U.S. patent application number 13/742175 was filed with the patent office on 2013-05-23 for new compounds.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. The applicant listed for this patent is Angelo CECI, Henri DOODS, Norbert HAUEL, Ingo KONETZKI, Juergen MACK, Henning PRIEPKE, Annette SCHULER-METZ, Rainer WALTER, Dieter WIEDENMAYER. Invention is credited to Angelo CECI, Henri DOODS, Norbert HAUEL, Ingo KONETZKI, Juergen MACK, Henning PRIEPKE, Annette SCHULER-METZ, Rainer WALTER, Dieter WIEDENMAYER.
Application Number | 20130131075 13/742175 |
Document ID | / |
Family ID | 42307969 |
Filed Date | 2013-05-23 |
United States Patent
Application |
20130131075 |
Kind Code |
A1 |
HAUEL; Norbert ; et
al. |
May 23, 2013 |
NEW COMPOUNDS
Abstract
The present invention relates to the compounds of general
formula I ##STR00001## wherein n, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11 and X are defined as described hereinafter, the
enantiomers, the diastereomers, the mixtures and the salts thereof,
particularly the physiologically acceptable salts thereof with
organic or inorganic acids or bases, which have valuable
properties, the preparation thereof, the medicaments containing the
pharmacologically effective compounds, the preparation thereof and
the use thereof.
Inventors: |
HAUEL; Norbert;
(Schemmerhofen, DE) ; CECI; Angelo;
(Mittelbiberach, DE) ; DOODS; Henri; (Warthausen,
DE) ; KONETZKI; Ingo; (Warthausen, DE) ; MACK;
Juergen; (Biberach, DE) ; PRIEPKE; Henning;
(Warthausen, DE) ; SCHULER-METZ; Annette; (Ulm,
DE) ; WALTER; Rainer; (Biberach, DE) ;
WIEDENMAYER; Dieter; (Biberach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HAUEL; Norbert
CECI; Angelo
DOODS; Henri
KONETZKI; Ingo
MACK; Juergen
PRIEPKE; Henning
SCHULER-METZ; Annette
WALTER; Rainer
WIEDENMAYER; Dieter |
Schemmerhofen
Mittelbiberach
Warthausen
Warthausen
Biberach
Warthausen
Ulm
Biberach
Biberach |
|
DE
DE
DE
DE
DE
DE
DE
DE
DE |
|
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim am Rhein
DE
|
Family ID: |
42307969 |
Appl. No.: |
13/742175 |
Filed: |
January 15, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12711716 |
Feb 24, 2010 |
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13742175 |
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Current U.S.
Class: |
514/252.03 ;
514/252.01; 514/256; 514/274; 544/238; 544/311; 544/335 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/06 20180101; A61P 37/02 20180101; C07C 237/24 20130101;
A61P 17/04 20180101; C07D 213/81 20130101; C07D 405/12 20130101;
A61P 11/06 20180101; C07D 207/277 20130101; A61P 11/14 20180101;
A61P 13/00 20180101; C07D 233/90 20130101; C07D 401/12 20130101;
A61P 37/08 20180101; C07D 271/10 20130101; A61P 3/04 20180101; A61P
9/12 20180101; A61P 25/28 20180101; C07C 2601/02 20170501; A61P
11/08 20180101; A61P 19/02 20180101; A61P 25/04 20180101; A61P
13/10 20180101; A61P 17/00 20180101; A61P 29/00 20180101; A61P 3/10
20180101; A61P 9/00 20180101; A61P 25/02 20180101; A61P 25/16
20180101; A61P 35/00 20180101; A61P 9/10 20180101; A61P 17/06
20180101; A61P 19/10 20180101; A61P 17/02 20180101; C07D 261/18
20130101; A61P 21/00 20180101; A61P 25/08 20180101; C07D 239/28
20130101; A61P 1/00 20180101; A61P 43/00 20180101; C07D 211/62
20130101; A61P 25/24 20180101; A61P 13/08 20180101; C07D 239/557
20130101; A61P 31/04 20180101 |
Class at
Publication: |
514/252.03 ;
544/335; 514/256; 544/311; 514/274; 544/238; 514/252.01 |
International
Class: |
C07D 405/12 20060101
C07D405/12; C07D 239/557 20060101 C07D239/557; C07D 239/28 20060101
C07D239/28 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 2009 |
EP |
09153778.7 |
Claims
1. A compound of the formula I ##STR01007## wherein n denotes one
of the numbers 0, 1 or 2, R.sup.1 denotes (a) a C.sub.1-6-alkyl
group optionally substituted by a group R.sup.1.1, (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, (c) a substituted
C.sub.3-6-cycloalkyl group optionally substituted by a group
R.sup.1.2 wherein a --CH.sub.2-- unit may be replaced by a --C(O)--
group, (d) an aryl-C.sub.0-2-alkylene group optionally substituted
by 1, 2 or 3 groups R.sup.1.3, (e) a five-membered
heteroaryl-C.sub.0-2-alkylene group optionally substituted by 1, 2
or 3 groups R.sup.1.4, which contains at least one N, O or S atom
and which optionally additionally contains one, two or three
further N-atoms and which may additionally be benzo-condensed, (f)
a six-membered heteroaryl-C.sub.0-2-alkylene group optionally
substituted by 1 or 2 groups R.sup.1.4, which contains one, two or
three N-atoms and which may additionally be benzo-condensed, (g) a
nine- or ten-membered heteroaryl group optionally substituted by 1
or 2 groups R.sup.1.4 substituted, which contains one, two or three
N-atoms, (h) a 5- or 6-membered heterocyclic group optionally
substituted by 1 or 2 groups R.sup.1.4, in which a --CH.sub.2--
unit may be replaced by a --C(O)-- group, (i) --O--R.sup.1.1.1, (j)
--NR.sup.1.1.3R.sup.1.1.4 or (k) --C(.dbd.NR.sup.1.5)--CN,
R.sup.1.1 denotes halogen, --NO.sub.2, --CN, C.sub.3-6-cycloalkyl,
--OR.sup.1.1.1, --SR.sup.1.1.1, --C(O)R.sup.1.1.1,
--S(O).sub.2--R.sup.1.1.2, --O--S(O).sub.2--R.sup.1.1.1,
--CO.sub.2R.sup.1.1.1, --O--C(O)--R.sup.1.1.1,
--NR.sup.1.1.3R.sup.1.1.4, --NR.sup.1.1,3-C(O)--R.sup.1.1.1,
--NR.sup.1.1,3-C(O)--R.sup.1.1.1,
--NR.sup.1.1,3-CO.sub.2--R.sup.1.1.1 or
--C(O)--NR.sup.1.1.3R.sup.1.1.4, R.sup.1.1.1 denotes (a) H, (b)
C.sub.1-4-alkyl, (c) a C.sub.1-3-alkyl group wherein each methylene
group may be substituted by 1 or 2 fluorine atoms and each methyl
group may be substituted by 1, 2 or 3 fluorine atoms, (d) a phenyl
group optionally substituted by 1, 2 or 3 groups R.sup.1.1.1.1, (e)
C.sub.3-6-cycloalkyl or (f) a pyridyl group optionally substituted
by 1, 2 or 3 groups R.sup.1.1.1.2, R.sup.1.1.1.1 independently of
one another denote (a) halogen, --NO.sub.2, --CN, --OH,
--O--C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-4-alkyl or (b)
a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.1.1.1.2
independently of one another denote halogen or C.sub.1-4-alkyl,
R.sup.1.1.2 denotes (a) C.sub.1-4-alkyl, (b) a C.sub.1-3-alkyl
group wherein each methylene group may be substituted by 1 or 2
fluorine atoms and each methyl group may be substituted by 1, 2 or
3 fluorine atoms, (c) --O--C.sub.1-4-alkyl or (d) a phenyl group
optionally substituted by 1, 2 or 3 groups R.sup.1.1.1.1
substituted, R.sup.1.1.3, R.sup.1.1.4 independently of one another
denote (a) H, (b) a C.sub.1-4-alkyl group optionally substituted by
1, 2 or 3 groups R.sup.1.1.4.1, (c) a phenyl group optionally
substituted by 1, 2 or 3 groups R.sup.1.1.1.1, (d)
C.sub.3-6-cycloalkyl, or R.sup.1.1.3 and R.sup.1.1.4 together with
the N atom to which they are attached form a 5- or 6-membered
heterocyclic ring, which may additionally contain a further
heteroatom selected from N, O and S, or R.sup.1.1.3 and R.sup.1.1.4
together with the N atom to which they are attached, form a cyclic
imide, R.sup.1.1.4.1 independently of one another halogen denote
--NH.sub.2, --NH(C.sub.1-4-alkyl), --N(C.sub.1-4-alkyl).sub.2 or
--SO.sub.2--R.sup.1.1.2, R.sup.1.2 denotes halogen, --NO.sub.2,
--CN, OH, --O--CH.sub.3 or phenyl, R.sup.1.3 denotes (a) halogen,
--NO.sub.2, --CN, --OR.sup.1.1.1, --SR.sup.1.1.1,
--CO.sub.2R.sup.1.1.1, C.sub.1-6-alkyl or (b) a C.sub.1-3-alkyl
group wherein each methylene group may be substituted by 1 or 2
fluorine atoms and each methyl group may be substituted by 1, 2 or
3 fluorine atoms, R.sup.1.4 independently of one another denote (a)
halogen, --NO.sub.2, --CN, --OR.sup.1.1.1, --SR.sup.1.1.1,
--S(O)--R.sup.1.1.2, S(O).sub.2--R.sup.1.1.2,
--NR.sup.1.1.3R.sup.1.1.4, --N(R.sup.1.4.1)--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, (b) a C.sub.1-3-alkyl group wherein each methylene
group may be substituted by 1 or 2 fluorine atoms and each methyl
group may be substituted by 1, 2 or 3 fluorine atoms, or (c) an oxo
group, R.sup.1.4.1 denotes H or C.sub.1-4-alkyl, R.sup.1.5 denotes
--OH or --O--C.sub.1-3-alkyl, R.sup.2 denotes (a) H, (b)
C.sub.1-4-alkyl, (c) C.sub.1-4-alkyl-C(O)--, R.sup.3 and R.sup.4
together with the carbon atom to which they are bound denote a
C.sub.3-6-cycloalkylene group optionally substituted by a group
R.sup.3.1 wherein a --CH.sub.2-- unit may be replaced by a
heteroatom O, N, S or by a group CO, SO or SO.sub.2, R.sup.3.1
denotes H, --OH, R.sup.5 denotes (a) H, (b) C.sub.1-4-alkyl, (c) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.6 independently of
one another denote (a) H, halogen, --CN, --OH, C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, --O--C.sub.1-4-alkyl, --O--CF.sub.3,
--O--C.sub.3-6-cycloalkyl, --N(C.sub.1-3-alkyl).sub.2,
--C(O)--NH.sub.2, --(SO.sub.2)NH.sub.2,
--SO.sub.2--C.sub.1-3-alkyl, or (b) a C.sub.1-3-alkyl group wherein
each methylene group may be substituted by 1 or 2 fluorine atoms
and each methyl group may be substituted by 1, 2 or 3 fluorine
atoms, R.sup.7 denotes (a) H, halogen, --CN, --OH, (b)
C.sub.1-6-alkyl, (c) C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl,
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, (d) C.sub.3-7-cycloalkyl, (e) --O--C.sub.1-6-alkyl,
(f) --O--C.sub.3-7-cycloalkyl, (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, (h)
--C(O)--R.sup.7.1, (i) --S--C.sub.1-4-alkyl, --SO.sub.2--R.sup.7.2,
(j) a five-membered heteroaryl group optionally substituted by one
or two C.sub.1-3-alkyl groups which is selected from among
pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and
tetrazolyl, or (k) a six-membered heteroaryl group optionally
substituted by one or two C.sub.1-3-alkyl groups which is selected
from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and
triazinyl, R.sup.7.1 denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl, N-morpholinyl, --OH, --O--C.sub.1-8-alkyl or
--O--C.sub.3-7-cycloalkyl, R.sup.7.2 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and R.sup.8 denotes
H, halogen, C.sub.1-4-alkyl, R.sup.9 denotes (a) H, halogen, --CN,
--OH, (b) C.sub.1-6-alkyl, (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, (d) C.sub.3-7-cycloalkyl,
(e) C.sub.2-4-alkynyl, (f) --O--C.sub.1-6-alkyl, (g)
--O--C.sub.3-7-cycloalkyl, (h) --NH.sub.2, --NH(C.sub.1-3-alkyl),
--N(C.sub.1-3-alkyl).sub.2, (i) --C(O)--R.sup.9.1, (j)
--S--C.sub.1-4-alkyl, --SO--C.sub.1-4-alkyl,
--SO.sub.2--C.sub.1-4-alkyl, R.sup.9.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, R.sup.10 denotes
H, halogen, C.sub.1-4-alkyl, R.sup.11 denotes (a) H, halogen, --CN,
--OH, (b) C.sub.1-6-alkyl, (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, (d) C.sub.3-7-cycloalkyl,
(e) --O--C.sub.1-6-alkyl, (f) --O--C.sub.3-7-cycloalkyl, (g)
--NH.sub.2, --NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, (h)
--C(O)--R.sup.11.1, (i) --S--C.sub.1-3-alkyl,
--SO.sub.2--R.sup.11.2, (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or (k) a six-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl
and triazinyl, R.sup.11.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, R.sup.11.2
denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and X independently of one another
denote C--R.sup.6 or N, or a salt thereof.
2. A compound of the formula I according to claim 1, wherein:
R.sup.1 denotes (a) a C.sub.1-6-alkyl group optionally substituted
by a group R.sup.1.1, (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(c) a C.sub.3-6-cycloalkyl group optionally substituted by a group
R.sup.1.2 wherein a --CH.sub.2-unit may be replaced by a --C(O)--
group, (d) a phenyl group optionally substituted by 1, 2 or 3
groups R.sup.1.3, (e) a five-membered heteroaryl group optionally
substituted by 1, 2 or 3 groups R.sup.1.4, which contains at least
one N, O or S atom and which optionally additionally contains one,
two or three further N-atoms, (f) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which contains
one, two or three N-atoms, (g) a nine- or ten-membered heteroaryl
group optionally substituted by 1 or 2 groups R.sup.1.4, which
contains one, two or three N-atoms, (h) a 5- or 6-membered
heterocyclic group optionally substituted by 1 or 2 groups
R.sup.1.4, in which a --CH.sub.2-- unit may be replaced by a
--C(O)-- group, (i) --O--R.sup.1.1.1 or (j)
--NR.sup.1.1.3R.sup.1.1.4, R.sup.1.1 denotes --CN,
C.sub.3-6-cycloalkyl, --OR.sup.1.1.1, NR.sup.1.1.3R.sup.1.1.4,
R.sup.1.1.1 denotes (a) H, (b) C.sub.1-4-alkyl, (c) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.1.1.3, R.sup.1.1.4
independently of one another denote (a) H, (b) C.sub.1-4-alkyl, (c)
C.sub.3-6-cycloalkyl, or R.sup.1.1.3 and R.sup.1.1.4 together with
the N atom to which they are attached form a 5- or 6-membered
heterocyclic ring, which may additionally contain a further
heteroatom selected from N, O and S, or R.sup.1.2 denotes halogen,
--NO.sub.2, --CN, --OH, --O--CH.sub.3 or phenyl, R.sup.1.3
independently of one another denote (a) halogen, --NO.sub.2, --CN,
--OR.sup.1.1.1, C.sub.1-6-alkyl or (b) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, R.sup.1.4 independently of one another denote (a)
halogen, --NO.sub.2, --CN, --OR.sup.1.1.1,
--NR.sup.1.1.3R.sup.1.1.4, --N(R.sup.1.4.1)--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
and R.sup.4.1 denotes H or C.sub.1-4-alkyl, or a salt thereof.
3. A compound of the formula I according to claim 1, wherein:
R.sup.1 denotes (a) a C.sub.1-6-alkyl group optionally substituted
by a group R.sup.1.1, (b) a phenyl group optionally substituted by
1, 2 or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which
contains at least one N, O or S atom and which optionally
additionally contains one, two or three further N-atoms, (d) a
six-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, (e) a
nine- or ten-membered heteroaryl group optionally substituted by 1
or 2 groups R.sup.1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by
1 or 2 groups R.sup.1.4, in which a --CH.sub.2-- unit may be
replaced by a --C(O)-- group, R.sup.1.1 denotes --CN,
C.sub.3-6-cycloalkyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, R.sup.1.3 independently of one another denote
(a) F, Cl, Br, --OH, --OCH.sub.3, C.sub.1-6-alkyl or (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4
independently of one another denote (a) F, Cl, Br, --OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
NHC.sub.2-3-alkyl, --N(C.sub.2-3-alkyl).sub.2,
--NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl, or (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, or a salt thereof.
4. A compound of the formula I according to claim 1, wherein:
R.sup.1 denotes (a) a C.sub.1-6-alkyl group optionally substituted
by a group R.sup.1.1, (b) a phenyl group optionally substituted by
1, 2 or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which is
##STR01008## (d) a six-membered heteroaryl group optionally
substituted by 1 or 2 groups R.sup.1.4 which is ##STR01009## (e) a
nine-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which is ##STR01010## (f) a 5- or 6-membered
heterocyclic group optionally substituted by 1 or 2 groups
R.sup.1.4, which is ##STR01011## R.sup.1.1 denotes --CN,
cyclopropyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, R.sup.1.3 independently of one another denotes
(a) F, Cl, Br, --OH, --OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or
(b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4
independently of one another denotes (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
or a salt thereof.
5. A compound of the formula I according to claim 1, wherein:
R.sup.1 is ##STR01012## ##STR01013## ##STR01014## ##STR01015## or a
salt thereof.
6. A compound of the formula I according to claim 1, wherein:
R.sup.1 is ##STR01016## ##STR01017## ##STR01018## or a salt
thereof.
7. A compound of the formula I according to claim 1, wherein: n
denotes one of the numbers 0, 1 or 2, R.sup.2 denotes (a) H, (b)
C.sub.1-4-alkyl, R.sup.3 and R.sup.4 together with the carbon atom
to which they are bound denote a C.sub.3-6-cycloalkylene group
optionally substituted by a group R.sup.3.1 wherein a --CH.sub.2--
unit may be replaced by a heteroatom O, N, S or by a group CO, SO
or SO.sub.2, R.sup.3.1 denotes H, --OH, R.sup.5 denotes (a) H, (b)
C.sub.1-4-alkyl, (c) a C.sub.1-3-alkyl group wherein each methylene
group may be substituted by 1 or 2 fluorine atoms and each methyl
group may be substituted by 1, 2 or 3 fluorine atoms, R.sup.6
independently of one another denotes (a) H, halogen, --CN, --OH,
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl, --O--C.sub.1-4-alkyl,
--O--CF.sub.3, --O--C.sub.3-6-cycloalkyl,
--N(C.sub.1-3-alkyl).sub.2, --C(O)--NH.sub.2, --(SO.sub.2)NH.sub.2,
--SO.sub.2--C.sub.1-3-alkyl, or (a) a C.sub.1-3-alkyl group wherein
each methylene group may be substituted by 1 or 2 fluorine atoms
and each methyl group may be substituted by 1, 2 or 3 fluorine
atoms, R.sup.7 denotes (a) H, halogen, --CN, --OH, (b)
C.sub.1-6-alkyl, (c) C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl,
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, (d) C.sub.3-7-cycloalkyl, (e) --O--C.sub.1-6-alkyl,
(f) --O--C.sub.3-7-cycloalkyl, (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, (h)
--C(O)--R.sup.7.1, (i) --S--C.sub.1-4-alkyl, R.sup.7.1 denotes
--NH.sub.2, --OH, --O--C.sub.1-8-alkyl, R.sup.8 denotes H, halogen,
C.sub.1-4-alkyl, R.sup.9 denotes (a) H, halogen, --CN, --OH, (b)
C.sub.1-6-alkyl, (c) C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl,
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, (d) C.sub.3-7-cycloalkyl, (e) C.sub.2-4-alkynyl,
(f) --O--C.sub.1-6-alkyl, (g) --O--C.sub.3-7-cycloalkyl, (h)
--NH.sub.2, --NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, (i)
--C(O)--R.sup.9.1, (j) --S--C.sub.1-4-alkyl, --SO--C.sub.1-4-alkyl,
--SO.sub.2--C.sub.1-4-alkyl, R.sup.9.1 denotes --NH.sub.2, --OH,
--O--C.sub.1-8-alkyl, R.sup.10 denotes H, halogen, C.sub.1-4-alkyl,
R.sup.11 denotes (a) H, halogen, --CN, --OH, (b) C.sub.1-6-alkyl,
(c) C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl, wherein each methylene
group may be substituted by 1 or 2 fluorine atoms and each methyl
group may be substituted by 1, 2 or 3 fluorine atoms, (d)
C.sub.3-7-cycloalkyl, (e) --O--C.sub.1-6-alkyl, (f)
--O--C.sub.3-7-cycloalkyl, (g) --NH.sub.2, --NH(C.sub.1-3-alkyl),
--N(C.sub.1-3-alkyl).sub.2, (h) --C(O)--R.sup.11.1, (i)
--S--C.sub.1-3-alkyl, R.sup.11.1 denotes --NH.sub.2, --OH,
--O--C.sub.1-8-alkyl, and X independently of one another represent
C--R.sup.6 or N, or a salt thereof.
8. A compound of the formula I according to claim 1, wherein:
R.sup.2 denotes H or CH.sub.3, or a salt thereof.
9. A compound of the formula I according to claim 1, wherein:
R.sup.2 denotes H, or a salt thereof.
10. A compound of the formula I according to claim 1, wherein:
R.sup.3 and R.sup.4 together with the carbon atom to which they are
bonded denote a C.sub.3-6-cycloalkylene group wherein a
--CH.sub.2-- unit may be replaced by an oxygen atom, or a salt
thereof.
11. A compound of the formula I according to claim 1, wherein:
R.sup.3 and R.sup.4 together with the carbon atom to which they are
bonded denote ##STR01019## or a salt thereof.
12. A compound of the formula I according to claim 1, wherein:
R.sup.5 denotes H or CH.sub.3, or a salt thereof.
13. A compound of the formula I according to claim 1, wherein:
R.sup.6 denotes H, F, Cl or methyl, or a salt thereof.
14. A compound of the formula I according to claim 1, wherein:
R.sup.7 denotes H, F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3 or
CHF.sub.2, R.sup.8 denotes H, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.10 denotes H and R.sup.11 denotes F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3 or CHF.sub.2, or a salt thereof.
15. A compound of the formula Ia, ##STR01020## wherein R.sup.1
denotes (a) a C.sub.1-6-alkyl group optionally substituted by a
group R.sup.1.1, (b) a phenyl group optionally substituted by 1, 2
or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which
contains at least one N, O or S atom and which optionally
additionally contains one, two or three further N-atoms, (d) a
six-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, (e) a
nine- or ten-membered heteroaryl group optionally substituted by 1
or 2 groups R.sup.1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by
1 or 2 groups R.sup.1.4, in which a --CH.sub.2 unit may be replaced
by a --C(O) group, R.sup.1.1 denotes --CN, C.sub.3-6-cycloalkyl,
--OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
R.sup.1.3 independently of one another denotes (a) F, Cl, Br, --OH,
--OCH.sub.3, C.sub.1-6-alkyl or (b) a C.sub.1-3-alkyl group wherein
each methylene group may be substituted by 1 or 2 fluorine atoms
and each methyl group may be substituted by 1, 2 or 3 fluorine
atoms, and R.sup.1.4 independently of one another denotes (a) F,
Cl, Br, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl,
or (a) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.2 denotes H or
CH.sub.3, R.sup.3 and R.sup.4 together with the carbon atom to
which they are bonded denote a C.sub.3-6-cycloalkylene group
wherein a --CH.sub.2-- unit may be replaced by an oxygen atom,
R.sup.5 denotes H or C.sub.1-4-alkyl, R.sup.6 denotes H, F, Cl, Br
or C.sub.1-4-alkyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
16. A compound of the formula Ia according to claim 14, wherein
R.sup.1 denotes (a) a C.sub.1-6-alkyl group optionally substituted
by a group R.sup.1.1, (b) a phenyl group optionally substituted by
1, 2 or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which is
##STR01021## (d) a six-membered heteroaryl group optionally
substituted by 1 or 2 groups R.sup.1.4, which is ##STR01022## (e) a
nine-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which is ##STR01023## (f) a 5- or 6-membered
heterocyclic group optionally substituted by 1 or 2 groups
R.sup.1.4, which is ##STR01024## R.sup.1.1 denotes --CN,
cyclopropyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3, or
--N(CH.sub.3).sub.2, R.sup.1.3 denotes independently of one another
(a) F, Cl, Br, --OH, --OCH.sub.3, --OCF.sub.3, or C.sub.1-4-alkyl
or (b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another (a) F, Cl, Br, --OH, --OCH.sub.3,
--OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl, or
C.sub.1-6-alkyl, or (a) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.2 denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with
the carbon atom to which they are bonded denote a
C.sub.3-6-cycloalkylene group wherein a --CH.sub.2 unit may be
replaced by an oxygen atom, R.sup.5 denotes H or CH.sub.3, R.sup.6
denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
17. A compound of the formula Ia according to claim 14, wherein
R.sup.1 denotes ##STR01025## ##STR01026## ##STR01027## ##STR01028##
R.sup.2 denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with
the carbon atom to which they are bonded denote a
C.sub.3-6-cycloalkylene group wherein a --CH.sub.2 unit may be
replaced by an oxygen atom, R.sup.5 denotes H or CH.sub.3, R.sup.6
denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
18. A compound of the formula Ia according to claim 15, wherein
R.sup.1 denotes ##STR01029## ##STR01030## ##STR01031## R.sup.2
denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with the carbon
atom to which they are attached denote a C.sub.3-6-cycloalkylene
group wherein a --CH.sub.2-- unit may be replaced by an oxygen
atom, R.sup.5 denotes H or CH.sub.3, R.sup.6 denotes H, F, Cl or
methyl, R.sup.7 denotes H, F, Cl, Br, --CN, C.sub.1-4-alkyl,
CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br, C.sub.1-4-alkyl,
--O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl, R.sup.11 denotes F, Cl,
Br, --CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, and X denotes CH or
N, or a salt thereof.
19. A compounds of the formula Ib ##STR01032## wherein: R.sup.1
denotes (a) a C.sub.1-6-alkyl group optionally substituted by a
group R.sup.1.1, (b) a phenyl group optionally substituted by 1, 2
or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which
contains at least one N, O or S atom and which optionally
additionally contains one, two or three further N-atoms, (d) a
six-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, (e) a
nine- or ten-membered heteroaryl group optionally substituted by 1
or 2 groups R.sup.1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by
1 or 2 groups R.sup.1.4, in which a --CH.sub.2-- unit may be
replaced by a --C(O)-- group, R.sup.1.1 denotes --CN,
C.sub.3-6-cycloalkyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, R.sup.1.3 denotes independently of one another
(a) F, Cl, Br, --OH, --OCH.sub.3, C.sub.1-6-alkyl or (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another (a) F, Cl, Br, --OH, --OCH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl, or (a) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.2 denotes H or
CH.sub.3, R.sup.5 denotes H or C.sub.1-4-alkyl, R.sup.6 denotes H,
F, Cl, Br or C.sub.1-4-alkyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
20. A compound of the formula Ib according to claim 17, wherein
R.sup.1 denotes (a) a C.sub.1-6-alkyl group optionally substituted
by a group R.sup.1.1, (b) a phenyl group optionally substituted by
1, 2 or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which is
##STR01033## (d) a six-membered heteroaryl group optionally
substituted by 1 or 2 groups R.sup.1.4, which is ##STR01034## (e) a
nine-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which is ##STR01035## (f) a 5- or 6-membered
heterocyclic group optionally substituted by 1 or 2 groups
R.sup.1.4, which is ##STR01036## R.sup.1.1 denotes --CN,
cyclopropyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3, or
--N(CH.sub.3).sub.2, R.sup.1.3 denotes independently of one another
(a) F, Cl, Br, --OH, --OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or
(b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another (a) F, Cl, Br, --OH, --OCH.sub.3,
--OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or (a) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
21. A compound of the formula Ib according to claim 17, wherein
R.sup.1 denotes ##STR01037## ##STR01038## ##STR01039## ##STR01040##
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
22. A compound of the formula Ib according to claim 19, wherein
R.sup.1 denotes ##STR01041## ##STR01042## ##STR01043## R.sup.2
denotes H, R.sup.5 denotes H or CH.sub.3, R.sup.6 denotes H, F, Cl
or methyl, R.sup.7 denotes H, F, Cl, Br, --CN, C.sub.1-4-alkyl,
CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br, C.sub.1-4-alkyl,
--O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl, R.sup.11 denotes F, Cl,
Br, --CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, and X denotes CH or
N, or a salt thereof.
23. A compound of the formula Ic, ##STR01044## wherein R.sup.1
denotes (a) a C.sub.1-6-alkyl group optionally substituted by a
group R.sup.1.1, (b) a phenyl group optionally substituted by 1, 2
or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which
contains at least one N, O or S atom and which optionally
additionally contains one, two or three further N-atoms, (d) a
six-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, (e) a
nine- or ten-membered heteroaryl group optionally substituted by 1
or 2 groups R.sup.1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by
1 or 2 groups R.sup.1.4, in which a --CH.sub.2-- unit may be
replaced by a --C(O)-- group, R.sup.1.1 denotes --CN,
C.sub.3-6-cycloalkyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, R.sup.1.3 denotes independently of one another
(a) F, Cl, Br, --OH, --OCH.sub.3, C.sub.1-6-alkyl or (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another (a) F, Cl, Br, --OH, --OCH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl, or (b) a C1-3-alkyl
group wherein each methylene group may be substituted by 1 or 2
fluorine atoms and each methyl group may be substituted by 1, 2 or
3 fluorine atoms, R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H
or C.sub.1-4-alkyl, R.sup.6 denotes H, F, Cl, Br or
C.sub.1-4-alkyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
24. A compound of the formula Ic according to claim 20, wherein
R.sup.1 denotes (a) a C.sub.1-6-alkyl group optionally substituted
by a group R.sup.1.1, (b) a phenyl group optionally substituted by
1, 2 or 3 groups R.sup.1.3, (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which is
##STR01045## (d) a six-membered heteroaryl group optionally
substituted by 1 or 2 groups R.sup.1.4, which is ##STR01046## (e) a
nine-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which is ##STR01047## (f) a 5- or 6-membered
heterocyclic group optionally substituted by 1 or 2 groups
R.sup.1.4, which is ##STR01048## R.sup.1.1 denotes --CN,
cyclopropyl, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, R.sup.1.3 denotes independently of one another
(a) F, Cl, Br, --OH, --OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or
(b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another (a) F, Cl, Br, --OH, --OCH.sub.3,
--OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or (a) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
25. A compound of the formula Ic according to claim 20, wherein
R.sup.1 denotes ##STR01049## ##STR01050## ##STR01051## ##STR01052##
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
26. A compound of the formula Ic according to claim 23, wherein
R.sup.1 denotes ##STR01053## ##STR01054## ##STR01055## R.sup.2
denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3, R.sup.6
denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, or a salt thereof.
