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EP1877376A1 - Novel compounds for treating inflammatory diseases - Google Patents

Novel compounds for treating inflammatory diseases

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Publication number
EP1877376A1
EP1877376A1 EP06725750A EP06725750A EP1877376A1 EP 1877376 A1 EP1877376 A1 EP 1877376A1 EP 06725750 A EP06725750 A EP 06725750A EP 06725750 A EP06725750 A EP 06725750A EP 1877376 A1 EP1877376 A1 EP 1877376A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
substituted
haloalkyl
optionally
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06725750A
Other languages
German (de)
French (fr)
Inventor
Rainer Walter
Ralf Anderskewitz
Jörg Kley
Horst Dollinger
Rolf Goeggel
Birgit Jung
Juergen Mack
Peter Nickolaus
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE102005019718A external-priority patent/DE102005019718A1/en
Priority claimed from DE102005023207A external-priority patent/DE102005023207A1/en
Priority claimed from DE102005035575A external-priority patent/DE102005035575A1/en
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP1877376A1 publication Critical patent/EP1877376A1/en
Withdrawn legal-status Critical Current

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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to novel compounds of the formula I and heteroderivatives thereof, as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof,
  • B 1 is phenyl or an aromatic or non-aromatic ring optionally containing one, two or three heteroatoms selected from the group oxygen, sulfur and nitrogen and is optionally substituted one or more times by one or more radicals selected from the group OH, OC 1 -6- alkyl, OC 1 .
  • B 2 is phenyl or a heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • X is O, S, NR 5 or CR 6 R 7;
  • n 0, 1, 2 or 3;
  • R 1 is H, C- ⁇ -alkyl, C 1- ⁇ - haloalkyl, COR 1 ⁇ COOR 1 1 CH 2 COOR 1 1 ; preferably H, C 1-e-alkyl, CL ⁇ -halolalkyl,
  • R 1 1 is H or d_ 6 alkyl
  • R 2 is H, C 1-6 alkyl or C 1-6 haloalkyl
  • Heterocycle which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen;
  • A is CO
  • R 3 is H or a residue selected from the group consisting of OH, C 1-6 -haloalkyl, a Ce- 10 aryl, a C. 5 10 heteroaryl and a C 3 _ 10 heterocycle, wherein the C 3-10 - heterocycle and the C 5 -i 0 heteroaryl one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen may contain, optionally with one or more radicals selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, optionally bridged C 3-8 cycloalkyl and d_ 6 haloalkyl may be substituted, optionally with a radical selected from the group from C 1-6 alkyl, C 1-6 haloalkyl, OH, halogen and C 6 .i 0 aryl may be substituted;
  • R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-C ⁇ -io-aryl, OH, O-C 1-6 -alkyl, OC 1-6 -haloalkyl , Halogen, SH, S-Ci-e-alkyl, SC 1-6 -haloalkyl,
  • SO 2 -C 1-6 alkanol SO 2 -C 1-6 alkyl, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 alkyl, SO 2 -N (C 1-8 alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 may be substituted,
  • R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl
  • C 5-8 cycloalkenyl, d_ 6 alkyl, and C 1-6 alkanol which is optionally substituted with one or more radicals selected from the group consisting of C 6-10 aryl, C 3-8 cycloalkyl, a C 5 _ 10 heteroaryl and C 3, 10 may be substituted heterocycle, optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 2 _ 6 alkenyl, C. 2 6- alkynyl, C 1-6 -haloalkyl, CN, CONH 2 ,
  • a C 3 . 10 heterocycle may be substituted, wherein the C 5 . 10 heteroaryl and the C 3 . 10 -heterocycle may optionally be substituted by a radical selected from oxo, hydroxyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 3 is a radical selected from a group consisting of C 6- io-aryl, a C 6 .io-heteroaryl and a C. 3 10 heterocycle, with one or more groups selected from the group consisting of C 6 -io aryl, CI_ 6 alkyl, C 2-6 alkenyl, C 2-6 -A!
  • R 3 is a radical selected from the group consisting of C 1-6 alkyl, C 6 -io-aryl d_ 6 alkylene, alkylene Cs ⁇ o-heteroaryl-C 1-6, C 3- 7 cycloalkyl, C 6 , 10 -aryl, a C 5-10 -heteroaryl and a Ca ⁇ o-heterocycle, which may optionally be substituted by one or more radicals from the group consisting of B, halogen, OH, C 1-6 -alkyl and oxo where B is a compound of formula 2
  • Z 1 is H, OH, halogen, C 1-6 alkyl, C 1-6 alkanol, 0 (Cv 6 -alkyl), C 6 - 10 aryl, 0-C 6 10 -aryl, NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 , or C 3-7 cycloalkyl; and Z 2 is OH, NH 2 , NH (C 1-6 -alkyl), N (C 1-6 -alkyl) 2 , O (C 1-6 -alkyl), mono- or bicyclic C 3-7 -cycloalkyl-alkyl, C 5- mean i 0 -heteroaryl or C 6-10 aryl mono- or bicyclic C 3-10 heterocycle, mono- or bicyclic;
  • R is a radical selected from the group consisting of C 6 . 10 -aryl and one
  • C 5 . 10 -Heteroaryl which may optionally be substituted by C 1-6 alkyl, which is optionally substituted by a radical selected from the group consisting of
  • -A- optionally with a radical selected from the group consisting of C 1-6 alkyl, C 2 . 6 -alkenyl, C 2 - ⁇ -alkynyl, CN, CI_ 6 -Haloalky !, CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 alkyl) 2, COOH, COO-C 1-6 alkyl, COH, CO-C 1-6 alkyl, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, halogen, SH, S-d_ 6 alkyl, S-Ci-6-haloalkyl, SO 2 -Ci.
  • a radical selected from the group consisting of C 1-6 alkyl, C 2 . 6 -alkenyl, C 2 - ⁇ -alkynyl, CN, CI_ 6 -Haloalky !, CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 alkyl
  • R 34 is H, C 1-6 -alkyl, C 6 . -Alkylene or 10 aryl-C ⁇ o-C 1-6 heteroaryl-C 1-6 - alkylene, or R 3 is a radical selected from a group consisting of C 6- - ⁇ 0 aryl, and a 5- C io-heteroaryl, which may optionally be substituted by NR 3 1 R 32 ; in which
  • R 3 is H, C 1-6 -alkyl, C- ⁇ -cycloalkyl, C 1-6 -haloalkyl, COR 3 1 ⁇ COOR 3 1 ⁇
  • R 3 1 2 H, C 1-6 alkyl, d_ 6 -Ha Oalkyl, C 3-6 cycloalkyl or C 6-10 aryl;
  • R 3 2 is H or a radical selected from the group consisting of C 1-6 alkyl, C 3 _ 7 cycloalkyl, and C 1-6 haloalkyl optionally substituted with one or more radicals selected from the group consisting of NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2, oxo and a non-aromatic C 3 _ 10 heterocycle which may contain one or two hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur , may be substituted, wherein the non-aromatic C ⁇ o-heterocycle may optionally be substituted by Ci_ 4 -alkyl substituted mean; or R 3 is a radical selected from a group consisting of C 6 -io-aryl and a
  • C 5 . 10 heteroaryl with a C 3 . 10 heterocycle, which is optionally substituted by one or more radicals selected from the group consisting of C ⁇ .i 0 -aryl, C 1-6 -alkyl, C 3-6 -cycloalkyl, CN, C 1-6 -haloalkyl, CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 alkyl) 2, COOH, COO-d_ 6 alkyl, COH, CO-d_ 6 alkyl,
  • Oxo, OH, O-C ⁇ -alkyl, halogen, SH, SC 1-6 alkyl, NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted;
  • R 3 is benzimidazolyl, which may be optionally substituted with a group selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and
  • R 4 C ⁇ alkyl, C3 .8 cycloalkyl, C 1- ⁇ haloalkyl, OR 4 ⁇ NR 4 1 R 4.2, CN or halogen; where R 4.1 is H, Ci. 6- alkyl, C 3-8 -cycloalkyl or C 1-6 -haloalkyl;
  • R 4 is H, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 haloalkyl; and R 5 is C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, COR 5 ⁇ 5 CONHR 1, CON (R 5 1) 2,
  • N (C 1-6 -alkyl) 2 may be substituted
  • R 5 -alkylene 1 Ci- 6 alkyl, Cs-urHeteroaryl-C 1-6 or C 6 aryl -io- d alkylene and R 52 -6 C 6 - 10 -aryl or a C 5 _ 10 -heteroaryl;
  • R 6 is HC 1-6 alkyl or d ⁇ haloalkyl
  • R 7 is H, C 1-6 -alkyl or C 1-6 -haloalkyne, or R 6 and R 7 together form a 3-6 membered carbocycle;
  • a CO, C NH, d- 4 alkylene or Ca ⁇ cycloalkylene;
  • B 1 is phenyl or a C 5-10 heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • B 2 is phenyl or pyridinyl
  • X is O, S, NR 5 or CR 6 R 7;
  • n 0, 1, 2 or 3;
  • R 1 is H, C 1-4 alkyl, C 1-4 haloalkyl
  • R 2 H, C 1-4 alkane! or C- M haloalkyl
  • R 1 and R 2 together with the nitrogen form a non-aromatic heterocycle which may contain one or two nitrogen atoms;
  • R 3 is H, OH, C 1-4 haloalkyl, C 6 . 10 -aryl, a C 5-10 heteroaryl, which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the C 6 _i 0 aryl and the C 5 -i 0 -Heteroaryl optionally with one or more groups selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 haloalkyl may be substituted; or R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl,
  • C 5 _ 8 -Cycloalkenyi and Ci- 6 alkyl optionally substituted with one or more radicals selected from the group consisting of C 6 -aryl or a C. 5 io-heteroaryl may be substituted, optionally with one or more
  • SO 2 -C 1-4 -haloalkyl SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 -N (C 1 -C 4 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-4 -alkyl and N (C 1-4 -alkyl) 2 ;
  • a radical selected from a group consisting of C 6 -io-aryl, Cs-10 heteroaryl, C 6-10 aryl-C 1 _ 4 -alkylene and C ⁇ ⁇ o-heteroaryl-C 1-4 -akylen which may optionally be substituted by one or more radicals selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 , NHCOOR 33 and phenyl which is optionally substituted by one or more radicals selected from the group consisting of C 1-4 Alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, C 1-4 -HaIOalkylk, CONH 2 , CONH-C 1-4 -alkyl, CON (C 1-4 -alkyl) 2 , COOH,
  • COO-C 1-4 -alkyl COH, CO-C 1-4 -alkyl, OH, OC 1-4 -alkyl, OC 1-4 -haloalkyl, halogen, SH, SC 1-4 -alkyl, SC 1- 4 haloalkyl, SO 2 -C 1-4 alkyl, SO 2 C 1-4 -HaIOaIkYl, SO 2 -NH 2, SO 2 -NH-C 1-4 alkyl, SO 2 -N (C 1- 4 alkyl) 2 , NO 2 , NH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 , and a C 5 .
  • R 3 is H or C 1-4 alkyl
  • R 34 is H, C 1-4 -alkyl, C is fM o-aryl-C 1-4 -alkylene or C 5-10 -heteroaryl-
  • R 3 is a radical selected from a group consisting of C 6 -io-aryl and a C 5 . 10 heterocycle, which may be substituted by NR 3 1 R 3 2 wherein
  • R 3 C 6-1O- Ai ⁇ I which may be substituted by a C 5-1 o-heteroaryl, which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which optionally with one or a plurality of radicals selected from the group consisting of C 6-1 o-aryl, d 1-4 -alkyl,
  • R 3 Ce-io-aryl which may be substituted with a C 3 _ 10 heterocycle which may contain one or two hetero atoms selected from the group of oxygen, sulfur and nitrogen and optionally selected with one or more groups selected from the group C 1-4 alkyl and oxo may be substituted; or R 3 is benzimidazolyl optionally substituted by a radical selected from
  • R 4 is C 1-4 -alkyl, C 3-6 -cycloalkyl, d- 4- haloalkyl, OR 4 1 , NR 4 1 R 4.2 , CN or halogen; and R 4.1 H, d. 4- alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl; R 4 2 H, d. 4- alkyl, C 3-6 -cycloalkyl or d. 4 -haloalkyl; and
  • R 5 Ci_4-alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, COR 5 1, 5 CONHR 1, CON (R 5 1) 2,
  • R 5 1 d-alkylene or C 6 _io-aryl-Ci- 6 Cs ⁇ o-heteroaryl-C 1-6 -alkylene 4 alkyl; R 5 is C 6 -io-aryl or C 5 _ 10 -heteroaryl;
  • R 6 is H 1 C 4 -alkyl or C 1-4 -haloalkyl
  • R 7 is H, d-4 alkyl or d. 4 -haloalkyl
  • R 6 and R 7 together form a 3-6 membered carbocycle
  • A is CO, C is NH, C 1-6 -alkylene or C 3-8 -cycloalkylene,
  • B 1 is phenyl or an aromatic or non-aromatic ring which may optionally contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally mono- or polysubstituted by one or more radicals selected from the group consisting of OH, O-- C 1-6 alkyl, 0-C 1 .
  • c 2 is phenyl or pyridinyl
  • X is O, S, NR 5 or CR 6 R 7;
  • n 0, 1, 2 or 3;
  • R 1 is H, C 1-4 alkyl or C 1-4 haloalkyl
  • R 2 is H, C 1-4 alkyl or C 1-4 haloalkyl
  • R 1 and R 2 together with the nitrogen form a non-aromatic heterocycle which may contain one or two nitrogen atoms;
  • R 3 is H, OH, C 1-6 -haloalkyl or a radical selected from the group consisting of C 6-10 -aryl, a C 5-10 -heteroaryl and a C 3-10 -heterocycle, optionally with a methyl group, Oxo or OH may be substituted;
  • R 3 is C 1-6 -alkyl which is optionally selected with one or more radicals from the group consisting of halogen, OH, CN, CONH 2, CONH-CI_ 6 alkyl, CON (C 1-6 alkyl) 2, COOH, COO-C 1-6 -alkyl, COH, CO-C 1-4 -alkyl, COAryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, S-C 1-6 Alkyl, SC ,.
  • R 3 is a radical selected from the group consisting of C 3-8 cycloalkyl, a bridged with Ci 3 alkylene-C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 1-6 alkyl and CI_ 6 - alkanol which optionally selected with one or more groups selected from the group consisting of C 6 -aryl, C 3-8 -cycloalkyl, C 5 heteroaryl .i 0 C and a third 10 may be substituted heterocycle, optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl , Halogen, S-Ci. 6 -alkyl, SC 1-6 -haloalkyl, NO 2 , NH 2 , NH-C 1-6 -alkyl
  • C 5 . 10 heteroaryl and a C 3 . 10 heterocycle may be substituted, wherein the C 5 . 10 heteroaryl and the C 3 . 1Q heterocycle optionally substituted with a radical selected from oxo, hydroxyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl groups; or R 3 is a radical selected from a group consisting of C 1-6 alkyl, C 6 .
  • Z 1 is H, OH, halogen, C 1-6 alkyl, C 1-6 alkanol, O (C 1-6 alkyl), C 6- io-aryl, 0-C 6- io-aryl, NH 2 , NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 or C 3 . 7 -cycloalkyl; and Z 2 OH, NH 2 , mono- or bicyclic C 3 . 7 -cycloalkyl, a mono- or bicyclic C 3 . 10 -heterocycle, a mono- or bicyclic C 5 _ 10 heteroary! or C 6 .
  • R 3 is phenyl substituted with one or more radicals selected from the group consisting of C 6 -aryl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 1-6 -HaIOaIKyI, CONH 2, CONH- C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-6 alkyl, COH, CO-C 1-6 alkyl, COAryl, OH, OC 1-6 alkyl , O-Ci -4 haloalkyl, halo, SH, SC 1-6 alkyl, S-Ci- 4 haloalkyl, SO 2 -C 1 -6 alkyl, SO 2 C 1-4 haloalkyl, SO 2 -NH 2 , SO 2 -N HC 1 -6- alkyl,
  • R 3 is phenyl which is substituted by C 1-4 -alkyl, which is optionally substituted by a radical selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 ,
  • NHCOOR 33 and phenyl which may optionally be substituted by one or more radicals selected from the group consisting of methyl, / -butyl, F, Cl, Br, CN, OH, and a heterocycle having one, two or three heteroatoms selected from the group may contain oxygen and nitrogen, may be substituted, wherein the heterocycle optionally with an oxo group or a
  • Methyl group may be substituted; in which
  • R 33 is H or C ⁇ -alkyl
  • Alkylene R 34 is H, C 1-6 -alkyl or C 6 .io-aryl-C 1-6, C 5-10 -heteroaryl-CI_ 6 - alkylene; or R 3 is phenyl substituted with NR 3 1 R 32 ; in which
  • R 3 is H, C 1-4 alkyl, C 1-4 haloalkyl, COR 3 1 ⁇ COOR 3 1 ⁇ CONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and
  • R 31 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 6- i 0 aryl;
  • R 3 C 6-10 -aryl which with a C 5 . 10 -Heteroaryl containing one, two or three heteroatoms selected from the group of oxygen, sulfur and nitrogen may be substituted, which may be substituted by one or more radicals selected from the group consisting of C 6-10 -aryl, C 1-4 -alkyl, C 3 _ 6 -Cyclolalkyl, CN, C 1-4 haloalkyl, CONH 2, CONH-C 1-4 -alkyl, CON (C 1-4 alkyl) 2, COOH,
  • COO-C 1-4 -alkyl COH, CO-C 1-4 -alkyl, OH, OC 1-4 -alkyl, halogen, SH, SC 1-4 -alkyl, NH 2 , NH-C 1-4 - alkyl and N (C 1 _ 4 alkyl) 2 may be substituted;
  • R 3 is C 6-10 aryl which may be substituted with a C 3-10 non-aromatic heterocycle which may contain one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, said C 3 .io Heterocycle may optionally be substituted by one or more radicals selected from the group consisting of C 1-4 alkyl and oxo;
  • R 3 is benzimidazolyl, which may be optionally substituted with one or more groups selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl; and R 4 is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, OR 4.1 , NR 4.1 R 4.2 , CN or halo;
  • R 4.1 is H, C 1-4 -alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl
  • R 4.2 is H, C 1-4 -alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl
  • R 5 is C 1-4 -alkyl, C 3-8 -cycloalkyl, C 1-4 -haloalkyl, COR 5 1 , CONHR 5 ⁇ CON (R 5 ⁇
  • CONH-C 1-4 -alkyl CON (C 1-4 -alkyl) 2 , COOH, COO-C 1-4 -alkyl, COH, CO-C 1-4 -alkyl, O-C 1-4 -cycloalkyl , OC 1-4 -haloalkyl, O-C 1-4 -alkyl, halogen, SO 2- C 1-4 -alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 - N (C 1-4 alkyl) 2 , NO 2 , NH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 may be substituted; in which
  • R 5 is C 1-6 -alkyl, C 5 . 10 -Heteroaryl-C 1-6 -alkylene or C 6-10 - aryl-C 1-6 -alkylene and
  • R 52 C 6 . 10 -aryl or a C 5 -i- 0 heteroaryl; and R 6 is H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 7 H Ci. 6 -alkyl or C- ,. 6 -haloalkyl
  • R 6 and R 7 together form a 3-6 membered carbocycle
  • R 3 C 1-6 -AlkVl, optionally with one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-1 o -aryl, OH,
  • R 3 is a radical selected from the group consisting of C 3-8 cycloalkyl, a bridged with C ⁇ - 3 -alkylene C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 1-6 alkyl, and C 1 -6 -alkanol, which may optionally be substituted by one or more radicals selected from the group consisting of C 6 .io-aryl, C 3-8 -CyClOaIkYl, a C 5 -io-heteroaryl and a C 3-10 heterocycle , which in turn is optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2 6 alkynyl, C 1-6 haloalkyl, CN, CONH 2, CONH-C 1-6 alkyl, CON (C 1-6 alkyl) 2, COOH, COO-C 1 -6 alkyl, COH, CO-C 1-6 -alkyl
  • R 3 is selected, a radical from the group consisting of C 6 -aryl, C 5-1 o-heteroaryl, and a C 3-10 heterocycle, the selected one or more radicals from the group consisting of C 6- io aryl, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 -AIRinyl, C ⁇ 6 -HaIOaIRyI, CONH 2, CONH-C 1-6 -AIRyI, CON (C 1-6 -AIRyI) 2 , COOH,
  • R 3 is a radical selected from the group consisting of C 1-6 -alkyl, C 6 -aryl-aryl-C 1-6 -alkylene, C 5-1 o-heteroaryl-C 1-6 -alRylene, C 3 . 7 -cycloalkyl, C 6-10 -aryl, C 5-10 -heteroaryl and a Cs-io-heterocycle optionally with one or more radicals selected from the group consisting of B, halogen, OH, C 1-6 alkyl and Oxo may be substituted, wherein B is a compound of formula 2
  • Z 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol, O (C 1-6 -alkyl), C 6 . 10 -aryl, OC 6 . 10 -aryl, NH 2 , NH (C 1-6 alkyl), N (C 1-6 -AIRyI) 2 or C 3-7 cycloalyl and
  • a CH 2 , CD 2 , C NH, CHMe, CMe 2 , 1, 1 '-cyclopropylene or 1, 1'-cyclobutylidene;
  • X is O or NR 5 ; wherein R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, which may be optionally substituted with F; and where
  • n 0 or 1
  • R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2, COOH, COO-Ci -6 alkyl, COH, CO-C 1-6 alkyl, CO-C 6-10 -Ary I, OH, OC 1-6 alkyl, SO 2 -C 1-6 alkanol; SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 -HaIOalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 may be substituted,
  • R 3 is a radical selected from the group consisting of C 3-8 -CyClOaIkYl, a C 1- 3 alkylene bridged C 3-8 cycloalkyl and C 1-6 alkyl that is optionally substituted with one or more groups selected from the group consisting of C ⁇ -io-aryl, C 3-8 -CyClOaIkYl, a C 5-10 heteroaryl and a C 3-10 heterocycle may be substituted, which in turn optionally with one or more radicals selected from the group consisting of C 1-6- alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -haloalkyl, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-Ci- ⁇ -alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH,
  • R 3 is a radical selected from a group consisting of C 6-10 aryl, a C 3-8 heterocycle having 1 to 4 heteroatoms selected from N, O. S and a C 5- 10 heteroaryl having 1 to 2 hetero atoms selected from N, O. S, optionally with one or more radicals selected from the group consisting of C 6 . 10 -aryl, C 1-6 -alkyl, C 1-6 -haloalkyl, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-6 - Alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH,
  • R 3 is a radical selected from the group consisting of alkylene C 1-6 alkyl, C 6- io aryl-C 1-6, C 5 _ 10 -heteroaryl-d_ 6 -alkylene, C 3 _ 7 cycloalkyl , C 6 . 10 -aryl, C 3-8 -heterocycle having 1 to 4 heteroatoms selected from N, O.S, and a C 5-10 -heteroaryl having 1 to 2 heteroatoms selected from N, O. S, which in each case optionally substituted with one or more radicals of the group consisting of B, halogen, OH, Ci_ 6 alkyl, oxo, where B is a compound of formula 2
  • Z 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol or O (C 1-6 -alkyl) and Z 2 OH, NH 2 , NH (C L6 -alkyl), N (C 1 ⁇ 6 -alkyl) 2, O (C 1-6 alkyl), mono- or bicyclic C 3 _ 7 cycloalkyl, mono- or bicyclic C 5 _ 10 -heteroaryl, mono or bicyclic C 3 _ 10 -heterocycle or C 6-10 aryl;
  • R 4 is H, F or Cl
  • a CO, C NH, C 1 6 alkylene or C 3 _ 8 cycloalkylene,
  • B 1 is phenyl or pyridinyl
  • B 2 is phenyl or pyridinyl
  • X is O or NR 5 ;
  • n O, 1, 2 or 3;
  • R 1 is H, methyl, ethyl or propyl;
  • R 2 is H, methyl, ethyl or propyl
  • R 3 is H, OH, C 1-6 haloalkyl or C 6 .i 0 aryl or a radical selected from the group consisting of a C 5-10 heteroaryl and a C 3 . 10 -cycloalkyl which may contain one, two or three nitrogen atoms and which may optionally be substituted by a methyl group;
  • R 3 is a radical selected from the group consisting of cyclopentyl, cyclohexyl,
  • Cyclopentenyl, cyclohexenyl, methyl, ethyl, propyl and butyl, which may optionally be substituted by one or more radicals selected from the group consisting of C 6-10 - aryl and a C 5-1 o heterocycle may be substituted, which in turn optionally with one or a plurality of radicals selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, CN, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen,
  • SC 1-6 alkyl, SC 1-6 haloalkyl, NO 2 , NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted;
  • R 3 is phenyl optionally substituted with one or more groups selected from the group consisting of C 6-10 aryl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl,
  • CONH 2 CONH-C 1-4 -alkyl, CON (C 1-4 alkyl) 2, COOH, COO-Ci -4 -alkyl, COH, CO-C 1-4 alkyl, CO-C 6-1 o-aryl, OH, OC 1-4 -alky], OC 1-4 -haloalkyl, halogen, SH, SC 1-4 -alkyl, SC 1-4 -haloalkyl, SO 2 -C 1-4 -alkyl, SO 2- C 1-4 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 -N (C 1-4 -alkyl) 2 , NO 2 , NO 2 , NH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 may be substituted;
  • R 3 is phenyl which may optionally be substituted by C 1-4 alkyl, which may in turn be a radical selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 , NHCOOR 33 , p-fluorophenyl and a heterocycle containing one, two or three heteroatoms selected from the group
  • R 33 is H or d-4-alkyl; 6- i 0 aryl-C 1-6 alkylene or C 5 R 34 H, C 1-4 alkyl, C - -alkylene - heteroaryl-C 1 _ 6 ur;
  • R 3 is phenyl which may be substituted by NR 3 1 R 3 2 ; in which
  • R 32 is H, C 1-4 -alkyl, optionally with one or more radicals selected from the group consisting of NH 2 , NH (C 1 ⁇ -alkyl), N (C 1 ⁇ -alkyl) 2 , oxo or a C 3-10 -heterocycle, which may contain one or two nitrogen atoms and which may optionally be substituted by a methyl group, may be substituted;
  • R 3 is phenyl which may be substituted by a C 5 .i 0 -heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the C 5 .i 0 -heteroaryl being optionally substituted by one or more radicals selected from the group consisting of C 6 .io aryl, CI_ 4 alkyl, d.
  • R 3 is phenyl, which with a C 5-10 heteroaryl containing one, two or three heteroatoms selected from the group of oxygen, sulfur and nitrogen, may be substituted, wherein the C 5 i 0 heteroaryl optionally substituted with one may be or more radicals selected from the group consisting of Ci -4 alkyl, and oxo;
  • R 3 is benzimidazolyl, which may be optionally substituted with one or more radicals selected from the group consisting of methyl, ethyl, propyl, CF 3 , CH 2 CF 3 , cyclopropyl, cyclopentyl and cyclohexyl; and R 4 is C 1-4 alkyl, C 1-4 haloalkyl or halo; and
  • R 5 is a radical selected from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl,
  • Alkylene COR 5 1, CONHR 5 1, C 6 -aryl, S0 2 -C 6 -io-aryl-C 1-6 alkyl, SO 2 -C 6-10 aryl, or Ce M o-aryl-C 1 -6- alkylene and C 5 _ 10 -heteroaryl-Ci.
  • C 1-4 alkyl optionally substituted with one or more radicals selected from the group consisting of C 1-4 alkyl, C 2 _ 4 alkenyl, C 2-4 alkynyl, CN, C 1-4 haloalkyl, CONH 2, CONH -C 1-4 alkyl, CON (C 1-4 alkyl) 2 , COOH, COO-C 1 .4 alkyl, COH, CO-C 1-4 alkyl, OH, OC 1-4 alkyl, Halogen, SO 2 -C 4 alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 alkyl, SO 2 -N (C 1-4 alkyl) 2 , NO 2 , NH 2 , NH -C. 4 alkyl and N (C 1-4 alkyl) 2 may be substituted; and
  • R 5 is C 1-4 alkyl or C 6-10 arylC 1-6 alkylene
  • A, X, n, R 1 , R 2 , R 3 and R 4 have the abovementioned meaning, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof ,
  • R 1 , R 2 , R 3 , R 4 and A, B 1 , B 2 and n have the meanings given above and wherein O;
  • R 1 , R 2 , R 3 , R 4 , R 5 and A, B 1 , B 2 and n have the abovementioned meanings and wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A, B 1 , B 2 and X have the meanings given above and live n is 0, 1, or 2, preferably 0 or 1, particularly preferably 0
  • a CH 2 , CHMe, CMe 2 , C NH, 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;
  • X is O or NR 5 ;
  • n 0, 1 or 2;
  • R 1 is H, methyl or ethyl
  • R 2 is H, methyl or ethyl
  • R 3 is H, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl or 4-phenylcyclohexanyl or R 3 phenyl, which is optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl , CF 3 , CONH 2 , CONHMe, CONMe 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl,
  • R 3 is phenyl which is substituted by a radical selected from the group consisting of methyl and ethyl, optionally substituted by one or more radicals selected from the group consisting of COOH, COOMe, NH 2 , NMe 2 , NHCOMe, NHCOO-ferf-butyl , NMe (benzyl), p-fluorophenyl, pyrolidinyl, piperidinyl, morpholinyl, pyrolidin-2onyl, imidazolyl and triazolyl; or
  • R 3 is phenyl substituted with NR 3 1 R 3 2 , wherein
  • R 3 1 H, methyl, COH, COMe, COOMe, CONH 2 , CONMe 2 , SO 2 Me,
  • R 32 is H or a radical selected from the group consisting of methyl, and ethyl optionally having one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 ,
  • N-piperidinyl, N-morpholinyl and N-methyl-piperazinyl may be substituted, wherein the N-piperidinyl, N-morpholinyl and the N-methyl-piperazinyl may be optionally substituted with another oxo; or
  • R 3 is phenyl which is reacted with a C 5 .
  • Is substituted 10 -heteroaryl which can contain selected from the group oxygen, sulfur and nitrogen one, two or three heteroatoms, wherein the C 5 - 10 -heteroaryl is optionally substituted with one or more radicals selected from the group consisting of phenyl, methyl, Ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 ,
  • COOH, COOMe 1 COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted; or
  • R 3 is phenyl which is substituted by a C 3-10 heterocycle which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen, the C 3 . 10 -Heterocyclus may optionally be substituted by one or more radicals selected from the group C 1-4 alkyl and oxo; or R 3 is benzimidazolyl, which may be optionally substituted with one or more groups selected from the group consisting of methyl, propyl, CF 3 , CH 2 CF 3 , cyclopropyl and cyclohexyl;
  • R 4 is methyl, ethyl, propyl, butyl, CF 3 , CH 2 CF 3 , F, Cl, or Br;
  • R 5 is a radical selected from the group consisting of methyl, ethyl, propyl, butyl,
  • R 5 is methyl, ethyl, propyl, butyl or benzyl
  • a CH 2 , CHMe, CMe 2 , CO, C NH, 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;
  • X is O or NR 5 ;
  • n O or 1;
  • R 1 is H, methyl or ethyl, preferably H;
  • R 2 is H, methyl or ethyl, preferably H
  • R 3 is H, OH, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl or 4-
  • R 3 is phenyl substituted with a radical selected from the group consisting of phenyl, OH, F and CONH 2 ;
  • R 3 is phenyl which is substituted by a radical selected from the group consisting of methyl and ethyl, which is optionally substituted by a radical selected from the group consisting of COOH, COOMe, NH 2 , NMe 2 , NHCOMe, NHCOO-terf-
  • R 3 is phenyl substituted with NR 3 1 R 3 ; in which
  • R 3 1 H, methyl, SO 2 Me, SO 2 CF 3 or SO 2 -phenyl
  • R 32 denotes H or a radical selected from the group consisting of methyl and ethyl which is optionally substituted by one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 , oxo,
  • N-piperidinyl, N-morpholinyl and N-methyl-piperazinyl may be substituted;
  • R 3 is phenyl which may be substituted by a C 5 .i 0 heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which may be one or more radicals selected from the group consisting of Phenyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted, or
  • R 3 is phenyl substituted with a Ca.io heterocycle. The one or two
  • Benzimidazolyl which may be optionally substituted with methyl
  • R 4 is F or Cl
  • R 5 is a radical selected from the group consisting of methyl, ethyl, cyclopropyl,
  • R 5 1 is butyl or benzyl
  • R 3 is H, 4-phenyl-cyclohexanyl or
  • R 3 is phenyl, which may optionally be substituted by NR 3 1 R 3 2 ;
  • R 3 1 H, methyl, SO 2 Me, SO 2 CF 3 , or SO 2 -Pheny ⁇
  • R 3 is phenyl which is substituted by a C 3 . 10 heterocycle containing one or two hetero atoms selected from the group may include oxygen and nitrogen, where the C 3 -i 0 -heterocycle optionally substituted with one or more radicals selected from the group C 1-4 -alkyl and oxo may be substituted, and where
  • R 4 is H, F or Cl
  • R 5 is methyl, ethyl, cyclopropyl, cyclobutyl CH 2 CF 3 or benzyl, where the benzyl may optionally be substituted by F;
  • X is O or NR 5 ;
  • R 13 is H, OH, 4-phenylcyclohexyl or a radical selected from the group consisting of
  • R 4 is H, F or Cl; and R 5 is methyl or a radical selected from the group consisting of
  • CH 2 , CD 2 , C NH, CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;
  • R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, optionally substituted with F;
  • R 3 is C 1- ⁇ - alkyl, optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2, COOH, COO-d_ 6 alkyl, COH, CO-C 1-6 -AIRyI,
  • COAryl OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, SO 2 -Ci- ⁇ -alkanol; SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 ,
  • R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl, one with d. 3- alkylene bridged C 3-8 -cycloalkyl, C 5-8 -cycloalkenyl and C 1-6 -alkyl, C ⁇ - 6 -alkanol, each optionally substituted by one or more radicals selected from the group consisting of C e- Aryl, C 3-8 cycloalkyl, C 5-10 heteroaryl and C 3-10 heterocycle optionally substituted with one or more radicals selected from the group consisting of C 1-6 alkyl, C 2-6 Alkenyl, C 2 .
  • e is alkynyl, C 1-6 haloalkyl, CN, CONH 2 , CONH C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1- ⁇ alkyl, COH, CO -C 1-6 alkyl, CO-C 6-10 aryl I 1 OH, OC 1-6 alkyl, OC 1-6 haloalkyl, halo, SH, S-Ci- ⁇ -alkyl, SC 1-6 Haloalkyl, SO 2 -C 1-6 -alkanol, SO 2 -C 1-6 -alkyl, SO 2 -d ⁇ -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 alkyl) 2, NO 2, NH 2, NH-Ci 6 alkyl, N (C 1-6 -alkyl) 2, C.
  • R 3 is a radical selected from a group consisting of C 6 . 10 -aryl, C 5 .
  • R 34 is a C 6-10 aryl, C 6 -io-arylC 1-6 alkylene or a C 5-10 heteroarylC 1-6 alkylene;
  • R 3 is a radical selected from a group consisting of C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, Cs-io-heteroaryl-C 1-6 -alkylene, C 3 . 7 -cycloalkyl, C 6 .i 0 -aryl, C 5 . 10 heteroaryl and a C 3 _i 0 heterocycle, which may be optionally substituted with one or more radicals of the group consisting of B, halogen, OH, C 1-6 alkyl, oxo, where B is a compound of formula 2
  • Z 1 is H, OH 1 is halogen, C 1-6 -alkyl, C 1-6 -alkanol, O (C 1- ⁇ -alkyl), C 6-10 -aryl, O-C ⁇ .io-aryl, NH 2 , NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 or C 3-7 cycloalkyl; and Z 2 OH, NH 2 , N (C 1-6 alkyl) 2 , O (C 1-6 alkyl), C 6 -io-aryl; mono- or bicyclic C 3-7 cycloalkyl, mono- or bicyclic aromatic or non-aromatic C 3 - 10 heterocycle means,
  • R 4 is H, F or Cl; optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.
  • a CH 2 , CD 2 , C NH, CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;
  • X is O or NR 5 ; in which
  • R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, optionally substituted with F;
  • R 2 H; and R 3 is C 1-6 -alkyl, optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl,
  • CON (C 1-6 -alkyl) 2 COOH, COO-C 1- ⁇ - alkyl, COH, CO-C 1-6 -alkyl, phenyl, CO-phenyl, OH, O-d_ 6 -alkyl, SO 2 -C 1-6 -AlkBnOl; SO 2 -C 1 -6 alkyl, SO 2 C 1-6 haloalkyl, SO 2 -NH 2, -NH-S ⁇ 2 CI_ 6 alkyl, SO 2 -N (C 1-6 alkyl) 2, NO 2 , NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 , may be substituted;
  • R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl, one with
  • C ⁇ alkylene bridged C 3 8 cycloalkyl and C 1-6 alkyl which in each case optionally selected with one or more radicals from the group consisting of phenyl or other aromatic or non-aromatic C 3 _ 8 ring, preferably a C 5-7 ring, more preferably a C 5-6 ring, each optionally substituted from 1 to 4 heteroatoms independently selected from N, O.
  • S may include, may be substituted, each of these radicals being optionally substituted with one or more groups selected from the group consisting of C 1-6 -alkyl, C 1- ⁇ haloalkyl, CN, CONH 2, CONH-C 1-6 -alkyl, CON (Ci.
  • R 3 is a radical selected from a group consisting of phenyl and other aromatic or non-aromatic C 3-8 ring, preferably a C 5- 7-membered ring, more preferably a C 5 _ 6 ring which optionally contains 1 to 4 Heteroatoms selected from N, O.
  • S may contain and optionally with one or more radicals selected from the group consisting of phenyl, C 1-6 alkyl, C 1-6 haloalkyl, CONH 2 , CONH-C 1-6 - Alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1- ⁇ - alkyl, COH, CO-C 1 -6- alkyl, CO-phenyl, OH, OC 1-6- alkyl, 0- C 1-6 haloalkyl, halogen, SO 2 -C 1-6 -alkyl 1 SO 2 -C 1-6 alkanol, SO 2 -C L6 -HaIOaIkYl, SO 2 -NH 2, SO 2 -NH-C 1 -6- alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl) 2 and N- (SO
  • R 34 is a means
  • R 3 or a radical selected from a group consisting of C 1-6 alkyl, C 1-0 heteroaryl C 1-6 alkylene, C 6-10 aryl C 1-6 alkylene, C 3-7 cycloalkyl, phenyl and an aromatic or non-aromatic C 3-8 ring, preferably a C 5-7 ring, more preferably a C 5 - 6 ring containing 1 to 4 heteroatoms selected contain from N, S and O. wherein each of these radicals may optionally be substituted with one or more radicals selected from the group consisting of B, halogen, OH, C 1-6 alkyl, oxo, and wherein B is a compound of formula 2
  • Z 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol or O (C 1-6 -alkyl) and Z 2 OH, NH 2 , NH (C L6 -alkyl), N ( C 1-6 alkyl) 2 , O (C 1-6 alkyl), mono- or bicyclic C 3 . 7 -cycloalkyl, mono- or bicyclic aromatic or non-aromatic C 3 _
  • R 4 is H, F or Cl
  • a CH 2 , CD 2 , C NH, CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;
  • X is O or NR 5 ; in which
  • R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, optionally substituted with F; n is 0 or 1;
  • R 3 is a radical selected from the group consisting of
  • R 4 is H, F or Cl
  • C 1-6 -alkyl (including those which are part of other groups) is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 10 by the term "C 1-4 -alkyl” 4 carbon atoms understood. Preferred are aikyl groups having 1 to 4 carbon atoms.
  • Examples include: methyl, ethyl, A7-propyl, / s ⁇ -propyl, n-butyl, / so-butyl, sec-butyl, tert-Buty ⁇ , n-pentyl, / so-pentyl, neo-pentyl or hexyl ,
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
  • the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / t-butyl, etc.
  • C 1-6 -alkylene (including those which are part of other radicals) is understood as meaning branched and unbranched alkylene groups having 1 to 6 carbon atoms and branched and unbranched alkylene groups having 1 to 3 by the term "C L s -alkylene” Understood carbon atoms. Preference is given to alkylene groups having 1 to 3
  • Carbon atoms For example: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethyls, pentylene, 1, 1-dimethylpropyls, 2, 2, -dimethylpropylene, 1, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene.
  • the definitions propylene, butylene, pentylene and hexylene include all conceivable isomeric forms of the respective radicals of the same carbon number.
  • propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.
  • C 2 - 6 alkenyl (including those which are part of other radicals) are branched and unbranched alkenyl groups having 2 to 6 carbon atoms and the term “C 2 - 4 alkenyl” branched and unbranched alkenyl groups having 2 to 4 Carbon atoms understood, as far as they have at least one double bond. Preferred are alkenyl groups having 2 to 4 carbon atoms. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise described, the definitions propenyl, butenyl, pentenyl and hexenyl include all conceivable isomeric forms of the respective radicals.
  • propenyl includes 1-propenyl and 2-propenyl
  • butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.
  • C 2 - 6 -alkynyl (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C 2-4 alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 Carbon atoms understood as far as they have at least one triple bond.
  • alkynyl groups having 2 to 4 carbon atoms are preferred.
  • Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all conceivable isomeric forms of the respective radicals.
  • propynyl includes 1-propynyl and 2-propynyl
  • butinyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.
  • C 2. 6, alkynylene (including those which are part of other groups) are meant having 2 to 6 carbon atoms branched and unbranched alkynylene groups and by the term "C 2. 4, alkynylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms understood. Alkynylene groups having 2 to 4 carbon atoms are preferred.
  • Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1, 1-Dimethylethinyien, 1, 2-dimethylethynylene, pentynylene, 1, 1-dimethylpropynylene, 2, 2, - dimethylpropynylene, 1, 2 Dimethylpropynylene, 1, 3-dimethylpropynylene or hexynylene.
  • the definitions propynylene, butynylene, pentynylene and hexynylene include all conceivable isomeric forms of the respective radicals of the same carbon number.
  • propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1, 1-dimethylethynylene, 1, 2-dimethylethynylene.
  • aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • aryl-alkylene or "C 6 -io-aryl-alkylene” (even if they are part of other radicals) are understood to mean branched and unbranched alkylene groups having 1 to 6 carbon atoms, which with an aromatic ring system having 6 or 10 carbon atoms are substituted.
  • aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, / so-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • heteroaryl-alkylene or "C 5 10 -heteroaryl-alkylene.” (Including those which are part of other groups) are meant - although already “aryl-alkylene includes - branched and unbranched alkylene groups having 1 to 6 carbon atoms which substituted with a heteroaryl.
  • Such a heteroaryl includes five- or six-membered heterocyclic aromatics or 5-10 membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and contain as many conjugated double bonds as an aromatic system is formed.
  • five- or six-membered heterocyclic aromatic compounds or bicyclic heteroaryl rings are:
  • heteroaryls may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, te / t-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • C 6 haloalkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups having 1 to 6 carbon atoms substituted with one or more halogen atoms are substituted, the term “C 1 4 alkyl” refers to branched and For example, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 are understood as meaning alkyl groups having 1 to 4 carbon atoms. Preferred are alkyl groups having 1 to 4 carbon atoms
  • C 3 8 -cycloalkyl (including those which are part of other groups) cychsche alkyl groups having 3 to 8 carbon atoms which are "3 6 cycloalkyl C" should be understood accordingly cychsche alkyl groups having 3 to 6 carbon atoms, the term For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, unless otherwise stated, the cyclic alkyl groups may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, / isopropyl, ferf-butyl, hydroxy, fluoro, Chlorine, bromine and iodine
  • C 5 -C 8 cycloalkenyl also includes cyclic alkenyl groups having 5 to 8 carbon atoms.
  • cyclopentenyl, cyclohexenyl or cyclohepentyl are mentioned.
  • the cyclic alkenyl groups may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, / so-propyl, te / t-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • heterocycle is meant five-, six- or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, in which case the ring may have a carbon atom or if present, be linked to the molecule via a nitrogen atom.
  • non-aromatic heterocycles defines five-, six- or seven-membered unsaturated rings. Examples are:
  • aromatic heterocycles defines five- or six-membered heterocyclic aromatics or 5-10 membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and contain as many conjugated double bonds that an aromatic is formed systems. Examples of five- or six-membered aromatic heterocycles are:
  • a heterocycle may be provided with a keto group. As an example for this are called.
  • bicyclic rings eight-, nine- or ten-membered bicyclic rings which may optionally contain one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • the ring may be linked to the molecule via a carbon atom of the ring or, if present, via a nitrogen atom of the ring.
  • fused bicyclic rings defines bicyclic rings in which the bridge separating the rings represents a direct single bond.
  • fused bicyclic ring are mentioned:
  • bicyclic hetero rings defines bicyclic 5-10 membered hetero rings containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and in which the rings separating bridge means a direct single bond.
  • examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,
  • bicyclic heterocycles defines eight-, nine- or ten-membered bicyclic rings which may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
  • Compounds of general formula 1 may have acid groups, mainly carboxyl groups, and / or basic groups such as e.g. Amino functions.
  • Compounds of general formula 1 can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.
  • pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid)
  • pharmaceutically acceptable bases such as Alkal
  • the compounds of formula 1 in their salts, in particular for the pharmaceutical application, in their physiological and be converted pharmacologically acceptable salts.
  • These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula 1 with inorganic or organic acids.
  • R equal to hydrogen by reaction with inorganic bases
  • the compound of formula 1 can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion.
  • Hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid come into consideration for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used.
  • the alkali metal and alkaline earth metal hydroxides and hydrides are preferably suitable, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium being preferred, sodium and potassium hydroxide are particularly preferred.
  • the compounds of general formula (1) can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid.
  • suitable acids are succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid,
  • Lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid into consideration. Furthermore, mixtures of the abovementioned acids can be used.
  • Particularly preferred salts according to the invention are selected from the group consisting of chloride, bromide, iodide, hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, and hydroxycarboxylate.
  • p-toluenesulfonate sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, furoates, preferably chloride, bromide, iodide, hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate , Hydrobenzoate. Hydro-p-toluenesulfonate and hydromethanesulfonate.
  • the invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid
  • pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid
  • the compounds of the invention may optionally be present as racemates, but may also be present as pure enantiomers, i. in (R) or (S) form. Preference is given to compounds which are present as racemates or as (S) -form.
  • the invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid
  • pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid
  • An object of the present invention are further all intermediates of the process according to Scheme 1, in particular the intermediates according to the formulas i, ii or iii
  • Another object of the present invention are all intermediates of the process according to Scheme 2, in particular the intermediates of the formulas II, III, IV or V
  • G is NO 2 or NH 2 and wherein X and R 3 have the meanings given above.
  • Example 40 Starting from 4-cyano-benzoic acid, the synthesis proceeded as in Example 40. Only the last stage differed as follows. 6.15 g of 3 - ⁇ (4-cyano-phenyl) - [4- (1-methyl-1 H- Imidazol-4-yl) -phenylamino] -nnethylen ⁇ -1-methyl-1, 3-dihydro-indol-2-one were dissolved in 200 ml of methanolic ammonia and tetrahydrofuran and with 5 g of Raney nickel at RT and a pressure hydrogenated at 50 psi.
  • the solid phase used was silica gel 60 F254 (manufacturer: Merck) and, as liquid phase, unless otherwise stated, a 9: 1: 0.1 mixture of dichloromethane: methanol: ammonia.
  • HPLC-MS-1 Waters ZMD, Alliance 2690/2695 HPLC, Waters 2700 Autosampler, Waters 996/2996 diode array detector
  • the mobile phase used was: A: water with 0.10% TFA B: acetonitrile with 0.10% TFA
  • the stationary phase used was a column of Merck Chromolith TM SpeedROD RP-18e, 4.6 mm x 50 mm (column temperature: constant at 25 0 C).
  • the diode array detection took place in the wavelength range 210-400 nm.
  • Example 40 Starting from 4-cyano-benzoic acid, the synthesis proceeded as in Example 40. Only the last stage differed as follows. 0.6 g of 3 - ⁇ (4-cyano-phenyl) - [4- (1-methyl-1H-imidazol-4-yl) -phenyl-amino] -methylene ⁇ -1-phenyl-1,3-dihydro-indole 2-on were dissolved in 20 ml of dichloromethane and 30 ml of 40% ethanolic hydrochloric acid and stored in the refrigerator for 12 hours. The solution was concentrated to the residue, treated with 50 ml of 6 N ethanolic ammonia solution and boiled under reflux for 3 h.
  • Example 40 The synthesis of Example 40 described above was continued until the Boc protective group was removed. 4.4 3 - ([4- (1-AMINO-1-METHYL-ETHYL) -HENYL] -K- (1-METHYL-1H-IMIDAZOILY-YL) -PHENYLAMINO] -METHYLENE-3H-BENZOFURAN-2 ON
  • Residue is crystallized from acetonitrile, the enantiomers by chromatographic
  • a solution of 12.72 g (120 mmol) of sodium carbonate in 120 ml of water is initially charged and treated with a solution of 7.00 g (38 mmol) of 4- (2-methyl- [1,3-dioxolan-2-yl). cyclohexylamine (cis / trans mixture) in 50 g of dioxane. After cooling to 0 ° C., a solution of 10.09 g (39 mmol) of Fmoc chloride in 100 g of dioxane is added dropwise within 0.2 hours. The reaction mixture is stirred for 16 hours, cooling being removed.
  • the compounds of formula 1 are characterized by a variety of possible applications in the therapeutic field. Worth mentioning are those applications for which the compounds of formula 1 according to the invention can preferably be used as a PDE4 inhibitor due to their pharmaceutical activity. Examples include his respiratory or gastrointestinal diseases or disorders, inflammatory diseases of the joints, the skin or the eyes, cancers, as well as diseases of the peripheral or peripheral nervous system.
  • respiratory or lung diseases which are associated with increased mucus production, inflammation and / or obstructive diseases of the respiratory tract.
  • examples include his, acute, allergic or chronic bronchitis, chronic obstructive pulmonary disease (COPD), cough, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, fibrosing alveolitis, idiopathic pulmonary fibrosis, ulcerative colitis, farmers ' disease, hyperresponsive respiratory tract, infectious bronchitis or pneumonitis, pediatric asthma, bronchiectasias, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial edema, pulmonary edema, bronchitis, pneumonia or interstitial
  • inflammatory diseases of the gastrointestinal tract examples of this are its called, acute or chronic inflammatory changes in gallbladder inflammation, Crohn's disease, ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitis cystica profunda, pneumatosis cystoides intestinales, diseases of the bile ducts and gallbladder, e.g. Gallstones and conglomerates for the treatment of inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and eyes.
  • gliomas such as oligodendroglioma and glioblastoma.
  • Depression bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain, and brain damage caused by stroke, hypoxia or craniocerebral trauma.
  • the present invention relates to the use of compounds of formula 1 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lung, such as allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.
  • the compounds of formula 1 for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.
  • COPD inflammatory and obstructive diseases
  • chronic bronchitis chronic sinusitis
  • asthma Crohn's disease
  • ulcerative colitis especially COPD, chronic bronchitis and asthma.
  • the compounds of formula 1 for the treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or craniocerebral trauma.
  • diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or craniocerebral trauma.
  • An outstanding aspect of the present invention is the reduced profile of side effects.
  • this is understood as being able to administer a dose of a pharmaceutical composition without inducing vomiting in the patient, preferably nausea, particularly preferably malaise.
  • administration of a therapeutically effective amount of substance without inducing emesis or nausea is at any stage of the disease process.
  • the compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1 according to the invention.
  • the compounds of formula 1 can also be used in combination with other pharmacologically active ingredients.
  • betamimetics with corticosteroids PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists, Anticholinergics with betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,
  • Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharines, isoprenalines, levosalbutamol, mabuterol, meluadrine , Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmeterol, Salmefamol, Soterenol, Sulphoneterol, Tiaramide, Terbutaline, Tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3- (4- ⁇ 6- [ 2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hex
  • the betamimetics are selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 3- (4- ⁇ 6- [2 -Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy ⁇ -butyl) -benzenesulfoneamides, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy -ethyl] -8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2 - ⁇ [2 - ⁇ [3- (2-phenylethoxy) propyl] sulphony
  • betamimetics are selected from the group consisting of fenoterol, formoterol, salmeterol, 3- (4- ⁇ 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy ⁇ -butyl ) -benzenesulfoneamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one, 1- [3- (4 -Methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1, 4 benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [
  • betamimetics particularly preferred according to the invention are formoterol, salmeterol, 3- (4- ⁇ 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy ⁇ -butyl) -benzenesulfoneamide, 6 -Hydroxy-8- ⁇ 1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl ⁇ -4 H -benzo [1,4] oxazin-3-one, 6 Hydroxy-8- ⁇ 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl ⁇ -4 H -benzo [1,4] oxazin-3-one, 6 Hydroxy-8- ⁇ 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1,
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate , preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.
  • Preferred anticholinergic compounds are compounds which are selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts 2,2-diphenylpropionic acid-triester-methobromide, 2,2-diphenylpropionic acid-co-ester methobromide, 2-fluoro-2, 2-Fluoro-2,2-diphenylacetic acid tropol ester methobromide, 3,3 ', 4,4'-tetrafluorobenzilic acid tropol ester methobromide, 3,3', 4,4'-tetrafluorobenzilic acid copoprene methobromide, 4-diphenylacetic acid-co-est
  • the cations tiotropium, oxitropium, fiutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active constituents.
  • the abovementioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, Acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions are.
  • the chlorides, bromides, iodide and methanesulfonate are particularly preferred.
  • the drug combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is employed in anhydrous form in the medicament combinations according to the invention, the anhydrous crystalline tiotropium bromide is preferably used, which is known from WO 03/000265.
  • Preferred corticosteroids are compounds selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort.
  • the steroid is selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] - 11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester and 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy -androsta-1, 4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) ester, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their Solvates and / or
  • the steroid is selected from the group consisting of budesonide, fluticasone, mometasone, ciclesonide and 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta -1, 4-diene-17-carbothionic acid (S) -fluoromethyl ester, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
  • any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates.
  • Examples of possible salts and derivatives of the steroids may be: alkali metal salts, for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
  • compounds are preferably used which are selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD
  • the PDE4 inhibitor is selected from the group consisting of enprofylline, roflumilast, ariflo (cilomilast), arofylline, atizoram, AW D-12-281 (GW-842470), T-440, T-2585, PD-168787, V-1 1294A, CI-1018, CDC-801, D-22888, YM-58997, Z-15370, N- (3,5-dichloro-1-oxo) pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- ( 3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3
  • the PDE4 inhibitor is selected from the group consisting of roflumilast, ariflo (cilomilast), arofyllin.
  • AWD 12-281 (GW-842470), 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4- difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3-cyclopethyidimethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], Atizoram, Z-15370, 9-cyclopentyl-5,6-dihydro-7- ethyl 3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl -3- (tert-butyl) -9H-pyrazolo [3,
  • suitable PDE4 inhibitors are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and Hydro-p-to! Uolsuifonat, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.
  • Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321, 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy -2- propyl) phenyl) thio) methylcyclopropane acetic acid, 1 - (((1 (R) -3 (3- (2- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - ( E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio)
  • the LTD4 antagonist is selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
  • the LTD4 antagonist is particularly preferably selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 and MEN-91507 (LM-1507), optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmaceutically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.
  • Acid addition salts with pharmacologically acceptable acids for which the LTD4 antagonists are optionally capable of being used are, for example, salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, Hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.
  • salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates , Preferred EGFR inhibitors are compounds which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (morpholinyl) -xy-1-oxo] -Buten-i-yamoyl-y-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-diethylamino) -1-oxo-2-butene] 1-yl] amino ⁇ -7-cyclopropy
  • Preferred EGFR inhibitors are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (morpholino-4-yl) -1-oxo-2-butene-1] yl] amino ⁇ -7-cyclopropylmethoxy-quinazolm, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-dimethyl) amino] - 1-oxo-2-butene 1 -yl] aminyl ⁇ -7-cyclopropylmethoxy-ch ⁇ nazol ⁇ n, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-dimethylamino) -1-oxo-2-butene 1-yl] aminyl ⁇ -7-cyclopropylmethoxy-ch ⁇ nazol ⁇
  • EGFR inhibitors which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (morpholin-4-yl ) -1-oxo-2-buten-1-yl] amino ⁇ -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ⁇ [4- (morpholine-4 -yl) - 1 -oxo-2-buten-1-yl] amino ⁇ -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6 - ⁇ [4 - (( R) -6-methyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino ⁇ -7 - [(S) -
  • EGFR inhibitor particularly preferred according to the invention as EGFR inhibitor are those compounds which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (morpholin-4-yl) -1- oxo-2-buten-1-yl] amino ⁇ -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ⁇ [4 - ((R) -6-methyl - 2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino ⁇ -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morph
  • salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, Hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.
  • Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan.
  • Reference to the aforementioned dopamine agonists in the context of the present invention includes a reference to the latter optionally existing pharmacologically acceptable acid addition salts and optionally their hydrates.
  • physiologically acceptable acid addition salts which can be formed from the aforementioned dopamine agonists are, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric , Tartaric acid and maleic acid are.
  • H1-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine,
  • H 1 -antihistamines in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts.
  • Preferred PAF antagonists here are compounds which are selected from the group consisting of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl] - 6H-thieno [3,2-f] - [1,2,4] triazolo [4,3-a] [1,4] diazepine, 6- (2-chlorophenyl) -8,9-dihydro-1- Methyl 8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclo-penta- [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine.
  • Preferred MRP4 inhibitors are compounds selected from the group consisting of ⁇ -acetyl-dinitrophenyl cysteines, cGMP, cholates, diclofenac, dehydroepiandrosterones 3-glucuronides, dehydroepiandrosterones 3-sulphates, dilazep, dinitrophenyl-S glutathiones, estradiol 17 ⁇ -glucuronides, estradiol 3,17-disulphates, estradiol 3-glucuronides, estradiol 3-sulphates, estrone 3-sulphates, flurbiprofen, folates, N5-formyltetrahydrofoiate, glycocholates, glycolithocholic acid sulphate, ibuprofen, indomethacin , Indoprofen, ketoprofen, lithocholic acid sulphate, methotrexate, MK571 ((E) -3 - [[[3- [2- (7-chlor
  • the invention relates to the use of MRP4 inhibitors for the preparation of a pharmaceutical composition for the treatment of respiratory diseases comprising the PDE4B inhibitors and MRP4 inhibitors according to the invention, wherein the MRP4 inhibitors are preferably selected from the group consisting of / V-acetyl dinitrophenyl cysteines, dehydroepiandrosterones 3-sulphate, dilazep, dinitrophenyl S-glutathione, estradiol 3,17-disulphate, flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833, sildenafil, taurochenodeoxycholate, Taurocholates, taurolithocholates, taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole, optionally
  • the invention relates to the use of MRP4 inhibitors for the manufacture of a pharmaceutical composition for the treatment of respiratory disorders comprising the PDE4B inhibitors and MRP4 inhibitors according to the invention, wherein the MRP4 inhibitors are preferably selected from the group consisting of
  • the separation of enantiomers from the racemates can be carried out by known methods known in the art (e.g., by chromatography on chiral phases, etc.).
  • Acid addition salts with pharmacologically acceptable acids include, for example, salts selected from the group consisting of hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and Hydro-p-toluenesulpho ⁇ aten, preferably hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and Hydromethanesulphonate meant.
  • Another object of the invention are pharmaceutical preparations, the triple combinations of the PDE4B inhibitors of the invention, MRP4 inhibitors and another active substance such. an anticholinergic, a steroid, a LTD4 antagonist or a betamimetic, as well as their preparation and their use for the treatment of respiratory diseases.
  • Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0, 1 to 90 wt .-%, preferably 0, 5 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.
  • Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension.
  • the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.
  • pharmaceutical formulations are preferably characterized by the content of one or more compounds of formula 1 according to the above preferred embodiments.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known auxiliaries, for example inert diluents, such as
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetening agent such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • auxiliaries for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg finely divided silicic acid and silicates), sugars (eg pipe, milk and dextrose) emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and Sodium lauryl sulfate).
  • paraffins eg petroleum fractions
  • oils of vegetable origin eg peanut or sesame oil
  • mono- or polyfunctional alcohols eg ethanol or glycerol
  • excipients such as natural minerals (eg kaolin, Clays, talc, chalk
  • the tablets may, of course, besides the abovementioned excipients also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • the compounds of the formula 1 are administered by inhalation, it being particularly preferred if the administration is carried out once or twice daily.
  • the compounds of formula 1 must be provided in inhaled dosage forms.
  • Suitable inhalable dosage forms are inhalable powders, propellant-containing metered-dose inhalers or propellant-free inhalable solutions which, if appropriate, are present in admixture with conventional physiologically compatible excipients.
  • propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions.
  • the administration forms which can be used in the context of the present invention will be described in detail in the following part of the description.
  • the compounds of the formula 1 are mixed with physiologically acceptable auxiliaries, the following physiologically acceptable excipients can be used to prepare the inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo - And polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose
  • oligo - And polysaccharides eg dextrans
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, calcium carbonate
  • Lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred.
  • Lactose most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
  • Process for the preparation of the inhalable powders according to the invention Grinding and micronizing, as well as final mixing of the ingredients are known in the art.
  • Propellant-containing inhalation aerosols The propellant-containing inhalable aerosols which can be used in the context of the use according to the invention can be dissolved in the propellant gas or in dispersed form.
  • the propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
  • the propellant-containing inhalation aerosols which can be used in the context of the use according to the invention may also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.
  • Propellant-Free Inhalation Solutions The use according to the invention of compounds of the formula 1 is preferably carried out for the production of propellant-free inhalable solutions and inhalable suspensions.
  • Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions.
  • the solvent may be water only or it may be a mixture of water and ethanol.
  • the solutions or suspensions are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids.
  • acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • organic acids examples include: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances.
  • the organic acids are Ascorbic acid, fumaric acid and citric acid are preferred.
  • mixtures of the abovementioned acids in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as flavorings, antioxidants or complexing agents, for example citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • Co-solvents and / or further auxiliaries can be added to the propellant-free inhalable solutions which can be used in the context of the inventive use.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives are understood as meaning any pharmacologically acceptable substance which is not an active substance but together with the substance (s).
  • Active ingredient (s) can be formulated in the pharmacologically suitable solvent to improve the qualitative properties of the drug formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy.
  • the auxiliaries and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or prolong the useful life of the finished drug formulation, flavorings, vitamins and / or other additives known in the art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonants.
  • Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism.
  • Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • ready-to-use packs of a medicament for the treatment of respiratory disorders including an enclosed description including, for example, the words respiratory disease, COPD or asthma, one of the compounds of the invention described above and one or more combination partners selected from the group described above are provided ,

