert-butylbenzyl)-2-(quinoxalin-6-yI)propanamide, [12] 2 -(l H-be nzo[d[ 1, ,2,3]triazol1-5-yI)-N -(4-te rt-b utyl be nzyl) pro pan am ide, 10[1 3] 2-(1 H-benzo[d]imidazol-5-yI)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, [14] 2-(1 H-benzo[d]imidazol-5-yI)-N-(4-tert-butylbenzyl)propanamide, [15] 2-(l H-be nzo [d] [1, 2,3]triazol1-5-yI)- N-((2-(4-methylp ipe rid in- 1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, 1s [16] N-(4-tert-butylbenzyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-6 yI) pro pan am ide, [17] N-(4-tert-butylbenzyl)-2-(2-thioxo-2 ,3-dihydrobenzo[d]oxazol-5 yI) pro pan am ide, [18] 2-(2-aminobenzo[d]oxazol-6-yI)-N-(4-tert-butylbenzyl)propanamide, 20 [19] N -(4-te rt-b utyl be nzyl)-2-(2-th ioxo-2,3-d ih yd robe nzo[d ]oxazo1-6 yI) pro pan am ide, [20] N-(4-tert-butylbenzyl)-2-(3,4-dihydro-2H-benzo[b][1 ,4]oxazin-7 yI) pro pan am ide, [21] N-(4-tert-butylbenzyl)-2-(quinolin-6-yI)propanamide, 25 [22] 2-(l H-benzo[d][1 ,2,3]triazol-5-yI)-N-((2-butoxy-6-tert-butylpyridin-3 yI)methyl)propanamide, [23] 2-(l H-benzo[d]imidazol-5-yI)-N-((2-butoxy-6-tert-butylpyridin-3 yI)methyl)propanamide, [24] 2-(l1 H-benzo[d][1 ,2 ,3]triazol-5-yI)-N-((6-tert-butyl-2-(4 30 methylpiperidin-1 -yI)pyridin-3-y)methyl)propanamide, [25] 2-(1 H-benzo[d]imidazol-5-yI)-N-((6-tert-butyl-2-(4-methylpiperidin-1 yI)pyrid in-3-yI)methyl)propanamide, [26] 2-(l1 H-benzo[d][1 ,2,3]triazol-5-yI)-N-((6-tert-butyl-2 (cyclohexylthio)pyridin-3-yI)methyl)propanamide, - 234 [27] 2-(l H -be nzo[d] imid azol1-5-yI)-N -((6-te rt-b utyl-2 (cyclohexylthio)pyridin-3-yI)methyl)propanamide, [28] N-((2-butoxy-6-tert-butylpyrid in-3-yI)methyl)-2-(2-oxo-2,3 dihyd robenzo[d]th iazol-6-yI)propanamide, 5 [29] N-(2-butoxy-6-tert-butyi-pyridin-3-ylmethyl)-2-(2-ethylsulfanyl benzothiazol-6-yI)-propionamide, [30] N -((2-(4-methyl p ipe rid i n-i1 -yI)-6-(triflu oro methyl)pyrid in-3-yl) methyl) 2-(2-(methylthio)benzo[d]th iazol-6-yI)propanamide, [31] N-((2-butoxy-6-tert-butylpyridin-3-yI)methyl)-2-hydroxy-2-(2 10 (methylthio)benzo[d]thiazol-6-yl)propanamide, [32] N-((2-(4-methyl p ipe rid in-1 -yI)-6-(trifIu o ro methyl)pyrid in-3-yI) methyl) 2-(2-th ioxo-2 ,3-dihydrobenzo[d]th iazol-6-yI)propanamide, [33] N -((6-te rt-b utyl-2-(4-methyl p ipe rid i n-i1 -yl) pyrid in-3-yI)meth yl)-2-(2 thioxo-2,3-d ihydrobenzo[d]thiazol-6-yI)propanamide, 5 [34] N -((6-te rt-b utyl-2-(4-methyl p ipe rid in- 1 -yI) pyrid in-3-yI)meth yl)-2- (2 (methylthio)benzo[d]thiazol-6-yI)propanamide, [35] 2-(2-a min obe nzo [d]oxazo-5-y)-N -((2-(4-methylp ipe rid in- 1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, [36] 2-(2-acetamidobenzo[d]thiazol-6-y)-N-(4-tert 20 butylbenzyl)propanamide, [37] 2-(2-acetamidobenzo[d]thiazol-6-y)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, [38] 