27. A compound of the formula Id, ##STR01056## wherein R.sup.1
denotes ##STR01057## R.sup.3 and R.sup.4 together with the carbon
atom to which they are attached denote a C.sub.3-6-cycloalkylene
group wherein a --CH.sub.2 unit may be replaced by an oxygen atom,
R.sup.5 denotes H or CH.sub.3, R.sup.6 denotes Cl or CH.sub.3,
R.sup.7 denotes H or F, and X denotes CH or N, or a salt
thereof.
28. A compound according to claim 1 selected from the group
consisting of: TABLE-US-00029 No. Structure (1) ##STR01058## (2)
##STR01059## (3) ##STR01060## (4) ##STR01061## (5) ##STR01062## (6)
##STR01063## (7) ##STR01064## (8) ##STR01065## (9) ##STR01066##
(10) ##STR01067## (11) ##STR01068## (12) ##STR01069## (13)
##STR01070## (14) ##STR01071## (15) ##STR01072## (16) ##STR01073##
(17) ##STR01074## (18) ##STR01075## (19) ##STR01076## (20)
##STR01077## (21) ##STR01078## (22) ##STR01079## (23) ##STR01080##
(24) ##STR01081## (25) ##STR01082## (26) ##STR01083## (27)
##STR01084## (28) ##STR01085## (29) ##STR01086## (30) ##STR01087##
(31) ##STR01088## (32) ##STR01089## (33) ##STR01090## (34)
##STR01091## (35) ##STR01092## (36) ##STR01093## (37) ##STR01094##
(38) ##STR01095## (39) ##STR01096## (40) ##STR01097## (41)
##STR01098## (42) ##STR01099## (43) ##STR01100## (44) ##STR01101##
(45) ##STR01102## (46) ##STR01103## (47) ##STR01104## (48)
##STR01105## (49) ##STR01106## (50) ##STR01107## (51) ##STR01108##
(52) ##STR01109## (53) ##STR01110## (54) ##STR01111## (55)
##STR01112## (56) ##STR01113## (57) ##STR01114## (58) ##STR01115##
(59) ##STR01116## (60) ##STR01117## (61) ##STR01118## (62)
##STR01119## (63) ##STR01120## (64) ##STR01121## (65) ##STR01122##
(66) ##STR01123## (67) ##STR01124## (68) ##STR01125## (69)
##STR01126## (70) ##STR01127## (71) ##STR01128## (72) ##STR01129##
(73) ##STR01130## (74) ##STR01131## (75) ##STR01132## (76)
##STR01133## (77) ##STR01134## (78) ##STR01135## (79) ##STR01136##
(80) ##STR01137## (81) ##STR01138## (82) ##STR01139## (83)
##STR01140## (84) ##STR01141## (85) ##STR01142## (86) ##STR01143##
(87) ##STR01144## (88) ##STR01145## (89) ##STR01146## (90)
##STR01147## (91) ##STR01148## (92) ##STR01149## (93) ##STR01150##
(94) ##STR01151## (95) ##STR01152## (96) ##STR01153## (97)
##STR01154## (98) ##STR01155## (99) ##STR01156## (100) ##STR01157##
(101) ##STR01158## (102) ##STR01159## (103) ##STR01160## (104)
##STR01161## (105) ##STR01162## (106) ##STR01163## (107)
##STR01164## (108) ##STR01165## (109) ##STR01166## (110)
##STR01167## (111) ##STR01168## (112) ##STR01169## (113)
##STR01170## (114) ##STR01171## (115) ##STR01172## (116)
##STR01173## (117) ##STR01174## (118) ##STR01175## (119)
##STR01176## (120) ##STR01177## (121) ##STR01178## (122)
##STR01179## (123) ##STR01180##
(124) ##STR01181## (125) ##STR01182## (126) ##STR01183## (127)
##STR01184## (128) ##STR01185## (129) ##STR01186## (130)
##STR01187## (131) ##STR01188## (132) ##STR01189## (133)
##STR01190## (134) ##STR01191## (135) ##STR01192## (136)
##STR01193## (137) ##STR01194## (138) ##STR01195## (139)
##STR01196## (140) ##STR01197## (141) ##STR01198## (142)
##STR01199## (143) ##STR01200## (144) ##STR01201## (145)
##STR01202## (146) ##STR01203## (147) ##STR01204## (148)
##STR01205## (149) ##STR01206## (150) ##STR01207## (151)
##STR01208## (152) ##STR01209## (153) ##STR01210## (154)
##STR01211## (155) ##STR01212## (156) ##STR01213## (157)
##STR01214## (158) ##STR01215## (159) ##STR01216## (160)
##STR01217## (161) ##STR01218## (162) ##STR01219## (163)
##STR01220## (164) ##STR01221## (165) ##STR01222## (166)
##STR01223## (167) ##STR01224## (168) ##STR01225## (169)
##STR01226## (170) ##STR01227## (171) ##STR01228## (172)
##STR01229## (173) ##STR01230## (174) ##STR01231## (175)
##STR01232## (176) ##STR01233## (177) ##STR01234## (178)
##STR01235## (179) ##STR01236## (180) ##STR01237## (181)
##STR01238## (182) ##STR01239## (183) ##STR01240## (184)
##STR01241## (185) ##STR01242## (186) ##STR01243## (187)
##STR01244## (188) ##STR01245## (189) ##STR01246## (190)
##STR01247## (191) ##STR01248## (192) ##STR01249## (193)
##STR01250## (194) ##STR01251## (195) ##STR01252## (196)
##STR01253## (197) ##STR01254## (198) ##STR01255## (199)
##STR01256## (200) ##STR01257## (201) ##STR01258## (202)
##STR01259## (203) ##STR01260## (203a) ##STR01261## (203b)
##STR01262## (204) ##STR01263## (205) ##STR01264## (206)
##STR01265## (207) ##STR01266## (208) ##STR01267## (209)
##STR01268## (210) ##STR01269## (211) ##STR01270## (212)
##STR01271## (212a) ##STR01272## (212b) ##STR01273## (213)
##STR01274## (213a) ##STR01275## (213b) ##STR01276## (214)
##STR01277## (215) ##STR01278## (216) ##STR01279## (217)
##STR01280## (218) ##STR01281## (219) ##STR01282## (220)
##STR01283## (221) ##STR01284## (222) ##STR01285## (223)
##STR01286## (224) ##STR01287## (225) ##STR01288## (226)
##STR01289## (227) ##STR01290## (228) ##STR01291## (229)
##STR01292## (230) ##STR01293## (231) ##STR01294## (232)
##STR01295## (233) ##STR01296## (234) ##STR01297## (235)
##STR01298## (236) ##STR01299## (237) ##STR01300## (238)
##STR01301## (239) ##STR01302## (240) ##STR01303## (241)
##STR01304## (242) ##STR01305## (243) ##STR01306##
(244) ##STR01307## (245) ##STR01308## (246) ##STR01309## (247)
##STR01310## (248) ##STR01311## (249) ##STR01312## (250)
##STR01313## (251) ##STR01314## (252) ##STR01315## (253)
##STR01316## (254) ##STR01317## (255) ##STR01318## (256)
##STR01319## (257) ##STR01320## (258) ##STR01321## (258)
##STR01322## (260) ##STR01323## (261) ##STR01324## (262)
##STR01325## (263) ##STR01326## (264) ##STR01327## (265)
##STR01328## (266) ##STR01329## (267) ##STR01330## (268)
##STR01331## (269) ##STR01332## (270) ##STR01333## (271)
##STR01334## (272) ##STR01335## (273) ##STR01336## (274)
##STR01337## (275) ##STR01338## (276) ##STR01339## (277)
##STR01340## (278) ##STR01341## (279) ##STR01342## (280)
##STR01343## (281) ##STR01344## (282) ##STR01345## (283)
##STR01346## (284) ##STR01347## (285) ##STR01348## (286)
##STR01349## (287) ##STR01350## (288) ##STR01351## (289)
##STR01352## (290) ##STR01353## (291) ##STR01354## (292)
##STR01355## (293) ##STR01356## (294) ##STR01357## (295)
##STR01358## (296) ##STR01359## (297) ##STR01360## (298)
##STR01361## (299) ##STR01362## (300) ##STR01363## (301)
##STR01364## (302) ##STR01365## (303) ##STR01366## (304)
##STR01367## (305) ##STR01368## (306) ##STR01369## (307)
##STR01370## (308) ##STR01371## (309) ##STR01372## (310)
##STR01373## (311) ##STR01374## (312) ##STR01375## (313)
##STR01376## (314) ##STR01377## (315) ##STR01378## (316)
##STR01379## (317) ##STR01380## (318) ##STR01381## (319)
##STR01382## (320) ##STR01383## (321) ##STR01384## (322)
##STR01385## (323) ##STR01386## (324) ##STR01387## (325)
##STR01388## (326) ##STR01389## (327) ##STR01390## (328)
##STR01391## (329) ##STR01392## (330) ##STR01393## (331)
##STR01394## (332) ##STR01395## (333) ##STR01396## (334)
##STR01397## (335) ##STR01398## (336) ##STR01399## (337)
##STR01400## (338) ##STR01401## (339) ##STR01402## (340)
##STR01403## (341) ##STR01404## (342) ##STR01405## (343)
##STR01406## (344) ##STR01407## (345) ##STR01408## (346)
##STR01409## (347) ##STR01410## (348) ##STR01411## (349)
##STR01412## (350) ##STR01413## (351) ##STR01414## (352)
##STR01415## (353) ##STR01416## (354) ##STR01417## (355)
##STR01418## (356) ##STR01419## (357) ##STR01420## (358)
##STR01421## (359) ##STR01422## (360) ##STR01423## (361)
##STR01424## (362) ##STR01425## (363) ##STR01426## (364)
##STR01427## (365) ##STR01428## (366) ##STR01429## (367)
##STR01430## (368) ##STR01431##
(369) ##STR01432## (370) ##STR01433## (371) ##STR01434## (372)
##STR01435## (373) ##STR01436## (374) ##STR01437## (375)
##STR01438## (376) ##STR01439## (377) ##STR01440## (378)
##STR01441## (379) ##STR01442## (380) ##STR01443## (381)
##STR01444## (382) ##STR01445## (383) ##STR01446## (384)
##STR01447## (385) ##STR01448## (386) ##STR01449## (387)
##STR01450## (388) ##STR01451## (389) ##STR01452## (390)
##STR01453## (391) ##STR01454## (392) ##STR01455## (393)
##STR01456## (394) ##STR01457## (395) ##STR01458## (396)
##STR01459##
or a salt thereof.
29. A physiologically acceptable salt of a compound according to
any one of claims 1 to 28.
30. A pharmaceutical composition comprising a compound according to
any one of claims 1 to 28 or a physiologically acceptable salt
thereof, together with an inert carrier and/or diluent.
31. A method for treatment of acute pain, visceral pain,
neuropathic pain, inflammatory/pain receptor-mediated pain, tumour
pain and headache which comprises administration to a host in need
of such treatment a therapeutically effective amount of a compound
according to any one of claims 1 to 28 or a physiologically
acceptable salt thereof.
32. A method for treatment of osteoarthritis which comprises
administration to a host in need of such treatment a
therapeutically effective amount of a compound according to any one
of claims 1 to 28 or a physiologically acceptable salt thereof.
Description
[0001] The present invention relates to the compounds of general
formula I
##STR00002##
wherein n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and X are as defined
hereinafter, the enantiomers, the diastereomers, the mixtures and
the salts thereof, particularly the physiologically acceptable
salts thereof with organic or inorganic acids or bases, which have
valuable properties, the preparation thereof, the medicaments
containing the pharmacologically effective compounds, the
preparation thereof and the use thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0002] In the above general formula I in one embodiment 1 [0003] n
denotes one of the numbers 0, 1 or 2, [0004] R.sup.1 denotes [0005]
(a) a C.sub.1-6-alkyl group optionally substituted by a group
R.sup.1.1, [0006] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
[0007] (c) a substituted C.sub.3-6-cycloalkyl group optionally
substituted by a group R.sup.1.2 wherein a --CH.sub.2-- unit may be
replaced by a --C(O)-- group, [0008] (d) an aryl-C.sub.0-2-alkylene
group optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0009]
(e) a five-membered heteroaryl-C.sub.0-2-alkylene group optionally
substituted by 1, 2 or 3 groups R.sup.1.4, which contains at least
one N, O or S atom and which optionally additionally contains one,
two or three further N-atoms and which may additionally be
benzo-condensed, [0010] (f) a six-membered
heteroaryl-C.sub.0-2-alkylene group optionally substituted by 1 or
2 groups R.sup.1.4, which contains one, two or three N-atoms and
which may additionally be benzo-condensed, [0011] (g) a nine- or
ten-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4 substituted, which contains one, two or three
N-atoms, [0012] (h) a 5- or 6-membered heterocyclic group
optionally substituted by 1 or 2 groups R.sup.1.4, in which a
--CH.sub.2-- unit may be replaced by a --C(O)-- group, [0013] (i)
--O--R.sup.1.1.1, [0014] (j) --NR.sup.1.1.3R.sup.1.1.4 or [0015]
(k) --C(.dbd.NR.sup.1.5)--CN, [0016] R.sup.1.1 denotes halogen,
--NO.sub.2, --CN, C.sub.3-6-cycloalkyl, --OR.sup.1.1.1,
--SR.sup.1.1.1, --C(O)R.sup.1.1.1, --S(O).sub.2--R.sup.1.1.2,
--O--S(O).sub.2--R.sup.1.1.1, --CO.sub.2R.sup.1.1.1,
--O--C(O)--R.sup.1.1.1, NR.sup.1.1.3R.sup.1.1.4,
--NR.sup.1.1,3-C(O)--R.sup.1.1.1, --NR.sup.1.1,3-C(O)--R.sup.1.1.1,
--NR.sup.1.1,3-CO.sub.2--R.sup.1.1.1 or
--C(O)--NR.sup.1.1.3R.sup.1.1.4, [0017] R.sup.1.1.1 denotes [0018]
(a) H, [0019] (b) C.sub.1-4-alkyl, [0020] (c) a C.sub.1-3-alkyl
group wherein each methylene group may be substituted by 1 or 2
fluorine atoms and each methyl group may be substituted by 1, 2 or
3 fluorine atoms, [0021] (d) a phenyl group optionally substituted
by 1, 2 or 3 groups R.sup.1.1.1.1, [0022] (e) C.sub.3-6-cycloalkyl
or [0023] (f) a pyridyl group optionally substituted by 1, 2 or 3
groups R.sup.1.1.1.2, [0024] R.sup.1.1.1.1 independently of one
another denote [0025] (a) halogen, --NO.sub.2, --CN, --OH,
--O--C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-4-alkyl or
[0026] (b) a C.sub.1-3-alkyl group wherein each methylene group may
be substituted by 1 or 2 fluorine atoms and each methyl group may
be substituted by 1, 2 or 3 fluorine atoms, [0027] R.sup.1.1.1.2
independently of one another denote halogen or C.sub.1-4-alkyl,
[0028] R.sup.1.1.2 denotes [0029] (a) C.sub.1-4-alkyl, [0030] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0031] (c)
--O--C.sub.1-4-alkyl or [0032] (d) a phenyl group optionally
substituted by 1, 2 or 3 groups R.sup.1.1.1.1 substituted, [0033]
R.sup.1.1.3, [0034] R.sup.1.1.4 independently of one another denote
[0035] (a) H, [0036] (b) a C.sub.1-4-alkyl group optionally
substituted by 1, 2 or 3 groups R.sup.1.1.4.1, [0037] (c) a phenyl
group optionally substituted by 1, 2 or 3 groups R.sup.1.1.1.1,
[0038] (d) C.sub.3-6-cycloalkyl, or [0039] R.sup.1.1.3 and
R.sup.1.1.4 together with the N atom to which they are attached
form a 5- or 6-membered heterocyclic ring, which may additionally
contain a further heteroatom selected from N, O and S, or [0040]
R.sup.1.1.3 and R.sup.1.1.4 together with the N atom to which they
are attached, form a cyclic imide, [0041] R.sup.1.1.4.1
independently of one another halogen denote --NH.sub.2,
--NH(C.sub.1-4-alkyl), --N(C.sub.1-4-alkyl).sub.2 or
--SO.sub.2--R.sup.1.1.2, [0042] R.sup.1.2 denotes halogen,
--NO.sub.2, --CN, OH, --O--CH.sub.3 or phenyl, [0043] R.sup.1.3
denotes [0044] (a) halogen, --NO.sub.2, --CN, --OR.sup.1.1.1,
--SR.sup.1.1.1, --CO.sub.2R.sup.1.1.1, C.sub.1-6-alkyl or [0045]
(b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0046] R.sup.1.4
independently of one another denote [0047] (a) halogen, --NO.sub.2,
--CN, --OR.sup.1.1.1, --SR.sup.1.1.1, --S(O)--R.sup.1.1.2,
--S(O).sub.2--R.sup.1.1.2, --NR.sup.1.1.3R.sup.1.1.4,
--N(R.sup.1.4.1)--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl, [0048]
(b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, or [0049] (c) an oxo
group, [0050] R.sup.1.4.1 denotes H or C.sub.1-4-alkyl, [0051]
R.sup.1.5 denotes --OH or --O--C.sub.1-3-alkyl, [0052] R.sup.2
denotes [0053] (a) H, [0054] (b) C.sub.1-4-alkyl, [0055] (c)
C.sub.1-4-alkyl-C(O)--, [0056] R.sup.3 and R.sup.4 together with
the carbon atom to which they are bound denote a
C.sub.3-6-cycloalkylene group optionally substituted by a group
R.sup.3.1 wherein a --CH.sub.2-- unit may be replaced by a
heteroatom O, N, S or by a group CO, SO or SO.sub.2, [0057]
R.sup.3.1 denotes H, --OH, [0058] R.sup.5 denotes [0059] (a) H,
[0060] (b) C.sub.1-4-alkyl, [0061] (c) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, [0062] R.sup.6 independently of one another denote
[0063] (a) H, halogen, --CN, --OH, C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, --O--C.sub.1-4-alkyl, --O--CF.sub.3,
--O--C.sub.3-6-cycloalkyl, --N(C.sub.1-3-alkyl).sub.2,
--C(O)--NH.sub.2, --(SO.sub.2)NH.sub.2,
--SO.sub.2--C.sub.1-3-alkyl, or [0064] (b) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, [0065] R.sup.7 denotes [0066] (a) H, halogen, --CN,
--OH, [0067] (b) C.sub.1-6-alkyl, [0068] (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0069] (d)
C.sub.3-7-cycloalkyl, [0070] (e) --O--C.sub.1-6-alkyl, [0071] (f)
--O--C.sub.3-7-cycloalkyl, [0072] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0073] (h)
--C(O)--R.sup.7.1, [0074] (i) --S--C.sub.1-4-alkyl,
--SO.sub.2--R.sup.7.2, [0075] (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or [0076] (k) a six-membered heteroaryl
group optionally substituted by one or two C.sub.1-3-alkyl groups
which is selected from among pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl and triazinyl, [0077] R.sup.7.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, [0078] R.sup.7.2
denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and [0079] R.sup.8 denotes H,
halogen, C.sub.1-4-alkyl, [0080] R.sup.9 denotes [0081] (a) H,
halogen, --CN, --OH, [0082] (b) C.sub.1-6-alkyl, [0083] (c)
C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl, wherein each methylene
group may be substituted by 1 or 2 fluorine atoms and each methyl
group may be substituted by 1, 2 or 3 fluorine atoms, [0084] (d)
C.sub.3-7-cycloalkyl, [0085] (e) C.sub.2-4-alkynyl, [0086] (f)
--O--C.sub.1-6-alkyl, [0087] (g) --O--C.sub.3-7-cycloalkyl, [0088]
(h) --NH.sub.2, --NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2,
[0089] (i) --C(O)--R.sup.9.1, [0090] (j) --S--C.sub.1-4-alkyl,
--SO--C.sub.1-4-alkyl, --SO.sub.2--C.sub.1-4-alkyl, [0091]
R.sup.9.1 denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl, N-morpholinyl, --OH, --O--C.sub.1-8-alkyl or
--O--C.sub.3-7-cycloalkyl, [0092] R.sup.10 denotes H, halogen,
C.sub.1-4-alkyl, [0093] R.sup.11 denotes [0094] (a) H, halogen,
--CN, --OH, [0095] (b) C.sub.1-6-alkyl, [0096] (c) C.sub.1-3-alkyl
or --O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0097] (d)
C.sub.3-7-cycloalkyl, [0098] (e) --O--C.sub.1-6-alkyl, [0099] (f)
--O--C.sub.3-7-cycloalkyl, [0100] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0101] (h)
--C(O)--R.sup.11.1, [0102] (i) --S--C.sub.1-3-alkyl,
--SO.sub.2--R.sup.11.2, [0103] (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or [0104] (k) a six-membered heteroaryl
group optionally substituted by one or two C.sub.1-3-alkyl groups
which is selected from among pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl and triazinyl, [0105] R.sup.11.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, [0106]
R.sup.11.2 denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and [0107] X independently of one
another denote C--R.sup.6 or N, the enantiomers, the diastereomers,
the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0108] One embodiment 2 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1 and [0109] R.sup.1 denotes [0110] (a) a
C.sub.1-6-alkyl group optionally substituted by a group R.sup.1.1,
[0111] (b) a C.sub.1-3-alkyl group wherein each methylene group may
be substituted by 1 or 2 fluorine atoms and each methyl group may
be substituted by 1, 2 or 3 fluorine atoms, [0112] (c) a
C.sub.3-6-cycloalkyl group optionally substituted by a group
R.sup.1.2 wherein a --CH.sub.2-unit may be replaced by a --C(O)--
group, [0113] (d) a phenyl group optionally substituted by 1, 2 or
3 groups R.sup.1.3, [0114] (e) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which
contains at least one N, O or S atom and which optionally
additionally contains one, two or three further N-atoms, [0115] (f)
a six-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, [0116]
(g) a nine- or ten-membered heteroaryl group optionally substituted
by 1 or 2 groups R.sup.1.4, which contains one, two or three
N-atoms, [0117] (h) a 5- or 6-membered heterocyclic group
optionally substituted by 1 or 2 groups R.sup.1.4, in which a
--CH.sub.2-- unit may be replaced by a --C(O)-- group, [0118] (i)
--O--R.sup.1.1.1 or [0119] (j) --NR.sup.1.1.3R.sup.1.1.4, [0120]
R.sup.1.1 denotes --CN, C.sub.3-6-cycloalkyl, --OR.sup.1.1.1,
--NR.sup.1.1.3R.sup.1.1.4, [0121] R.sup.1.1.1 denotes [0122] (a) H,
[0123] (b) C.sub.1-4-alkyl, [0124] (c) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, [0125] R.sup.1.1.3, [0126] R.sup.1.1.4
independently of one another denote [0127] (a) H, [0128] (b)
C.sub.1-4-alkyl, [0129] (c) C.sub.3-6-cycloalkyl, or [0130]
R.sup.1.1.3 and R.sup.1.1.4 together with the N atom to which they
are attached form a 5- or 6-membered heterocyclic ring, which may
additionally contain a further heteroatom selected from N, O and S,
or [0131] R.sup.1.2 denotes halogen, --NO.sub.2, --CN, --OH,
--O--CH.sub.3 or phenyl, [0132] R.sup.1.3 independently of one
another denote [0133] (a) halogen, --NO.sub.2, --CN,
--OR.sup.1.1.1, C.sub.1-6-alkyl or [0134] (b) a C.sub.1-3-alkyl
group wherein each methylene group may be substituted by 1 or 2
fluorine atoms and each methyl group may be substituted by 1, 2 or
3 fluorine atoms, [0135] R.sup.1.4 independently of one another
denote [0136] (a) halogen, --NO.sub.2, --CN, --OR.sup.1.1.1,
--NR.sup.1.1.3R.sup.1.1.4, --N(R.sup.1.4.1)--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or [0137] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
and [0138] R.sup.1.4.1 denotes H or C.sub.1-4-alkyl, the
enantiomers, the diastereomers, the mixtures and the salts thereof,
particularly the physiologically acceptable salts thereof with
organic or inorganic acids or bases.
[0139] An embodiment 3 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1 and [0140] R.sup.1 denotes [0141] (a) a
C.sub.1-6-alkyl group optionally substituted by a group R.sup.1.1,
[0142] (b) a phenyl group optionally substituted by 1, 2 or 3
groups R.sup.1.3, [0143] (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which
contains at least one N, O or S atom and which optionally
additionally contains one, two or three further N-atoms, [0144] (d)
a six-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, [0145]
(e) a nine- or ten-membered heteroaryl group optionally substituted
by 1 or 2 groups R.sup.1.4, which contains one, two or three
N-atoms, [0146] (f) a 5- or 6-membered heterocyclic group
optionally substituted by 1 or 2 groups R.sup.1.4, in which a
--CH.sub.2-- unit may be replaced by a --C(O)-- group, [0147]
R.sup.1.1 denotes --CN, C.sub.3-6-cycloalkyl, --OH, --OCH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, [0148] R.sup.1.3
independently of one another denote [0149] (a) F, Cl, Br, --OH,
--OCH.sub.3, C.sub.1-6-alkyl or [0150] (b) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, and [0151] R.sup.1.4 independently of one another
denote [0152] (a) F, Cl, Br, --OH, --OCH.sub.3, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, NHC.sub.2-3-alkyl,
--N(C.sub.2-3-alkyl).sub.2--NH--C(O)--C.sub.1-4-Alkyl,
C.sub.1-6-alkyl, or [0153] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0154] An embodiment 4 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1 and [0155] R.sup.1 denotes [0156] (a) a
C.sub.1-6-alkyl group optionally substituted by a group R.sup.1.1,
[0157] (b) a phenyl group optionally substituted by 1, 2 or 3
groups R.sup.1.3, [0158] (c) a five-membered heteroaryl group
optionally substituted by 1, 2 or 3 groups R.sup.1.4, which is
selected from among
[0158] ##STR00003## [0159] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4 which is selected
from among
[0159] ##STR00004## [0160] (e) a nine-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0160] ##STR00005## [0161] (f) a 5- or 6-membered heterocyclic
group optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0161] ##STR00006## [0162] R.sup.1.1 denotes --CN, cyclopropyl,
--OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
[0163] R.sup.1.3 independently of one another denotes [0164] (a) F,
Cl, Br, --OH, --OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or [0165]
(b) a C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and [0166] R.sup.1.4
independently of one another denotes [0167] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or [0168] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0169] An embodiment 5 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1 and [0170] R.sup.1 is selected from among
##STR00007## ##STR00008##
[0170] the enantiomers, the diastereomers, the mixtures and the
salts thereof, particularly the physiologically acceptable salts
thereof with organic or inorganic acids or bases.
[0171] An embodiment 6 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1 and [0172] R.sup.1 is selected from among
##STR00009## ##STR00010##
[0172] the enantiomers, the diastereomers, the mixtures and the
salts thereof, particularly the physiologically acceptable salts
thereof with organic or inorganic acids or bases.
[0173] An embodiment 7 of the present invention consists of the
compounds of the above general formula I, wherein R.sup.1 is
defined as mentioned hereinbefore under embodiment 2, 3, 4, 5 or 6
and
n denotes one of the numbers 0, 1 or 2, R.sup.2 denotes [0174] (a)
H, [0175] (b) C.sub.1-4-alkyl, R.sup.3 and R.sup.4 together with
the carbon atom to which they are bound denote a
C.sub.3-6-cycloalkylene group optionally substituted by a group
R.sup.3.1 wherein a --CH.sub.2 unit may be replaced by a heteroatom
O, N, S or by a group CO, SO or SO.sub.2, R.sup.3.1 denotes H,
--OH, R.sup.5 denotes [0176] (a) H, [0177] (b) C.sub.1-4-alkyl,
[0178] (c) a C.sub.1-3-alkyl group wherein each methylene group may
be substituted by 1 or 2 fluorine atoms and each methyl group may
be substituted by 1, 2 or 3 fluorine atoms, R.sup.6 independently
of one another denotes [0179] (a) H, halogen, --CN, --OH,
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl, --O--C.sub.1-4-alkyl,
--O--CF.sub.3, --O--C.sub.3-6-cycloalkyl,
--N(C.sub.1-3-alkyl).sub.2, --C(O)--NH.sub.2, --(SO.sub.2)NH.sub.2,
--SO.sub.2--C.sub.1-3-alkyl, or [0180] (b) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, R.sup.7 denotes [0181] (a) H, halogen, --CN, --OH,
[0182] (b) C.sub.1-6-alkyl, [0183] (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0184] (d)
C.sub.3-7-cycloalkyl, [0185] (e) --O--C.sub.1-6-alkyl, [0186] (f)
--O--C.sub.3-7-cycloalkyl, [0187] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0188] (h)
--C(O)--R.sup.7.1, [0189] (i) --S--C.sub.1-4-alkyl, R.sup.7.1
denotes --NH.sub.2, --OH, --O--C.sub.1-8-alkyl, R.sup.8 denotes H,
halogen, C.sub.1-4-alkyl, R.sup.9 denotes [0190] (a) H, halogen,
--CN, --OH, [0191] (b) C.sub.1-6-alkyl, [0192] (c) C.sub.1-3-alkyl
or --O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0193] (d)
C.sub.3-7-cycloalkyl, [0194] (e) C.sub.2-4-alkynyl, [0195] (f)
--O--C.sub.1-6-alkyl, [0196] (g) --O--C.sub.3-7-cycloalkyl, [0197]
(h) --NH.sub.2, --NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2,
[0198] (i) --C(O)--R.sup.9.1, [0199] (j) --S--C.sub.1-4-alkyl,
--SO--C.sub.1-4-alkyl, --SO.sub.2--C.sub.1-4-alkyl, R.sup.9.1
denotes --NH.sub.2, --OH, --O--C.sub.1-8-alkyl, R.sup.10 denotes H,
halogen, C.sub.1-4-alkyl, R.sup.11 denotes [0200] (a) H, halogen,
--CN, --OH, [0201] (b) C.sub.1-6-alkyl, [0202] (c) C.sub.1-3-alkyl
or --O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0203] (d)
C.sub.3-7-cycloalkyl, [0204] (e) --O--C.sub.1-6-alkyl, [0205] (f)
--O--C.sub.3-7-cycloalkyl, [0206] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0207] (h)
--C(O)--R.sup.11.1, [0208] (i) --S--C.sub.1-3-alkyl, R.sup.11.1
denotes --NH.sub.2, --OH, --O--C.sub.1-8-alkyl, and X independently
of one another represent C--R.sup.6 or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0209] An embodiment 8 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1, 2, 3, 4, 5 or 6 and
R.sup.2 denotes H or CH.sub.3, the enantiomers, the diastereomers,
the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0210] An embodiment 8 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1, 2, 3, 4, 5, 6 or 7 and
R.sup.2 denotes H or CH.sub.3, the enantiomers, the diastereomers,
the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0211] An embodiment 9 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.2,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, n
and X are defined as mentioned hereinbefore in embodiment 1, 2, 3,
4, 5, 6 or 7 and
R.sup.2 denotes H, the enantiomers, the diastereomers, the mixtures
and the salts thereof, particularly the physiologically acceptable
salts thereof with organic or inorganic acids or bases.