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Abstract

The invention relates to novel compounds of formula (1), heteroderivatives thereof, and pharmacologically compatible salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof, that are suitable for treating respiratory or gastrointestinal complaints or illnesses, inflammatory diseases of the joints, skin or eyes, diseases relating to the peripheral or central nervous system, or cancerous diseases. The invention also relates to pharmaceutical compositions containing said compounds.

Description

NEUE VERBINDUNGEN ZUR BEHANDLUNG VON ENTZÜNDLICHEN NEW COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY

ERKRANKUNGENDISEASES

Die Erfindung betrifft neue Verbindungen der Formel 1 und Heteroderivate davon, sowie pharmakologisch verträgliche Salz, Diastereomere, Enantiomere, Racemate, Hydrate oder Solvate davon,The invention relates to novel compounds of the formula I and heteroderivatives thereof, as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof,

die geeignet sind zur Behandlung von Atemwegs- oder gastrointestinalen Beschwerden oder Erkrankungen, entzündlichen Erkrankungen der Gelenke, der Haut oder der Augen, Erkrankungen des periphären oder zentralen Nervensystems oder Krebserkrankungen, sowie pharmazeutische Zusammensetzungen die diese Verbindungen beinhalten.which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, the skin or the eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions containing these compounds.

BESCHREIBUNG DER ERFINDUNGDESCRIPTION OF THE INVENTION

Überraschenderweise konnte nun gefunden werden, dass die Verbindungen der Formel 1 geeignet sind zur Behandlung entzündlicher Erkrankungen. Gegenstand der vorliegenden Erfindung sind deshalb Verbindungen der Formel 1Surprisingly, it has now been found that the compounds of the formula 1 are suitable for the treatment of inflammatory diseases. The present invention therefore relates to compounds of the formula 1

worin wherein

A CO, C=NH, C1-6-Alkylen oder C3-8-Cycloalkylen B1 Phenyl oder ein aromatischer oder nicht aromatischer Ring der gegebenenfalls ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und der gegebenenfalls ein- oder mehrfach mit einem oder mehreren Resten ausgewählt aus der Gruppe OH, O-C1-6-Alkyl, O-C1.A is CO, C = NH, C 1-6 -alkylene or C 3-8 -cycloalkylene May B 1 is phenyl or an aromatic or non-aromatic ring optionally containing one, two or three heteroatoms selected from the group oxygen, sulfur and nitrogen and is optionally substituted one or more times by one or more radicals selected from the group OH, OC 1 -6- alkyl, OC 1 .

6-Haloalkyl, Halogen, C1-6 -alkyl und C1-6-Haloalkyl substituiert sein kann; 6 haloalkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl may be substituted;

B2 Phenyl oder ein Heteroaryl, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann;B 2 is phenyl or a heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

X O, S, NR5 oder CR6R7;X is O, S, NR 5 or CR 6 R 7;

n 0, 1 , 2 oder 3;n is 0, 1, 2 or 3;

R1 H, C-β-Alkyl, C1-β-Halolalkyl, COR1 \ COOR1 1 CH2COOR1 1; bevorzugt H, Ci-e-Alkyl, CLβ-Halolalkyl,R 1 is H, C-β-alkyl, C 1-β- haloalkyl, COR 1 \ COOR 1 1 CH 2 COOR 1 1 ; preferably H, C 1-e-alkyl, CLβ-halolalkyl,

R1 1 H oder d_6-Alkyl;R 1 1 is H or d_ 6 alkyl;

R2 H, C1-6-Alkyl oder C1-6-Halolalkyl;R 2 is H, C 1-6 alkyl or C 1-6 haloalkyl;

oder R1 und R2 bilden gemeinsam mit dem Stickstoff einen nichtaromatischenor R 1 and R 2 together with the nitrogen form a non-aromatic

Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann;Heterocycle which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen;

oder R2, N, A und B1 bilden gemeinsam eine bicyclische Gruppe der Formel (i)or R 2 , N, A and B 1 together form a bicyclic group of the formula (i)

worin A CO, C=NH oder C1-3-Alkyl m 1 , 2 oder 3 bedeuten, undwherein A is CO, C = NH or C 1-3 -alkyl m is 1, 2 or 3, and

R3 H oder ein Rest ausgewählt aus der Gruppe bestehend aus OH, C1-6-Haloalkyl, ein Ce-10-Aryl, ein C5.10-Heteroaryl und einem C3_10-Heterocyclus, wobei der C3-10- Heterocyclus und das C5-i0-Heteroaryl ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten können, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-10-Aryl, gegebenenfalls überbrücktes C3-8-Cycloalkyl und d_6-Haloalkyl substituiert sein kann, der gegebenenfalls mit einem Rest aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl, OH, Halogen und C6.i0-Aryl substituiert sein kann;R 3 is H or a residue selected from the group consisting of OH, C 1-6 -haloalkyl, a Ce- 10 aryl, a C. 5 10 heteroaryl and a C 3 _ 10 heterocycle, wherein the C 3-10 - heterocycle and the C 5 -i 0 heteroaryl one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen may contain, optionally with one or more radicals selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, optionally bridged C 3-8 cycloalkyl and d_ 6 haloalkyl may be substituted, optionally with a radical selected from the group from C 1-6 alkyl, C 1-6 haloalkyl, OH, halogen and C 6 .i 0 aryl may be substituted;

oder R3 C1-6-Alkyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-Cβ-io-Aryl, OH, 0-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-Ci-e-Alkyl, S-C1-6-Haloalkyl,or R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-C β -io-aryl, OH, O-C 1-6 -alkyl, OC 1-6 -haloalkyl , Halogen, SH, S-Ci-e-alkyl, SC 1-6 -haloalkyl,

SO2-C1-6-Alkanol; SO2-C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, Sθ2-N(Ci.e-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann,SO 2 -C 1-6 alkanol; SO 2 -C 1-6 alkyl, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 alkyl, SO 2 -N (C 1-8 alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 may be substituted,

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl,or R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl,

C5-8-Cycloalkenyl,d_6-Alkyl und C1-6-Alkanol, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10-Aryl, C3-8-Cycloalkyl, einem C5_10-Heteroaryl und einem C3,10-Heterocyclus substituiert sein kann, der gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-Alkyl, C2_6-Alkenyl, C2.6-Alkinyl, C1-6-Haloalkyl, CN, CONH2,C 5-8 cycloalkenyl, d_ 6 alkyl, and C 1-6 alkanol which is optionally substituted with one or more radicals selected from the group consisting of C 6-10 aryl, C 3-8 cycloalkyl, a C 5 _ 10 heteroaryl and C 3, 10 may be substituted heterocycle, optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 2 _ 6 alkenyl, C. 2 6- alkynyl, C 1-6 -haloalkyl, CN, CONH 2 ,

CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1. β-Alkyl, COH, CO-C1-6-Alkyl, COCβ-io-Aryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-d_6-Haloalkyl, SO2-C1-6-Alkanol, SO2-C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(d_6-Alkyl)2, NO2, NH2, N H -C L6-Al ky I, N(C1-6-Alkyl)2, einem C5.10-Heteroary) und einem C3.10-Heterocyclus substituiert sein kann, wobei das C5.10-Heteroaryl und der C3.10-Heterocyclus gegebenenfalls mit einem Rest ausgewählt aus Oxo-, Hydroxyl-, Halogen, C1-6-Alkyl und C1-6-Haloalkyl substituiert sein kann; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-io-Aryl, einem einem C6.io-Heteroaryl und einem C3.10-Heterocyclus, der mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, Ci_6-Alkyl, C2-6-Alkenyl, C2-6-A!kinyl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-AIkYl)2, COOH, COO-d_6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6.! O-Aryl, OH,CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1 . β- alkyl, COH, CO-C 1-6 -alkyl, COCβ-io-aryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6- alkyl, S- d_ 6 haloalkyl, SO 2 -C 1-6 alkanol, SO 2 -C 1-6 alkyl, SO 2 C 1-6 haloalkyl, SO 2 -NH 2, SO 2 -NH-C 1-6 alkyl, SO 2 -N (d_ 6 alkyl) 2, NO 2, NH 2, NH -C L6 -Al ky I, N (C 1-6 alkyl) 2, C. 5 10 heteroary) and a C 3 . 10 heterocycle may be substituted, wherein the C 5 . 10 heteroaryl and the C 3 . 10 -heterocycle may optionally be substituted by a radical selected from oxo, hydroxyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl; or R 3 is a radical selected from a group consisting of C 6- io-aryl, a C 6 .io-heteroaryl and a C. 3 10 heterocycle, with one or more groups selected from the group consisting of C 6 -io aryl, CI_ 6 alkyl, C 2-6 alkenyl, C 2-6 -A! Kinyl, C 1-6 haloalkyl , CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2, COOH, COO-d_ 6 alkyl, COH, CO-C 1-6 alkyl, CO-C. 6 ! O -aryl, OH,

0-d.e-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-Ci_6-Haloalkyl, SO2-C1-6-AIkYl, SO2-d_6-Alkanol, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-AIkYl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2 und N-(SO2-C1-4- Alkyl)(R34) substituiert sein kann;0-de-alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 -alkyl, S-Ci_ 6 -haloalkyl, SO 2 -C 1-6 -alkyl, SO 2 -d_ 6 -alkanol, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 alkyl, SO 2 -N (C 1-6 alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 alkyl, N (C 1-6 alkyl) 2 and N- (SO 2 C 1-4 alkyl) (R 34 ) may be substituted;

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-io-Aryl- d_6-alkylen, Cs^o-Heteroaryl-C1-6-alkylen, C3-7-Cycloalkyl, C6,10-Aryl, einem C5-10- Heteroaryl und einem Ca^o-Heterocyclus, der gegebenenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl und Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 istor R 3 is a radical selected from the group consisting of C 1-6 alkyl, C 6 -io-aryl d_ 6 alkylene, alkylene Cs ^ o-heteroaryl-C 1-6, C 3- 7 cycloalkyl, C 6 , 10 -aryl, a C 5-10 -heteroaryl and a Ca ^ o-heterocycle, which may optionally be substituted by one or more radicals from the group consisting of B, halogen, OH, C 1-6 -alkyl and oxo where B is a compound of formula 2

in der Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol, 0(Cv6-AIkYl), C6-10-Aryl, 0-C6 10-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2, oder C3-7-Cycloalkyl; und Z2 OH, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2, O(C1-6-Alkyl), mono- oder bicyclisches C3-7-CyClOaIkYl, mono- oder bicyclischer C3-10-Heterocyclus, mono- oder bicyclisches C5-i0-Heteroaryl oder C6-10-Aryl bedeuten;Z 1 is H, OH, halogen, C 1-6 alkyl, C 1-6 alkanol, 0 (Cv 6 -alkyl), C 6 - 10 aryl, 0-C 6 10 -aryl, NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 , or C 3-7 cycloalkyl; and Z 2 is OH, NH 2 , NH (C 1-6 -alkyl), N (C 1-6 -alkyl) 2 , O (C 1-6 -alkyl), mono- or bicyclic C 3-7 -cycloalkyl-alkyl, C 5- mean i 0 -heteroaryl or C 6-10 aryl mono- or bicyclic C 3-10 heterocycle, mono- or bicyclic;

oder R ein Rest ausgewählt aus der Gruppe bestehend aus C6.10-Aryl und einemor R is a radical selected from the group consisting of C 6 . 10 -aryl and one

C5.10-Heteroaryl, der gegebenenfalls mit C1-6-Alkyl substituiert sein kann, welches gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend ausC 5 . 10 -Heteroaryl, which may optionally be substituted by C 1-6 alkyl, which is optionally substituted by a radical selected from the group consisting of

COOR33, NR33R3 4, NHCOR33, NHCOOR33, Phenyl substituiert sein kann, wobei PhenylCOOR 33 , NR 33 R 3 4 , NHCOR 33 , NHCOOR 33 , phenyl may be substituted, wherein phenyl

-A- gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C2.6-Alkenyl, C2-β-Alkinyl, CN, Ci_6-Haloalky!, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-d_6-Alkyl, S-Ci-6-Haloalkyl, SO2-Ci. β-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-Ci-6-Alkyl, SO2-N(C1-6-Alkyl)2l NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2, einem C3_10-Heterocyclus und einem C5.10-Heteroaryl substituiert sein kann, wobei der C3-10- Heterocyclus und das C5-i0-Heteroaryl gegebenenfalls mit einer Oxogruppe oder einer Methylgruppe substituiert sein können; wobei R33 H oder C1-6-Alkyl;-A- optionally with a radical selected from the group consisting of C 1-6 alkyl, C 2 . 6 -alkenyl, C 2 -β-alkynyl, CN, CI_ 6 -Haloalky !, CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 alkyl) 2, COOH, COO-C 1-6 alkyl, COH, CO-C 1-6 alkyl, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, halogen, SH, S-d_ 6 alkyl, S-Ci-6-haloalkyl, SO 2 -Ci. β-alkyl, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-Ci-6-alkyl, SO 2 -N (C 1-6 -alkyl) 2l NO 2 , NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2, a C 3 _ 10 heterocycle and a C. 5 10 heteroaryl may be substituted, wherein the C 3-10 - heterocycle and the C 5 -i 0 heteroaryl may optionally be substituted by an oxo group or a methyl group; wherein R 33 is H or C 1-6 alkyl;

R34 H, C1-6-Alkyl, C6.10-Aryl-C1-6-alkylen oder C^o-Heteroaryl-C1-6- alkylen, bedeuten, oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6--ι0-Aryl und einem C5-io-Heteroaryl, das gegebenenfalls mit NR3 1R32 substituiert sein kann; wobeiR 34 is H, C 1-6 -alkyl, C 6 . -Alkylene or 10 aryl-C ^ o-C 1-6 heteroaryl-C 1-6 - alkylene, or R 3 is a radical selected from a group consisting of C 6- -ι 0 aryl, and a 5- C io-heteroaryl, which may optionally be substituted by NR 3 1 R 32 ; in which

R3 1 H, C1-6-Alkyl, Ca-β-Cycloalkyl, C1-6-Haloalkyl, COR3 1 \ COOR3 1 \R 3 is H, C 1-6 -alkyl, C-β-cycloalkyl, C 1-6 -haloalkyl, COR 3 1 \ COOR 3 1 \

CONR3 1 1R3 1 2 oder SO2-R3 1 1; und R3 1 1 H, C1-6-Alkyl, Ci_6-Haloaikyl, C3_6-Cycloalkyl oder C6- 10-Aryl;undCONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and R 3 1 1 H, C 1-6 alkyl, CI_ -Haloaikyl 6, C 3 _ 6 cycloalkyl or C 6- 10 -aryl; and

R3 1 2 H, C1-6-Alkyl, d_6-Ha!oalkyl, C3-6-Cycloalkyl oder C6-10-Aryl; und! R 3 1 2 H, C 1-6 alkyl, d_ 6 -Ha Oalkyl, C 3-6 cycloalkyl or C 6-10 aryl; and

R3 2 H oder ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C3_7-Cycloalkyl und C1-6-Haloalkyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2, Oxo und einem nichtaromatischen C3_10-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthalten kann, substituiert sein kann, wobei der nichtaromatische C^o-Heterocyclus gegebenenfalls mit Ci_4-AIkyl substituiert sein kann, bedeuten; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-io-Aryi und einemR 3 2 is H or a radical selected from the group consisting of C 1-6 alkyl, C 3 _ 7 cycloalkyl, and C 1-6 haloalkyl optionally substituted with one or more radicals selected from the group consisting of NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2, oxo and a non-aromatic C 3 _ 10 heterocycle which may contain one or two hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur , may be substituted, wherein the non-aromatic C ^ o-heterocycle may optionally be substituted by Ci_ 4 -alkyl substituted mean; or R 3 is a radical selected from a group consisting of C 6 -io-aryl and a

C5.10-Heteroaryl, der mit einem C3.10-Heterocyclus substituiert ist, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Cβ.i0-Aryl, C1-6-Alkyl, C3-6-Cycloalkyl, CN, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-d_6-Alkyl, COH, CO-d_6-Alkyl,C 5 . 10 heteroaryl, with a C 3 . 10 heterocycle, which is optionally substituted by one or more radicals selected from the group consisting of C β .i 0 -aryl, C 1-6 -alkyl, C 3-6 -cycloalkyl, CN, C 1-6 -haloalkyl, CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 alkyl) 2, COOH, COO-d_ 6 alkyl, COH, CO-d_ 6 alkyl,

Oxo, OH, O-Cβ-Alkyl, Halogen, SH, S-C1-6-Alkyl, NH2, NH-C1-6-Alkyl und N (C1-6-Alkyl)2 substituiert sein kann;Oxo, OH, O-Cβ-alkyl, halogen, SH, SC 1-6 alkyl, NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted;

oder R3 Benzimdazolyl, welches gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Cycloalkyl substituiert sein kann; undor R 3 is benzimidazolyl, which may be optionally substituted with a group selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and

R4 Cβ-Alkyl, C3.8-Cycloalkyl, C1-β-Haloalkyl, OR4 \ NR4 1R4.2, CN oder Halogen; wobei R4.1 H, Ci.6-Alkyl, C3-8-Cycloalkyl oder C1-6-Haloalkyl;R 4 Cβ alkyl, C3 .8 cycloalkyl, C 1-β haloalkyl, OR 4 \ NR 4 1 R 4.2, CN or halogen; where R 4.1 is H, Ci. 6- alkyl, C 3-8 -cycloalkyl or C 1-6 -haloalkyl;

R4 2 H, C1-6-Alkyl, C3-8-Cycloalkyl oder C1-6-Haloalkyl bedeuten; und R5 C1-6-Alkyl, C3-8-Cycloalkyl, C1-6-Haloalkyl, COR5 \ CONHR5 1, CON(R5 1)2, R 4 is H, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 haloalkyl; and R 5 is C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, COR 5 \ 5 CONHR 1, CON (R 5 1) 2,

SO2-C1 -6-Alkyl, SO2-C1-6-Haloalkyl, SO2-C6.10-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus R52, SO2-C1-6-Alkyl-R5 2 und C1-6-Alkyl-R52, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, CN, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, O-Cs-e-Cycloalkyl, O-C1-6-Haloalkyl, O-C1-6-Alkyl, Halogen, SO2-C1-6-AIKyI, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl undSO 2 -C 1-6 alkyl, SO 2 C 1-6 haloalkyl, SO 2 -C. 6 10 -aryl or a radical selected from the group consisting of R 52 , SO 2 -C 1-6 alkyl R 5 2 and C 1-6 alkyl R 52 , optionally with one or more radicals selected from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, CN, C 1-6 -haloalkyl, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -Alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, O-Cs-e-cycloalkyl, OC 1-6 -haloalkyl, OC 1-6 -alkyl, halogen , SO 2 -C 1-6 -alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH -C 1-6 alkyl and

N(C1-6-AIRyI)2 substituiert sein kann; worinN (C 1-6 -alkyl) 2 may be substituted; wherein

R5 1 Ci-6-Alkyl, Cs-urHeteroaryl-C1-6-alkylen oder C6-io- Aryl-d-6-alkylen und R52 C6-10-Aryl oder ein C5_10-Heteroaryl; undR 5 -alkylene 1 Ci- 6 alkyl, Cs-urHeteroaryl-C 1-6 or C 6 aryl -io- d alkylene and R 52 -6 C 6 - 10 -aryl or a C 5 _ 10 -heteroaryl; and

R6 H.C1-6-Alkyl oder d^-Haloalkyl bedeuten;R 6 is HC 1-6 alkyl or d ^ haloalkyl;

R7 H,C1-6-Alkyl oder C1-6-Haloalkyr, oder R6 und R7 bilden gemeinsam einen 3-6 gliedrigen Carbocyclus;R 7 is H, C 1-6 -alkyl or C 1-6 -haloalkyne, or R 6 and R 7 together form a 3-6 membered carbocycle;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Bevorzugt sind die obigen Verbindungen der Formel 1 , worinPreferred are the above compounds of formula 1 wherein

A CO, C=NH, d-4-Alkylen oder Ca^-Cycloalkylen;A CO, C = NH, d- 4 alkylene or Ca ^ cycloalkylene;

B1 Phenyl oder ein C5-10-Heteroaryl, der ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann;B 1 is phenyl or a C 5-10 heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen;

B2 Phenyl oder Pyridinyl;B 2 is phenyl or pyridinyl;

X O, S, NR5 oder CR6R7;X is O, S, NR 5 or CR 6 R 7;

n 0, 1 , 2 oder 3;n is 0, 1, 2 or 3;

R1 H, C1-4-Alkyl, C1-4-Halolalkyl;R 1 is H, C 1-4 alkyl, C 1-4 haloalkyl;

R2 H, C1-4-Alky! oder C-M-Halolalkyl;R 2 H, C 1-4 alkane! or C- M haloalkyl;

oder R1 und R2 bilden gemeinsam mit dem Stickstoff einen nichtaromatischen Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann;or R 1 and R 2 together with the nitrogen form a non-aromatic heterocycle which may contain one or two nitrogen atoms;

R3 H, OH, C1-4-Haloalkyl, C6.10-Aryl, ein C5-10-Heteroaryl, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, wobei das C6_i0-Aryl und das C5-i0-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-4-Alkyl, C3-6-Cycloalkyl und C1-4-Haloalkyl substituiert sein kann; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-CyClOaIkYl,R 3 is H, OH, C 1-4 haloalkyl, C 6 . 10 -aryl, a C 5-10 heteroaryl, which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the C 6 _i 0 aryl and the C 5 -i 0 -Heteroaryl optionally with one or more groups selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 haloalkyl may be substituted; or R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl,

C5_8-Cycloalkenyi und Ci-6-Alkyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl oder einem C5. io-Heteroaryl substituiert sein kann, der gegebenfalls mit einem oder mehrerenC 5 _ 8 -Cycloalkenyi and Ci- 6 alkyl, optionally substituted with one or more radicals selected from the group consisting of C 6 -aryl or a C. 5 io-heteroaryl may be substituted, optionally with one or more

Resten ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl, CN, OH, 0-C1-6-AIkYl, O-C1-6-Haloalkyl, Halogen, S-C1-6-Alkyl, S-C1-6-Haloalkyl, NO2, NH2, NH-Ci-6-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann;Radicals selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, CN, OH, O-C 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SC 1-6 -alkyl, SC 1-6 haloalkyl, NO 2 , NH 2 , NH-Ci-6-alkyl and N (C 1-6 alkyl) 2 may be substituted;

ein Rest ausgewählt aus einer Gruppe bestehend aus C6-10-Aryl und einem heterocyclischen, aromatischen Ring, substituiert mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6„i0-Aryl, C2.4-Alkenyl, C2-4-Alkinyl, C1-4-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1-4-Alkyl, COH, CO-Ci.4-Alkyl, CO-C6-10-Aryl, OH, O-C1-4-Alkyl, O-C1-4-Haloalkyl, Halogen, SH, S-C1-4-Alkyl, S-C1-4-HaIOaIkYl, SO2-C1-4-Alkyl,a radical selected from a group consisting of C 6-10 aryl and a heterocyclic aromatic ring substituted with one or more radicals selected from the group consisting of C 6 "i 0 aryl, C 2 . 4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CONH 2 , CONH C 1-4 alkyl, CON (C 1-4 alkyl) 2 , COOH, COO-C 1-4 Alkyl, COH, CO-Ci. 4- alkyl, CO-C 6-10 -aryl, OH, OC 1-4 -alkyl, OC 1-4 -haloalkyl, halogen, SH, SC 1-4 -alkyl, SC 1-4 -HaIOalkylk, SO 2 - C 1-4 alkyl,

SO2-C1-4-Haloalkyl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(C1^-AIkYl)2, NO2, NH2, NH-C1-4-Alkyl und N(C1-4-Alkyl)2;SO 2 -C 1-4 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 -N (C 1 -C 4 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-4 -alkyl and N (C 1-4 -alkyl) 2 ;

ein Rest ausgewählt aus einer Gruppe bestehend aus C6-io-Aryl, einem Cs- 10-Heteroaryl, C6-10-Aryl-C1_4-alkylen und Cδ^o-Heteroaryl-C1-4-akylen, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus COOR33, NR33R34, NHCOR33, NHCOOR33 und Phenyl substituiert sein kann, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-4-Alkyl, C2-4-Alkenyl, C2-4-Alkinyl, CN, C1-4-HaIOaIkYl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH,a radical selected from a group consisting of C 6 -io-aryl, Cs-10 heteroaryl, C 6-10 aryl-C 1 _ 4 -alkylene and C δ ^ o-heteroaryl-C 1-4 -akylen, which may optionally be substituted by one or more radicals selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 , NHCOOR 33 and phenyl which is optionally substituted by one or more radicals selected from the group consisting of C 1-4 Alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, C 1-4 -HaIOalkylk, CONH 2 , CONH-C 1-4 -alkyl, CON (C 1-4 -alkyl) 2 , COOH,

COO-C1-4-Alkyl, COH, CO-C1-4-Alkyl, OH, O-C1-4-Alkyl, O-C1-4-Haloalkyl, Halogen, SH, S-C1-4-AIkYl, S-C1-4-Haloalkyl, SO2-C1-4-Alkyl, SO2-C1-4-HaIOaIkYl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(C1-4-Alkyl)2, NO2, NH2, NH-C1-4-AIKyI und N(C1-4-Alkyl)2, und einem C5.10-Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Stickstoff und Schwefel enthalten kann und der gegebenenfalls mit einer Oxogruppe substituiert ist, substituiert sein kann, wobei R3 3 H oder C1-4-AIkYl; R34 H, C1-4-AIkYl, CfMo-Aryl-C-^-alkylen oder C5-10-Heteroaryl-COO-C 1-4 -alkyl, COH, CO-C 1-4 -alkyl, OH, OC 1-4 -alkyl, OC 1-4 -haloalkyl, halogen, SH, SC 1-4 -alkyl, SC 1- 4 haloalkyl, SO 2 -C 1-4 alkyl, SO 2 C 1-4 -HaIOaIkYl, SO 2 -NH 2, SO 2 -NH-C 1-4 alkyl, SO 2 -N (C 1- 4 alkyl) 2 , NO 2 , NH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 , and a C 5 . 10 -heterocycle which may contain one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and which may be substituted by an oxo group, where R 3 is H or C 1-4 alkyl; R 34 is H, C 1-4 -alkyl, C is fM o-aryl-C 1-4 -alkylene or C 5-10 -heteroaryl-

C1-6-alkylen; bedeuten, oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-io-Aryl und einem C5.10-Heterocyclus,der mit NR3 1R3 2 substituiert sein kann wobeiC 1-6 alkylene; or R 3 is a radical selected from a group consisting of C 6 -io-aryl and a C 5 . 10 heterocycle, which may be substituted by NR 3 1 R 3 2 wherein

R3 1 H, CL4-AIkYl, C3-6-Cycloalkyl, C1-4-Haloalkyl, COR3 1 \ COOR3 1 \R 3 1 H, C L4 -alkyl, C 3-6 -cycloalkyl, C 1-4 -haloalkyl, COR 3 1 \ COOR 3 1 \

CONR3 1 1R3 1 2 oder SO2-R3 1 1; und R3 1 1 H, d-4-Alkyl, C1-4-Haloalkyl, C3-6-Cycloalkyl oder C6-10-Aryl;CONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and R 3 1 1 H, d- C4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 6-10 aryl;

R3 1 2 H, C1-4-Alkyl, C1-4-Haloalkyl, C3-6-Cycloalkyl oder C6-10-Aryl; und R32 H oder ein Rest ausgewählt aus der Gruppe bestehend aus C1-4-Alkyl, C3_6-Cycloalkyl und C1-4-Haloalkyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NH(C1-4-AIkYl), N(C1-4-AIkYl)2, Oxo und einem C3-1o-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthalten kann und der gegebenenfalls mit substituiert sein kann;R 3 1 2 H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 6-10 aryl; and R 32 is H or a residue selected from the group consisting of C 1-4 alkyl, C 3 _ 6 cycloalkyl, and C 1-4 haloalkyl, which is optionally substituted with one or more radicals selected from the group consisting of NH 2, NH (C 1-4 alkyl), N (C 1-4 alkyl) 2 , oxo and a C 3-1 o heterocycle which may contain one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and if necessary with may be substituted;

oder R3 C6-1O-Ai^I, das mit einem C5-1o-Heteroaryl substituiert sein kann, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-1o-Aryl, d^-Alkyl,or R 3 C 6-1O- Ai ^ I, which may be substituted by a C 5-1 o-heteroaryl, which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which optionally with one or a plurality of radicals selected from the group consisting of C 6-1 o-aryl, d 1-4 -alkyl,

Ca-β-Cyclolalkyl, CN, CM-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1-4-Alkyl, COH, CO-CM-Alkyl, OH, O-C1-4-Alkyl, Halogen, SH, S-CL4-AIkYl, NH2, NH-C1-4-Alkyl und N(C1-4-Alkyl)2 substituiert sein kann;Ca-β-cyclolalkyl, CN, C M haloalkyl, CONH 2 , CONH-C 1-4 alkyl, CON (C 1-4 alkyl) 2 , COOH, COO-C 1-4 alkyl, COH, CO -C M-alkyl, OH, OC 1-4 alkyl, halo, SH, SC L4 -alkyl, NH 2, NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 may be substituted;

oder R3 Ce-io-Aryl, das mit einem einem C3_10-Heterocyclus substituiert sein kann, der ein oder zwei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe C1-4-Alkyl und Oxo substituiert sein kann; oder R3 Benzimdazolyl, welches gegebenenfallsmit einem Rest ausgewählt aus deror R 3 Ce-io-aryl which may be substituted with a C 3 _ 10 heterocycle which may contain one or two hetero atoms selected from the group of oxygen, sulfur and nitrogen and optionally selected with one or more groups selected from the group C 1-4 alkyl and oxo may be substituted; or R 3 is benzimidazolyl optionally substituted by a radical selected from

Gruppe bestehend aus C1-4-Alkyl, C1-4-Haloalkyl und C3-6-Cycloalkyl substituiert sein kann;Group consisting of C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl may be substituted;

und wobeiand where

R4 C1-4-Alkyl, C3-6-Cycloalkyl, d-4-Haloalkyl, OR4 1, NR4 1R4.2, CN oder Halogen; und R4.1 H, d.4-Alkyl, C3-6-Cycloalkyl oder C1-4-Haloalkyl; R4 2 H, d.4-Alkyl, C3-6-Cycloalkyl oder d.4-Haloalkyl; undR 4 is C 1-4 -alkyl, C 3-6 -cycloalkyl, d- 4- haloalkyl, OR 4 1 , NR 4 1 R 4.2 , CN or halogen; and R 4.1 H, d. 4- alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl; R 4 2 H, d. 4- alkyl, C 3-6 -cycloalkyl or d. 4 -haloalkyl; and

R5 Ci_4-Alkyl, C3-8-Cycloalkyl, C1-4-Haloalkyl, COR5 1, CONHR5 1, CON(R5 1)2,R 5 Ci_4-alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, COR 5 1, 5 CONHR 1, CON (R 5 1) 2,

SO2-Ci-4-Alkyl, SO2-C1-4-Haloalkyl, SO2-C6-10-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus R52, SO2-C1-4- Alkyl-R52 und d-4-Alkyl-R52, wobei dieser Rest gegebenenfalls mit einem oder mehreren Resten ausgewählt aus derSO 2 -C 4 -alkyl, SO 2 -C 1-4 -haloalkyl, SO 2 -C 6-10 -aryl or a radical selected from the group consisting of R 52 , SO 2 -C 1-4 -alkyl- R 52 and d- 4 alkyl R 52 , wherein this radical is optionally selected with one or more radicals selected from

Gruppe bestehend aus C1-4-Alkyl, C2.4-Alkenyl, C2-4-Alkinyl, CN, Ci-4-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-CM-Alkyl, COH, CO-C1-4-Alkyl, O-C1-4-Cycloalkyl, O-C1-4-Haloalkyl, O-C1-4-Alkyl, Halogen, SO2-C1-4-Alkyl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(C1-4-Alkyl)2, NO2, NH2, NH-d-4-Alkyl und N(C1 4-AIkVl)2 substituiert sein kann; wobeiGroup consisting of C 1-4 alkyl, C 2 . 4 alkenyl, C 2-4 alkynyl, CN, Ci- 4 haloalkyl, CONH 2, CONH-C 1-4 -alkyl, CON (C 1-4 alkyl) 2, COOH, COO-C M alkyl , COH, CO-C 1-4 -alkyl, OC 1-4 -cycloalkyl, OC 1-4 -haloalkyl, OC 1-4 -alkyl, halogen, SO 2- C 1-4 -alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 -N (C 1-4 -alkyl) 2 , NO 2 , NH 2 , NH-d- 4- alkyl and N (C 1 4 -AlkVl) 2 may be substituted; in which

R5 1 d-4-Alkyl, C6_io-Aryl-Ci-6-alkylen oder Cs^o-Heteroaryl-C1-6-alkylen; R5 2 C6-io-Aryl oder ein C5_10-Heteroaryl bedeuten;R 5 1 d-alkylene or C 6 _io-aryl-Ci- 6 Cs ^ o-heteroaryl-C 1-6 -alkylene 4 alkyl; R 5 is C 6 -io-aryl or C 5 _ 10 -heteroaryl;

und wobeiand where

R6 H1C4-AKyI oder Ci-4-Haloalkyl;R 6 is H 1 C 4 -alkyl or C 1-4 -haloalkyl;

R7 H,d-4-Alkyl oder d.4-Haloalkyl;R 7 is H, d-4 alkyl or d. 4 -haloalkyl;

oder R6 und R7 bilden gemeinsam einen 3-6 gliedrigen Carbocyclus;or R 6 and R 7 together form a 3-6 membered carbocycle;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon. Bevorzugt sind die obigen Verbindungen der Formel 1 , worinoptionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. Preferred are the above compounds of formula 1 wherein

A CO, C=NH, C1-6-Alkylen oder C3-8-Cycloalkylen,A is CO, C is NH, C 1-6 -alkylene or C 3-8 -cycloalkylene,

B1 Phenyl oder ein aromatischer oder nicht aromatischer Ring, der gegebenenfalls ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und der gegebenenfalls ein- oder mehrfach mit einem oder mehreren Resten ausgewählt aus der Gruppe OH, O- C1-6-Alkyl, 0-C1.B 1 is phenyl or an aromatic or non-aromatic ring which may optionally contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally mono- or polysubstituted by one or more radicals selected from the group consisting of OH, O-- C 1-6 alkyl, 0-C 1 .

6-Haloalkyl, Halogen, C1-6-Alkyl und C1-6-Haloalkyl substituiert sein kann; 6 haloalkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl may be substituted;

c2 Phenyl oder Pyridinyl;c 2 is phenyl or pyridinyl;

X O, S, NR5 oder CR6R7;X is O, S, NR 5 or CR 6 R 7;

n 0, 1 , 2 oder 3;n is 0, 1, 2 or 3;

R1 H, C1-4-Alkyl oder C1-4-Halolalkyl;R 1 is H, C 1-4 alkyl or C 1-4 haloalkyl;

R2 H, C1-4-Alkyl oder C1-4-Halolalkyl;R 2 is H, C 1-4 alkyl or C 1-4 haloalkyl;

oder R1 und R2 bilden gemeinsam mit dem Stickstoff einen nichtaromatischen Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann;or R 1 and R 2 together with the nitrogen form a non-aromatic heterocycle which may contain one or two nitrogen atoms;

R3 H, OH, C1-6-Haloalkyl oder ein Rest ausgewählt aus der Gruppe bestehend aus C6-10- Aryl, ein C5-10-Heteroaryl und ein C3-10-Heterocyclus, der gegebenenfalls mit einer Methylgruppe, Oxo oder OH substituiert sein kann;R 3 is H, OH, C 1-6 -haloalkyl or a radical selected from the group consisting of C 6-10 -aryl, a C 5-10 -heteroaryl and a C 3-10 -heterocycle, optionally with a methyl group, Oxo or OH may be substituted;

oder R3 C1-6-AIKyI, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-Ci_6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-4-Alkyl, COAryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S- C1-6-Alkyl, S-C,.6-Haloalkyl, SO2- C1-6-Alkanol; SO2-C1-4-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1^-Alkyl)2, NO2, NH2, NH-C,.6-Alkyl und N(CL6-AIRyI)2 substituiert sein kann; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl, einem mit Ci- 3-Alkylen überbrückten C3-8-Cycloalkyl, C5-8-Cycloalkenyl, C1-6-Alkyl und Ci_6-Alkanol, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl ,C3-8-Cycloalkyl, C5.i0-Heteroaryl und einem C3.10-Heterocyclus substituiert sein kann, welcher gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl, CN, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, S-Ci.6-Alkyl, S-C1-6-Haloalkyl, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2, einemor R 3 is C 1-6 -alkyl which is optionally selected with one or more radicals from the group consisting of halogen, OH, CN, CONH 2, CONH-CI_ 6 alkyl, CON (C 1-6 alkyl) 2, COOH, COO-C 1-6 -alkyl, COH, CO-C 1-4 -alkyl, COAryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, S-C 1-6 Alkyl, SC ,. 6 -haloalkyl, SO 2 - C 1-6 -alkanol; SO 2 -C 1-4 -alkyl, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1 -alkyl) 2 , NO 2 , NH 2 , NH-C ,. 6 alkyl and N (CL 6 -AIRyI) 2 may be substituted; or R 3 is a radical selected from the group consisting of C 3-8 cycloalkyl, a bridged with Ci 3 alkylene-C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 1-6 alkyl and CI_ 6 - alkanol which optionally selected with one or more groups selected from the group consisting of C 6 -aryl, C 3-8 -cycloalkyl, C 5 heteroaryl .i 0 C and a third 10 may be substituted heterocycle, optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl , Halogen, S-Ci. 6 -alkyl, SC 1-6 -haloalkyl, NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl) 2 , a

C5.10-Heteroaryl und einem C3.10-Heterocyclus substituiert sein kann, wobei der C5.10-Heteroaryl und der C3.1Q-Heterocyclus gegebenenfalls mit einem Rest ausgewählt aus Oxo, Hydroxyl, Halogen, C1-6-Alkyl und C1-6-Haloalkyl substituiert sein können; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C1-6-Alkyl, C6.10-Aryl- Cs-urHeteroaryl-C1-6-alkylen, C3_7-Cycloalkyl, C6-io-Aryl, C5-10-Heteroaryl und einem OMo-Heterocyclus, welcher mit einem oder mehreren Resten der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl, Oxo substituiert ist, wobei B eine Verbindung der Formel 2 istC 5 . 10 heteroaryl and a C 3 . 10 heterocycle may be substituted, wherein the C 5 . 10 heteroaryl and the C 3 . 1Q heterocycle optionally substituted with a radical selected from oxo, hydroxyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl groups; or R 3 is a radical selected from a group consisting of C 1-6 alkyl, C 6 . 10 -aryl Cs-urHeteroaryl-C 1-6 -alkylene, C 3 _ 7 cycloalkyl, C 6 -aryl, C 5-10 -heteroaryl and an O M o-heterocycle containing one or more radicals from the group consisting of B , Halogen, OH, C 1-6 alkyl, oxo, where B is a compound of formula 2

worin wherein

Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol, O(C1-6-Alkyl), C6-io-Aryl, 0-C6-io-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2 oder C3.7-Cycloalkyl; und Z2 OH, NH2, mono- oder bicyclisches C3.7-Cycloalkyl, einen mono- oder bicyclischen C3.10-Heterocyclus, ein mono- oder bicyclisches C5_10-Heteroary! oder C6.10-Aryl bedeutet; oder R3 Phenyl, das mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, C2-6-Alkenyl, C2-6-Alkinyl, C1-6-HaIOaIKyI, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, COAryl, OH, O-C1-6-Alkyl, O-Ci-4-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-Ci-4-Haloalkyl, SO2-C1 -6-Alkyl, SO2-C1-4-Haloalkyl, SO2-NH2, SO2-N H-C1 -6-Alkyl,Z 1 is H, OH, halogen, C 1-6 alkyl, C 1-6 alkanol, O (C 1-6 alkyl), C 6- io-aryl, 0-C 6- io-aryl, NH 2 , NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 or C 3 . 7 -cycloalkyl; and Z 2 OH, NH 2 , mono- or bicyclic C 3 . 7 -cycloalkyl, a mono- or bicyclic C 3 . 10 -heterocycle, a mono- or bicyclic C 5 _ 10 heteroary! or C 6 . 10 -aryl; or R 3 is phenyl substituted with one or more radicals selected from the group consisting of C 6 -aryl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 1-6 -HaIOaIKyI, CONH 2, CONH- C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-6 alkyl, COH, CO-C 1-6 alkyl, COAryl, OH, OC 1-6 alkyl , O-Ci -4 haloalkyl, halo, SH, SC 1-6 alkyl, S-Ci- 4 haloalkyl, SO 2 -C 1 -6 alkyl, SO 2 C 1-4 haloalkyl, SO 2 -NH 2 , SO 2 -N HC 1 -6- alkyl,

SO2-N(C1,6-Alkyl)2, NO2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2 substituiert ist ;SO 2 -N (C 1 , 6 -alkyl) 2 , NO 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 ;

oder R3 Phenyl, welches mit C1-4-Alkyl substituiert ist, das gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus COOR33, NR33R34, NHCOR33,or R 3 is phenyl which is substituted by C 1-4 -alkyl, which is optionally substituted by a radical selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 ,

NHCOOR33 und Phenyl substituiert sein kann, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, /-Butyl, F, Cl, Br, CN, OH, und einem Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, substituiert sein kann, wobei der Heterocyclus gegebenenfalls mit einer Oxogruppe oder einerNHCOOR 33 and phenyl which may optionally be substituted by one or more radicals selected from the group consisting of methyl, / -butyl, F, Cl, Br, CN, OH, and a heterocycle having one, two or three heteroatoms selected from the group may contain oxygen and nitrogen, may be substituted, wherein the heterocycle optionally with an oxo group or a

Methylgruppe substituiert sein kann; wobeiMethyl group may be substituted; in which

R33 H oder Cβ-Alkyl;R 33 is H or Cβ-alkyl;

R34 H, C1-6-Alkyl oder C6.io-Aryl-C1-6-alkylen, C5-10-Heteroaryl-Ci_6- alkylen; bedeuten, oder R3 Phenyl, substituiert mit NR3 1R32; wobeiAlkylene R 34 is H, C 1-6 -alkyl or C 6 .io-aryl-C 1-6, C 5-10 -heteroaryl-CI_ 6 - alkylene; or R 3 is phenyl substituted with NR 3 1 R 32 ; in which

R3 1 H, C1-4-Alkyl, C1-4-Haloalkyl, COR3 1 \ COOR3 1 \ CONR3 1 1R3 1 2 oder SO2-R3 1 1; undR 3 is H, C 1-4 alkyl, C 1-4 haloalkyl, COR 3 1 \ COOR 3 1 \ CONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and

R3 1 1 H, Ci-4-Alkyl, C1-4-Haloalkyl, C3-6-Cycloalkyl oder C6-10-Aryl; R31 2 H, C1-4-Alkyl, C1-4-Haloalkyl, C3-6-Cycloalkyl oder C6-i0-Aryl; und R3 2 H, Ct-4-Alkyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NH(C1-4-Alkyl), N(C1-4-AIKyI)2, Oxo oder einem nichtaromatischen C3- 10-Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann und der gegebenenfalls mit einer Methylgruppe substituiert sein kann; bedeutetR 3 1 1 H, Ci -4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 6-10 aryl; R 31 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 6- i 0 aryl; and R 3 2 H, C t - 4- alkyl, optionally with one or more radicals selected from the group consisting of NH 2 , NH (C 1-4 alkyl), N (C 1-4 -AIKyI) 2 , oxo or a non-aromatic C 3 10 heterocycle, which may contain one or two nitrogen atoms and which may optionally be substituted with a methyl group; means

oder R3 C6-10-Aryl, das mit einem C5.10-Heteroaryl enthaltend ein, zwei oder drei Heteroatomen ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff substituiert sein kann, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10-Aryl, C1-4-Alkyl, C3_6-Cyclolalkyl, CN, C1-4-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH,or R 3 C 6-10 -aryl, which with a C 5 . 10 -Heteroaryl containing one, two or three heteroatoms selected from the group of oxygen, sulfur and nitrogen may be substituted, which may be substituted by one or more radicals selected from the group consisting of C 6-10 -aryl, C 1-4 -alkyl, C 3 _ 6 -Cyclolalkyl, CN, C 1-4 haloalkyl, CONH 2, CONH-C 1-4 -alkyl, CON (C 1-4 alkyl) 2, COOH,