2-(2-aminobenzo[d]thiazol-6-y)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, 25 [39] N-((2-(4-methylp ipe rid i n-i1 -yI)-6-(trifl u oromethyl) pyrid in-3-yI) methyl) 2-(2-(methylsu Ifonamido)benzo[d]thiazol-6-yI)propanamide, [40] tert-butyl 6-(1 -((2-(4-methylpiperidin-1 -yI)-6-(trifluoromethyl)pyridin-3 yI)methylamino)-1 -oxop ro pan -2-yI) be nzo[d]th iazol-2 -ylca rba mate, [41] 2-(2-acetamidobenzo[d]thiazol-6-y)-N-((2-(4-methylpiperidin-1 -yI)-6 30 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, [42] 2-(2-acetamidobenzo[d]thiazol-5-y)-N-((2-(4-methylpiperidin-1 -yI)-6 (trif lu oromethyl) py rid in-3-yI) methyl) propa nam ide, [43] 2-(2-acetamidobenzo[d]thiazol-4-yi)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide, -235 [44] 2-(l H-i nd azol1-5-yi)-N-((2-(4-methyl pipe rid in -1 -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, [45] 2-(3-f luoro- 1 H -ind azol-5-yI)-N-((2-(4-methylp ipe rid in- 1 -yI)-6 (trifluoromethyl)pyrid in-3-yI)methyl)propanamide, 5 [46] N-((2-butoxy-6-tert-butylpyridin-3-yI)methyl)-2-(1 H-indazol-5 yI )pro pan amid e, [48] N-((6-tert-butyi-2-(cyclohexylthio)pyridin-3-yI)methyl)-2-(1 H-indazol-5 yI)propanamide [49] N-(2-butoxy-6-tert-butyl-pyridin-3-ylmethyl)-2-(2-thioxo-2,3-dihydro 10 benzothiazol-6-yI)-propionamide; [50] tert-butyl 6-(1 -(4-tert-butylbenzylamino)-1 -oxopropan-2 yI) be nzo [d]th iazol1-2-ylca rba mate, [51] 2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-tert-butylbenzyl)propanamide, [52] 2-(2 -am in obenzo[d]th iazo1-6-yl)- N-((2-(4-methyl pipe rid in -1 -yI)-6 15 (trifluoromethyl)pyridin-3-y)methyl)propanamide, [53] 2-(2-acetamidobenzo[d]thiazol-6-yI)-N-((6-tert-butyl-2-(4 methylpiperidin-1 -yI) pyrid in-3-y)methyl) pro pan am ide; [54] tert-butyl 6-(1 -((2-(4-methylpiperidin-1 -yI)-6-(trifluoromethyl)pyridin-3 yi)methylamino)-1 -oxopropan-2-yI)benzo[d]thiazol-2-ylcarbamate;, 20 [55] tert-butyl 6-(1 -((6-tert-butyl-2-(4-methylpiperidin-1 -yI)pyridin-3 yl)methylamino)-1 -oxo propa n-2-yI) be nzo[d ]th iazol1-2-ylca rba mate; [56] 2-(2 -am in obenzo[d ]th iazo1-6-y)- N-((6-te rt-b utyl-2-(4-methyl p ipe rid in 1 -yI)pyridin-3-y)methyl)propanamide; [57] N-(4-tert-butylbenzyl)-2-(2-(methylsulfonamide)benzo[dlthiazol-6 25 yI)propanamide; [58] 2-(2,3-dihydrobenzo[b][1 ,4]dioxin-6-yI)-N-((2-(4-methylpiperidin-1 -yI) 6-(trifluoromethyl)pyridin-3-yI)methyl)acetamide; [59] N-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yI)methyl)-2-(2,3 dihydrobenzo[b][1 ,4]dioxin-6-yI)acetamide; 30 [60] 2 -(be nzo[d ][1 , 3]d ioxol1-5-yI)-N-((2-(4-methylp ipe rid in- 1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyi)propanamide; [61] 2-(benzo[d][1 ,3]dioxol-4-yi)-N-((2-(4-methylpiperidin-1 -yI)-6 (trifluoromethyl)pyridin-3-yI)methyl)propanamide; - 236 [62] 2-(2,3-dihydrobenzo[b][1, 4]dioxin-6-yl)-N-((2-(4-methylpiperidin-1 -yl) 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide; [63] 2-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-N-((2-(4-methylpiperidin-1 -yl) 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide 5 [64] 2-(isoquinolin-7-yl)-N-((2-(4-methylpiperidin-1-yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [65] 2-(isoquinolin-6-yl)-N-((2-(4-methylpiperidin-1-yI)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [66] N-((2-(4-methylpiperid in-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) 10 2-(quinolin-6-yl)propanamide [67] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) 2-(quinoxalin-6-yl)propanamide [68] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) 2-(quinazolin-6-yl)propanamide is [69] 2-(1H-indazol-5-yl)-N-(2-(4-methylpiperidin-1-yl)-4 (trifluoromethyl)benzyl)propanamide [70] 2-(1 H-indazol-4-yl)-N-((2-(4-methylpiperid in-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [71] 2-(1H-indazol-6-yl)-N-((2-(4-methylpiperidin-1-yl)-6 20 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [72] 2-(1 H-indazol-7-yl)-N-((2-(4-methylpiperidin-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [73] 2-(1-(2-fluorophenyl)-1H-indazol-4-yl)-N-((2-(4-methylpiperidin-1-yI) 6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide 25 [74] 2-(indolin-5-yl)-N-((2-(4-methylpiperidin-1 -yl)-6 (trifluoromethyl)pyridin-3-yl)methyl)propanamide [75] N-((2-(4-methylpiperidin-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) 2-(1,2,3,4-tetrahydroquinolin-6-yl)propanamide [76] N-((2-(4-methylpiperid in-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) 30 2-(2-oxoindolin-5-yl)propanamide and [77] N-((2-(4-methylpiperid in-1 -yl)-6-(trifluoromethyl)pyridin-3-yl)methyl) 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanamide in each case optionally in the form of one of the pure stereoisomers thereof, in particular enantiomers or diastereomers, the racemates thereof or in - 237 the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or in each case in the form of corresponding salts or in each case in the form of corresponding solvates;
15. A compound according to one or more of claims 1 to 14, 5 characterised in that, in a FLIPR assay with CHO K1 cells which have been transfected with the human gene VR1, in a concentration of less than 2000 nM, preferably of less than 1000 nM, particularly preferably of less than 300 nM, very particularly preferably of less than 100 nM, still more preferably of less than 75 nM, further preferably of less than 50 nM and most preferably of less than 10 io nM, bring about a 50% displacement of capsaicin which is present in a concentration of 100 nM.