[0212] An embodiment 10 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.2,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, n
and X are defined as mentioned hereinbefore in embodiment 1, 2, 3,
4, 5, 6, 7, 8 or 9 and
R.sup.3 and R.sup.4 together with the carbon atom to which they are
bonded denote a C.sub.3-6-cycloalkylene group wherein a
--CH.sub.2-- unit may be replaced by an oxygen atom, the
enantiomers, the diastereomers, the mixtures and the salts thereof,
particularly the physiologically acceptable salts thereof with
organic or inorganic acids or bases.
[0213] An embodiment 11 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.2,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, n
and X are defined as mentioned hereinbefore in embodiment 1, 2, 3,
4, 5, 6, 7, 8 or 9 and
R.sup.3 and R.sup.4 together with the carbon atom to which they are
bonded denote a group selected from
##STR00011##
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0214] An embodiment 12 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 and
R.sup.5 denotes H or CH.sub.3, the enantiomers, the diastereomers,
the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0215] An embodiment 13 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, n and X are defined as mentioned hereinbefore in
embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 and
R.sup.6 denotes H, F, Cl or methyl, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0216] An embodiment 14 of the present invention comprises the
compounds of the above general formula I, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, n and X are defined as
mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12 or 13 and
R.sup.7 denotes H, F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, R.sup.8 denotes H, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.10 denotes H and R.sup.11 denotes F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0217] An embodiment 15 of the present invention comprises the
compounds of general formula Ia
##STR00012##
wherein R.sup.1 denotes [0218] (a) a C.sub.1-6-alkyl group
optionally substituted by a group R.sup.1.1, [0219] (b) a phenyl
group optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0220]
(c) a five-membered heteroaryl group optionally substituted by 1, 2
or 3 groups R.sup.1.4, which contains at least one N, O or S atom
and which optionally additionally contains one, two or three
further N-atoms, [0221] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which contains
one, two or three N-atoms, [0222] (e) a nine- or ten-membered
heteroaryl group optionally substituted by 1 or 2 groups R.sup.1.4,
which contains one, two or three N-atoms, [0223] (f) a 5- or
6-membered heterocyclic group optionally substituted by 1 or 2
groups R.sup.1.4, in which a --CH.sub.2-- unit may be replaced by a
--C(O)-- group, R.sup.1.1 denotes --CN, C.sub.3-6-cycloalkyl, --OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
R.sup.1.3 independently of one another denotes [0224] (a) F, Cl,
Br, --OH, --OCH.sub.3, C.sub.1-6-alkyl or [0225] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4
independently of one another denotes [0226] (a) F, Cl, Br, --OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl, or [0227] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.2 denotes H or
CH.sub.3, R.sup.3 and R.sup.4 together with the carbon atom to
which they are bonded denote a C.sub.3-6-cycloalkylene group
wherein a --CH.sub.2 unit may be replaced by an oxygen atom,
R.sup.5 denotes H or C.sub.1-4-alkyl, R.sup.6 denotes H, F, Cl, Br
or C.sub.1-4-alkyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0228] An embodiment 16 of the present invention comprises the
compounds of general formula Ia, wherein
R.sup.1 denotes [0229] (a) a C.sub.1-6-alkyl group optionally
substituted by a group R.sup.1.1, [0230] (b) a phenyl group
optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0231] (c) a
five-membered heteroaryl group optionally substituted by 1, 2 or 3
groups R.sup.1.4, which is selected from among
[0231] ##STR00013## [0232] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0232] ##STR00014## [0233] (e) a nine-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0233] ##STR00015## [0234] (f) a 5- or 6-membered heterocyclic
group optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
##STR00016##
[0234] R.sup.1.1 denotes --CN, cyclopropyl, --OH, --OCH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, R.sup.1.3 denotes
independently of one another [0235] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or [0236] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another [0237] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or [0238] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.2 denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with
the carbon atom to which they are bonded denote a
C.sub.3-6-cycloalkylene group wherein a --CH.sub.2 unit may be
replaced by an oxygen atom, R.sup.5 denotes H or CH.sub.3, R.sup.6
denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0239] An embodiment 17 of the present invention comprises the
compounds of general formula Ia, wherein
R.sup.1 denotes a group selected from
##STR00017## ##STR00018## ##STR00019##
R.sup.2 denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with
the carbon atom to which they are bonded denote a
C.sub.3-6-cycloalkylene group wherein a --CH.sub.2 unit may be
replaced by an oxygen atom, R.sup.5 denotes H or CH.sub.3, R.sup.6
denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0240] An embodiment 18 of the present invention comprises the
compounds of general formula Ia wherein
R.sup.1 denotes a group selected from
##STR00020## ##STR00021##
R.sup.2 denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with
the carbon atom to which they are bound denote a
C.sub.3-6-cycloalkylene group wherein a --CH.sub.2 unit may be
replaced by an oxygen atom, R.sup.5 denotes H or CH.sub.3, R.sup.6
denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0241] An embodiment 19 of the present invention comprises the
compounds of general formula Ib
##STR00022##
wherein R.sup.1 denotes [0242] (a) a C.sub.1-6-alkyl group
optionally substituted by a group R.sup.1.1, [0243] (b) a phenyl
group optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0244]
(c) a five-membered heteroaryl group optionally substituted by 1, 2
or 3 groups R.sup.1.4, which contains at least one N, O or S atom
and which optionally additionally contains one, two or three
further N-atoms, [0245] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which contains
one, two or three N-atoms, [0246] (e) a nine- or ten-membered
heteroaryl group optionally substituted by 1 or 2 groups R.sup.1.4,
which contains one, two or three N-atoms, [0247] (f) a 5- or
6-membered heterocyclic group optionally substituted by 1 or 2
groups R.sup.1.4, in which a --CH.sub.2-- unit may be replaced by a
--C(O)-- group, R.sup.1.1 denotes --CN, C.sub.3-6-cycloalkyl, --OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
R.sup.1.3 denotes independently of one another [0248] (a) F, Cl,
Br, --OH, --OCH.sub.3, C.sub.1-6-alkyl or [0249] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another [0250] (a) F, Cl, Br, --OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl, or [0251] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, R.sup.2 denotes H or
CH.sub.3, R.sup.5 denotes H or C.sub.1-4-alkyl, R.sup.6 denotes H,
F, Cl, Br or C.sub.1-4-alkyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0252] An embodiment 20 of the present invention comprises the
compounds of general formula Ib, wherein
R.sup.1 denotes [0253] (a) a C.sub.1-6-alkyl group optionally
substituted by a group R.sup.1.1, [0254] (b) a phenyl group
optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0255] (c) a
five-membered heteroaryl group optionally substituted by 1, 2 or 3
groups R.sup.1.4, which is selected from among
[0255] ##STR00023## [0256] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0256] ##STR00024## [0257] (e) a nine-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0257] ##STR00025## [0258] (f) a 5- or 6-membered heterocyclic
group optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
##STR00026##
[0258] R.sup.1.1 denotes --CN, cyclopropyl, --OH, --OCH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, R.sup.1.3 denotes
independently of one another [0259] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or [0260] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4 denotes
independently of one another [0261] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or [0262] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0263] An embodiment 21 of the present invention comprises the
compounds of general formula Ib, wherein
R.sup.1 denotes a group selected from
##STR00027## ##STR00028## ##STR00029##
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0264] An embodiment 22 of the present invention comprises the
compounds of general formula Ib, wherein
R.sup.1 denotes a group selected from
##STR00030## ##STR00031##
R.sup.2 denotes H, R.sup.5 denotes H or CH.sub.3, R.sup.6 denotes
H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0265] An embodiment 23 of the present invention comprises the
compounds of general formula IC
##STR00032##
wherein R.sup.1 denotes [0266] (a) a C.sub.1-6-alkyl group
optionally substituted by a group R.sup.1.1, [0267] (b) a phenyl
group optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0268]
(c) a five-membered heteroaryl group optionally substituted by 1, 2
or 3 groups R.sup.1.4, which contains at least one N, O or S atom
and which optionally additionally contains one, two or three
further N-atoms, [0269] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which contains
one, two or three N-atoms, [0270] (e) a nine- or ten-membered
heteroaryl group optionally substituted by 1 or 2 groups R.sup.1.4
which contains one, two or three N-atoms, [0271] (f) a 5- or
6-membered heterocyclic group optionally substituted by 1 or 2
groups R.sup.1.4, wherein a --CH.sub.2-- unit may be replaced by a
--C(O)-- group, R.sup.1.1 denotes --CN, C.sub.3-6-cycloalkyl, --OH,
--OCH.sub.3, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
R.sup.1.3 independently of one another denote [0272] (a) F, Cl, Br,
--OH, --OCH.sub.3, C.sub.1-6-alkyl or [0273] (b) a C.sub.1-3-alkyl
group wherein each methylene group may be substituted by 1 or 2
fluorine atoms and each methyl group may be substituted by 1, 2 or
3 fluorine atoms, and R.sup.1.4 independently of one another denote
[0274] (a) F, Cl, Br, --OH, --OCH.sub.3, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NH--C(O)--C.sub.1-4-alkyl, C.sub.1-6-alkyl,
or [0275] (b) a C.sub.1-3-alkyl group wherein each methylene group
may be substituted by 1 or 2 fluorine atoms and each methyl group
may be substituted by 1, 2 or 3 fluorine atoms, R.sup.2 denotes H
or CH.sub.3, R.sup.5 denotes H or C.sub.1-4-alkyl, R.sup.6 denotes
H, F, Cl, Br or C.sub.1-4-alkyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0276] An embodiment 24 of the present invention comprises the
compounds of general formula IC, wherein
R.sup.1 denotes [0277] (a) a C.sub.1-6-alkyl group optionally
substituted by a group R.sup.1.1, [0278] (b) a phenyl group
optionally substituted by 1, 2 or 3 groups R.sup.1.3, [0279] (c) a
five-membered heteroaryl group optionally substituted by 1, 2 or 3
groups R.sup.1.4, which is selected from among
[0279] ##STR00033## [0280] (d) a six-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0280] ##STR00034## [0281] (e) a nine-membered heteroaryl group
optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
[0281] ##STR00035## [0282] (f) a 5- or 6-membered heterocyclic
group optionally substituted by 1 or 2 groups R.sup.1.4, which is
selected from among
##STR00036##
[0282] R.sup.1.1 denotes --CN, cyclopropyl, --OH, --OCH.sub.3,
--NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2, R.sup.1.3
independently of one another denotes [0283] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, C.sub.1-4-alkyl or [0284] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, and R.sup.1.4
independently of one another denote [0285] (a) F, Cl, Br, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH--C.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2, --NH--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, or [0286] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0287] An embodiment 25 of the present invention comprises the
compounds of general formula Ic, wherein
R.sup.1 denotes a group selected from
##STR00037## ##STR00038## ##STR00039##
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0288] An embodiment 26 of the present invention comprises the
compounds of general formula Ic, wherein
R.sup.1 denotes a group selected from
##STR00040## ##STR00041##
R.sup.2 denotes H or CH.sub.3, R.sup.5 denotes H or CH.sub.3,
R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F, Cl, Br,
--CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.9 denotes F, Cl,
Br, C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X denotes CH or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0289] An embodiment 27 of the present invention comprises the
compounds of general formula Id
##STR00042##
wherein R.sup.1 denotes a group selected from
##STR00043##
R.sup.3 and R.sup.4 together with the carbon atom to which they are
attached denote a C.sub.3-6-cycloalkylene group wherein a
--CH.sub.2 unit may be replaced by an oxygen atom, R.sup.5 denotes
H or CH.sub.3, R.sup.6 denotes Cl or CH.sub.3, R.sup.7 denotes H or
F, X denotes CH or N, the enantiomers, the diastereomers, the
mixtures and the salts thereof, particularly the physiologically
acceptable salts thereof with organic or inorganic acids or
bases.
[0290] An embodiment 28 of the present invention comprises the
compounds of general formula I, Ia, Ib, Ic or Id, wherein n,
R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11 and X are defined as described
hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27
and
R.sup.2 denotes H, the enantiomers, the diastereomers, the mixtures
and the salts thereof, particularly the physiologically acceptable
salts thereof with organic or inorganic acids or bases.
[0291] The following are mentioned as examples of most particularly
preferred compounds of the above general formula I:
TABLE-US-00001 No. Structure (1) ##STR00044## (2) ##STR00045## (3)
##STR00046## (4) ##STR00047## (5) ##STR00048## (6) ##STR00049## (7)
##STR00050## (8) ##STR00051## (9) ##STR00052## (10) ##STR00053##
(11) ##STR00054## (12) ##STR00055## (13) ##STR00056## (14)
##STR00057## (15) ##STR00058## (16) ##STR00059## (17) ##STR00060##
(18) ##STR00061## (19) ##STR00062## (20) ##STR00063## (21)
##STR00064## (22) ##STR00065## (23) ##STR00066## (24) ##STR00067##
(25) ##STR00068## (26) ##STR00069## (27) ##STR00070## (28)
##STR00071## (29) ##STR00072## (30) ##STR00073## (31) ##STR00074##
(32) ##STR00075## (33) ##STR00076## (34) ##STR00077## (35)
##STR00078## (36) ##STR00079## (37) ##STR00080## (38) ##STR00081##
(39) ##STR00082## (40) ##STR00083## (41) ##STR00084## (42)
##STR00085## (43) ##STR00086## (44) ##STR00087## (45) ##STR00088##
(46) ##STR00089## (47) ##STR00090## (48) ##STR00091## (49)
##STR00092## (50) ##STR00093## (51) ##STR00094## (52) ##STR00095##
(53) ##STR00096## (54) ##STR00097## (55) ##STR00098## (56)
##STR00099## (57) ##STR00100## (58) ##STR00101## (59) ##STR00102##
(60) ##STR00103## (61) ##STR00104## (62) ##STR00105## (63)
##STR00106## (64) ##STR00107## (65) ##STR00108## (66) ##STR00109##
(67) ##STR00110## (68) ##STR00111## (69) ##STR00112## (70)
##STR00113## (71) ##STR00114## (72) ##STR00115## (73) ##STR00116##
(74) ##STR00117## (75) ##STR00118## (76) ##STR00119## (77)
##STR00120## (78) ##STR00121## (79) ##STR00122## (80) ##STR00123##
(81) ##STR00124## (82) ##STR00125## (83) ##STR00126## (84)
##STR00127## (85) ##STR00128## (86) ##STR00129## (87) ##STR00130##
(88) ##STR00131## (89) ##STR00132## (90) ##STR00133## (91)
##STR00134## (92) ##STR00135## (93) ##STR00136## (94) ##STR00137##
(95) ##STR00138## (96) ##STR00139## (97) ##STR00140## (98)
##STR00141## (99) ##STR00142## (100) ##STR00143## (101)
##STR00144## (102) ##STR00145## (103) ##STR00146## (104)
##STR00147## (105) ##STR00148## (106) ##STR00149## (107)
##STR00150## (108) ##STR00151## (109) ##STR00152## (110)
##STR00153## (111) ##STR00154## (112) ##STR00155## (113)
##STR00156## (114) ##STR00157## (115) ##STR00158## (116)
##STR00159## (117) ##STR00160## (118) ##STR00161## (119)
##STR00162## (120) ##STR00163## (121) ##STR00164## (122)
##STR00165## (123) ##STR00166## (124) ##STR00167##
(125) ##STR00168## (126) ##STR00169## (127) ##STR00170## (128)
##STR00171## (129) ##STR00172## (130) ##STR00173## (131)
##STR00174## (132) ##STR00175## (133) ##STR00176## (134)
##STR00177## (135) ##STR00178## (136) ##STR00179## (137)
##STR00180## (138) ##STR00181## (139) ##STR00182## (140)
##STR00183## (141) ##STR00184## (142) ##STR00185## (143)
##STR00186## (144) ##STR00187## (145) ##STR00188## (146)
##STR00189## (147) ##STR00190## (148) ##STR00191## (149)
##STR00192## (150) ##STR00193## (151) ##STR00194## (152)
##STR00195## (153) ##STR00196## (154) ##STR00197## (155)
##STR00198## (156) ##STR00199## (157) ##STR00200## (158)
##STR00201## (159) ##STR00202## (160) ##STR00203## (161)
##STR00204## (162) ##STR00205## (163) ##STR00206## (164)
##STR00207## (165) ##STR00208## (166) ##STR00209## (167)
##STR00210## (168) ##STR00211## (169) ##STR00212## (170)
##STR00213## (171) ##STR00214## (172) ##STR00215## (173)
##STR00216## (174) ##STR00217## (175) ##STR00218## (176)
##STR00219## (177) ##STR00220## (178) ##STR00221## (179)
##STR00222## (180) ##STR00223## (181) ##STR00224## (182)
##STR00225## (183) ##STR00226## (184) ##STR00227## (185)
##STR00228## (186) ##STR00229## (187) ##STR00230## (188)
##STR00231## (189) ##STR00232## (190) ##STR00233## (191)
##STR00234## (192) ##STR00235## (193) ##STR00236## (194)
##STR00237## (195) ##STR00238## (196) ##STR00239## (197)
##STR00240## (198) ##STR00241## (199) ##STR00242## (200)
##STR00243## (201) ##STR00244## (202) ##STR00245## (203)
##STR00246## (203a) ##STR00247## (203b) ##STR00248## (204)
##STR00249## (205) ##STR00250## (206) ##STR00251## (207)
##STR00252## (208) ##STR00253## (209) ##STR00254## (210)
##STR00255## (211) ##STR00256## (212) ##STR00257## (212a)
##STR00258## (212b) ##STR00259## (213) ##STR00260## (213a)
##STR00261## (213b) ##STR00262## (214) ##STR00263## (215)
##STR00264## (216) ##STR00265## (217) ##STR00266## (218)
##STR00267## (219) ##STR00268## (220) ##STR00269## (221)
##STR00270## (222) ##STR00271## (223) ##STR00272## (224)
##STR00273## (225) ##STR00274## (226) ##STR00275## (227)
##STR00276## (228) ##STR00277## (229) ##STR00278## (230)
##STR00279## (231) ##STR00280## (232) ##STR00281## (233)
##STR00282## (234) ##STR00283## (235) ##STR00284## (236)
##STR00285## (237) ##STR00286## (238) ##STR00287## (239)
##STR00288## (240) ##STR00289## (241) ##STR00290## (242)
##STR00291## (243) ##STR00292##
(244) ##STR00293## (245) ##STR00294## (246) ##STR00295## (247)
##STR00296## (248) ##STR00297## (249) ##STR00298## (250)
##STR00299## (251) ##STR00300## (252) ##STR00301## (253)
##STR00302## (254) ##STR00303## (255) ##STR00304## (256)
##STR00305## (257) ##STR00306## (258) ##STR00307## (258)
##STR00308## (260) ##STR00309## (261) ##STR00310## (262)
##STR00311## (263) ##STR00312## (264) ##STR00313## (265)
##STR00314## (266) ##STR00315## (267) ##STR00316## (268)
##STR00317## (269) ##STR00318## (270) ##STR00319## (271)
##STR00320## (272) ##STR00321## (273) ##STR00322## (274)
##STR00323## (275) ##STR00324## (276) ##STR00325## (277)
##STR00326## (278) ##STR00327## (279) ##STR00328## (280)
##STR00329## (281) ##STR00330## (282) ##STR00331## (283)
##STR00332## (284) ##STR00333## (285) ##STR00334## (286)
##STR00335## (287) ##STR00336## (288) ##STR00337## (289)
##STR00338## (290) ##STR00339## (291) ##STR00340## (292)
##STR00341## (293) ##STR00342## (294) ##STR00343## (295)
##STR00344## (296) ##STR00345## (297) ##STR00346## (298)
##STR00347## (299) ##STR00348## (300) ##STR00349## (301)
##STR00350## (302) ##STR00351## (303) ##STR00352## (304)
##STR00353## (305) ##STR00354## (306) ##STR00355## (307)
##STR00356## (308) ##STR00357## (309) ##STR00358## (310)
##STR00359## (311) ##STR00360## (312) ##STR00361## (313)
##STR00362## (314) ##STR00363## (315) ##STR00364## (316)
##STR00365## (317) ##STR00366## (318) ##STR00367## (319)
##STR00368## (320) ##STR00369## (321) ##STR00370## (322)
##STR00371## (323) ##STR00372## (324) ##STR00373## (325)
##STR00374## (326) ##STR00375## (327) ##STR00376## (328)
##STR00377## (329) ##STR00378## (330) ##STR00379## (331)
##STR00380## (332) ##STR00381## (333) ##STR00382## (334)
##STR00383## (335) ##STR00384## (336) ##STR00385## (337)
##STR00386## (338) ##STR00387## (339) ##STR00388## (340)
##STR00389## (341) ##STR00390## (342) ##STR00391## (343)
##STR00392## (344) ##STR00393## (345) ##STR00394## (346)
##STR00395## (347) ##STR00396## (348) ##STR00397## (349)
##STR00398## (350) ##STR00399## (351) ##STR00400## (352)
##STR00401## (353) ##STR00402## (354) ##STR00403## (355)
##STR00404## (356) ##STR00405## (357) ##STR00406## (358)
##STR00407## (359) ##STR00408## (360) ##STR00409## (361)
##STR00410## (362) ##STR00411## (363) ##STR00412## (364)
##STR00413## (365) ##STR00414## (366) ##STR00415## (367)
##STR00416## (368) ##STR00417## (369) ##STR00418##
(370) ##STR00419## (371) ##STR00420## (372) ##STR00421## (373)
##STR00422## (374) ##STR00423## (375) ##STR00424## (376)
##STR00425## (377) ##STR00426## (378) ##STR00427## (379)
##STR00428## (380) ##STR00429## (381) ##STR00430## (382)
##STR00431## (383) ##STR00432## (384) ##STR00433## (385)
##STR00434## (386) ##STR00435## (387) ##STR00436## (388)
##STR00437## (389) ##STR00438## (390) ##STR00439## (391)
##STR00440## (392) ##STR00441## (393) ##STR00442## (394)
##STR00443## (395) ##STR00444## (396) ##STR00445##
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0292] A further embodiment of the present invention comprises the
compounds of general formula II
##STR00446##
wherein n denotes one of the numbers 0, 1 or 2, [0293] R.sup.2
denotes [0294] (a) H, [0295] (b) C.sub.1-4-alkyl, [0296] (c)
C.sub.1-4-alkyl-C(O)--, [0297] R.sup.5 denotes [0298] (a) H, [0299]
(b) C.sub.1-4-alkyl, [0300] (c) a C.sub.1-3-alkyl group wherein
each methylene group may be substituted by 1 or 2 fluorine atoms
and each methyl group may be substituted by 1, 2 or 3 fluorine
atoms, [0301] R.sup.6 independently of one another denotes [0302]
(a) H, halogen, --CN, --OH, C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
--O--C.sub.1-4-alkyl, --O--CF.sub.3, --O--C.sub.3-6-cycloalkyl,
--N(C.sub.1-3-alkyl).sub.2, --C(O)--NH.sub.2, --(SO.sub.2)NH.sub.2,
--SO.sub.2--C.sub.1-3-alkyl, or [0303] (b) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, [0304] R.sup.7 denotes [0305] (a) H, halogen, --CN,
--OH, [0306] (b) C.sub.1-6-alkyl, [0307] (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0308] (d)
C.sub.3-7-cycloalkyl, [0309] (e) --O--C.sub.1-6-alkyl, [0310] (f)
--O--C.sub.3-7-cycloalkyl, [0311] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0312] (h)
--C(O)--R.sup.7.1, [0313] (i) --S--C.sub.1-4-alkyl,
--SO.sub.2--R.sup.7.2, [0314] (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or [0315] (k) a six-membered heteroaryl
group optionally substituted by one or two C.sub.1-3-alkyl groups
which is selected from among pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl and triazinyl, [0316] R.sup.7.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, [0317] R.sup.7.2
denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and [0318] R.sup.8 denotes H,
halogen, C.sub.1-4-alkyl, [0319] R.sup.9 denotes [0320] (a) H,
halogen, --CN, --OH, [0321] (b) C.sub.1-6-alkyl, [0322] (c)
C.sub.1-3-alkyl or --O--C.sub.1-3-alkyl, wherein each methylene
group may be substituted by 1 or 2 fluorine atoms and each methyl
group may be substituted by 1, 2 or 3 fluorine atoms, [0323] (d)
C.sub.3-7-cycloalkyl, [0324] (e) C.sub.2-4-alkynyl, [0325] (f)
--O--C.sub.1-6-alkyl, [0326] (g) --O--C.sub.3-7-cycloalkyl, [0327]
(h) --NH.sub.2, --NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2,
[0328] (i) --C(O)--R.sup.9.1, [0329] (j) --S--C.sub.1-4-alkyl,
--SO--C.sub.1-4-alkyl, --SO.sub.2--C.sub.1-4-alkyl, [0330]
R.sup.9.1 denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl, N-morpholinyl, --OH, --O--C.sub.1-8-alkyl or
--O--C.sub.3-7-cycloalkyl, [0331] R.sup.10 denotes H, halogen,
C.sub.1-4-alkyl, [0332] R.sup.11 denotes [0333] (a) H, halogen,
--CN, --OH, [0334] (b) C.sub.1-6-alkyl, [0335] (c) C.sub.1-3-alkyl
or --O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0336] (d)
C.sub.3-7-cycloalkyl, [0337] (e) --O--C.sub.1-6-alkyl, [0338] (f)
--O--C.sub.3-7-cycloalkyl, [0339] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0340] (h)
--C(O)--R.sup.11.1, [0341] (i) --S--C.sub.1-3-alkyl,
--SO.sub.2--R.sup.11.2, [0342] (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or [0343] (k) a six-membered heteroaryl
group optionally substituted by one or two C.sub.1-3-alkyl groups
which is selected from among pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl and triazinyl, [0344] R.sup.11.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, [0345]
R.sup.11.2 denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and [0346] X independently of one
another denotes C--R.sup.6 or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0347] A further embodiment of the present invention comprises the
compounds of the above general formula II, wherein
n denotes one of the numbers 0, 1 or 2, R.sup.2 denotes H or
CH.sub.3, R.sup.5 denotes H or CH.sub.3, R.sup.6 denotes H, F, Cl
or methyl, R.sup.7 denotes H, F, Cl, Br, --CN, C.sub.1-4-alkyl,
CF.sub.3, CHF.sub.2, R.sup.8 denotes H, R.sup.9 denotes F, Cl, Br,
C.sub.1-4-alkyl, --O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl,
R.sup.10 denotes H, R.sup.11 denotes F, Cl, Br, --CN,
C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, and X independently of one
another represent C--R.sup.6 or N, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0348] The following compounds are mentioned as examples of
particularly preferred compounds of the above general formula
II:
TABLE-US-00002 No. Structure (1.1) ##STR00447## (1.2) ##STR00448##
(1.3) ##STR00449## (1.4) ##STR00450## (1.5) ##STR00451## (1.6)
##STR00452## (1.7) ##STR00453## (1.8) ##STR00454## (1.9)
##STR00455## (1.10) ##STR00456## (1.11) ##STR00457## (1.12)
##STR00458## (1.13) ##STR00459## (1.14) ##STR00460## (1.15)
##STR00461## (1.16) ##STR00462## (1.17) ##STR00463## (1.18)
##STR00464## (1.19) ##STR00465## (1.20) ##STR00466## (1.21)
##STR00467## (1.22) ##STR00468## (1.23) ##STR00469## (1.24)
##STR00470## (1.25) ##STR00471## (1.26) ##STR00472## (1.27)
##STR00473## (1.28) ##STR00474## (1.29) ##STR00475## (1.30)
##STR00476## (1.31) ##STR00477##
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0349] A further embodiment of the present application relates to
the use of the compounds of general formula II, wherein R.sup.2,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11
are as hereinbefore defined, the diastereomers, the enantiomers and
the salts thereof, particularly the physiologically acceptable
salts thereof with inorganic or organic acids or bases for
preparing compounds of general formula I, which have
B1-antagonistic properties.