COO-C1-4-Alkyl, COH, CO-C1-4-Alkyl, OH, O-C1-4-Alkyl, Halogen, SH, S-C1-4-Alkyl, NH2, NH-C1-4-Alkyl und N(C1_4-Alkyl)2 substituiert sein kann;COO-C 1-4 -alkyl, COH, CO-C 1-4 -alkyl, OH, OC 1-4 -alkyl, halogen, SH, SC 1-4 -alkyl, NH 2 , NH-C 1-4 - alkyl and N (C 1 _ 4 alkyl) 2 may be substituted;

oder R3 C6-10-Aryl, das mit einem einem nichtaromatischen C3-10-Heterocyclus, der ein oder zwei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert sein kann, wobei der C3.io-Heterocyclus gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe C1-4-Alkyl und Oxo substituiert sein kann;or R 3 is C 6-10 aryl which may be substituted with a C 3-10 non-aromatic heterocycle which may contain one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, said C 3 .io Heterocycle may optionally be substituted by one or more radicals selected from the group consisting of C 1-4 alkyl and oxo;

oder R3 Benzimdazolyl, das gegebenenfalls mit einem Rest oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-4-Alkyl, C1-4-Haloalkyl und C3-6-Cycloalkyl substituiert sein kann; und R4 C1-4-Alkyl, C3-6-Cycloalkyl, C1-4-Haloalkyl, OR4.1, NR4.1R4.2, CN oder Halogen;or R 3 is benzimidazolyl, which may be optionally substituted with one or more groups selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl; and R 4 is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, OR 4.1 , NR 4.1 R 4.2 , CN or halo;

R4.1 H, C1-4-Alkyl, C3-6-Cycloalkyl oder C1-4-Haloalkyl; R4.2 H, C1-4-Alkyl, C3-6-Cycloalkyl oder C1-4-Haloalkyl; und R5 C1-4-Alkyl, C3-8-Cycloalkyl, C1-4-Haloalkyl, COR5 1, CONHR5 \ CON(R5 \R 4.1 is H, C 1-4 -alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl; R 4.2 is H, C 1-4 -alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl; and R 5 is C 1-4 -alkyl, C 3-8 -cycloalkyl, C 1-4 -haloalkyl, COR 5 1 , CONHR 5 \ CON (R 5 \

SO2- C1-4-Alkyl, SO2-C1-4-Haloalkyl, SO2-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus R52, SO2-Ci_4-Alkyl-R5 2 und C1-4-Alkyl-R52, der gegebenenfalls mit C1-4-Alkyl, C2-4-Alkenyl, C2.4-Alkinyl, CN, C1-4-Haloalkyl, CONH2,SO 2 - C 1-4 alkyl, SO 2 -C 1-4 haloalkyl, SO 2 aryl or a radical selected from the group consisting of R 52 , SO 2 -Ci_ 4 alkyl R 5 2 and C 1 4- alkyl-R 52 optionally substituted by C 1-4 alkyl, C 2-4 alkenyl, C 2 . 4- alkynyl, CN, C 1-4 -haloalkyl, CONH 2 ,

CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1-4-Alkyl, COH, CO-C1-4-Alkyl, O- C1-4-Cycloalkyl, O-C1-4-Haloalkyl, O- C1-4-Alkyl, Halogen, SO2-C1-4-Alkyl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(C1-4-Alkyl)2, NO2, NH2, NH-C1-4-Alkyl und N( C1-4-Alkyl)2 substituiert sein kann; wobeiCONH-C 1-4 -alkyl, CON (C 1-4 -alkyl) 2 , COOH, COO-C 1-4 -alkyl, COH, CO-C 1-4 -alkyl, O-C 1-4 -cycloalkyl , OC 1-4 -haloalkyl, O-C 1-4 -alkyl, halogen, SO 2- C 1-4 -alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 - N (C 1-4 alkyl) 2 , NO 2 , NH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 may be substituted; in which

R5 1 C1-6-Alkyl, C5.10-Heteroaryl-C1-6-alkylen oder C6-10- Aryl-C1-6-alkylen undR 5 is C 1-6 -alkyl, C 5 . 10 -Heteroaryl-C 1-6 -alkylene or C 6-10 - aryl-C 1-6 -alkylene and

R52 C6.10-Aryl oder ein C5-i0-Heteroaryl; und R6 H, C1-6-AIkYl oder C1-6-Haloalkyl bedeuten;R 52 C 6 . 10 -aryl or a C 5 -i- 0 heteroaryl; and R 6 is H, C 1-6 alkyl or C 1-6 haloalkyl;

R7 H,Ci.6-Alkyl oder C-,.6-Haloalkyl;R 7 H, Ci. 6 -alkyl or C- ,. 6 -haloalkyl;

oder R6 und R7 bilden gemeinsam einen 3-6 gliedrigen Carbocyclus;or R 6 and R 7 together form a 3-6 membered carbocycle;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon. .optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. ,

Bevorzugt sind die obigen Verbindungen der Formel 1 , worin R1, R2, R4, R5, R6, R7 sowie A, B1, B2, X und n die oben genannten Bedeutungen haben und worinPreference is given to the abovementioned compounds of the formula I in which R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and A, B 1 , B 2 , X and n have the abovementioned meanings and

R3 C1-6-AIkVl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-AIkYl, COH, CO-C1-6-Alkyl, CO-C6-1 o-Ary I, OH,R 3 C 1-6 -AlkVl, optionally with one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-1 o -aryl, OH,

0-C1-6-AIkYl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-Ci.β-Alkanol; SO2-C1-6-AIkYl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-AIkYl, SO2-N(C1-B-AIkYl)2, NO2, NH2, NH-Cm-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann,0-C 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, SO 2- Ci.β-alkanol; SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2, SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1 - B -alkyl) 2 , NO 2 , NH 2 , NH-C 1 -alkyl and N (C 1-6 -alkyl) 2 may be substituted,

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl, einem mit Cτ-3-Alkylen überbrückten C3-8-Cycloalkyl, C5-8-Cycloalkenyl, C1-6-Alkyl, und C1-6-Alkanol, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6.io-Aryl, C3-8-CyClOaIkYl, einem C5-io-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, der wiederum gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2,6-Alkinyl, C1-6-Haloalkyl, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1 -6-Alkyl, COH, CO-C1-6-AIkYl, CO-C6-io-Aryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, S02-C1-6-Alkano!, SO2-Cv6-AIRyI, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, N H -C ^6- Al ky I, N(C1-6-AIRyI)2, C5-i0-Heteroaryl und einem C3_10-Heterocyclus substituiert sein kann, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus Oxo-, Hydroxyl-, Halogen- oder C1-6-Alkyl und C1-6-Haloalkyl substituiert sein kann;or R 3 is a radical selected from the group consisting of C 3-8 cycloalkyl, a bridged with Cτ- 3 -alkylene C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 1-6 alkyl, and C 1 -6 -alkanol, which may optionally be substituted by one or more radicals selected from the group consisting of C 6 .io-aryl, C 3-8 -CyClOaIkYl, a C 5 -io-heteroaryl and a C 3-10 heterocycle , which in turn is optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2 6 alkynyl, C 1-6 haloalkyl, CN, CONH 2, CONH-C 1-6 alkyl, CON (C 1-6 alkyl) 2, COOH, COO-C 1 -6 alkyl, COH, CO-C 1-6 -alkyl, CO-C 6 -io-aryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, S0 2 -C 1-6 -alkano !, SO 2 -Cv 6 -alkyl, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 - N (C 1-6 alkyl) 2, NO 2, NH 2, NH -C 6 - Al ky I, N (C 1-6 -AIRyI) 2, C 5 i 0 -heteroaryl and a C 3 _ 10 -Heterocyclus may be substituted, which may optionally be substituted by one or more radicals selected from oxo, hydroxyl, halogen or C 1-6 alkyl and C 1-6 haloalkyl;

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, C5-1o-Heteroaryl und einem C3-10-Heterocyclus, der mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, Ci-6-Alkyl, C2-6-Alkenyl, C2-6-AIRinyl, C^6-HaIOaIRyI, CONH2, CONH-C1-6-AIRyI, CON(C1-6-AIRyI)2, COOH,or R 3 is selected, a radical from the group consisting of C 6 -aryl, C 5-1 o-heteroaryl, and a C 3-10 heterocycle, the selected one or more radicals from the group consisting of C 6- io aryl, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 -AIRinyl, C ^ 6 -HaIOaIRyI, CONH 2, CONH-C 1-6 -AIRyI, CON (C 1-6 -AIRyI) 2 , COOH,

COO-C1-6-AIRyI, COH, CO-CL6-AIRyI, CO-C6-1 o-Aryl, OH, 0-C1-6-AlRyI, 0-C1-6-HaIOaIRyI, Halogen, SH, S-C1-6-AIRyI, S-C1-6-Haloalkyl, SO2-C1-6-Alkyl, SO2-C1-6-Alkanol, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2 und N-(SO2-C1-4- Alkyl)(R34) substituiert sein kann;COO-C 1-6 -AIRyI, COH, CO-C L6 -AIRyI, CO-C 6-1 o-Aryl, OH, O-C 1-6 -AlRyI, O-C 1-6 -HaIOaIRyI, halogen, SH, SC 1-6 -AIRyI, SC 1-6 haloalkyl, SO 2 -C 1-6 alkyl, SO 2 -C 1-6 alkanol, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 - Alkyl) 2 and N- (SO 2 -C 1-4 -alkyl) (R 34 ) may be substituted;

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6.io-Aryl-C1-6- alkylen, C5-1o-Heteroaryl-C1-6-alRylen, C3.7-Cycloalkyl, C6-10-Aryl, C5-10-Heteroaryl und einem Cs-io-Heterocyclus, der gegebenenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl und Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 istor R 3 is a radical selected from the group consisting of C 1-6 -alkyl, C 6 -aryl-aryl-C 1-6 -alkylene, C 5-1 o-heteroaryl-C 1-6 -alRylene, C 3 . 7 -cycloalkyl, C 6-10 -aryl, C 5-10 -heteroaryl and a Cs-io-heterocycle optionally with one or more radicals selected from the group consisting of B, halogen, OH, C 1-6 alkyl and Oxo may be substituted, wherein B is a compound of formula 2

wobei in which

Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol, O(C1-6-Alkyl), C6.10-Aryl, O-C6.10-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-AIRyI)2 oder C3-7-CycloalRyl undZ 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol, O (C 1-6 -alkyl), C 6 . 10 -aryl, OC 6 . 10 -aryl, NH 2 , NH (C 1-6 alkyl), N (C 1-6 -AIRyI) 2 or C 3-7 cycloalyl and

Z2 OH, NH2, NH(C1-6-AIRyI), N(C1-6-AIRyI)2, O(C1-6-Alkyl), mono- oder bicyclisches C3-7-Cycloalkyl, mono- oder bicyclischer C5-i0-Heteroaryl, mono- oder bicyclischer C3,10-Heterocyclus oder C6-10-Aryl sind; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Soivate oder Hydrate, sowie deuterierte Formen davon.Z 2 OH, NH 2 , NH (C 1-6 -AIRyI), N (C 1-6 -AIRyI) 2 , O (C 1-6 alkyl), mono- or bicyclic C 3 -7 cycloalkyl, mono - or bicyclic C 5 i 0 heteroaryl, mono- or bicyclic C 3, 10 heterocycle or C 6-10 -aryl; optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, derivatives or hydrates, and deuterated forms thereof.

Bevorzugt sind die obigen Verbindungen der Formel 1 , worin R3 und R4 die vorstehend genannten Bedeutungen haben und worinPreference is given to the above compounds of the formula 1 in which R 3 and R 4 have the meanings given above and in which

A CH2, CD2, C=NH, CHMe, CMe2, 1 ,1 '-Cyclopropylen oder 1 ,1'-Cyclobutyliden;A CH 2 , CD 2 , C = NH, CHMe, CMe 2 , 1, 1 '-cyclopropylene or 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl;B 2 phenyl;

X O oder NR5; wobei R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl, CONHCH2-Phenyl, CH2CF3 oder Benzyl, welches gegebenenfalls mit F substituiert sein kann, bedeutet; und wobeiX is O or NR 5 ; wherein R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, which may be optionally substituted with F; and where

n 0 oder 1 ;n is 0 or 1;

R1 H;R 1 H;

R2 HR 2 H

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Soivate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, derivatives or hydrates, and deuterated forms thereof.

Bevorzugt sind die obigen Verbindungen der Formel 1, worin R1, R2, R5, R6, R7 sowie A, B1, B2, X und n die oben genannten Bedeutungen haben und worinPreference is given to the abovementioned compounds of the formula I in which R 1 , R 2 , R 5 , R 6 , R 7 and A, B 1 , B 2 , X and n have the abovementioned meanings and

worin R3 C1-6-Alkyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-AIRyI)2, COOH, COO-Ci -6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Ary I, OH, O-C1-6-Alkyl, SO2-C1-6-Alkanol; SO2-C1-6-Alkyl, SO2-C1-6-HaIOaIkYl, SO2-NH2, SO2-NH-C1-6-AIkYl, SO2-N(C1-6-AIkYl)2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Aikyl)2 substituiert sein kann,in which R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2, COOH, COO-Ci -6 alkyl, COH, CO-C 1-6 alkyl, CO-C 6-10 -Ary I, OH, OC 1-6 alkyl, SO 2 -C 1-6 alkanol; SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 -HaIOalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 may be substituted,

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-CyClOaIkYl, einem mit C1- 3-Alkylen überbrückten C3-8-Cycloalkyl und C1-6-Alkyl, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Cβ-io-Aryl, C3-8-CyClOaIkYl, einem C5-10-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, der wiederum gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C1-6-Haloalkyl, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-Ci-β-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Aryl, OH, O-C1-e-Alkyl, 0-d.e-Haloalkyl, Halogen, SH, S-C1-6-AIkYl, S-d_6-Haloalkyl, SO2-C1-6-Alkanol, SO2-Cv6-AIkYl, SO2-C1-6-HaIOaIkYl, SO2-NH2, SO2-NH-C1-6-AIkYl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2, C5-10-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus Oxo-, Hydroxyl-, Halogen- oder C1-6-Alkyl und C1-6-Haloalkyl substituiert sein kann;or R 3 is a radical selected from the group consisting of C 3-8 -CyClOaIkYl, a C 1- 3 alkylene bridged C 3-8 cycloalkyl and C 1-6 alkyl that is optionally substituted with one or more groups selected from the group consisting of Cβ-io-aryl, C 3-8 -CyClOaIkYl, a C 5-10 heteroaryl and a C 3-10 heterocycle may be substituted, which in turn optionally with one or more radicals selected from the group consisting of C 1-6- alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -haloalkyl, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-Ci-β-alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH, OC 1-e- alkyl, O-de-haloalkyl, halogen, SH , SC 1-6 -alkyl, S-d_ 6 haloalkyl, SO 2 -C 1-6 alkanol, SO 2 -CV 6 -alkyl, SO 2 -C 1-6 -HaIOaIkYl, SO 2 -NH 2, SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl) 2 , C 5-10 heteroaryl, and a C 3-10 heterocycle optionally substituted with one or more may be substituted radicals of oxo, hydroxyl, halogen or C 1-6 alkyl and C 1-6 haloalkyl;

oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-10-Aryl, einem C3-8-Heterocyclus mit 1 bis 4 Heteroatomen ausgewählt aus N, O. S und einem C5- 10-Heteroaryl mit 1 bis 2 Heteroatomen ausgewählt aus N, O. S, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6.10-Aryl, C1-6-Alkyl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Aryl, OH,or R 3 is a radical selected from a group consisting of C 6-10 aryl, a C 3-8 heterocycle having 1 to 4 heteroatoms selected from N, O. S and a C 5- 10 heteroaryl having 1 to 2 hetero atoms selected from N, O. S, optionally with one or more radicals selected from the group consisting of C 6 . 10 -aryl, C 1-6 -alkyl, C 1-6 -haloalkyl, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-6 - Alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH,

O-C1-6-Alkyl, 0-C1-6-Haloalkyl, Halogen, SO2-C1-6-Alkyl, SOrC1-6-Alkanol, SO2-C1 -6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-AIkYl, N(C1-6-Alkyl)2 und N-(SO2-C1-4-Alkyl)(R34), wobei R34 ein ist, substituiert sein kann;OC 1-6 alkyl, 0-C 1-6 haloalkyl, halogen, SO 2 -C 1-6 alkyl, sorc 1-6 alkanol, SO 2 -C 1 -6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl ) 2 and N- (SO 2 -C 1-4 alkyl) (R 34 ) wherein R 34 is a is, may be substituted;

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-io-Aryl- C1-6-alkylen, C5_10-Heteroaryl-d_6-alkylen, C3_7-Cycloalkyl, C6.10-Aryl, C3-8- Heterocyclus mit 1 bis 4 Heteroatomen ausgewählt aus N, O. S, und ein C5-10- Heteroaryl mit 1 bis 2 Heteroatomen ausgewählt aus N, O. S, welcher jeweils gegebenenfalls mit einem oder mehreren Resten der Gruppe bestehend aus B, Halogen, OH, Ci_6-Alkyl, Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 istor R 3 is a radical selected from the group consisting of alkylene C 1-6 alkyl, C 6- io aryl-C 1-6, C 5 _ 10 -heteroaryl-d_ 6 -alkylene, C 3 _ 7 cycloalkyl , C 6 . 10 -aryl, C 3-8 -heterocycle having 1 to 4 heteroatoms selected from N, O.S, and a C 5-10 -heteroaryl having 1 to 2 heteroatoms selected from N, O. S, which in each case optionally substituted with one or more radicals of the group consisting of B, halogen, OH, Ci_ 6 alkyl, oxo, where B is a compound of formula 2

worin wherein

Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol oder O(C1-6-Alkyl) und Z2 OH, NH2, NH(CL6-AIkYl), N(C1^6-AIkYl)2, O(C1-6-Alkyl), mono- oder bicyclisches C3_7-Cycloalkyl, mono- oder bicyclischer C5_10-Heteroaryl, mono- oder bicyclischer C3_10-Heterocyclus oder C6-io-Aryl ist ;Z 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol or O (C 1-6 -alkyl) and Z 2 OH, NH 2 , NH (C L6 -alkyl), N (C 1 ^ 6 -alkyl) 2, O (C 1-6 alkyl), mono- or bicyclic C 3 _ 7 cycloalkyl, mono- or bicyclic C 5 _ 10 -heteroaryl, mono or bicyclic C 3 _ 10 -heterocycle or C 6-10 aryl;

und worin R4 H, F oder Cl;and wherein R 4 is H, F or Cl;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Bevorzugt sind die obigen Verbindungen der Formel 1, worinPreferred are the above compounds of formula 1 wherein

A CO, C=NH, C1 6-Alkylen oder C3_8-Cycloalkylen,A CO, C = NH, C 1 6 alkylene or C 3 _ 8 cycloalkylene,

B1 Phenyl oder Pyridinyl;B 1 is phenyl or pyridinyl;

B2 Phenyl oder Pyridinyl;B 2 is phenyl or pyridinyl;

X O oder NR5;X is O or NR 5 ;

n O, 1 , 2 oder 3; R1 H, Methyl, Ethyl oder Propyl;n is O, 1, 2 or 3; R 1 is H, methyl, ethyl or propyl;

R2 H, Methyl, Ethyl oder Propyl;R 2 is H, methyl, ethyl or propyl;

R3 H, OH, C1-6-Haloalkyl oder C6.i0-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus einem C5-10-Heteroaryl und einem C3.10-Cycloalkyl, der ein, zwei oder drei Stickstoffatome enthalten kann und der gegebenenfalls mit einer Methylgruppe substituiert sein kann;R 3 is H, OH, C 1-6 haloalkyl or C 6 .i 0 aryl or a radical selected from the group consisting of a C 5-10 heteroaryl and a C 3 . 10 -cycloalkyl which may contain one, two or three nitrogen atoms and which may optionally be substituted by a methyl group;

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus Cyclopentyl, Cyclohexyl,or R 3 is a radical selected from the group consisting of cyclopentyl, cyclohexyl,

Cyclopentenyl, Cyclohexenyl, Methyl, Ethyl, Propyl und Butyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10- Aryl und einem C5-1o-Heterocyclus substituiert sein kann, der gegebenfalls wiederum mit einem oder mehreren Resten ausgewählt aus der Gruppe aus C1-6-Alkyl, C1-6-Haloalkyl, CN, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen,Cyclopentenyl, cyclohexenyl, methyl, ethyl, propyl and butyl, which may optionally be substituted by one or more radicals selected from the group consisting of C 6-10 - aryl and a C 5-1 o heterocycle may be substituted, which in turn optionally with one or a plurality of radicals selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, CN, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen,

S-C1-6-Alkyl, S-C1-6-Haloalkyl, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann;SC 1-6 alkyl, SC 1-6 haloalkyl, NO 2 , NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted;

oder R3 Phenyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10-Aryl, C2-4-Alkenyl, C2-4-Alkinyl, C1-4-Haloalkyl,or R 3 is phenyl optionally substituted with one or more groups selected from the group consisting of C 6-10 aryl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl,

CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-Ci -4-Aikyl, COH, CO-C1-4-Alkyl, CO-C6-1 o-Aryl, OH, O-C1-4-Alky], O-C1-4-Haloalkyl, Halogen, SH, S-C1-4-Alkyl, S-C1-4-Haloalkyl, SO2-C1-4-AIkYl, SO2-C1-4-Haloalkyl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(C1-4-Alkyl)2, NO2, NO2, NH2, NH-C1-4-Alkyl und N(C1-4-Alkyl)2 substituiert sein kann;CONH 2, CONH-C 1-4 -alkyl, CON (C 1-4 alkyl) 2, COOH, COO-Ci -4 -alkyl, COH, CO-C 1-4 alkyl, CO-C 6-1 o-aryl, OH, OC 1-4 -alky], OC 1-4 -haloalkyl, halogen, SH, SC 1-4 -alkyl, SC 1-4 -haloalkyl, SO 2 -C 1-4 -alkyl, SO 2- C 1-4 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl, SO 2 -N (C 1-4 -alkyl) 2 , NO 2 , NO 2 , NH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 may be substituted;

oder R3 Phenyl, das gegebenenfalls mit C1-4-AIkYl substituiert sein kann, welches gegebenenfalls wiederum mit einem Rest ausgewählt aus der Gruppe bestehend aus COOR33, NR33R34, NHCOR33, NHCOOR33, p-Fluorphenyl und einem Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppeor R 3 is phenyl which may optionally be substituted by C 1-4 alkyl, which may in turn be a radical selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 , NHCOOR 33 , p-fluorophenyl and a heterocycle containing one, two or three heteroatoms selected from the group

Sauerstoff und Stickstoff enthalten kann und der gegebenenfalls mit einer Oxogruppe substituiert sein kann, substituiert sein kann; wobeiMay contain oxygen and nitrogen and which may optionally be substituted by an oxo group may be substituted; in which

R33 H oder d-4-Alkyl; R34 H, C1-4-Alkyl, C6-i0-Aryl-C1-6-alkylen oder C5--urHeteroaryl-C1_6- alkylen bedeuten;R 33 is H or d-4-alkyl; 6- i 0 aryl-C 1-6 alkylene or C 5 R 34 H, C 1-4 alkyl, C - -alkylene - heteroaryl-C 1 _ 6 ur;

oder R3 Phenyl, das mit NR3 1R3 2 substituiert sein kann; wobeior R 3 is phenyl which may be substituted by NR 3 1 R 3 2 ; in which

R3 1 Hr C1-4-Alkyl, COR3 1 \ COOR3 1 1, CONR3 1 1R3 1 2 oder SO2-R3 1 1; undR 3 1 H r C 1-4 alkyl, COR 3 1 \ COOR 3 1 1 , CONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and

R3 1 1 H, C1-4-Alkyl oder C6.10-Aryl; R3 1 2 H1 C1-4-Alkyl oder C6.10-Aryl;R 3 1 1 H, C 1-4 alkyl or C 6 . 10 -aryl; R 3 1 2 H 1 C 1-4 alkyl or C 6 . 10 -aryl;

R32 H, C1-4-Alkyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NH(C1^-Alkyl), N(C1^-Alkyl)2, Oxo oder einem C3-10-Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann und der gegebenenfalls mit einer Methylgruppe substituiert sein kann, substituiert sein kann;R 32 is H, C 1-4 -alkyl, optionally with one or more radicals selected from the group consisting of NH 2 , NH (C 1 ^ -alkyl), N (C 1 ^ -alkyl) 2 , oxo or a C 3-10 -heterocycle, which may contain one or two nitrogen atoms and which may optionally be substituted by a methyl group, may be substituted;

oder R3 Phenyl, welches mit einem C5.i0-Heteroaryl, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert sein kann, wobei das C5.i0-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6.io-Aryl, Ci_4-Alkyl, d.4-Haloalkyl, C3-6-Cycloalkyl, CN, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1-4-Alkyl, COH, CO-C1-4-Alkyl, OH, O-C1-4-Alkyl, Halogen, NH2 und N(C1-4-A^yI)2 substituiert sein kann;or R 3 is phenyl which may be substituted by a C 5 .i 0 -heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the C 5 .i 0 -heteroaryl being optionally substituted by one or more radicals selected from the group consisting of C 6 .io aryl, CI_ 4 alkyl, d. 4- haloalkyl, C 3-6 -cycloalkyl, CN, CONH 2 , CONH-C 1-4 -alkyl, CON (C 1-4 -alkyl) 2 , COOH, COO-C 1-4 -alkyl, COH, CO C 1-4 alkyl, OH, OC 1-4 alkyl, halogen, NH 2 and N (C 1-4 -A ^ yI) 2 may be substituted;

oder R3 Phenyl, welches mit einem C5-10-Heteroaryl, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert sein kann, wobei das C5-i0-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe aus Ci-4-Alkyl und Oxo substituiert sein kann;may contain or R 3 is phenyl, which with a C 5-10 heteroaryl containing one, two or three heteroatoms selected from the group of oxygen, sulfur and nitrogen, may be substituted, wherein the C 5 i 0 heteroaryl optionally substituted with one may be or more radicals selected from the group consisting of Ci -4 alkyl, and oxo;

oder R3 Benzimdazolyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Propyl, CF3, CH2CF3, Cyclopropyl, Cyclopentyl und Cyclohexyl substituiert sein kann; und R4 C1-4-Alkyl, C1-4-Haloalkyl oder Halogen; undor R 3 is benzimidazolyl, which may be optionally substituted with one or more radicals selected from the group consisting of methyl, ethyl, propyl, CF 3 , CH 2 CF 3 , cyclopropyl, cyclopentyl and cyclohexyl; and R 4 is C 1-4 alkyl, C 1-4 haloalkyl or halo; and

R5 ein Rest ausgewählt aus der Gruppe bestehend aus C1-4-AIRyI, C3-6-Cycloalkyl,R 5 is a radical selected from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl,

COR5 1, CONHR5 1, C6-io-Aryl, S02-C6-io-Aryl-C1-6-alkylen, SO2-C6-10-Aryl oder CeMo-Aryl-C1-6-alkylen und C5_10-Heteroaryl-Ci.6-alkylen, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe aus C1-4-Alkyl, C2_4-Alkenyl, C2-4-Alkinyl, CN, C1-4-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1.4-Alkyl, COH, CO-C1-4-Alkyl, OH, O-C1-4-Alkyl, Halogen, SO2-Ci -4-Alkyl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(C1-4-Alkyl)2, NO2, NH2, NH-Ci.4-Alkyl und N(C1-4-Alkyl)2 substituiert sein kann; undAlkylene COR 5 1, CONHR 5 1, C 6 -aryl, S0 2 -C 6 -io-aryl-C 1-6 alkyl, SO 2 -C 6-10 aryl, or Ce M o-aryl-C 1 -6- alkylene and C 5 _ 10 -heteroaryl-Ci. 6 alkylene, optionally substituted with one or more radicals selected from the group consisting of C 1-4 alkyl, C 2 _ 4 alkenyl, C 2-4 alkynyl, CN, C 1-4 haloalkyl, CONH 2, CONH -C 1-4 alkyl, CON (C 1-4 alkyl) 2 , COOH, COO-C 1 .4 alkyl, COH, CO-C 1-4 alkyl, OH, OC 1-4 alkyl, Halogen, SO 2 -C 4 alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 alkyl, SO 2 -N (C 1-4 alkyl) 2 , NO 2 , NH 2 , NH -C. 4 alkyl and N (C 1-4 alkyl) 2 may be substituted; and

R5 1 C1-4-Alkyl oder C6-10- Aryl-C1-6-alkylen;R 5 is C 1-4 alkyl or C 6-10 arylC 1-6 alkylene;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die Verbindungen der Formel 1a,Particular preference is given to the compounds of the formula 1a,

worin A, X, n, R1, R2, R3 und R4 die vorstehend genannte Bedeutung haben, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.wherein A, X, n, R 1 , R 2 , R 3 and R 4 have the abovementioned meaning, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof ,

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worin R1, R2, R3 , R4 sowie A, B1, B2 und n die oben genannten Bedeutungen haben und worin O;Particularly preferred are the above compounds of formula 1 or 1a, wherein R 1 , R 2 , R 3 , R 4 and A, B 1 , B 2 and n have the meanings given above and wherein O;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worin R1, R2, R3 , R4, R5 sowie A, B1, B2 und n die oben genannten Bedeutungen haben und worinParticularly preferred are the above compounds of formula 1 or 1a, wherein R 1 , R 2 , R 3 , R 4 , R 5 and A, B 1 , B 2 and n have the abovementioned meanings and wherein

NR 50.;NR 5 0 .

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worin R1, R2, R3 , R4, R6 und R7 sowie A, B1 , B2 und n die oben genannten Bedeutungen haben und worinParticularly preferred are the above compounds of formula 1 or 1a, wherein R 1 , R 2 , R 3 , R 4 , R 6 and R 7 and A, B 1 , B 2 and n have the meanings given above and wherein

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worin R1, R2, R3, R4, R5, R6, R7 sowie A, B1, B2 und X die oben genannten Bedeutungen haben und wohn n 0, 1 , oder 2, bevorzugt 0 oder 1 , besonders bevorzugt 0Particularly preferred are the above compounds of formula 1 or 1a, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A, B 1 , B 2 and X have the meanings given above and live n is 0, 1, or 2, preferably 0 or 1, particularly preferably 0

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worinParticularly preferred are the above compounds of formula 1 or 1a wherein

A CH2, CHMe, CMe2, C=NH, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;A CH 2 , CHMe, CMe 2 , C = NH, 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl;B 2 phenyl;

X O oder NR5;X is O or NR 5 ;

n 0, 1 oder 2;n is 0, 1 or 2;

R1 H, Methyl oder Ethyl;R 1 is H, methyl or ethyl;

R2 H, Methyl oder Ethyl;R 2 is H, methyl or ethyl;

R3 H, Cyclopropyl, Cyclobutyl, N-Methyl-piperidinyl, Pyridinyl, Phenyl oder 4-Phenyl- cyclohexanyl oder R3 Phenyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl, Ethyl, Propyl, Butyl, CF3, CONH2, CONHMe, CONMe2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl,R 3 is H, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl or 4-phenylcyclohexanyl or R 3 phenyl, which is optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl , CF 3 , CONH 2 , CONHMe, CONMe 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl,

Br, SH, SO2Me, SONH2, SONMe2, NO2, NH2, NHMe und NMe2 substituiert sein kann; oder R3 Phenyl, welches mit einem Rest ausgewählt aus der Gruppe bestehend aus Methyl und Ethyl substituiert ist, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus COOH, COOMe, NH2, NMe2, NHCOMe, NHCOO-ferf-Butyl, NMe(Benzyl), p-Fluorphenyl, Pyrolidinyl, Piperidinyl, Morpholinyl, Pyrolidin-2onyl, Imidazolyl und Triazolyl substituiert sein kann; oderBr, SH, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NHMe and NMe 2 may be substituted; or R 3 is phenyl which is substituted by a radical selected from the group consisting of methyl and ethyl, optionally substituted by one or more radicals selected from the group consisting of COOH, COOMe, NH 2 , NMe 2 , NHCOMe, NHCOO-ferf-butyl , NMe (benzyl), p-fluorophenyl, pyrolidinyl, piperidinyl, morpholinyl, pyrolidin-2onyl, imidazolyl and triazolyl; or

R3 Phenyl, das mit NR3 1R3 2 substituiert ist, wobeiR 3 is phenyl substituted with NR 3 1 R 3 2 , wherein

R3 1 H, Methyl, COH, COMe, COOMe, CONH2, CONMe2, SO2Me,R 3 1 H, methyl, COH, COMe, COOMe, CONH 2 , CONMe 2 , SO 2 Me,

SO2CF3 oder SO2-Phenyl, und wobei R32 H oder ein Rest ausgewählt aus der Gruppe bestehend aus Methyl, und Ethyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NHMe, NMe2,SO 2 CF 3 or SO 2 -phenyl, and wherein R 32 is H or a radical selected from the group consisting of methyl, and ethyl optionally having one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 ,

N-Piperidinyl, N-Morpholinyl und N-Methyl-piperazinyl substituiert sein kann, wobei das N-Piperidinyl, N-Morpholinyl und das N-Methyl-piperazinyl gegebenenfalls mit einem weiteren Oxo substituiert sein kann bedeutet; oderN-piperidinyl, N-morpholinyl and N-methyl-piperazinyl may be substituted, wherein the N-piperidinyl, N-morpholinyl and the N-methyl-piperazinyl may be optionally substituted with another oxo; or

R3 Phenyl, das mit einem C5.10-Heteroaryl, welches ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert ist, wobei das C5-10-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl, Ethyl, Propyl, Butyl, Cyclopropyl, Cyclobutyl, CF3, CN, CONH2, CONMe2, CONEt2,R 3 is phenyl which is reacted with a C 5 . Is substituted 10 -heteroaryl, which can contain selected from the group oxygen, sulfur and nitrogen one, two or three heteroatoms, wherein the C 5 - 10 -heteroaryl is optionally substituted with one or more radicals selected from the group consisting of phenyl, methyl, Ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 ,

COOH, COOMe1 COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, NH2, NMe2, NEt2 und NPr2 substituiert sein kann; oderCOOH, COOMe 1 COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted; or

R3 Phenyl, das mit einem C3-10-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, substituiert ist, wobei der C3.10-Heterocyclus gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe C1-4-Alkyl und Oxo substituiert sein kann; oder R3 Benzimdazolyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Propyl, CF3, CH2CF3, Cyclopropyl und Cyclohexyl substituiert sein kann;R 3 is phenyl which is substituted by a C 3-10 heterocycle which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen, the C 3 . 10 -Heterocyclus may optionally be substituted by one or more radicals selected from the group C 1-4 alkyl and oxo; or R 3 is benzimidazolyl, which may be optionally substituted with one or more groups selected from the group consisting of methyl, propyl, CF 3 , CH 2 CF 3 , cyclopropyl and cyclohexyl;

und worinand in which

R4 Methyl, Ethyl, Propyl, Butyl, CF3, CH2CF3, F, Cl, oder Br;R 4 is methyl, ethyl, propyl, butyl, CF 3 , CH 2 CF 3 , F, Cl, or Br;

R5 ein Rest ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Propyl, Butyl,R 5 is a radical selected from the group consisting of methyl, ethyl, propyl, butyl,

Cyclopropyl, Cyclobutyl, CF3, CH2CF3, COR5 1, CONHR5 1, Phenyl, Phenylsulfonyl und Benzyl, wobei Benzyl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Propyl, Butyl, CF3, CN, CONH2, CONMe2, CONEt2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO2Me, SONH2, SONMe2, NO2, NH2, NMe2, NEt2 und NPr2 substituiert sein kann;Cyclopropyl, cyclobutyl, CF 3 , CH 2 CF 3 , COR 5 1 , CONHR 5 1 , phenyl, phenylsulfonyl and benzyl, where benzyl is optionally one or more radicals selected from the group consisting of methyl, ethyl, propyl, butyl, CF 3 , CN, CONH 2 , CONME 2 , CONEt 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted;

R5 1 Methyl, Ethyl, Propyl, Butyl oder Benzyl;R 5 is methyl, ethyl, propyl, butyl or benzyl;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worinParticularly preferred are the above compounds of formula 1 or 1a wherein

A CH2, CHMe, CMe2, CO, C=NH, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;A CH 2 , CHMe, CMe 2 , CO, C = NH, 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl;B 2 phenyl;

X O oder NR5;X is O or NR 5 ;

n O oder 1 ; R1 H, Methyl oder Ethyl, bevorzugt H;n is O or 1; R 1 is H, methyl or ethyl, preferably H;

R2 H, Methyl oder Ethyl, bevorzugt H;R 2 is H, methyl or ethyl, preferably H;

R3 H, OH, Cyclopropyl, Cyclobutyl, N-Methyl-piperidinyl, Pyridinyl, Phenyl oder 4-R 3 is H, OH, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl or 4-

Phenyl-cyclohexanyl oderPhenylcyclohexanyl or

R3 Phenyl, das mit einem Rest ausgewählt aus der Gruppe bestehend aus Phenyl, OH, F und CONH2 substituiert ist;R 3 is phenyl substituted with a radical selected from the group consisting of phenyl, OH, F and CONH 2 ;

oder R3 Phenyl, das mit einem Rest ausgewählt aus der Gruppe bestehend aus Methyl und Ethyl substituiert ist, der gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus COOH, COOMe, NH2, NMe2, NHCOMe, NHCOO-terf-or R 3 is phenyl which is substituted by a radical selected from the group consisting of methyl and ethyl, which is optionally substituted by a radical selected from the group consisting of COOH, COOMe, NH 2 , NMe 2 , NHCOMe, NHCOO-terf-

Butyl, NMe(Benzyl), p-Flourphenyl, Pyrolidinyl, Piperidinyl, Morpholinyl, Pyrolidin- 2onyl, Imidazolyl und Triazolyl substituiert sein kann;Butyl, NMe (benzyl), p-fluorophenyl, pyrolidinyl, piperidinyl, morpholinyl, pyrolidin-2onyl, imidazolyl and triazolyl;

oder R3 Phenyl, das mit NR3 1R3 Substituiert ist; wobeior R 3 is phenyl substituted with NR 3 1 R 3 ; in which

R3 1 H, Methyl, SO2Me, SO2CF3 oder SO2-Phenyl;R 3 1 H, methyl, SO 2 Me, SO 2 CF 3 or SO 2 -phenyl;

R32 H oder ein Rest ausgewählt aus der Gruppe bestehend aus Methyl und Ethyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe aus NH2, NHMe, NMe2, Oxo,R 32 denotes H or a radical selected from the group consisting of methyl and ethyl which is optionally substituted by one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 , oxo,

N-Piperidinyl, N-Morpholinyl und N-Methyl-piperazinyl substituiert sein kann; oderN-piperidinyl, N-morpholinyl and N-methyl-piperazinyl may be substituted; or

R3 Phenyl, das mit einem C5.i0-Heteroaryl substituiert sein kann, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl, Ethyl, Propyl, Butyl, Cyclopropyl, Cyclobutyl, CF3, CN, CONH2, CONMe2, CONEt2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO2Me, SONH2, SONMe2, NO2, NH2, NMe2, NEt2 und NPr2 substituiert sein kann, oderR 3 is phenyl which may be substituted by a C 5 .i 0 heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which may be one or more radicals selected from the group consisting of Phenyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted, or

R3 Phenyl, das mit einem Ca.io-Heterocyclus substituiert ist.der ein oder zweiR 3 is phenyl substituted with a Ca.io heterocycle. The one or two

Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann und der gegebenenfallsmit einem oder mehreren Resten ausgewählt aus der Gruppe Ci_4-Alkyl und Oxo substituiert sein kann.Heteroatoms selected from the group consisting of oxygen and nitrogen and may be optionally substituted with one or more radicals selected from the group Ci_ 4 alkyl and oxo may be substituted.

oderor

Benzimdazolyl, das gegebenenfalls mit Methyl substituiert sein kann;Benzimidazolyl, which may be optionally substituted with methyl;

und wobei R4 F oder Cl;and wherein R 4 is F or Cl;

undand

R5 ein Rest ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Cyclopropyl,R 5 is a radical selected from the group consisting of methyl, ethyl, cyclopropyl,

COMe, CONHR5 1, Phenyl, Phenylsulfonyl und Benzyl, der gegebenenfalls mit F substituiert sein kann; worinCOMe, CONHR 5 1 , phenyl, phenylsulfonyl and benzyl, which may optionally be substituted by F; wherein

R5 1 Butyl oder Benzyl bedeuten,R 5 1 is butyl or benzyl,

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worinParticularly preferred are the above compounds of formula 1 or 1a wherein

A CH2, CHMe, CMe2, 1 , 1 '-Cyclopropylen, 1 , 1 '-Cyclobutyliden;A CH 2 , CHMe, CMe 2 , 1, 1 '-cyclopropylene, 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl; X O oder NR5;B 2 phenyl; X is O or NR 5 ;

n O odeM ;n odeM;

R1 H;R 1 H;

R2 H;R 2 H;

R3 H, 4-Phenyl-cyclohexanyl oderR 3 is H, 4-phenyl-cyclohexanyl or

R3 Phenyl, welches gegebenenfalls mit NR3 1R3 2 substituiert sein kann; worinR 3 is phenyl, which may optionally be substituted by NR 3 1 R 3 2 ; wherein

R3 1 H, Methyl, SO2Me, SO2CF3, oder SO2-Phenyϊ, undR 3 1 H, methyl, SO 2 Me, SO 2 CF 3 , or SO 2 -Phenyϊ, and

R3 2 H oder ein Rest ausgewählt aus der Gruppe bestehend aus Methyl und Ethyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NHMe, NMe2, Oxo, N-Piperidinyl, N-Morpholinyl und N-Methyl-piperazinyl substituiert sein kann, bedeutet, oder R3 Phenyt, das mit einem C5-i0-Heteroaryl, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert ist, wobei das C5.10-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl,R 3 2 H or a radical selected from the group consisting of methyl and ethyl which is optionally substituted by one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 , oxo, N-piperidinyl, N-morpholinyl and N- methyl-piperazinyl may be substituted, or R 3 Phenyt provided with a C 5 i 0 heteroaryl containing one, two or three heteroatoms selected from the group oxygen, sulfur and nitrogen, can be substituted, wherein the C 5 . 10 heteroaryl optionally with one or more radicals selected from the group consisting of phenyl, methyl,

Ethyl, Propyl, Butyl, Cyclopropyl, Cyclobutyl, CF3, CN, CONH2, CONMe2, CONEt2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO2Me, SONH2, SONMe2, NO2, NH2, NMe2, NEt2 und NPr2 substituiert sein kann, oderEthyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted, or

R3 Phenyl, das mit einem C3.10-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, wobei der C3-i0-Heterocyclus gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe C1-4-Alkyl und Oxo substituiert sein kann, und wobeiR 3 is phenyl which is substituted by a C 3 . 10 heterocycle containing one or two hetero atoms selected from the group may include oxygen and nitrogen, where the C 3 -i 0 -heterocycle optionally substituted with one or more radicals selected from the group C 1-4 -alkyl and oxo may be substituted, and where

R4 H, F oder Cl;R 4 is H, F or Cl;

R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl CH2CF3 oder Benzyl, wobei das Benzyl gegebenenfalls mit F substituiert sein kann;R 5 is methyl, ethyl, cyclopropyl, cyclobutyl CH 2 CF 3 or benzyl, where the benzyl may optionally be substituted by F;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Ebenfalls besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worinAlso particularly preferred are the above compounds of formula 1 or 1a wherein

A ein Rest ausgewählt aus der Gruppe bestehend aus CH2, CHMe, CMe2, CO, C=NH undA is a radical selected from the group consisting of CH 2 , CHMe, CMe 2 , CO, C = NH and

B1 Phenyl;B 1 phenyl;

B2 Phenyl;B 2 phenyl;

X O oder NR5;X is O or NR 5 ;

n O odeM;n odeM;

R1 H;R 1 H;

R2 H;R 2 H;

R 13 H, OH, 4-Phenyl-cyclohexyl oder ein Rest ausgewählt aus der Gruppe bestehend aus R 13 is H, OH, 4-phenylcyclohexyl or a radical selected from the group consisting of

und R4 H, F oder Cl; und R5 Methyl oder ein Rest ausgewählt aus der Gruppe bestehend ausand R 4 is H, F or Cl; and R 5 is methyl or a radical selected from the group consisting of

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Ebenfalls besonders bevorzugt sind die obigen Verbindungen der Formel 1 oder 1a, worinAlso particularly preferred are the above compounds of formula 1 or 1a wherein

CH2, CD2, C=NH, CHMe, CMe2, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;CH 2 , CD 2 , C = NH, CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl; X O oder NR5; wobeiB 2 phenyl; X is O or NR 5 ; in which

R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl, CONHCH2-Phenyl, CH2CF3 oder Benzyl, gegebenenfalls substituiert mit F;R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, optionally substituted with F;

n O odeM ;n odeM;

R1 H;R 1 H;

R2 H;R 2 H;

worin R3 C1-β-Alkyl, gegebenenfalls substituiert mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-AIKyI)2, COOH, COO-d_6-Alkyl, COH, CO-C1-6-AIRyI,in which R 3 is C 1-β- alkyl, optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2, COOH, COO-d_ 6 alkyl, COH, CO-C 1-6 -AIRyI,

COAryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, Sθ2-Ci-β-Alkanol; SO2-C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2,COAryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, SO 2 -Ci-β-alkanol; SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 ,

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl, einem mit d.3-Alkylen überbrückten C3-8-Cycloalkyl, C5-8-Cycloalkenyl und C1-6-Alkyl, Cτ-6-Alkanol, der jeweils gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Ce-io-Aryl, C3-8-Cycloalkyl, C5-10-Heteroaryl und C3-10-Heterocyclus substituiert sein kann, der gegebenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2.e-Alkinyl, C1-6-Haloalkyl, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-β-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Ary I1 OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-Ci-β-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol, SO2-C1-6-Alkyl, SO2-d^-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-Ci-6-Alkyl, N(C1-6-AIKyI)2, C5.10-Heteroaryl und einem C3_10-Heterocyclus substituiert sein kann, der gegebenenfalls mit einem Rest ausgewählt aus Oxo-, Hydroxyl-, Halogenoder d_6-Alkyl und C1-6-Haloalkyl substituiert sein kann; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6.10-Aryl, C5.10-Heteroaryl und einem C3_10-Heterocyclus, der jeweils mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6.i0-Aryl, C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C1-6-Haloalkyl, CONH2, CONH-C1-β-Alkyl, CON(CL6-AIKyI)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-I o-Ary I, OH, O-C1-6-Alkyl, O-Ci-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-AIKyI1 SO2-C1-β-Alkanol, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1_6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2 und N-(SO2-C1-4-Alkyl)(R34) substituiert sein kann,or R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl, one with d. 3- alkylene bridged C 3-8 -cycloalkyl, C 5-8 -cycloalkenyl and C 1-6 -alkyl, Cτ- 6 -alkanol, each optionally substituted by one or more radicals selected from the group consisting of C e- Aryl, C 3-8 cycloalkyl, C 5-10 heteroaryl and C 3-10 heterocycle optionally substituted with one or more radicals selected from the group consisting of C 1-6 alkyl, C 2-6 Alkenyl, C 2 . e is alkynyl, C 1-6 haloalkyl, CN, CONH 2 , CONH C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-β alkyl, COH, CO -C 1-6 alkyl, CO-C 6-10 aryl I 1 OH, OC 1-6 alkyl, OC 1-6 haloalkyl, halo, SH, S-Ci-β-alkyl, SC 1-6 Haloalkyl, SO 2 -C 1-6 -alkanol, SO 2 -C 1-6 -alkyl, SO 2 -d ^ -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 alkyl) 2, NO 2, NH 2, NH-Ci 6 alkyl, N (C 1-6 -alkyl) 2, C. 5 10 -Heteroaryl and a C 3 _ 10 heterocycle may be substituted, which may be optionally substituted by a radical selected from oxo, hydroxyl, halo or d_ 6 alkyl and C 1-6 haloalkyl; or R 3 is a radical selected from a group consisting of C 6 . 10 -aryl, C 5 . 10 -heteroaryl and a C 3 _ 10 heterocycle which in each case with one or more radicals selected from the group consisting of C 6 .i 0 aryl, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, CONH 2, CONH-C 1-β alkyl, CON (C L6 -alkyl) 2, COOH, COO-C 1-6 alkyl, COH, CO-C 1- 6 alkyl, CO-C 6 - I o-ary I, OH, OC 1-6 alkyl, O-Ci- 6 haloalkyl, halo, SH, SC 1-6 alkyl, SC 1-6 haloalkyl, SO 2 -C 1-6 -alkyl 1 SO 2 -C 1-β alkanol, SO 2 C 1-6 haloalkyl, SO 2 -NH 2, SO 2 -NH-C 1-6 alkyl, SO 2 -N (C 1 _ 6 alkyl) 2, NO 2, NH 2, NH-C 1-6 alkyl, N (C 1-6 alkyl) 2 and N (SO 2 C 1-4 alkyl ) (R 34 ) may be substituted,

wobei R34 ein C6-10-Aryl, C6-io-Aryl-C1-6-alkylen oder ein C5-10-Heteroaryl-C1-6-alkylen ist;wherein R 34 is a C 6-10 aryl, C 6 -io-arylC 1-6 alkylene or a C 5-10 heteroarylC 1-6 alkylene;

oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C1-6-Alkyi, C6-10-Aryl- C1-6-alkylen, Cs-io-Heteroaryl-C1-6-alkylen, C3.7-Cycloalkyl, C6.i0-Aryl, C5.10-Heteroaryl und einem C3_i0-Heterocyclus , welcher jeweils gegebenenfalls mit einem oder mehreren Resten der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl, Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 istor R 3 is a radical selected from a group consisting of C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, Cs-io-heteroaryl-C 1-6 -alkylene, C 3 . 7 -cycloalkyl, C 6 .i 0 -aryl, C 5 . 10 heteroaryl and a C 3 _i 0 heterocycle, which may be optionally substituted with one or more radicals of the group consisting of B, halogen, OH, C 1-6 alkyl, oxo, where B is a compound of formula 2

wobei Z1 H, OH1 Halogen, C1-6-Alkyl, C1-6-Alkanol, O(C1-β-Alkyl), C6-10-Aryl, O- Cβ.io-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2 oder C3-7-Cycloalkyl; und Z2 OH, NH2, N(C1-6-Alkyl)2, O(C1-6-Alkyl), C6-io-Aryl; mono- oder bicyclisches C3-7-Cycloalkyl, mono- oder bicyclischer aromatischer oder nicht aromatischer C3-10-Heterocyclus bedeuten,wherein Z 1 is H, OH 1 is halogen, C 1-6 -alkyl, C 1-6 -alkanol, O (C 1-β -alkyl), C 6-10 -aryl, O-Cβ.io-aryl, NH 2 , NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 or C 3-7 cycloalkyl; and Z 2 OH, NH 2 , N (C 1-6 alkyl) 2 , O (C 1-6 alkyl), C 6 -io-aryl; mono- or bicyclic C 3-7 cycloalkyl, mono- or bicyclic aromatic or non-aromatic C 3 - 10 heterocycle means,

und wobeiand where

R4 H, F oder Cl; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.R 4 is H, F or Cl; optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Besonders bevorzugt sind weiterhin Verbindungen der Formel 1 oder 1a , worinParticular preference is furthermore given to compounds of the formula I or 1a in which

A CH2, CD2, C=NH, CHMe, CMe2, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;A CH 2 , CD 2 , C = NH, CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl;B 2 phenyl;

X O oder NR5; wobeiX is O or NR 5 ; in which

R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl, CONHCH2-Phenyl, CH2CF3 oder Benzyl, gegebenenfalls substituiert mit F;R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, optionally substituted with F;

n O odeM ;n odeM;

R1 H;R 1 H;

R2 H; und worin R3 C1-6-AIkVl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl,R 2 H; and R 3 is C 1-6 -alkyl, optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl,

CON(C1-6-A!kyl)2, COOH, COO-C1-β-Alkyl, COH, CO-C1-6-Alkyl, Phenyl, CO-Phenyl, OH, O-d_6-Alkyl, SO2-C1-6-AIkBnOl; SO2-C1 -6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, Sθ2-NH-Ci_6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2, substituiert sein kann;CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-β- alkyl, COH, CO-C 1-6 -alkyl, phenyl, CO-phenyl, OH, O-d_ 6 -alkyl, SO 2 -C 1-6 -AlkBnOl; SO 2 -C 1 -6 alkyl, SO 2 C 1-6 haloalkyl, SO 2 -NH 2, -NH-Sθ 2 CI_ 6 alkyl, SO 2 -N (C 1-6 alkyl) 2, NO 2 , NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 , may be substituted;

oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl, einem mitor R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl, one with

C^-Alkylen überbrückten C3,8-Cycloalkyl und C1-6-Alkyl, der jeweils gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl oder einem anderen aromatischen oder nicht aromatischen C3_8-Ring, vorzugsweise einem C5-7-Ring, stärker bevorzugt einem C5-6-Ring, der jeweils gegebenenfalls 1 bis 4 Heteroatome unabhängig voneinander ausgewählt aus N, O. S enthalten kann, substituiert sein kann, wobei jeder dieser Reste gegebenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-6-AIkVl, C1-β-Haloalkyl, CN, CONH2, CONH-C1-6-AIkVl, CON(Ci.6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, Phenyl, CO-Phenyl, OH, O-C1-6-Alkyl, O-Cβ-Haloalkyl, Halogen, SH, S-Cm-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol, SO2-C1-6-Alkyl, NH-C1-6-AIKyI und N(C-ι.6-Alkyl)2, einem aromatischen oder nicht aromatischen C3-8-Ring, vorzugsweise einem C5_7-Ring, stärker bevorzugt einem C5-6-Ring, der gegebenenfalls 1 bis 4 Heteroatome unabhängig voneinander ausgewählt aus N, O. S enthält substituiert sein kann,, wobei dieser aromatische oder nicht aromatische C3-8-Ring gegebenenfalls mit einem Rest ausgewählt aus Oxo-, Hydroxyl-, Halogen- oder C1-6-AIkVl und substituiert sein kann;C ^ alkylene bridged C 3 8 cycloalkyl and C 1-6 alkyl, which in each case optionally selected with one or more radicals from the group consisting of phenyl or other aromatic or non-aromatic C 3 _ 8 ring, preferably a C 5-7 ring, more preferably a C 5-6 ring, each optionally substituted from 1 to 4 heteroatoms independently selected from N, O. S may include, may be substituted, each of these radicals being optionally substituted with one or more groups selected from the group consisting of C 1-6 -alkyl, C 1-β haloalkyl, CN, CONH 2, CONH-C 1-6 -alkyl, CON (Ci. 6 alkyl) 2, COOH, COO- C 1-6 alkyl, COH, CO-C 1-6 alkyl, phenyl, CO-phenyl, OH, OC 1-6 alkyl, O-Cβ-haloalkyl, halogen, SH, S-Cm-alkyl, SC , SO 2 -C (ι-C. 6 alkyl) 1-6 haloalkyl, SO 2 -C 1-6 alkanol 1-6 alkyl, NH-C 1-6 -alkyl, and N 2, an aromatic or non-aromatic C 3-8 ring, preferably a C 5 _ 7 ring, more preferably a C 5-6 ring, optionally containing from 1 to 4 heteroatoms independently selected from N, O. S contains may be substituted ,, wherein this aromatic or non-aromatic C 3-8 ring optionally having a radical selected from oxo, hydrox yl, halogen or C 1-6 -AlkVl and may be substituted;

oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus Phenyl und einem anderen aromatischen oder nicht aromatischen C3-8-Ring, vorzugsweise einem C5-7-Ring, stärker bevorzugt einem C5_6-Ring, der gegebenenfalls 1 bis 4 Heteroatomen ausgewählt aus N, O. S enthalten kann und der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, C1-6-Alkyl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-β-Alkyl, COH, CO-C1 -6-Alkyl, CO- Phenyi, OH, O-C1-6-Alkyl, 0-C1-6-Haloalkyl, Halogen, SO2-C1-6-AIkYl1 SO2-C1-6-Alkanol , SO2-CL6-HaIOaIkYl, SO2-NH2, SO2-NH-C1-6-AIkYl, SO2-N(C1-6-AIkYl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2 und N-(SO2-C1-4-Alkyl)(R34) substituiert sein kann,or R 3 is a radical selected from a group consisting of phenyl and other aromatic or non-aromatic C 3-8 ring, preferably a C 5- 7-membered ring, more preferably a C 5 _ 6 ring which optionally contains 1 to 4 Heteroatoms selected from N, O. S may contain and optionally with one or more radicals selected from the group consisting of phenyl, C 1-6 alkyl, C 1-6 haloalkyl, CONH 2 , CONH-C 1-6 - Alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-β- alkyl, COH, CO-C 1 -6- alkyl, CO-phenyl, OH, OC 1-6- alkyl, 0- C 1-6 haloalkyl, halogen, SO 2 -C 1-6 -alkyl 1 SO 2 -C 1-6 alkanol, SO 2 -C L6 -HaIOaIkYl, SO 2 -NH 2, SO 2 -NH-C 1 -6- alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl) 2 and N- (SO 2 C 1-4 alkyl) (R 34 ) may be substituted,

wobei R34 ein bedeutet;where R 34 is a means;

oder R3 oder ein Rest ausgewählt aus einer Gruppe bestehend aus C1-6-AIkYl, C^o-Heteroaryl-C1-6-alkylen, C6-10-Aryi-C1-6-alkylen, C3-7-Cycloalkyl, Phenyl und einem aromatischen oder nicht aromatischen C3-8-Ring, vorzugsweise einem C5-7-Ring, stärker bevorzugt einem C5-6-Ring, der 1 bis 4 Heteroatomen ausgewählt aus N, O. und S enthalten kann, wobei jeder dieser Reste gegebenenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus B, Halogen, OH, C1-6-AIkYl, Oxo substituiert sein kann und wobei B eine Verbindung der Formel 2 ist or R 3 or a radical selected from a group consisting of C 1-6 alkyl, C 1-0 heteroaryl C 1-6 alkylene, C 6-10 aryl C 1-6 alkylene, C 3-7 cycloalkyl, phenyl and an aromatic or non-aromatic C 3-8 ring, preferably a C 5-7 ring, more preferably a C 5 - 6 ring containing 1 to 4 heteroatoms selected contain from N, S and O. wherein each of these radicals may optionally be substituted with one or more radicals selected from the group consisting of B, halogen, OH, C 1-6 alkyl, oxo, and wherein B is a compound of formula 2

wobei Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol oder O(C1-6-Alkyl) und Z2 OH, NH2, NH(CL6-AIkYl), N(C1-6-Alkyl)2, O(C1-6-Alkyl), mono- oder bicyclisches C3.7-Cycloalkyl, mono- oder bicyclischer aromatischer oder nicht aromatischer C3_where Z 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol or O (C 1-6 -alkyl) and Z 2 OH, NH 2 , NH (C L6 -alkyl), N ( C 1-6 alkyl) 2 , O (C 1-6 alkyl), mono- or bicyclic C 3 . 7 -cycloalkyl, mono- or bicyclic aromatic or non-aromatic C 3 _

10-Heterocyclus oder Phenyl ist; 10 -heterocycle or phenyl;

und R4 H, F oder Cl;and R 4 is H, F or Cl;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof.