16. A method for producing a compound according to one or more of claims 1 to 15, characterised in that at least one compound of the general formula 11, 15 R8 UN (CH 2 )m 11, in which R 8 , U, T, V, and W have the meanings according to one or more of 20 claims 1 to 15, m denotes 0, 1, 2 or 3 and R denotes hydrogen or denotes a linear or branched C 1 . 6 alkyl residue, is reacted in a reaction medium, in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, sodium, potassium hydride, lithium aluminium hydride, sodium borohydride and 25 di(isobutyl)aluminium hydride to yield at least one compound of the general formula Ill, W (CH 2 )m OH -238 in which R 8 , U, T, V and W have the meanings according to one or more of claims 1 to 15 and m denotes 0, 1, 2 or 3 and said compound is optionally purified and/or isolated, and at least one compound of the general formula Ill is reacted in a s reaction medium in the presence of diphenylphosphoryl azide or in the presence of HN 3 to yield at least one compound of the general formula IV, V 8 W (CH 2 )m N 3 IV, 10 in which R 8 , U, T, V and W have the meanings according to one or more of claims 1 to 15 and m denotes 0, 1, 2 or 3 and said compound is optionally purified and/or isolated, and at least one compound of the general formula IV is reacted in a 15 reaction medium in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, potassium hydride, lithium aluminium hydride, sodium borohydride and di(isobutyl)aluminium hydride or in a reaction medium in the presence of a catalyst, preferably in the 20 presence of a catalyst based on platinum or palladium, particularly preferably in the presence of palladium on carbon, and in the presence of hydrogen or in the presence of hydrazine or in a reaction medium in the presence of triphenylphosphine to yield at least one compound of the general formula V, 25 W (CH 2 )m NH 2 V, -239 in which R 8 , U, T, V and W have the meanings according to one or more of claims 1 to 15 and m denotes 0, 1, 2 or 3 and said compound is optionally purified and/or isolated, or at least one compound of the general formula VI, 8 ,_ RS Vl ,,CN W (CH 2 )m VI, in which R 8 , U, T, V and W have the meanings according to one or more of 10 claims 1 to 15 and m denotes 0, 1, 2 or 3, is reacted in a reaction medium in the presence of at least one catalyst, preferably in the presence of at least one catalyst based on palladium or platinum, particularly preferably in the presence of palladium on carbon, under a hydrogen atmosphere, optionally in the presence of at least one acid, preferably in the presence of hydrochloric is acid, or in the presence of at least one reducing agent selected from the group consisting of BH 3 -S(CH 3 ) 2 , lithium aluminium hydride and sodium borohydride, optionally in the presence of NiCl 2 , to yield at least one compound of the general formula V, optionally in the 20 form of a corresponding salt, preferably in the form of a corresponding hydrochloride, and said compound is optionally purified and/or isolated, and at least one compound of the general formula V is reacted with at least one compound of the general formula VII, R 6 R7R' HO R2 HO R 5 R3 25 VIl, in which R', R 2 , R 3 , R 4 , R', R 6 and R 7 have the meanings according to one or more of claims 1 to 15, in a reaction medium, optionally in the presence of at - 240 least one suitable coupling agent, optionally in the presence of at least one base, or with at least one compound of the general formula Vill, R 6 R7 R LG R2 0R5 R3 R R4 Vill, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings according to one or more of claims 1 to 15 and LG denotes a leaving group, preferably a chlorine io or bromine atom, in a reaction medium, optionally in the presence of at least one base, to yield at least one compound of the general formula 1, R 8 UNR R I H R R7R Vz -W K 11N R2 (CH 2 )n R 4 15 in which T, U, V, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 R 7 and R 8 have the meanings according to one or more of claims 1 to 15 and n denotes 1, 2, 3 or 4 and said compound is optionally purified and/or isolated.
17. A method for producing at least one compound according to one or 20 more the claims 1 to 15, characterised in that at least one compound of the general formula X, R 8 UN% W NH 2 X, 25 -241 in which R 8 , U, T, V and W have the meanings according to one or more of claims 1 to 15, is reacted with at least one compound of the general formula VII, R 6 R7 R HO R2 HO 0R5 R3 R4 5 Vil, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings according to one or more of claims 1 to 15, in a reaction medium, optionally in the presence of at least one suitable coupling agent, optionally in the presence of at least one 10 base, or with at least one compound of the general formula Vill, R 6 R7 R LG R2 0 / R 5 R 3 R4 Vill, 15 in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the meanings according to one or more of claims 1 to 15 and LG denotes a leaving group, preferably a chlorine or bromine atom, in a reaction medium, optionally in the presence of at least one base, to yield at least one compound of the general formula Im, 20 R 8 U RS UR6 R7 R1 W NH R2 0/ R 5 R 3 R 4 Im, - 242 in which T, U, V, W, R 1 , R 2 , R 3 , R 4 , R', R 6 , R 7 and R 8 have the meanings according to one or more of claims 1 to 15, and this compound is optionally purified and/or isolated.