[0350] A further embodiment of the present invention comprises the
compounds of general formula III
##STR00478##
wherein [0351] R.sup.1 denotes [0352] (a) a C.sub.1-6-alkyl group
optionally substituted by a group R.sup.1.1, [0353] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0354] (c) a
C.sub.3-6-cycloalkyl group optionally substituted by a group
R.sup.1.2 wherein a --CH.sub.2-unit may be replaced by a --C(O)--
group, [0355] (d) an aryl-C.sub.0-2-alkylene group optionally
substituted by 1, 2 or 3 groups R.sup.1.3, [0356] (e) a
five-membered heteroaryl-C.sub.0-2-alkylene group optionally
substituted by 1, 2 or 3 groups R.sup.1.4, which contains at least
one N, O or S atom and which optionally additionally contains one,
two or three further N-atoms and which may additionally be
benzo-condensed, [0357] (f) a six-membered
heteroaryl-C.sub.0-2-alkylene group optionally substituted by 1 or
2 groups R.sup.1.4, which contains one, two or three N-atoms and
which may additionally be benzo-condensed, [0358] (g) a nine or
ten-membered heteroaryl group optionally substituted by 1 or 2
groups R.sup.1.4, which contains one, two or three N-atoms, [0359]
(h) a 5- or 6-membered heterocyclic group optionally substituted by
1 or 2 groups R.sup.1.4, wherein a --CH.sub.2-- unit may be
replaced by a --C(O)-- group, [0360] (i) --O--R.sup.1.1.1, [0361]
(j) --NR.sup.1.1.3R.sup.1.1.4 or [0362] (k)
--C(.dbd.NR.sup.1.5)--CN, [0363] R.sup.1.1 denotes halogen,
--NO.sub.2, --CN, C.sub.3-6-cycloalkyl, --OR.sup.1.1.1,
--SR.sup.1.1.1, --C(O)R.sup.1.1.1, --S(O).sub.2--R.sup.1.1.2,
--O--S(O).sub.2--R.sup.1.1.1, --CO.sub.2R.sup.1.1.1,
--O--C(O)--R.sup.1.1.1, --NR.sup.1.1.3R.sup.1.1.4,
--NR.sup.1.1,3-C(O)--R.sup.1.1.1, --NR.sup.1.1,3-C(O)--R.sup.1.1.1,
--NR.sup.1.1,3-CO.sub.2--R.sup.1.1.1 or
--C(O)--NR.sup.1.1.3R.sup.1.1.4, R.sup.1.1.1 denotes [0364] (a) H,
[0365] (b) C.sub.1-4-alkyl, [0366] (c) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, [0367] (d) a phenyl group optionally substituted by
1, 2 or 3 groups R.sup.1.1.1.1, [0368] (e) C.sub.3-6-cycloalkyl or
[0369] (f) a pyridyl group optionally substituted by 1, 2 or 3
groups R.sup.1.1.1.2, [0370] R.sup.1.1.1.1 independently of one
another denotes [0371] (a) halogen, --NO.sub.2, --CN, --OH,
--O--C.sub.1-4-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-4-alkyl or
[0372] (b) a C.sub.1-3-alkyl group wherein each methylene group may
be substituted by 1 or 2 fluorine atoms and each methyl group may
be substituted by 1, 2 or 3 fluorine atoms, [0373] R.sup.1.1.1.2
independently of one another denotes halogen or C.sub.1-4-alkyl,
[0374] R.sup.1.1.2 denotes [0375] (a) C.sub.1-4-alkyl, [0376] (b) a
C.sub.1-3-alkyl group wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0377] (c)
--O--C.sub.1-4-alkyl or [0378] (d) a phenyl group optionally
substituted by 1, 2 or 3 groups R.sup.1.1.1.1, [0379] R.sup.1.1.3,
[0380] R.sup.1.1.4 independently of one another denote [0381] (a)
H, [0382] (b) a C.sub.1-4-alkyl group optionally substituted by 1,
2 or 3 groups R.sup.1.1.4.1, [0383] (c) a phenyl group optionally
substituted by 1, 2 or 3 groups R.sup.1.1.1.1, [0384] (d)
C.sub.3-6-cycloalkyl, or [0385] R.sup.1.1.3 and R.sup.1.1.4
together with the N atom to which they are attached form a 5- or
6-membered heterocyclic ring, which may additionally contain a
further heteroatom selected from N, O and S, or [0386] R.sup.1.1.3
and R.sup.1.1.4 together with the N atom to which they are
attached, form a cyclic imide, [0387] R.sup.1.1.4.1 independently
of one another denote halogen, --NH.sub.2, --NH(C.sub.1-4-alkyl),
--N(C.sub.1-4-alkyl).sub.2 or --SO.sub.2--R.sup.1.1.2, [0388]
R.sup.1.2 denotes halogen, --NO.sub.2, --CN, OH, --O--CH.sub.3 or
phenyl, [0389] R.sup.1.3 denotes [0390] (a) halogen, --NO.sub.2,
--CN, --OR.sup.1.1.1, --SR.sup.1.1.1, --CO.sub.2R.sup.1.1.1,
C.sub.1-6-alkyl or [0391] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
[0392] R.sup.1.4 independently of one another denotes [0393] (a)
halogen, --NO.sub.2, --CN, --OR.sup.1.1.1, --SR.sup.1.1.1,
--S(O)--R.sup.1.1.2, S(O).sub.2--R.sup.1.1.2,
--NR.sup.1.1.3R.sup.1.1.4, --N(R.sup.1.4.1)--C(O)--C.sub.1-4-alkyl,
C.sub.1-6-alkyl, [0394] (b) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
or [0395] (c) a oxo group, [0396] R.sup.1.4.1 denotes H or
C.sub.1-4-alkyl, [0397] R.sup.1.5 denotes --OH or
--O--C.sub.1-3-alkyl, [0398] R.sup.2 denotes [0399] (a) H, [0400]
(b) C.sub.1-4-alkyl, [0401] (c) C.sub.1-4-alkyl-C(O)--, [0402]
R.sup.3 and R.sup.4 together with the carbon atom to which they are
attached denote a C.sub.3-6-cycloalkylene group optionally
substituted by a group R.sup.3.1 wherein a --CH.sub.2-- unit may be
replaced by a heteroatom O, N, S or by a group CO, SO or SO.sub.2,
and [0403] R.sup.3.1 denotes H, --OH, the enantiomers, the
diastereomers, the mixtures and the salts thereof, particularly the
physiologically acceptable salts thereof with organic or inorganic
acids or bases.
[0404] A further embodiment of the present invention comprises the
compounds of the above general formula III, wherein
R.sup.1 is selected from among
##STR00479## ##STR00480## ##STR00481## ##STR00482##
##STR00483##
R.sup.2 denotes H or CH.sub.3, R.sup.3 and R.sup.4 together with
the carbon atom to which they are attached denote a
C.sub.3-6-cycloalkylene group optionally substituted by a group
R.sup.3.1 wherein a --CH.sub.2-- unit may be replaced by a
heteroatom O, N, S or by a group CO, SO or SO.sub.2, and R.sup.3.1
denotes H, --OH, the enantiomers, the diastereomers, the mixtures
and the salts thereof, particularly the physiologically acceptable
salts thereof with organic or inorganic acids or bases.
[0405] The following compounds are mentioned as examples of most
particularly preferred compounds of the above general formula
III:
TABLE-US-00003 No. Structure (2.1) ##STR00484## (2.2) ##STR00485##
(2.3) ##STR00486## (2.4) ##STR00487## (2.5) ##STR00488## (2.6)
##STR00489## (2.7) ##STR00490## (2.8) ##STR00491## (2.9)
##STR00492## (2.10) ##STR00493## (2.11) ##STR00494##
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0406] A further embodiment of the present application relates to
the use of the compounds of general formula III, wherein R.sup.2,
R.sup.3, and R.sup.4 are as hereinbefore defined, the
diastereomers, the enantiomers and the salts thereof, particularly
the physiologically acceptable salts thereof with inorganic or
organic acids or bases for preparing compounds of general formula I
which have B1-antagonistic properties.
[0407] A further embodiment of the present invention comprises the
compounds of general formula IV
##STR00495##
wherein n denotes one of the numbers 0, 1 or 2, R.sup.2 denotes
[0408] (a) H, [0409] (b) C.sub.1-4-alkyl, [0410] (c)
C.sub.1-4-alkyl-C(O)--, R.sup.3 and R.sup.4 together with the
carbon atom to which they are attached denote a
C.sub.3-6-cycloalkylene group optionally substituted by a group
R.sup.3.1 wherein a --CH.sub.2-- unit may be replaced by a
heteroatom O, N, S or by a group CO, SO or SO.sub.2, R.sup.3.1
denotes H, --OH, R.sup.5 denotes [0411] (a) H, [0412] (b)
C.sub.1-4-alkyl, [0413] (c) a C.sub.1-3-alkyl group wherein each
methylene group may be substituted by 1 or 2 fluorine atoms and
each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R.sup.6 independently of one another denote [0414] (a) H, halogen,
--CN, --OH, C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
--O--C.sub.1-4-alkyl, --O--CF.sub.3, --O--C.sub.3-6-cycloalkyl,
--N(C.sub.1-3-alkyl).sub.2, --C(O)--NH.sub.2, --(SO.sub.2)NH.sub.2,
--SO.sub.2--C.sub.1-3-alkyl, or [0415] (b) a C.sub.1-3-alkyl group
wherein each methylene group may be substituted by 1 or 2 fluorine
atoms and each methyl group may be substituted by 1, 2 or 3
fluorine atoms, R.sup.7 denotes [0416] (a) H, halogen, --CN, --OH,
[0417] (b) C.sub.1-6-alkyl, [0418] (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0419] (d)
C.sub.3-7-cycloalkyl, [0420] (e) --O--C.sub.1-6-alkyl, [0421] (f)
--O--C.sub.3-7-cycloalkyl, [0422] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0423] (h)
--C(O)--R.sup.7.1, [0424] (i) --S--C.sub.1-4-alkyl,
--SO.sub.2--R.sup.7.2, [0425] (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or [0426] (k) a six-membered heteroaryl
group optionally substituted by one or two C.sub.1-3-alkyl groups
which is selected from among pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl and triazinyl, R.sup.7.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl, R.sup.7.2
denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and R.sup.8 denotes H, halogen,
C.sub.1-4-alkyl, R.sup.9 denotes [0427] (a) H, halogen, --CN, --OH,
[0428] (b) C.sub.1-6-alkyl, [0429] (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0430] (d)
C.sub.3-7-cycloalkyl, [0431] (e) C.sub.2-4-alkynyl, [0432] (f)
--O--C.sub.1-6-alkyl, [0433] (g) --O--C.sub.3-7-cycloalkyl, [0434]
(h) --NH.sub.2, --NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2,
[0435] (i) --C(O)--R.sup.9.1, [0436] (j) --S--C.sub.1-4-alkyl,
--SO--C.sub.1-4-alkyl, --SO.sub.2--C.sub.1-4-alkyl, R.sup.9.1
denotes --NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl, N-morpholinyl, --OH, --O--C.sub.1-8-alkyl or
--O--C.sub.3-7-cycloalkyl, R.sup.10 denotes H, halogen,
C.sub.1-4-alkyl, R.sup.11 denotes [0437] (a) H, halogen, --CN,
--OH, [0438] (b) C.sub.1-6-alkyl, [0439] (c) C.sub.1-3-alkyl or
--O--C.sub.1-3-alkyl, wherein each methylene group may be
substituted by 1 or 2 fluorine atoms and each methyl group may be
substituted by 1, 2 or 3 fluorine atoms, [0440] (d)
C.sub.3-7-cycloalkyl, [0441] (e) --O--C.sub.1-6-alkyl, [0442] (f)
--O--C.sub.3-7-cycloalkyl, [0443] (g) --NH.sub.2,
--NH(C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl).sub.2, [0444] (h)
--C(O)--R.sup.11.1, [0445] (i) --S--C.sub.1-3-alkyl,
--SO.sub.2--R.sup.11.2, [0446] (j) a five-membered heteroaryl group
optionally substituted by one or two C.sub.1-3-alkyl groups which
is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,
triazolyl and tetrazolyl, or [0447] (k) a six-membered heteroaryl
group optionally substituted by one or two C.sub.1-3-alkyl groups
which is selected from among pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl and triazinyl, R.sup.11.1 denotes --NH.sub.2,
--NH(C.sub.1-6-alkyl), --N(C.sub.1-6-alkyl).sub.2, N-acetidinyl,
N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, --OH,
--O--C.sub.1-8-alkyl or --O--C.sub.3-7-cycloalkyl,
R.sup.11.2--NH.sub.2, --NH(C.sub.1-6-alkyl),
--N(C.sub.1-6-alkyl).sub.2, N-acetidinyl, N-pyrrolidinyl,
N-piperidinyl or N-morpholinyl and X independently of one another
denotes C--R.sup.6 or N, the enantiomers, the diastereomers, the
mixtures and the salts thereof, particularly the physiologically
acceptable salts thereof with organic or inorganic acids or
bases.
[0448] A further embodiment of the present invention comprises the
compounds of the above general formula IV, wherein
n denotes one of the numbers 0, 1 or 2, R.sup.2 denotes H or
CH.sub.3, R.sup.3 and R.sup.4 together with the carbon atom to
which they are attached denote a C.sub.3-6-cycloalkylene group
optionally substituted by a group R.sup.3.1 wherein a --CH.sub.2
unit may be replaced by a heteroatom O, N, S or by a group CO, SO
or SO.sub.2, R.sup.3.1 denotes H, --OH, R.sup.5 denotes H or
CH.sub.3, R.sup.6 denotes H, F, Cl or methyl, R.sup.7 denotes H, F,
Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3, CHF.sub.2, R.sup.8 denotes
H, R.sup.9 denotes F, Cl, Br, C.sub.1-4-alkyl,
--O--C.sub.1-4-alkyl, --S--C.sub.1-4-alkyl, R.sup.10 denotes H,
R.sup.11 denotes F, Cl, Br, --CN, C.sub.1-4-alkyl, CF.sub.3,
CHF.sub.2, and X independently of one another denotes C--R.sup.6 or
N, the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0449] The following compounds are mentioned as examples of most
particularly preferred compounds of the above general formula
IV:
TABLE-US-00004 No. Structure (3.1) ##STR00496## (3.2) ##STR00497##
(3.3) ##STR00498## (3.4) ##STR00499## (3.5) ##STR00500## (3.6)
##STR00501## (3.7) ##STR00502## (3.8) ##STR00503## (3.9)
##STR00504## (3.10) ##STR00505## (3.11) ##STR00506## (3.12)
##STR00507## (3.13) ##STR00508## (3.14) ##STR00509## (3.15)
##STR00510## (3.16) ##STR00511## (3.17) ##STR00512## (3.18)
##STR00513## (3.19) ##STR00514## (3.20) ##STR00515## (3.21)
##STR00516## (3.22) ##STR00517##
the enantiomers, the diastereomers, the mixtures and the salts
thereof, particularly the physiologically acceptable salts thereof
with organic or inorganic acids or bases.
[0450] A further embodiment of the present application relates to
the use of the compounds of general formula IV, wherein R.sup.2,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11
are as hereinbefore defined, the diastereomers, the enantiomers and
the salts thereof, particularly the physiologically acceptable
salts thereof with inorganic or organic acids or bases for
preparing compounds of general formula I which have B1-antagonistic
properties.
TERMS AND DEFINITIONS USED
[0451] Unless otherwise stated, all the substituents are
independent of one another. If for example there are a plurality of
C.sub.1-6-alkyl groups as substituents in one group, in the case of
three substituents C.sub.1-6-alkyl, one may represent methyl, one
n-propyl and one tert-butyl.
[0452] Within the scope of this application, in the definition of
possible substituents, these may also be represented in the form of
a structural formula. If present, an asterisk (*) in the structural
formula of the substituent is to be understood as being the linking
point to the rest of the molecule.
[0453] Also included in the subject matter of this invention are
the compounds according to the invention, including the salts
thereof, in which one or more hydrogen atoms, for example one, two,
three, four or five hydrogen atoms, are replaced by deuterium.
[0454] By the term "C.sub.1-3-alkyl" (including those that are part
of other groups) are meant alkyl groups with 1 to 3 carbon atoms,
by the term "C.sub.1-4-alkyl" are meant branched and unbranched
alkyl groups with 1 to 4 carbon atoms, by the term
"C.sub.1-6-alkyl" are meant branched and unbranched alkyl groups
with 1 to 6 carbon atoms, and by the term "C.sub.1-8-alkyl" are
meant branched and unbranched alkyl groups with 1 to 8 carbon
atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl,
n-hexyl, n-heptyl and n-octyl. The abbreviations Me, Et, n-Pr, Pr,
n-Bu, i-Bu, t-Bu, etc. May optionally also be used for the
above-mentioned groups. Unless stated otherwise, the definitions
propyl and butyl include all the possible isomeric forms of the
groups in question. Thus, for example, propyl includes n-propyl and
iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl.
[0455] Moreover the definitions mentioned previously also include
those groups wherein each methylene group may be substituted by up
to two and each methyl group may be substituted by up to three
fluorine atoms.
[0456] By the term "C.sub.0-2-alkylene" are meant branched and
unbranched alkylene groups with 0 to 2 carbon atoms, while a
C.sub.0-alkylene group denotes a bond. Examples include: methylene,
ethylene and ethane-1,1-diyl. Moreover the definitions mentioned
previously also include those groups wherein each methylene group
may be substituted by up to two fluorine atoms.
[0457] By the term "C.sub.3-7-cycloalkyl" (including those that are
part of other groups) are meant cyclic alkyl groups with 3 to 7
carbon atoms and by the term "C.sub.3-6-cycloalkyl" are meant
cyclic alkyl groups with 3 to 6 carbon atoms. Examples include:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Unless otherwise stated, the cyclic alkyl groups may be substituted
by one or more groups selected from among methyl, ethyl,
iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and
iodine.
[0458] By the term "C.sub.3-6-cycloalkylene" (including those that
are part of other groups) are meant cyclic alkylene groups with 3
to 6 carbon atoms. Examples include: cyclopropylene, cyclobutylene,
cyclopentylene or cyclohexylene. Unless otherwise stated, the
cyclic alkylene groups may be substituted by one or more groups
selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy,
fluorine, chlorine, bromine and iodine.
[0459] By the term "C.sub.2-4-alkynyl" (including those that are
part of other groups) are meant branched and unbranched alkynyl
groups with 2 to 4 carbon atoms, provided that they have at least
one triple bond. Examples include: ethynyl, propynyl or butynyl.
Unless stated otherwise, the definitions propynyl and butynyl
include all the possible isomeric forms of the groups in question.
Thus for example propynyl includes 1-propynyl and 2-propynyl,
butynyl includes 1-butynyl, 2-butynyl and 3-butynyl etc.
[0460] "Halogen" within the scope of the present invention denotes
fluorine, chlorine, bromine or iodine. Unless stated to the
contrary, fluorine, chlorine and bromine are regarded as preferred
halogens.
[0461] By the term "heterocyclic rings" or "heterocyclic group" are
meant stable 5- or 6-membered monocyclic ring systems, which may be
both saturated and mono- or di-unsaturated and besides carbon atoms
may carry one or two heteroatoms, which are selected from among
nitrogen, oxygen and sulphur. Both nitrogen and sulphur heteroatoms
may optionally be oxidised. The previously mentioned heterocycles
may be attached to the rest of the molecule via a carbon atom or a
nitrogen atom. The following compounds are mentioned as
examples:
##STR00518##
[0462] "Cyclic imides" includes for example succinimides, maleimide
and phthalimide.
[0463] By the term "aryl" (including those that are part of other
groups) are meant aromatic ring systems with 6 or 10 carbon atoms.
Examples of these are phenyl, 1-naphthyl or 2-naphthyl; the
preferred aryl group is phenyl. Unless otherwise stated, the
aromatic groups may be substituted by one or more groups selected
from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl,
hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and
iodine, while the groups may be identical or different.
[0464] By the term "heteroaryl" are meant five- or six-membered
heterocyclic aromatic groups, which may contain one, two, three or
four heteroatoms, selected from among oxygen, sulphur and nitrogen,
and additionally contain so many conjugated double bonds that an
aromatic system is formed. These heteroaryls may additionally be
benzo-condensed with a phenyl ring, so as to form nine- or
ten-membered bicyclic heteroaryls.
[0465] The following are examples of five- or six-membered
heteroaromatic groups:
##STR00519##
[0466] The following are examples of nine- or ten-membered
heteroaromatic groups:
##STR00520##
[0467] Unless otherwise stated, the heteroaryls mentioned
previously may be substituted by one or more groups selected from
among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy,
methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine,
while the groups may be identical or different.
[0468] In addition, any nitrogen atom present in the heteroaryl
group may be oxidised, thereby forming an N-oxide.
[0469] By the term "oxo group" is meant an oxygen substituent at a
carbon atom, which leads to the formation of a carbonyl group
--C(O)--. The introduction of an oxo group as substituent at a
non-aromatic carbon atom leads to a conversion of a --CH.sub.2
group into a --C(O)-- group. The introduction of an oxo group at an
aromatic carbon atom leads to the conversion of a --CH-- group into
a --C(O)-- group and may result in the loss of aromaticity.
[0470] If they contain suitable basic functions, for example amino
groups, compounds of general formula I may be converted,
particularly for pharmaceutical use, into the physiologically
acceptable salts thereof with inorganic or organic acids. Examples
of inorganic acids for this purpose include hydrobromic acid,
phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid,
methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid
or p-toluenesulphonic acid, while organic acids that may be used
include malic acid, succinic acid, acetic acid, fumaric acid,
maleic acid, mandelic acid, lactic acid, tartaric acid or citric
acid.
[0471] In addition, the compounds of general formula I, if they
contain suitable carboxylic acid functions, may be converted into
the physiologically acceptable salts thereof with inorganic or
organic bases, particularly for pharmaceutical applications.
Examples of inorganic bases include alkali or alkaline earth metal
hydroxides, e.g. sodium hydroxide or potassium hydroxide, or
carbonates, ammonia, zinc or ammonium hydroxides; examples of
organic amines include diethylamine, triethylamine, ethanolamine,
diethanolamine, triethanolamine, cyclohexylamine or
dicyclohexylamine.
[0472] The compounds according to the invention may be present as
racemates, provided that they have only one chiral element, but may
also be obtained as pure enantiomers, i.e. In the (R) or (S)
form.
[0473] However, the application also includes the individual
diastereomeric pairs of antipodes or mixtures thereof, which are
obtained if there is more than one chiral element in the compounds
of general formula I, as well as the individual optically active
enantiomers of which the above-mentioned racemates are made up.
[0474] Compounds with a carbon double bond may be present in both
the E and Z form.
[0475] If a compound is present in different tautomeric forms, the
compound prepared is not limited to one tautomeric form but
includes all the tautomeric forms. This also applies particularly
to nitrogen-containing heteroaryls:
##STR00521##
Preparation Methods
[0476] According to the invention the compounds of general formula
I are obtained by methods known per se, for example by the
following methods:
(A) Amide Coupling:
##STR00522##
[0478] The linking of carboxylic acids of general formula II as
shown, wherein all the groups are as hereinbefore defined, with
amines of general formula III, wherein all the groups are as
hereinbefore defined, to form carboxylic acid amides of general
formula I wherein all the groups are as hereinbefore defined, may
be carried out by conventional methods of amide formation.
[0479] The coupling is preferably carried out using methods known
from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der
Organischen Chemie, Vol. 15/2), for example using carbodiimides
such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl
carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide,
0-(1H-benzotriazol-1-yl)-N,N--N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or
1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt)
or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the
reaction speed can be increased. The couplings are normally carried
out with equimolar amounts of the coupling components as well as
the coupling reagent in solvents such as dichloromethane,
tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF),
dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures. If
necessary, an auxiliary base such as diisopropylethylamine (DIPEA,
Hunig base) is additionally used.
B) Amide Coupling:
##STR00523##
[0481] An alternative method of preparing compounds of general
formula I consists in linking carboxylic acids of general formula
V, wherein all the groups are as hereinbefore defined, with amines
of general formula IV, wherein all the groups are as hereinbefore
defined.
[0482] The compounds of general formula V are either commercially
obtainable or may be prepared by methods known from the
literature
[0483] It is also possible to convert the carboxylic acids of
general formula V into carboxylic acid chlorides and then react
these with amines of general formula IV. Carboxylic acid chlorides
are synthesised by methods known from the literature (cf. e.g.
Houben-Weyl, Methoden der Organischen Chemie, vol. E5/1).
(C) Reduction of the Nitrile Group:
##STR00524##
[0485] The reduction of a nitrile of general formula VI to an amine
of general formula III, wherein the group R.sup.2 at the amine
nitrogen denotes hydrogen and all the other groups are as
hereinbefore defined, may be carried out under standard conditions
of catalytic hydrogenolysis with a catalyst such as Raney nickel,
for example, in a solvent such as ammoniacal methanol or ethanol or
with a reducing agent such as lithium aluminium hydride or sodium
borohydride in a solvent such as tetrahydrofuran, optionally in the
presence of a Lewis acid such as aluminium chloride.
[0486] Compounds of general formula III, wherein the group R.sup.2
at the amine nitrogen denotes not hydrogen but an alkyl group, for
example, may also be prepared from compounds of general formula VI.
Thus, for example, the reaction of a nitrile of general formula VI
with an alkyl Grignard reagent produces ketones which can be
converted by reductive amination into the compounds of general
formula III. The reductive amination is carried out using known
methods, for example with a reducing agent such as sodium
triacetoxyborohydride, sodium borohydride or sodium
cyanoborohydride, conveniently in a solvent such as tetrahydrofuran
or dichloromethane optionally substituted by the addition of acetic
acid.
[0487] Alternatively the ketones obtained may also be converted
into oximes. The subsequent reduction of the oximes then yields
compounds of general formula III.
(D) Nucleophilic Aromatic Substitution or
Transition-Metal-Catalysed Coupling:
##STR00525##
[0489] The reaction of an aniline of general formula VIII, wherein
all the groups are as hereinbefore defined, with a nitrile of
general formula VII, wherein X, R.sub.6 and n are as hereinbefore
defined, and Hal denotes a fluorine, chlorine or bromine atom, is
carried out using known methods, for example in a solvent such as
tetrahydrofuran, dimethylformamide or dimethylsulphoxide and
conveniently in the presence of a base such as triethylamine,
sodium hydroxide solution or potassium carbonate at a temperature
of 20.degree. C. to 160.degree. C. If the aniline of general
formula VIII is liquid, the reaction may also be carried out
without a solvent and additional base.
[0490] An alternative method of preparing compounds of general
formula VI is the palladium-catalysed reaction of a nitrile of
general formula VII, wherein Hal denotes bromine or chlorine, with
an aniline of general formula VIII. Reaction conditions for this
reaction, which is also known as a Buchwald-Hartwig reaction, are
known from the literature.
Description of the Method of Binding the cynoBK1-Receptor
[0491] CHO cells that express the cynomolgus BK1-receptor are
cultivated in "HAM'S F-12 Medium". The medium is removed from
confluent cultures, the cells are washed with PBS buffer, scraped
off or detached using Versene and isolated by centrifuging. Then
the cells are homogenised in suspension, the homogenate is
centrifuged and resuspended. After the protein content has been
determined 200 .mu.l of the homogenate (50 to 250 .mu.g
protein/assay) are incubated for 60-180 minutes at ambient
temperature with 0.5 to 5.0 nM kallidine (DesArg10,Leu9),
[3,4-Prolyl-3,43H(N)] and increasing concentrations of the test
substance in a total volume of 250 .mu.l. The incubation is stopped
by rapid filtration through GF/B glass fibre filters that have been
pre-treated with polyethyleneimine (0.3%). The radioactivity bound
to the protein is measured with a TopCount NXT. The radioactivity
bound in the presence of 1.0 .mu.M kallidine (DesArg10) is defined
as non-specific binding. The concentration binding curve may be
analysed using computer-aided non-linear curve fitting to determine
the corresponding K.sub.i value for the test substance.
[0492] Test results of the cynoBK1-receptor binding assay:
TABLE-US-00005 Example % inhibition K.sub.i No. at 10 .mu.gmol/L
[nM] (1) 54 (2) 100 25 (3) 65 (4) 109 (5) 88 (6) 59 (7) 100 (8) 75
(9) 78 (10) 58 (11) 99 (12) 78 (13) 101 (14) 84 (15) 99 (16) 91
(17) 75 (18) 67 (19) 96 (20) 81 (21) 68 (22) 60 (23) 110 (24) 107
(25) 86 (26) 109 (27) 104 (28) 101 0.6 (29) 113 6.2 (30) 111 13
(31) 112 13 (32) 93 200 (33) 110 1.9 (34) 94 >500 (35) 111 70
(36) 113 21 (37) 77 >500 (38) (39) 110 5.5 (40) 110 2.9 (41) 108
2.6 (42) 89 (43) 94 36 (44) 109 7.0 (45) 104 2 (46) 88 290 (47) 94
39 (48) 71 (49) 103 365 (50) 115 0.7 (51) 112 38 (52) 63 312 (53)
101 197 (54) 112 3.8 (55) 108 3.3 (56) 99 (57) 111 77 (58) 109 (59)
22 (60) 84 (61) 97 >500 (62) 60 (63) 108 118 (64) 109 98 (65) 76
(66) 81 (67) 63 (68) 78 (69) 42 (70) 107 (71) 80 (72) 89 416 (74)
56 (75) 71 (76) 80 (77) 96 (78) 73 (79) 104 292 (80) 88 (81) 113
(82) 107 (83) 113 9 (84) 104 90 (85) 93 (86) 108 100 (87) 112 (88)
80 (89) 96 (90) 109 135 (91) 100 (92) 110 62 (93) 84 (94) 57 (95)
86 (96) 78 (97) 132 (98) 103 417 (99) 96 (100) 103 (102) 105 87
(103) 87 (104) 54 (105) 113 20 (106) 69 (107) 95 (108) 101 135
(109) 27 (110) 33 (111) 20 (112) 45 (113) 7 (114) 77 >500 (115)
99 >500 (116) 83 >500 (117) 111 2.8 (118) 109 64 (119) 82 375
(120) 113 2.4 (121) 113 2 (122) 113 6.3 (123) 110 8.3 (124) 112 33
(125) 108 12 (126) 103 46 (127) 108 17 (128) 103 84 (129) 107 11
(130) 101 101 (131) 105 33 (132) 98 180 (133) 101 (134) 101 4.7
(135) 106 15 (136) 104 42 (138) 107 6.7 (139) 107 2.8 (140) 106 14
(141) 100 7.6 (142) 106 12 (143) 106 12 (144) 97 126 (145) 99 2.8
(146) 107 7.6 (147) 107 4.4 (148) 96 (149) 100 (150) 105 37 (151)
107 1.8 (152) 105 3.2 (153) 106 9.7 (154) 101 89 (155) 101 143
(156) 107 8.5 (157) 96 56 (158) 101 115 (159) 91 97 (160) 106 17
(161) 69 >500 (162) 104 17 (163) 87 288 (164) 106 3.4 (165) 101
(166) 104 45 (167) 104 19 (168) 90 235 (169) 90 292 (170) 104 35
(171) 97 (172) 100 9.8 (173) 105 2.7 (174) 99 (175) 96 63 (176) 100
(177) 99 (178) 107 11 (179) 101 (180) 106 1.6 (181) 99 19 (182) 99
20 (183) 100 21 (184) 99 (185) 87 (186) 82 (187) 100 (188) 92 43
(189) 96 >500 (190) 91 (191) 56 (192) 95 (193) 101 (194) 95
(195) 42 >500 (196) 82 >500 (197) 81 >500 (198) 64 >500
(200) 92 (201) (202) (203) 1.9 (204) 402 (205) 17 (206) 5.1 (207)
84 (208) 6.8 (209) 73 (210) 187 (211) 25 (212) 8 (213) 1.9 (214) 13
(215) 3.5 (216) 7.8 (217) 12 (218) 3.7 (219) 8.9 (220) 15 (221) 13
(222) 68 (223) 75 (224) 6.3 (225) 68 (226) 157 (227) 97 (228) 78
(229) 27 (230) 6.1 (231) 4.2 (232) 5.6 (233) 10 (234) 105 (235) 489
(236) 8.2 (237) 151 (238) 6.6 (239) 182 (240) 506 (241) 68 (242) 15
(243) 28 (244) 8.4 (245) 18 (246) 21 (247) 3.9 (248) 276 (249)
518
(250) 175 (251) 14 (252) 120 (253) 49 (254) 257 (255) 15 (256) 72
(257) 17 (258) 37 (259) 394 (260) 43 (261) 456 (262) 37 (263) 485
(264) 60 (265) 75 (266) 78 (267) 5.5 (268) 281 (269) 47 (270) 51
(271) 17 (272) 35 (273) 141 (274) 4.0 (275) 405 (276) 17 (277) 10
(278) 16 (279) 5.5 (280) 25 (281) 21 (282) 7.9 (283) 1.3 (284) 5.1
(285) 27 (286) 36 (287) 11 (288) 9.1 (289) 21 (290) 46 (291) 40
(292) 7.2 (293) 65 (294) 1.2 (295) 31 (296) 28 (297) 59 (298) 0.7
(299) 222 (300) 45 (301) 1.1 (302) 42 (303) 82 (304) 135 (305) 76
(306) 2.0 (307) 54 (308) 427 (309) 184 (310) 39 (311) 349 (312) 57
(313) 95 (314) 15 (315) 40 (316) 57 (317) 30 (318) 316 (319) 58
(320) 19 (321) 57 (322) 12 (323) 69 (324) 22 (325) 374 (326) 504
(327) 89 (328) 33 (329) 24 (330) 35 (331) 66 (332) 41 (333) 89
(334) 20 (335) 28 (336) 567 (337) 312 (338) 27 (339) 49 (340) 28
(341) 69 (342) 50 (343) 7.2 (344) 1.9 (345) 17 (346) 48 (347) 12
(348) 31 (349) 648 (350) 43 (351) 24 (352) 59 (353) 52 (354) 27
(355) 433 (356) 22 (357) 44 (358) 37 (359) 125 (360) 2.5 (361) 10
(362) 101 (363) 45 (364) 77 (365) 376 (366) 33 (367) 508 (368) 42
(369) 37 (370) 1.4 (371) 6.1 (372) 24 (373) 95 (374) 5.5 (375) 48
(376) 61 (377) 45 (378) 4.6 (379) 5.5 (380) 6.5 (381) 93 (382) 6.8
(383) 225 (384) 21 (385) 9.4 (386) 15 (387) 10 (388) 386 (389) 15
(390) 7.3 (391) 9.3 (392) 11 (393) (394) (395) 37 (396) 6.6
Indications
[0493] In view of their pharmacological properties, the novel
compounds and their physiologically acceptable salts are suitable
for treating diseases and symptoms of diseases caused at least to
some extent by stimulation of bradykinin-B1 receptors, or in which
antagonisation of the of bradykinin-B1 receptor can bring about an
improvement in symptoms.