Ebenfalls besonders bevorzugt sind Verbindungen der der obigen Formel 1 oder 1a , worinAlso particularly preferred are compounds of the above formula 1 or 1a, wherein

A CH2, CD2, C=NH, CHMe, CMe2, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;A CH 2 , CD 2 , C = NH, CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene;

B1 Phenyl;B 1 phenyl;

B2 Phenyl;B 2 phenyl;

X O oder NR5; wobeiX is O or NR 5 ; in which

R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl, CONHCH2-Phenyl, CH2CF3 oder Benzyl, gegebenenfalls substituiert mit F; n 0 oder 1 ;R 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, optionally substituted with F; n is 0 or 1;

R1 H;R 1 H;

R2 H;R 2 H;

worin R3 ein Rest ausgewählt aus der Gruppe bestehend auswherein R 3 is a radical selected from the group consisting of

und wobei R4 H, F oder Cl;and wherein R 4 is H, F or Cl;

bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssaize, Solvate oder Hydrate, sowie deuterierte Formen davon. VERWENDETE BEGRIFFE UND DEFINITIONENoptionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. USED TERMS AND DEFINITIONS

Soweit nicht anders angegeben, sind alle Substituenten voneinander unabhängig. Sollten an einer Gruppe z. B. mehrere Ci.6-Alkylgruppen als Substituenten sein, so könnte, im Fall von drei Substituenten CV6-Alkyl unabhängig voneinander einmal Methyl, einmal n-Propyl und einmal terf-Butyl bedeuten.Unless otherwise indicated, all substituents are independent of each other. Should a group z. B. several Ci. 6- Alkylgruppen as substituents, so could, in the case of three substituents CV 6 alkyl independently of one another once methyl, once n-propyl and once terf-butyl.

Im Rahmen dieser Anmeldung können bei der Definition von möglichen Substituenten, diese auch in Form einer Strukturformel dargestellt werden. Dabei wird ein Stern (*) in der Strukturformel des Substituenten als der Verknüpfungspunkt zum Rest des Moleküls verstanden. Weiterhin wird das auf den Verknüpfungspunkt folgende Atom des Substituenten als das Atom mit der Positionsnummer 1 verstanden. So werden zum Beispiel die Reste N-Piperidinyl (I)1 4-Piperidinyl (II), 2-ToIyI (III), 3-ToIyI (IV) und 4-ToIyI (V) wie folgt dargestellt:In the context of this application, in the definition of possible substituents, these can also be represented in the form of a structural formula. An asterisk ( * ) in the structural formula of the substituent is understood to be the point of attachment to the remainder of the molecule. Furthermore, the atom of the substituent following the point of attachment is understood as the atom with the position number 1. For example, the residues N-piperidinyl (I) 1 4-piperidinyl (II), 2-ToIyI (III), 3-ToIyI (IV) and 4-ToIyI (V) are shown as follows:

Unter dem Begriff "C1-6-Alkyl" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkylgruppen mit 1 bis 6 Kohlenstoffatomen verstanden und unter dem Begriff "C1-4-Alkyl" verzweigte und unverzweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen verstanden. Bevorzugt sind Aikylgruppen mit 1 bis 4 Kohlenstoff- atome. Beispielsweise werden hierfür genannt: Methyl, Ethyl, A7-Propyl, /sσ-Propyl, n- Butyl, /so-Butyl, sec-Butyl, tert-Buty\, n-Pentyl, /so-Pentyl, neo-Pentyl oder Hexyl. Gegebenenfalls werden für vorstehend genannten Gruppen auch die Abkürzungen Me, Et, n-Pr, /-Pr, n-Bu, /-Bu, t-Bu, etc. verwendet. Sofern nicht anders beschrieben, umfassen die Definitionen Propyl, Butyl, Pentyl und Hexyl alle denkbaren isomeren Formen der jeweiligen Reste. So umfasst beispielsweise Propyl n-Propyl und /so-Propyl, Butyl umfasst /so-Butyl, sec-Butyl und te/t-Butyl etc. Unter dem Begriff "C1-6-Alkylen" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkylengruppen mit 1 bis 6 Kohlenstoffatomen verstanden und unter dem Begriff "CLs-Alkylen" verzweigte und unverzweigte Alkylengruppen mit 1 bis 3 Kohlenstoffatomen verstanden. Bevorzugt sind Alkylengruppen mit 1 bis 3The term "C 1-6 -alkyl" (including those which are part of other groups) is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 10 by the term "C 1-4 -alkyl" 4 carbon atoms understood. Preferred are aikyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, A7-propyl, / sσ-propyl, n-butyl, / so-butyl, sec-butyl, tert-Buty \, n-pentyl, / so-pentyl, neo-pentyl or hexyl , Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise specified, the definitions of propyl, butyl, pentyl and hexyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / t-butyl, etc. The term "C 1-6 -alkylene" (including those which are part of other radicals) is understood as meaning branched and unbranched alkylene groups having 1 to 6 carbon atoms and branched and unbranched alkylene groups having 1 to 3 by the term "C L s -alkylene" Understood carbon atoms. Preference is given to alkylene groups having 1 to 3

Kohlenstoffatome. Beispielsweise werden hierfür genannt: Methylen, Ethylen, Propylen, 1- Methylethylen, Butylen, 1-Methylpropylen, 1 , 1-Dimethylethylen, 1 , 2-Dimethylethyien, Pentylen, 1 , 1-Dimethylpropyien, 2, 2, -Dimethylpropylen, 1 , 2-Dimethylpropylen, 1 , 3- Dimethylpropylen oder Hexylen. Sofern nicht anders beschrieben, umfassen die Definitionen Propylen, Butylen, Pentylen und Hexylen alle denkbaren isomeren Formen der jeweiligen Reste gleicher Kohlenstoffanzahl. So umfasst beispielsweise Propyl auch 1 -Methylethylen und Butylen umfasst 1-Methylpropylen, 1 , 1-Dimethylethylen, 1 , 2- Dimethylethylen.Carbon atoms. For example: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethyls, pentylene, 1, 1-dimethylpropyls, 2, 2, -dimethylpropylene, 1, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless otherwise stated, the definitions propylene, butylene, pentylene and hexylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.

Sollte die Kohlenstoffkette mit einem Rest substituiert sein, der gemeinsam mit einem oder zwei Kohlenstoffatomen der Alkylenkette einen carbocyclischen Ring mit 3, 5 oder 6 Kohlenstoffatomen bildet, so sind damit folgende Beispiele der Ringe umfasst:Should the carbon chain be substituted with a radical which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, the following examples of the rings are included:

Unter dem Begriff "C2-6-Alkenyl" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkenylgruppen mit 2 bis 6 Kohlenstoffatomen und unter dem Begriff "C2-4-Alkenyl" verzweigte und unverzweigte Alkenylgruppen mit 2 bis 4 Kohlenstoffatomen verstanden, soweit sie mindestens eine Doppelbindung aufweisen. Bevorzugt sind Alkenylgruppen mit 2 bis 4 Kohlenstoffatome. Beispielsweise werden hierfür genannt: Ethenyl oder Vinyl, Propenyl, Butenyl, Pentenyl, oder Hexenyl. Sofern nicht anders beschrieben, umfassen die Definitionen Propenyl, Butenyl, Pentenyl und Hexenyl alle denkbaren isomeren Formen der jeweiligen Reste. So umfasst beispielsweise Propenyl 1 -Propenyl und 2-Propenyl, Butenyl umfasst 1-, 2- und 3-Butenyl, 1- Methyl- 1 -propenyl, 1-Methyl-2-propenyl etc.. Unter dem Begriff "C2-6-Alkinyl" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkinylgruppen mit 2 bis 6 Kohlenstoffatomen und unter dem Begriff "C2-4-Alkinyl" verzweigte und unverzweigte Alkinylgruppen mit 2 bis 4 Kohlenstoffatomen verstanden, soweit sie mindestens eine Dreifachbindung aufweisen. Bevorzugt sind Alkinylgruppen mit 2 bis 4 Kohlenstoffatome. Beispielsweise werden hierfür genannt: Ethinyl, Propinyl, Butinyl, Pentinyl, oder Hexinyl. Sofern nicht anders beschrieben, umfassen die Definitionen Propinyl, Butinyl, Pentinyl und Hexinyl alle denkbaren isomeren Formen der jeweiligen Reste. So umfasst beispielsweise Propinyl 1 -Propinyl und 2- Propinyl, Butinyl umfasst 1-, 2- und 3-Butinyl, 1-Methyl-1 -propinyl, 1 -Methyl-2-propinyl etc..The term "C 2 - 6 alkenyl" (including those which are part of other radicals) are branched and unbranched alkenyl groups having 2 to 6 carbon atoms and the term "C 2 - 4 alkenyl" branched and unbranched alkenyl groups having 2 to 4 Carbon atoms understood, as far as they have at least one double bond. Preferred are alkenyl groups having 2 to 4 carbon atoms. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise described, the definitions propenyl, butenyl, pentenyl and hexenyl include all conceivable isomeric forms of the respective radicals. For example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc. The term "C 2 - 6 -alkynyl" (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term "C 2-4 alkynyl" are meant branched and unbranched alkynyl groups with 2 to 4 Carbon atoms understood as far as they have at least one triple bond. Preferred are alkynyl groups having 2 to 4 carbon atoms. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all conceivable isomeric forms of the respective radicals. For example, propynyl includes 1-propynyl and 2-propynyl, butinyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.

Unter dem Begriff "C2.6-Alkinylen" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkinylengruppen mit 2 bis 6 Kohlenstoffatomen verstanden und unter dem Begriff "C2.4-Alkinylen" verzweigte und unverzweigte Alkylengruppen mit 2 bis 4 Kohlenstoffatomen verstanden. Bevorzugt sind Alkinylengruppen mit 2 bis 4 Kohlenstoffatome. Beispielsweise werden hierfür genannt: Ethinylen, Propinylen, 1-Methylethinylen, Butinylen, 1-Methylpropinylen, 1 , 1- Dimethylethinyien, 1 , 2-Dimethylethinylen, Pentinylen, 1 , 1-Dimethylpropinylen, 2, 2, - Dimethylpropinylen, 1 , 2-Dimethylpropinylen, 1 , 3-Dimethylpropinylen oder Hexinylen. Sofern nicht anders beschrieben, umfassen die Definitionen Propinylen, Butinylen, Pentinylen und Hexinylen alle denkbaren isomeren Formen der jeweiligen Reste gleicher Kohlenstoffanzahl. So umfasst beispielsweise Propinyl auch 1 -Methylethinylen und Butinylen umfasst 1-Methylpropinylen, 1 , 1-Dimethylethinylen, 1 , 2-Dimethylethinylen.The term "C 2. 6, alkynylene" (including those which are part of other groups) are meant having 2 to 6 carbon atoms branched and unbranched alkynylene groups and by the term "C 2. 4, alkynylene" are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms understood. Alkynylene groups having 2 to 4 carbon atoms are preferred. Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1, 1-Dimethylethinyien, 1, 2-dimethylethynylene, pentynylene, 1, 1-dimethylpropynylene, 2, 2, - dimethylpropynylene, 1, 2 Dimethylpropynylene, 1, 3-dimethylpropynylene or hexynylene. Unless otherwise stated, the definitions propynylene, butynylene, pentynylene and hexynylene include all conceivable isomeric forms of the respective radicals of the same carbon number. For example, propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1, 1-dimethylethynylene, 1, 2-dimethylethynylene.

Unter dem Begriff "Aryl" (auch soweit sie Bestandteil anderer Reste sind) werden aromatische Ringsysteme mit 6 oder 10 Kohlenstoffatomen verstanden. Beispielsweise werden hierfür genannt: Phenyl oder Naphthyl, bevorzugter Arylrest ist Phenyl. Soweit nicht anders beschreiben, können die Aromaten substituiert sein mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, /so-Propyl, terf-Butyi, Hydroxy, Fluor, Chlor, Brom und Jod. Unter dem Begriff "Aryl-alkylen" oder "C6-io-Aryl-alkylen" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkylengruppen mit 1 bis 6 Kohlenstoffatomen verstanden, die mit einem aromatischen Ringsystem mit 6 oder 10 Kohlenstoffatomen substituiert sind. Beispielsweise werden hierfür genannt: Benzyl, 1- oder 2-Phenylethyl oder 1- oder 2-Naphthylethyl. Soweit nicht anders beschreiben, können die Aromaten substituiert sein mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, /so-Propyl, tert-Butyl, Hydroxy, Fluor, Chlor, Brom und Jod.The term "aryl" (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. The term "aryl-alkylene" or "C 6 -io-aryl-alkylene" (even if they are part of other radicals) are understood to mean branched and unbranched alkylene groups having 1 to 6 carbon atoms, which with an aromatic ring system having 6 or 10 carbon atoms are substituted. For example: benzyl, 1- or 2-phenylethyl or 1- or 2-naphthylethyl. Unless otherwise stated, the aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, / so-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

Unter dem Begriff "Heteroaryl-alkylen" oder "C5.10-Heteroaryl-alkylen" (auch soweit sie Bestandteil anderer Reste sind) werden - obwohl auch bereits unter "Aryl-alkylen umfasst - verzweigte und unverzweigte Alkylengruppen mit 1 bis 6 Kohlenstoffatomen verstanden, die mit einem Heteroaryl substituiert sind.The term "heteroaryl-alkylene" or "C 5 10 -heteroaryl-alkylene." (Including those which are part of other groups) are meant - although already "aryl-alkylene includes - branched and unbranched alkylene groups having 1 to 6 carbon atoms which substituted with a heteroaryl.

Ein solches Heteroaryl umfasst fünf- oder sechsgliedrige heterocyclische Aromaten oder 5-10 gliedrige, bicyclische Heteroarylringe, die ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff, enthalten können und so viele konjugierte Doppelbindungen enthalten, dass ein aromatisches Systeme gebildet wird. Als Beispiele für fünf- oder sechsgliedrige heterocyclische Aromaten oder für bicyclische Heteroarylringe, werden genannt:Such a heteroaryl includes five- or six-membered heterocyclic aromatics or 5-10 membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and contain as many conjugated double bonds as an aromatic system is formed. Examples of five- or six-membered heterocyclic aromatic compounds or bicyclic heteroaryl rings are:

Soweit nicht anders beschreiben, können diese Heteroaryle substituiert sein mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, /so-Propyl, te/t-Butyl, Hydroxy, Fluor, Chlor, Brom und Jod.Unless otherwise stated, these heteroaryls may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, te / t-butyl, hydroxy, fluoro, chloro, bromo and iodo.

Für die Heteroaryl-alkylene werden die folgenden Beispiele genannt: For the heteroaryl-alkylene the following examples are mentioned:

Unter dem Begriff "Ci 6-Haloalkyl" (auch soweit sie Bestandteil anderer Reste sind) werden verzweigte und unverzweigte Alkylgruppen mit 1 bis 6 Kohlenstoffatomen verstanden, die mit einem oder mehreren Halogenatomen substituiert sind Unter dem Begriff "C1 4-Alkyl" verzweigte und unverzweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen verstanden, die mit einem oder mehreren Halogenatomen substituiert sind Bevorzugt sind Alkylgruppen mit 1 bis 4 Kohlenstoffatome Beispielsweise werden hierfür genannt CF3, CHF2, CH2F, CH2CF3 The term "Ci 6 haloalkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups having 1 to 6 carbon atoms substituted with one or more halogen atoms are substituted, the term "C 1 4 alkyl" refers to branched and For example, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 are understood as meaning alkyl groups having 1 to 4 carbon atoms. Preferred are alkyl groups having 1 to 4 carbon atoms

Unter dem Begriff "C3 8-Cycloalkyl" (auch soweit sie Bestandteil anderer Reste sind) werden cychsche Alkylgruppen mit 3 bis 8 Kohlenstoffatomen verstanden Unter dem Begriff "C3 6-Cycloalkyl" werden entsprechend cychsche Alkylgruppen mit 3 bis 6 Kohlenstoffatomen verstanden Beispielsweise werden hierfür genannt Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl oder Cycloheptyl Soweit nicht anders beschrieben, können die cyclischen Alkylgruppen substituiert sein mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, /so-Propyl, ferf-Butyl, Hydroxy, Fluor, Chlor, Brom und JodThe term "C 3 8 -cycloalkyl" (including those which are part of other groups) cychsche alkyl groups having 3 to 8 carbon atoms which are "3 6 cycloalkyl C" should be understood accordingly cychsche alkyl groups having 3 to 6 carbon atoms, the term For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, unless otherwise stated, the cyclic alkyl groups may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, / isopropyl, ferf-butyl, hydroxy, fluoro, Chlorine, bromine and iodine

Unter dem Begriff "C5 8-Cycloalkenyl" (auch soweit sie Bestandteil anderer Reste sind) werden cyclische Alkenylgruppen mit 5 bis 8 Kohlenstoffatomen verstanden Beispielsweise werden hierfür genannt Cyclopentenyl, Cyclohexenyl oder Cyclohepentyl Soweit nicht anders beschrieben, können die cyclischen Alkenylgruppen substituiert sein mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, /so-Propyl, te/t-Butyl, Hydroxy, Fluor, Chlor, Brom und Jod.The term "C 5 -C 8 cycloalkenyl" (including those which are part of other groups) also includes cyclic alkenyl groups having 5 to 8 carbon atoms. For example, cyclopentenyl, cyclohexenyl or cyclohepentyl are mentioned. Unless otherwise stated, the cyclic alkenyl groups may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, / so-propyl, te / t-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

Unter dem Begriff "Heterocyclus" werden fünf-, sechs- oder siebengliedrige, gesättigte oder ungesättigte heterocyclische Ringe verstanden, die ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten können, dabei kann der Ring über ein Kohlenstoffatom oder falls vorhanden über ein Stickstoffatom mit dem Molekül verknüpft sein. Obwohl unter dem Begriff "Heterocyclus" umfasst, definiert der Begriff "nichtaromatische Heterocyclen" fünf-, sechs- oder siebengliedrige ungesättigte Ringe. Als Beispiele werden genannt:By the term "heterocycle" is meant five-, six- or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, in which case the ring may have a carbon atom or if present, be linked to the molecule via a nitrogen atom. Although included within the term "heterocycle", the term "non-aromatic heterocycles" defines five-, six- or seven-membered unsaturated rings. Examples are:

Obwohl unter dem Begriff "Heterocyclus" umfasst, definiert der Begriff "aromatische Heterocyclen" fünf- oder sechsgliedrige heterocyclische Aromaten oder 5-10 gliedrige, bicyclische Heteroarylringe die ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff, enthalten können und so viele konjugierte Doppelbindungen enthalten, dass ein aromatisches gebildet Systeme wird. Als Beispiele für fünf- oder sechsgliedrige aromatische Heterocyclen, werden genannt:Although included within the term "heterocycle", the term "aromatic heterocycles" defines five- or six-membered heterocyclic aromatics or 5-10 membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and contain as many conjugated double bonds that an aromatic is formed systems. Examples of five- or six-membered aromatic heterocycles are:

Soweit nicht anders erwähnt, kann ein Heterocyclus mit einer Ketogruppe versehen sein. Als Beispiel hierfür werden genannt. Unless otherwise stated, a heterocycle may be provided with a keto group. As an example for this are called.

Unter dem Begriff "bicyclische Ringe" werden acht-, neun- oder zehngliedrige, bicyclische Ringe verstanden, die gegebenenfalls ein oder mehrere Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten können. Der Ring kann dabei über ein Kohlenstoffatom des Rings oder falls vorhanden über ein Stickstoffatom des Rings mit dem Molekül verknüpft sein. Beispielhaft werden genannt,By the term "bicyclic rings" is meant eight-, nine- or ten-membered bicyclic rings which may optionally contain one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The ring may be linked to the molecule via a carbon atom of the ring or, if present, via a nitrogen atom of the ring. By way of example,

Obwohl unter dem Begriff "bicyciische Ringe" umfasst, definiert der Begriff "kondensierte bicyclische Ringe", bicyclische Ringe, in denen die die Ringe trennende Brücke eine direkte Einfachbindung bedeutet. Als Beispiel für einen kondensierten, bicyclischen Ring werden genannt:Although encompassed by the term "bicyciic rings", the term "fused bicyclic rings" defines bicyclic rings in which the bridge separating the rings represents a direct single bond. As an example of a fused, bicyclic ring are mentioned:

Obwohl unter dem Begriff "bicyclische Ringe" umfasst, definiert der Begriff "kondensierte, bicyclische Heteroringe", bicyclische 5-10 gliedrige Heteroringe die ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten und in denen die die Ringe trennende Brücke eine direkte Einfachbindung bedeutet. Beispielhaft werden genannt Pyrrolizin, Indol, Indolizin, Isoindol, Indazol, Purin, Chinolin, Isochinolin, Benzimidazol, Benzofuran, Benzopyran, Benzothiazol, Benzothiazol, Benzoisothiazol, Pyridopyrimidin, Pteridin, Pyrimidopyrimidin, Although encompassed by the term "bicyclic rings", the term "fused bicyclic hetero rings" defines bicyclic 5-10 membered hetero rings containing one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and in which the rings separating bridge means a direct single bond. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

Obwohl unter dem Begriff "bicyclische Ringe" umfasst, definiert der Begriff "bicyclische Heterocyclen", acht-, neun- oder zehngliedrige, bicyclische Ringe, die ein oder mehrere Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten können. Als Beispiele für "bicyclische Heterocycien" werden genannt:Although encompassed by the term "bicyclic rings", the term "bicyclic heterocycles" defines eight-, nine- or ten-membered bicyclic rings which may contain one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. As examples of "bicyclic heterocycles" are mentioned:

"Halogen" steht im Rahmen der vorliegenden Erfindung für Fluor, Chlor, Brom oder Jod. Sofern nicht gegenteilig angegeben, gelten Fluor, Chlor und Brom als bevorzugte Halogene."Halogen" in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.

Verbindungen der allgemeinen Formel 1 können Säuregruppen besitzen, hauptsächlich Carboxylgruppen, und/oder basische Gruppen wie z.B. Aminofunktionen. Verbindungen der allgemeinen Formel 1 können deshalb als innere Salze, als Salze mit pharmazeutisch verwendbaren anorganischen Säuren wie Salzsäure, Schwefelsäure, Phosphorsäure, Sulfonsäure oder organischen Säuren (wie beispielsweise Maleinsäure, Fumarsäure, Zitronensäure, Weinsäure oder Essigsäure) oder als Salze mit pharmazeutisch verwendbaren Basen wie Alkali- oder Erdalkalimetallhydroxiden oder Carbonaten, Zinkoder Ammoniumhydroxiden oder organischen Aminen wie z.B. Diethylamin, Triethylamin, Triethanolamin u.a. vorliegen.Compounds of general formula 1 may have acid groups, mainly carboxyl groups, and / or basic groups such as e.g. Amino functions. Compounds of general formula 1 can therefore be used as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as Alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine, and the like. available.

Wie vorstehend genannt, können die Verbindungen der Formel 1 in ihre Salze, insbesondere für die pharmazeutische Anwendung, in ihre physiologisch und pharmakologisch verträglichen Salze überführt werden. Diese Salze können einerseits als physiologisch und pharmakologisch verträgliche Säureadditionssalze der Verbindungen der Formel 1 mit anorganischen oder organischen Säuren vorliegen. Andererseits kann die Verbindung der Formel 1 im Falle von R gleich Wasserstoff durch Umsetzung mit anorganischen Basen auch in physiologisch und pharmakologisch verträgliche Salze mit Alkali- oder Erdalkalimetallkationen als Gegenion überführt werden. Zur Darstellung der Säureadditionssalze kommen beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Fumarsäure, Bemsteinsäure, Milchsäure, Zitronensäure, Weinsäure oder Maleinsäure in Betracht. Ferner können Mischungen der vorgenannten Säuren eingesetzt werden. Zur Darstellung der Alkali- und Erdalkalimetallsalze der Verbindung der Formel 1 in der R Wasserstoff bedeutet, kommen vorzugsweise die Alkali- und Erdalkalihydroxide und -hydride in Betracht, wobei die Hydroxide und Hydride der Alkalimetalle, besonders des Natriums und Kaliums bevorzugt, Natrium- und Kaliumhydroxid besonders bevorzugt sind.As mentioned above, the compounds of formula 1 in their salts, in particular for the pharmaceutical application, in their physiological and be converted pharmacologically acceptable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula 1 with inorganic or organic acids. On the other hand, in the case of R equal to hydrogen by reaction with inorganic bases, the compound of formula 1 can also be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid come into consideration for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used. For the preparation of the alkali metal and alkaline earth metal salts of the compound of formula 1 in which R is hydrogen, the alkali metal and alkaline earth metal hydroxides and hydrides are preferably suitable, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium being preferred, sodium and potassium hydroxide are particularly preferred.

Gegebenenfalls können die Verbindungen der allgemeinen Formel (1 ) in ihre Salze, insbesondere für die pharmazeutische Anwendung, in ihre pharmakologisch unbedenklichen Säureadditionssalze mit einer anorganischen oder organischen Säure, überführt werden. Als Säuren kommen hierfür beispielsweise Bernsteinsäure, Bromwasserstoffsäure, Essigsäure, Fumarsäure, Maleinsäure, Methansulfonsäure,Optionally, the compounds of general formula (1) can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid. Examples of suitable acids are succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid,

Milchsäure, Phosphorsäure, Salzsäure, Schwefelsäure, Weinsäure oder Zitronensäure in Betracht. Ferner können Mischungen der vorgenannten Säuren eingesetzt werden.Lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid into consideration. Furthermore, mixtures of the abovementioned acids can be used.

Besonders bevorzugte erfindungsgemäße Salze sind ausgewählt aus der Gruppe bestehend aus Chlorid, Bromid, Jodid, Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrobenzoat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, und Hydro-p-toluolsulfonat, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate, Furoate, bevorzugt Chlorid, Bromid, Jodid, Hydrochlorid, Hydrobromid, Hydrosulfat, Hydrophosphat, Hydrofumarat, Hydroacetat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat. Hydro-p-toluolsulfonat und Hydromethansulfonat. Gegenstand der Erfindung sind die jeweiligen Verbindungen gegebenenfalls in Form der einzelnen optischen Isomeren, Mischungen der einzelnen Enantiomeren oder Racemate, in Form der Tautomere sowie in Form der freien Basen oder der entsprechenden Säureadditionssalze mit pharmakologisch unbedenklichen Säuren - wie beispielsweise Säureadditionssalze mit Halogenwasserstoffsäuren - beispielsweise Chlor- oder Bromwasserstoffsäure - oder organische Säuren - wie beispielsweise Oxal-, Fumar-, Diglycol- oder MethansulfonsäureParticularly preferred salts according to the invention are selected from the group consisting of chloride, bromide, iodide, hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, and hydroxycarboxylate. p-toluenesulfonate, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates, furoates, preferably chloride, bromide, iodide, hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate , Hydrobenzoate. Hydro-p-toluenesulfonate and hydromethanesulfonate. The invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid

Die erfindungsgemäßen Verbindungen können gegebenenfalls als Racemate vorliegen, sie können aber auch als reine Enantiomere, d.h. in (R)- oder (S)-Form gewonnen werden. Bevorzugt sind Verbindungen die als Racemate bzw. als (S)-Form vorliegen.The compounds of the invention may optionally be present as racemates, but may also be present as pure enantiomers, i. in (R) or (S) form. Preference is given to compounds which are present as racemates or as (S) -form.

Gegenstand der Erfindung sind die jeweiligen Verbindungen gegebenenfalls in Form der einzelnen optischen Isomeren, Mischungen der einzelnen Enantiomeren oder Racemate, in Form der Tautomere sowie in Form der freien Basen oder der entsprechenden Säureadditionssalze mit pharmakologisch unbedenklichen Säuren - wie beispielsweise Säureadditionssalze mit Halogenwasserstoffsäuren - beispielsweise Chlor- oder Bromwasserstoffsäure - oder organische Säuren - wie beispielsweise Oxal-, Fumar-, Diglycol- oder MethansulfonsäureThe invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid

Die nachstehenden Tabellen der Beispiele A und B fassen erfindungsgemäß dargestellte Verbindungen der Formel 1 zusammen.The following Tables of Examples A and B summarize represented compounds of formula 1 according to the invention.

BEISPIELE AEXAMPLES A

R1 R4 R 1 R 4

1. H H H Me CH2 1. HHH Me CH 2

# R1 R4 # R 1 R 4

R1 R 1

R1 R4 R 1 R 4

R1 R2 R3 R4 R5 R 1 R 2 R 3 R 4 R 5

33. H H H H Me CH2 33. HHHH Me CH 2

R1 R4 R 1 R 4

R1 R4 R 1 R 4

i H H H CONHCH2Ph CH2 i HH H CONHCH 2 Ph CH 2

j H H H CONHCH2Ph CH2 j HHH CONHCH 2 Ph CH 2

# R1 R4 # R 1 R 4

BEISPIELE B EXAMPLES B

R1 R4 R 1 R 4

R1 R4 R 1 R 4

43. H H H H CH2 43. HHHH CH 2

# R1 R4 # R 1 R 4

# R1 R4 # R 1 R 4

62. H H H CH2 R1 R4 62. HHH CH 2 R 1 R 4

BEISPIELECBEISPIELEC

R1 R4 R 1 R 4

BEISPIELE DEXAMPLES D

Weitere erfindungsgemäße Beispiele sind die folgenden:Further examples according to the invention are the following:

Beispiel 101 Example 101

Beispiel 102Example 102

Beispiel 103Example 103

Im folgenden ist das allgemeine Synthese-Schema 1 dargestellt, nach dem die erfindungsgemäßen Verbindungen nach Formel 1 (Coumaranone bzw. Indolinone) hergestellt werden können. Anstelle der im Schema 1 verwendeten Allyloxycarbonyl- Schutzgruppe für den Schutz der Aminofunktion können alternativ auch andere Schutzgruppen, vorzugsweise die tertiär-Butyioxycarbonyl-Schutzgruppe (BOC- Schutzgruppe) verwendet werden. The following is the general synthesis scheme 1, according to which the compounds according to the invention of formula 1 (coumaranone or indolinone) can be prepared. Instead of the allyloxycarbonyl protecting group used in Scheme 1 for protecting the amino function, other protecting groups, preferably the tertiary-butyioxycarbonyl (BOC) protecting group, may alternatively be used.

Synthese-Schema 1Synthesis Scheme 1

1 Kopplung der tBu-O-Schutzgruppe an die substituierte Benzoesäure1 Coupling of the tBu-O-protecting group to the substituted benzoic acid

tBuOH lntermediat A lntermediat BtBuOH Intermediate A Intermediate B

2 Kopplung der Allyloxycarbonyl-Schutzgruppe an lntermediat B2 Coupling of allyloxycarbonyl protecting group to intermediate B

lntermediat B Intermediate B

Chlorameisensaure- lntermediat C allylesterChloroformate-intermediate C allylester

3 Abspaltung der tBu-O-Schutzgruppe3 cleavage of the tBu-O-protecting group

lntermediat C lntermediat D Intermediate C Intermediate D

4 Kopplung des Intermediats D mit Coumaranon bzw Indohnon4 Coupling of Intermediate D with Coumaranon or Indohnon

1 + Tπethylamin lntermediat D lntermediat E + TBTU1 + trimethylamine intermediate D intermediate E + TBTU

2 + Me3O+ BF4 2 + Me 3 O + BF 4

+ Diisopropylethylamin 5. Kopplung des lntermediats E mit einem R3-substituierten Amin+ Diisopropylethylamine 5. Coupling of Intermediate E with an R 3 -substituted Amine

lntermediat F Intermediate F

6. Abspaltung der Allyloxycarbonyl-Schutzgruppe vom lntermediat F6. Cleavage of the allyloxycarbonyl protective group from the intermediate F

+ Palladium H-+ Palladium H-

lntermediat F Intermediate F

Endproduktend product

Ein Gegenstand der vorliegenden Erfindung sind weiterhin sämtliche Zwischenprodukte des Verfahrens nach Schema 1 , insbesondere die Zwischenprodukte nach den Formeln i, ii oder iiiAn object of the present invention are further all intermediates of the process according to Scheme 1, in particular the intermediates according to the formulas i, ii or iii

wobei X, A, R2 und R3 die oben genannten Bedeutungen haben und wobei PG (=protective group) Wasserstoff oder eine geeignete Schutzgruppe ist, vorzugsweise die Allyloxycarbonyl-Schutzgruppe oder die tertiär-Butyloxycarbonyl-Schutzgruppe.where X, A, R 2 and R 3 have the abovementioned meanings and where PG (= protective group) is hydrogen or a suitable protective group, preferably the allyloxycarbonyl protective group or the tertiary-butyloxycarbonyl protective group.

Im folgenden sind beispielhafte Synthesen zur Darstellung von Verbindungen der Formel 1 nach dem obigen Synthese-Schema 1 gezeigt. The following are exemplary syntheses for the preparation of compounds of formula 1 according to the above Synthetic Scheme 1 are shown.

BEISPIEL 40EXAMPLE 40

1. 3-([4-(1-AMINO-CYCLOPROPYL)-PHENYL]-^-(I -METHYL-1 H-IMIDAZ0L-4-YL)- PHENYLAMINO]-METHYLENJ-SH-BENZOFURAN^-ON (ENDPRODUKT)1. 3 - ([4- (1-AMINO-CYCLOPROPYL) -PHENYL] - ^ - (I-METHYL-1H-IMIDAZOL-4-YL) - PHENYLAMINO] -METHYLENE-SH-BENZOFURANE -ON (END PRODUCT)

1.1 4-(1-AMIN0-CYCL0PR0PYL)-BENZ0ESÄURE TERT-BUTYL ESTER (INTERMEDIAT B)1.1 4- (1-AMINO-CYCL0PR0PYL) -BENZOIC ACID TERT-BUTYL ESTER (INTERMEDIATE B)

50 ml einer 2 m Lithiumisopylat-Lösung in THF wurden unter Argon-Atmosphäre vorgelegt und 13,4 g wasserfreies Lthiumiodid dazu gegeben. Nach 15 min tropfte man 45 ml einer 1 M Methyltitanisopropoxid-Lösung in THF dazu. Danach versetzte man die Mischung mit50 ml of a 2 M lithium isopylate solution in THF were placed under argon atmosphere and added to 13.4 g of anhydrous Lthiumiodid to it. After 15 minutes, 45 ml of a 1 M methyltitanium isopropoxide solution in THF were added dropwise. Thereafter, the mixture was added

8.1 g 4-Cyanobenzoesäure-tert.butylester und rührte 10 min. Danach gab man innerhalb von 60 min 47,3 ml einer 15% igen Diethylzink-Lösung in Hexan hinzu und rührte bei RT 12 h. Nach Hydrolyse mit 20 ml Wasser wurde weitere 30 min gerührt, abfiltriert und 3x mit je 100 ml Ether gewaschen. Nach Extraktion der organischen Phase mit Wasser wurde mit Kieselgel eingeengt und die Substanz mit Dichlormethan/Methanol 98:2 bei 20 ml/min über Kieselgel 70 chromatographiert. Rückstand: 3 g Öl.8.1 g tert.butyl 4-cyanobenzoate and stirred for 10 min. 47.3 ml of a 15% strength diethylzinc solution in hexane were then added over the course of 60 minutes, and the mixture was stirred at RT for 12 hours. After hydrolysis with 20 ml of water was stirred for a further 30 min, filtered off and washed 3x with 100 ml of ether. After extraction of the organic phase with water was concentrated with silica gel and the substance with dichloromethane / methanol 98: 2 chromatographed through silica gel 70 at 20 ml / min. Residue: 3 g of oil.

1.2 4-(1 -ALLYLOXYCARBONYLAMINO-CYCLOPROPYL)-BENZOESAURE TERT- BUTYL ESTER (INTERMEDIAT C)1.2 4- (1-ALOXYCARBONYLAMINO-CYCLOPROPYL) -BENZOESAURE TERT-BUTYL ESTER (INTERMEDIATE C)

3 g 4-(1-Amino-cyclopropyl)-benzoesäure-tert.butylester wurden in 30 ml Dichlormethan und 1 ,8 ml Pyridin vorgelegt. Die Lösung wurde auf 00C abgekühlt und beo 0-5cC tropfenweisen mit 1 ,2 ml Chlorameisensäureallylester (in 5 ml Dichlormethan gelöst) versetzt. Man ließ 30 min bei 00C und 2 h bei RT nachreagieren. Die Lösung wurde mit Kieselgel versetzt und bis zum Rückstand eingeengt. Dieser wurde mit Dichlormethan über Kieselgel 70 chromatographiert. Ausbeute: 1 ,46 g Öl. 3 g of 4- (1-amino-cyclopropyl) benzoic acid tert-butyl ester were placed in 30 ml of dichloromethane and 1, 8 ml of pyridine. The solution was cooled to 0 ° C. and treated dropwise at 0 ° -5 ° C. with 1, 2 ml allyl chloroformate (dissolved in 5 ml dichloromethane). Was allowed for 30 min at 0 0 C and 2 hours at room temperature to react further. The solution was treated with silica gel and concentrated to dryness. This was chromatographed over silica gel 70 with dichloromethane. Yield: 1, 46 g of oil.

1.3 4-(1 -ALLYLOXYCARBONYLAMINO-CYCLOPROPYL)-BENZOESAURE1.3 4- (1-ALOXYCARBONYLAMINO-CYCLOPROPYL) -BENZOESAURE

Eine Lösung von 1 ,46 g 4-(1-Allyloxycarbonylamino-cyclopropyl)-benzoesäure- tert.butylester in 10 ml Acetonitril wurden mit 1 g Montmorillonit versetzt und 3 h unter Rückfluß erhitzt. Danach wurde nochmals Montmorillonit zugegeben und 4 h gekocht. Die Suspension wurde heiß filtriert, das anorganische Material 3x mit heißem Acetonitril ausgerührt und abfiltriert, die Acetonitrillösungen vereinigt und eingeengt. Rückstand: 0,8 g Kristalle.A solution of 1.46 g of tert-butyl 4- (1-allyloxycarbonylamino-cyclopropyl) benzoate in 10 ml of acetonitrile was admixed with 1 g of montmorillonite and refluxed for 3 hours. Thereafter, montmorillonite was again added and boiled for 4 h. The suspension was filtered hot, the inorganic material was stirred 3x with hot acetonitrile and filtered off, the acetonitrile solutions were combined and concentrated. Residue: 0.8 g of crystals.

1.4 (1 -(4-[HYDROXY^-OXO-BENZOFURAN-S-YLIDENE)-METHYL]-PHENYL)- CYCLOPROPYL)-CARBAMINSAURE ALLYL ESTER (INTERMEDIAT D)1.4 (1 - (4- [HYDROXY ^ -OXO-BENZOFURAN-S-YLIDENE) -METHYL] -PHENYL) - CYCLOPROPYL) -CARBAMINE SERUM ALLYL ESTER (INTERMEDIATE D)

0,8 g 4-(1-Allyloxycarbonylamιno-cyclopropyl)-benzoesaure und 0,585 ml Tπethylamin wurden in 10 ml wasserfreiem DMF gelost und mit 1 ,16 g TBTU versetzt, 15 min bei RT rühren gelassen, anschließend mit 0,4 g Coumaranon versetzt und weitere 10 min rühren gelassen Unter Eisbadkuhlung wurden portionsweise 0,42 g NaH als (60%ιge Suspension in Weißol) zugegeben, 2 h bei RT gerührt und nach Beendigung der Reaktion mit Wasser auf ca 150 ml Gesamtvolumen verdünnt Man säuerte mit 2 N Essigsaure an Die Kristalle wurden abgesaugt und mit Wasser gewaschen Ausbeute 1 ,1 g Feststoff vom Schmelzpunkt 125-1260C 0.8 g of 4- (1-Allyloxycarbonylamιno-cyclopropyl) benzoic acid and 0.585 ml Tπethylamin were dissolved in 10 ml of anhydrous DMF and treated with 1, 16 g TBTU, allowed to stir for 15 min at RT, then treated with 0.4 g coumaranone and stirring was continued for a further 10 minutes. Under ice cooling, 0.42 g of NaH (60% suspension in white oil) were added in portions, stirred at RT for 2 h and, after completion of the reaction, diluted with water to about 150 ml of total volume. Acetic acid was acidified with 2N to the crystals were filtered off with suction and washed with water yield 1, 1 g of solid of melting point 125-126 0 C.

1 5 (1-{4-[METHOXY-(2-OXO-BENZOFURAN-3-YLIDEN)-METHYL]-PHENYL}- CYCLOPROPYL)-CARBAMINSAURE ALLYL ESTER (INTERMEDIAT E)1 5 (1- {4- [METHOXY- (2-OXO-BENZOFURAN-3-YLIDEN) -METHYL] -PHENYL} - CYCLOPROPYL) -CARBAMINE SERUM ALLYL ESTER (INTERMEDIATE E)

1 g (1-{4-[Hydroxy-(2-oxo-benzofuran-3-ylιden)-methyl]-pheny!}-cyc!opropyl)- carbaminsaure-allylester, 0,78 g Tπmethyloxonium-tetrafluoroborat (Meerwein-Salz) und 1 ml Diisopropyl-ethylamin (Hunig-Base) wurden in 20 ml Dichlormethan 2 h unter Ruckfluss gekocht, erneut mit 1ml Hunig-Base und 0,5 g Meerweinsalz versetzt und nochmals 2 h unter Ruckfluss erhitzt Nach dem Abkühlen extrahierte man 3x mit Wasser, trocknete die organische Phase über MgSO4 und engte bis zum Ruckstand ein Ausbeute 1 ,05 g roh 1 g (1- {4- [hydroxy- (2-oxo-benzofuran-3-yl-enyl) -methyl] -phenyl} -cyclopropyl) -carbaminic acid allyl ester, 0.78 g of trimethyl-oxonium tetrafluoroborate (Meerwein salt ) and 1 ml of diisopropyl-ethylamine (Hunig base) were refluxed in 20 ml of dichloromethane for 2 h, treated again with 1 ml of Hunig base and 0.5 g of seaweed salt and heated under reflux for a further 2 h. After cooling, the mixture was extracted 3 times Water, the organic phase dried over MgSO 4 and concentrated to residue a yield 1, 05 g crude

1.6 (1 -(4-[[4-(1 -METHYL-I H-IMIDAZOL^- YL)-PHENYLAMIN0]-(2-0X0- BENZOFURAN-S-YLIDENE)-METHYL]-PHENYL)-CYCLOPROPYL)-CARBAMINSAURE ALLYL ESTER (INTERMEDIAT F)1.6 (1 - (4 - [[4- (1-METHYL-I H -imidazole-YL-PHENYLAMINEO] - (2-0X0-BENZOFURAN-S-YLIDENE) -METHYL] -PHENYL) -CYCLOPROPYL) -CARBAMINE SOW ALLYL ESTER (INTERMEDIATE F)

1 ,05 g (1-{4-[Methoxy-(2-oxo-benzofuran-3-yliden)-methyl]-phenyl}-cyclopropyl)- carbaminsäure-allylester und 0,47 g 4-(4-Amino-phenyl)-1-methyl-imidazol in 3 ml DMPU wurden im Mikrowellenreaktor bei 1800C zur Reaktion gebracht. Nach dem Abkühlen wurde mit Essigsäureethylester auf 150 ml verdünnt, 2x mit Wasser extrahiert, die organische Phase über MgSO4 getrocknet und mit Kieselgel bis zum Rückstand eingeengt. Die Substanz wurde mit Dichlormethan/Methanol 97:3 über Kieselgel 70 mit einer Flussgeschwindigkeit von 30 ml/min chromatographiert. Rückstand: 0,6 g gelbes öl.1.05 g of (1- {4- [methoxy- (2-oxo-benzofuran-3-ylidene) -methyl] -phenyl} -cyclopropyl) -carbamic acid allyl ester and 0.47 g of 4- (4-amino-phenyl ) -1-Methyl-imidazole in 3 ml of DMPU were reacted in a microwave reactor at 180 ° C. After cooling, the mixture was diluted to 150 ml with ethyl acetate, extracted twice with water, the organic phase was dried over MgSO 4 and concentrated to the residue with silica gel. The material was chromatographed on silica gel 70 with dichloromethane / methanol 97: 3 at a flow rate of 30 ml / min. Residue: 0.6 g of yellow oil.

1.7 3-{[4-(1 -AMINO-CYCLOPROPYL)-PHENYL]-^-(I -METHYL-1 H-IMIDAZOL-4-YL)- PHENYLAMINO]-METHYLEN}-3H-BENZOFURAN-2-ON (ENDPRODUKT)1.7 3 - {[4- (1-AMINO-CYCLOPROPYL) -PHENYL] - ^ - (I-METHYL-1 H-IMIDAZOLE-4-YL) - PHENYLAMINO] -METHYLENE} -3H-BENZOFURAN-2-ON (END PRODUCT )

0,58 g (1-{4-[[4-(1-Methyl-1 H-imidazol-4-yl)-phenylamino]-(2-oxo-benzofuran-3-yliden)- methylj-phenylj-cyclopropyO-carbaminsäure-allylester wurden in 20 ml Dichiormethan gelöst. Mit Argon wurde die Lösung von Sauerstoff befreit. Anschließend gab man bei RT 0,52 ml Diethylamin und 0,058 g Tetrakis-triphenylphosphin-palladium(O) hinzu. Bei RT wurde 2 h gerührt, die Suspension mit Kieselgel eingeengt und mit Dichlormethan / Methanol 97:3 über Kieselgel 70 mit einer Flussgeschwindigkeit von 30 ml/min chromato- graphiert. Die sauberen Fraktionen wurden vereinigt, bis zum Rückstand eingeengt, in Dichlormethan gelöst, filtriert und mit Diisopropylether versetzt. Das Dichlormethan wurde abdestilliert, die entstehenden Kristalle wurden abgesaugt und mit Diisopropylether gewaschen. Ausbeute: 0,26 g gelbe Kristalle vom Schmelzpunkt 190-191 °C als Base. Rr Wert: 0,51 (Dichlormethan/Methanol 9:1).0.58 g (1- {4 - [[4- (1-methyl-1 H -imidazol-4-yl) -phenylamino] - (2-oxo-benzofuran-3-ylidene) -methyl] -phenylj-cyclopropyl-O- Carbamic acid allyl esters were dissolved in 20 ml of dichloromethane, the solution was purged with argon, and then it was added at RT Add 0.52 ml of diethylamine and 0.058 g of tetrakis-triphenylphosphine-palladium (O). The mixture was stirred at RT for 2 h, the suspension was concentrated with silica gel and chromatographed on silica gel 70 with dichloromethane / methanol 97: 3 at a flow rate of 30 ml / min. The clean fractions were combined, concentrated to dryness, dissolved in dichloromethane, filtered and treated with diisopropyl ether. The dichloromethane was distilled off, the resulting crystals were filtered off with suction and washed with diisopropyl ether. Yield: 0.26 g of yellow crystals of melting point 190-191 ° C as the base. R r value: 0.51 (dichloromethane / methanol 9: 1).

Analog zu Synthese-Schema 1 bzw. zu Bsp. 40 wurden folgende Verbindungen hergestellt:Analogously to synthesis scheme 1 or to example 40, the following compounds were prepared:

Beispiel Salzform Schmelzpunkt (0C)Example salt form melting point ( 0 C)

60 x HCl > 25060x HCl> 250

61 x HCl 185-18761x HCl 185-187

64 x HCl 261-26264x HCl 261-262

65 x HCl 210-21165x HCl 210-211

67 x HCl 254-25567x HCl 254-255

74 x HCl 290-29174 x HCl 290-291

75 x HCl 285-28675x HCl 285-286

77 x HCl 275-27677x HCl 275-276

78 x HCl 214-21678x HCl 214-216

37k x HCl 263-26537k x HCl 263-265

37m x HCl > 27037mx HCl> 270

68 x HCl 286-287 Zers.68 x HCl 286-287 calc.