18. A pharmaceutical containing at least one compound according to one 5 or more of claims 1 to 15 and optionally one or more physiologically acceptable auxiliary substances.
19. A method for the treatment and/or prevention of one or more diseases in a human selected from the group consisting of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain io and visceral pain; joint pain; hyperalgesia; allodynia; causalgia and migraine; or for the treatment and/or prevention of one or more diseases in a human selected from the group consisting of depression; neuropathy; nerve injury; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's is chorea; cognitive dysfunction, preferably cognitive deficiency states, particularly preferably memory disorders; and epilepsy; or for the treatment and/or prevention of one or more diseases in a human selected from the group consisting of airways diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughing; urinary incontinence; 20 an overactive bladder (OAB); diseases and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritation; skin irritation; neurotic skin conditions; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammation, preferably inflammation of the intestines, the eyes, the bladder, the skin or the nasal mucosa; diarrhoea; 25 pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; disorders of food intake, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; dependency on medicines; abuse of medicines; withdrawal symptoms associated with dependency on medicines; development of tolerance towards medicines, preferably towards natural or synthetic opioids; 30 dependency on drugs; drug abuse; withdrawal symptoms associated with dependency on drugs; dependency on alcohol; alcohol abuse and withdrawal symptoms associated with dependency on alcohol; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing -243 vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing libido; for modulating locomotor activity; for anxiolysis; for local anaesthesia; and/or for inhibiting undesired side-effects, preferably selected from the group consisting of hyperthermia, high blood pressure and 5 constriction of bronchial tubes, triggered by the administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ 249482, nuvanil and capsavanil.
20. Use of at least one compound according to one or more of claims 10 1 to 15 for the production of a pharmaceutical for the treatment and/or prevention of one or more diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; joint pain; hyperalgesia; allodynia; causalgia and migraine; or for the production of a pharmaceutical for the is treatment and/or prevention of one or more diseases selected from the group consisting of depression; neuropathy; nerve injury; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's chorea; cognitive dysfunction, preferably cognitive deficiency states, particularly preferably memory disorders; 20 and epilepsy; or for the production of a pharmaceutical for the treatment and/or prevention of one or more diseases selected from the group consisting of airways diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughing; urinary incontinence; an overactive bladder (OAB); diseases and/or injuries of the gastrointestinal tract; 25 duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritation; skin irritation; neurotic skin conditions; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammation, preferably inflammation of the intestine, the eyes, the bladder, the skin or the nasal mucosa; diarrhoea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; disorders of food intake, preferably 30 selected from the group consisting of bulimia, cachexia, anorexia and obesity; dependency on medicines; abuse of medicines; withdrawal symptoms associated with dependency on medicines; development of tolerance towards medicines, preferably towards natural or synthetic opioids; dependency on drugs; drug abuse; withdrawal symptoms associated with dependency on - 244 drugs; dependency on alcohol; alcohol abuse and withdrawal symptoms associated with dependency on alcohol; for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for the treatment of wounds and/or burns; for the treatment of severed nerves; for increasing s libido; for modulating locomotor activity; for anxiolysis; for local anaesthesia; and/or for inhibiting undesired side-effects, preferably selected from the group consisting of hyperthermia, high blood pressure and constriction of bronchial tubes, triggered by the administration of vanilloid receptor 1 (VR1/TRPV1 receptor) agonists, preferably selected from the group consisting of capsaicin, i resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil. Dated 19 December 2012 Grunenthal GmbH Patent Attorneys for the Applicant/Nominated Person is SPRUSON & FERGUSON
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