[0494] In a further aspect the present invention encompasses the
compounds of the above-mentioned general formula I according to the
invention for use as medicaments.
[0495] In view of their pharmacological effect the substances are
suitable for the treatment of
(a) acute pain such as for example toothache, peri- and
postoperative pain, traumatic pain, muscle pain, the pain caused by
burns, sunburn, trigeminal neuralgia, pain caused by colic, as well
as spasms of the gastro-intestinal tract or uterus; (b) visceral
pain such as for example chronic pelvic pain, gynaecological pain,
pain before and during menstruation, pain caused by pancreatitis,
peptic ulcers, interstitial cystitis, renal colic, cholecystitis,
prostatitis, angina pectoris, pain caused by irritable bowel,
non-ulcerative dyspepsia and gastritis, prostatitis, non-cardiac
thoracic pain and pain caused by myocardial ischaemia and cardiac
infarct; (c) neuropathic pain such as for example painful
neuropathies, pain of diabetic neuropathy, AIDS-associated
neuropathic pain non-herpes-associated neuralgia, post-zoster
neuralgia, nerve damage, cerebro-cranial trauma, pain of nerve
damage caused by toxins or chemotherapy, phantom pain, pain of
multiple sclerosis, nerve root tears and painful
traumatically-caused damage to individual nerves, and central pain
such as for example pain after stroke, spinal injuries or tumours;
d) inflammatory/pain receptor-mediated pain in connection with
diseases such as for example osteoarthritis, rheumatoid arthritis,
rheumatic fever, tendo-synovitis, bursitis, tendonitis, gout and
gout-arthritis, traumatic arthritis, vulvodynia, damage to and
diseases of the muscles and fascia, juvenile arthritis,
spondylitis, psoriasis-arthritis, myositides, dental disease,
influenza and other viral infections such as colds, systemic lupus
erythematodes or pain caused by burns, (e) tumour pain associated
with cancers such asfe lymphatic or myeloid leukaemia, Hodgkin's
disease, non-Hodgkin's lymphomas, lymphogranulomatosis,
lymphosarcomas, solid malignant tumours and extensive metastases;
(f) headache diseases of various origins, such as for example
cluster headaches, migraine (with or without aura) and tension
headaches. (g) painful conditions of mixed origin, such as for
example chronic back pain including lumbago, or fibromyalgia.
[0496] The compounds are also suitable for treating
(h) inflammatory complaints or phenomena caused by sunburn and
burns, inflammation of the gums, oedema after burns trauma,
cerebral oedema and angiooedema, intestinal complaints including
Crohn's disease and ulcerative colitis, irritable bowel syndrome,
pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis;
inflammatory skin diseases (such as psoriasis and eczema), vascular
diseases of the connective tissue, sprains and fracture, and
musculoskeletal diseases with inflammatory symptoms such as acute
rheumatic fever, polymyalgia rheumatica, reactive arthritis,
rheumatoid arthritis, spondylarthritis, and also osteoarthritis,
and inflammation of the connective tissue of other origins, and
collagenoses of all origins such as systemic lupus erythematodes,
scleroderma, polymyositis, dermatomyositis, Sjogren syndrome,
Still's disease or Felty syndrome; (i) inflammatory changes
connected with diseases of the airways such as bronchial asthma,
including allergic asthma (atopic and non-atopic) as well as
bronchospasm on exertion, occupationally induced asthma, viral or
bacterial exacerbation of an existing asthma and other
non-allergically induced asthmatic diseases; (j) chronic bronchitis
and chronic obstructive pulmonary disease (COPD) including
pulmonary emphysema, viral or bacterial exacerbation of chronic
bronchitis or chronic obstructive bronchitis, acute adult
respiratory distress syndrome (ARDS), bronchitis, lung
inflammation, allergic rhinitis (seasonal and all year round)
vasomotor rhinitis and diseases caused by dust in the lungs such as
aluminosis, anthracosis, asbestosis, chalicosis, siderosis,
silicosis, tabacosis and byssinosis, exogenous allergic alveolitis,
cystic fibrosis, bronchiectasis, pulmonary diseases in
alpha1-antitrypsin deficiency and cough; (k) diabetes mellitus and
its effects (such as e.g. diabetic vasculopathy, diabetic
neuropathy, diabetic retinopathy) and diabetic symptoms in
insulitis (for example hyperglycaemia, diuresis, proteinuria and
increased renal excretion of nitrite and kallikrein); (l) sepsis
and septic shock after bacterial infections or after trauma; (m)
syndromes that cause itching and allergic skin reactions; (n)
damage to the central nervous system; (o) wounds and tissue damage;
(p) benign prostatic hyperplasia and hyperactive bladder; (q)
neurodegenerative diseases such as Parkinson's disease and
Alzheimer's disease; (m) osteoporosis; epilepsy; (q) vascular
diseases such as panarteriitis nodosa, polyarthritis nodosa,
periarteriitis nodosa, arteriitis temporalis, Wegner's
granulomatosis, giant cell arteriitis, arteriosclerosis and
erythema nodosum; inflammation of the gums; (r) disorders of the
motility or spasms of respiratory, genito-urinary,
gastro-intestinal including biliary or vascular structures and
organs; (s) post-operative fever; (t) for the treatment and
prevention of cardiovascular diseases such as high blood pressure
and related complaints; (u) for the treatment and prevention of
cancer and related complaints; (v) for the treatment and prevention
of psychiatric diseases such as depression; (w) for the treatment
and prevention of urinary incontinence and related complaints; (x)
for the treatment and prevention of morbid obesity and related
complaints; (y) for the treatment and prevention of atherosclerosis
and related complaints. (z) for the treatment and prevention of
epilepsy.
[0497] The substances are suitable for causal treatment in the
sense of slowing down or stopping the progress of chronically
progressive diseases, particularly osteoarthritis, rheumatoid
arthritis and spondylarthritis.
[0498] In another aspect the present invention encompasses the use
of the compounds of the above-mentioned general formula I according
to the invention for preparing a medicament for therapeutic use in
the above-mentioned indications.
[0499] Preferably, the compounds of general formula I according to
the invention are used for the treatment of osteoarthritis,
rheumatoid arthritis or COPD.
[0500] The term "treatment" or "therapy" refers to a therapeutic
treatment of patients with a manifest, acute or chronic indication,
including on the one hand symptomatic (palliative) treatment to
relieve the symptoms of the disease and on the other hand causal or
curative treatment of the indication with the aim of ending the
pathological condition, reducing the severity of the pathological
condition or delaying the progression of the pathological
condition, depending on the nature or gravity of the
indication.
[0501] The present invention further relates to the use of a
compound of general formula I for preparing a medicament for the
acute and prophylactic treatment of acute pain, visceral pain,
neuropathic pain, inflammatory/pain receptor-mediated pain, tumour
pain, headache pain and pain of mixed causes and other diseases as
mentioned above. This use is characterised in that it comprises
administering an effective amount of a compound of general formula
I or a physiologically acceptable salt thereof to a patient
requiring such treatment.
[0502] The term "patient" preferably refers to a human being.
[0503] In addition to their suitability as therapeutic drugs for
humans, these substances are also useful in the veterinary medical
treatment of domestic pets, exotic animals and farmed animals.
Combinations
[0504] For treating pain, it may be advantageous to combine the
compounds according to the invention with stimulating substances
such as caffeine or other pain-alleviating active compounds. If
active compounds suitable for treating the cause of the pain are
available, these can be combined with the compounds according to
the invention.
[0505] The following compounds may be used for combination therapy,
for example:
[0506] Non-steroidal antirheumatics (NSAR) such as for example
propionic acid derivatives which may be selected from among
alminoprofen bucloxic acid, carprofen, fenoprofen, ibuprofen,
ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and
tiaprofenic acid; acetic acid derivatives which may be selected
from among indomethacin, acemetacin, alclofenac, isoxepac, sulindac
and tolmetin; fenamic derivatives which may be selected from among
meclofenamic acid, mefenamic acid and tolfenamic acid;
biphenyl-carboxylic acid derivatives; oxicams which may be selected
from among meloxicam, piroxicam and tenoxicam; salicylic acid
derivatives which may be selected from among acetylsalicylic and
sulphasalazine; pyrazolones which may be selected from among
apazone and feprazone; and coxibs which may be selected from among
celecoxib and etoricoxib).
[0507] Opiate receptor agonists which may for example be selected
from among morphine, Darvon, tramadol and buprenorphine;
[0508] Cannabinoid agonists such as for example GW-1000;
[0509] Sodium channel blockers which may for example be selected
from among carbamazepine, mexiletin, pregabalin, tectin and
ralfinamide.
[0510] N-type calcium channel blockers such as for example
ziconotide.
[0511] Serotonergic and noradrenergic modulators which may be
selected from among for example duloxetine and amitriptyline.
[0512] Corticosteroids which may be selected from among for example
betamethasone, budesonide, cortisone, dexamethasone,
hydrocortisone, methylprednisolone, prednisolone, prednisone and
triamcinolone.
[0513] Histamine H1-receptor antagonists which may for example be
selected from among bromopheniramine, chloropheniramine,
dexchloropheniramine, triprolidine, clemastine, diphenhydramine,
diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,
promethazine, trimeprazine azatadine, cyproheptadine, antazoline,
pheniramine, pyrilamine, loratadine, cetirizine, desloratadine,
fexofenadine and levocetirizine.
[0514] Leukotriene antagonists and 5-lipoxygenase inhibitors which
may for example be selected from among zafirlukast, montelukast,
pranlukast and zileuton.
[0515] Local anaesthetics which may for example be selected from
among ambroxol and lidocaine.
[0516] TRVP1 antagonists which may for example be selected from
among AZD-1386, JTS-653 and PHE-377.
[0517] Nicotine receptor agonists such as for example A-366833.
[0518] P2X3-receptor antagonists such as e.g. A-317491.
[0519] anti-NGF antibodies and NGF antagonists which may for
example be selected from among JNJ-42160443 and PPH 207.
[0520] NK1 and NK2 antagonists such as e.g. CP-728663.
[0521] NMDA antagonists which may for example be selected from
among CNS-5161, AZ-756 and V-3381.
[0522] Potassium channel modulators such as e.g. CL-888.
[0523] GABA modulators such as e.g. baclofen.
[0524] Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan,
naratriptan and eletriptan.
[0525] For treating one or more of the above-mentioned respiratory
complaints it may be advantageous to combine the compounds of
general formula I according to the invention with other active
substances for treating respiratory complaints. If suitable active
substances for treating the cause of the respiratory complaints are
available, these may be combined with the compounds according to
the invention.
[0526] The compounds of general formula I may optionally also be
used in conjunction with other pharmacologically active substances.
It is preferable to use active substances of the type selected from
among the betamimetics, anticholinergics, corticosteroids, other
PDE4-inhibitors, LTD4-receptor (CysLT1, CysLT2, CysLT3)
antagonists, inhibitors of MAP kinases such as for example p38,
ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, LTB4-receptor (BLT1, BLT2)
antagonists, EGFR-inhibitors, H1-receptor antagonists,
antihistamines, H4-receptor antagonists, PAF-antagonists and
P13-kinase inhibitors CXCR1 and/or CXCR2 receptor antagonists and
anti-tussives.
[0527] The compounds of general formula I may also be used in the
form of double or triple combinations thereof, such as for example
combinations of compounds of formula I with one or two compounds
selected from among [0528] betamimetics, corticosteroids,
PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists, [0529]
anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors,
EGFR-inhibitors and LTD4-antagonists, [0530] PDE4-inhibitors,
corticosteroids, EGFR-inhibitors and LTD4-antagonists, [0531]
EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists, [0532]
EGFR-inhibitors and LTD4-antagonists, [0533] CCR3-inhibitors,
iNOS-inhibitors (inducible nitric oxide synthase-inhibitors),
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to
as "BH4") and the derivatives thereof which are mentioned in WO
2006/120176, and SYK-inhibitors (spleen tyrosine kinase
inhibitors), [0534] anticholinergics, betamimetics,
corticosteroids, PDE4-inhibitors and MRP4-inhibitors.
[0535] Combinations of three active substances of one of the above
mentioned categories of compounds are also covered by the
invention.
[0536] Betamimetics used according to the invention are preferably
compounds selected from among arformoterol, carmoterol, formoterol,
indacaterol, salmeterol, albuterole, bambuterol, bitolterol,
broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin,
ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol,
meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol,
procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenol,
sulphonterol, terbutalin, tiaramid, tolubuterol and zinterol or
[0537]
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one, [0538]
8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one, [0539]
8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one, [0540]
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one, [0541]
8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one, [0542]
N-(5-{2-[3-(4.4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-p-
ropylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
[0543]
N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-d-
imethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamid-
e, [0544]
N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-
-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanes-
ulphonamide, [0545]
N-(5-{2-[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)--
propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
[0546]
8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propyla-
mino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, [0547]
8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propy-
lamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
[0548]
8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1--
yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
[0549]
8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl-
)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
[0550]
N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylam-
ino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide, [0551]
8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl-
]-ethylamino}-ethyl)-1H-quinolin-2-one, [0552]
8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-qui-
nolin-2-one, [0553]
5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethyla-
mino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, [0554]
[3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-
-hexyloxy}-butyl)-5-methyl-phenyl]-urea, [0555]
4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-et-
hyl)-2-hydroxymethyl-phenol, [0556]
3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]--
hexyloxy}-butyl)-benzenesulphonamide, [0557]
3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]--
heptyloxy}-propyl)-benzenesulphonamide, [0558]
4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hy-
droxy-ethyl)-2-hydroxymethyl-phenol, [0559]
N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymeth-
yl)-phenyl]ethyl}amino)propyl]phenyl}acetamide, [0560]
(1R)-5-{2-[6-(2.2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}--
8-hydroxy-1H-quinolin-2-one [0561]
(R,S)-4-(2-{[6-(2.2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxyl-methyl)phenol, [0562]
(R,S)-4-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxyl-methyl)phenol, [0563]
(R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxyl-methyl)phenol, [0564]
(R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxyl-methyl)phenol, [0565]
(R,S)-5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-
-8-hydroxyquinolin-2(1H)-one, [0566]
(R,S)-[2-({6-[2.2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydrox-
yethyl]-2-(hydroxymethyl)phenol, [0567]
4-(1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2--
(hydroxyl-methyl)phenol, [0568]
(R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4.4.5l5-tetrafluoro-6-(3-phenylp-
ropoxy)-hexyl]amino}ethyl)phenol, [0569]
(R,S)-[5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl-
)-2-hydroxy-phenyl]formamide, [0570]
(R,S)-4-[2-({6-[2-(3-bromophenyl)-2.2-difluoroethoxy]hexyl}amino)-1-hydro-
xyethyl]-2-(hydroxymethyl)phenol, [0571]
(R,S)--N-[3-(1.1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl-
)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea, [0572]
3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl-
]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4-dione, [0573]
(R,S)-4-[2-({6-[2.2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hyd-
roxyethyl]-2-(hydroxymethyl)phenol, [0574]
5-((1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-
-hydroxyquinolin-2(1H)-one, [0575]
4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)--
2-(hydroxyl-methyl)phenol, [0576]
(R,S)-4-(2-{[6-(3.3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl-
)-2-(hydroxylmethyl)phenol, [0577]
(R,S)-(2-{[6-(2.2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hyd-
roxyethyl)-2-(hydroxymethyl)phenol, [0578]
(R,S)-4-(2-{[6-(2.2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-
-2-(hydroxyl-methyl)phenol, [0579]
3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydrox-
y-2-oxo-2,3-dihydro-benzothiazole-7-yl)-ethylamino]-ethyl}-propionamide,
[0580]
N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benz-
othiazole-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionami-
de, [0581]
7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-et-
hylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one,
optionally in the form of their racemates, enantiomers,
diastereomers and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, the acid addition salts of
the betamimetics are selected from among hydrochloride,
hydrobromide, hydriodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,
hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
[0582] Anticholinergics used according to the invention are
preferably compounds selected from among the tiotropium salts,
preferably the bromide salt, oxitropium salts, preferably the
bromide salt, flutropium salts, preferably the bromide salt,
Ipratropiumsalzen, preferably the bromide salt, aclidinium salts,
preferably the bromide salt, glycopyrronium salts, preferably the
bromide salt, trospium salts, preferably the chloride salt,
tolterodine,
(3R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octa-
ne salts. In the above-mentioned salts the cations are the
pharmacologically active constituents. As anions X.sup.- the
above-mentioned salts may preferably contain chloride, bromide,
iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,
acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate
or p-toluenesulphonate, while the chloride, bromide, iodide,
sulphate, methanesulphonate or p-toluenesulphonate are preferred as
counter-ions. Of all the salts the chlorides, bromides, iodides and
methanesulphonates are particularly preferred.
[0583] Other anticholinergics may be selected from among [0584]
tropenol 2,2-diphenylpropionate-methobromide, [0585] scopine
2,2-diphenylpropionate-methobromide, [0586] scopine
2-fluoro-2,2-diphenylacetate methobromide, [0587] tropenol
2-fluoro-2,2-diphenylacetate methobromide, [0588] tropenol
3,3',4,4'-tetrafluorobenzilate methobromide, [0589] scopine
3,3',4,4'-tetrafluorobenzilate methobromide, [0590] tropenol
4,4'-difluorobenzilate methobromide, [0591] scopine
4,4'-difluorobenzilate methobromide, [0592] tropenol
3,3'-difluorobenzilate methobromide, [0593] scopine
3,3'-difluorobenzilate methobromide, [0594] tropenol
9-hydroxy-fluorene-9-carboxylate methobromide, [0595] tropenol
9-fluoro-fluorene-9-carboxylate methobromide, [0596] scopine
9-hydroxy-fluorene-9-carboxylate methobromide, [0597] scopine
9-fluoro-fluorene-9-carboxylate methobromide, [0598] tropenol
9-methyl-fluorene-9-carboxylate methobromide, [0599] scopine
9-methyl-fluorene-9-carboxylate methobromide, [0600]
cyclopropyltropine benzilate methobromide, [0601]
cyclopropyltropine 2,2-diphenylpropionate methobromide, [0602]
cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide,
[0603] cyclopropyltropine 9-methyl-fluorene-9-carboxylate
methobromide, [0604] cyclopropyltropin
9-methyl-xanthene-9-carboxylate methobromide, [0605]
cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide,
[0606] cyclopropyltropine methyl 4,4'-difluorobenzilate
methobromide, [0607] tropenol 9-hydroxy-xanthene-9-carboxylate
methobromide, [0608] scopine 9-hydroxy-xanthene-9-carboxylate
methobromide, [0609] tropenol 9-methyl-xanthene-9-carboxylate
methobromide, [0610] scopine 9-methyl-xanthene-9-carboxylate
methobromide, [0611] tropenol 9-ethyl-xanthene-9-carboxylate
methobromide, [0612] tropenol
9-difluoromethyl-xanthene-9-carboxylate methobromide, and [0613]
scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.
[0614] The above-mentioned compounds may also be used as salts
within the scope of the present invention, wherein the metho-X
salts are used instead of the methobromide, where X may have the
meanings given for X.sup.- hereinbefore.
[0615] Corticosteroids used according to the invention are
preferably compounds selected from among beclomethasone
betamethasone, budesonide, butixocort, ciclesonide, deflazacort,
dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol,
mometasone, prednisolone, prednisone, rofleponide, triamcinolone
and tipredane orpregna-1,4-dien-3,20-dione,
6-fluoro-11-hydroxy-16.17-[(1-methylethyliden)-bis(oxy)]-21-[[4-[(nitroxy-
)methyl]benzoyl]oxy], (6-alpha,11-beta,16-alpha)-(9Cl) (NCX-1024)
[0616]
16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-
-3-one (RPR-106541), [0617] (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate, [0618]
(S)-(2-oxo-tetrahydrofuran-3S-yl)
6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-
e-17-carbothionate, and [0619] cyanomethyl
6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,-
2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxy-
late, optionally in the form of their racemates, enantiomers or
diastereomers and optionally in the form of the salts and
derivatives thereof, the solvates and/or hydrates thereof. Every
reference to steroids includes a reference to any salts or
derivatives, hydrates or solvates thereof which may exist. Examples
of possible salts and derivatives of the steroids may be: alkali
metal salts, such as for example sodium or potassium salts,
sulphobenzoates, phosphates, isonicotinates, acetates,
dichloroacetates, propionates, dihydrogen phosphates, palmitates,
pivalates or furoates.
[0620] PDE4-inhibitors used according to the invention are
preferably compounds selected from among enprofyllin, theophyllin,
roflumilast, ariflo (cilomilast), tofimilast, pumafentrin,
lirimilast, apremilast, arofyllin, atizoram, oglemilast and
tetomilast or [0621]
5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamid]-8-methoxy-quinoline
(D-4418), [0622]
N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamid]-8-methoxy-2-(trifluorome-
thyl)-quinoline (D-4396 (Sch-351591)),
N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyox-
ylamide (AWD-12-281 (GW-842470)),
9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine
(NCS-613), [0623]
4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine
(CDP-840), [0624]
N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]b-
enzodiazepin-3-yl]-4-pyridinecarboxamide (PD-168787), [0625]
4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-
-2(1H)-pyridinone (T-440), [0626]
2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4--
(3-pyridinyl)-1(2H)-phthalazinone (T-2585), [0627]
(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine
(V-11294A), [0628]
beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoind-
ole-2-propanamide (CDC-801), [0629]
imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one,
9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888) [0630]
5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenylmethyl],
(3S,5S)-2-piperidinone (HT-0712), [0631]
4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)eth-
yl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141),
[0632]
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethox-
ybenzamide, [0633]
(-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbe-
nzo[s]-[1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, [0634]
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone, [0635]
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-5-methyl-isothioure-
ido]-benzyl)-2-pyrrolidone, [0636]
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid], [0637]
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-c-
yclohexan-1-one, [0638]
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol], [0639]
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]ac-
etate, [0640]
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]ac-
etate, [0641]
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo-[4.3-a]pyridine and [0642]
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, diastereomers and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. Preferably, according to the invention, acid
addition salts are selected from among hydrochloride, hydrobromide,
hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0643] EGFR-inhibitors used according to the invention are
preferably compounds selected from among cetuximab, trastuzumab,
panitumumab (=ABX-EGF), Mab ICR-62, gefitinib, canertinib and
erlotinib or [0644]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxy-quinazoline, [0645]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, [0646]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, [0647]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]a-
mino}-7-cyclopentyloxy-quinazoline, [0648]
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-cyclopropylmethoxy-quinazoline,
[0649]
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]-quinazoli-
ne, [0650]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl--
6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quina-
zoline, [0651]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline, [0652]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
[0653]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxy-quinazoline, [0654]
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, [0655]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, [0656]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, [0657]
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
[0658]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, [0659]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, [0660]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, [0661]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-
-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, [0662]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
[0663]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
[0664]
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
[0665]
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy-
]-6-[(vinylcarbonyl)-amino]-quinazoline, [0666]
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine, [0667]
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-ox-
o-2-buten-1-yl]amino}-7-ethoxy-quinoline, [0668]
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulpho-
nyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, [0669]
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-quinazoline, [0670]
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, [0671]
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino-
]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
[0672]
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4--
yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, [0673]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline, [0674]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
[0675]
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,
[0676]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperi-
din-1-yl]-ethoxy}-7-methoxy-quinazoline, [0677]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidi-
n-4-yloxy]-7-methoxy-quinazoline, [0678]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-
-7-methoxy-quinazoline, [0679]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexane-1-yloxy)-7-methoxy-quinazoline, [0680]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline, [0681]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline, [0682]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline, [0683]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
din-4-yloxy}-7-methoxy-quinazoline, [0684]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline, [0685]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin--
4-yloxy]-7-methoxy-quinazoline, [0686]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline, [0687]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hyd-
roxy-quinazoline, [0688]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline, [0689]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline, [0690]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline, [0691]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonyl-
amino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline, [0692]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline, [0693]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline, [0694]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline, [0695]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4--
yloxy)-7-methoxy-quinazoline, [0696]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
[0697]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
[0698]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphony-
l]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
[0699]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cycloh-
exane-1-yloxy)-7-methoxy-quinazoline, [0700]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-ethoxy-quinazoline, [0701]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline, [0702]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline, [0703]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1-yl-
oxy)-7-methoxy-quinazoline, [0704]
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-ylox-
y]-7-methoxy-quinazoline, [0705]
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line, [0706]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl-
]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
[0707]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl-
)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
[0708]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carb-
onylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline, [0709]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline, [0710]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, [0711]
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline, [0712]
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline, [0713]
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline, [0714]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-me-
thoxy-ethoxy)-quinazoline, [0715]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-
-yloxy)-7-methoxy-quinazoline, [0716]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexane-1-yl-
oxy)-7-methoxy-quinazoline, [0717]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline, [0718]
4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,
[0719]
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yl-
oxy]-7-methoxy-quinazoline, [0720]
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline, [0721]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-y-
l)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, [0722]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbon-
yl]-piperidin-4-yloxy}-7-methoxy-quinazoline, [0723]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,-
1]hept-5-yl)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
[0724]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amin-
o)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, [0725]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline, [0726]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline, [0727]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbony-
l]-piperidin-4-yloxy}-7-methoxy-quinazoline, [0728]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline, [0729]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexane-1-yloxy]-7-methoxy-quinazoline, [0730]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1--
yloxy)-7-methoxy-quinazoline, [0731]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline, [0732]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane--
1-yloxy)-7-methoxy-quinazoline, [0733]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
[0734]
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,
[0735]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline, [0736]
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline, [0737]
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-ox-
o-2-buten-1-yl]amino}-7-ethoxy-quinoline; [0738]
[4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]-amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,
[0739]
4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5--
yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,
[0740]
4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpho-
lin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline, [0741]
4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-y-
l)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, [0742]
4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-y-
l)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, and [0743]
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N--
[(ethoxy-carbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmet-
hoxy-quinazoline, optionally in the form of their racemates,
enantiomers or diastereomers, optionally in the form of the
pharmacologically acceptable acid addition salts, solvates and/or
hydrates thereof. Preferably, according to the invention, acid
addition salts are selected from among hydrochloride, hydrobromide,
hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0744] LTD4-receptor antagonists used according to the invention
are preferably compounds selected from among montelukast,
pranlukast and zafirlukast, or
(E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl-
)-4H-1-benzopyran-4-one (MEN-91507), [0745]
4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propyl-
phenoxy]-butyric acid (MN-001), [0746]
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropane-acetic acid, [0747]
1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phen-
yl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneac-
etic acid and [0748]
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic
acid, optionally in the form of their racemates, enantiomers,
diastereomers and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, acid addition salts are
selected from among hydrochloride, hydrobromide, hydriodide,
hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate. By salts or
derivatives which the LTD4-receptor antagonists may optionally be
capable of forming are meant, for example: alkali metal salts, such
as for example sodium or potassium salts, alkaline earth salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates or furoates.
[0749] Histamine H1 receptor antagonists used according to the
invention are preferably compounds selected from among epinastin,
cetirizin, azelastin, fexofenadin, levocabastin, loratadin,
mizolastin, ketotifen, emedastin, dimetinden, clemastin, bamipin,
cexchlorpheniramin, pheniramin, doxylamine, chlorophenoxamin,
dimenhydrinat, diphenhydramin, promethazin, ebastin, olopatadine,
desloratidin and meclozin, optionally in the form of their
racemates, enantiomers, diastereomers and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. Preferably, according to the invention, the acid
addition salts are selected from among hydrochloride, hydrobromide,
hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0750] Histamine H4 receptor antagonists used according to the
invention are preferably compounds such as for example
(5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)-methanone
(JNJ-7777120), optionally in the form of their racemates,
enantiomers, diastereomers and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. Preferably, according to the invention, acid
addition salts selected from among hydrochloride, hydrobromide,
hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate are used.
[0751] MAP Kinase inhibitors used according to the invention are
preferably compounds selected from among: [0752] Bentamapimod
(AS-602801) [0753] Doramapimod, [0754] 5-carbamoylindole (SD-169),
[0755]
6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyr-
idinecarboxamide (VX-702), [0756]
alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacet-
onitrile (AS-601245), [0757]
9,12-epoxy-1H-diindolo[1,2,3-fg:3'.2'.1'-kl]pyrrolo[3,4-i][1.6]benzodiazo-
cine-10-carboxylic acid (CEP-1347), and [0758]
4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazol-4-yl]-pyrimid-
ine (SC-409), optionally in the form of their racemates,
enantiomers, diastereomers and optionally in the form of the
pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.
[0759] Neurokinin (NK1 or NK2) antagonists used according to the
invention are preferably compounds selected from among: Saredutant,
Nepadutant and Figopitant, optionally in the form of their
racemates, enantiomers, diastereomers and optionally in the form of
the pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.
[0760] Antitussive substances used according to the invention are
preferably compounds selected from among hydrocodone, caramiphen,
carbetapentane and dextramethorphane, optionally in the form of
their racemates, enantiomers, diastereomers and optionally in the
form of the pharmacologically acceptable acid addition salts,
prodrugs, solvates or hydrates thereof.
[0761] Substances of preferred CXCR1 or CXCR2 antagonists used
according to the invention are preferably compounds such as e.g.