97 x HC! 234-23597 x HC! 234-235

102 Base 196-197102 base 196-197

In Schema 2 ist das Herstellungsverfahren zur Synthese der Verbindung nach Bsp. 47 dargestellt. Analog dieses Herstellungsverfahrens nach Schema 2 lassen sich auch die meisten erfindungsgemäßen Verbindungen nach Formel 1 (Coumaranone bzw. Indolinone) herstellen, insbesondere die auf den folgenden Seiten genannten erfindungsgemäßen Verbindungen. In Scheme 2, the preparation process for the synthesis of the compound according to Ex. 47 is shown. Analogously to this preparation process according to Scheme 2, it is also possible to prepare most of the compounds according to the invention of formula 1 (coumaranones or indolinones), in particular the compounds according to the invention mentioned on the following pages.

käuflich erhältlich commercially available

Ein weiterer Gegenstand der vorliegenden Erfindung sind sämtliche Zwischenprodukte des Verfahrens nach Schema 2, insbesondere die Zwischenprodukte nach den Formeln II, III, IV oder VAnother object of the present invention are all intermediates of the process according to Scheme 2, in particular the intermediates of the formulas II, III, IV or V

worin G NO2 oder NH2 bedeutet und worin X und R3 die oben genannten Bedeutungen haben.wherein G is NO 2 or NH 2 and wherein X and R 3 have the meanings given above.

Im folgenden sind beispielhaft Synthesen einiger Beispiel-Verbindungen beschrieben, die im wesentlichen analog zum obigen Synthese Schema 2 verlaufen.The following are exemplary syntheses of some example compounds described which proceed essentially analogously to the above synthesis Scheme 2.

BEISPIEL 36EXAMPLE 36

2. 3-{(4-AMINOMETHYL-PHENYL)-[4-(1 -METH YL-1H-IMIDAZOL-4- YL)- PHENYLAMINO]-METHYLEN}-1-METHYL-1 ,3-DIHYDRO-INDOL-2-ON2. 3 - {(4-AMINOMETHYL-PHENYL) - [4- (1-METHYL-1H-IMIDAZOLE-4-YL) - PHENYLAMINO] -METHYLENE} -1-METHYL-1,3-DIHYDRO-INDOL-2 -ON

Ausgehend von 4-Cyano-benzoesäure verlief die Synthese analog Beispiel 40. Lediglich die letzte Stufe unterschied sich wie folgt. 6,15 g 3-{(4-Cyano-phenyl)-[4-(1-methyl-1 H- imidazol-4-yl)-phenylamino]-nnethylen}-1-methyl-1 ,3-dihydro-indol-2-on wurden in je 200 ml methanolischem Ammoniak und Tetrahydrofuran gelöst und mit 5 g Raney-Nickel bei RT und einem Druck von 50 psi hydriert. Nach etwa 10 h wurde der Katalysator abgesaugt und das Filtrat erneut über ein Glasfilter filtriert, eingeengt und der kristalline Rückstand mit Diisopropylether abgesaugt. Die Kristalle wurden in 400 ml Methanol suspendiert, mit 10%iger ethanolischer Salzsäure auf pH 1 gestellt und auf Siedetemperatur erhitzt. Man filtrierte ab, engte das Filtrat bis auf ca. 100 ml Restvolumen ein und versetzte mit 300 ml Ethanol. Nach erneutem Einengen auf ca. 100 ml Restvolumen kristallisierte die Substanz aus. Nach dem Abkühlen wurde sie abgesuagt und mit eiskaltem Ethanol gewaschen. Ausbeute: 6,15 gelbe Kristalle vom Schmelzpunkt > 3000C. RrWert = 0,32 (Dichlormethan/Methanol/Ammoniak 85:15:1).Starting from 4-cyano-benzoic acid, the synthesis proceeded as in Example 40. Only the last stage differed as follows. 6.15 g of 3 - {(4-cyano-phenyl) - [4- (1-methyl-1 H- Imidazol-4-yl) -phenylamino] -nnethylen} -1-methyl-1, 3-dihydro-indol-2-one were dissolved in 200 ml of methanolic ammonia and tetrahydrofuran and with 5 g of Raney nickel at RT and a pressure hydrogenated at 50 psi. After about 10 hours, the catalyst was filtered off with suction and the filtrate filtered again through a glass filter, concentrated and the crystalline residue was filtered off with diisopropyl ether. The crystals were suspended in 400 ml of methanol, adjusted to pH 1 with 10% strength ethanolic hydrochloric acid and heated to boiling temperature. It was filtered off, the filtrate was concentrated to about 100 ml residual volume and mixed with 300 ml of ethanol. After renewed concentration to about 100 ml residual volume, the substance crystallized out. After cooling, it was sloughed off and washed with ice-cold ethanol. Yield: 6.15 yellow crystals of melting point> 300 0 C. R f value = 0.32 (dichloromethane / methanol / ammonia 85: 15: 1).

Analog wurden hergestellt:Analog were produced:

Beispiel Salzform SchmelzpunkExample salt form melting point

1 Base1 base

2 x TFA 0,38 (CH2CI2/CH3OH/NH3 9:1 :0,1)2 x TFA 0.38 (CH 2 Cl 2 / CH 3 OH / NH 3 9: 1: 0.1)

3 x TFA 0,5 (CH2CI2/CH3OH/NH3 4:1 :0,1)3 x TFA 0.5 (CH 2 Cl 2 / CH 3 OH / NH 3 4: 1: 0.1)

4 Base 0,34 (CH2CI2/CH3OH/NH3 9:1 :0,1)4 base 0.34 (CH 2 Cl 2 / CH 3 OH / NH 3 9: 1: 0.1)

5 x TFA 0,25 (CHzCIa/CHaOH/NHa 4:1:0,1)5 x TFA 0.25 (CHzCla / CHaOH / NHa 4: 1: 0.1)

6 Base 0,27 (CH2CI2/CH3OH/NH3 9:1 :0,1)6 base 0.27 (CH 2 Cl 2 / CH 3 OH / NH 3 9: 1: 0.1)

7 Base 0,54 (CH2CI2/CH3OH/NH3 4:1 :0,1)7 base 0.54 (CH 2 Cl 2 / CH 3 OH / NH 3 4: 1: 0.1)

8 Base 0,33 (CH2CI2/CH3OH/NH3 9:1 :0,1)8 base 0.33 (CH 2 Cl 2 / CH 3 OH / NH 3 9: 1: 0.1)

9 Base 0,21 (CH2CI2/CH3OH/NH3 9:1 :0,1)9 base 0.21 (CH 2 Cl 2 / CH 3 OH / NH 3 9: 1: 0.1)

10 x HCl 294 Zers.10 x HCl 294 dec.

1 1 Base 0,27 (CH2CI2/CH3OH/NH3 9:1 :0,1 )1 1 base 0.27 (CH 2 Cl 2 / CH 3 OH / NH 3 9: 1: 0.1)

12 x HCl 27212x HCl 272

13 x HCl > 25013x HCl> 250

15 x HCl 27815x HCl 278

16 x HCl 214-215 Zers16 x HCl 214-215 calc

17 x HCl > 245 Zers.17x HCl> 245 dec.

18 Base 225 Zers.18 base 225 dec.

19 x HCl 295-29619x HCl 295-296

20 x HCl 265-26720x HCl 265-267

21 x HCl 274-275 22 x HCl 259-260 Zers.21x HCl 274-275 22x HCl 259-260 calc.

23 X HCl 281 Zers.23 X HCl 281 calc.

24 x HCl 245-246 Zers.24 x HCl 245-246 calc.

26 x HCl > 260 Zers.26 x HCl> 260 dec.

27 Base 230-23227 base 230-232

28 Base 153-15528 base 153-155

29 Base 168-17129 Base 168-171

30 Base 233-23830 base 233-238

31 Base 194-19731 base 194-197

32 x HCl 210-21232x HCl 210-212

33 Base 157-15933 base 157-159

34 Base 22934 base 229

35 Base 22835 base 228

36 Base 214-21736 base 214-217

37a Base 204-20637a Base 204-206

37b Base 214-21637b Base 214-216

37c Base 186-18837c base 186-188

37d Base 227-22937d base 227-229

37e Base 263-26537e Base 263-265

37f Base 198-20037f Base 198-200

37g x HCl 255-25637g x HCl 255-256

37h x HCl 28437h x HCl 284

37i x HCl 251-25237i x HCl 251-252

37j x HCl 226-22737j x HCl 226-227

37I Base 172-17337I Base 172-173

37n x HCl 195-19837n x HCl 195-198

37o x HCl 297-29837o x HCl 297-298

39 x HCl > 29039x HCl> 290

41 Base 167-16941 base 167-169

42 Base 201-20342 base 201-203

43 x HCl 95-97 Zers.43x HCl 95-97 dec.

44 Base 222-22444 base 222-224

45 Base 208-21045 base 208-210

46 Base 186-188 47 x HCl 27446 base 186-188 47x HCl 274

48 x HCl 186-18848x HCl 186-188

49 Base 171-17349 base 171-173

50 Base 164-16650 base 164-166

51 Base 177-17951 base 177-179

52 x HCl 232-23352x HCl 232-233

53 x HCl > 28553x HCl> 285

54 x HCl 245-24754x HCl 245-247

55 Base 149-15155 base 149-151

57 Base 161-16457 base 161-164

58 Base 168-17258 base 168-172

59 Base 153-15659 base 153-156

62 x HCl 285-28662x HCl 285-286

63 x HCl 289-29063x HCl 289-290

66 Base 215-21766 base 215-217

69 Base 204-20569 Base 204-205

70 x HCl 285-28670x HCl 285-286

71 x HCl > 29071 x HCl> 290

72 x HCl 28972x HCl 289

73 Base 163-16673 Base 163-166

76 x HCl 28876x HCl 288

79 Base 182-18479 base 182-184

80 Base 135-13780 base 135-137

81 x HCl 294-29581x HCl 294-295

82 x HCl 254-25582x HCl 254-255

83 x HCl > 27583x HCl> 275

84 x HCl 215-22084 x HCl 215-220

85 Base 135-13785 base 135-137

86 x HCl 20786 x HCl 207

87 x HCl 253-25487x HCl 253-254

88 x HCl > 29088 x HCl> 290

89 x HCl > 27089 x HCl> 270

90 x HCl 85-88 (amorph?) 91 x HCl 283-28490x HCl 85-88 (amorphous?) 91x HCl 283-284

92 x TFA amorph92 x TFA amorphous

93 Base 161-16293 base 161-162

94 x HCl 271-27294x HCl 271-272

95 x HCl 18895x HCl 188

96 x HCl 268-26996x HCl 268-269

98 x HCl 241 Zersetzung98 x HCl 241 decomposition

99 x HCl 19699 x HCl 196

100 - 140100 - 140

101 x HCl 253-254101x HCl 253-254

103 x TFA amorph103 x TFA amorphous

Beispiel # m+H Rf-Wert Retentionszeit [miniExample # m + H Rf value Retention time [mini

104 0,5104 0.5

105 380105,380

106 0,5106 0.5

107 0,4 108 0,5107 0.4 108 0.5

109 0,2109 0.2

110 0,4110 0.4

111 0,5111 0.5

112 0,3 113 352112 0.3 113 352

114 0,3114 0.3

115 0,6115 0.6

116 0,4116 0.4

117 0,4 118 0,2117 0.4 118 0.2

119 0,3119 0.3

120 0,3120 0.3

121 0,3121 0.3

122 1,7 123 0,6 124 539 125 0,2122 1.7 123 0.6 124 539 125 0.2

METHODE FÜR DIE DÜNNSCHICHTCHROMATOGRAPHIE ZUR BESTIMMUNG DER RF-WERTE:METHOD FOR THIN-LAYER CHROMATOGRAPHY FOR DETERMINING THE RF VALUES:

Als Festphase wurde Kieselgel 60 F254 (Hersteller: Firma Merck) und als Flüssigphase - soweit nicht anders angegeben - eine 9 : 1 : 0,1 - Mischung von Dichlormethan: Methanol: Ammoniak eingesetzt.The solid phase used was silica gel 60 F254 (manufacturer: Merck) and, as liquid phase, unless otherwise stated, a 9: 1: 0.1 mixture of dichloromethane: methanol: ammonia.

Methode Chromolith:Method Chromolith:

HPLC-MS-1 Waters ZMD, Alliance 2690/2695 HPLC, Waters 2700 Autosampier, Waters 996/2996 DiodenarraydetektorHPLC-MS-1 Waters ZMD, Alliance 2690/2695 HPLC, Waters 2700 Autosampler, Waters 996/2996 diode array detector

Als mobile Phase wurde eingesetzt: A: Wasser mit 0.10% TFA B: Acetonitril mit 0.10% TFAThe mobile phase used was: A: water with 0.10% TFA B: acetonitrile with 0.10% TFA

Zeit in min %A %B Flussrate in ml/minTime in min% A% B Flow rate in ml / min

0.00 95 5 2.000.00 95 5 2.00

0.10 95 5 2.000.10 95 5 2.00

2.10 2 98 2.002.10 2 98 2.00

3.00 2 98 2.003.00 2 98 2.00

3.25 95 5 2.003.25 95 5 2.00

Als stationäre Phase diente eine Säule Merck Chromolith™ SpeedROD RP-18e, 4.6 mm x 50 mm (Säulentemperatur: konstant bei 250C). Die Diodenarraydetektion erfolgte im Wellenlängenbereich 210-400 nm.The stationary phase used was a column of Merck Chromolith ™ SpeedROD RP-18e, 4.6 mm x 50 mm (column temperature: constant at 25 0 C). The diode array detection took place in the wavelength range 210-400 nm.

Beispiel 14Example 14

3. 4-[[4-(1-METHYL-1 H-IMIDAZOL-4-YL)-PHENYLAMINO]-(2-OXO-1-PHENYL-1 ,2- DIHYDRO-INDOL-3- YLIDEN)-METHYL]-BENZAMIDIN3. 4 - [[4- (1-METHYL-1H-IMIDAZOLE-4-YL) -HENYLAMINO] - (2-OXO-1-PHENYL-1, 2-DIHYDRO-INDOL-3-YLIDENE) METHYL] benzamidine

Ausgehend von 4-Cyano-benzoesäure verlief die Synthese analog Beispiel 40. Lediglich die letzte Stufe unterschied sich wie folgt. 0,6 g 3-{(4-Cyano-phenyl)-[4-(1-methyl-1H- imidazol-4-yl)-phenylamino]-methylen}-1-phenyl-1 ,3-dihydro-indol-2-on wurden in 20 ml Dichlormethan und 30 ml 40%iger ethanolischer Salzsäure gelöst und im Kühlschrank 12 h aufbewahrt. Die Lösung wurde bis zum Rückstand eingeengt, mit 50 ml 6 N ethanolischer Ammoniaklösung versetzt und 3 h unter Rückfluss gekocht. Die Lösung wurde mit Kieselgel eingeengt und chromatographisch mit Dichlormethan/Methanol 8:2 über Kieselgel 70 (Flussrate 20 ml/min) gereinigt. Die sauberen Fraktionen wurden eingeengt und die Kristalle mit Aceton abgesaugt und gewaschen. Ausbeute: 0,2 g gelbe Kristalle vom Schmelzpunkt 241 °C (Zers.). Analog wurde Beispiel 25 hergestellt (Schmelzpunkt 230-2320C als Hydrochlorid), ebenso Beispiel 38 (Schmelzpunkt > 275°C unter Zers. als Hydrochlorid).Starting from 4-cyano-benzoic acid, the synthesis proceeded as in Example 40. Only the last stage differed as follows. 0.6 g of 3 - {(4-cyano-phenyl) - [4- (1-methyl-1H-imidazol-4-yl) -phenyl-amino] -methylene} -1-phenyl-1,3-dihydro-indole 2-on were dissolved in 20 ml of dichloromethane and 30 ml of 40% ethanolic hydrochloric acid and stored in the refrigerator for 12 hours. The solution was concentrated to the residue, treated with 50 ml of 6 N ethanolic ammonia solution and boiled under reflux for 3 h. The solution was concentrated with silica gel and purified by chromatography with dichloromethane / methanol 8: 2 on silica gel 70 (flow rate 20 ml / min). The clean fractions were concentrated and the crystals were filtered off with suction and washed with acetone. Yield: 0.2 g of yellow crystals of melting point 241 ° C (dec.). Analogously to Example 25 was produced (melting point 230-232 0 C as hydrochloride), as well as Example 38 (mp> 275 ° C dec., As the hydrochloride).

BEISPIEL 56EXAMPLE 56

4. 3-{[4-(1 -AMINO-1 -METHYL-ETHYL)-PHENYL]-[4-(1 -METHYL- 1 H-I M I DAZO L-4- YL)-PHENYLAMINO]-METHYLEN}-3H-BENZOFURAN-2-ON4. 3 - {[4- (1 -AMINO-1-METHYL-ETHYL) -PHENYL] - [4- (1-METHYL-1 HI-MI-DAZO L-4-YL) -PHENYLAMINO] -METHYLENE-3H- bENZOFURAN-2-ONE

4.1 1-[4-(4,4-DIMETHYL-4,5-DIHYDRO-OXAZOL-2-YL)-PHENYL]-1 -METHYL- ETHYLAMIN4.1 1- [4- (4,4-DIMETHYL-4,5-DIHYDRO-OXAZOLE-2-YL) PHENYL] -1-METHYL ETHYLAMINE

130 g wasserfreies Cer(lll)-chlohd wurden in 1 I THF suspendiert und 1 h gerührt, unter gutem mechanischen Rühren auf -6O0C abgekühlt und tropfenweise mit 330 ml einer 1 ,5 M Methyllithium-Lösung in THF/Cumol versetzt, wobei die Innentemperatur nicht -5O0C überstieg. Die gelbe Suspension wurde 30 min nachgerührt und bei -500C mit einer Lösung von 34,4 g 2-(4-Cyanophenyl)-4,4-dimethyl-4,5-dihydro-oxazol in 50 ml THF versetzt. Nach weiteren 12 h bei -55°C wurde tropfenweise 330 ml konz. Ammoniaklösung hinzugegeben, wobei ein violetter Niederschlag ausfiel. Man ließ auf RT erwärmen, filtirerte und wusch den Rückstand mit 1 I THF. Die organische Phase wurde eingeengt. Der gelbe ölige Rückstand wurde chromatographisch gereinigt (Dichlormethan/Methanol 9:1 , Kieselgel 70, Flussgeschwindigkeit 50 ml/min). Die sauberen Fraktionen ergaben 33,3 g gelbes Öl mit dem RrWert 0,20 (Dichlormethan/Methanol 7:3). 4.2 (1 -[4-(4,4-DIMETHYLAS-DIHYDRO-OXAZOL^-YL)-PHENYL]-I-METHYL- ETHYL}-CARBAMINSÄURE TERT-BUTYL ESTER130 g of anhydrous cerium (III) -chlohd were suspended in 1 I THF and stirred for 1 h, cooled to -6O 0 C with good mechanical stirring and treated dropwise with 330 ml of a 1, 5 M methyl lithium solution in THF / cumene, the internal temperature did not exceed -50 0 C The yellow suspension was stirred for 30 min and treated at -50 0 C with a solution of 34.4 g of 2- (4-cyanophenyl) -4,4-dimethyl-4,5-dihydro-oxazole in 50 ml of THF. After a further 12 h at -55 ° C was added dropwise 330 ml of conc. Ammonia solution added, whereby a violet precipitate precipitated. The mixture was allowed to warm to RT, filtered and washed the residue with 1 l THF. The organic phase was concentrated. The yellow oily residue was purified by chromatography (dichloromethane / methanol 9: 1, silica gel 70, flow rate 50 ml / min). The clean fractions gave 33.3 g of yellow oil with the R r value 0.20 (dichloromethane / methanol 7: 3). 4.2 (1 - [4- (4,4-DIMETHYLAS-DIHYDRO-OXAZOLE-YL) -PHENYL] -I-METHYL-ETHYL} -CARBAMINIC ACID TERT-BUTYL ESTER

Zu einer Lösung von 0,8 g 1-[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-1-methyl- ethylamin in 15 ml Dioxan gab man eine Lösung von 0,4 g Natriumcarbonat in 4 ml Wasser. Anschließend wurde innerhalb von 10 min eine Lösung von 0,83 g Boc-anhydrid in Dioxan zugetropft. Die gelbe Lösung wurde 12 h bei RT gerührt. Das Dioxan wurde abdestilliert und der wässrige Rückstand 2x mit Essigester extrahiert. Die organischen Phasen wurden vereinigt, über MgSO4 getrocknet, filtriert und bis zum Rückstand eingeengt. Nach Kristallisation erhielt man 0,87 g weiß-gelbes Produkt.To a solution of 0.8 g of 1- [4- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -phenyl] -1-methyl-ethylamine in 15 ml of dioxane was added a solution of 0.4 g of sodium carbonate in 4 ml of water. Subsequently, a solution of 0.83 g Boc anhydride in dioxane was added dropwise within 10 min. The yellow solution was stirred at RT for 12 h. The dioxane was distilled off and the aqueous residue extracted 2x with ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered and concentrated to dryness. After crystallization, 0.87 g of white-yellow product was obtained.

4.3 4-(1-TERT-BUTOXYCARBONYLAMINO-1 -METHYL-ETHYL)-BENZOESAURE4.3 4- (1-TERT-BUTOXYCARBONYLAMINO-1-METHYL-ETHYL) -BENZOESAURE

Eine Lösung von 0,83 g {1-[4-(4,4-Dimethyl-4,5~dihydro-oxazol-2-yl)-phenyl]-1-methyl- ethyl}-carbaminsäure-tert-butylester und 3,1 ml Methyliodid in 2 ml DMF wurden im Druckröhrchen 12 h bei 600C gerührt und nach dem Abkühlen bis zum Rückstand eingeengt. Das Öl wurde mit 15 ml 1 M NaOH 3h bei RT gerührt. Die Suspension wurde mit Ether ausgeschüttelt. Die wässrige Phase wurde mit 1 M HCl auf pH 2 angesäuert und der ausgefallene Niederschlag in Ether aufgenommen. Nach erneutem 2-maligem Ausschütteln der wässrigen Phase mit Ether wurden die organischen Phasen vereinigt, über MgSO4 getrocknet, filtriert und das Filtrat bis zum Rückstand eingeengt. Ausbeute: 0,4 g Kristalle vom RrWert 0,41 (Dichlormethan/Methanol 9:1 ).A solution of 0.83 g of tert-butyl {1- [4- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -phenyl] -1-methyl-ethyl} -carbamate and 3 , 1 ml of methyl iodide in 2 ml of DMF were stirred in a pressure tube for 12 h at 60 0 C and concentrated after cooling to the residue. The oil was stirred with 15 ml of 1 M NaOH for 3 h at RT. The suspension was shaken out with ether. The aqueous phase was acidified to pH 2 with 1 M HCl and the precipitate precipitated was taken up in ether. After again shaking the aqueous phase twice with ether, the organic phases were combined, dried over MgSO 4 , filtered and the filtrate was concentrated to dryness. Yield: 0.4 g of crystals of R r value 0.41 (dichloromethane / methanol 9: 1).

Analog der oben beschriebenen Synthese von Beispiel 40 wurde fortgefahren bis zur Abspaltung der Boc-Schutzgruppe. 4.4 3-([4-(1-AMINO-I-METHYL-ETHYL)-PHENYL]-K-(I-METHYL-I H-IMIDAZOL^- YL)-PHENYLAMINO]-METHYLEN}-3H-BENZOFURAN-2-ONThe synthesis of Example 40 described above was continued until the Boc protective group was removed. 4.4 3 - ([4- (1-AMINO-1-METHYL-ETHYL) -HENYL] -K- (1-METHYL-1H-IMIDAZOILY-YL) -PHENYLAMINO] -METHYLENE-3H-BENZOFURAN-2 ON

2,5 g (1-Methyl-1-{4-[[4-(1-methyl-1H-imidazol-4-yl)-phenylamino]-(2-oxo-benzofuran-3- yliden)-methyl]-phenyl}ethyl)-carbaminsäure-tert-butylester (N-Boc-Derivat von Beispiel 56) wurden in 50 ml Dioxan gelöst und mit 50 ml einer 4 N Lösung von Chlorwasserstoff in Dioxan versetzt. Die Lösung wurde 1 h bei RT gerührt und eingeengt. Der Rückstand wurde in 50 ml Methanol gelöst und mit weiteren 150 ml Isopropanol bis fast zum Rückstand eingeengt und kristallisiert. Nach Verdünnen mit Aceton wurde abgesaugt und mit Aceton gewaschen. Ausbeute: 1 ,9 g gelbe Kristalle vom Schmelzpunkt >280°C als Hydrochlorid. RrWert: 0,18 (Dichlormethan/Methanol 8:2).2.5 g (1-methyl-1- {4 - [[4- (1-methyl-1 H -imidazol-4-yl) -phenylamino] - (2-oxo-benzofuran-3-ylidene) -methyl] - tert-butyl phenyl} ethylcarbamates (N-Boc derivative of Example 56) were dissolved in 50 ml of dioxane and 50 ml of a 4N solution of hydrogen chloride in dioxane were added. The solution was stirred at RT for 1 h and concentrated. The residue was dissolved in 50 ml of methanol and concentrated with further 150 ml of isopropanol to almost the residue and crystallized. After dilution with acetone, the product was filtered off with suction and washed with acetone. Yield: 1.9 g of yellow crystals of melting point> 280 ° C. as hydrochloride. R r value: 0.18 (dichloromethane / methanol 8: 2).

Die oben genannten Bausteine zur Synthese sind in der Literatur bekannt, kommerziell erhältlich oder wurden wie folgt dargestellt:The above-mentioned building blocks for synthesis are known in the literature, are commercially available or have been prepared as follows:

BAUSTEIN 1MODULE 1

26,3 g 2-Brom-phenylessigsäure wurden in 200 ml Dichlormethan gelöst und mit 15 ml Oxalylchlorid und einem Tropfen DMF versetzt. Nach 1 h bei RT wurde die Lösung eingeengt und das Säurechlorid direkt weiterverwendet. Das Säurechlorid wurde in 40 ml Dichlormethan gelöst und zu einer Lösung von 9 g Cyclobutylamin und 27 ml Diisopropylethylamin in Dichlormethan bei 15-2O0C zugetropft. Nach 12 h bei RT wurde das Dichlormethan abdestilliert, der Rückstand in 600 ml Essigester gelöst und 2x mit 4 N HCl, 2x mit 4 N NaOH und 3x mit Wasser extrahiert. Die organische Phase wurde über MgSO4 getrocknet, filtriert und bis zum kristallinen Rückstand eingeengt. Nach Zugabe von Diisopropylether saugte man ab und erhielt 24,1 g 2-Brom-phenylessigsäure- cyclobutylamid vom Schmelzpunkt 159-1610C. RrWert: 0,67 (Dichlormethan/Methanol 9:1 ).26.3 g of 2-bromo-phenylacetic acid were dissolved in 200 ml of dichloromethane and mixed with 15 ml of oxalyl chloride and one drop of DMF. After 1 h at RT, the solution was concentrated and the acid chloride used directly. The acid chloride was dissolved in 40 ml Dissolved dichloromethane and added dropwise to a solution of 9 g of cyclobutylamine and 27 ml of diisopropylethylamine in dichloromethane at 15-2O 0 C. After 12 h at RT, the dichloromethane was distilled off, the residue was dissolved in 600 ml of ethyl acetate and extracted 2x with 4 N HCl, 2x with 4 N NaOH and 3x with water. The organic phase was dried over MgSO 4 , filtered and concentrated to the crystalline residue. After addition of diisopropyl ether, filtered off with suction and obtained 24.1 g of 2-bromo-phenylacetic acid cyclobutylamide of melting point 159-161 0 C. R r value: 0.67 (dichloromethane / methanol 9: 1).

400 ml Toluol wurden mit Argon entgast und danach 13,4 g 2-Brom-phenylessigsäure- cyclobutylamid, 9,7 g gepulvertes K2CO3, 0,9 g Tris(dibenzylidenaceton)dipalladium(0) und 1 ,2 g Tri-o-tolylphosphin hinzugegeben. Nach 72 Rühren bei 100°C und Abkühlen wurde mit Diethylether auf 2 I verdünnt, vom Unlöslichen abfiltriert und bis zum Rückstand eingeengt. Nach Kristallisieren in Diisopropylether wurde abgesaugt und das Filtrat mit Kieselgel bis zum Rückstand eingeengt. Die Reinigung erfolgte durch Chromatographie über Kieselgel 60 (Laufmittel Dichlormethan). Ausbeute: 3,75 g Öl vom RrWert: 0,18 (Dichlormethan).400 ml of toluene were degassed with argon, followed by 13.4 g of 2-bromo-phenylacetic acid cyclobutylamide, 9.7 g of powdered K 2 CO 3 , 0.9 g of tris (dibenzylideneacetone) dipalladium (0) and 1.2 g of triethylamine. Added o-tolylphosphine. After 72 hours of stirring at 100 ° C and cooling was diluted with diethyl ether to 2 l, filtered from the insolubles and concentrated to the residue. After crystallization in diisopropyl ether was filtered off and the filtrate was concentrated with silica gel to residue. The purification was carried out by chromatography on silica gel 60 (mobile phase dichloromethane). Yield: 3.75 g of R r oil. Value: 0.18 (dichloromethane).

BAUSTEIN 2MODULE 2

100 g p-Nitro-phenacylbromid und 400 ml Formamid wurden 2 h bei 175°C gerührt. Nach dem Abkühlen wurde die Mischung mit 20 ml Ammoniak alkalisch gestellt, in 800 ml Wasser verrührt und der Niederschlag abgesaugt. Die Kristalle wurden in Methanol umkristallisiert und abgesaugt. Ausbeute: 46,5 g vom Schmelzpunkt 217-219°C.100 g of p-nitro-phenacyl bromide and 400 ml of formamide were stirred at 175 ° C for 2 h. After cooling, the mixture was made alkaline with 20 ml of ammonia, in 800 ml Stirred water and the precipitate sucked off. The crystals were recrystallized in methanol and filtered with suction. Yield: 46.5 g of melting point 217-219 ° C.

45 g 1 H-4-(4-Nitro-phenyl)-imidazol wurden in 300 ml DMSO vorgelegt und unter Eiskühlung 30 g Kalium-tert.butylat portionsweise zugegeben. Das Gemisch wurde auf RT erwärmt und 1 h nachgerührt. Anschließend wurden 16,5 ml Methyliodidzwischen 20-250C zugetropft und weitere 2 h bei RT gerührt. Anschließend wurde das Gemisch auf 300 g Eis gegossen, verrührt, der ausgefallene Niederschlag abgesaugt und gründlich mit Wasser gewaschen. Ausbeute: 39,8 g.45 g of 1 H-4- (4-nitro-phenyl) -imidazole were initially charged in 300 ml of DMSO and, while cooling with ice, 30 g of potassium tert-butylate were added in portions. The mixture was warmed to RT and stirred for 1 h. Subsequently, 16.5 ml of methyl iodide were added dropwise between 20-25 0 C and stirred for a further 2 h at RT. The mixture was then poured into 300 g of ice, stirred, the precipitate was filtered off with suction and washed thoroughly with water. Yield: 39.8 g.

22 g 1-Methyl-4-(4-nitro-phenyl)-imidazol wurden in 1 ,6 I Methanol gelöst und mit 4 g Pd/C (10 %) vesetzt. Die Mischung wurde bei 50 psi und RT ca. 5 h hydriert. Danach wurde ein weiteres Gramm Katalysator zugegeben und 18 hydriert, danach mit weiteren 2 g Katalysatorzugabe weitere 12 h. Schließlich wurde der Katalysator abgesaugt und das Filtrat eingeengt. Man nahm den Rückstand in Toluol und etwas Methanol auf, engte etwas ein bis ein dunkelgrauer Niederschlag entstand. Dieser wurde abgesaugt, in22 g of 1-methyl-4- (4-nitro-phenyl) -imidazole were dissolved in 1.6 l of methanol and used with 4 g of Pd / C (10%). The mixture was hydrogenated at 50 psi and RT for about 5 hours. Thereafter, another gram of catalyst was added and 18 hydrogenated, then with a further 2 g of catalyst addition for another 12 h. Finally, the catalyst was filtered off with suction and the filtrate was concentrated. The residue was taken up in toluene and a little methanol, a little concentrated until a dark gray precipitate formed. This was sucked off, in

Methanol aufgenommen, mit 4 g Aktivkohle versetzt und abfiltriert. Das Filtrat wurde mit 100 ml Toluol versetzt, einrotiert und kristallisiert. Ausbeute: 22 g vom RrWert: 0,34 (Dichlormethan/Methanol 9:1 ). BAUSTEIN 3Methanol taken up, mixed with 4 g of activated charcoal and filtered off. The filtrate was mixed with 100 ml of toluene, evaporated and crystallized. Yield: 22 g of R r value: 0.34 (dichloromethane / methanol 9: 1). MODULE 3

100 g 3-Nitroanilin wurden in 400 ml Pyridin gelöst und unter leichter Eiskühlung 57 ml Methansulfonsäurechlorid zugetropft. Nach 12 h bei RT wurde das rote Reaktionsgemisch auf 1 ,2 I Eis gegossen, verrührt, abgesaugt, der feststoff mit viel Wasser aufgeschlämmt, gewaschen und getrocknet. Ausbeute: 148 g Feststoff vom Schmelzpunkt 165-1660C. Rr Wert. 0,65 (Dichlormethan/Methanol 9:1).100 g of 3-nitroaniline were dissolved in 400 ml of pyridine and 57 ml of methanesulfonyl chloride were added dropwise with gentle ice cooling. After 12 h at RT, the red reaction mixture was poured onto 1, 2 l of ice, stirred, filtered with suction, the solid slurried with plenty of water, washed and dried. Yield: 148 g of solid of melting point 165-166 0 C. R r value. 0.65 (dichloromethane / methanol 9: 1).

50 g 3-Methansulfonylamino-nitrobenzol wurden in 200 ml DMF vorgelegt, 31 g Kalium- tert.butylat hinzugegeben und das Reaktionsgemisch 1 h bei RT gerührt. Nach Zugabe von 28,5 g 2-Chlor-N,N-dimethylacetamid wurde das Gemisch 12 h bei 6O0C gerührt. Nach Abkühlen auf RT wurde Wasser hinzugegeben und 5x mit Essigester extrahiert. Die organischen Phasen wurden mit Wasser gewaschen, über MgSO4 getrocknet, filtriert und das Filtrat bis zum Rückstand eingeengt. Der Rückstand wurde aus Diisopropylether kristallisiert. Ausbeute: 31 ,5 g.50 g of 3-methanesulfonylamino-nitrobenzene were initially charged in 200 ml of DMF, 31 g of potassium tert-butylate were added and the reaction mixture was stirred at RT for 1 h. After addition of 28.5 g of 2-chloro-N, N-dimethylacetamide, the mixture was stirred at 6O 0 C for 12 h. After cooling to RT, water was added and extracted 5x with ethyl acetate. The organic phases were washed with water, dried over MgSO 4 , filtered and the filtrate was concentrated to dryness. The residue was crystallized from diisopropyl ether. Yield: 31.5 g.

31 ,5 g 2-(N-Methansulfonyl-N-(3-Nitrophenyl)-amino)-N,N-dimethylacetamid wurden mit 3 g Pd/C bei RT und 50 psi in ammoniakalischem Methanol 24 h hydriert. Anschließend wurde der Katalysator warm abgesaugt und mehrmals mit Essigester gewaschen. Das Filtrat wurde bis zum Rückstand eingeengt. Ausbeute: 20 g Feststoff vom Schmelzpunkt 143-1440C.31.5 g of 2- (N-methanesulfonyl-N- (3-nitrophenyl) -amino) -N, N-dimethylacetamide were hydrogenated with 3 g of Pd / C at RT and 50 psi in ammoniacal methanol for 24 h. Subsequently, the catalyst was filtered off while warm and washed several times with ethyl acetate. The Filtrate was concentrated to dryness. Yield: 20 g of solid of melting point 143-144 0 C.

Baustein 4:Module 4:

9,25 g (47 mmol) 4-Aminophenylpyrazolhydrochlorid werden in 150 ml Methanol vorgelegt, mit 1 ,00 g Nishimura Katalysator bei Raumtemperatur und einem Druck von 50 psi hydriert. Anschließend wird der Katalysator abfiltriert, das Filtrat eingedampft. Der9.25 g (47 mmol) of 4-aminophenylpyrazole hydrochloride are initially charged in 150 ml of methanol, hydrogenated with 1 00 g of Nishimura catalyst at room temperature and a pressure of 50 psi. Then the catalyst is filtered off, the filtrate is evaporated. Of the

Rückstand wird aus Acetonitril kristallisiert, die Enantiomere durch chromatographischeResidue is crystallized from acetonitrile, the enantiomers by chromatographic

Trennung erhalten.Separation received.

Ausbeute: 1 ,89 g (20%) eis Verbindung NMR: LH201668Yield: 1.89 g (20%) of ice. Compound NMR: LH201668

MP: 175°-177° CMP: 175 ° -177 ° C

Baustein 5: Module 5:

4,00 g (15 mmol) Baustein 3 werden in 60 ml Eisessig vorgelegt, mit 0,600 g Nishimura Katalysator bei Raumtemperatur und einem Druck von 50 psi hydriert. Anschließend wird der Katalysator abfiltriert, das Filtrat eingedampft. Der Rückstand wird in wenig Wasser gelost, mit Aktivkohle behandelt und filtriert. Das Filtrat wird lyophylisiert. Ausbeute: 4,90 g (84%) NMR: LH2015654.00 g (15 mmol) of building block 3 are initially charged in 60 ml of glacial acetic acid, hydrogenated with 0.600 g of Nishimura catalyst at room temperature and a pressure of 50 psi. Then the catalyst is filtered off, the filtrate is evaporated. The residue is dissolved in a little water, treated with charcoal and filtered. The filtrate is lyophilized. Yield: 4.90 g (84%) NMR: LH201565

Baustein 6:Module 6:

2-Methyl-2-(4-nitro-phenyl)-[1 ,3]dioxolan:2-Methyl-2- (4-nitro-phenyl) - [1,3] dioxolane:

33,03 g (200 mmol) 4-Nitroacetophenon, 12,30 ml (220 mmol) Ethylenglycol und 1 ,00 g (5 mmol) p-Toluolsulfonsäure werden in 250 ml Toluol vorgelegt, dann 16 Stunden am Wasserabscheider unter Rückfluss gerührt. Anschließend wird das Reaktionsgemisch abgekühlt und mit Wasser extrahiert. Die organische Phase wird getrocknet und zur Trockene eingedampft. Der Rückstand wird mit Diisopropylether ausgerührt und abgesaugt. Ausbeute: 34,45 g (82%)33.03 g (200 mmol) of 4-nitroacetophenone, 12.30 ml (220 mmol) of ethylene glycol and 1 00 g (5 mmol) of p-toluenesulfonic acid are initially charged in 250 ml of toluene, then 16 hours Water separator stirred under reflux. Then the reaction mixture is cooled and extracted with water. The organic phase is dried and evaporated to dryness. The residue is stirred with diisopropyl ether and filtered with suction. Yield: 34.45 g (82%)

4-(2-Methyl-[1 ,3]dioxolan-2-yl)-cyclohexylamin:4- (2-Methyl- [1,3-dioxolan-2-yl] -cyclohexylamine:

8,37 g (40 mmol) 2-Methyl-2-(4-nitro-phenyl)-[1 ,3]dioxolan werden in 160 ml Methanol vorgelegt, mit 1 ,00 g Nishimura Katalysator bei Raumtemperatur und einem Druck von 50 psi hydriert. Anschließend wird der Katalysator abfiltriert, das Filtrat eingedampft. Der Rückstand wird in Cyclohexan gelöst, Unlösliches abfiltriert und das Filtrat zur Trockene eingedampft. Ausbeute: 7,00 g (94%), cis/trans Verhältnis 77:23 NMR: LG2016168.37 g (40 mmol) of 2-methyl-2- (4-nitrophenyl) - [1,3] dioxolane are initially charged in 160 ml of methanol, with 1.00 g of Nishimura catalyst at room temperature and a pressure of 50 psi hydrogenated. Then the catalyst is filtered off, the filtrate is evaporated. The residue is dissolved in cyclohexane, insolubles are filtered off and the filtrate is evaporated to dryness. Yield: 7.00 g (94%), cis / trans ratio 77:23 NMR: LG201616

[4-(2-Methyl-[1 ,3]dioxolan-2-yl)-cyclohexyl]-carbamic acid 9H-fluoren-9-ylmethyl ester:[4- (2-Methyl- [1,3-dioxolan-2-yl) -cyclohexyl] -carbamic acid 9H-fluoren-9-ylmethyl ester:

Eine Lösung aus 12,72 g (120 mmol) Natriumcarbonat in 120 ml Wasser wird vorgelegt und mit einer Lösung aus 7,00 g (38 mmol) 4-(2-Methyl-[1 ,3]dioxolan-2-yl)-cyc!ohexylamin (cis/trans Gemisch) in 50 g Dioxan versetzt. Nach Abkühlen auf 0° C wird innerhalb 0,2 Stunden eine Lösung aus 10,09 g (39 mmol) Fmoc-chlorid in 100 g Dioxan zugetropft. Das Reaktionsgemisch wird 16 Stunden gerührt, wobei die Kühlung entfernt wird.A solution of 12.72 g (120 mmol) of sodium carbonate in 120 ml of water is initially charged and treated with a solution of 7.00 g (38 mmol) of 4- (2-methyl- [1,3-dioxolan-2-yl). cyclohexylamine (cis / trans mixture) in 50 g of dioxane. After cooling to 0 ° C., a solution of 10.09 g (39 mmol) of Fmoc chloride in 100 g of dioxane is added dropwise within 0.2 hours. The reaction mixture is stirred for 16 hours, cooling being removed.

Anschließend wird auf Wasser gegossen und mit Ethylacetat extrahiert. Die organische Phase wird mit Wasser gewaschen, getrocknet und zur Trockene eingedampft. Der Rückstand wird chromatographisch gereinigt. Ausbeute: 13,10 g (85%) cis/trans Verhältnis 4:1 NMR: LH201618It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. The residue is purified by chromatography. Yield: 13.10 g (85%) cis / trans ratio 4: 1 NMR: LH201618

(4-Acetyl-cyclohexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester: 13,10 g (32 mmol) [4-(2-Methyl-[1 ,3]dioxolan-2-yl)-cyclohexyl]-carbamic acid 9H-fluoren-9- ylmethyl ester {cis/trans Gemisch) und 1 ,30 g p-Toluolsulfonsäure werden in 25 ml Wasser und 500 ml Aceton 16 Stunden unter Rückfluss gerührt. Anschließend wird das Reaktionsgemisch eingedampft, der Rückstand in Ethylacetat gelöst und mit Wasser extrahiert. Die organische Phase wird getrocknet und zur Trockene eingedampft. Der Rückstand wird mit Diisopropylether ausgerührt und abgesaugt. Ausbeute: 7,77 g (89%) eis Verbindung NMR: LH201628(4-Acetylcyclohexyl) carbamic acid 9H-fluoren-9-ylmethyl ester: 13.10 g (32 mmol) of [4- (2-methyl-1,3,3-dioxolan-2-yl) -cyclohexyl] -carbamic acid 9H-fluoren-9-ylmethyl ester {cis / trans mixture) and 1, 30 g of p-toluenesulfonic acid are stirred in 25 ml of water and 500 ml of acetone for 16 hours under reflux. Then the reaction mixture is evaporated, the residue dissolved in ethyl acetate and extracted with water. The organic phase is dried and evaporated to dryness. The residue is stirred with diisopropyl ether and filtered with suction. Yield: 7.77 g (89%) of ice. Compound NMR: LH201628

[4-(2-Bromo-acetyl)-cyclohexyl]-carbamic aeid 9H-fluoren-9-ylmethyl ester:[4- (2-Bromo-acetyl) -cyclohexyl] carbamic acid 9H-fluoren-9-ylmethyl ester:

7,77 g (21 mmol) (4-Acetyl-cyclohexyl)-carbamic aeid 9H-fluoren-9-ylmethyl ester (eis Verbindung) werden bei Raumtemperatur in 100 ml Methanol gelöst und mit 1 ,09 ml (21 mmol) Brom versetzt. Es wird 16 Stunden bei Raumtemperatur gerührt, abgekühlt und die ausgefallenen Kristalle abgesaugt. Ausbeute: 6,35 g (50%) NMR: LG2016417.77 g (21 mmol) of (4-acetyl-cyclohexyl) -carbamic aleid 9H-fluoren-9-ylmethyl ester (ice compound) are dissolved at room temperature in 100 ml of methanol and treated with 1, 09 ml (21 mmol) of bromine , It is stirred for 16 hours at room temperature, cooled and the precipitated crystals are filtered off with suction. Yield: 6.35 g (50%) NMR: LG201641

[4-(2-Methyl-thiazol-4-yl)-cyclohexyl]-carbamic aeid 9H-fluoren-9-ylmethyl ester:[4- (2-Methylthiazol-4-yl) cyclohexyl] carbamic acid 9H-fluoren-9-ylmethyl ester:

4,00 g (7 mmol) [4-(2-Bromo-acetyl)-cyclohexyl]-carbamic aeid 9H-f)uoren-9-ylmethyl ester (eis Verbindung) und 0,700 g (9 mmol) Thioacetamid werden in 50 ml Acetonitril 724.00 g (7 mmol) of [4- (2-bromo-acetyl) -cyclohexyl] -carbamic aeid 9H-f) uoren-9-ylmethyl ester (ice compound) and 0.700 g (9 mmol) of thioacetamide are dissolved in 50 ml Acetonitrile 72

Stunden unter Rückfluss gerührt. Anschließend wird das Reaktionsgemisch eingedampft, der Rückstand chromatographisch gereinigt. Entsprechende Fraktionen werden vereinigt und zur Trockene eingedampft. Der kristalline Rückstand wird mit Diisopropylether ausgerührt und abgesaugt.Stirred under reflux for hours. Subsequently, the reaction mixture is evaporated, the residue purified by chromatography. Appropriate fractions are combined and evaporated to dryness. The crystalline residue is stirred with diisopropyl ether and filtered with suction.

Ausbeute: 1 ,10 g (39%) eis VerbindungYield: 1, 10 g (39%) of ice compound

NMR: LH201648 MP: 140°-141 ° CNMR: LH201648 MP: 140 ° -141 ° C

4-(2-Methy(-thiazol-4-yl)-cyclohexylamin (Baustein 6): 1 ,10 g (2mmol) [4-(2-Methyl-thiazol-4-yl)-cyclohexyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (eis Verbindung) und 15 ml Diethylamin werden in 30 ml Tetrahydrofuran 16 Stunden bei Raumtemperatur gerührt. Anschließend wird das Reaktionsgemisch eingedampft, der Rückstand mit Tetrahydrofuran versetzt und wieder eingedampft. Der Rückstand wird chromatographisch gereinigt. Ausbeute: 0,13 g (36%)4- (2-Methy (-thiazol-4-yl) -cyclohexylamine (building block 6): 1.10 g (2 mmol) of [4- (2-methyl-thiazol-4-yl) -cyclohexyl] -carbamic acid 9H-fluoren-9-ylmethyl ester (ice compound) and 15 ml of diethylamine are dissolved in 30 ml of tetrahydrofuran for 16 hours stirred at room temperature. The reaction mixture is then evaporated, the residue treated with tetrahydrofuran and evaporated again. The residue is purified by chromatography. Yield: 0.13 g (36%)

INDIKATIONSGEBIETEINDICATIONS

Wie gefunden wurde, zeichnen sich die Verbindungen der Formel 1 durch vielfältige Anwendungsmöglichkeiten auf therapeutischem Gebiet aus. Hervorzuheben sind solche Anwendungsmöglichkeiten, für welche die erfindungsgemäßen Verbindungen der Formel 1 aufgrund ihrer pharmazeutischen Wirksamkeit als PDE4-Inhibitor bevorzugt zur Anwendung gelangen können. Beispielhaft genannt seinen Atemwegs- oder gastrointestinalen Erkrankungen oder Beschwerden, entzündliche Erkrankungen der Gelenke, der Haut oder der Augen, Krebserkrankungen, sowie Erkrankungen des periph ren oder zentralen Nervensystems.As has been found, the compounds of formula 1 are characterized by a variety of possible applications in the therapeutic field. Worth mentioning are those applications for which the compounds of formula 1 according to the invention can preferably be used as a PDE4 inhibitor due to their pharmaceutical activity. Examples include his respiratory or gastrointestinal diseases or disorders, inflammatory diseases of the joints, the skin or the eyes, cancers, as well as diseases of the peripheral or peripheral nervous system.

Hierbei bevorzugt genannt sei die Vorbeugung und Behandlung von Atemwegs- oder Lungenerkrankungen, welche mit einer erhöhten Schleimproduktion, Entzündungen und/oder obstruktiven Erkrankungen der Atemwege einher gehen. Beispielhaft hierfür seinen genannt, akute, allergische oder chronische Bronchitis, chronisch obstruktive Bronchitis (COPD), Husten, Lungenemphysem, allergische oder nicht-allergische Rhinitis oder Sinusitis, chronische Rhinitis oder Sinusitis, Asthma, Alveolitis, fibrosierende Alveolitis, idiopathische Lungenfibrose, Colitis ulcerosa, Farmers' Krankheit, hyperreaktive Atemwege, infektiöse Bronchitis oder Pneumonitis, pediatrisches Asthma, Bronchiectasien, Lungenfibrose, ARDS (akutes Atemnotsyndrom des Erwachsenen), Bronchialödem, Lungenödem, Bronchitis, Pneumonie oder interstitielle Pneumonie ausgelöst durch verschiedene Ursachen wie Aspiration, Inhalation von toxischen Gasen oder Bronchitis, Pneumonie oder interstitielle Pneumonie ausgelöst durch Herzinsuffizienz, Bestrahlung, Chemotherapie zystische Fibrose oder Mukoviszidose, alpha"! -Antitrypsin-Mangel.Preference is given here to the prevention and treatment of respiratory or lung diseases, which are associated with increased mucus production, inflammation and / or obstructive diseases of the respiratory tract. Examples include his, acute, allergic or chronic bronchitis, chronic obstructive pulmonary disease (COPD), cough, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, fibrosing alveolitis, idiopathic pulmonary fibrosis, ulcerative colitis, Farmers ' disease, hyperresponsive respiratory tract, infectious bronchitis or pneumonitis, pediatric asthma, bronchiectasias, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial edema, pulmonary edema, bronchitis, pneumonia or interstitial pneumonia caused by various causes such as aspiration, inhalation of toxic gases or bronchitis , Pneumonia or interstitial pneumonia triggered by Heart failure, radiation, chemotherapy cystic fibrosis or cystic fibrosis, alpha-antitrypsin deficiency.

Ebenfalls bevorzugt genannt sei die Behandlung von entzündlichen Erkrankungen des Gastrointestinaltraktes. Beispielhaft hierfür seinen genannt, akute oder chronische entzündliche Veränderungen bei Gallenblasenentzündung, Morbus Crohn, Colitis ulcerosa, entzündliche Pseudopolypen, juvenile Polypen, Colitis cystica profunda, Pneumatosis cystoides intestinales, Erkrankungen der Gallengänge und Gallenblase, z.B. Gallensteine und Konglomerate, zur Behandlung von entzündlichen Erkrankungen der Gelenke wie rheumatoide Arthritis oder entzündliche Erkrankungen der Haut und der Augen.Likewise preferred is the treatment of inflammatory diseases of the gastrointestinal tract. Examples of this are its called, acute or chronic inflammatory changes in gallbladder inflammation, Crohn's disease, ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitis cystica profunda, pneumatosis cystoides intestinales, diseases of the bile ducts and gallbladder, e.g. Gallstones and conglomerates for the treatment of inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and eyes.

Ebenfalls bevorzugt genannt sei die Behandlung von Krebserkrankungen. Beispielhaft hierfür seinen genannt alle Formen von akuten und chronischen Leukämien wie, akute lymphatische und akute myeloische Leukämie, chronisch lymphatische und chronisch myeloische Leukämie, sowie Knochentumoren wie das Osteosarkom und sowie alle Arten von Gliomen wie Oligodendrogliom und Glioblastom.Likewise preferred is the treatment of cancer. Exemplary of this are called all forms of acute and chronic leukemias such as, acute lymphoblastic and acute myeloid leukemia, chronic lymphocytic and chronic myeloid leukemia, as well as bone tumors such as osteosarcoma and as well as all types of gliomas such as oligodendroglioma and glioblastoma.

Des Weiteren bevorzugt genannt sei die Vorbeugung und Behandlung von Erkrankungen des periphären oder zentralen Nervensystems. Beispielhaft hierfür seien genanntPreference is furthermore given to the prevention and treatment of diseases of the peripheral or central nervous system. Examples of this are mentioned

Depression, bipolare oder manische Depression, akute und chronische Angstzustände, Schizophrenie, Alzheimer'sche Erkrankung, Parkinson'sche Erkrankung, akute und chronische Multiple Sklerose oder akute und chronische Schmerzzustände sowie Verletzungen des Gehirns hervorgerufen durch Schlaganfall, Hypoxie oder Schädel-Hirn-Trauma.Depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain, and brain damage caused by stroke, hypoxia or craniocerebral trauma.