3-[[3-[(dimethylamino)carbonyl]-2-hydroxyphenyl]amino]-4-[[(R)-1-(5-methy-
lfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione (SCH-527123),
optionally in the form of its racemates, enantiomers, diastereomers
and optionally in the form of its pharmacologically acceptable acid
addition salts, prodrugs, solvates or hydrates.
[0762] The dosage necessary for obtaining a pain-alleviating effect
is, in the case of intravenous administration, expediently from
0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg,
and, in the case of oral administration, from 0.1 to 8 mg/kg of
body weight, preferably from 0.5 to 3 mg/kg, in each case 1 to 3
times per day. The compounds prepared according to the invention
can be administered intravenously, subcutaneously, intramuscularly,
intrarectally, intranasally, by inhalation, transdermally or
orally, aerosol formulations being particularly suitable for
inhalation. They can be incorporated into customary pharmaceutical
preparations, such as tablets, coated tablets, capsules, powders,
suspensions, solutions, metered-dose aerosols or suppositories, if
appropriate together with one or more customary inert carriers
and/or diluents, for example with maize starch, lactose, cane
sugar, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water,
water/ethanol, water/glycerol, water/sorbitol, water/polyethylene
glycol, propylene glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances, such as hardened fat,
or suitable mixtures thereof.
EXPERIMENTAL SECTION
[0763] Generally, there are mass spectra and .sup.1H NMR spectra
for the compounds that have been prepared. The ratios given for the
eluants are in volume units of the solvents in question. For
ammonia, the given volume units are based on a concentrated
solution of ammonia in water.
[0764] Unless indicated otherwise, the acid, base and salt
solutions used for working up the reaction solutions are aqueous
systems having the stated concentrations.
[0765] For chromatographic purification, silica gel from Millipore
(MATREX.TM., 35 to 70 .mu.m) or Alox (E. Merck, Darmstadt, Alumina
90 standardized, 63 to 200 .mu.m, article No. 1.01097.9050) is
used.
[0766] In the descriptions of the experiments, the following
abbreviations are used: [0767] TLC thin layer chromatograph [0768]
DIPEA diisopropylethylamine [0769] DMA N, N-dimethylacetamide
[0770] DMAP 4-dimethylaminopyridine [0771] DMF
N,N-dimethylformamide [0772] DMSO dimethylsulphoxide [0773] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0774] RP reverse phase [0775] R.sub.t
retention time [0776] tert tertiary [0777] TBTU
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
[0778] TEA triethylamine [0779] THF tetrahydrofuran
[0780] The following analytical HPLC methods were used:
[0781] Method 1: Column: Interchim Strategy C18, 5 .mu.M,
4.6.times.50 mm [0782] Detection: 220-320 nm [0783] Eluant A:
water/0.1% acetic acid [0784] Eluant B: acetonitrile [0785]
Gradient:
TABLE-US-00006 [0785] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 3.0 0.3 95.0 5.0 3.0 2.0 2.0 98.0 3.0 2.4 2.0 98.0 3.0
2.45 95.0 5.0 3.0 2.8 95.0 5.0 3.0
[0786] Method 2: Column: Merck Cromolith Flash RP18e, 4.6.times.25
mm [0787] Eluant A: water/0.1% formic acid [0788] Eluant B:
acetonitrile/0.1% formic acid [0789] Gradient:
TABLE-US-00007 [0789] time in flow rate min % A % B in mL/min 0.0
90.0 10.0 1.6 2.7 10.0 90.0 1.6 3.0 10.0 90.0 1.6 3.3 90.0 10.0
1.6
[0790] Method 3: Column: YMC-Pack ODS-AQ, 3 .mu.M, 4.6.times.75 mm
[0791] Eluant A: water/0.15% formic acid [0792] Eluant B:
acetonitrile [0793] Gradient:
TABLE-US-00008 [0793] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 1.6 2.0 10.0 90.0 1.6 5.0 10.0 90.0 1.6 5.5 90.0 10.0
1.6
[0794] Method 4: Column: Zorbax Stable Bond C18, 1.8 .mu.M,
3.times.30 mm [0795] Eluant A: water/0.15% formic acid [0796]
Eluant B: acetonitrile [0797] Gradient:
TABLE-US-00009 [0797] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 1.6 1.0 10.0 90.0 1.6 2.5 10.0 90.0 1.6 2.75 95.0 5.0
1.6
[0798] Method 5: Column: Sunfire C18, 3.5 .mu.M, 4.6.times.50
mm
[0799] Detection: 180-820 nm [0800] Eluant A: water/0.1%
trifluoroacetic acid [0801] Eluant B: acetonitrile/0.1%
trifluoroacetic acid [0802] Temperature: 40.degree. C. [0803]
Gradient:
TABLE-US-00010 [0803] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 1.5 2.0 0.0 100.0 1.5 2.5 0.0 100.0 1.5 2.6 95.0 5.0
1.5
[0804] Method 6: Column: Sunfire C18, 3.5 .mu.M, 4.6.times.50 mm
[0805] Detection: 180-820 nm [0806] Eluant A: water/0.1%
trifluoroacetic acid [0807] Eluant B: acetonitrile/0.1%
trifluoroacetic acid [0808] Temperature: 40.degree. C. [0809]
Gradient:
TABLE-US-00011 [0809] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 1.5 2.0 0.0 100.0 1.5 3.0 0.0 100.0 1.5 3.4 95.0 5.0
1.5
[0810] Method 7: Column: YMC-Pack ODS-AQ, 3 .mu.M, 4.6.times.75 mm
[0811] Eluant A: water/0.15% formic acid [0812] Eluant B:
acetonitrile [0813] Gradient:
TABLE-US-00012 [0813] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 1.6 4.5 10.0 90.0 1.6 5.0 10.0 90.0 1.6 5.50 90.0 10.0
1.6
[0814] Method 8: Column: Zorbax Stable Bond C18, 1.8 .mu.M,
3.times.30 mm [0815] Eluant A: water/0.15% formic acid [0816]
Eluant B: acetonitrile [0817] Gradient:
TABLE-US-00013 [0817] time in flow rate min % A % B in mL/min 0.0
95.0 5.0 1.6 2.00 50.0 50.0 1.6 2.25 10.0 90.0 1.6 2.50 10.0 90.0
1.6 2.75 95.0 5.0 1.6
[0818] Method 9: Column: Zorbax Stable Bond C18, 1.8 .mu.M,
3.times.30 mm [0819] Eluant A: water/0.15% formic acid [0820]
Eluant B: acetonitrile [0821] Gradient:
TABLE-US-00014 [0821] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 1.6 2.25 10.0 90.0 1.6 2.50 10.0 90.0 1.6 2.75 95.0 5.0
1.6
[0822] Method 10: Column: Zorbax Stable Bond C18, 3.5 .mu.M,
4.6.times.75 mm [0823] Eluant A: water/0.15% formic acid [0824]
Eluant B: acetonitrile [0825] Gradient:
TABLE-US-00015 [0825] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 1.6 4.5 10.0 90.0 1.6 5.0 10.0 90.0 1.6 5.50 90.0 10.0
1.6
[0826] Method 11: Column: X Terra C18, 3.5 .mu.M, 4.6.times.50 mm
[0827] Detection: 180-820 nm [0828] Eluant A: water/0.1%
trifluoroacetic acid [0829] Eluant B: acetonitrile/0.1%
trifluoroacetic acid [0830] Temperature: 40.degree. C. [0831]
Gradient:
TABLE-US-00016 [0831] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 1.5 2.0 0.0 100.0 1.5 3.0 0.0 100.0 1.5 3.4 95.0 5.0
1.5
[0832] Method 12: Column: Merck Cromolith Flash RP18e, 4.6.times.25
mm [0833] Eluant A: water/0.1% formic acid [0834] Eluant B:
acetonitrile/0.1% formic acid [0835] Gradient:
TABLE-US-00017 [0835] time in min % A % B flow rate in mL/min 0.0
90.0 10.0 1.6 2.7 10.0 90.0 1.6 3.0 10.0 90.0 1.6 3.3 95.0 5.0
1.6
[0836] Method 13: Column: Merck Cromolith SpeedROD RP-18e,
4.6.times.50 mm [0837] Eluant A: water/0.1% formic acid [0838]
Eluant B: acetonitrile/0.1% formic acid [0839] Gradient:
TABLE-US-00018 [0839] time in min % A % B flow rate in mL/min 0.0
90.0 10.0 1.5 4.5 10.0 90.0 1.5 5.0 10.0 90.0 1.5 5.5 95.0 5.0
1.5
[0840] Method 14: Column: Zorbax Stable Bond C18, 3.5 .mu.M,
4.6.times.75 mm [0841] Eluant A: water/0.15% formic acid [0842]
Eluant B: acetonitrile [0843] Gradient:
TABLE-US-00019 [0843] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 1.6 2.0 10.0 90.0 1.6 5.0 10.0 90.0 1.6 5.5 90.0 10.0
1.6
[0844] The following preparative methods were used for the
reversed-phase chromatography:
[0845] Method 1: Column: Atlantis C18, 5 .mu.M, 100.times.30 mm
[0846] Detection: 210-500 nm [0847] Eluant A: water/0.1%
trifluoroacetic acid [0848] Eluant B: acetonitrile [0849]
Gradient:
TABLE-US-00020 [0849] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 5 0.5 95.0 5.0 50 8.0 5.0 95.0 50 9.0 5.0 95.0 50 9.5 95.0
5.0 50 10.0 95.0 5.0 50 10.1 95.0 5.0 5
[0850] Method 2: Column: Varian Pursuit 5 .mu.M, 50.times.200 mm
[0851] Eluant A: water/0.1% trifluoroacetic acid [0852] Eluant B:
acetonitrile/0.1% trifluoroacetic acid [0853] Gradient:
TABLE-US-00021 [0853] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 180 1.15 95.0 5.0 180 12.4 2.0 98.0 180 14.0 2.0 98.0 180
15.3 95.0 5.0 180 15.3 95.0 5.5 180
[0854] Method 3: Column: YMC-Pack ODS-AQ 5 .mu.M, 30.times.100 mm
[0855] Eluant A: water/0.15% formic acid [0856] Eluant B:
acetonitrile [0857] Gradient:
TABLE-US-00022 [0857] time in min % A % B flow rate in mL/min 0.0
95.0 5.0 50 2.0 95.0 5.0 50 6.0 10.0 90.0 50 12.0 10.0 90.0 50 13
90.0 10.0 50
Preparation of the Starting Compounds:
[0858] The compounds of general formula I may be prepared from the
following intermediates A, B and C:
##STR00526## ##STR00527##
AAV 1: Amide Coupling
[0859] A solution of the carboxylic acid component (1
mol-equivalent), triethylamine (2.5 mol-equivalents) and TBTU (1.1
mol-equivalents) in THF was stirred for 30 minutes at ambient
temperature. Then the amine component (1.1 mol-equivalent as
hydrochloride) was added and stirring was continued overnight. Then
the mixture was evaporated down, mixed with water, made alkaline
with dilute potassium carbonate solution and extracted with ethyl
acetate. The product was isolated and purified by column
chromatography (either silica gel or reversed phase
chromatography).
AAV 2: Ester Hydrolysis
[0860] 2N sodium hydroxide solution (2 mol-equivalents) was added
to a solution of the ester (1 mol-equivalent) in methanol and the
mixture was stirred for 1 to 5 hours at ambient temperature. Then
it was acidified with acetic acid and the mixture was evaporated to
dryness in vacuo. The crude product thus obtained was purified in
the normal way by column chromatography on silica gel.
AAV 3: Cleaving the Tert-Butyloxycarbonyl Protective Group
[0861] A solution of the tert-butoxycarbonyl-amino compound (1
mol-equivalent) in dichloromethane was combined with
trifluoroacetic acid (3 to 10 mol-equivalents) and stirred at
ambient temperature until the protective group had been cleaved
completely. The reaction mixture was then evaporated to dryness and
the crude product thus obtained was purified by chromatography.
AAV 4: Preparation of the Intermediate A
##STR00528##
[0863] A solution of the aniline component (1 mol-equivalent) and a
strong base such as e.g. potassium-tert-butoxide (1 mol-equivalent)
in DMSO was stirred for one hour at ambient temperature, then
combined with the 4-fluoro-benzonitrile component (1
mol-equivalent) and stirred overnight at approx. 80.degree. C. For
working up the mixture was filtered through Alox and evaporated to
dryness in vacuo.
[0864] The nitrile group of the diphenylamine intermediate product
thus obtained was then reduced to the aminomethyl group with the
addition of Raney nickel at 55.degree. C. and 3 bar excess hydrogen
pressure and the product obtained was purified by chromatography.
In order to prepare the intermediate A with an alpha-alkylbenzyl
group (e.g. A1, A4, A5) the nitrile derivative (1 mol-equivalent)
was dissolved in diethyl ether and at 0 to 5.degree. C. it was
added with stirring to a solution of alkylmagnesium bromide (4
mol-equivalents) in diethyl ether and then stirred for another 30
minutes approx. The reaction mixture was then stirred into 1M
hydrochloric acid at -5.degree. C. and the alkylketone thus
obtained was isolated and purified by chromatography in the usual
way.
[0865] A solution of the ketone thus obtained (1 mol-equivalent) in
acetonitrile was combined with triethylamine (2 mol-equivalents)
and hydroxylamine-hydrochloride (1.3 mol-equivalents) and refluxed
for 4 hours. Then water was added and the mixture was extracted
with dichloromethane. The resulting oxime was isolated from the
organic phase and purified by conventional methods.
[0866] A solution of the oxime (1 mol-equivalent) in methanol was
combined with methanolic hydrochloric acid (6.6 mol-equivalents).
After the addition of zinc powder (1.4 mol-equivalents) the mixture
was refluxed for 3 hours with stirring. After cooling the mixture
was combined with water and extracted with dichloromethane. If
necessary, the amine thus obtained was purified by
chromatography.
[0867] Another possible way of reducing the oxime to the
corresponding amine is by catalytic hydrogenation. For this, the
oxime was hydrogenated in methanolic ammonia solution after the
addition of Raney nickel at 50.degree. C. and at an excess hydrogen
pressure of 50 psi until the uptake of hydrogen had ended. If
necessary, the amine thus obtained was purified by
chromatography.
Preparation of the Intermediates A
##STR00529##
[0869] The following intermediates A1 to A31 were prepared
according to general working method AAV4:
intermediate A1:
[6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phe-
nyl)-amine
##STR00530##
[0871] HPLC: R.sub.t=1.98 minutes (method 2)
[0872] Mass spectrum (ESI): [M+H]+=334
intermediate A2:
(6-aminomethyl-pyridin-3-yl)-(4-isopropyl-2-trifluoromethyl-phenyl)-amine
##STR00531##
[0874] HPLC: R.sub.t=1.95 minutes (method 2)
[0875] Mass spectrum (ESI): [M+H]+=310
intermediate A3:
(6-aminomethyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
##STR00532##
[0877] HPLC: R.sub.t=1.74 minutes (method 13)
[0878] Mass spectrum (ESI): [M+H]+=302
intermediate A4:
2-[6-(1-amino-ethyl)-5-fluoro-pyridin-3-ylamino]-5-fluoro-benzonitrile
##STR00533##
[0880] HPLC: R.sub.t=1.39 minutes (method 2)
[0881] Mass spectrum (ESI): [M+H]+=275; [M-H]-=273
intermediate A5:
[6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phen-
yl)-amine
##STR00534##
[0883] HPLC: R.sub.t=1.92 minutes (method 2)
intermediate A6:
(4-aminomethyl-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
##STR00535##
[0885] Mass spectrum (ESI): [M+H]+=285
[0886] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol 19:1): R.sub.t=0.16
intermediate A7:
(6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
##STR00536##
[0888] HPLC: R.sub.t=2.06 minutes (method 3)
[0889] Mass spectrum (ESI): [M+H]+=286; [M-H]-=284
intermediate A8:
(6-aminomethyl-5-chloro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine
##STR00537##
[0891] Mass spectrum (ESI): [M+H]+=320; [M-H]-=320
intermediate A9:
(6-aminomethyl-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine
##STR00538##
[0893] HPLC: R.sub.t=1.97 minutes (method 2)
[0894] Mass spectrum (ESI): [M+H]+=346
intermediate A10:
(6-aminomethyl-5-chloro-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
##STR00539##
[0896] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol/NH.sub.4OH 9:1:0.1): R.sub.f=0.52
intermediate A11:
(4-aminomethyl-3-fluoro-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
##STR00540##
[0898] Mass spectrum (ESI): [M+H]+=303
[0899] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol 19:1): R.sub.f=0.08
intermediate A12:
(4-aminomethyl-3-fluoro-phenyl)-(2-trifluoromethyl-phenyl)-amine
##STR00541##
[0901] Mass spectrum (ESI): [M-H]-=283
[0902] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol 19:1): R.sub.f=0.09
intermediate A13:
(6-aminomethyl-5-chloro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-
-amine
##STR00542##
[0904] Mass spectrum (ESI): [M+H]+=320
[0905] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol/NH.sub.4OH 9:1:0.1): R.sub.f=0.58
intermediate A14:
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine
##STR00543##
[0907] Mass spectrum (ESI): [M+H]+=304
[0908] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol/NH.sub.4OH 9:1:0.1): R.sub.f=0.56
intermediate A15:
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-
-amine
##STR00544##
[0910] Mass spectrum (ESI): [M+H]+=320; [M-H]-=318
intermediate A16:
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-
-amine
##STR00545##
[0912] HPLC: R.sub.t=1.44 minutes (method 2)
intermediate A17:
(4-aminomethyl-phenyl)-(2-trifluoromethyl-phenyl)-amine
##STR00546##
[0914] HPLC: R.sub.t=1.36 minutes (method 1)
[0915] Mass spectrum (ESI): [M+H-NH.sub.3]+=250
intermediate A18:
(6-aminomethyl-5-chloro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-
-amine
##STR00547##
[0917] HPLC: R.sub.t=2.05 minutes (method 2)
intermediate A19:
(4-aminomethyl-3-fluoro-phenyl)-(6-fluoro-2-trifluoromethyl-phenyl)-amine
##STR00548##
[0919] thin layer chromatogram (silica gel,
CH.sub.2Cl.sub.2/ethanol 9:1): R.sub.f=0.18
intermediate A20:
2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-benzonitrile
##STR00549##
[0921] HPLC: R.sub.t=1.14 minutes (method 2)
[0922] Mass spectrum (ESI): [M+H]+=243
intermediate A21:
(6-aminomethyl-5-methyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine
##STR00550##
[0924] HPLC: R.sub.t=1.79 minutes (method 2)
[0925] Mass spectrum (ESI): [M+H]+=300
intermediate A22:
(4-aminomethyl-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
##STR00551##
[0927] Mass spectrum (ESI): [M+H-NH.sub.3]+=284/286
intermediate A23:
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
##STR00552##
[0929] Mass spectrum (ESI): [M+H]+=286
intermediate A24:
(6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-6-fluorophenyl)-amine
##STR00553##
[0931] HPLC: R.sub.t=1.87 minutes (method 2)
[0932] Mass spectrum (ESI): [M+H]+=330
intermediate A25:
(6-aminomethyl-pyridin-3-yl)-(2-bromo-6-fluoro-phenyl)-amine
##STR00554##
[0934] HPLC: R.sub.t=2.18 minutes (method 2)
[0935] Mass spectrum (ESI): [M+H]+=296
intermediate A26:
(6-aminomethyl-5-methyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-
-amine
##STR00555##
[0937] HPLC: R.sub.t=2.33 minutes (method 2)
intermediate A27:
(6-aminomethyl-5-methyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
##STR00556##
[0939] Mass spectrum (ESI): [M+H]+=282
intermediate A28:
(6-aminomethyl-pyridin-3-yl)-(4-chloro-2-difluoromethyl-phenyl)-amine
##STR00557##
[0941] HPLC: R.sub.t=1.66 minutes (method 2)
[0942] Mass spectrum (ESI): [M+H]+=284
intermediate A29:
(4-aminomethyl-3-fluoro-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
##STR00558##
[0944] HPLC: R.sub.t=1.83 minutes (method 2)
intermediate A30:
2-(4-aminomethyl-3-fluoro-phenylamino)-benzonitrile
##STR00559##
[0946] HPLC: R.sub.t=1.38 minutes (method 2)
intermediate A31:
(4-aminomethyl-phenyl)-(4-bromo-2-trifluoromethyl-phenyl)-amine
##STR00560##
[0948] HPLC: R.sub.t=1.81 minutes (method 2)
Preparation of the Intermediates B
##STR00561##
[0950] The following Intermediates B1 to B11 were prepared by amide
coupling according to general working method AAV1 and subsequent
ester saponification according to general working method AAV2:
intermediate B1:
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid
##STR00562##
[0952] Mass spectrum (ESI): [M+H]+=208; [M-H]-=206
intermediate B2:
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid
##STR00563##
[0954] HPLC: R.sub.t=0.85 minutes (method 7)
[0955] Mass spectrum (ESI): [M+H]+=252
intermediate B3:
(S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid
##STR00564##
[0957] Mass spectrum (ESI): [M+H]+=238; [M-H]-=236
intermediate B4:
1-[(5-amino-pyridine-3-carbonyl)-amino]cyclopropanecarboxylic
acid
##STR00565##
[0959] Mass spectrum (ESI): [M+H]+=222
intermediate B5:
(S)-3-[(3H-imidazo[4,5-1D]pyridin-6-carbonyl)-amino]-tetrahydro-furan-3-c-
arboxylic acid
##STR00566##
[0961] HPLC: R.sub.t=1.49 minutes (method 3)
[0962] Mass spectrum (ESI): [M-H]-=275
intermediate B6:
(S)-3-[(2-methylamino-pyrimidine-5-carbonyl)-amino]-tetrahydro-furan-3-ca-
rboxylic acid
##STR00567##
[0964] HPLC: R.sub.t=0.47 minutes (method 2)
[0965] Mass spectrum (ESI): [M+H]+=267
intermediate B7:
(S)-3-[(2-methyl-pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxyl-
ic acid
##STR00568##
[0967] HPLC: R.sub.t=0.43 minutes (method 2)
[0968] Mass spectrum (ESI): [M+H]+=252; [M-H]-=250
intermediate B8:
(S)-3-[(5-hydroxy-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxyli-
c acid
##STR00569##
[0970] HPLC: R.sub.t=0.48 minutes (method 2)
[0971] Mass spectrum (ESI): [M+H]+=253
intermediate B9:
(S)-3-[(6-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid
##STR00570##
[0973] HPLC: R.sub.t=0.33 minutes (method 2)
[0974] Mass spectrum (ESI): [M+H]+=252; [M-H]-=250
intermediate B10:
(S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydro-furan--
3-carboxylic acid
##STR00571##
[0976] HPLC: R.sub.t=0.33 minutes (method 2)
[0977] Mass spectrum (ESI): [M+H]+=254
intermediate B11:
1-[(2-methyl-pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic
acid
##STR00572##
[0979] Mass spectrum (ESI): [M+H]+=222; [M-H]-=220
[0980] The following Intermediates B12 to B15 may be prepared
analogously:
Intermediate B12
##STR00573##
[0981] Intermediate B13
##STR00574##
[0982] Intermediate B14
##STR00575##
[0983] Intermediate B15
##STR00576##
[0984] Preparation of the Intermediates C
##STR00577##
[0986] The following Intermediates C1 to C22 were prepared by amide
coupling according to general working method AAV1 and subsequent
cleaving of the tert-butyloxycarbonyl-protective group according to
general working method AAV3:
intermediate C1: 1-amino-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00578##
[0988] HPLC: R.sub.t=1.55 minutes (method 13)
[0989] Mass spectrum (ESI): [M-H]-=383
intermediate C2: 1-amino-cyclopropanecarboxylic
acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00579##
[0991] HPLC: R.sub.t=2.33 minutes (method 7)
[0992] Mass spectrum (ESI): [M+H]+=369; [M-H]-=367
intermediate C3: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00580##
[0994] Mass spectrum (ESI): [M+H]+=433
intermediate C4: 1-amino-cyclopropanecarboxylic
acid-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
##STR00581##
[0996] HPLC: R.sub.t=1.65 minutes (method 2)
[0997] Mass spectrum (ESI): [M+H]+=429
intermediate C5: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00582##
[0999] Mass spectrum (ESI): [M+H]+=433
intermediate C6: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00583##
[1001] Mass spectrum (ESI): [M+H]+=417
intermediate C7: 1-amino-cyclopropanecarboxylic
acid-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00584##
[1003] HPLC: R.sub.t=1.50 minutes (method 2)
intermediate C8: 3-amino-oxetan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00585##
[1004] (a) 3-dibenzylamino-oxetan-3-carbonitrile
[1005] A solution of 3-oxetanone (908 mg, 12.6 mmol), dibenzylamine
(6.08 mL, 31.6 mmol) and trimethylsilylcyanide (2.00 mL, 15.8 mmol)
in 20 mL concentrated acetic acid was stirred overnight at
60.degree. C. After cooling it was adjusted to pH 10 with
concentrated ammonia and the solution was extracted with
chloroform. After evaporation, the crude product was obtained,
which was purified by chromatography through silica gel.
[1006] C.sub.18H.sub.18N.sub.2O (278.35)
[1007] Mass spectrum (ESI): [M+H]+=279
(b) 3-dibenzylamino-oxetan-3-carboxylic acid
[1008] A solution of 3-dibenzylamino-oxetan-3-carbonitrile (370 mg,
1.33 mmol) and 5 mL 4M sodium hydroxide solution in 20 mL ethanol
was refluxed overnight, then neutralised with 1M hydrochloric acid
neutralisiert and evaporated to dryness. The crude product thus
obtained was purified by chromatography.
[1009] C.sub.18H.sub.19NO.sub.3 (297.35)
[1010] Mass spectrum (ESI): [M+H]+=298
(c) 3-dibenzylamino-oxetan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
[1011] Prepared from 3-dibenzylamino-oxetan-3-carboxylic acid and
4-(2-trifluoromethyl-phenyl-amino)-benzylamine by amide coupling
according to general working method AAV1.
[1012] C.sub.32H.sub.30F.sub.3N.sub.3O.sub.2 (545.59)
[1013] Mass spectrum (ESI): [M+H]+=546
(d) 3-amino-oxetan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
[1014] 3-dibenzylamino-oxetan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide (32.0 mg, 0.059
mmol) was dissolved in 10 mL methanol, combined with 20 mg
Pd/charcoal (10%) and debenzylated at ambient temperature under 3
bar hydrogen pressure.
[1015] C.sub.18H.sub.18F.sub.3N.sub.3O.sub.2 (365.35)
[1016] HPLC: R.sub.t=1.93 minutes (method 5)
[1017] Mass spectrum (ESI): [M+H]+=366
intermediate C9: (S)-3-amino-tetrahydrofuran-3-carboxlic
acid-2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamide
##STR00586##
[1019] Mass spectrum (ESI): [M+H]+=416
intermediate C10:1-amino-cyclopropanecarboxylic
acid-2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamide
##STR00587##
[1021] Mass spectrum (ESI): [M+H]+=386
intermediate C11: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylamide
##STR00588##
[1023] Mass spectrum (ESI): [M+H]+=416
intermediate C12: 1-amino-cyclopropanecarboxylic
acid-2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00589##
[1025] Mass spectrum (ESI): [M+H]+=368
intermediate C13: 1-amino-cyclopropanecarboxylic
acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00590##
[1027] Mass spectrum (ESI): [M+H]+=387
intermediate C14: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamide
##STR00591##
[1029] HPLC: R.sub.t=1.99 minutes (method 2)
[1030] Mass spectrum (ESI): [M+H]+=398
intermediate C15: 1-amino-cyclopropanecarboxylic
acid-[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00592##
[1032] Mass spectrum (ESI): [M+H]+=385
intermediate C16: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00593##
[1034] HPLC: R.sub.t=1.34 minutes (method 2)
[1035] Mass spectrum (ESI): [M+H]+=399
intermediate C17: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmet-
hyl]-amide
##STR00594##
[1037] HPLC: R.sub.t=2.35 minutes (method 2)
intermediate C18: (S)-3-amino-tetrahydrofuran-3-carboxylic
acid-4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylamide
##STR00595##
[1039] HPLC: R.sub.t=2.41 minutes (method 2)
intermediate C19: 1-amino-cyclopropanecarboxylic
acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmet-
hyl]-amide
##STR00596##
[1041] HPLC: R.sub.t=1.24 minutes (method 2)
[1042] Mass spectrum (ESI): [M+H]+=383
intermediate C20:1-amino-cyclopropanecarboxylic
acid-[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00597##
[1044] HPLC: R.sub.t=1.30 minutes (method 2)
[1045] Mass spectrum (ESI): [M+H]+=365
intermediate C21: 1-amino-cyclopropanecarboxylic
acid-[5-(4-chloro-2-difluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
##STR00598##
[1047] HPLC: R.sub.t=1.48 minutes (method 2)
[1048] Mass spectrum (ESI): [M+H]+=367
intermediate C22: (S)-3-amino-tetrahydrofuran-3-carboxylic acid
2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00599##
[1050] Mass spectrum (ESI): [M+H]+=398
[1051] The following intermediates C23 to C25 may be prepared
analogously:
Intermediate C23
##STR00600##
[1052] Intermediate C24
##STR00601##
[1053] Intermediate C25
##STR00602##
[1054] Preparation of the End Compounds:
Example 1
Pyrimidine-5-carboxylic acid
N-(1-(4-(2,3-dichlorophenylamino)benzyl-carbamoyl)cyclopropyl)amide
##STR00603##
[1055] 1a) ethyl
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylate
[1056] A solution of 15.74 g (126.9 mmol) pyrimidine-5-carboxylic
acid, 43.57 mL (312.6 mmol) triethylamine and 44.61 g (138.9 mmol)
TBTU in 460 mL THF was stirred for 30 minutes at ambient
temperature. Then 9.11 g (127.3 mmol) ethyl
1-amino-cyclopropane-carboxylate hydrochloride were added and the
mixture was stirred further overnight. Then the mixture was
evaporated down and the residue was combined with 200 mL water,
made alkaline with dilute potassium carbonate solution and
extracted with ethyl acetate. The intermediate product was purified
by column chromatography (silica gel, dichloromethane+0-4%
methanol).
[1057] Yield: 95% of theory
[1058] C.sub.11H.sub.13N.sub.3O.sub.3 (235.24)
[1059] R.sub.t=1.23 min. method 1
1b) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic
acid
[1060] 28.39 mL of a 2N sodium hydroxide solution were added to a
solution of 13.36 g (56.79 mmol) ethyl
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylate in 240 mL
methanol and the mixture was stirred for one hour at ambient
temperature. Then it was acidified with concentrated acetic acid
and evaporated to dryness in vacuo. The crude product thus obtained
was purified by column chromatography (silica gel,
dichloromethane+5-30% 10% acetic acid in methanol).