Besonders bevorzugt betrifft die vorliegende Erfindung die Verwendung von Verbindungen der Formel 1 zur Herstellung eines Arzneimittels zur Behandlung entzündlicher oder obstruktiver Erkrankungen der oberen und unteren Atmungsorgane einschließlich der Lunge wie beispielsweise allergische Rhinitis, chronische Rhinitis, Bronchiectasis, zystische Fibrose, idiopathische Lungenfibrose, fibrosierende Alveolitis, COPD, chronische Bronchitis, chronischer Sinusitis, Asthma, Morbus Crohn, Colitis ulcerosa, insbesondere COPD, chronische Bronchitis und Asthma. Am meisten bevorzugt ist die Verwendung der Verbindungen der Formel 1 zur Behandlung von entzündlichen und obstruktiven Erkrankungen wie COPD, chronische Bronchitis, chronischer Sinusitis, Asthma, Morbus Crohn, Colitis ulcerosa, insbesondere COPD, chronische Bronchitis und Asthma.More particularly, the present invention relates to the use of compounds of formula 1 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lung, such as allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma. Most preferred is the use of the compounds of formula 1 for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.

Ebenfalls bevorzugt ist die Verwendung der Verbindungen der Formel 1 zur Behandlung von Erkrankungen des periphären oder zentralen Nervensystems wie Depression, bipolare oder manische Depression, akute und chronische Angstzustände, Schizophrenie, Alzheimer'sche Erkrankung, Parkinson'sche Erkrankung, akute und chronische Multiple Sklerose oder akute und chronische Schmerzzustände sowie Verletzungen des Gehirns hervorgerufen durch Schlaganfall, Hypoxie oder Schädel-Hirn-Trauma.Also preferred is the use of the compounds of formula 1 for the treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or craniocerebral trauma.

Ein herausragender Aspekt der vorliegenden Erfindung ist das reduzierte Profil an Nebenwirkungen. Darunter wird im Rahmen der Erfindung verstanden, eine Dosis einer pharmazeutischen Zusammensetzung verabreichen zu können, ohne beim Patienten Erbrechen, bevorzugt Übelkeit, besonders bevorzugt Unwohlsein auszulösen. Höchst bevorzugt ist die Verabreichung einer therapeutisch wirksamen Substanzmengen, ohne Emesis oder Nausea auszulösen, in jedem Stadium des Krankheitsverlaufs.An outstanding aspect of the present invention is the reduced profile of side effects. In the context of the invention, this is understood as being able to administer a dose of a pharmaceutical composition without inducing vomiting in the patient, preferably nausea, particularly preferably malaise. Most preferably, administration of a therapeutically effective amount of substance without inducing emesis or nausea is at any stage of the disease process.

KOMBINATIONENCOMBINATIONS

Die Verbindungen der Formel 1 können allein oder in Kombination mit anderen erfindungsgemäßen Wirkstoffen der Formel 1 zur Anwendung gelangen. Gegebenenfalls können die Verbindungen der Formel 1 auch in Kombination mit weiteren pharmakologisch aktiven Wirkstoffen eingesetzt werden. Bevorzugt gelangen hierbei solche Wirkstoffe zur Anwendung, die beispielsweise ausgewählt sind aus der Gruppe bestehend aus Betamimetika, Anticholinergika, Corticosteroiden, weitere PDE4-Inhibitoren, LTD4- Antagonisten, EGFR-Hemmern, Dopamin-Agonisten, H 1 -Antihistaminika, PAF- Antagonisten und PI3-Kinase Inhibitoren oder zwei- oder dreifach Kombinationen davon, wie beispielsweise Kombinationen vonThe compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1 according to the invention. Optionally, the compounds of formula 1 can also be used in combination with other pharmacologically active ingredients. Preference is given here to those active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H 1 -antihistamines, PAF antagonists and PI3 Kinase inhibitors or two or three combinations thereof, such as combinations of

• Betamimetika mit Corticosteroiden, PDE4-Inhibitoren, EGFR-Hemmern oder LTD4- Antagonisten, • Anticholinergika mit Betamimetika, Corticosteroiden, PDE4-Inhibitoren, EGFR- Hemmern oder LTD4-Antagonisten,• betamimetics with corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists, Anticholinergics with betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,

• Corticosteroiden mit PDE4-Inhibitoren, EGFR-Hemmem oder LTD4-Antagonisten• Corticosteroids with PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists

• PDE4-inhibitoren mit EGFR-Hemmern oder LTD4-Antagonisten • EGFR-Hemmern mit LTD4-Antagonisten• PDE4 inhibitors with EGFR inhibitors or LTD4 antagonists • EGFR inhibitors with LTD4 antagonists

• MRP4-Inhibitoren.• MRP4 inhibitors.

Auch die Kombinationen dreier Wirkstoffe je einer der o.g. Verbindυngsklassen ist Bestandteil der Erfindung.Also, the combinations of three active ingredients each one of the o.g. Verbindυngsklassen is part of the invention.

Als Betamimetika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Albuterol, Bambuterol, Bitolterol, Broxaterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Arformoterol, Zinterol, Hexoprenaline, Ibuterol, Isoetharine, Isoprenaline, Levosalbutamol, Mabuterol, Meluadrine, Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmeterol, Salmefamol, Soterenol, Sulphonterol, Tiaramide, Terbutaline, Tolubuterol, CHF-1035, HOKU-81 , KUL-1248, 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3- hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulfonamid, 5-[2-(5,6-Diethyl- indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-on, 4-Hydroxy-7-[2-{[2-{[3-(2- phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolon, 1-(2-Fluoro-4- hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1 -[3-(4- Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2- butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N- dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1 ,4- benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5- hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2- propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-{4-[3-(4- methoxyphenyl)-1 ,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-Hydroxy-8-(1 - hydroxy-2-isopropylaminobutyl)-2H-1 ,4-benzoxazin-3-(4H)-on, 1 -(4-Amino-3-chloro-5- trifluormethylphenyl)-2-tert.-butylamino)ethanol, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy- phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1- hydroxy-2-[2-(4-phenoxy-essigsäureethylester)-1 ,1-dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäure)-1 ,1- dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[1 ,1-Dimethyl-2-(2,4,6- trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 6- Hydroxy-8-{1 -hydroxy-2-[2-(4-hydroxy-phenyl)-1 , 1 -dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1 ,1dimethyl- ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethyl-phenyl)-1 ,1-dimethyl- ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethoxy- phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-ethylamino]- 2-methyl-propyl}-phenoxy)-buttersäure, 8-{2-[2-(3,4-Difluor-phenyl)-1 ,1-dimethyl- ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on und 1-(4-Ethoxy- carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate.Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharines, isoprenalines, levosalbutamol, mabuterol, meluadrine , Metaproterenol, Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmeterol, Salmefamol, Soterenol, Sulphoneterol, Tiaramide, Terbutaline, Tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3- (4- {6- [ 2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide, 5- [2- (5,6-diethyl-indan-2-ylamino) - 1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4 - methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butyl amino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2 -propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol , 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1, 2,4-triazole-3 -yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one, 1 - (4 -Amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol, 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl -ethylamino] ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl -ethylamino] ethyl} -4H-benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1, 1-dimethyl -ethylamino] ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylp henyl) -ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 6- Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxy-phenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6- Hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1, 1-dimethylethylamino] ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2 - [2- (4-ethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2 - [2- (4-ethoxyphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4 - {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2-methyl-propyl} -phenoxy) -butyric acid, 8- {2- [2- (3,4-difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1, 4] oxazin-3-one and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Bevorzugt sind die Betamimetika ausgewählt aus der Gruppe bestehend aus Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenaline, Ibuterol, Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulphonterol, Terbutaline, Tolubuterol, 3-(4- {6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)- benzenesulfoneamide, 5-[2-(5,6-Diethyl-indan-2-ylamino)-1 -hydroxy-ethyl]-8-hydroxy-1 H- quinolin-2-on , 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]- 2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2- butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1- benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1 ,4- benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2- propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-n- butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1 ,4- benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1 ,2,4-triazol-3-yl]-2-methyl-2- butylamino}ethanol, 5-hydroxy-8-(1 -hydroxy-2-isopropylaminobutyl)-2H-1 ,4-benzoxazin-3- (4H)-on, 1 -(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol, 6- Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-pheny])-1 ,1-dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-phenoxy-essigsäureethylester)- 1 , 1 -dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1 -hydroxy-2-[2- (4-phenoxy-essigsäure)-1 ,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2- [1 ,1 -Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1 ,1-dimethyl- ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-isopropyl- phenyl)-1 ,1dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethyl- phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethoxy-phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-on, 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-buttersäure, 8-{2-[2-(3,4- Difluor-phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin- 3-on und 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate.Preferably, the betamimetics are selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 3- (4- {6- [2 -Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzenesulfoneamides, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy -ethyl] -8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7- [2 - {[2 - {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] - 2 (3H) -benzothiazolones, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [3- (4-methoxybenzyl -amino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine -8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1, 4- benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8 yl ] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1, 2,4-triazol-3-yl] -2-methyl-2-butylamino} ethanol, 5-hydroxy-8- (1-hydroxy-2 -isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol, 6-hydroxy-8 - {1-hydroxy-2- [2- (4-methoxy-phenyl) -l, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy 8- {1-Hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -l, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy 8- {1-Hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4-oxazino-3-one, 8- {2 - [1, 1-Dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 6- Hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1, 1-dimethyl ethylamino] ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1, 1-dimethylethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethylphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl} - 6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxy-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} - 6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H- benzo [1,4] oxazin-8-yl) -ethylamino] -2-methyl-propyl} -phenoxy) -butyric acid, 8- {2- [2- (3,4-difluorophenyl) -1, 1- dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert .-Butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Besonders bevorzugte Betamimetika sind ausgewählt aus der Gruppe bestehend aus Fenoterol, Formoterol, Salmeterol, 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl- phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamid, 5-[2-(5,6-Diethyl-indan-2- ylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-on, 1-[3-(4-Methoxybenzyl-amino)-4- hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy- 3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2- propylaminojethanol, 1-[2H-5-Hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4- methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1 -[2H-5-Hydroxy-3-oxo-4H-1 ,4- benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 6-Hydroxy-8- {1-hydroxy-2-[2-(4-methoxy-phenyl)-1 ,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin- 3-on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäureethylester)-1 ,1-dimethyl- ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-phenoxy- essigsäure)-1 , 1 -dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[1 , 1 -Dimethyl- 2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3- on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1 ,1-dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1 ,1dimethyl- ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethyl-phenyl)-1 ,1-dimethyl- ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethoxy- phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-ethylamino]- 2-methyl-propyl}-phenoxy)-buttersäure, 8-{2-[2-(3,4-Difluor-phenyl)-1 , 1 -dimethyl- ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on und 1-[2H-5-Hydroxy- 3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1 ,2,4-triazol-3-yl]-2-methyl-2- butylamino}ethanol, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate.Particularly preferred betamimetics are selected from the group consisting of fenoterol, formoterol, salmeterol, 3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -hexyloxy} -butyl ) -benzenesulfoneamide, 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one, 1- [3- (4 -Methoxybenzylamino) -4-hydroxyphenyl] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1, 4 benzoxazin-8-yl] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1, 4- benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol, 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8 -yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol, 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy - acetic acid) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [1, 1-dimethyl-2- (2,4,6 -trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4 -hydroxy-phenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4 -isopropylphenyl) -1, 1-dimethylethylamino] -ethyl} -4 H -benzo [1,4-oxazino-3-one, 8- {2- [2- (4-ethylphenyl) -1, 1- dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxyphenyl) -1, 1- dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-hydroxy-2- (6-hydroxy) 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2-methyl-propyl} -phenoxy) -butyric acid, 8- {2- [2- (3 , 4-difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one and 1- [2H-5-hydroxy - 3-oxo-4H-1,4-benzoxazin-8-yl] -2- {4- [3- (4-methoxyphenyl) -1, 2,4-triazol-3-yl] -2-methyl-2 - butylamino} ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Von diesen Betamimetika sind erfindungsgemäß besonders bevorzugt Formoterol, Salmeterol, 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]- hexyloxy}-butyl)-benzenesulfoneamide, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)- 1 ,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1-hydroxy-2-[2- (4-phenoxy-essigsäureethylester)-1 , 1 -dimethyl-ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3- on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-essigsäure)-1 ,1-dimethyl-ethylamino]-ethyl}- 4H-benzo[1 ,4]oxazin-3-on, 8-{2-[1 ,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1- hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on,Of these betamimetics, particularly preferred according to the invention are formoterol, salmeterol, 3- (4- {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzenesulfoneamide, 6 -Hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6 Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6 Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4] oxazin-3-one, 8 - {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) -ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one .

6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1 ,1-dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-on, 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1 ,1dimethyl- ethylamino]-ethyl}-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethyl-phenyl)-1 ,1-dimethyl- ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 8-{2-[2-(4-Ethoxy- phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on, 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-ethylamino]- 2-methyl-propyl}-phenoxy)-buttersäure, 8-{2-[2-(3,4-Difluor-phenyl)-1 ,1-dimethyl- ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1 ,4]oxazin-3-on und 5-[2-(5,6-Diethyl- indan-2-y!amino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-on, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate.6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1, 1-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one, 6-hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1, 1-dimethylethylamino] ethyl} -4 H -benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethylphenyl) -1, 1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 8- {2- [2- (4-ethoxyphenyl) -1, 1-dimethyl-ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one, 4- (4- {2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -ethylamino] -2-methyl- propyl} phenoxy) butyric acid, 8- {2- [2- (3,4-difluoro-phenyl) -1, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo 1, 4] oxazin-3-one and 5- [2- (5,6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.

Erfindungsgemäß bevorzugt sind die Säureadditionssalze der Betamimetika ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrobenzoat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat, bevorzugt Hydrochlorid, Hydrobromid, Hydrosulfat, Hydrophosphat, Hydrofumarat und Hydromethansulfonat verstanden. Von den vorstehend genannten Säureadditionssalzen sind die Salze der Chlorwasserstoffsäure, der Methansulfonsäure, der Benzoesäure und der Essigsäure erfindungsgemäß besonders bevorzugt. Als Anticholinergika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Tiotropiumsalzen, Oxitropiumsalzen, Flutropiumsalzen, Ipratropiumsalzen, Glycopyrroniumsalzen, Trospiumsalzen 2,2- Diphenylpropionsäuretropenolester-methobromid, 2,2-Diphenylpropionsäurescopinester- methobromid, 2-Fluor-2,2-Diphenylessigsäurescopinester-methobromid, 2-Fluor-2,2- Diphenylessigsäuretropenolester-methobromid, 3,3',4,4'-Tetrafluorbenzilsäure- tropenolester-Methobromid, 3,3',4,4'-Tetrafluorbenzilsäurescopinester-Methobromid, 4,4'- Difluorbenzilsäuretropenolester-Methobromid, 4,4'-Difluorbenzilsäurescopinester- Methobromid, 3,3'-Difluorbenzilsäuretropenolester-Methobromid, 3,3'-Difluorbenzilsäure- scopinester-Methobromid, 9-Hydroxy-fluoren-9-carbonsäuretropenolester -Methobromid, 9-Fluor-fluoren-9-carbonsäuretropenolester -Methobromid, 9-Hydroxy-fluoren-9- carbonsäurescopinester -Methobromid, 9-Fluor-fluoren-9-carbonsäurescopinester Methobromid, 9-Methyl-fluoren-9-carbonsäuretropenolester Methobromid, 9-Methyl- fluoren-9-carbonsäurescopinester Methobromid, Benzilsäurecyclopropyltropinester-According to the invention, the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate , preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood. Of the above-mentioned acid addition salts, the salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred in the present invention. Preferred anticholinergic compounds here are compounds which are selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts 2,2-diphenylpropionic acid-triester-methobromide, 2,2-diphenylpropionic acid-co-ester methobromide, 2-fluoro-2, 2-Fluoro-2,2-diphenylacetic acid tropol ester methobromide, 3,3 ', 4,4'-tetrafluorobenzilic acid tropol ester methobromide, 3,3', 4,4'-tetrafluorobenzilic acid copoprene methobromide, 4-diphenylacetic acid-co-ester methobromide, 4, 4'-Difluorobenzylic acid-tropol ester-methobromide, 4,4'-difluorobenzilic acid-co-ester methobromide, 3,3'-difluorobenzilic acid-tropol ester-methobromide, 3,3'-difluorobenzilic acid scopine ester-methobromide, 9-hydroxy-fluorene-9-carboxylic acid-tropol ester -methobromide, 9- Fluorofluorene-9-carboxylic acid tropol ester -methobromide, 9-hydroxyfluorene-9-carboxylic acid copoester -methobromide, 9-fluoro-fluorene-9-carboxylic acid copopinester M ethobromide, 9-methyl-fluorene-9-carboxylic acid-tropol ester, methobromide, 9-methyl-fluorene-9-carboxylic acid-co-ester methobromide, benzylic acid cyclopropyltin-ester

Methobromid, 2,2-Diphenylpropionsäurecyclopropyltropinester -Methobromid, 9-Hydroxy- xanthen-θ-carbonsäurecyclopropyltropinesterMethobromid, 9-Methyl-fluoren-9- carbonsäurecyclopropyltropinester-Methobromid, 9-Methyl-xanthen-9-carbonsäure- cyclopropyltropinester -Methobromid, 9-Hydroxy-fluoren-9-carbonsäurecyclopropyl- tropinester -Methobromid, 4,4'-Difluorbenzilsäuremethylestercyclopropyltropinester -Methobromide, 2,2-diphenylpropionic acid cyclopropyltropine ester -methobromide, 9-hydroxy-xanthene---carboxylic acid cyclopropyltropine ester methobromide, 9-methyl-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide, 9-methyl-xanthene-9-carboxylic acid cyclopropyltropine ester -methobromide, 9-hydroxy fluorene-9-carboxylic acid cyclopropyl-tropine ester methobromide, methyl 4,4'-difluorobenzilate cyclopropyltropyne ester -

Methobromid, 9-Hydroxy-xanthen-9-carbonsäuretropenolester -Methobromid, 9-Hydroxy- xanthen-9-carbonsäurescopinester Methobromid, 9-Methyl-xanthen-9-carbonsäure- tropenolester -Methobromid, 9-Methyl-xanthen-9-carbonsäurescopinester -Methobromid, 9-Ethyl-xanthen-9-carbonsäuretropenolester Methobromid, 9-Difluormethyl-xanthen-9- carbonsäuretropenolester -Methobromid. 9-Hydroxymethyl-xanthen-9-carbonsäure- scopinester -Methobromid, gegebenenfalls in Form ihrer Solvate oder Hydrate.Methobromide, 9-hydroxy-xanthene-9-carboxylic acid tropol ester -methobromide, 9-hydroxy-xanthene-9-carboxylic acid cophenester, methobromide, 9-methyl-xanthene-9-carboxylic acid tropol ester -methobromide, 9-methyl-xanthene-9-carboxylic acid cophenester -methobromide , 9-Ethyl-xanthene-9-carboxylic acid-tropol ester methobromide, 9-difluoromethyl-xanthene-9-carboxylic acid-tropol ester -methobromide. 9-hydroxymethyl-xanthene-9-carboxylic acid scopine ester methobromide, optionally in the form of its solvates or hydrates.

In den vorstehend genannten Salzen stellen die Kationen Tiotropium, Oxitropium, Fiutropium, Ipratropium, Glycopyrronium und Trospium die pharmakologisch aktiven Bestandteile dar. Als Anionen können die vorstehend genannten Salze bevorzugt enthalten Chlorid, Bromid, lodid, Sulfat, Phosphat, Methansulfonat, Nitrat, Maleat, Acetat, Citrat, Fumarat, Tartrat, Oxalat, Succinat, Benzoat oder p-Toluolsulfonat, wobei Chlorid, Bromid, lodid, Sulfat, Methansulfonat oder p-Toluolsulfonat als Gegenionen bevorzugt sind. Von allen Salzen sind die Chloride, Bromide, lodid und Methansulfonat besonders bevorzugt.In the abovementioned salts, the cations tiotropium, oxitropium, fiutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active constituents. As anions the abovementioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, Acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions are. Of all the salts, the chlorides, bromides, iodide and methanesulfonate are particularly preferred.

Von besonderer Bedeutung ist das Tiotropiumbromid. Im Falle des Tiotropiumbromids enthalten die erfindungsgemäßen Arzneimittelkombinationen dieses bevorzugt in Form des kristallinen Tiotropiumbromid Monohydrats, welches aus der WO 02/30928 bekannt ist. Wird das Tiotropiumbromid in den erfindungsgemäßen Arzneimittelkombinationen in wasserfreier Form eingesetzt, so gelangt bevorzugt das wasserfreie kristalline Tiotropiumbromid zur Anwendung, welches aus der WO 03/000265 bekannt ist.Of particular importance is the tiotropium bromide. In the case of tiotropium bromide, the drug combinations according to the invention preferably contain this in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is employed in anhydrous form in the medicament combinations according to the invention, the anhydrous crystalline tiotropium bromide is preferably used, which is known from WO 03/000265.

Als Corticosteroide gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Prednisolon, Prednison, Butixocortpropionat, Flunisolid, Beclomethason, Triamcinolon, Budesonid, Fluticason, Mometason, Ciclesonid, Rofleponid, Dexamethason, Betamethason, Deflazacort.RPR- 106541 , NS-126, 6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11 -hydroxy-16-methyl-3-oxo- androsta-1 ,4-dien-17-carbothionsäure (S)-fluoromethylester und 6,9-Difluoro-11-hydroxy- 16-methyl-3-oxo-17-propionyloxy-androsta-1 ,4-dien-17-carbothionsäure (S)-(2-oxo- tetrahydro-furan-3S-yl)ester, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate.Preferred corticosteroids here are compounds selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort. RPR-106541, NS -126,6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester and 6 , 9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid (S) - (2-oxo-tetrahydro-furan-3S-yl) ester optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Besonders bevorzugt ist das Steroid ausgewählt aus der Gruppe bestehend aus Flunisolid, Beclomethason, Triamcinolon, Budesonid, Fluticason, Mometason, Ciclesonid, Rofleponid, Dexamethason, NS-126, 6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy- 16-methyl-3-oxo-androsta-1 ,4-dien-17-carbothionsäure (S)-fluoromethylester und 6,9- Difiuoro-11 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1 ,4-dien-17- carbothionsäure (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate.More preferably, the steroid is selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] - 11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester and 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy -androsta-1, 4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) ester, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their Solvates and / or hydrates.

Besonders bevorzugt ist das Steroid ausgewählt aus der Gruppe bestehend aus Budesonid, Fluticason, Mometason, Ciclesonid und 6,9-Difluoro-17-[(2- furanylcarbonyl)oxy]-11 -hydroxy-16-methy!-3-oxo-androsta-1 ,4-dien-17-carbothionsäure (S)-fluoromethylester, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate.Most preferably, the steroid is selected from the group consisting of budesonide, fluticasone, mometasone, ciclesonide and 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta -1, 4-diene-17-carbothionic acid (S) -fluoromethyl ester, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Jede Bezugnahme auf Steroide schließt eine Bezugnahme auf deren gegebenenfalls existierende Salze oder Derivate, Hydrate oder Solvate mit ein. Beispiele möglicher Salze und Derivate der Steroide können sein: Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate.Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.

Als weitere PDE4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Enprofyllin, Theophyllin, Roflumilast, Ariflo (Cilomilast), Tofimilast, Pumafentrin, Lirimilast, Arofyllin, Atizoram, D- 4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-As further PDE4 inhibitors, compounds are preferably used which are selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD

168787, T-440, T-2585, V-11294A, CI-1018, CDC-801 , CDC-3052, D-22888, YM-58997, Z-15370,N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxy- benzamid, (-)p-[(4aR*,10bS*)-9-Ethoxy-1 , 2,3,4,4a, 10b-hexahydro-8-methoxy-2-methyl- benzo[s][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid, (R)-(+)-1-(4-Bromobenzyl)-4-[(3- cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon, 3-(Cyclopentyloxy-4-methoxyphenyl)-1 -(4- N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidon, cis[4-Cyano-4-(3-cyclo- pentyloxy-4-methoxyphenyl)cyclohexan-1 -carbonsäure], 2-carbomethoxy-4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-on, cis[4-Cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-Ethyl[4-(3- cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat, (S)-(-)-Ethyl[4-(3- cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat, 9-Cyclopentyl-5,6-dihydro-7- ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3-a]pyridin und 9-Cyclopentyl-5,6- dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3-a]pyridin, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate und/oder Hydrate.168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, N- (3,5-dichloro-1-oxo -pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, (-) p - [(4aR * , 10bS * ) -9-ethoxy-1,2,3,4,4a, 10b-hexahydroxy) 8-methoxy-2-methyl-benzo [s] [1, 6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, (R) - (+) - 1- (4-bromobenzyl) -4 - [( 3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone, 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido] benzyl) -2- pyrrolidone, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1 -one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine 2-ylidene] acetate, (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate, 9-cyclopentyl-5,6-dihydro-7-ethyl-3 - (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine and 9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,2,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers or diastereomers, and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

Besonders bevorzugt ist der PDE4-Inhibitor ausgewählt aus der Gruppe bestehend aus Enprofyllin, Roflumilast, Ariflo (Cilomilast), Arofyllin, Atizoram, AW D-12-281 (GW-842470), T-440, T-2585, PD-168787, V-1 1294A, CI-1018, CDC-801 , D-22888, YM-58997, Z-15370, N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamid, Cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carbonsäure], 2- Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1- on, Cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], 9- Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3J4-c]-1 ,2,4-triazolo[4,3-a]pyridin und 9-Cyc!opentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3- ajpyridin, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate und/oder Hydrate.Most preferably, the PDE4 inhibitor is selected from the group consisting of enprofylline, roflumilast, ariflo (cilomilast), arofylline, atizoram, AW D-12-281 (GW-842470), T-440, T-2585, PD-168787, V-1 1294A, CI-1018, CDC-801, D-22888, YM-58997, Z-15370, N- (3,5-dichloro-1-oxo) pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide, cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4- ( 3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], 9-cyclopentyl-5,6-dihydro-7- ethyl 3- (2-thienyl) -9H-pyrazolo [3 J 4-c] -1,4,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7 -ethyl-3- (tert-butyl) -9H-pyrazolo [3,4-c] -1, 2,4-triazolo [4,3-ajpyridin, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates and / or hydrates.

Besonders bevorzugt ist der PDE4-Inhibitor ausgewählt aus der Gruppe bestehend aus Roflumilast, Ariflo (Cilomilast), Arofyllin.AWD- 12-281 (GW-842470), 2-Carbomethoxy-4- cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-on, Cis[4-cyano-4- (3-cycIopropyimethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], Atizoram, Z-15370, 9- Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3-a]pyridin und 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3- a]pyridin gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate und/oder Hydrate.More preferably, the PDE4 inhibitor is selected from the group consisting of roflumilast, ariflo (cilomilast), arofyllin. AWD 12-281 (GW-842470), 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4- difluoromethoxyphenyl) cyclohexan-1-one, cis [4-cyano-4- (3-cyclopethyidimethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol], Atizoram, Z-15370, 9-cyclopentyl-5,6-dihydro-7- ethyl 3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl -3- (tert-butyl) -9H-pyrazolo [3,4-c] -1, 2,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of their pharmacological compatible acid addition salts, solvates and / or hydrates.

Unter Säureadditionssalzen mit pharmakologisch verträglichen Säuren zu deren Bildung die o.g. PDE4-inhibitoren gegebenenfalls in der Lage sind, werden beispielsweise Salze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrobenzoat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-to!uolsuifonat, bevorzugt Hydrochlorid, Hydrobromid, Hydrosulfat, Hydrophosphat, Hydrofumarat und Hydromethansulfonat verstanden.Among acid addition salts with pharmacologically acceptable acids for their formation the o.g. Examples of suitable PDE4 inhibitors are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and Hydro-p-to! Uolsuifonat, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.

Als LTD4-Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001 , MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L- 733321 , 1-(((R)-(3-(2-(6,7-Difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2- propyl)phenyl)thio)methylcyclopropan-essigsäure, 1 -(((1 (R)-3(3-(2-(2,3-Dichloro- thieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)- propyl)thio)methyl)cyclopropanessigsäure und [2-[[2-(4-tert-Butyl-2-thiazolyl)-5- benzofuranyl]oxymethyl]phenyl]essigsäure gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate.Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321, 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy -2- propyl) phenyl) thio) methylcyclopropane acetic acid, 1 - (((1 (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - ( E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid and [2 - [[2- (4-tert-butyl-2-thiazolyl ) -5-benzofuranyl] oxymethyl] phenyl] acetic acid, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Bevorzugt ist der LTD4-Antagonist ausgewählt aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001 , MEN-91507 (LM- 1507), VUF-5078, VUF-K-8707 und L-733321 , gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate.Preferably, the LTD4 antagonist is selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Besonders bevorzugt ist der LTD4-Antagonist ausgewählt aus der Gruppe bestehend aus Montelukast, Pranlukast, Zafirlukast, MCC-847 (ZD-3523), MN-001 und MEN-91507 (LM- 1507) gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakoligisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form ihrer Salze und Derivate, ihrer Solvate und/oder Hydrate.The LTD4 antagonist is particularly preferably selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 and MEN-91507 (LM-1507), optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmaceutically acceptable acid addition salts and optionally in the form of their salts and derivatives, their solvates and / or hydrates.

Unter Säureadditionssalzen mit pharmakologisch verträglichen Säuren zu deren Bildung die LTD4-Antagonisten gegebenenfalls in der Lage sind, werden beispielsweise Salze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrobenzoat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat, bevorzugt Hydrochlorid, Hydrobromid, Hydrosulfat, Hydrophosphat, Hydrofumarat und Hydromethansulfonat verstanden. Unter Salzen oder Derivaten zu deren Bildung die LTD4-antagonisten gegebenenfalls in der Lage sind, werden beispielsweise verstanden : Alkalisalze, wie beispielsweise Natrium- oder Kaliumsalze, Erdalkalisalze, Sulfobenzoate, Phosphate, Isonicotinate, Acetate, Propionate, Dihydrogenphosphate, Palmitate, Pivalate oder auch Furoate. Als EGFR-Hemmer gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4- (morphoIin^-yO-i-oxo^-buten-i-yöaminoJ-y-cyclopropylmethoxy-chinazolin, 4-[(3-Chlor- 4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7- cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N- dimethylamino^i-oxo^-buten-i-y^aminoJ-Z-cyclopropylmethoxy-chinazolin, 4-[(R)-(I- Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1- oxo-2-buten-1 -yOaminoJ-T-cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)- (tetrahydrofuran-3-yl)oxy]-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2- methoxymethyl-6-oxo-moφholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy- ethyO-N-methyl-aminoJ-i-oxo^-buten-i-yljamino^-cyclopropylmethoxy-chinazolin, 4-[(3- Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- cyclopentyloxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)- amino^i-oxo^-buten-i-yllamino^-cyclopropyimethoxy-chinazolin, 4-[(R)-(1-Phenyl- ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7- cyclopropylmethoxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)- N-methyl-aminol-i-oxo^-buten-i-ylJamino^-cyclopropylmethoxy-chinazolin, 4-[(R)-(I- Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1- yl}amino)-7-cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N- dimethylamino)-1-oxo-2-buteπ-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin, 4- [(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7- ((S)-tetrahydrofuran-3-yloxy)-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2- methoxy-ethyO-N-methyl-aminol-i-oxo^-buten-i-ylJamino^-cyclopentyloxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1- yl]amino}-7-cyclopentyloxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N- dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]- chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyl)amino]- 6,7-bis-(2-methoxy-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4- yl)-propyloxy]-6-[(vinylcarbonyl)amino]-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-(4- hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin, 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-chinolin, 4-{[3-Chlor-4-(3- fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl-ethyl)amino]methyl}-furan-2- yl)chinazolin, 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1 - oxo-2-buten-1-yl]amino}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4- (morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1- yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-{[4- (5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2- yl)rnethoxy]-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)- piperidin-1-yl]-ethoxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.- butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyOaminol-θ-^rans^-amino-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl- oxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1- [(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3- ChloM-fluor-phenyOaminol-β-Ctetrahydropyran^-yloxyJ^-ethoxy-chinazolin, 4-[(3-Chlor- 4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4- yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- acetylamino-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)aminoj-6-(tetrahydropyran-4- yloxy)-7-(2-methansulfonylamino-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6- {1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyOaminoJ-e-O-aminocarbonylmethyl-piperidin^-yloxy^-methoxy-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}- cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N- [(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4- [(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}- cyclohexan-1 -yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4- ethansulfonylamino-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-ethoxy-chinazolin, 4-[(3-Chlor-4- fluor-pheπyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7- (2-methoxy-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino- cyclohexan-1 -yloxy)-7-methoxy-chinazoiin, 4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert.- butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6- (tetrahydropyran-4-yloxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis- 4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fiuor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1- yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]- piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1- [(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-chinazolin, 4-[(3- Ethinyl-phenyOaminoJ-θ^i-acetyl-piperidin^-yloxyJ-Z-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N- methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6- (piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy- acetyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-{1- [(morpholιn-4-yl)carbonyl]-pιpeπdιn-4-yloxy}-7-methoxy-chιnazolιn, 4-[(3-Chlor-4-fluor- phenyl)amιno]-6-{1-[(cιs-2,6-clιnnethyl-morpholιn-4-yl)carbonyl]-pipeπdιn-4-yloxy}-7- methoxy-chinazohn, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-{1-[(2-methyl-morpholιn-4- yl)carbonyl]-pιperιdιn-4-yloxy}-7-πnethoxy-chιnazolιn, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6- {1-[(S,S)-(2-oxa-5-aza-bιcyclo[2 2 1]hept-5-yl)carbonyl]-pιpeπdιn-4-yloxy}-7-methoxy- chinazolin, 4-[(3-Chlor-4-fiuor-phenyl)amιno]-6-{1-[(N-methyl-N-2-methoxyethyl- amιno)carbonyl]-pιpeπdιn-4-yloxy}-7-methoxy-chιnazolιn, 4-[(3-Chlor-4-fluor- phenyl)amιno]-6-(1-ethyl-pιpeπdιn-4-yloxy)-7-methoxy-ch(nazolιn, 4-[(3-Chlor-4-fluor- phenyOaminoJ-β-li-^-methoxyethyOcarbonyll-pipeπdin^-yloxyJ^-methoxy-chinazolin, A- [(3-Chlor-4-fluor-phenyl)amιno]-6-{1-[(3-methoxypropyl-amιno)-carbonyl]-pιpeπdιn-4- yloxy}-7-methoxy-chιnazolιn, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-[cιs-4-(N-methansulfonyl- N-methyl-aminoJ-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amιno]-6-[cιs-4-(N-acetyl-N-methyl-amιno)-cyclohexan-1-yloxy]-7-methoxy- chinazolin, 4-[(3-Chlor-4-fiuor-phenyi)amιno]-6-(trans-4-methylamιno-cyclohexan-1-yloxy)- 7-methoxy-chιnazolιn, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-[trans-4-(N-methansulfonyl-N- methyl-amιno)-cyclohexan-1-yloxy]-7-methoxy-chιnazolιn, 4-[(3-Chlor-4-fluor- phenyOaminoJ-θ-^rans^-dimethylannino-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3- Chlor-4-f)uor-phenyl)amιno]-6-(trans-4-{N-[(morphol)n-4-yl)carbony)]-N-methyl-amιno}- cyclohexan-1-yloxy)-7-methoxy-chιnazol/n, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-[2-(2,2- dιmethyl-6-oxo-morpholιn-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chιnazolιn, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-(1-methansulfonyl-pιpeπdιn-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amιno]-6-(1-cyano-pιperιdιn-4-yloxy)-7-methoxy- chinazolin, Cetuximab, Trastuzumab, ABX-EGF und Mab ICR-62, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch vertraglichen Säureadditionssalze, ihrer Solvate und/oder HydrateAcid addition salts with pharmacologically acceptable acids for which the LTD4 antagonists are optionally capable of being used are, for example, salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, Hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood. Examples of salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates , Preferred EGFR inhibitors are compounds which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholinyl) -xy-1-oxo] -Buten-i-yamoyl-y-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-diethylamino) -1-oxo-2-butene] 1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -oxo-butyne-1-yl amino-Z-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholine-4] yl) -1-oxo-2-buten-1-y-amino-J-T-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6 -methyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -2-methoxymethyl-6-oxo-4-methyl-4-yl) -1-oxo-2-butene-1 -yl] amino} -7-cyclopropylmethoxy-c hinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethoxy-N-methylamino) -j-oxo-butyne-1-yl] amino ^ -cyclopropylmethoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} - 7-cyclopentyloxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) -amino] -oxo ^ -butene-i-ylamino ^ -cyclopropyl-methoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-ethyl- amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxy-ethyl) - N -methyl-aminol-i-oxo -but-i-yl-amino-cyclopropyl-methoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6- ( {4- [N- (tetrahydropyran-4-yl) -N-methyl-amino] -1-oxo-2-buten-1-yl} -amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro) 4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-but-1-yl] amino} -7 - ((R) -tetrahydrofur an-3-yloxy) quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7- ((S) -tetrahydrofuran-3-yloxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethoxy) N-methyl-aminol-i-oxo -but-i-yl-amino-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N-cyclopropyl-N- methyl-amino) -1-oxo-2-buten-1-yl] -amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl ) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] - quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (morpholin-4 yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2, 3-d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] amino} -7-ethoxy-quinoline, 4 - {[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl-ethyl) -amino] -methyl } -furan-2-yl) quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxomorpholine-4-] yl) -1-oxo-2-buten-1-yl] amino} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholine-4- yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N, N-bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] - quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl ] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 -methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phe nyl) amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxomorpholin-4-yl) -piperidine -1-yl] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyaminol-θ-rans-amino-cyclohexan-i-yloxy) -methoxy-quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran 3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(methoxymethy l) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline , 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3 ChloM-fluorophenyl amino-β-Ctetrahydropyran ^ -yloxy-J-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7 -hydroxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {trans-4 - [(morpholin-4-yl) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2- acetylamino-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino-6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4 -fluorophenyl amino-E-amino-carbonylmethyl-piperidine ^ -yloxy-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran- 4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4 - {N- [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino ] -6- (cis-4- {N - [(morpholin-4-yl) sulfonyl] -N-methyl-amino} -cyclohexane-1-ylxy) -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-i-yloxy) -methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- ( 1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulf onyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexane-1 - yloxy) -7-methoxy-quinazoiin, 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4- [ (3-ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis -4 {N - [(piperidin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) amino] -6- {1- [(morph olin-4-yl) carbonyl] -piperidin-4-yloxy} -7- (2-methoxyethoxy) quinazoline, 4 - [(3-ethynyl-phenoxy-amino-1-yl-i-acetyl-piperidine] -xyloxy-Z -methoxy-quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy ) -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro -phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3 Ethynylphenyl) amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidine 4-yloxy] -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- {1- [(morpholino-4-yl) carbonyl] -pιpeπdιn-4-yloxy} -7-methoxy-chιnazolιn, 4 - [(3-chloro-4-fluoro-phenyl) amιno] -6- {1 - [(cs- s 2,6-trimethyl-morpholino-4-yl) carbonyl] -piphenyl-4-yloxy} -7-methoxy-quinazone, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1- [(2-methyl-morpholine-4-yl) -carbonyl] -pιperιdιn-4-yloxy} -7-methoxy-quinazole, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- {1- [(S, S) - (2-oxa-5-aza-bicyclic [2 2 1] hept-5-yl) carbonyl] -pιpeπdιn-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 Chloro-4-fluoro-phenyl) amino] -6- {1 - [(N-methyl-N-2-methoxyethyl-amino) carbonyl] -pιpeπdιn-4-yloxy} -7-methoxy-chιnazolιn, 4 - [( 3-chloro-4-fluoro-phenyl) aminol] -6- (1-ethyl-pyridin-4-yloxy) -7-methoxy-ch (nazolene, 4 - [(3-chloro-4-fluoro-phenoxy-amino-β -li - ^ -methoxyethylcarbonyl-piperidine ^ -yloxy-1-methoxy-quinazoline, A- [(3-chloro-4-fluoro-phenyl) -mino] -6- {1 - [(3-methoxy-propyl-amino-carbonyl] -pιpeπdιn-4-yloxy} -7-methoxy-chιnazolιn, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [cιs-4- (N-methanesulfonyl-N-methyl-amino-c yclohexan-i-yloxy-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- [cis-4- (N-acetyl-N-methylamino) -cyclohexane-1 -yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazole, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-chιnazolιn, 4- [(3-chloro-4-fluorophenylamino) -J-methyl-dimethyl-cyclohexan-1-yloxy-methoxy-quinazoline, 4 - [(3-chloro-4-f) -urour-phenyl) amino] - 6- (trans-4- {N - [(morphol) n-4-yl) carbonyl)] - N -methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazole / n, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholino-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2 -yl) methoxy] -quinazole, 4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-4-pyrido-4-yloxy) -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) aminol] -6- (1-cyano-pyridinyl-4-yloxy) -7-methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, g optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates

Bevorzugte EGFR-Hemmer sind ausgewählt aus der Gruppe bestehend aus 4-[(3-Chlor- 4-fluorphenyl)amιno]-6-{[4-(morpholιn-4-yl)-1-oxo-2-buten-1-yl]amιno}-7- cyclopropylmethoxy-chinazolm, 4-[(3-Chlor-4-fluorphenyl)amιno]-6-{[4-(N,N-dιethy)amιno)- 1 -oxo-2-buten-1 -yl]amιno}-7-cyclopropylmethoxy-chιnazolιn, 4-[(3-Chlor-4- fluorphenyl)amιno]-6-{[4-(N,N-dιmethylamιno)-1-oxo-2-buten-1-yl]amιno}-7- cyclopropylmethoxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amιno]-6-{[4-(morpholιn-4-yl)- 1 -oxo-2-buten-1 -yl]amιno}-7-cyclopentyloxy-chιnazolιn, 4-[(3-Chlor-4-fluor-phenyl)amιno]- 6-{[4-((R)-6-methyl-2-oxo-morpholιn-4-yl)-1-oxo-2-buten-1-yl]amιno}-7- cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl- 2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy3- chinazolin, 4-[(3-Chlor-4-fluor-pheny])amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin- 4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazolin, 4- [(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten- 1-yl}amino)-7-cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N- dimethylaminoj-i-oxo^-buten-i-yljamino^-cyclopentyloxy-chinazolin, 4-[(R)-(1-Phenyl- ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7- cyclopropylmethoxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)- N-ethyl-aminol-i-oxo^-buten-i-ylJamino^-cyclopropylmethoxy-chinazolin, 4-[(R)-(I- Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1- yl}amino)-7-cyclopropylmethoxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N- (tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy- chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6- {[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)- chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]- 1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]- 6-{[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo-2-buten-1 -yl]amino}-7-cyclopentyloxy- chinazolin, 4-[(3-Chlor-4-fiuorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4- fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)- (tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy- ethoxy)-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6- [(vinylcarbonyl)amino]-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H- pyrrolo[2,3-d]pyrimidin, 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N- dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-chinolin, 4-{[3-Chlor-4-(3-fluor- benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl-ethyl)amino]methyl}-furan-2- yl)chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1- oxo-2-buten-1-yl]amino}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4- (morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1- yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-{[4- (5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)- ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2- yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)- piperidin-1-yl]-ethoxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.- butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyOaminol-θ-Ctrans^-methansulfonylamino-cyclohexan-i-yloxy^-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl- oxy}-7-methoxy-chinazolin, 4-[(3-Ch(or-4-fluor-phenyl)amino]-6-{1- [(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazolin, 4-[(3-Chlor- 4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4- yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- acetylamino-ethoxy)-chinazo!in, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4- yloxy)-7-(2-methansulfonylamino-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6- {1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl- amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6- (cis-4-{N-[(morpholin-4-yl)carbonyl]-N-nnethy[-annino}-cyclohexan-1-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N- methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- pheny^aminoJ-e^trans^-ethansulfonylamino-cyclohexan-i-yloxy^Z-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-pipericlin-4-yloxy)-7-ethoxy- chinazolin, 4-[(3-Chlor-4-fiuor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)- piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6- (cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3- Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yioxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1- yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl- piperazin-1 -yOcarbonylJ-N-methyl-aminoJ-cyclohexan-i -yloxy)-7-methoxy-chinazolin, 4- [(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1- yl)ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1- [(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-chinazolin, 4-[(3- Ethinyl-phenyOaminol-θ-CI-acetyl-piperidin^-yloxy^-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N- methyl-aminoj-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6- (piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy- acetyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-{1 -Preferred EGFR inhibitors are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholino-4-yl) -1-oxo-2-butene-1] yl] amino} -7-cyclopropylmethoxy-quinazolm, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethyl) amino] - 1-oxo-2-butene 1 -yl] aminyl} -7-cyclopropylmethoxy-chιnazolιn, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-butene 1-yl] aminyl} -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholino-4-yl)-1-oxo-2-yl] buten-1-yl] amino} -7-cyclopentyloxy-chiazolene, 4 - [(3-chloro-4-fluoro-phenyl) aminol] - 6 - {[4 - ((R) -6-methyl-2-oxo -morpholιn-4-yl) -1-oxo-2-buten-1-yl] amιno} -7- cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo -2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy-3-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4 - ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4- [( 3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-buten-1-yl} amino) - 7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino-i-oxo-buten-1-yl-ylino) -cyclopentyloxy-quinazoline, 4 - [(R) - (1-Phenylethyl) amino] -6 - {[4- (N, N-bis (2-methoxy-ethyl) amino] -1-oxo-2-butene-1 -yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethyl- aminol-i-oxo -but-i-yl-amino-cyclopropyl-methoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl ) -Nm ethyl-amino] -1-oxo-2-buten-1-yl} -amino) -7-cyclopropyl-methoxy-quinazoline, 4 - [(R) - (1-phenyl-ethyl) -amino] -6 - ({4- [ N- (tetrahydropyran-4-yl) - N -methyl-amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline, 4- [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran 3-yloxy) - quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo -2-buten-1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] - 6 - {[4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) -amino] -6 - {[4- (N, N-dimethylamino) 1-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] - 6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -china zoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -7- [3 - (morpholin-4-yl) propyloxy] -6- [(vinylcarbonyl) amino] quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6- (4-hydroxy-phenyl) - 7H-pyrrolo [2,3-d] pyrimidine, 3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2 -but-1-yl] -amino} -7-ethoxy-quinoline, 4 - {[3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5 - {[(2-methanesulfonyl -ethyl) amino] methyl} -furan-2-yl) quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-] oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4 - (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluorophenyl ) amino] -6 - ({4- [N, N-bis (2-methoxyethyl) amino] -1-oxo-2-buten-1-yl} amino) -7 - [(tetrahydrofuran-2 -yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(R) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -6 - [(S) - (tetrahydrofuran-2 - yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxomorpholin-4-yl) -piperidin-1-yl ] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-aminocyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-amino) 4-fluoro-phenyl-amino-η-C-trans -methanesulfonylamino-cyclohexan-i-yloxy-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-p iperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidine-4 yl-oxy} -7-methoxy-quinazoline, 4 - [(3-Ch (or-4-fluoro-phenyl) -amino] -6- {1- [(methoxymethyl) -carbonyl] -piperidin-4-yloxy} -7 -methoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -6- {trans-4 - [(dimethylamino) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {trans-4 - [(morp holin-4-yl) sulfonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7 - (2-acetylamino-ethoxy) quinazo!, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- (cis-4- {N - [(tetrahydropyran-4-yl) carbonyl] -N-methylamino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) carbonyl] -N-naphthyl [-annino} -cyclohexan-1-yloxy) -7-methoxy quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexane-1 -yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro phenyl-amino-e-trans-ethanesulfonylamino-cyclohexan-i-yloxy-Z-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-pipericlin-4 -yloxy) -7-ethoxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynylphenyl ) amino] -6- [1- (tert -butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- (tetrahydropyran-4-yioxy ] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) carbonyl] -N-methyl- amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methyl-piperazine -1-o-carbonylJ-N-methyl-amino-1-cyclohexane-i-oxy) -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [( morpho lin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2- oxopyrrolidin-1-yl) ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(morpholine-4- yl) carbonyl] -piperidin-4-yloxy} -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-ethynyl-phenoxy-olefin-θ-Cl-acetyl-piperidine] -yloxy-methoxy-quinazoline, 4 - [(3-Ethynylphenyl) amino] -6- (1-methylpiperidin-4-yloxy) -7-methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1 -methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2 -methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino-cyclohexan-1-yloxy} -methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6 - (piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- methoxyquinazoline, 4 - [(3-ethynylphenyl) amino] -6- {1 -

[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyi]-piperidin-4-yloxy}-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholin-4- yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6- {1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy- chinazolin, 4-t(3-Chlor-4-fluor-phenyl)aminσ]-6-{1-[(N-methyl-N-2-methoxyethyl- amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, A- [(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4- yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl- N-methyl-aminoJ-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)- 7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N- methyl-aminoj-cyclohexan-i-yloxy^-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}- cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2- dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy- chinazolin, und Cetuximab, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate.[(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [(cis] 2,6-dimethyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(2-methyl-morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [(S, S) - (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4-t (3 Chloro-4-fluoro-phenyl) aminσ] -6- {1 - [(N-methyl-N-2-methoxyethylamino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, A- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 -Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino-1-cyclohexan-1-yloxy) -methoxy-quinazoline, 4 - [(3-chloro-4 -fluorophenyl) amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4- fluorophenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans -4- (N-methanesulfonyl-N-methyl-amino-cyclohexan-1-yloxy) -methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl ] -N-methyl-amino} - cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl 6-oxo-morpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) -methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin- 4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, and cetuximab optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Besonders bevorzugt gelangen im Rahmen der vorliegenden Erfindung diejenigen EGFR- Hemmer zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus 4-[(3-Chlor- 4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7- cyclopropylmethoxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)- 1 -oxo-2-buten-1 -yl]amino}-7-cyclopentyloxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]- 6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)- (tetrahydrofuran-3-yl)oxy]-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl- 2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6- ({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7- cyclopropylmethoxy-chinazolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4- yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin, 4-[(3- Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1- yl}amino)-7-cyclopentyloxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N- dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]- chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin, 4-[(R)-(I- Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin, 3-Cyano-4-[(3-chlor- 4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy- chinolin, 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2- buten-1-yl]amino}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4- (morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyi)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1- yl]amino}-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)- ρiperidin-1-yl]-ethoxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4- amino-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6- (trans-4-methansulfonyiamino-cydohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4- [(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-chinazolin, 4- [(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1- yloxy}-7-methoxy-chinazolin,Particularly preferred for the purposes of the present invention are those EGFR inhibitors which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl ) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4- (morpholine-4 -yl) - 1 -oxo-2-buten-1-yl] amino} -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6 - {[4 - (( R) -6-methyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] - quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- ({4- [N- (2-methoxyethyl) -N-methyl-amino] -1-oxo-2-butene 1-yl} amino) -7-cyclopropylmethoxy-quinazoline, 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methyl -amino] -1-oxo-2-buten-1-yl} amino) -7-cyclopropylmethoxy quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- ( 2-methoxy-ethyl) -N-methyl-amino] -1-oxo-2-b uten-1-yl} amino) -7-cyclopentyloxy-quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-one] buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-yl) methoxyethoxy) quinazoline, 4 - [(R) - (1-phenyl-ethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine, 3-cyano- 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-ethoxy quinoline, 4 - [(R) - (1-phenylethyl) amino] -6 - {[4 - ((R) -6-methyl-2-oxomorpholin-4-yl) -1-oxo-2 - buten-1-yl] amino} -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2 -but-1-yl] -amino} -7 - [(tetrahydrofuran-2-yl) -methoxy] -quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6 - {[4- (5,5-dimethyl -2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {2 - [4- (2-oxomorpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonyiamino-cyclohexane-1 -yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro -phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (2-ac ethyl-amino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline , 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexan-1-yloxy} -7-methoxy-quinazoline,

4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4- y!)carbonyl]-N-methyl-amino}-cyc!ohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-1-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)- piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6- (tetrahydropyran-4-yloxy]-7-methoxy-chinazo!in, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis- 4-{N-[(pipeπdin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]- cyclohexan-1-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2- oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Ethinyl- phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazolin, 4-[(3- Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl- amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)- cyclohexan-1-yloxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4- methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino- cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-nnethoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)- (tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1- methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]- 6-(1 -cyano-piperidin-4-yloxy)-7-methoxy-chinazolin, und 4-[(3-Chlor-4-fluor-phenyl)amino]- 6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate.4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidin-1-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (cis-4- {N - [(morpholin-4-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-chloro-4-fluoro -phenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxy-ethoxy) -quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazo! In, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(pipeπdine) 1-yl) carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] - cyclohexan-1-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl] piperidin-4-yloxy} -7-methoxy-chi nazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-Methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline , 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methylpiperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline, 4 - [(3-ethynyl -phenyl) -amino] -6- {1 - [(morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino ] -6- {1 - [(N-methyl-N-2-methoxyethylamino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4 ( N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N -acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexane 1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexane 1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-nnethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) 7-methoxy-quinazoline, 4 - [(3-chloro 4-fluoro-phenyl) amino] - 6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, and 4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Erfindungsgemäß besonders bevorzugt sind als EGFR-Hemmer diejenigen Verbindungen, die ausgewählt sind aus der Gruppe bestehend aus 4-[(3-Chlor-4- fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7- cyclopropylmethoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl- 2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]- chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)- ethoxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy- ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazolin, 4-[(3- Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazolin, 4-[(3-Chlor-4- fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2- yl)methoxy]-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4- yl)-1 -oxo-2-buten-1 -yl]amino}-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4- methansulfonylamino-cyclohexan-1 -yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazolin, 4- [(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7- methoxy-chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Ethinyl-phenyi)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin, 4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]- piperidin-4-yloxy}-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N- methansulfonyl-N-methyl-aminoJ-cyclohexan-i-yloxyj^-methoxy-chinazolin, 4-[(3-Chlor-4- fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy- chinazolin, 4-[(3-Chlor-4-fluor-phenyi)amino]-6-(trans-4-methylamino-cydohexan-1-yloxy)- 7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N- methyl-amino)-cyclohexan-1 -yloxy]-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor- phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3- Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}- cyclohexan-1-yloxy)-7-methoxy-chinazolin, 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2- dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazolin, 4-[(3-Chlor-4-f luor-phenyl)amino]-6-(1 -methansulfonyl-piperidin-4-yloxy)-7-methoxy- chinazolin und 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -cyano-piperidin-4-yloxy)-7-methoxy- chinazolin gegebenenfalls in Form ihrer Racemate, Enantiomere oder Diastereomere, gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, ihrer Solvate und/oder Hydrate.Particularly preferred according to the invention as EGFR inhibitor are those compounds which are selected from the group consisting of 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1- oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6 - {[4 - ((R) -6-methyl - 2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] -quinazoline, 4 - [( 3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline, 4- [ (3-chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methylamino] -1-oxo-2-buten-1-yl} amino) 7-cyclopropylmethoxy quinazoline, 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(tetrahydrofuran-2-yl) methoxy] quinazoline, 4 - [(3 Ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl} amino} quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-me thansulfonylamino-cyclohexane-1-oxy) -7-methoxyquinazoline, 4 - [(3-chloro-4-fluorophenyl) amino] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline, 4- [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4- [(3 Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxo-pyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline, 4 - [(3 ethynyl-phenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy- quinazoline, 4 - [(3-ethynylphenyl) amino] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline, 4 - [(3-ethynyl-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidine-4 -yloxy} - 7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) carbonyl] -piperidin-4-yloxy} -7- methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino-1-cyclohexan-1-yloxy) -methoxy-quinazoline, 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro) phenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-oxy] -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-) {N- [ (morpholin-4-yl) carbonyl] - N -methyl-amino} - cyclohexan-1-yloxy) -7-methoxy-quinazoline, 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [ 2- (2,2-dimethyl-6-oxomorpholin-4-yl) -ethoxy] -7 - [(S) - (tetrahydrofuran-2-yl) -methoxy] -quinazoline, 4 - [(3-chloro) 4-fluoro-phenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline and 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- ( 1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.