[1061] Yield: 100% of theory
[1062] C.sub.9H.sub.9N.sub.3O.sub.3 (207.19)
[1063] R.sub.t=1.23 min. method 1
1c)
N-(4-aminomethyl)phenyl)-2,3-dichloraniline-trifluoroacetate
[1064] A solution of 32 mg (0.2 mmol) 2,3-dichloroaniline and 22 mg
(0.2 mmol) potassium-tert-butoxide in 9 mL DMSO was stirred for one
hour at ambient temperature, then combined with 24 mg (0.2 mmol)
4-fluorobenzonitrile and stirred further overnight at 80.degree. C.
For working up the reaction mixture was filtered through Alox B,
washed with DMF and evaporated to dryness in vacuo. The residue was
hydrogenated in 100 .mu.L methanolic ammonia solution with 20 mg
Raney nickel as catalyst at 55.degree. C. under a hydrogen pressure
of 3 bar for 5 hours. Then the catalyst was filtered off, the
filtrate was freed from the solvent and the crude product was
purified by HPLC (method 1).
[1065] Yield: 47% of theory
[1066] C.sub.13H.sub.12Cl.sub.2N.sub.2 (267.15)
1d) pyrimidine-5-carboxylic acid
N-(1-(4-(2,3-dichlorophenylamino)benzylcarbamoyl)-cyclopropyl)amide
[1067] 0.5 mL (3.6 mmol) triethylamine, 433 mg (1.35 mmol) TBTU and
326 mg (1.2 mmol)
N-(4-aminomethyl)phenyl)-2,3-dichloroaniline-trifluoroacetate (from
1c) were added to a solution of 250 mg (1.2 mmol)
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid (from
1b) in 15 mL tetrahydrofuran. The mixture was stirred overnight at
ambient temperature, then evaporated to dryness and purified by
HPLC (method 1).
[1068] Yield: 16% of theory
[1069] C.sub.22H.sub.19Cl.sub.2N.sub.5O.sub.3 (456.32)
[1070] R.sub.t=2.1 min. method 5
Example 2
pyrimidine-5-carboxylic
acid-N-(1-(4-(2-chlorophenylamino)benzylcarbamoyl)cyclopropyl)amide
##STR00604##
[1071] 2a) N-(4-(aminomethyl)phenyl)-2-chloroaniline
[1072] Analogously to method (1c) the title compound was prepared
starting from 2-chloroaniline, 4-fluorobenzonitrile and Raney
nickel.
[1073] C.sub.13H.sub.9ClN.sub.2 (228.68)
2b) pyrimidine-5-carboxylic
acid-N-(1-(4-(2-chlorophenylamino)benzylcarbamoyl)cyclo-propyl)amide
[1074] Analogously to method (1d) the title compound was prepared
starting from N-(4-(aminomethyl)phenyl)-2-chloroaniline (from 2a)
and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid
(from 1b).
[1075] C.sub.22H.sub.20ClN.sub.5O.sub.2 (421.88)
[1076] R.sub.t=2.13 min. method 6
Example 3
pyrimidine-5-carboxylic
acid-N-(1-(4-(phenylamino)benzylcarbamoyl)cyclo-propyl)amide
##STR00605##
[1077] 3a) 4-(aminomethyl)-N-phenylaniline
[1078] Analogously to method (1c) the title compound was prepared
starting from aniline, 4-fluorobenzonitrile and Raney nickel.
[1079] C.sub.13H.sub.14N.sub.2 (199.26)
3b) pyrimidine-5-carboxylic
acid-N-(1-(4-(phenylamino)benzylcarbamoyl)cyclopropyl)-amide
[1080] Analogously to method (1d) the title compound was prepared
starting from 4-(aminomethyl)-N-phenylaniline (from 3a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1081] C.sub.22H.sub.20ClN.sub.5O.sub.2 (421.88)
[1082] R.sub.t=1.82 min. method 5
Example 4
pyrimidine-5-carboxylic
acid-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-
amide
##STR00606##
[1083] 4a) N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline
[1084] Analogously to method (1c) the title compound was prepared
starting from 2-(trifluoromethyl)aniline, 4-fluorobenzonitrile and
Raney nickel.
[1085] C.sub.14H.sub.13F.sub.3N.sub.2 (266.26)
4b) pyrimidine-5-carboxylic
acid-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzyl-carbamoyl)cyclopropyl-
)amide
[1086] Analogously to method (1d) the title compound was prepared
starting from N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline
(from 4a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1087] C.sub.23H.sub.20F.sub.3N.sub.5O.sub.2 (455.43)
[1088] R.sub.t=2.27 min. method 6
Example 5
5-oxo-pyrrolidine-2-carboxylic
acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}--
amide
##STR00607##
[1089] 5a)
1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropan-
ecarboxamide
[1090] A solution of 376 mg (1.87 mmol)
1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid in 20 mL
DMF was combined with 0.4 mL (2.85 mmol) triethylamine and 600 mg
(1.87 mmol) TBTU and stirred for 5 minutes at ambient temperature.
Then 500 mg N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline
(from 4a) were added and the mixture was stirred at ambient
temperature over the weekend. The mixture was then filtered through
Alox B, washed with DMF:methanol=9:1 and evaporated to dryness in
vacuo. The residue was combined with a 1:1 mixture of
dichloromethane and trifluoroacetic acid and stirred for one hour
at ambient temperature. The reaction mixture was evaporated to
dryness in vacuo and the crude product was purified by column
chromatography (silica gel, dichloromethane+2-8%
methanol:ammonia=9:1).
[1091] Yield: 16% of theory
[1092] C.sub.22H.sub.19Cl.sub.2N.sub.5O.sub.3 (456.32)
5b) 5-oxo-pyrrolidine-2-carboxylic
acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}--
amide
[1093] Analogously to method (1d) the title compound was prepared
starting from
1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarb-
oxamide (from 5a) and 5-oxopyrrolidine-2-carboxylic acid.
[1094] C.sub.23H.sub.23F.sub.3N.sub.4O.sub.3 (460.46)
[1095] R.sub.t=1.89 min. method 5
[1096] Examples 6 to 22 that follow were prepared analogously to
method (1d) from
1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropan-
ecarboxamide and the corresponding acids:
Example 6
1-(4-dimethylamino-butyrylamino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00608##
[1098] C.sub.24H.sub.29F.sub.3N.sub.4O.sub.2 (462.5)
[1099] R.sub.t=1.67 min. method 5
Example 7
1-(3,3,3-trifluoro-propionylamino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00609##
[1101] C.sub.21H.sub.19F.sub.6N.sub.3O.sub.2 (459.4)
[1102] R.sub.t=2.21 min. method 5
Example 8
1-(3-dimethylamino-propionylamino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00610##
[1104] C.sub.23H.sub.27F.sub.3N.sub.4O.sub.2 (448.5)
[1105] R.sub.t=1.67 min. method 5
Example 9
2,4-dihydroxy-pyrimidine-5-carboxylic
acid-{1-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-cyclopropyl}-
-amide
##STR00611##
[1107] C.sub.23H.sub.20F.sub.3N.sub.5O.sub.4 (487.4)
[1108] R.sub.t=1.93 min. method 5
Example 10
1-(5-dimethylamino-pentanoylamino)-cyclopropanecarboxylic
acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00612##
[1110] C.sub.25H.sub.31F.sub.3N.sub.4O.sub.2 (476.5)
[1111] R.sub.t=1.69 min. method 5
Example 11
N-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-nico-
tinamide
##STR00613##
[1113] C.sub.24H.sub.21F.sub.3N.sub.4O.sub.2 (454.4)
[1114] R.sub.t=1.79 min. method 5
Example 12
1-(2-dimethylamino-acetylamino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00614##
[1116] C.sub.22H.sub.25F.sub.3N.sub.4O.sub.2 (434.5)
[1117] R.sub.t=1.68 min. method 5
Example 13
1-propionylamino-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenyl-amino)-benzylamide
##STR00615##
[1119] C.sub.21H.sub.22F.sub.3N.sub.3O.sub.2 (405.4)
[1120] R.sub.t=2.09 min. method 5
Example 14
1-(2-methoxy-acetylamino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00616##
[1122] C.sub.21H.sub.22F.sub.3N.sub.3O.sub.3 (421.4)
[1123] R.sub.t=2.07 min. method 5
Example 15
1-(cyclopropanecarbonyl-amino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00617##
[1125] C.sub.22H.sub.22F.sub.3N.sub.3O.sub.2 (417.4)
[1126] R.sub.t=2.13 min. method 5
Example 16
1-pentanoylamino-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenyl-amino)-benzylamide
##STR00618##
[1128] C.sub.23H.sub.26F.sub.3N.sub.3O.sub.2 (433.5)
[1129] R.sub.t=2.24 min. method 5
Example 17
1-methyl-1H-imidazol-4-carboxylic
acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}--
amide
##STR00619##
[1131] C.sub.23H.sub.22F.sub.3N.sub.5O.sub.2 (457.5)
[1132] R.sub.t=1.73 min. method 5
Example 18
1-methyl-4H-imidazole-2-carboxylic
acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}--
amide
##STR00620##
[1134] C.sub.23H.sub.22F.sub.3N.sub.5O.sub.2 (457.5)
[1135] R.sub.t=1.88 min. method 5
Example 19
1-(2-cyclopropyl-acetylamino)-cyclopropanecarboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00621##
[1137] C.sub.23H.sub.24F.sub.3N.sub.3O.sub.2 (431.5)
[1138] R.sub.t=2.18 min. method 5
Example 20
N-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-benz-
amide
##STR00622##
[1140] C.sub.25H.sub.22F.sub.3N.sub.3O.sub.2 (453.5)
[1141] R.sub.t=2.26 min. method 5
Example 21
pyridine-2-carboxylic acid
{1-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amid-
e
##STR00623##
[1143] C.sub.24H.sub.21F.sub.3N.sub.4O.sub.2 (454.4)
[1144] R.sub.t=2.20 min. method 5
Example 22
1-methyl-piperidine-4-carboxylic acid
{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
##STR00624##
[1146] C.sub.25H.sub.29F.sub.3N.sub.4O.sub.2 (474.5)
[1147] R.sub.t=1.68 min. method 5
Example 23
1-(2,2,2-trifluoracetamido)-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)-c-
yclopropanecarboxamide
##STR00625##
[1149] Analogously to method (1d) the title compound was prepared
starting from
1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarb-
oxamide (from 5a) and trifluoroacetic acid.
[1150] C.sub.20H.sub.17F.sub.6N.sub.3O.sub.2 (445.37)
[1151] R.sub.t=2.27 min. method 5
Example 24
N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-isoxa-
zole-5-carboxamide
##STR00626##
[1153] 20 mg (0.15 mmol) isoxazole-5-carbonyl chloride were added
to a solution of 35 mg (0.1 mmol)
1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxami-
de (from 5a) and 70 .mu.L (0.50 mmol) triethylamine in 1 mL DMF and
the mixture was stirred overnight at ambient temperature. The
reaction mixture was purified by preparative RP-HPLC-MS with an
eluant gradient (water:acetonitrile+0.1% trifluoroacetic acid=95:5
to 5:95).
[1154] Yield: 29% of theory
[1155] C.sub.22H.sub.19F.sub.3N.sub.4O.sub.3 (444.41)
[1156] R.sub.t=2.42 min. method 6
Example 25
pyrimidine-5-carboxylic acid
N-(1-(1-(4-(4-(difluoromethoxy)phenylamino)-phenyl)ethylcarbamoyl)cyclopr-
opyl)amide
##STR00627##
[1157] 25a)
1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone
[1158] The reaction is carried out under protective gas (argon). A
mixture of 2.39 g (12 mmol) 1-(4-bromophenyl)ethanone, 0.99 mL (8
mmol) 4-(difluoromethoxy)aniline, 2.21 g (16 mmol) potassium
carbonate, 150 mg (0.8 mmol) copper iodide and 180 mg (1.6 mmol)
L-proline in 12 mL DMSO was stirred for 72 hours at 95.degree. C.
The reaction mixture was added to water, mixed with a little
ammonia extracted twice with tert-butyl-methylether. The combined
organic phases were dried on sodium sulphate and evaporated to
dryness in vacuo. The residue was purified by column chromatography
(silica gel, petroleum ether+30% ethyl acetate). The product was
further reacted directly.
[1159] Yield: 33% of theory
[1160] C.sub.15H.sub.13F.sub.2NO.sub.2 (277.27)
[1161] R.sub.t=1.98 min. method 1
25b)
(Z)-1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone-oxime
[1162] A mixture of 1.08 g (3.9 mmol)
1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone and 0.92 mL
(15.58 mmol) aqueous 50% hydroxylamine solution in 10 mL ethanol
was stirred for 3 hours at 100.degree. C. The reaction mixture was
evaporated to dryness in vacuo and the residue was purified by
preparative HPLC (method 2).
[1163] Yield: 19% of theory
[1164] C.sub.15H.sub.14F.sub.2N.sub.2O.sub.2 (292.28)
[1165] R.sub.t=1.96 min. method 1
25c) 4-(1-aminoethyl)-N-(4-(difluoromethoxy)phenyl)aniline
[1166] 0.22 g (0.75 mmol)
(Z)-1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone-oxime in
20 mL methanolic ammonia solution were hydrogenated with the
addition of 50 mg Raney nickel at 50.degree. C. at a hydrogen
pressure of 50 psi for 5 hours. Then the catalyst was filtered off
and the filtrate was evaporated to dryness. The crude product thus
obtained was further reacted directly.
[1167] C.sub.15H.sub.16F.sub.2N.sub.2O (278.3)
[1168] R.sub.t=1.37 min. method 1
25d) pyrimidine-5-carboxylic acid
N-(1-(1-(4-(4-(difluoromethoxy)phenylamino)phenyl)-ethylcarbamoyl)cyclopr-
opyl) amide
[1169] Analogously to method (1d) the title compound was prepared
starting from 4-(1-aminoethyl)-N-(4-(difluoromethoxy)phenyl)aniline
(from 25c) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1170] C.sub.24H.sub.23F.sub.2N.sub.5O.sub.3 (467.47)
[1171] R.sub.t=1.78 min. method 1
Example 26
5-(trifluoromethyl)-N-(1-(4-(2-(trifluoromethyl)phenylamino)-benzylcarbamo-
yl)cyclopropyl)nicotinamide
##STR00628##
[1172] 26a) 5-(trifluoromethyl)nicotinic acid
[1173] A solution of 1.5 g 3-bromo-5-(trifluoromethyl)pyridine in
50 ml of toluene was added dropwise at -75.degree. C. to a mixture
of 9.96 mL (15.9 mmol) 1.6 molar butyllithium solution in hexane
and 3.98 mL (8 mmol) 2 molar butylmagnesium chloride solution in
diethyl ether and 10 mL THF. After 20 minutes 20 g (454 mmol) dry
ice were added and the mixture was again stirred for 20 minutes at
-75.degree. C. and for 3 hours at RT. The reaction mixture was
combined with 50 mL 1 molar sodium hydroxide solution and extracted
twice with diethyl ether. The aqueous phase was acidified with 4
molar hydrochloric acid and extracted three times with diethyl
ether. The combined organic phases were dried on sodium sulphate
and evaporated to dryness in vacuo. The residue was mixed with
dichloromethane and the precipitate formed was suction filtered and
dried in the circulating air dryer at 55.degree. C.
[1174] Yield: 9% of theory
[1175] C.sub.7H.sub.4F.sub.3NO.sub.2 (191.11)
26b)
5-(trifluoromethyl)-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcar-
bamoyl)-cyclopropyl)nicotinamide
[1176] Analogously to method (1d) the title compound was prepared
starting from
1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarb-
oxamide (from 5a) and 5-(trifluoromethyl)nicotinic acid (from
26a).
[1177] C.sub.22H.sub.20F.sub.3N.sub.5O.sub.3 (459.42)
[1178] R.sub.t=2.41 min. method 6
Example 27
5-methyl-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopro-
pyl)-1,3,4-oxadiazole-2-carboxamide
##STR00629##
[1179] 27a)
5-methyl-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopro-
pyl)-1,3,4-oxadiazole-2-carboxamide
[1180] Analogously to method (1d) the title compound was prepared
starting from
1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarb-
oxamide (from 5a) and 5-methyl-1,3,4-oxadiazole-2-carboxylic
acid.
[1181] C.sub.22H.sub.20F.sub.3N.sub.5O.sub.3 (459.42)
[1182] R.sub.t=1.66 min. method 6
Example 28
pyrimidine-5-carboxylic
acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)phenylamino)benzylcarbamo-
yl)cyclopropyl)amide
##STR00630##
[1183] 28a)
N-(4-(aminomethyl)phenyl)-4-(methylthio)-2-(trifluoromethyl)aniline
[1184] Analogously to method (1c) the title compound was prepared
starting from 4-(methylthio)-2-(trifluoromethyl)aniline and
4-fluorobenzonitrile.
[1185] C.sub.15H.sub.15F.sub.3N.sub.2S (312.35)
[1186] R.sub.t=1.88 min. method 2
28b) pyrimidine-5-carboxylic
acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)phenylamino)benzylcarbamo-
yl)cyclopropyl)amide
[1187] Analogously to method (1d) the title compound was prepared
starting from
N-(4-(aminomethyl)phenyl)-4-(methylthio)-2-(trifluoromethyl)aniline
(from 28a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1188] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.2S (501.53)
[1189] R.sub.t=2.33 min. method 2
Example 29
N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopro-
pyl)thiazole-5-carboxamide
##STR00631##
[1190] 29a)
N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline
[1191] Analogously to method (1c) the title compound was prepared
starting from 2-trifluoromethyl-4-fluoraniline and
4-fluorobenzonitrile.
[1192] C.sub.14H.sub.8F.sub.4N.sub.2 (280.22)
[1193] R.sub.t=0.38 min. method 4
29b) tea-butyl
1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropy-
lcarbamate
[1194] 0.98 mL (7.04 mmol) triethylamine and 1.24 g (3.87 mmol)
TBTU were added to a solution of 710 mg (3.52 mmol)
1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid in 60 mL
DMF and the mixture was stirred for 30 minutes at ambient
temperature. Then 1 g
N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline was added and
the mixture was stirred for 1 hour at ambient temperature. The
reaction mixture was evaporated to dryness in vacuo. The residue
was taken up in ethyl acetate and washed twice with 5% sodium
hydrogen carbonate solution. The organic phase was dried on sodium
sulphate and evaporated to dryness in vacuo.
[1195] Yield: 96% of theory
[1196] C.sub.23H.sub.25F.sub.4N.sub.3O.sub.3 (467.46)
[1197] R.sub.t=1.50 min. method 4
29c)
1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl-cyclopro-
panecarboxamide
[1198] 1.57 g (3.36 mmol) tert-butyl
1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl-carbamoyl)cyclopropy-
lcarbamate in 10 mL diethyl ether were combined with 20 mL 4 molar
hydrogen chloride in dioxane and stirred for 10 minutes at ambient
temperature. The reaction mixture was combined with ethyl acetate
and made alkaline with saturated potassium carbonate solution. The
organic phase was dried on sodium sulphate and evaporated to
dryness in vacuo.
[1199] Yield: 101% of theory
[1200] C.sub.18H.sub.17F.sub.4N.sub.3O (367.34)
[1201] R.sub.t=1.33 min. method 4
29d)
N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cycl-
opropyl)-thiazole-5-carboxamide
[1202] Analogously to method (1d) the title compound was prepared
starting from
1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopr-
opanecarboxamide (from 29c) and thiazole-5-carboxylic acid.
[1203] C.sub.22H.sub.18F.sub.4N.sub.4O.sub.3S (478.46)
[1204] R.sub.t=2.76 min. method 3
Example 30
N-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzyl)-1-(3,3,3-trifluoro-p-
ropanamido)cyclopropanecarboxamide
##STR00632##
[1205] 30a)
N-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzyl)-1-(3,3,3-trifluorop-
ropanamido)cyclopropanecarboxamide
[1206] 44.0 mg (0.15 mmol) 3,3,3-trifluoropropionyl chloride,
dissolved in 5 mL dichloromethane, were added dropwise to a
solution of 110.2 mg (0.3 mmol)
1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclop-
ropanecarboxamide (from 29c) and 80 .mu.L (0.6 mmol) triethylamine
in 10 mL dichloromethane. Then the reaction mixture was left at
ambient temperature for the weekend with stirring and it was then
purified by preparative RP-HPLC-MS (method 3). The eluate was made
alkaline with conc. Ammonia and the acetonitrile was distilled off.
The aqueous mixture was extracted with ethyl acetate and the
organic phase was dried on sodium sulphate and evaporated to
dryness in vacuo.
[1207] Yield: 44% of theory
[1208] C.sub.21H.sub.18F.sub.7N.sub.3O.sub.2 (477.38)
[1209] R.sub.t=2.85 min. method 3
Example 31
N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)-cyclopro-
pyl)isoxazole-5-carboxamide
##STR00633##
[1211] Analogously to method (30a) the title compound was prepared
starting from
1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropane-
carboxamide (from 29c) and isoxazole-5-carbonyl chloride.
[1212] C.sub.22H.sub.18F.sub.4N.sub.4O.sub.3 (462.4)
[1213] R.sub.t=2.79 min. method 3
Example 32
pyrimidine-5-carboxylic
acid-N-(1-(4-(4-(methylsulphonyl)-2-(trifluoromethyl)phenylamine)benzylca-
rbamoyl)cyclopropyl)amide
##STR00634##
[1215] 34 mg (0.2 mmol) 3-chloroperoxybenzoic acid were added to 66
mg (0.13 mmol) pyrimidine-5-carboxylic
acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)-phenylamino)benzylcarbam-
oyl)cyclopropyl)amide (from 28b), dissolved in 5 mL
dichloromethane, and the mixture was left at ambient temperature
overnight with stirring. Then the mixture was added to saturated
sodium hydrogen carbonate solution and extracted with
dichloromethane. The organic phase was dried through a phase
separation cartridge and the filtrate was evaporated to dryness in
vacuo.
[1216] Yield: 40% of theory
[1217] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.4S (533.52)
[1218] R.sub.t=1.84 min. method 2
Example 33
pyrimidine-5-carboxylic
acid-N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)cyc-
lopropyl)amide
##STR00635##
[1220] Analogously to method (1d) the title compound was prepared
starting from
1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopr-
opanecarboxamide (from 29c) and pyrimidine-5-carboxylic acid.
[1221] C.sub.23H.sub.19F.sub.4N.sub.5O.sub.2 (473.42)
[1222] R.sub.t=2.09 min. method 2
Example 34
1-(2-(pyrimidin-5-yl)acetamido)-N-(4-(2-(trifluoromethyl)phenylamino)-benz-
yl)cyclopropanecarboxamide
##STR00636##
[1224] Analogously to method (1d) the title compound was prepared
starting from
1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopr-
opanecarboxamide (from 29c) and pyrimidine-5-carboxylic acid.
[1225] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.2 (469.46)
[1226] R.sub.t=2.21 min. method 6
Example 35
pyrimidine-5-carboxylic
acid-N-(1-(4-(2-cyanphenylamine)benzylcarbamoyl)cyclopropyl)amide
##STR00637##
[1227] 35a) tert-butyl-4-aminobenzylcarbamate
[1228] 92.65 g (424.5 mmol) di-tert-butyl-dicarbonate were added to
61.85 g (424.4 mmol) 4-aminomethyl-aniline dissolved in 850 mL
chloroform and the mixture was stirred at ambient temperature until
no more educt was present. The mixture was evaporated to dryness in
vacuo and the residue was recrystallised from ethyl acetate/hexane
(approx. 3 mL/g).
[1229] Yield: 66% of theory
[1230] C.sub.12H.sub.18N.sub.2O.sub.2 (222.28)
[1231] R.sub.f=0.49 hexane:ethyl acetate (1/1)
35b) tert-butyl-4-(2-cyanophenylamino)benzylcarbamate
[1232] The reaction was carried out under protective gas
(nitrogen). 8 mg (0.01 mmol) of
tris(dibenzylideneacetone)dipalladium and 17 mg (0.04 mmol)
Xantphos were added to 100 mg (0.45 mmol)
tert-butyl-4-aminobenzylcarbamate, 138 mg (0.63 mmol) potassium
sulphate and 98 mg (0.54 mmol) 2-bromobenzonitrile in 5 mL toluene.
The mixture was stirred overnight at 110.degree. C. and then the
inorganic salts were filtered off. The filtrate was evaporated to
dryness in vacuo and the residue was purified through an RP column
with a solvent gradient (water/acetonitrile+0.1% trifluoroacetic
acid).
[1233] Yield: 82% of theory
[1234] C.sub.19H.sub.21N.sub.3O.sub.2 (323.39)
[1235] R.sub.t=2.57 min. method 2
35c)
2-(4-(aminomethyl)phenylamino)benzonitrile-2,2,2-trifluoroacetate
[1236] 119 mg (0.37 mmol) tert-butyl
4-(2-cyanophenylamino)benzylcarbamate were dissolved in 5 mL
dichloromethane and combined with 1 mL (13.06 mmol) trifluoroacetic
acid. The reaction was stirred overnight at ambient temperature and
then evaporated to dryness in vacuo.
[1237] Yield: 99% of theory
[1238] C.sub.14H.sub.13N.sub.3*C.sub.2HF.sub.3O.sub.2 (337.3)
[1239] R.sub.t=1.30 min. method 2
35d) pyrimidine-5-carboxylic
acid-N-(1-(4-(2-cyanophenylamine)benzylcarbamoyl)cyclo-propyl)amide
[1240] Analogously to method (1d) the title compound was prepared
starting from 2-(4-(aminomethyl)phenylamino)benzonitrile
2,2,2-trifluoroacetate (from 35c) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1241] C.sub.23H.sub.20N.sub.6O.sub.2 (412.44)
[1242] R.sub.t=1.84 min. method 2
Example 36
pyrimidine-5-carboxylic
acid-N-(1-(4-(2-cyano-4-fluorophenylamine)benzyl-carbamoyl)cyclopropyl)am-
ide
##STR00638##
[1243] 36a)
Tert-butyl-4-(2-cyano-4-fluorophenylamino)benzylcarbamate
[1244] Analogously to method (35b) the title compound was prepared
starting from tert-butyl-4-aminobenzylcarbamate (from 35a),
potassium sulphate, 2-bromo-5-fluorobenzonitrile,
tris(dibenzylideneacetone)dipalladium and Xantphos.
[1245] C.sub.19H.sub.20FN.sub.6O.sub.2 (341.38)
[1246] R.sub.t=2.61 min. method 2
36b) 2-(4-(aminomethyl)phenylamino)-5-fluorobenzonitrile
2,2,2-trifluoroacetate
[1247] Analogously to method (35c) the title compound was prepared
starting from
tert-butyl-4-(2-cyano-4-fluorophenylamino)benzylcarbamate and
trifluoroacetic acid.
[1248] C.sub.14H.sub.12FN.sub.3*C.sub.2HF.sub.3O.sub.2 (355.29)
[1249] R.sub.t=1.39 min. method 2
36c) pyrimidine-5-carboxylic
acid-N-(1-(4-(2-cyano-4-fluorophenylamine)benzylcarbamoyl)cyclopropyl)ami-
de
[1250] Analogously to method (1d) the title compound was prepared
from 2-(4-(aminomethyl)phenylamino)-5-fluorobenzonitrile
2,2,2-trifluoroacetate (from 36b) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1251] C.sub.23H.sub.19FN.sub.6O.sub.2 (430.43)
[1252] R.sub.t=1.91 min. method 2
Example 37
pyrimidine-5-carboxylic
acid-N-(1-(4-(4-fluorophenylamino)benzylcarbamoyl)cyclopropyl)amide
##STR00639##
[1253] 37a) 4-(aminomethyl)-N-(4-fluorophenyl)aniline
[1254] Analogously to method (1c) the title compound was prepared
starting from 2-bromo-4-fluoro-aniline, 4-fluorobenzonitrile and
Raney nickel.
[1255] C.sub.13H.sub.13FN.sub.2 (216.25)
37b) pyrimidine-5-carboxylic
acid-N-(1-(4-(4-fluorophenylamino)benzylcarbamoyl)cyclo-propyl)amide
[1256] Analogously to method (1d) the title compound was prepared
from 4-(aminomethyl)-N-(4-fluorophenyl)aniline (from 37a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1257] C.sub.22H.sub.20FN.sub.5O.sub.2 (405.43)
[1258] mass spectroscopy [M+H].sup.+=406
Example 38
pyrimidine-5-carboxylic
acid-N-(1-((5-(2-chlorophenylamino)-3-fluoropyridin-2-yl)methylcarbamoyl)-
cyclopropyl)amide
##STR00640##
[1259] 38a)
6-(aminomethyl)-N-(2-chlorophenyl)-5-fluoropyridin-3-amine
[1260] Analogously to method (1c) the title compound was prepared
starting from 2-chloro-aniline, 2-cyano-3,5-difluoropyridine and
Raney nickel.
[1261] C.sub.12H.sub.11FN.sub.3 (251.69)
[1262] R.sub.t=1.295 min. method 1
38b) pyrimidine-5-carboxylic
acid-N-(1-((5-(2-chlorophenylamino)-3-fluoropyridin-2-yl)-methylcarbamoyl-
)cyclopropyl)amide
[1263] Analogously to method (1d) the title compound was prepared
from 6-(aminomethyl)-N-(2-chlorophenyl)-5-fluoropyridin-3-amine
(from 38a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1264] C.sub.21H.sub.18FN.sub.6O.sub.2 (440.86)
[1265] R.sub.t=1.73 min. method 1
Example 39
pyrimidine-5-carboxylic
acid-N-(1-((5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoy-
l)cyclopropyl)amide
##STR00641##
[1266] 39a)
6-(aminomethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine
[1267] Analogously to method (1c) the title compound was prepared
starting from 2-(trifluoromethyl)aniline, 5-fluoro-picolinic acid
nitrile and Raney nickel.
[1268] C.sub.13H.sub.12F.sub.3N.sub.3 (267.25)
[1269] R.sub.t=1.29 min. method 1
39b) pyrimidine-5-carboxylic
acid-N-(1-((5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)-methylcarbamo-
yl)cyclopropyl)amide
[1270] Analogously to method (1d) the title compound was prepared
from 6-(aminomethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 39a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1271] C.sub.22H.sub.19F.sub.3N.sub.6O.sub.2 (456.42)
[1272] R.sub.t=1.39 min. method 1
Example 40
pyrimidine-5-carboxylic
acid-N-(1-(1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamo-
yl)cyclopropyl)amide
##STR00642##
[1273] 40a) 5-(2-(trifluoromethyl)phenylamino)picolinic acid
nitrile
[1274] 820 mg (6.72 mmol) 5-fluoropicolinic acid nitrile and 0.84
mL (6.72 mmol) 2-(trifluoromethyl)aniline in 10 mL DMSO were
combined with 1.51 g (13.43 mmol) potassium-tert-butoxide and
stirred for 2 hours at ambient temperature. The mixture was poured
onto an aqueous sodium chloride solution and extracted with
tert-butylmethylether. The organic phase was evaporated to dryness
in vacuo and the crude product thus obtained was purified by HPLC
(method 2).