Unter Säureadditionssalzen mit pharmakologisch verträglichen Säuren zu deren Bildung die EGFR-Hemmer gegebenenfalls in der Lage sind, werden beispielsweise Salze ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Hydroiodid, Hydrosulfat, Hydrophosphat, Hydromethansulfonat, Hydronitrat, Hydromaleat, Hydroacetat, Hydrobenzoat, Hydrocitrat, Hydrofumarat, Hydrotartrat, Hydrooxalat, Hydrosuccinat, Hydrobenzoat und Hydro-p-toluolsulfonat, bevorzugt Hydrochlorid, Hydrobromid, Hydrosulfat, Hydrophosphat, Hydrofumarat und Hydromethansulfonat verstanden.By acid addition salts with pharmacologically acceptable acids for the formation of which the EGFR inhibitors are optionally capable, for example, salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, Hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate understood.

Als Dopamin-Agonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Bromocriptin, Cabergolin, Alpha- Dihydroergocryptin, Lisurid, Pergolid, Pramipexol, Roxindol, Ropinirol, Talipexol, Tergurid und Viozan. Eine Bezugnahme auf die vorstehend genannten Dopamin-Agonisten schließt im Rahmen der vorliegenden Erfindung eine Bezugnahme auf deren gegebenenfalls existierende pharmakologisch verträgliche Säureadditionssalze und gegebenenfalls deren Hydrate ein. Unter den physiologisch verträglichen Säureadditionssalzen, die von den vorstehend genannten Dopamin-Agonisten gebildet werden können, werden beispielsweise pharmazeutisch verträgliche Salze verstanden, die ausgewählt aus den Salzen der Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weinsäure und Maleinsäure sind.Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan. Reference to the aforementioned dopamine agonists in the context of the present invention includes a reference to the latter optionally existing pharmacologically acceptable acid addition salts and optionally their hydrates. Among the physiologically acceptable acid addition salts which can be formed from the aforementioned dopamine agonists are, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric , Tartaric acid and maleic acid are.

Als H1-Antihistaminika gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Epinastin, Cetirizin, Azelastin,As H1-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine,

Fexofenadin, Levocabastin, Loratadin, Mizolastin, Ketotifen, Emedastin, Dimetinden, Clemastin, Bamipin, Cexchlorpheniramin, Pheniramin, Doxylamin, Chlorphenoxamin, Dimenhydrinat, Diphenhydramin, Promethazin, Ebastin, Desloratidin und Meclozin. Eine Bezugnahme auf die vorstehend genannten H 1 -Antihistaminika schließt im Rahmen der vorliegenden Erfindung eine Bezugnahme auf deren gegebenenfalls existierende pharmakologisch verträgliche Säureadditionssalze ein.Fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin. Reference to the above-mentioned H 1 -antihistamines in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts.

Als PAF-Antagonisten gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus 4-(2-Chlorphenyl)-9-methyl-2-[3(4- morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1 ,2,4]triazolo[4,3-a][1 ,4]diazepin, 6-(2- Chlorphenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta- [4,5]thieno-[3,2-f][1 ,2,4]triazolo[4,3-a][1 ,4]diazepin.Preferred PAF antagonists here are compounds which are selected from the group consisting of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl] - 6H-thieno [3,2-f] - [1,2,4] triazolo [4,3-a] [1,4] diazepine, 6- (2-chlorophenyl) -8,9-dihydro-1- Methyl 8 - [(4-morpholinyl) carbonyl] -4H, 7H-cyclo-penta- [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] diazepine.

Als MRP4-Inhibitoren gelangen hierbei vorzugsweise Verbindungen zur Anwendung, die ausgewählt sind aus der Gruppe bestehend aus Λ/-Acetyl-dinitrophenyl-Cysteine, cGMP, Cholate, Diclofenac, Dehydroepiandrosterone 3-glucuronide, Dehydroepiandrosterone 3- sulphate, Dilazep, Dinitrophenyl-S-glutathione, Estradiol 17-ß-glucuronide, Estradiol 3,17- disulphate, Estradiol 3-glucuronide, Estradiol 3-sulphate, Estrone 3-sulphate, Flurbiprofen, Folate, N5-formyl-tetrahydrofoiate, Glycocholate, Glycolithocholic acid sulphate, Ibuprofen, Indomethacin, Indoprofen, Ketoprofen, Lithocholic acid sulphate, Methotrexate, MK571 ((E)-3-[[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3- oxopropyl]thio]methyl]thio]-propanoic acid), α-Naphthyl-ß-D-glucuronide, Nitrobenzyl mercaptopurine riboside, Probeneeid, PSC833, Sildenafil, Sulfinpyrazone, Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate, Taurolithocholate, Taurolithocholic acid sulphate, Topotecan, Trequinsin und Zaprinast, Dipyridamol, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und ihrer pharmakologisch verträglichen Säure- Additionssalze und Hydrate.Preferred MRP4 inhibitors are compounds selected from the group consisting of Λ-acetyl-dinitrophenyl cysteines, cGMP, cholates, diclofenac, dehydroepiandrosterones 3-glucuronides, dehydroepiandrosterones 3-sulphates, dilazep, dinitrophenyl-S glutathiones, estradiol 17β-glucuronides, estradiol 3,17-disulphates, estradiol 3-glucuronides, estradiol 3-sulphates, estrone 3-sulphates, flurbiprofen, folates, N5-formyltetrahydrofoiate, glycocholates, glycolithocholic acid sulphate, ibuprofen, indomethacin , Indoprofen, ketoprofen, lithocholic acid sulphate, methotrexate, MK571 ((E) -3 - [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] - [[3-dimethylamino] -3- oxopropyl] thio] methyl] thio] propanoic acid), α-naphthyl-β-D-glucuronides, nitrobenzyl mercaptopurine riboside, sample sapon, PSC833, sildenafil, sulfinpyrazones, taurochenodeoxycholates, taurocholates, taurodeoxycholates, Taurolithocholate, Taurolithocholic acid sulphate, topotecan, trequinsin and zaprinast, dipyridamole, optionally in the form of their racemates, enantiomers, diastereomers and their pharmacologically acceptable acid addition salts and hydrates.

Vorzugsweise bezieht sich die Erfindung auf die Verwendung von MRP4-Inhibitoren zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von Atemwegserkrankungen enthaltend die erfindungsgemäßen PDE4B-Inhibitoren und MRP4-Inhibitoren, wobei die MRP4-Inhibitoren vorzugsweise ausgewählt sind aus der Gruppe bestehend aus /V-Acetyl-dinitrophenyl-Cysteine, Dehydroepiandrosterone 3- sulphate, Dilazep, Dinitrophenyl-S-glutathione, Estradiol 3,17-disulphate, Flurbiprofen, Glycocholate, Glycolithocholic acid sulphate, Ibuprofen, Indomethacin, Indoprofen, Lithocholic acid sulphate, MK571 , PSC833, Sildenafil, Taurochenodeoxycholate, Taurocholate, Taurolithocholate, Taurolithocholic acid sulphate, Trequinsin und Zaprinast, Dipyridamol, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und ihrer pharmakologisch verträglichen Säure- Additionssafze und Hydrate.Preferably, the invention relates to the use of MRP4 inhibitors for the preparation of a pharmaceutical composition for the treatment of respiratory diseases comprising the PDE4B inhibitors and MRP4 inhibitors according to the invention, wherein the MRP4 inhibitors are preferably selected from the group consisting of / V-acetyl dinitrophenyl cysteines, dehydroepiandrosterones 3-sulphate, dilazep, dinitrophenyl S-glutathione, estradiol 3,17-disulphate, flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833, sildenafil, taurochenodeoxycholate, Taurocholates, taurolithocholates, taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole, optionally in the form of their racemates, enantiomers, diastereomers and their pharmacologically acceptable acid addition fats and hydrates.

Stärker bevorzugt bezieht sich die Erfindung auf die Verwendung von MRP4-Inhibitoren zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung von Atemwegserkrankungen enthaltend die erfindungsgemäßen PDE4B-Inhibitoren und MRP4-Inhibitoren, wobei die MRP4-Inhibitoren vorzugsweise ausgewählt sind aus der Gruppe bestehend ausMore preferably, the invention relates to the use of MRP4 inhibitors for the manufacture of a pharmaceutical composition for the treatment of respiratory disorders comprising the PDE4B inhibitors and MRP4 inhibitors according to the invention, wherein the MRP4 inhibitors are preferably selected from the group consisting of

Dehydroepiandrosterone 3-sulphate, Estradiol 3,17-disulphate, Flurbiprofen, Indomethacin, Indoprofen, MK571 , Taurocholate, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diastereomere und ihrer pharmakologisch verträglichen Säure- Additionssalze und Hydrate. Die Trennung von Enantiomeren aus den Racematen kann durch bekannte Verfahren nach dem Stand der Technik durchgeführt werden (z.B. durch Chromatographie an chiralen Phasen etc.).Dehydroepiandrosterone 3-sulphate, estradiol 3,17-disulphate, flurbiprofen, indomethacin, indoprofen, MK571, taurocholate, optionally in the form of their racemates, enantiomers, diastereomers and their pharmacologically acceptable acid addition salts and hydrates. The separation of enantiomers from the racemates can be carried out by known methods known in the art (e.g., by chromatography on chiral phases, etc.).

Mit Säure-Additionssalzen mit pharmakologisch verträglichen Säuren sind z.B. Salze ausgewählt aus der Gruppe bestehend aus Hydrochloriden, Hydrobromiden, Hydroiodiden, Hydrosulphaten, Hydrophosphaten, Hydromethanesulphonaten, Hydronitraten, Hydromaleaten, Hydroacetaten, Hydrobenzoaten, Hydrocitraten, Hydrofumaraten, Hydrotartraten, Hydrooxalaten, Hydrosuccinaten, Hydrobenzoaten and Hydro-p-toluenesulphoπaten, vorzugsweise Hydrochloride, Hydrobromide, Hydrosulphate, Hydrophosphate, Hydrofumarate and Hydromethanesulphonate gemeint.Acid addition salts with pharmacologically acceptable acids include, for example, salts selected from the group consisting of hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and Hydro-p-toluenesulphoπaten, preferably hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and Hydromethanesulphonate meant.

Ein weiterer Gegenstand der Erfindung sind pharmazeutische Zubereitungen, die Dreifachkombinationen von den erfindungsgemäßen PDE4B-Inhibitoren, von MRP4- Inhibitoren und einer weiteren aktiven Substanz wie z.B. einem Anticholinergikum, einem Steroid, einem LTD4-Antagonist oder einem Betamimetikum enthalten, sowie deren Herstellung und deren Verwendung zur Behandlung von Atemwegserkrankungen.Another object of the invention are pharmaceutical preparations, the triple combinations of the PDE4B inhibitors of the invention, MRP4 inhibitors and another active substance such. an anticholinergic, a steroid, a LTD4 antagonist or a betamimetic, as well as their preparation and their use for the treatment of respiratory diseases.

DARREICHUNGSFORMENPRESENTATIONS

Geeignete Anwendungsformen sind beispielsweise Tabletten, Kapseln, Lösungen, Säfte, Emulsionen oder Inhalationspulver oder -aerosole. Hierbei soll der Anteil der pharmazeutisch wirksamen Verbindung(en) jeweils im Bereich von 0, 1 bis 90 Gew.-%, bevorzugt 0, 5 bis 50 Gew.-% der Gesamtzusammensetzung liegen, d.h. in Mengen die ausreichend sind, um den unten angegebenen Dosierungsbereich zu erreichen.Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols. In this case, the proportion of the pharmaceutically active compound (s) in each case in the range of 0, 1 to 90 wt .-%, preferably 0, 5 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.

Die orale Gabe kann in Form einer Tablette, als Pulver, als Pulver in einer Kapsel (z.B. Hartgelatinekapsel), als Lösung oder Suspension erfolgen. Im Fall einer inhalativen Gabe kann die Wirkstoffkombination als Pulver, als wässrige oder wässrig-ethanolische Lösung oder mittels einer Treibgasformulierung erfolgen.Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension. In the case of an inhalative administration, the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.

Bevorzugt sind deshalb pharmazeutische Formulierungen gekennzeichnet durch den Gehalt an einer oder mehrerer Verbindungen der Formel 1 gemäß der obigen bevorzugten Ausführungsformen.Therefore, pharmaceutical formulations are preferably characterized by the content of one or more compounds of formula 1 according to the above preferred embodiments.

Besonders bevorzugt ist es, wenn die Verbindungen der Formel 1 oral verabreicht werden, besonders bevorzugt ist es, wenn die Verabreichung ein oder zweimal täglich erfolgt. Entsprechende Tabletten können beispielsweise durch Mischen des oder der Wirkstoffe mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wieIt is particularly preferred if the compounds of the formula 1 are administered orally, it is particularly preferred if the administration takes place once or twice daily. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known auxiliaries, for example inert diluents, such as

Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Maisstärke oder Alginsäure, Bindemitteln, wie Stärke oder Gelatine, Schmiermitteln, wie Magnesiumstearat oder Talk, und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxymethylcellulose, Celluloseacetatphthalat, oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as Carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Kollidon oder Schellack, Gummi arabicum, Talk, Titandioxid oder Zucker, hergestellt werden. Zur Erzielung eines Depoteffektes oder zur Vermeidung von Inkompatibilitäten kann der Kern auch aus mehreren Schichten bestehen. Desgleichen kann auch die Drageehülle zur Erzielung eines Depoteffektes aus mehreren Schichten bestehen wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.

Säfte der erfindungsgemäßen Wirkstoffe beziehungsweise Wirkstoffkombinationen können zusätzlich noch ein Süßungsmittel, wie Saccharin, Cyclamat, Glycerin oder Zucker sowie ein Geschmack verbesserndes Mittel, z.B. Aromastoffe, wie Vanillin oder Orangenextrakt, enthalten. Sie können außerdem Suspendierhilfsstoffe oder Dickungsmittel, wie Natriumcarboxymethylcellulose, Netzmittel, beispielsweise Kondensationsprodukte von Fettalkoholen mit Ethylenoxid, oder Schutzstoffe, wie p-Hydroxybenzoate, enthalten.Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Die eine oder mehrere Wirkstoffe beziehungsweise Wirkstoffkombinationen enthaltenden Kapseln können beispielsweise hergestellt werden, indem man die Wirkstoffe mit inerten Trägern, wie Milchzucker oder Sorbit, mischt und in Gelatinekapseln einkapselt. Geeignete Zäpfchen lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln, wie Neutralfetten oder Polyäthylenglykol beziehungsweise dessen Derivaten, herstellen.The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules. Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

Als Hilfsstoffe seien beispielsweise Wasser, pharmazeutisch unbedenkliche organische Lösemittel, wie Paraffine (z.B. Erdölfraktionen), Öle pflanzlichen Ursprungs (z.B. Erdnuss- oder Sesamöl), mono- oder polyfunktionelle Alkohole (z.B. Ethanol oder Glycerin), Trägerstoffe wie z.B. natürliche Gesteinsmehle (z.B. Kaoline, Tonerden, Talkum, Kreide) synthetische Gesteinsmehle (z.B. hochdisperse Kieselsäure und Silikate), Zucker (z.B. Rohr-, Milch- und Traubenzucker) Emulgiermittel (z.B. Lignin, Sulfitablaugen, Methylcellulose, Stärke und Polyvinylpyrrolidon) und Gleitmittel (z.B. Magnesiumstearat, Talkum, Stearinsäure und Natriumlaurylsulfat) erwähnt. Im Falle der oralen Anwendung können die Tabletten selbstverständlich außer den genannten Trägerstoffen auch Zusätze, wie z.B. Natriumeitrat, Calciumcarbonat und Dicalciumphosphat zusammen mit verschiedenen Zuschlagstoffen, wie Stärke, vorzugsweise Kartoffelstärke, Gelatine und dergleichen enthalten. Weiterhin können Gleitmittel, wie Magnesiumstearat, Natriumlaurylsulfat und Talkum zum Tablettieren mit verwendet werden. Im Falle wässriger Suspensionen können die Wirkstoffe außer den oben genannten Hilfsstoffen mit verschiedenen Geschmacksaufbesserern oder Farbstoffen versetzt werden.As auxiliaries, for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg finely divided silicic acid and silicates), sugars (eg pipe, milk and dextrose) emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and Sodium lauryl sulfate). In the case of oral administration, the tablets may, of course, besides the abovementioned excipients also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.

Ebenfalls bevorzugt ist es, wenn die Verbindungen der Formel 1 inhalativ verabreicht werden, besonders bevorzugt ist es, wenn die Verabreichung ein oder zweimal täglich erfolgt. Hierzu müssen die Verbindungen der Formel 1 in inhalierbaren Darreichungsformen bereitgestellt werden. Als inhalierbare Darreichungsformen kommen Inhalationspulver, treibgashaltige Dosieraerosole oder treibgasfreie Inhalationslösungen in Betracht, die gegebenenfalls im Gemisch mit gebräuchlichen physiologisch verträglichen Hilfsstoffen vorliegen.It is likewise preferred if the compounds of the formula 1 are administered by inhalation, it being particularly preferred if the administration is carried out once or twice daily. For this purpose, the compounds of formula 1 must be provided in inhaled dosage forms. Suitable inhalable dosage forms are inhalable powders, propellant-containing metered-dose inhalers or propellant-free inhalable solutions which, if appropriate, are present in admixture with conventional physiologically compatible excipients.

Im Rahmen der vorliegenden Erfindung sind von dem Begriff treibgasfreie Inhalationslösungen auch Konzentrate oder sterile, gebrauchsfertige Inhalationslösungen umfasst. Die im Rahmen der vorliegenden Erfindung einsetzbaren Darreichungsformen werden im nachfolgenden Teil der Beschreibung detailliert beschrieben.In the context of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions. The administration forms which can be used in the context of the present invention will be described in detail in the following part of the description.

Inhalationspulver: Sind die Verbindungen der Formel 1 im Gemisch mit physiologisch unbedenklichen Hilfsstoffen enthalten, können zur Darstellung der erfindungsgemäßen Inhalationspulver die folgenden physiologisch unbedenklichen Hilfsstoffe zur Anwendung gelangen: Monosaccharide (z.B. Glucose oder Arabinose), Disaccharide (z.B. Lactose, Saccharose, Maltose), Oligo- und Polysaccharide (z.B. Dextrane), Polyalkohole (z.B. Sorbit, Mannit, Xylit), Salze (z.B. Natriumchlorid, Calciumcarbonat) oder Mischungen dieser Hilfsstoffe miteinander. Bevorzugt gelangen Mono- oder Disaccharide zurInhalation powder: If the compounds of the formula 1 are mixed with physiologically acceptable auxiliaries, the following physiologically acceptable excipients can be used to prepare the inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo - And polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with each other. Mono- or disaccharides are preferably added

Anwendung, wobei die Verwendung von Lactose oder Glucose, insbesondere, aber nicht ausschließlich in Form ihrer Hydrate, bevorzugt ist. Als besonders bevorzugt im Sinne der Erfindung gelangt Lactose, höchst bevorzugt Lactosemonohydrat als Hilfsstoff zur Anwendung. Verfahren zur Herstellung der erfindungsgemäßen Inhalationspulver durch Mahlen und Mikronisieren sowie durch abschließendes Mischen der Bestandteile sind aus dem Stand der Technik bekannt.Application, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention. Process for the preparation of the inhalable powders according to the invention Grinding and micronizing, as well as final mixing of the ingredients are known in the art.

Treibgashaltige Inhalationsaerosole: Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgashaltigen Inhalationsaerosole können 1 im Treibgas gelöst oder in dispergierter Form enthalten. Die zur Herstellung der Inhalationsaerosole einsetzbaren Treibgase sind aus dem Stand der Technik bekannt. Geeignete Treibgase sind ausgewählt aus der Gruppe bestehend aus Kohlenwasserstoffen wie n-Propan, n-Butan oder Isobutan und Halogenkohlenwasserstoffen wie bevorzugt fluorierten Derivaten des Methans, Ethans, Propans, Butans, Cyclopropans oder Cyclobutans. Die vorstehend genannten Treibgase können dabei allein oder in Mischungen derselben zur Verwendung kommen. Besonders bevorzugte Treibgase sind fluorierte Alkanderivate ausgewählt aus TG134a (1 , 1 , 1 , 2-Tetrafluorethan), TG227 (1 , 1 , 1, 2, 3, 3, 3-Heptafluorpropan) und Mischungen derselben. Die im Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgashaltigen Inhalationsaerosole können ferner weitere Bestandteile wie Co-Solventien, Stabilisatoren, oberflächenaktive Mittel (Surfactants), Antioxidantien, Schmiermittel sowie Mittel zur Einstellung des pH-Werts enthalten. All diese Bestandteile sind im Stand der Technik bekannt.Propellant-containing inhalation aerosols: The propellant-containing inhalable aerosols which can be used in the context of the use according to the invention can be dissolved in the propellant gas or in dispersed form. The propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-containing inhalation aerosols which can be used in the context of the use according to the invention may also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.

Treibgasfreie Inhalationslösungen: Die erfindungsgemäße Verwendung von Verbindungen der Formel 1 erfolgt bevorzugt zur Herstellung von treibgasfreien Inhalationslösungen und Inhalationssuspensionen. Als Lösungsmittel kommen hierzu wässrige oder alkoholische, bevorzugt ethanolische Lösungen in Betracht. Das Lösungsmittel kann ausschließlich Wasser sein oder es ist ein Gemisch aus Wasser und Ethanol. Die Lösungen oder Suspensionen werden mit geeigneten Säuren auf einen pH-Wert von 2 bis 7, bevorzugt von 2 bis 5 eingestellt. Zur Einstellung dieses pH-Werts können Säuren ausgewählt aus anorganischen oder organischen Säuren Verwendung finden. Beispiele für besonders geeignete anorganische Säuren sind Salzsäure, Bromwasserstoffsäure, Salpetersäure, Schwefelsäure und/oder Phosphorsäure. Beispiele für besonders geeignete organische Säuren sind: Ascorbinsäure, Zitronensäure, Äpfelsäure, Weinsäure, Maleinsäure, Bernsteinsäure, Fumarsäure, Essigsäure, Ameisensäure und/oder Propionsäure und andere. Bevorzugte anorganische Säuren sind Salzsäure, Schwefelsäure. Es können auch die Säuren verwendet werden, die bereits mit einem der Wirkstoffe ein Säureadditionssalz bilden. Unter den organischen Säuren sind Ascorbinsäure, Fumarsäure und Zitronensäure bevorzugt. Gegebenenfalls können auch Gemische der genannten Säuren eingesetzt werden, insbesondere in Fällen von Säuren, die neben ihren Säuerungseigenschaften auch andere Eigenschaften, z.B. als Geschmackstoffe, Antioxidantien oder Komplexbildner besitzen, wie beispielsweise Zitronensäure oder Ascorbinsäure. Erfindungsgemäß besonders bevorzugt wird Salzsäure zur Einstellung des pH-Werts verwendet.Propellant-Free Inhalation Solutions: The use according to the invention of compounds of the formula 1 is preferably carried out for the production of propellant-free inhalable solutions and inhalable suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water only or it may be a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids. To adjust this pH, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances. Among the organic acids are Ascorbic acid, fumaric acid and citric acid are preferred. Optionally, it is also possible to use mixtures of the abovementioned acids, in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as flavorings, antioxidants or complexing agents, for example citric acid or ascorbic acid. Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.

Den im Rahmen der erfindungsgemäßen Verwendung einsetzbaren treibgasfreien Inhalationslösungen können Co-Solventien und/oder weitere Hilfsstoffe zugesetzt werden. Bevorzugte Co-Solventien sind solche, die Hydroxylgruppen oder andere polare Gruppen enthalten, beispielsweise Alkohole - insbesondere Isopropylalkohol, Glykole - insbesondere Propylenglykol, Polyethylenglykol, Polypropylenglykol, Glykolether, Glycerol, Polyoxyethylenalkohole und Polyoxyethylen-Fettsäureester. Unter Hilfs- und Zusatzstoffen wird in diesem Zusammenhang jeder pharmakologisch verträgliche Stoff verstanden, der kein Wirkstoff ist, aber zusammen mit dem (den)Co-solvents and / or further auxiliaries can be added to the propellant-free inhalable solutions which can be used in the context of the inventive use. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, auxiliaries and additives are understood as meaning any pharmacologically acceptable substance which is not an active substance but together with the substance (s).

Wirkstoff(en) in dem pharmakologisch geeigneten Lösungsmittel formuliert werden kann, um die qualitativen Eigenschaften der Wirkstoffformulierung zu verbessern. Bevorzugt entfalten diese Stoffe keine oder im Kontext mit der angestrebten Therapie keine nennenswerte oder zumindest keine unerwünschte pharmakologische Wirkung. Zu den Hilfs- und Zusatzstoffen zählen z.B. oberflächenaktive Stoffe, wie z.B. Sojalecithin, Ölsäure, Sorbitanester, wie Polysorbate, Polyvinylpyrrolidon sonstige Stabilisatoren, Komplexbildner, Antioxidantien und/oder Konservierungsstoffe, die die Verwendungsdauer der fertigen Arzneimittelformulierung gewährleisten oder verlängern, Geschmackstoffe, Vitamine und/oder sonstige dem Stand der Technik bekannte Zusatzstoffe. Zu den Zusatzstoffen zählen auch pharmakologisch unbedenkliche Salze wie beispielsweise Natriumchlorid als Isotonantien. Zu den bevorzugten Hilfsstoffen zählen Antioxidantien, wie beispielsweise Ascorbinsäure, sofern nicht bereits für die Einstellung des pH-Werts verwendet, Vitamin A, Vitamin E, Tocopherole und ähnliche im menschlichen Organismus vorkommende Vitamine oder Provitamine. Konservierungs- Stoffe können eingesetzt werden, um die Formulierung vor Kontamination mit Keimen zu schützen. Als Konservierungsstoffe eignen sich die dem Stand der Technik bekannten, insbesondere Cetylpyridiniumchlorid, Benzalkoniumchlorid oder Benzoesäure bzw. Benzoate wie Natriumbenzoat in der aus dem Stand der Technik bekannten Konzentration. Für die oben beschriebenen Behandlungsformen werden gebrauchsfertige Packungen eines Medikaments zur Behandlung von Atemwegserkrankungen, beinhaltend eine beigelegte Beschreibung, welche beispielsweise die Worte Atemwegserkrankung, COPD oder Asthma enthält, eine der vorangehend beschriebenen erfindungsgemäßen Verbindungen und einen oder mehrere Kombinationspartner ausgewählt aus der oben beschriebenen Gruppe, bereitgestellt. Active ingredient (s) can be formulated in the pharmacologically suitable solvent to improve the qualitative properties of the drug formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy. The auxiliaries and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or prolong the useful life of the finished drug formulation, flavorings, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonants. Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism. Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. For the above-described forms of treatment, ready-to-use packs of a medicament for the treatment of respiratory disorders including an enclosed description including, for example, the words respiratory disease, COPD or asthma, one of the compounds of the invention described above and one or more combination partners selected from the group described above are provided ,

Claims

PATENTANSPRÜCHE 1. Verbindungen der Formel 1 ,1. Compounds of the formula 1, worin wherein A CO, C=NH, Ci_6-Alkylen oder C3-8-Cycloalkylen,A CO, C = NH, CI_ 6 alkylene or C 3-8 cycloalkylene, B1 Phenyl oder ein aromatischer oder nicht aromatischer Ring, der gegebenenfalls ein, zwei oder drei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und der gegebenenfalls ein- oder mehrfach mit einem oder mehreren Resten ausgewählt aus der Gruppe OH, O-C1-6-Alkyl, 0-C1. 6-Haloalkyl, Halogen, C1-6 -alkyl und C1-6-Haloalkyl substituiert sein kann;B 1 is phenyl or an aromatic or non-aromatic ring which may optionally contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which optionally mono- or polysubstituted with one or more radicals selected from the group OH, OC 1-6- alkyl, 0-C 1 . 6 haloalkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl may be substituted; B2 Phenyl oder ein Heteroaryl, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann;B 2 is phenyl or a heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; X O, S, NR5 oder CR6R7;X is O, S, NR 5 or CR 6 R 7; n 0, 1 , 2 oder 3;n is 0, 1, 2 or 3; R1 H, C1-6-Alkyl, C1-6-Halolalkyl, COR1 \ COOR1 1 CH2COOR1 1;R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, COR 1 \ COOR 1 1 CH 2 COOR 1 1 ; R1 1 H oder C1-6-Alkyl;R 1 is H or C 1-6 alkyl; R2 H, C1-6-Alkyl oder C1-6-HaIoIaIk^; oder R1 und R2 bilden gemeinsam mit dem Stickstoff einen nichtaromatischenR 2 is H, C 1-6 -alkyl or C 1-6 -haloalkyl; or R 1 and R 2 together with the nitrogen form a non-aromatic Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann;Heterocycle which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen; oder R2 , N, A und B1 bilden gemeinsam eine bicyclische Gruppe der Formel (i)or R 2 , N, A and B 1 together form a bicyclic group of the formula (i) worin wherein A CO, C=NH oder C1 -3-Alkyl m 1 , 2 oder 3 bedeuten, undA is CO, C is NH or C 1-3 -alkyl m is 1, 2 or 3, and R3 H oder ein Rest ausgewählt aus der Gruppe bestehend aus OH, C1-6-Haloalkyl, ein C6-io-Aryl, ein C5_i0-Heteroaryl und einem C3--ι0-Heterocyclus, wobei der C3-I0- Heterocyclus und das C5-1o-Heteroaryl ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten können, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-10-Aryl, gegebenenfalls überbrücktes C3-8-Cycloalkyl und C1-6-Haloalkyl substituiert sein kann, der gegebenenfalls mit einem Rest aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl, OH, Halogen und C6-10-Aryl substituiert sein kann; oder R3 C1-6-Alkyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl, CON(C1^-AIkYl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-Cβ-io-Aryl, OH, 0-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol; SO2-C1-6-Alkyl, SO2-C1-6-HaIOaIkYl, SO2-NH2, SO2-NH-C1-6-Alkyl,R 3 H or a radical selected from the group consisting of OH, C 1-6 haloalkyl, a C 6 -io-aryl, a C 5 _i 0 -Heteroaryl and a C 3 --ι 0 heterocycle, wherein the C 3-I0 - heterocycle and the C 5-1 o-heteroaryl one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen may contain, optionally with one or more radicals selected from the group consisting of C 1-6 - Alkyl, C 6-10 -aryl, optionally bridged C 3-8 -cycloalkyl and C 1-6 -haloalkyl which may be substituted by a radical selected from the group consisting of C 1-6 -alkyl, C 1-6 - Haloalkyl, OH, halogen and C 6-10 aryl may be substituted; or R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1 -alkyl- 2) , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-Cβ-io-aryl, OH, O-C 1-6 -alkyl, OC 1-6 -haloalkyl, halogen , SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, SO 2 -C 1-6 -alkanol; SO 2 -C 1-6 alkyl, SO 2 -C 1-6 -HaIOalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2substituiert sein kann, oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-CyClOaIRyI,SO 2 -N (C 1-6 alkyl) 2, NO 2, NH 2, NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted, or R 3 is a radical selected from the group consisting of C 3-8 -CyClOaIRyI, C5.8-Cycloalkenyl,C1-6-Alkyl und C1-6-Alkanol, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-i0-Aryl,C 5 . 8 cycloalkenyl, C 1-6 alkyl and C 1-6 alkanol optionally selected with one or more groups selected from the group consisting of C 6- i 0 aryl, C^s-Cycloalkyl, einem C5-1o-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, der gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-AIKyI, C2-6-Alkenyl, C2-6-Alkinyl, C1-6-Haloalkyl, CN, CONH2, CONH-Cβ-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, COAryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SCVC1-6-Alkanol, SO2-d_6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-Ci.6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2, einem C5.10-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, wobei das C5.10-Heteroaryl und der C3-i0-Heterocyclus gegebenenfalls mit einem Rest ausgewählt aus Oxo-, Hydroxyl-, Halogen, C1-6-Alkyl und Ci.6-Haloalkyl substituiert sein kann;C ^ s-cycloalkyl, a C 5-1 o-heteroaryl, and a C 3-10 heterocycle may be substituted optionally with one or more radicals from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2 - 6 alkynyl, C 1-6 haloalkyl, CN, CONH 2, CONH-Cβ-alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, COAryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 Alkyl, SC 1-6 -haloalkyl, SCVC 1-6 -alkanol, SO 2 -d- 6- alkyl, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-Ci. 6- alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl) 2 , a C 5 . 10 heteroaryl and a C 3-10 heterocycle may be substituted, wherein the C 5 . 10 -Heteroaryl and the C 3 -i 0 -Heterocyclus optionally with a radical selected from oxo, hydroxyl, halogen, C 1-6 alkyl and Ci. 6 -haloalkyl may be substituted; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-io-Aryl, einem einem C6-i0-Heteroaryl und einem C3-10-Heterocyclus, der mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Aryl, Ci_6-Alkyl, C2_6-Alkenyl, C2-6-Alkinyl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1 -6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Aryl, OH,or R 3 is a radical selected from a group consisting of C 6 -io-aryl, a C 6 -i 0 -heteroaryl and a C 3-10 heterocycle, with one or more radicals selected from the group consisting of aryl, CI_ 6 alkyl, C 2 _ 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CONH 2, CONH-C 1-6 -alkyl, CON (C 1-6 alkyl) 2, COOH , COO-C 1 -6- alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH, O-Ci_6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-β-Alkyl, SO2-C1-6-Alkanol, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(CL6-AIKyI)2, NO2, NH2, NH-C1-6-Alkyl, N(d_6-Alkyl)2 und N-(SO2-C1-4- Alkyl)(R34) substituiert sein kann;O-CI_ 6 alkyl, OC 1-6 haloalkyl, halo, SH, SC 1-6 alkyl, SC 1-6 haloalkyl, SO 2 -C 1-β alkyl, SO 2 -C 1-6 - Alkanol, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C L6 -alkyl) 2 , NO 2 , NH 2 , NH- C 1-6 alkyl, N (d_ 6 alkyl) 2 and N (SO 2 -C 1-4 - alkyl) (R 34) may be substituted; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-10-Aryl- C1-6-alkylen, C^o-Heteroaryl-C1-6-alkylen, C3-7-Cycloalkyl, C6_i0-Aryl, einem C5-10- Heteroaryl und einem C3-10-Heterocyclus, der gegebenenfalls mit einem oder mehreren Resten der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl und Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 istor R 3 is a radical selected from the group consisting of C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, C 1-8 -heteroaryl-C 1-6 -alkylene, C 3-7 - Cycloalkyl, C 6 _i 0 -aryl, a C 5-10 -heteroaryl and a C 3-10 -heterocycle, optionally with one or more radicals of the group consisting of B, halogen, OH, C 1-6 -alkyl and oxo may be substituted, wherein B is a compound of formula 2 in der Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol, O(C1-6-Alkyl), C6-10-Aryl, 0-C6_ 10-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2, oder C3-7-Cycloalkyl; und Z2 OH, NH2, NH(C1-6 lkyl), N(C1-6-Alkyl)2, O(C1-6-Alkyl), mono- oder bicyclisches C3-7-Cycloalkyl, mono- oder bicyclischer Cs-io-Heterocyclus, mono- oder bicyclisches C5-10-Heteroaryl oder C6-io-Aryl bedeuten;in the Z 1 H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol, O (C 1-6 -alkyl), C 6-10 -aryl, O-C 6 _ 10 -aryl, NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2, or C 3-7 cycloalkyl; and Z 2 is OH, NH 2, NH (C 1-6 lkyl), N (C 1-6 alkyl) 2, O (C 1-6 alkyl), mono- or bicyclic C 3-7 cycloalkyl, mono - or bicyclic Cs-io heterocycle, mono- or bicyclic C 5-10 heteroaryl or C 6 -io-aryl; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C6-10-Aryl und einem C5-10-Heteroaryl, der gegebenenfalls mit Ci_6-Alkyl substituiert sein kann, welches gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus COOR33, NR33R34, NHCOR33, NHCOOR33, Phenyl substituiert sein kann, wobei Phenyl gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2.6-Alkinyl, CN, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CONCC1-6-AlkyOa, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, OH, O-C1-6-Alkyl, 0-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1 _6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-Ci_6-Alkyl und NCd^AlkyO^ einem C3-i0-Heterocyclus und einem C5-I0-R 3 is a residue or selected from the group composed of C 6-10 aryl and a C 5 - 10 -heteroaryl, optionally 6 alkyl may be substituted with CI_ which is optionally substituted with a radical selected from the group comprising COOR 33 , NR 33 R 34, NHCOR 33, NHCOOR 33, phenyl which may be substituted, said phenyl being optionally substituted with a radical selected from the group consisting of C 1-6 alkyl, C 2 - 6 alkenyl, C. 2 6- alkynyl, CN, C 1-6 -haloalkyl, CONH 2 , CONH-C 1-6 -alkyl, CONCC 1-6 -alkyl, COOH, COO-C 1-6 -alkyl, COH, CO-C 1- 6 alkyl, OH, OC 1-6 alkyl, 0-C 1-6 haloalkyl, halo, SH, SC 1-6 alkyl, SC 1-6 haloalkyl, SO 2 -C 1 _ 6 alkyl, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH- Ci_ 6 alkyl and NCd ^ AlkyO ^ a C 3 -i 0 -Heterocyclus and a C 5- I 0 - Heteroaryl substituiert sein kann, wobei der C3-i0-Heterocyclus und der C5-10- Heteroaryl gegebenenfalls mit einer Oxogruppe oder einer Methylgruppe substituiert sein können; wobei R3 3 H oder C1-6-Alkyl;Heteroaryl may be substituted, wherein the C 3 i 0 heterocycle and C 5-10 - heteroaryl may be optionally substituted with an oxo group or a methylene group; wherein R 3 is 3 H or C 1-6 alkyl; R34 H, Ci-6-Alkyl oder C7.n-Aralkyl, C5.10-Heteroaryl-C1-6-alkylen; bedeuten, oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-10-Aryl und einem C5-10-Heteroaryl , das gegebenenfalls mit NR3 1R3 2 substituiert sein kann; wobeiR 34 is H, Ci- 6 alkyl or C 7 .n aralkyl, C. 5 10 -heteroaryl-C 1-6 -alkylene; , or R 3 is a radical selected from a group consisting of C 6-10 aryl and a C 5 - 10 -heteroaryl, which can optionally be substituted with NR 3 R 1 3 2; in which R3 1 H, C1-6-Alkyl, C3-6-Cycloalkyl, C1-6-Haloalkyl, COR3 1 \ COOR3 1 1,R 3 is H, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -haloalkyl, COR 3 1 \ COOR 3 1 1 , CONR3 1 1R3 1 2 oder SO2-R3 1 1; undCONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and R3 1 1 H, Cβ-Alkyl, C1-6-Haloalkyl, C3-6-Cycloalkyl oder C6- 10-Aryl;undR 3 1 1 H, Cβ alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or C 6 - 10 aryl; and R3 1 2 H, C1-6-Alkyl, C1-6-Haloalkyl, C3-6-Cycloalkyl oder C6-10-Aryl; und R32 H oder ein Rest ausgewählt aus der Gruppe bestehend ausR 3 is H 2 , C 1-6 -alkyl, C 1-6 -haloalkyl, C 3-6 -cycloalkyl or C 6-10 -aryl; and R 32 is H or a radical selected from the group consisting of C1-6-Alkyl, C3-6-Cycloalkyl und C1-6-Haloalkyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2, Oxo und einem nichtaromatischen C3.10-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe bestehend aus Stickstoff, Sauerstoff und Schwefel enthalten kann, substituiert sein kann, wobei der nichtaromatische C3.i0-Heterocyclus gegebenenfalls mit C1-4-Alkyl substituiert sein kann, bedeuten;C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 haloalkyl, optionally with one or more radicals selected from the group consisting of NH 2 , NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 , oxo and a non-aromatic C 3 . 10 heterocycle, which may contain one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur may be substituted, wherein the non-aromatic C 3 .i 0 heterocycle may optionally be substituted by C 1-4 alkyl ; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-10-Aryl und einem C5-10-Heteroaryl, der mit einem C3-10-Heterocyclus substituiert ist, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10-Aryl, C1-6-Alkyl, C3-6-Cycloalkyl, CN, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO- C1-6-Alkyl, Oxo, OH, O-C1-6-Alkyl, Halogen, SH, S-C1-6-Alkyl, NH2, NH- v1-6-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann;or R 3 is a radical selected from a group consisting of C 6-10 aryl and a C 5-10 heteroaryl substituted with a C 3-10 heterocycle optionally containing one or more radicals selected from the group consisting of from C 6-10 -aryl, C 1-6 -alkyl, C 3-6 -cycloalkyl, CN, C 1-6 -haloalkyl, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 - Alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, oxo, OH, OC 1-6 -alkyl, halogen, SH, SC 1-6 -alkyl, NH 2 , NH-v 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted; oder R3 Benzimdazolyl, welches gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Cyc\oa\ky\ substituiert sein kann; undor R 3 is benzimidazolyl, which may be optionally substituted with a radical selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and R4 d_6-Alkyl, C1-6-Cycloalkyl, C1-6-Haloalkyl, OR4 1, NR4 1R4 2, CN oder Halogen; wobei R4.1 H, C1-6-Alkyl, C3-8-Cycloalkyl oder C1-6-Haloalkyl; R4.2 H, C1-6-Alkyl, C3-8-Cycloalkyl oder C1-6-Haloalkyl bedeuten; undR 4 d_ 6 alkyl, C 1-6 cycloalkyl, C 1-6 haloalkyl, OR 4 1, 4 NR 1 R 4 2, CN or halogen; wherein R 4.1 is H, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 1-6 -haloalkyl; R 4.2 is H, C 1-6 -alkyl, C 3-8 -cycloalkyl or C 1-6 -haloalkyl; and R5 C1-6-Aikyl, C3-8-Cycloalkyl, C1-6-Haloalkyl, COR5.1 CONHR5.1 CON(R5.1)2,R 5 is C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-6 -haloalkyl, COR 5.1 CONHR 5.1 CON (R 5.1 ) 2 , SO2-C1_6-Alkyl, SO2- C1-6-Haloalkyl, SO2-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus R5.2, SO2- C1-6-Alkyl- R5.2 und d_6-Alkyl- R5.2, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2.6-Alkinyl, CN, C1-6-Haloalkyl, CONH2,SO 2 -C 1 _ 6 -alkyl, SO 2 - C 1-6 -haloalkyl, SO 2 -aryl or a radical selected from the group consisting of R 5.2 , SO 2 - C 1-6 -alkyl- R 5.2 and d_ 6 alkyl R 5.2, which may optionally be substituted with one or more groups selected from the group consisting of C 1-6 alkyl, C 2 - 6 alkenyl, C. 2 6- alkynyl, CN, C 1-6 -haloalkyl, CONH 2 , CONH-C1-6-Alkyl, CON(C1-6-Alky!)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, O-C3_6-Cycloalkyl, O- C1-6-Haloalkyl, O-C1-6-Alkyl, Halogen, SO2- C1-6-Alkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N( C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl und N(d_6-Alkyl)2 substituiert sein kann; worinCONH-C 1-6 -alkyl, CON (C 1-6 -Alky!) 2, COOH, COO-C 1-6 alkyl, COH, CO-C 1-6 alkyl, OC 3 _ 6 cycloalkyl, O-C 1-6 haloalkyl, OC 1-6 alkyl, halo, SO 2 C 1-6 alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 alkyl, SO 2 -N (C 1-6 alkyl) 2, NO 2, NH 2, NH-C 1-6 alkyl and N (d_ 6 alkyl) 2 may be substituted; wherein R5 1 C1-6-Alkyl, C5-1o-Heteroaryl-C1-6-alkylen oder C6-10- Aryl-C1-6-alkylen undR 5 is C 1-6 -alkyl, C 5-1 o -heteroaryl-C 1-6 -alkylene or C 6-10 -aryl-C 1-6 -alkylene and R5 2 C6.10-Aryl oder ein C5-10-Heteroaryl; und R6 H,Ci-6-Alkyl oder C1-6-Haloalkyl bedeuten;R 5 2 C 6 . 10 -aryl or a C 5-10 heteroaryl; and R 6 is H, Ci- 6 alkyl or C 1-6 haloalkyl; R7 H,Ci_6-Alkyl oder C1-6-Haloalkyl;R 7 is H, CI_ 6 alkyl or C 1-6 haloalkyl; oder R6 und R7 bilden gemeinsam einen 3-6 gliedrigen Carbocyclus;or R 6 and R 7 together form a 3-6 membered carbocycle; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon. .optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. , 2. Verbindungen der Formel 1 nach Anspruch 1 , worin2. Compounds of formula 1 according to claim 1, wherein A CO, C=NH, C-e-Alkylen oder Cs-e-Cycloalkylen,A is CO, C is NH, C-e-alkylene or Cs-e-cycloalkylene, B1 Phenyl oder ein aromatischer oder nicht aromatischer Ring, der gegebenenfalls ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann und der gegebenenfalls ein- oder mehrfach mit einem oder mehreren Resten ausgewählt aus der Gruppe OH, O-C1-6-Alkyl, 0-C1. 6-Haloalkyl, Halogen, C1-6 -alkyl und C1-6-Haloalkyl substituiert sein kann; B2 Phenyl oder Pyridinyl;B may contain 1 is phenyl or an aromatic or non-aromatic ring which optionally contains one, two or three heteroatoms selected from the group oxygen, sulfur and nitrogen and is optionally substituted one or more times by one or more radicals selected from the group OH, OC 1 -6- alkyl, 0-C 1 . 6 haloalkyl, halogen, C 1-6 alkyl and C 1-6 haloalkyl may be substituted; B 2 is phenyl or pyridinyl; X O, S, NR5 oder CR6R7;X is O, S, NR 5 or CR 6 R 7; n O1 1 , 2 oder 3;n is O 1 1, 2 or 3; R1 H, Ci_4-Alkyl oder C1-4-Halolalkyl;R 1 H, CI_ 4 alkyl or C 1-4 -Halolalkyl; R2 H, C1-4-Alkyl oder C1-4-Halolalkyl; oder R1 und R2 bilden gemeinsam mit dem Stickstoff einen nichtaromatischen Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann;R 2 is H, C 1-4 alkyl or C 1-4 haloalkyl; or R 1 and R 2 together with the nitrogen form a non-aromatic heterocycle which may contain one or two nitrogen atoms; R3 H, OH, C1-6-Haloalkyl oder ein Rest ausgewählt aus der Gruppe bestehend aus C6-IO- Aryl, ein C5-10-Heteroaryl und ein C3.10-Heterocyclus, der gegebenenfalls mit einer Methylgruppe, Oxo oder OH substituiert sein kann;R 3 is H, OH, C 1-6 haloalkyl or a group selected from the group consisting of C 6 - I O- aryl, C 5-10 heteroaryl and C. 3 10 -heterocycle, which may optionally be substituted by a methyl group, oxo or OH; oder R3 C1-6-Alkyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-CLβ-Alkyl, CON(Ci.6-Alkyl)2, COOH, COO-C1 -6-Alkyl, COH, CO-C1-6-Alkyl, COAryl, OH,or R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C L β-alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1 -6- alkyl, COH, CO-C 1-6 -alkyl, COAryl, OH, O-Ci-β-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol; SO2-C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SOrNH-C1-6-Alkyl, SO2-NCC1-6-Alkyl^, NO2, NH2, NH-C1-6-Alkyl und N^-e-Alkyl^ substituiert sein kann; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl, einem mit Ci- 3-Alkylen überbrückten C3-8-Cycloalkyl, C5.8-Cycloalkenyl, C1-6-Alkyl und d.6-Alkanol, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl ,C3-8-Cycloalkyl, C5_10-Heteroaryl und einem C3.10-Heterocyclus substituiert sein kann, welcher gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-Alkyl, C1-6-Haloalkyl, CN, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, S-C1-6-Alkyl, S-CLβ-Haloalkyl, NO2, NH2, NH-Ci.6-Alkyl, N(C1-6-Alkyl)2, einem C5.10-Heteroaryl und einem C3.10-Heterocyclus substituiert sein kann, wobei der C5-10-Heteroaryl und der C3.10-Heterocyclus gegebenenfalls mit einem Rest ausgewählt aus Oxo, Hydroxyl, Halogen, C1-6-A!kyl und C-^-Haloalkyl substituiert sein können; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C1-6-Alkyl, C6.10-Aryl- C1-6-alkylen, C3-7-Cycloalkyl, C6-io-Aryl, C5.10-Heteroaryl und einem C3.10-Heterocyclus, welcher mit einem oder mehreren Resten der Gruppe bestehend aus B, Halogen, OH, C1-6-Alky!, Oxo substituiert ist, wobei B eine Verbindung der Formel 2 ist worinO-Ci-β-alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, SO 2 -C 1-6 -alkanol; SO 2 -C 1-6 alkyl, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SOrNH-C 1-6 alkyl, SO 2 -NCC 1-6 alkyl ^, NO 2 , NH 2 , NH-C 1-6 alkyl and N ^ -e-alkyl ^ may be substituted; or R 3 is a radical selected from the group consisting of C 3-8 cycloalkyl, a Ci 3 alkylene bridged with C 3-8 cycloalkyl, C. 5 8 cycloalkenyl, C 1-6 alkyl and d.6 alkanol which optionally selected with one or more groups selected from the group consisting of C 6 -aryl, C 3-8 -cycloalkyl, C 5 _ 10 -heteroaryl and a C 3 . 10 may be substituted heterocycle, optionally substituted with one or more radicals from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, CN, OH, OC 1-6 alkyl, OC 1-6 haloalkyl , Halogen, SC 1-6 alkyl, SC L β-haloalkyl, NO 2 , NH 2 , NH-Ci. 6 alkyl, N (C 1-6 alkyl) 2 , a C 5 . 10 heteroaryl and a C 3 . 10 heterocycle may be substituted, wherein the C 5-10 heteroaryl and the C 3 . 10 heterocycle may optionally be substituted by a radical selected from oxo, hydroxyl, halogen, C 1-6 -Alkyl and C - ^ - haloalkyl; or R 3 is a radical selected from a group consisting of C 1-6 alkyl, C 6 . 10 -aryl-C 1-6 -alkylene, C 3-7 -cycloalkyl, C 6 -io-aryl, C 5 . 10 heteroaryl and a C 3 . 10 -heterocycle which is substituted by one or more radicals of the group consisting of B, halogen, OH, C 1-6 -alkyl, oxo, where B is a compound of formula 2 wherein Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol, 0(C1^-AIKyI), Cβ-10-Aryl, 0-C6-io-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2 oder C3.7-Cycloalkyl; und Z2 OH, NH2, NH(C1_6-Alkyl), N(C1-6-Alkyl)2, O(C1-6-Alkyl), mono- oder bicyclisches C3-7-CyClOa I ky I, einen mono- oder bicyclischen Ca^o-Heterocyclus, ein mono- oder bicyclisches C5.10-Heteroaryl oder C6-io-Aryl bedeutet;Z 1 is H, OH, halogen, C 1-6 alkyl, C 1-6 alkanol, 0 (C1 ^ -alkyl), Cβ- C10 aryl, 0-C 6 -io-aryl, NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 or C 3 . 7 -cycloalkyl; and Z 2 is OH, NH 2, NH (C 1 _ 6 alkyl), N (C 1-6 alkyl) 2, O (C 1-6 alkyl), mono- or bicyclic C 3-7 -CyClOa I ky I, a mono- or bicyclic Ca ^ o heterocycle, a mono- or bicyclic C 5 . 10 -heteroaryl or C 6 -10 aryl; oder R3 Phenyl, das mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10-Aryl, C2-6-Alkenyl, C2.6-Alkinyl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-AIkYl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, COAryl, OH, O-C1-6-Alkyl, O-C1-4-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-4-HaIOaIkYl, SO2-C1-6-Alkyl, SO2-C1-4-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(Cv6-AIkYl)2, NO2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2 substituiert ist ;or R 3 is phenyl which is selected by one or more radicals from the group consisting of C 6-10 aryl, C 2 - 6 alkenyl, C. 2 6 alkynyl, C 1-6 haloalkyl, CONH 2 , CONH C 1-6 alkyl, CON (C 1-6 alkyl) 2 , COOH, COO-C 1-6 alkyl, COH, CO-C 1-6- alkyl, COAryl, OH, OC 1-6 -alkyl, OC 1-4 -haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-4 -HaIOalkylk, SO 2 -C 1-6 - Alkyl, SO 2 -C 1-4 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (Cv 6 -alkyl) 2 , NO 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 substituted; oder R3 Phenyl, welches mit C1-4-Alkyl substituiert ist, das gegebenenfalls mit einem Rest ausgewählt aus der Gruppe bestehend aus COOR33, NR33R34, NHCOR3 3, NHCOOR33 und Phenyl substituiert sein kann, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, f-Butyl, F, Cl, Br, CN, OH, und einem Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, substituiert sein kann, wobei der Heterocyclus gegebenenfalls mit einer Oxogruppe oder einer Methylgruppe substituiert sein kann; wobeior R 3 is phenyl which is substituted by C 1-4 alkyl which may be optionally substituted by a group selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 3 3 , NHCOOR 33 and phenyl which may be substituted with one or more radicals selected from the group consisting of methyl, f-butyl, F, Cl, Br, CN, OH, and a heterocycle which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen may be substituted wherein the heterocycle may optionally be substituted with an oxo group or a methyl group; in which R33 H oder C1-6-Alkyl;R 33 is H or C 1-6 alkyl; R34 H1 C1-6-Alkyl oder C6.10-Aryl-C1-6-alkylen, C5_10-Heteroaryl-C1-6- alkylen; bedeuten, oder R3 Phenyl, substituiert mit NR3 1R32; wobeiR 34 is H 1 C 1-6 -alkyl or C 6 . 10 -aryl-C 1-6 -alkylene, C 5 _ 10 -heteroaryl-C 1-6 -alkylene; or R 3 is phenyl substituted with NR 3 1 R 32 ; in which R3 1 H1 CL4-AIkYl1 C1-4-HaIOaIkYl1 COR3 1 1, COOR3 1 1, CONR3 1 1R3 1 2 oder SO2-R3 1 1; undR 3 1 H 1 C 1 C 1-4 -alkyl L4 -HaIOaIkYl COR 1 3 1 1 3 1 1 COOR, CONR 3 1 1 1 2 R 3 or SO 2 -R 3 1 1; and R3 1 1 H1 C1-4-Alkyl, C1-4-Haloalkyl, C1-6-Cycloalkyl oder C6.10-Aryl; R3 1 2 H1 C1-4-AIkYl, C1-4-Haloalkyl, C3-6-Cycloalkyl oder C6-10-Aryl; und R32 H, C1-4-Alkyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NH(C1-4-Alkyl), N(C1-4-AIkYl)2, Oxo oder einem nichtaromatischen C3. 10-Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann und der gegebenenfalls mit einer Methylgruppe substituiert sein kann ;R 3 1 1 H 1 C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 cycloalkyl or C 6 . 10 -aryl; R 3 1 2 1 H C 1-4 -alkyl, C 1-4 -haloalkyl, C 3-6 cycloalkyl, or C 6 - 10 aryl; and R 32 is H, C 1-4 alkyl optionally substituted with one or more radicals selected from the group consisting of NH 2 , NH (C 1-4 alkyl), N (C 1-4 alkyl) 2 , oxo or a non-aromatic C 3 . 10 -heterocycle, which may contain one or two nitrogen atoms and which may optionally be substituted by a methyl group; oder R3 C6-1o-Aryl, das mit einem C5-10-Heteroaryl enthaltend ein, zwei oder dreior R 3 is C 6-1 o-aryl, containing a C 5 - 10 heteroaryl containing one, two or three Heteroatomen ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff substituiert sein kann, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, C1-4-Alkyl, C3-6-CyCIoIaIkYl1 May be heteroatoms selected from the group of oxygen, sulfur and nitrogen substituted, which optionally selected with one or more groups selected from the group consisting of C 6 -aryl, C 1-4 alkyl, C 3-6 -CyCIoIaIkYl 1 CN, CM-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2l COOH,CN, C M haloalkyl, CONH 2 , CONH-C 1-4 -alkyl, CON (C 1-4 -alkyl) 2 l COOH, COO-Ci-4-Alkyl, COH, CO-C1-4-Alkyl, OH, O-C1-4-Alkyl, Halogen, SH, S-d^-Alkyl, NH2, NH-Ci-4-Alkyl und N (C1-4-Alkyl)2 substituiert sein kann;COO-C 1-4 -alkyl, COH, CO-C 1-4 -alkyl, OH, OC 1-4 -alkyl, halogen, SH, Sd ^ -alkyl, NH 2 , NH-Ci- 4 -alkyl and N ( C 1-4 alkyl) 2 may be substituted; oder R3 C6.10-Aryl, das mit einem einem nichtaromatischen der ein oder zwei Heteroatome, ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert sein kann, wobei der C3-10-Heterocyclus gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe C1-4-Alkyl und Oxo substituiert sein kann;or R 3 C 6 . 10 -Aryl, with a non-aromatic which may be substituted by one or two heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the C 3-10 heterocycle optionally being substituted by one or more radicals selected from the group consisting of C 1-4 alkyl and oxo can; oder R3 Benzimdazolyl, das gegebenenfalls mit einem Rest oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C1-4-Alkyl, C1-4-Haloalkyl und C3-6-CyClOaIkYl substituiert sein kann; und R4 C1-4-AIkYl, Cs-e-Cycloalkyl, C1-4-Haloalkyl, OR4.1, NR4 1R4.2, CN oder Halogen;or R 3 is benzimidazolyl which may be optionally substituted with one or more groups selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl; and R 4 is C 1-4 -alkyl, Cs-e-cycloalkyl, C 1-4 -haloalkyl, OR 4.1 , NR 4 1 R 4.2 , CN or halogen; R4.1 H, C1-4-Alkyl, C3-6-Cycloalkyl oder C1-4-Haloalkyl; R4.2 H, C1-4-Alkyl, C3-6-Cycloalkyl oder C1-4-Haloalkyl; undR 4.1 is H, C 1-4 -alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl; R 4.2 is H, C 1-4 -alkyl, C 3-6 -cycloalkyl or C 1-4 -haloalkyl; and R5 C1-4-Alkyl, Ca-s-Cycloalkyl, C1-4-Haloalkyl, COR5 1, CONHR5 1, CON(R5 1)2, R 5 is C 1-4 -alkyl, C 5 -s-cycloalkyl, C 1-4 -haloalkyl, COR 5 1 , CONHR 5 1 , CON (R 5 1 ) 2, 802-C^^AIkyl, SO2-C1-4-HaIOaIkYl, SO2-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus R52, SO2-d.4-Alkyl-R5 2 und C1-4-Alkyl-R5 2, der gegebenenfalls mit C1-4-Alkyl, C2-4-Alkenyl, C2-4-Alkinyl, CN, C1-4-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1-4-Alkyl, COH, CO-C1-4-Alkyl,80 2 -C ^ alkyl, SO 2 -C 1-4 -HaIOaIkYl, SO 2 -aryl or a radical selected from the group consisting of R 52 , SO 2 -d. 4 alkyl-R 5 2, and C 1-4 alkyl-R 5 2, optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2 - 4 alkynyl, CN, C 1-4 - Haloalkyl, CONH 2 , CONH-C 1-4 -alkyl, CON (C 1-4 -alkyl) 2 , COOH, COO-C 1-4 -alkyl, COH, CO-C 1-4 -alkyl, O-C1-4-Cycloalkyl, O-C1-4-Haloalkyl, O-C1-4-Alkyl, Halogen, SO2-C1-4-Alkyl, SO2-NH2, SO2-NH-C1-4-Alkyl, SO2-N(Ci-4-Alkyl)2, NO2, NH2, NH-Ci-4-Alkyl und N(Ci-4-Alkyl)2 substituiert sein kann; wobei R5 1 C1-6-AIkYl, C5_1crHeteroaryl-C1-6-alkylen oder C6-10- Aryl-C-|.6-alkylen undOC 1-4 -cycloalkyl, OC 1-4 -haloalkyl, OC 1-4 -alkyl, halogen, SO 2 -C 1-4 -alkyl, SO 2 -NH 2 , SO 2 -NH-C 1-4 -alkyl , SO 2 -N (Ci- 4 alkyl) may be 2, NO 2, NH 2, NH-Ci -4 alkyl and N (Ci -4 alkyl) 2 substituted; wherein R 5 1 C 1-6 -Alkyl, C 5 _ 1cr heteroaryl-C 1-6 alkylene or C 6-10 - aryl-C- |. 6 -alkylene and R5 2 C6-10-Aryl oder ein C5-1o-Heteroaryl; undR 5 is C 6-10 aryl or C 5-1 o heteroaryl; and R6 H,C1-6-Alkyl oder C1-6-Haloalkyl bedeuten;R 6 is H, C 1-6 alkyl or C 1-6 haloalkyl; R7 H,C1-6-Aikyl oder C1-6-Haloalkyl;R 7 is H, C 1-6 -alkyl or C 1-6 -haloalkyl; oder R6 und R7 bilden gemeinsam einen 3-6 gliedrigen Carbocyclus;or R 6 and R 7 together form a 3-6 membered carbocycle; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon. .optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. , 3. Verbindungen der Formel 1 nach Anspruch 1 oder 2, worin3. Compounds of formula 1 according to claim 1 or 2, wherein R3 C1-6-Alkyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-AIkYl, COH, CO-C1-6-Alkyl, COAryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol; SO2-C1-6-Alkyl, SOrCvg-Haloalkyl, SO2-NH2, SO2-NH-C1^-AIkYl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann,R 3 is C 1-6 -alkyl, optionally with one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, COAryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, SC 1-6 - Alkyl, SC 1-6 haloalkyl, SO 2 -C 1-6 alkanol; SO 2 -C 1-6 -alkyl, SOrCvg-haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1 ^ -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 may be substituted, oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3„8-Cycloalkyl, einem mit d- 3-Alkylen überbrückten C3-8-Cycloalkyl, C5_8-Cycloalkenyl, C1-6-Alkyl, und C1-6-Alkanol, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, C3_8-Cycloalkyl, einem C5.10-Heteroaryl und einem C3-10-Heterocycius substituiert sein kann, der wiederum gegebenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2.6-Alkinyl, C1-6-Haloalkyl, CN, CONH2, CONH-C1-6-Alkyl,or R 3 is a radical selected from the group consisting of C 3 "8 cycloalkyl, with a d- 3 alkylene bridged C 3-8 cycloalkyl, C 5 _ 8 cycloalkenyl, C 1-6 alkyl, and C 1 -6- alkanol, which is optionally substituted by one or more radicals selected from the group consisting of C 6 -io-aryl, C 3 _ 8 -cycloalkyl, a C 5 . 10 heteroaryl and a C 3-10 heterocyci which may in turn optionally be substituted by one or more radicals selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2 . 6- alkynyl, C 1-6 -haloalkyl, CN, CONH 2 , CONH-C 1-6 -alkyl, CON(Ci.6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1 -6-Alkyl, CO-C6-10-Aryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol, SO2-C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2, C5.10-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus Oxo-, Hydroxyl-, Halogen- oder C1-6-Alkyl und d_6-Haloalkyl substituiert sein kann;CON (Ci. 6 alkyl) 2, COOH, COO-C 1-6 alkyl, COH, CO-C 1 -6 -alkyl, CO-C 6 - 10 -aryl, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, halogen, SH, SC 1-6 alkyl, SC 1-6 haloalkyl, SO 2 -C 1-6 alkanol, SO 2 -C 1-6 alkyl, SO 2 -C 1 -6- haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 - Alkyl, N (C 1-6 alkyl) 2 , C 5 . 10 -heteroaryl and a C 3-10 heterocycle may be substituted optionally with one or more groups selected from oxo, hydroxy, halogen or C 1-6 alkyl and d_ 6 haloalkyl may be substituted; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C6-1Q-Aryl, C5.10-Heteroaryl und einem C3_10-Heterocyclus, der mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6.10-Aryl, C1-6-Alkyl, C2-6-Alkenyl, C2.6-Alkinyl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-AIk^)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Aryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-Ci.6-Alkyi, S-C1-6-Haloalkyl, SO2-C1-6-Alkyl, SO2-d,6-Alkanol, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-d_6-Alkyl,or R 3 is a radical selected from the group consisting of C 6 - 1 Q-aryl, C 5 . 10 heteroaryl and a C 3 _ 10 heterocycle having one or more radicals selected from the group consisting of C 6 . 10 -aryl, C 1-6 -alkyl, C 2-6 -alkenyl, C 2 . 6- alkynyl, C 1-6 -haloalkyl, CONH 2 , CONH-C 1-6 -alkyl, CON (C 1-6 -alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO- C 1-6 -alkyl, CO-C 6-10 -aryl, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SH, S-Ci. 6 -alkyl, SC 1-6 -haloalkyl, SO 2 -C 1-6 -alkyl, SO 2 -d, 6- alkanol, SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH -d_ 6 alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1-6-Alkyl)2 und N-(SO2-C1-4- Alkyl)(R34) substituiert sein kann;SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl, N (C 1-6 -alkyl) 2 and N- (SO 2 -C 1-4 - alkyl) (R 34 ) may be substituted; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-io-Aryl-C1-6- alkylen, C3.7-Cycloalkyl, C6-10-Aryl, C5-1o-Heteroaryl und einem C3-10-Heterocyclus, der gegebenenfalls mit einem oder mehreren Resten aus der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl und Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 ist wobeior R 3 is a radical selected from the group consisting of C 1-6 -alkyl, C 6 -io-aryl-C 1-6 -alkylene, C 3 . 7 -cycloalkyl, C 6-10 -aryl, C 5-1 o-heteroaryl and a C 3-10 -heterocycle optionally substituted by one or more radicals from the group consisting of B, halogen, OH, C 1-6 - Alkyl and oxo may be substituted, wherein B is a compound of formula 2 in which Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol, 0(C1-B-AIRyI), C6-10-Aryl, O-C6_10-Aryl, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2 oder C3-7-Cycloalkyl und Z2 OH, NH2, NH(C1-6-Alkyl), N(C1-6-Alkyl)2, 0(C1-6-AIRyI), mono- oder bicyclischesZ 1 is H, OH, halogen, C 1-6 alkyl, C 1-6 alkanol, 0 (C 1 - B -AIRyI), C 6-10 aryl, OC 6 _ 10 aryl, NH 2, NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 or C 3-7 cycloalkyl and Z 2 OH, NH 2 , NH (C 1-6 alkyl), N (C 1-6 -Alkyl) 2 , 0 (C 1-6 -AIRyI), mono- or bicyclic C3_7-Cycloalkyl, mono- oder bicyclischer C5.i0-Heteroaryl, mono- oder bicyclischer C3.10-Heterocyclus oder C6.10-Aryl sind;C 3 _ 7 cycloalkyl, mono- or bicyclic C 5 .i 0 heteroaryl, mono- or bicyclic C. 3 10 -heterocycle or C 6 . 10 -aryl are; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 4. Verbindungen der Formel 1 nach Anspruch 3, worin4. Compounds of formula 1 according to claim 3, wherein A CH2, CD2, C=NH, CHMe, CMe2, 1 ,1'-Cyclopropylen oder 1 ,1 '-Cyclobutyliden;A CH 2 , CD 2 , C = NH, CHMe, CMe 2 , 1, 1'-cyclopropylene or 1, 1'-cyclobutylidene; B1 Phenyl;B 1 phenyl; B2 Phenyl;B 2 phenyl; X O oder NR5; wobeiX is O or NR 5 ; in which R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl, CONHCH2-Phenyl, CH2CF3 oder Benzyi, welches gegebenenfalls mit F substituiert sein kann, bedeutet; und wobeiR 5 is methyl, ethyl, cyclopropyl, cyclobutyl, CONHCH 2 -phenyl, CH 2 CF 3 or benzyl, which may optionally be substituted by F; and where n O oder 1 ;n is O or 1; R1 H; HR 1 H; H bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 5. Verbindungen der Formel 1 nach Anspruch 3 oder 4,5. Compounds of formula 1 according to claim 3 or 4, worin R3 C1-6-Alkyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Halogen, OH, CN, CONH2, CONH-C1-6-Alkyl,in which R 3 is C 1-6 -alkyl which is optionally substituted by one or more radicals selected from the group consisting of halogen, OH, CN, CONH 2 , CONH-C 1-6 -alkyl, CON(C1-S-AIkVl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Aryl, OH, O-Ci_6-Alkyl, SO2-C1-6-Alkanol; SO^C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-AIkVl und N(C1-6-Alkyl)2 substituiert sein kann,CON (C 1 -S-Al kVl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH, O-C 1-6 -alkyl, SO 2 -C 1-6 alkanol; SO ^ C 1-6 alkyl, SO 2 -C 1-6 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 alkyl, SO 2 -N (C 1-6 alkyl) 2 , NO 2 , NH 2 , NH-C 1-6 -alkyl and N (C 1-6 -alkyl) 2 may be substituted, oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C3-8-Cycloalkyl, einem mit C^-Alkylen überbrückten C3-8-Cycloalkyl und C1-6-Alkyl, welcher gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-io-Aryl, C3-8-CyClOaIKyI, einem C5.10-Heteroaryl und einem C3-1o-Heterocyclus substituiert sein kann, der wiederum gegebenfalls mit einem oder mehrerenor R 3 is a radical selected from the group consisting of C 3-8 -cycloalkyl, a C 3-8 alkylene-bridged C 3-8 -cycloalkyl and C 1-6 -alkyl, optionally with one or more radicals selected from the group consisting of C 6 -io-aryl, C 3-8 -cycloalkyl, a C 5 . 10 heteroaryl and a C 3-1 o-heterocycle may be substituted, which in turn optionally with one or more Resten aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C1-6-Haloalkyl, CN, CONH2, CONH-CLe-Aikyl, CON(C1-6-Alkyl)2, COOH, COO-C1-6-Alkyl, COH, CO-C1-6-Alkyl, CO-C6-10-Aryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SH, S-C1-6-Alkyl, S-C1-6-Haloalkyl, SO2-C1-6-Alkanol, SO2-C1-6-Alkyl, SO2-C1-6-Haloalkyl, SO2-NH2, SO2-NH-C1-6-Alkyl, SO2-NCCLe-AlkyOz, NO2, NH2, NH-C1-6-Alkyl, NCC1-6-Alkyl^, C5.10-Heteroaryl und einem C3-10-Heterocyclus substituiert sein kann, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus Oxo-, Hydroxyl-, Halogen- oder Ci.6-Alkyl und C1-6-HaIOaIkVl substituiert sein kann;Radicals from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -haloalkyl, CN, CONH 2 , CONH-C L e-Aikyl, CON (C 1-6- alkyl) 2 , COOH, COO-C 1-6 -alkyl, COH, CO-C 1-6 -alkyl, CO-C 6-10 -aryl, OH, OC 1-6 -alkyl, OC 1 -6- haloalkyl, halogen, SH, SC 1-6 -alkyl, SC 1-6 -haloalkyl, SO 2 -C 1-6 -alkanol, SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 Haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-6 -alkyl, SO 2 -NCC L e-AlkyOz, NO 2 , NH 2 , NH-C 1-6 -alkyl, NCC 1-6 - Alkyl, C 5 . 10 heteroaryl and a C 3-10 heterocycle may be substituted, optionally with one or more radicals selected from oxo, hydroxyl, halogen or Ci. 6 -alkyl and C 1-6 -HaIOaIkVl can be substituted; oder R3 ein Rest ausgewählt aus einer Gruppe bestehend aus C6-1o-Aryl, einem C3-8- Heterocyclus mit 1 bis 4 Heteroatomen ausgewählt aus N, O. S und einem Cs-10- Heteroaryl mit 1 bis 2 Heteroatomen ausgewählt aus N, O. S, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Ce.io-Aryl, C1-6-AIkYl, C1-6-Haloalkyl, CONH2, CONH-C1-6-Alkyl, CON(C1-6-AIRyI)2, COOH, COO-d-s-Alkyl, COH, CO-Cm-Alkyl, CO-C6-i0-Aryl, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, SO2-C1-6-Alkyl, S02-C1-6-Alkanol, SO2-C1-6-HaIOaIkYl, SO2-NH2, SO2-NH-Ci-β-Alkyl, SO2-N(C1-6-Alkyl)2, NO2, NH2, NH-C1-6-Alkyl, N(C1^-AIkYl)2 und N- (SO2-Ci_4-Alkyl)(R34), wobei R34 ein C5-10-Heteroaryl-C1-6-alkylen ist, substituiert sein kann;or R 3 is a radical selected from a group consisting of C 6-1 o-aryl, a C 3-8 heterocycle having 1 to 4 heteroatoms selected from N, O.S and a Cs- 10 - heteroaryl having 1 to 2 heteroatoms selected from among N, O.S, optionally substituted by one or more radicals selected from the group consisting of C e .io-aryl, C 1-6 alkyl, C 1-6 haloalkyl, CONH 2 , CONH C 1-6 alkyl, CON (C 1-6 -AIR yl) 2 , COOH, COO-ds-alkyl, COH, CO-Cm alkyl, CO-C 6- i 0 aryl, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, halogen, SO 2 -C 1-6 alkyl, S0 2 C 1-6 -alkanol , SO 2 -C 1-6 -haloalkyl, SO 2 -NH 2 , SO 2 -NH-C 1-β-alkyl, SO 2 -N (C 1-6 -alkyl) 2 , NO 2 , NH 2 , NH- C 1-6 alkyl, N (C 1 ^ -alkyl) 2 and N (SO 2 -Ci_ 4 alkyl) (R 34), wherein R 34 alkylene, a C 5-10 heteroaryl-C 1-6 is, may be substituted; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus C1-6-Alkyl, C6-10-Aryl-C1-6- alkylen, C5.10-Heteroaryl-C1-6-alkylen, C3_7-Cycloalkyl, C6.10-Aryl, Cs-s-Heterocyclus mit 1 bis 4 Heteroatomen ausgewählt aus N, O. S, und ein C5.10-Heteroaryl mit 1 bis 2or R 3 is a radical selected from the group consisting of C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, C 5 . 10 -heteroaryl-C 1-6 -alkylene, C 3 _ 7 cycloalkyl, C. 6 10 -aryl, Cs-s-heterocycle having 1 to 4 heteroatoms selected from N, O. S, and a C 5 . 10 heteroaryl with 1 to 2 Heteroatomen ausgewählt aus N, O. S, welcher jeweils gegebenenfalls mit einem oder mehreren Resten der Gruppe bestehend aus B, Halogen, OH, C1-6-Alkyl, Oxo substituiert sein kann, wobei B eine Verbindung der Formel 2 istHeteroatoms selected from N, O. S, which may be optionally substituted with one or more radicals of the group consisting of B, halogen, OH, C 1-6 alkyl, oxo, where B is a compound of formula 2 wohn residential Z1 H, OH, Halogen, C1-6-Alkyl, C1-6-Alkanol oder O(C1-6-Alkyl) und Z2 OH, NH2, NH(C1-6-AIkYl), N(C1-6-Alkyl)2, O(C1-6-Alkyl), mono- oder bicyclisches C3_7-Cycloalkyl, mono- oder bicyclischer C5-i0-Heteroaryl, mono- oder bicyclischer C3-10-HeIeTOCyClUs oder C6-10-Aryl ist ;Z 1 is H, OH, halogen, C 1-6 -alkyl, C 1-6 -alkanol or O (C 1-6 -alkyl) and Z 2 OH, NH 2 , NH (C 1-6 -alkyl), N (C 1-6 alkyl) 2, O (C 1-6 alkyl), mono- or bicyclic C 3 _ 7 cycloalkyl, mono- or bicyclic C 5 i 0 heteroaryl, mono- or bicyclic C 3- 10 -HeIeTOCyClUs or C 6-10 -aryl; und worin R4 H, F oder Cl;and wherein R 4 is H, F or Cl; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 6. Verbindungen der Formel 1 nach einem der Ansprüche 1 bis 3, worin A CO, C=NH, Ci-4-Alkylen oder C3-6-Cycloalkylen, C1-6-Alkylen oder C3-8-Cycloalkylen,6. Compounds of formula 1 according to any one of claims 1 to 3, wherein A CO, C = NH, Ci- 4 alkylene or C 3-6 cycloalkylene, C 1-6 alkylene or C 3-8 cycloalkylene, B1 Phenyl oder Pyridinyl;B 1 is phenyl or pyridinyl; B2 Phenyl oder Pyridinyl;B 2 is phenyl or pyridinyl; X O oder NR5;X is O or NR 5 ; n 0, 1 , 2 oder 3;n is 0, 1, 2 or 3; R1 H, Methyl, Ethyl oder Propyl;R 1 is H, methyl, ethyl or propyl; R2 H, Methyl, Ethyl oder Propyl;R 2 is H, methyl, ethyl or propyl; R3 H, OH, oder C6-io-Aryl oder ein Rest ausgewählt aus der Gruppe bestehend aus einem C5_i0-Heteroaryl und einem C3-i0-Cycloalkyl, der ein, zwei oder drei Stickstoff atome enthalten kann und der gegebenenfalls mit einer Methylgruppe substituiert sein kann;R 3 H, OH, or C 6 -io-aryl or a radical selected from the group consisting of a C 5 _i 0 -Heteroaryl and a C 3 -i 0 -cycloalkyl which may contain one, two or three nitrogen atoms and which may be substituted by a methyl group can be; oder R3 ein Rest ausgewählt aus der Gruppe bestehend aus Cyclopentyl, Cyclohexyl,or R 3 is a radical selected from the group consisting of cyclopentyl, cyclohexyl, Cyclopentenyl, Cyclohexenyl, Methyl, Ethyl, Propyl und Butyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6-10- Aryl und einem C5-10-Heterocyclus substituiert sein kann, der gegebenfalls wiederum mit einem oder mehreren Resten ausgewählt aus der Gruppe aus C1-6-Alkyl, C1-6-Haloalkyl, CN, OH, O-C1-6-Alkyl, O-C1-6-Haloalkyl, Halogen, S-C1-6-Alkyl, S-C1-6-Haloalkyl, NO2, NH2, NH-C1-6-Alkyl und N(C1-6-Alkyl)2 substituiert sein kann;Cyclopentenyl, cyclohexenyl, methyl, ethyl, propyl and butyl, which may optionally be substituted by one or more radicals selected from the group consisting of C 6 - 10 aryl and a C 5 - 10 heterocycle, which may in turn be substituted by one or more Radicals selected from among C 1-6 -alkyl, C 1-6 -haloalkyl, CN, OH, OC 1-6 -alkyl, OC 1-6 -haloalkyl, halogen, SC 1-6 -alkyl, SC 1- 6 haloalkyl, NO 2 , NH 2 , NH-C 1-6 alkyl and N (C 1-6 alkyl) 2 may be substituted; oder R3 Phenyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus C6.10-Aryl, C2.4-Alkenyl, C2-4-Alkinyl, C1-4-Haloalkyl, CONH2, CONH-Ci-4-Alkyl, CON(C1-4-Alkyl)2, COOH, COO-C1-4-Alkyl, COH, CO-C1-4-Alkyl, CO-C6-10-Aryl, OH, O-Ci.4-Alkyl, O-C1-4-Haloalkyl, Halogen, SH, S-C1-4-Alkyl, S-C1-4-Haloalkyl, SO2-C1-4-Alkyl, SO2-C1-4-Haloalkyl, SO2-NH2, SO2-NH-CM-Alkyl, SO2-N(Ci-4-AIRyI)2, NO2, NO2, NH2, NH-C1-4-Alkyl und N(Ci_4-Alkyl)2 substituiert sein kann;or R 3 is phenyl optionally with one or more radicals selected from the group consisting of C 6 . 10 -aryl, C 2 . 4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CONH 2, CONH-Ci 4 alkyl, CON (C 1-4 alkyl) 2, COOH, COO-C 1-4 alkyl , COH, CO-C 1-4 alkyl, CO-C 6-10 aryl, OH, O-Ci. 4 alkyl, OC 1-4 haloalkyl, halo, SH, SC 1-4 alkyl, SC 1-4 haloalkyl, SO 2 -C 1-4 alkyl, SO 2 -C 1-4 haloalkyl, SO 2 -NH 2 , SO 2 -NH-C M alkyl, SO 2 -N (Ci -4 -AIRyI) 2, NO 2, NO 2, NH 2, NH-C 1-4 alkyl and N (CI_ 4 alkyl) 2 substituted can be; oder R3 Phenyl, das gegebenenfalls mit C1-4-Alkyl substituiert sein kann, welches gegebenenfalls wiederum mit einem Rest ausgewählt aus der Gruppe bestehend aus COOR33, NR33R34, NHCOR33, NHCOOR33, p-Fluorphenyl und einem Heterocyclus, der ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann und der gegebenenfalls mit einer Oxogruppe substituiert sein kann, substituiert sein kann; wobeior R 3 is phenyl, which may optionally be substituted by C 1-4 -alkyl, which in turn may be in turn selected from the group consisting of COOR 33 , NR 33 R 34 , NHCOR 33 , NHCOOR 33 , p-fluorophenyl and a heterocycle which may contain one, two or three heteroatoms selected from the group consisting of oxygen and nitrogen and which may optionally be substituted by an oxo group, may be substituted; in which R3 3 H oder d-4-Alkyl;R 3 is H or d-4-alkyl; R34 H, alkylen bedeuten;R 34 H, alkylene; oder R3 Phenyl, das mit NR3 1R32 substituiert sein kann; wobeior R 3 is phenyl which may be substituted by NR 3 1 R 32 ; in which R3 1 H, C1-4-Alkyl, COR3 1 \ COOR3 1 \ CONR3 1 1R3 1 2 oder SO2-R3 1 1; undR 3 is H, C 1-4 alkyl, COR 3 1 \ COOR 3 1 \ CONR 3 1 1 R 3 1 2 or SO 2 -R 3 1 1 ; and R3 1 1 H, C1-4-Alkyl oder C6-10-Aryϊ, R3 1 2 H, C1-4-Alkyl oder C6-10-Aryl;R 3 1 1 H, C 1-4 alkyl or C 6-10 aryl, R 3 1 2 H, C 1-4 alkyl or C 6-10 aryl; R32 H, C-M-Alkyl, das gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, N(C1-4-AIk^)2, Oxo oder einem C3-10-Heterocyclus, der ein oder zwei Stickstoffatome enthalten kann und der gegebenenfalls mit einerR 32 is H, C M alkyl, optionally substituted with one or more radicals selected from the group consisting of NH 2, N (C 1-4 -Alk ^) 2 , oxo or a C 3-10 heterocycle, which may contain one or two nitrogen atoms and which optionally with a Methylgruppe substituiert sein kann, substituiert sein kann;Methyl group may be substituted, may be substituted; oder R3 Phenyl, welches mit einem C5.i0-Heteroaryl, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert sein kann, wobei das C5-10-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Ce-10-Aryl, C1-4-Alkyl, Ci_4-Haloalkyl, C3_6-Cycloalkyl, CN, CONH2, CONH-C1-4-Alkyl, CON(Ci-4-Alkyl)2, COOH, C00-Ci_4-Alkyl, COH, CO-CM-Alkyl, OH, O-C1-4-Alkyl, Halogen, NH2 und N(C1_4-Alkyl)2 substituiert sein kann; oder R3 Phenyl, welches mit einem C5.i0-Heteroaryl, das ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert sein kann, wobei das C5-10-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe aus C1-4-Alkyl und Oxo substituiert sein kann;or R 3 is phenyl which may be substituted by a C 5 .i 0 heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the C 5-10 heteroaryl being optionally substituted by a or more radicals selected from the group consisting of C e-10 aryl, C 1-4 alkyl, CI_ 4 haloalkyl, C 3 _ 6 cycloalkyl, CN, CONH 2, CONH-C 1-4 -alkyl, CON (Ci- 4 alkyl) 2, COOH, C00-CI_ 4 alkyl, COH, CO-C M-alkyl, OH, OC 1-4 alkyl, halo, NH 2 and N (C 1 _ 4 alkyl) 2 may be substituted; or R 3 is phenyl which may be substituted by a C 5 .i 0 heteroaryl which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the C 5-10 heteroaryl being optionally substituted by a or a plurality of radicals selected from the group consisting of C 1-4 alkyl and oxo may be substituted; oder R3 Benzimdazolyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Propyl, CF3, CH2CF3, Cyclopropyl, Cyclopentyl und Cyclohexyl substituiert sein kann; undor R 3 is benzimidazolyl, which may be optionally substituted with one or more radicals selected from the group consisting of methyl, ethyl, propyl, CF 3 , CH 2 CF 3 , cyclopropyl, cyclopentyl and cyclohexyl; and R4 C1-4-Alkyl, C-,_4-Haloalkyl oder Halogen; undR 4 is C 1-4 alkyl, C -, _ 4 haloalkyl or halogen; and R5 ein Rest ausgewählt aus der Gruppe bestehend aus C1-4-Alkyl, C3-6-Cycloalkyl, COR5 1, CONHR5 \ Cβ-10-Aryl, S02-Cβ.1o-Aryl-C1.β-alkylen, SO2-C6-10-Aryl oderR 5 is a radical selected from the group consisting of C 1-4 -alkyl, C 3-6 -cycloalkyl, COR 5 1 , CONHR 5 \ Cβ- 1 0-aryl, S0 2 -C β . 1 o-aryl-C 1 . β- alkylene, SO 2 -C 6-10 -aryl or C6-io-Aryl-C1-6-alkylen und Cs-io-Heteroaryl-C1-6-alkylen, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe aus C1-4-Alkyl, C2-4-Alkenyl, C2-4-Alkinyl, CN, C1-4-Haloalkyl, CONH2, CONH-C1-4-Alkyl, CON(C1-4-AIRyI)2, COOH, COO-C1-4-Alkyl, COH, CO-C1 -4-Alkyl, OH, O-C1-4-Alkyl, Halogen, SO2-NH2, SO2-NH-Ci-4-Alkyl, SO2-N(C1-4-Alkyl)2, NO2,C 6 -io-aryl-C 1-6 -alkylene and Cs-io-heteroaryl-C 1-6 -alkylene, optionally with one or more radicals selected from the group consisting of C 1-4 -alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, CN, C 1-4 haloalkyl, CONH 2 , CONH C 1-4 alkyl, CON (C 1-4 -AIRyl) 2 , COOH, COO-C 1-4 Alkyl, COH, CO-C 1 -4 -alkyl, OH, OC 1-4 -alkyl, halogen, SO 2 -NH 2, SO 2 -NH-Ci -4 alkyl, SO 2 -N (C 1-4 alkyl) 2, NO 2, NH2, NH-C1-4-Alkyl und N(C1-4-Alkyl)2 substituiert sein kann; undNH 2 , NH-C 1-4 alkyl and N (C 1-4 alkyl) 2 may be substituted; and R5 1 C1-4-Alkyl oder C6-io- Aryl-C1-6-alkylen;R 5 1 is C 1-4 alkyl or C 6- io aryl-C 1-6 alkylene; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 7. Verbindungen der Formel 1a, 7. Compounds of the formula 1a, worin A, X, n, R1, R2, R3 und R4 die in den Ansprüchen 1 bis 3 genannte Bedeutung haben, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.wherein A, X, n, R 1 , R 2 , R 3 and R 4 have the meaning given in claims 1 to 3, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates , as well as deuterated forms of it. 8. Verbindungen der Formel 1 oder 1a nach einem der Ansprüche 1 bis 7 worin8. Compounds of formula 1 or 1a according to any one of claims 1 to 7 wherein X O;X O; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 9. Verbindungen der Formel 1 oder 1a nach einem der Ansprüche 1 bis 7 worin9. Compounds of formula 1 or 1a according to any one of claims 1 to 7 wherein X NR5;X NR 5 ; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 10. Verbindungen der Formel 1 oder 1a nach einem der Ansprüche 1 bis 7 worin10. Compounds of formula 1 or 1a according to any one of claims 1 to 7 wherein X CR6R7; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.X CR 6 R 7 ; optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 11. Verbindungen der Formel 1 oder 1a nach einem der Ansprüche 1 bis 7, worin11. Compounds of formula 1 or 1a according to any one of claims 1 to 7, wherein A CH2, CHMe, CMe2, C=NH, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;A CH 2 , CHMe, CMe 2 , C = NH, 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene; B1 Phenyl;B 1 phenyl; B2 Phenyl;B 2 phenyl; X O oder NR5;X is O or NR 5 ; n 0, 1 oder 2;n is 0, 1 or 2; R1 H, Methyl oder Ethyl;R 1 is H, methyl or ethyl; R2 H, Methyl oder Ethyl;R 2 is H, methyl or ethyl; R3 H, Cyclopropyl, Cyclobutyl, N-Methyl-piperidinyl, Pyridinyl, Phenyl oder 4-Phenyl- cyclohexan oder R3 Phenyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl, Ethyl, Propyl, Butyl, CF3, CONH2, CONHMe, CONMe2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SH, SO2Me, SONH2, SONMe2, NO2, NH2, NHMe und NMe2 substituiert sein kann; oderR 3 is H, cyclopropyl, cyclobutyl, N-methyl-piperidinyl, pyridinyl, phenyl or 4-phenylcyclohexane or R 3 is phenyl which is optionally substituted by one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl , CF 3 , CONH 2 , CONHMe, CONMe 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SH, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NHMe and NMe 2 may be substituted; or R3 Phenyl, welches mit einem Rest ausgewählt aus der Gruppe bestehend aus Methyl und Ethyl substituiert ist, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus COOH, COOMe, NH2, NMe2, NHCOMe, NHCOO-terf-Butyl, NMe(Benzyl), p-Fluorphenyl, Pyrolidinyl, Pipβridinyl, Morpholinyl, Pyrolidin-2onyl, Imidazolyl und Triazolyl substituiert sein kann; oderR 3 is phenyl which is substituted by a radical selected from the group consisting of methyl and ethyl, which is optionally substituted by one or more radicals selected from the group consisting of COOH, COOMe, NH 2 , NMe 2 , NHCOMe, NHCOO-tert-butyl, NMe (benzyl), p-fluorophenyl, pyrrolidinyl, piptridinyl, morpholinyl, pyrolidinyl-2-nyl, imidazolyl and triazolyl; or R3 Phenyl, das mit NR3 1R3 Substituiert ist, wobeiR 3 is phenyl substituted with NR 3 1 R 3 , wherein R3 1 H, Methyl, COH, COMe, COOMe, CONH2, CONMe2, SO2Me,R 3 1 H, methyl, COH, COMe, COOMe, CONH 2 , CONMe 2 , SO 2 Me, SO2CF3 oder SO2-Phenyl, und wobei R3 2 H oder ein Rest ausgewählt aus der Gruppe bestehend aus Methyl, und Ethyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NHMe, NMe2, N-Piperidinyl, N-Morpholinyl und N-Methyl-piperazinyl substituiert sein kann, wobei das N-Piperidinyl, N-Morpholinyl und das N-Methyl-piperazinyl gegebenenfalls mit einem weiteren Oxo substituiert sein kann bedeutet; oder R3 Phenyl, das mit einem C5.10-Heteroaryl, welches ein, zwei oder drei Heteroatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert ist, wobei das C5.10-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl, Ethyl, Propyl, Butyl, Cyclopropyl, Cyclobutyl, CF3, CN, CONH2, CONMe2, CONEt2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, NH2, NMe2, NEt2 und NPr2 substituiert sein kann; oderSO 2 CF 3 or SO 2 -phenyl, and wherein R 3 2 H or a radical selected from the group consisting of methyl, and ethyl, optionally with one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 , N-piperidinyl, N-morpholinyl and N-methyl-piperazinyl, wherein the N-piperidinyl, N-morpholinyl and the N-methyl-piperazinyl may be optionally substituted with another oxo; or R 3 is phenyl which is reacted with a C 5 . 10 -Heteroaryl, which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, is substituted, wherein the C 5 . 10 -Heteroaryl optionally with one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 , COOH, COOMe, COOEt, COH , COMe, OH, OMe, OEt, F, Cl, Br, NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted; or R3 Phenyl, das mit einem C3-i0-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, substituiert ist, wobei der C3_10-Heterocyclus gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe C1-4-Alkyl und Oxo substituiert sein kann;R 3 is phenyl which is substituted with a C 3 -i 0 heterocycle which may contain one or two hetero atoms selected from the group of oxygen and nitrogen, wherein the C 3 _ 10 -heterocycle optionally substituted with one or more radicals selected from the C 1-4 alkyl and oxo may be substituted; oder R3 Benzimdazolyl, welches gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Propyl, CF3, CH2CF3, Cyclopropyl und Cyclohexyl substituiert sein kann; und worinor R 3 is benzimidazolyl, which may be optionally substituted with one or more groups selected from the group consisting of methyl, propyl, CF 3 , CH 2 CF 3 , cyclopropyl and cyclohexyl; and in which R4 Methyl, Ethyl, Propyl, Butyl, CF3, CH2CF3, F, Cl, oder Br;R 4 is methyl, ethyl, propyl, butyl, CF 3 , CH 2 CF 3 , F, Cl, or Br; R5 ein Rest ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Propyl, Butyl, Cyclopropyl, Cyclobutyl, CF3, CH2CF3, COR5 1, CONHR5 1, Phenyl, Phenylsulfonyl und Benzyl, wobei Benzyl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Methyl, Ethyl, Propyl, Butyl, CF3, CN, CONH2, CONMe2, CONEt2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO2Me, SONH2, SONMe2, NO2, NH2, NMe2, NEt2 und NPr2 substituiert sein kann;R 5 is a radical selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CH 2 CF 3 , COR 5 1 , CONHR 5 1 , phenyl, phenylsulfonyl and benzyl, where benzyl is optionally with one or a plurality of radicals selected from the group consisting of methyl, ethyl, propyl, butyl, CF 3 , CN, CONH 2 , CONME 2 , CONEt 2 , COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted; R5 1 Methyl, Ethyl, Propyl, Butyl oder Benzyl;R 5 is methyl, ethyl, propyl, butyl or benzyl; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon.optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 12. Verbindungen der Formel 1 oder 1a nach einem der Ansprüche 1 bis 7 oder 11, worin12. Compounds of formula 1 or 1a according to any one of claims 1 to 7 or 11, wherein A CH2, CHMe, CMe2, 1 ,1'-Cyclopropylen, 1 ,1'-Cyclobutyliden;A CH 2 , CHMe, CMe 2 , 1, 1'-cyclopropylene, 1, 1'-cyclobutylidene; B1 Phenyl;B 1 phenyl; B2 Phenyl;B 2 phenyl; X O oder NR5;X is O or NR 5 ; n O oder 1 ;n is O or 1; R1 H;R 1 H; R2 H; H, 4-Phenyl-cyclohexanyl oderR 2 H; H, 4-phenylcyclohexanyl or R Phenyl, welches gegebenenfalls mit NR R 2 substituiert sein kann; worin R3 1 H, Methyl, SO2Me, SO2CF3, oder SO2-Phenyl; undR is phenyl, which may optionally be substituted by NR R 2 ; wherein R 3 is 1 H, methyl, SO 2 Me, SO 2 CF 3 , or SO 2 -phenyl; and R32 H oder ein Rest ausgewählt aus der Gruppe bestehend aus Methyl und Ethyl, der gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus NH2, NHMe, NMe2, Oxo, N-Piperidinyl, N-Morpholinyl und N-Methyl-piperazinyl substituiert sein kann, bedeutet, oder R3 Phenyl, das mit einem C5-i0-Heteroaryl, das ein, zwei oder drei Heteraatome ausgewählt aus der Gruppe Sauerstoff, Schwefel und Stickstoff enthalten kann, substituiert ist, wobei das C5-i0-Heteroaryl gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe bestehend aus Phenyl, Methyl, Ethyl, Propyl, Butyl, Cyclopropyl, Cyclobutyl, CF3, CN, CONH2, CONMe2, CONEt2, COOH, COOMe, COOEt, COH, COMe, OH, OMe, OEt, F, Cl, Br, SO2Me, SONH2, SONMe2, NO2, NH2, NMe2, NEt2 und NPr2 substituiert sein kann, oderR 32 is H or a radical selected from the group consisting of methyl and ethyl, optionally with one or more radicals selected from the group consisting of NH 2 , NHMe, NMe 2 , oxo, N-piperidinyl, N-morpholinyl and N-methyl piperazinyl may be substituted, or R 3 is phenyl which may contain a C 5 i 0 heteroaryl containing one, two or three Heteraatome selected from the group of oxygen, sulfur and nitrogen, is substituted, wherein the C 5 -i 0 -Heteroaryl optionally with one or more radicals selected from the group consisting of phenyl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, CF 3 , CN, CONH 2 , CONMe 2 , CONEt 2 , COOH, COOMe, COOEt , COH, COMe, OH, OMe, OEt, F, Cl, Br, SO 2 Me, SONH 2 , SONMe 2 , NO 2 , NH 2 , NMe 2 , NEt 2 and NPr 2 may be substituted, or R3 Phenyl, das mit einem C3.i0-Heterocyclus, der ein oder zwei Heteroatome ausgewählt aus der Gruppe Sauerstoff und Stickstoff enthalten kann, wobei der C3_10-Heterocyclus gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe d-4-Alkyl und Oxo substituiert sein kann, und wobei R4 H, F oder Cl;R 3 is phenyl which may contain one or more heteroatoms selected from the group of oxygen and nitrogen with a C 3 .i 0 -heterocycle, where the C 3 _ 10 -heterocycle optionally contains one or more radicals selected from the group d - 4 alkyl and oxo may be substituted, and wherein R 4 is H, F or Cl; R5 Methyl, Ethyl, Cyclopropyl, Cyclobutyl CH2CF3 oder Benzyl, wobei das Benzyl gegebenenfalls mit F substituiert sein kann;R 5 is methyl, ethyl, cyclopropyl, cyclobutyl CH 2 CF 3 or benzyl, where the benzyl may optionally be substituted by F; bedeutet, gegebenenfalls in Form ihrer Racemate, Enantiomere, Diasteromere und gegebenenfalls in Form ihrer pharmakologisch verträglichen Säureadditionssalze, Solvate oder Hydrate, sowie deuterierte Formen davon. optionally, in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates, and deuterated forms thereof. 13. Verbindungen nach einem der Ansprüche 1 bis 12 als Arzneimittel.13. Compounds according to any one of claims 1 to 12 as a medicament. 14. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 12, zur Herstellung eines Medikaments zur Behandlung von Krankheiten, die sich durch Inhibition des PDE4-Enzyms behandeln lassen.Use of compounds according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of diseases which can be treated by inhibition of the PDE4 enzyme. 15. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikaments zur Behandlung von Atemwegs- oder gastrointestinalen Beschwerden oder Erkrankungen, wie auch entzündliche Erkrankungen der Gelenke, der Haut oder der Augen, Krebserkrankungen, sowie von Erkrankungen des periph ren oder zentralen Nervensystems.15. Use of compounds according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of respiratory or gastrointestinal disorders or diseases, such as inflammatory diseases of the joints, the skin or the eyes, cancers, as well as diseases of the periph ren or central nervous system. 16. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikaments zur Vorbeugung und Behandlung von Atemwegs- oder Lungenerkrankungen, die mit einer erhöhten Schleimproduktion, Entzündungen und / oder obstruktiven Erkrankungen der Atemwege einher gehen.16. Use of compounds according to any one of claims 1 to 12 for the manufacture of a medicament for the prevention and treatment of respiratory or pulmonary diseases associated with increased mucus production, inflammation and / or obstructive respiratory diseases. 17. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikament zur Behandlung von entzündlichen und obstruktiven Erkrankungen wie COPD, chronischer Sinusitis, Asthma, Morbus Crohn, Colitis ulcerosa,17. Use of compounds according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of inflammatory and obstructive diseases such as COPD, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, 18. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikaments zur Behandlung von entzündlichen Erkrankungen des Gastrointestinaltraktes.18. Use of compounds according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of inflammatory diseases of the gastrointestinal tract. 19. Verwendung von Verbindungen nach einem der Ansprüche 1 bis 12 zur Herstellung eines Medikaments zur Vorbeugung und Behandlung von Erkrankungen des periphären oder zentralen Nervensystems wie Depression, bipolare oder manische Depression, akute und chronische Angstzustände, Schizophrenie, Alzheimer'sche Erkrankung, Parkinson'sche Erkrankung, akute und chronische Multiple Sklerose oder akute und chronische Schmerzzustände sowie Verletzungen des Gehirns hervorgerufen durch Schlaganfall, Hypoxie oder Schädel-Hirn-Trauma.19. Use of compounds according to any one of claims 1 to 12 for the manufacture of a medicament for the prevention and treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain, and brain injury caused by stroke, hypoxia or skull injury. brain injury. 20. Pharmazeutische Formulierungen gekennzeichnet durch den Gehalt an einer oder mehreren Verbindungen der Formel 1 oder 1a nach einem der Ansprüche 1 bis 12.20. Pharmaceutical formulations characterized by the content of one or more compounds of the formula 1 or 1a according to one of claims 1 to 12. 21. Inhalativ applizierbare pharmazeutische Formulierung, gekennzeichnet durch einen Gehalt einer Verbindung der Formel 1 oder 1a gemäß einem Ansprüche 1 bis 12.21. An inhalable pharmaceutical formulation, characterized by a content of a compound of formula 1 or 1a according to one of claims 1 to 12. 22. Arzneimittelkombinationen, die neben einer oder mehrerer Verbindungen der Formel 1 oder 1a gemäß einem der Ansprüche 1 bis 12 als weiteren Wirkstoff einen oder mehrere Verbindungen enthalten, die ausgewählt sind aus den Klassen der Betamimetika, Anticholinergika, Corticosteroiden, weitere PDE4-Inhibitoren, LTD4-Antagonisten, EGFR- Hemmern, Dopamin-Agonisten, H1-Antihistaminika, PAF-Antagonisten und PI3-Kinase Inhibitoren oder zwei- oder dreifach Kombinationen davon.22. Medicament combinations which comprise, in addition to one or more compounds of the formula 1 or 1a according to one of claims 1 to 12 as further active ingredient one or more compounds selected from the classes of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 Antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 kinase inhibitors or two or three combinations thereof. 23. Zwischenprodukte des Verfahrens nach Schema 1 nach den Formeln i, ii oder iii23. Intermediates of the process according to Scheme 1 according to the formulas i, ii or iii wobei X, A, R2 und R3 die in den Ansprüchen 1 bis 12 definierten Bedeutungen haben und wobei PG Wasserstoff oder eine geeignete Schutzgruppe ist.wherein X, A, R 2 and R 3 have the meanings defined in claims 1 to 12 and wherein PG is hydrogen or a suitable protective group. 24. Zwischenprodukte nach Anspruch 23, worin PG die Allyloxycarbonyl-Schutzgruppe oder die tertiär-Butyloxycarbonyl-Schutzgruppe ist und worin X entweder O oder NR5 ist, worin R5 die in Anspruch 1 definierte Bedeutung hat.24. Intermediates according to claim 23, wherein PG is the allyloxycarbonyl protecting group or the tertiary-butyloxycarbonyl protecting group and wherein X is either O or NR 5 , wherein R 5 has the meaning as defined in claim 1. 25. Zwischenprodukte des Verfahrens nach Schema 2 nach den Formeln I, II, III, IV oder V25. Intermediates of the process according to Scheme 2 according to formulas I, II, III, IV or V worin G NO2 oder NH2 bedeutet und worin X und R3 die in den Ansprüchen 1 bis 12 definierten Bedeutungen haben. wherein G is NO 2 or NH 2 and wherein X and R 3 have the meanings defined in claims 1 to 12.
EP06725750A 2005-04-28 2006-04-13 Novel compounds for treating inflammatory diseases Withdrawn EP1877376A1 (en)

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DE102005019718A DE102005019718A1 (en) 2005-04-28 2005-04-28 New heteroaryl derivatives are phosphodiesterase-4 enzyme inhibitors useful for the treatment of e.g. respiratory or gastrointestinal complaints or diseases, depression, Alzheimer's disease and Parkinson's disease
DE102005023207A DE102005023207A1 (en) 2005-05-20 2005-05-20 New heteroaryl derivatives are phosphodiesterase-4 enzyme inhibitors useful for the treatment of e.g. respiratory or gastrointestinal complaints or diseases, depression, Alzheimer's disease and Parkinson's disease
DE102005035575A DE102005035575A1 (en) 2005-07-29 2005-07-29 New compounds for the treatment of inflammatory diseases
PCT/EP2006/061586 WO2006114371A1 (en) 2005-04-28 2006-04-13 Novel compounds for treating inflammatory diseases

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