[1275] Yield: 54% of theory
[1276] C.sub.13H.sub.8F.sub.3N.sub.3 (263.22)
40b) 1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-ylethanone
[1277] The reaction was carried out under protective gas
(nitrogen). 860 mg (3.27 mmol)
5-(2-(trifluoromethyl)phenylamino)picolinic acid nitrile in 5 mL
diethyl ether at -10.degree. C. were added dropwise to 9.34 mL
(13.07 mmol) of a 1.4 molar solution of methylmagnesium bromide in
toluene/THF (3:1) and the mixture was left for 15 minutes at this
temperature with stirring. The reaction mixture was combined with
saturated ammonium chloride solution, neutralised with 1 molar
aqueous hydrochloric acid at -5.degree. C. and extracted with
tert-butylmethylether. The organic phase was evaporated to dryness
in vacuo.
[1278] Yield: 96% of theory
[1279] C.sub.14H.sub.11F.sub.3N.sub.2O (280.25)
[1280] R.sub.t=1.97 min. method 1
40c)
(Z)-1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-ylethanone-oxime
[1281] 0.73 mL (12.42 mmol) of a 50% aqueous hydroxylamine solution
were added to 870 mg (3.1 mmol)
1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone in 5 mL
ethanol. The mixture was stirred for 2 hours at 100.degree. C. and
then the solvents were distilled off.
[1282] Yield: 98% of theory
[1283] C.sub.14H.sub.12F.sub.3N.sub.3O (295.26)
[1284] R.sub.t=1.75 min. method 1
40d)
6-(1-aminoethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine
[1285] 900 mg (3.05 mmol)
(Z)-1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-oxime
and 100 mg Raney nickel in 25 mL methanolic ammonia were
hydrogenated for 1.5 days at ambient temperature and 50 psi
hydrogen pressure. The reaction mixture was filtered, evaporated to
dryness and then further reacted directly.
[1286] Yield: 96% of theory
[1287] C.sub.14H.sub.14F.sub.3N.sub.3 (281.28)
[1288] R.sub.t=1.33 min. method 1
40e) pyrimidine-5-carboxylic
acid-N-(1-(1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamo-
yl)cyclopropyl)amide
[1289] Analogously to method (1d) the title compound was prepared
from 6-(1-aminoethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 40d) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1290] C.sub.23H.sub.21F.sub.3N.sub.6O.sub.2 (470.45)
[1291] R.sub.t=1.46 min. method 1
Example 41
pyrimidine-5-carboxylic
acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
##STR00643##
[1292] 41a)
6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
[1293] Analogously to method (1c) the title compound was prepared
starting from 2-trifluoromethyl-4-fluoro-aniline,
2-cyano-5-fluoropyridine and Raney nickel.
[1294] C.sub.13H.sub.11F.sub.4N.sub.3 (285.24)
[1295] R.sub.t=1.50 min. method 9
41b) pyrimidine-5-carboxylic
acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
[1296] Analogously to Example (1d) the title compound was prepared
from
6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 41a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1297] C.sub.22H.sub.18F.sub.4N.sub.6O.sub.2 (474.41)
[1298] R.sub.t=2.96 min. method 7
Example 42
pyrimidine-5-carboxylic
acid-N-(1-((5-(5-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
##STR00644##
[1299] 42a)
6-(aminomethyl)-N-(5-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
[1300] Analogously to method (1c) the title compound was prepared
starting from 2-fluoro-6-(trifluoromethyl)aniline,
2-cyano-5-fluoropyridine and Raney nickel.
[1301] C.sub.13H.sub.11F.sub.4N.sub.3 (281.24)
[1302] R.sub.t=1.95 min. method 8
42b) pyrimidine-5-carboxylic
acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
[1303] Analogously to method (1d) the title compound was prepared
starting from
6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amin-
e (from 41a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1304] C.sub.22H.sub.18F.sub.4N.sub.6O.sub.2 (474.41)
[1305] R.sub.t=3.10 min. method 7
Example 43
(S)-pyrimidine-5-carboxylic
acid-N-(3-((5-(4-fluoro-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)meth-
ylcarbamoyl)tetrahydrofuran-3-yl)amide
##STR00645##
[1306] 43a) (S)-phenethyl-3-aminotetrahydrofuran-3-carboxylate
[1307] 19.37 g (50 mmol)
(S)-phenethyl-3-aminotetrahydrofuran-3-carboxylate
(S)-2-hydroxy-2-phenylacetate were suspended in 75 mL THF and 75 mL
water, combined with 6.3 g (75 mmol) sodium hydrogen carbonate and
stirred for 3 hours at ambient temperature. The mixture was
extracted twice with dichloromethane. The organic phases were
washed with 14% sodium chloride solution, dried on sodium sulphate
and evaporated to dryness in vacuo. The crude product thus obtained
was further reacted directly.
[1308] Yield: 85% of theory
[1309] C.sub.13H.sub.17NO.sub.3 (235.28)
[1310] R.sub.t=1.19 min. method 1
43b)
(S)-phenethyl-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxyla-
te
[1311] 4.43 mL (40.3 mmol) N-methylmorpholine and 5.69 g (17.7
mmol) TBTU were added to a solution of 2 g (16.1 mmol)
pyrimidine-5-carboxylic acid in 50 mL DMF. The mixture was left for
30 minutes at ambient temperature with stirring and then combined
with 3.8 g (16.16 mmol)
(S)-phenethyl-3-aminotetrahydrofuran-3-carboxylate. The mixture was
stirred overnight at ambient temperature and then evaporated to
dryness. The crude product thus obtained was purified by HPLC
(method 2).
[1312] Yield: 93% of theory
[1313] C.sub.18H.sub.19N.sub.3O.sub.4 (341.36)
[1314] R.sub.t=1.60 min. method 1
43c) (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic
acid
[1315] 60.24 mL (60.24 mmol) of a 1 molar sodium hydroxide solution
were added to a solution of 5.14 g (15.1 mmol) (S)-phenethyl
3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylate in 97 mL
ethanol. The mixture was stirred for 1 hour at ambient temperature
and then acidified with 4 molar hydrochloric acid. The purification
was carried out by HPLC (method 2).
[1316] Yield: 93% of theory
[1317] C.sub.10H.sub.11N.sub.3O.sub.4 (237.21)
[1318] R.sub.t=0.87 min. method 1
43d) pyrimidine-5-carboxylic
acid-(S)--N-(3-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)-pyridin-2-yl-
)methylcarbamoyl)tetrahydrofuran-3-0amide
[1319] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 41a) and
(S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid
(from 43c).
[1320] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3 (504.44)
[1321] R.sub.t=2.86 min. method 7
Example 44
pyrimidine-5-carboxylic
acid-N-(1-((5-(2-fluoro-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
##STR00646##
[1322] 44a)
6-(aminomethyl)-N-(2-fluoro-6-(trifluoromethyl)phenyl)pyridin-3-amine
[1323] Analogously to method (1c) the title compound was prepared
starting from 2-trifluoromethyl-5-fluoro-aniline,
2-cyano-5-fluoropyridine and Raney nickel.
[1324] C.sub.13H.sub.11F.sub.4N.sub.3 (285.24)
[1325] R.sub.t=1.95 min. method 8
44b) pyrimidine-5-carboxylic
acid-N-(1-((5-(2-fluoro-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
[1326] Analogously to method (1d) the title compound was prepared
starting from
6-(aminomethyl)-N-(2-fluoro-6-(trifluoromethyl)phenyl)pyridin-3-amin-
e (from 44a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1327] C.sub.22H.sub.18F.sub.4N.sub.6O.sub.2 (474.41)
[1328] R.sub.t=2.71 min. method 7
Example 45
pyrimidine-5-carboxylic
acid-N-(1-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)eth-
ylcarbamoyl)cyclopropyl)amide
##STR00647##
[1329] 45a) 5-(4-fluoro-2-(trifluoromethyl)phenylamino)picolinic
acid nitrile
[1330] Analogously to method (40a) the title compound was prepared
starting from 5-fluoro-picolinic acid nitrile,
4-fluoro-2-(trifluoromethyl)aniline and potassium-tert-butoxide in
DMSO.
[1331] C.sub.13H.sub.8F.sub.3N.sub.3 (281.21)
[1332] R.sub.t=1.40 min. method 4
45b)
1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-ylethanone
[1333] Analogously to method (40b) the title compound was prepared
from methylmagnesium bromide and
5-(4-fluoro-2-(trifluoromethyl)phenylamino)picolinic acid
nitrile.
[1334] C.sub.14H.sub.11F.sub.4N.sub.2O (298.24)
[1335] R.sub.t=1.43 min. method 4
45c)
(E)-1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-ylethanon-
e-oxime
[1336] Analogously to method (40c) the title compound was prepared
starting from
1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone and a
50% aqueous hydroxylamine solution.
[1337] C.sub.14H.sub.11F.sub.4N.sub.3O (313.25)
[1338] R.sub.t=1.31 min. method 4
45d)
6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amin-
e
[1339] Analogously to method (40d) the title compound was prepared
starting from
(E)-1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-o-
xime and Raney nickel.
[1340] C.sub.14H.sub.14F.sub.4N.sub.3 (299.27)
[1341] R.sub.t=1.65 min. method 9
45e) pyrimidine-5-carboxylic
acid-N-(1-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)eth-
ylcarbamoyl)cyclopropyl)amide
[1342] Analogously to method (1d)
6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 45d) and
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid (from
1b) were reacted to form the title compound.
[1343] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.2 (488.44)
[1344] R.sub.t=3.01 min. method 7
Example 46
(S)-pyrimidine-5-carboxylic
acid-N-(3-((5-(2-fluoro-6-(trifluoromethyl)phenyl-amino)pyridin-2-yl)meth-
ylcarbamoyl)tetrahydrofuran-3-yl)amide
##STR00648##
[1346] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 41a) and
(S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid
(from 43c).
[1347] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3 (504.44)
[1348] R.sub.t=2.74 min. method 7
Example 47
(S)-pyrimidine-5-carboxylic
acid-N-(-3-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)et-
hylcarbamoyl)tetrahydrofuran-3-yl)amide
##STR00649##
[1350] Analogously to method (1d) the title compound was prepared
from
6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 45d) and
(S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid
(from 43c).
[1351] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.3 (518.46)
[1352] R.sub.t=3.00 min. method 7
Example 48
(S)-pyrimidine-5-carboxylic
acid-N-(3-((5-(5-fluoro-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)meth-
ylcarbamoyl)tetrahydrofuran-3-yl)amide
##STR00650##
[1354] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(5-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 42a) and
(S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid
(from 43c).
[1355] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3 (504.44)
[1356] R.sub.t=3.15 min. method 7
Example 49
pyrimidine-5-carboxylic
acid-N-(1-((5-(2-methyl-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
##STR00651##
[1357] 49a)
6-(aminomethyl)-N-(2-methyl-6-(trifluoromethyl)phenyl)pyridin-3-amine
[1358] Analogously to method (1c) the title compound was prepared
from 2-methyl-6-(trifluoromethyl)-aniline and
2-cyano-5-fluoropyridine with Raney nickel as catalyst.
[1359] C.sub.14H.sub.14F.sub.3N.sub.3 (281.28)
[1360] R.sub.t=1.52 min. method 2
49b) pyrimidine-5-carboxylic
acid-N-(1-((5-(2-methyl-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
[1361] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(2-methyl-6-(trifluoromethyl)phenyl)pyridin-3-amine
(from 49a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1362] C.sub.22H.sub.18F.sub.4N.sub.6O.sub.2 (470.45)
[1363] R.sub.t=1.57 min. method 2
Example 50
pyrimidine-5-carboxylic
acid-N-(1-((5-(4-methoxy-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)met-
hylcarbamoyl)cyclopropyl)amide
##STR00652##
[1364] 50a)
6-(aminomethyl)-N-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-amine
[1365] Analogously to method (1c) the title compound was prepared
starting from 2-amino-5-methoxybenzotrifluoride and
2-cyano-5-fluoropyridine with Raney nickel as catalyst.
[1366] C.sub.14H.sub.14F.sub.3N.sub.3O (297.28)
[1367] R.sub.t=0.21 ethyl acetate/methanol/ammonia=9:1:0.1
50b) pyrimidine-5-carboxylic
acid-N-(1-((5-(4-methoxy-2-(trifluoromethyl)phenylamino)-pyridin-2-yl)met-
hylcarbamoyl)cyclopropyl)amide
[1368] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 50a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1369] C.sub.23H.sub.21F.sub.3N.sub.6O.sub.3 (486.45)
[1370] R.sub.t=2.82 min. method 7
Example 51
pyrimidine-5-carboxylic
acid-N-(1-((5-(4-methyl-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)meth-
ylcarbamoyl)cyclopropyl)amide
##STR00653##
[1371] 51a)
6-(aminomethyl)-N-(4-methyl-2-(trifluoromethyl)phenyl)pyridin-3-amine
[1372] Analogously to method (1c) the title compound was prepared
from 2-amino-5-methylbenzotrifluoride and 2-cyano-5-fluoropyridine
using Raney nickel.
[1373] C.sub.14H.sub.14F.sub.3N.sub.3 (281.28)
[1374] R.sub.t=1.63 min. method 2
51b) pyrimidine-5-carboxylic
acid-N-(1-((5-(4-methyl-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
[1375] 0.1 mL (0.56 mmol) DIPEA and 87 mg (0.27 mmol)
O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium
tetrafluoroborate, dissolved in 0.5 mL DMF, were added to a
solution of 50 mg (0.24 mmol)
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b) in 2 mL THF. The mixture was left for 15 minutes at ambient
temperature with stirring and then 82 mg (0.29 mmol) of
6-(aminomethyl)-N-(4-methyl-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 51a) in 0.5 mL DMF were added. The mixture was stirred
overnight at ambient temperature and then purified by HPLC
(Microsorb C18; 41.4.times.250 mm with
acetonitrile/water/trifluoroacetic
acid=10/90/0.1=>100/0/0.1).
[1376] Yield: 33% of theory
[1377] C.sub.23H.sub.21F.sub.3N.sub.6O.sub.2 (470.45)
[1378] R.sub.t=1.63 min. method 2
Example 52
pyrimidine-5-carboxylic
acid-N-(1-((5-(2,4-bis(trifluoromethyl)phenylamino)-pyridin-2-yl)methylca-
rbamoyl)cyclopropyl)amide
##STR00654##
[1379] 52a)
6-(aminomethyl)-N-(2,4-bis(trifluoromethyl)phenyl)pyridin-3-amine
[1380] Analogously to method (1c) the title compound was prepared
from 2,4-bis(trifluoromethyl)aniline and 2-cyano-5-fluoropyridine
using Raney nickel.
[1381] C.sub.14H.sub.11F.sub.6N.sub.3 (335.25)
52b) pyrimidine-5-carboxylic
acid-N-(1-((5-(2,4-bis(trifluoromethyl)phenylamino)pyridin-2-yl)methylcar-
bamoyl)cyclopropyl)amide
[1382] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(2,4-bis(trifluoromethyl)phenyl)pyridin-3-amine
(from 52a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1383] C.sub.23H.sub.18F.sub.6N.sub.6O.sub.2 (524.42)
[1384] R.sub.t=3.63 min. method 10
Example 53
pyrimidine-5-carboxylic
acid-N-(1-((5-(4-bromo-2-methylphenylamino)pyridin-2-yl)methylcarbamoyl)c-
yclopropyl)amide
##STR00655##
[1385] 53a)
5-(4-bromo-2-(trifluoromethyl)phenylamino)picolinonitrile
[1386] Analogously to method (40a) the title compound was prepared
starting from 2-cyano-5-fluoropyridine,
2-amino-5-bromo-benzotrifluoride and potassium-tert-butoxide with
DMSO as solvent.
[1387] C.sub.13H.sub.7BrF.sub.3N.sub.3 (342.11)
[1388] R.sub.t=2.50 min. method 2
53b-1) 6-(aminomethyl)-N-(4-bromo-2-methylphenyl)pyridin-3-amine
2,2,2-trifluoroacetate
[1389] 1.65 mL (3.3 mmol) 2 molar lithium aluminium hydride
solution in THF were added to a solution of 564 mg (1.65 mmol)
5-(4-bromo-2-(trifluoromethyl)phenylamino)picolinic acid nitrile in
5 mL THF. The reaction mixture was stirred for 30 minutes at
ambient temperature and then mixed with water. The salts were
suction filtered and the filtrate was evaporated down in vacuo. The
residue was purified by HPLC (with solvent gradient, acetonitrile
and water with 0.1% trifluoroacetic acid). 2 products are
formed.
[1390] Yield: 65% of theory
[1391] C.sub.13H.sub.14BrN.sub.3*C.sub.2HF.sub.3O.sub.2 (406.2)
[1392] R.sub.t=1.63 min. method 2
53b-2)
6-(aminomethyl)-N-(4-bromo-2-(trifluoromethyl)phenyl)pyridin-3-amin-
e
[1393] Yield: 11% of theory
[1394] C.sub.13H.sub.11Br.sub.FF.sub.3N.sub.3 (346.15)
[1395] R.sub.t=1.72 min. method 2
53c) pyrimidine-5-carboxylic
acid-N-(1-((5-(4-bromo-2-methylphenylamino)pyridin-2-yl)-methylcarbamoyl)-
cyclopropyl)amide
[1396] Analogously to method (1d) the title compound was prepared
starting from
6-(aminomethyl)-N-(4-bromo-2-methylphenyl)pyridin-3-amine
2,2,2-trifluoroacetate (from 53b-1) and
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid (from
1b).
[1397] C.sub.22H.sub.21BrN.sub.6O.sub.2 (481.35)
[1398] R.sub.t=1.61 min. method 2
Example 54
pyrimidine-5-carboxylic
acid-N-(1-((5-(4-bromo-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methyl-
carbamoyl)cyclopropyl)amide
##STR00656##
[1400] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(4-bromo-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 53b-2) and
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid (from
1b).
[1401] C.sub.22H.sub.18BrF.sub.3N.sub.6O.sub.2 (535.32)
[1402] R.sub.t=1.82 min. method 2
Example 55
pyrimidine-5-carboxylic
acid-N-(1-((5-(4-chloro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
##STR00657##
[1403] 55a)
5-(4-chloro-2-(trifluoromethyl)phenylamino)picolinonitrile
[1404] The reaction took place under protective gas (nitrogen). 21
mg (0.04 mmol) Xantphos and 10 mg (0.01 mmol)
tris(dibenzylideneacetone)dipalladium were added to a solution of
100 mg (0.55 mmol) 5-bromo-2-cyanopyridine, 93 .mu.L (0.66 mmol)
2-amino-5-chlorobenzotrifluoride and 167 mg (0.77 mmol) potassium
phosphate in 5 mL toluene. The mixture was stirred overnight at
110.degree. C., the salts were filtered off and the filtrate was
evaporated to dryness in vacuo. The residue was purified by HPLC
(with eluant gradient, acetonitrile and water with 0.1%
trifluoroacetic acid).
[1405] Yield: 68% of theory
[1406] C.sub.13H.sub.7ClF.sub.3N.sub.3 (297.66)
[1407] R.sub.t=2.53 min. method 2
55b)
6-(aminomethyl)-N-(4-chloro-2-(trifluoromethyl)phenyl)pyridin-3-amine
[1408] Analogously to method (53b) the title compound was prepared
starting from 5-(4-chloro-2-(trifluoromethyl)phenylamino)picolinic
acid nitrile and 2 molar lithium aluminium hydride solution.
[1409] C.sub.13H.sub.11ClF.sub.3N.sub.3 (301.69)
[1410] R.sub.t=1.72 min. method 2
55c) pyrimidine-5-carboxylic
acid-N-(1-((5-(4-chloro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methy-
lcarbamoyl)cyclopropyl)amide
[1411] Analogously to method (1d) the title compound was prepared
from
6-(aminomethyl)-N-(4-chloro-2-(trifluoromethyl)phenyl)pyridin-3-amine
(from 55b) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from
1b).
[1412] C.sub.22H.sub.18ClF.sub.3N.sub.6O.sub.2 (490.87)
[1413] R.sub.t=1.76 min. method 2
Example 56
5-oxo-N--((S)-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrah-
ydrofuran-3-yl)pyrrolidine-2-carboxamide
##STR00658##
[1414] 56a)
(S)-phenethyl-3-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylate
[1415] 2 g (9.18 mmol) di-tert-butyldicarbonate and 11.29 mL (9.18
mmol) TEA were added to a solution of 1.8 g (7.65 mmol)
(S)-phenethyl 3-aminotetrahydrofuran-3-carboxylate (from 43a) in 30
mL dichloromethane. The mixture was stirred overnight at ambient
temperature and then more di-tert-butyldicarbonate and 50 mg
dimethylaminopyridine were added. The reaction mixture was
evaporated to dryness in vacuo and the residue was taken up in 50
mL dioxane and stirred for 6 hours at 60.degree. C. The solvent was
distilled off and the residue was divided between ethyl acetate and
0.5 molar potassium hydrogen sulphate solution. The organic phase
was washed with sodium hydrogen sulphate solution, dried on sodium
sulphate and evaporated to dryness in vacuo. The residue was
purified on silica gel with petroleum ether/ethyl acetate in the
ratio 4:1.
[1416] Yield: 63% of theory
[1417] C.sub.18H.sub.25NO.sub.5 (335.39)
[1418] R.sub.t=2.05 min. method 1
56b) (S)-3-tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic
acid
[1419] 8.94 mL (17.89 mmol) 2 molar sodium hydroxide solution were
added to a solution of 1.5 g (4.47 mmol)
(S)-phenethyl-3-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylate
in 20 mL ethanol. The mixture was stirred for 2 hours at ambient
temperature and then 8.94 mL (17.89 mmol) 2 molar hydrochloric acid
were added thereto. The mixture was evaporated down, the residue
was suspended in ethanol and the salts were suction filtered. The
filtrate was freed from the solvent and further reacted in crude
form.
[1420] Yield: 100% of theory
[1421] C.sub.10H.sub.17NO.sub.5 (231.25)
[1422] R.sub.t=1.53 min. method 1
56c)
(S)-tert-butyl-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)--
tetrahydrofuran-3-ylcarbamate
[1423] Analogously to method (1d) the title compound was prepared
from N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline (from 4a)
and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid
(from 56b).
[1424] C.sub.24H.sub.28F.sub.3N.sub.3O.sub.4 (479.49)
56d)
(S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofur-
an-3-carboxamide
[1425] 2 g (4.17 mmol)
(S)-tert-butyl-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetr-
ahydrofuran-3-ylcarbamate were stirred in 15 mL of a 1:1 mixture of
dichloromethane and trifluoroacetic acid for 30 minutes at ambient
temperature. After evaporation of the reaction mixture the residue
was dissolved in dichloromethane, made basic with 4 molar sodium
hydroxide solution and added to a phase separation cartridge. The
filtrate was freed from the solvent and the crude product was
chromatographed on silica gel with cyclohexane/ethyl acetate in the
ratio 1:1 and then a second time with dichloromethane/methanol in
the ratio 9:1.
[1426] Yield: 77% of theory
[1427] C.sub.19H.sub.20F.sub.3N.sub.3O.sub.2 (379.38)
[1428] R.sub.t=1.97 min. method 6
56e)
(S)-5-oxo-N-(-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)te-
trahydro-furan-3-yl)pyrrolidine-2-carboxamide
[1429] Analogously to method (1d) the title compound was prepared
starting from
(S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofu-
ran-3-carboxamide (from 56d) and 5-oxopyrrolidine-2-carboxylic
acid.
[1430] C.sub.24H.sub.25F.sub.3N.sub.4O.sub.4 (490.49)
[1431] R.sub.t=1.84 min. method 5
[1432] Examples 57 to 107 that follow were prepared analogously to
the method (1d) from
(S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofuran-3-
-carboxamide and the corresponding acids.
Example 57
(S)-6-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetra-
hydro-furan-3-yl}-nicotinamide
##STR00659##
[1434] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.5)
[1435] R.sub.t=1.66 min. method 5
Example 58
(S)-6-methyl-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydro-furan-3-yl}-nicotinamide
##STR00660##
[1437] C.sub.26H.sub.25F.sub.3N.sub.4O.sub.3 (498.5)
[1438] R.sub.t=1.69 min. method 5
Example 59
3-(2-pyridin-2-yl-acetylamino)-tetrahydro-furan-3-carboxylic acid
4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00661##
[1440] C.sub.26H.sub.25F.sub.3N.sub.4O.sub.3 (498.5)
[1441] R.sub.t=1.64 min. method 5
Example 60
(S)-3-[(tetrahydro-furan-3-carbonyl)-amino]-tetrahydro-furan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00662##
[1443] C.sub.24H.sub.26F.sub.3N.sub.3O.sub.4 (477.5)
[1444] R.sub.t=1.96 min. method 5
Example 61
(S)-2-chloro-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydro-furan-3-yl}-isonicotinamide
##STR00663##
[1446] C.sub.25H.sub.22ClF.sub.3N.sub.4O.sub.3 (518.9)
[1447] R.sub.t=2.15 min. method 5
Example 62
(S)-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-
-yl}-amide
##STR00664##
[1449] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.4 (501.5)
[1450] R.sub.t=1.91 min. method 5
Example 63
(S)-2-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetra-
hydro-furan-3-yl}-isonicotinamide
##STR00665##
[1452] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.5)
[1453] R.sub.t=1.64 min. method 5
Example 64
(S)-pyridazine-4-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-
-yl}-amide
##STR00666##
[1455] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.3 (485.5)
[1456] R.sub.t=1.92 min. method 5
Example 65
(S)-tetrahydropyran-4-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3--
yl}-amide
##STR00667##
[1458] C.sub.25H.sub.28F.sub.3N.sub.3O.sub.4 (491.5)
[1459] R.sub.t=1.97 min. method 5
Example 66
(S)-3-(2-cyano-2-hydroxyimino-acetylamino)-tetrahydro-furan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00668##
[1461] C.sub.22H.sub.20F.sub.3N.sub.5O.sub.4 (475.4)
[1462] R.sub.t=2.07 min. method 5
Example 67
(S)-6-chloro-pyridine-2-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-fu-
ran-3-yl}-amide
##STR00669##
[1464] C.sub.25H.sub.22ClF.sub.3N.sub.4O.sub.3 (518.9)
[1465] R.sub.t=2.25 min. method 5
Example 68
(S)-5-methoxy-furan-2-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00670##
[1467] C.sub.25H.sub.24F.sub.3N.sub.3O.sub.5 (503.5)
[1468] R.sub.t=2.12 min. method 5
Example 69
(S)-3-[(3-oxo-cyclohexanecarbonyl)-amino]-tetrahydro-furan-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00671##
[1470] C.sub.26H.sub.28F.sub.3N.sub.3O.sub.4 (503.5)
[1471] R.sub.t=2.00 min. method 5
Example 70
(S)-6-hydroxy-pyridine-2-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00672##
[1473] C.sub.25H.sub.23F.sub.3N.sub.4O.sub.4 (500.5)
[1474] R.sub.t=1.94 min. method 5
Example 71
(S)-1-methyl-5-oxo-pyrrolidine-3-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3--
yl}-amide
##STR00673##
[1476] C.sub.25H.sub.27F.sub.3N.sub.4O.sub.4 (504.5)
[1477] R.sub.t=1.85 min. method 5
Example 72
(S)-6-amino-pyridine-2-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3--
yl}-amide
##STR00674##
[1479] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.5)
[1480] R.sub.t=1.72 min. method 5
Example 73
(S)-5-hydroxy-1H-pyrazole-3-carboxylic acid
{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofuran-3-
-yl}-amide
##STR00675##
[1482] C.sub.23H.sub.22F.sub.3N.sub.5O.sub.4 (489.5)
[1483] R.sub.t=1.89 min. method 5
Example 74
(S)-pyridazine-3-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3--
yl}-amide
##STR00676##
[1485] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.3 (485.5)
[1486] R.sub.t=2.02 min. method 5
Example 75
(S)-3-[(3-methoxy-cyclobutanecarbonyl)-amino]-tetrahydro-furan-3-carboxyli-
c acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00677##
[1488] C.sub.25H.sub.28F.sub.3N.sub.3O.sub.4 (491.5)
[1489] R.sub.t=2.02 min. method 5
Example 76
(S)-6-oxo-piperidine-3-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00678##
[1491] C.sub.25H.sub.27F.sub.3N.sub.4O.sub.4 (504.5)
[1492] R.sub.t=1.81 min. method 5
Example 77
(S)-4-methyl-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00679##
[1494] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.5)
[1495] R.sub.t=1.96 min. method 5
Example 78
(S)-3-[(3-oxo-cyclopentanecarbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00680##
[1497] C.sub.25H.sub.26F.sub.3N.sub.3O.sub.4 (489.5)
[1498] R.sub.t=1.97 min. method 5
Example 79
(S)-2-methoxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-isonicotinamide
##STR00681##
[1500] C.sub.26H.sub.25F.sub.3N.sub.4O.sub.4 (514.5)
[1501] R.sub.t=2.11 min. method 5
Example 80
(S)-2,4-dimethyl-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00682##
[1503] C.sub.26H.sub.26F.sub.3N.sub.5O.sub.3 (513.5)
[1504] R.sub.t=1.95 min. method 5
Example 81
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofu-
ran-3-yl}-amide
##STR00683##
[1506] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.4 (515.5)
[1507] R.sub.t=2.04 min. method 5
Example 82
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00684##
[1509] C.sub.25H.sub.25F.sub.3N.sub.6O.sub.3 (514.5)
[1510] R.sub.t=1.91 min. method 5
Example 83
(S)-2-methyl-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00685##
[1512] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.5)
[1513] R.sub.t=1.97 min. method 5
Example 84
(S)-1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00686##
[1515] C.sub.26H.sub.25F.sub.3N.sub.4O.sub.4 (514.5)
[1516] R.sub.t=1.90 min. method 5
Example 85
(S)-oxazole-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofu-
ran-3-yl}-amide
##STR00687##
[1518] C.sub.23H.sub.21F.sub.3N.sub.4O.sub.4 (474.4)
[1519] R.sub.t=1.97 min. method 5
Example 86
(S)-2-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-isonicotinamide
##STR00688##
[1521] C.sub.25H.sub.23F.sub.3N.sub.4O.sub.4 (500.5)
[1522] R.sub.t=1.85 min. method 5
Example 87
(S)-5-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-nicotinamide
##STR00689##
[1524] C.sub.25H.sub.23F.sub.3N.sub.4O.sub.4 (500.5)
[1525] R.sub.t=1.72 min. method 5
Example 88
(S)-1-methyl-1H-[1.2.3]triazole-4-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3--
yl}-amide
##STR00690##
[1527] C.sub.23H.sub.23F.sub.3N.sub.6O.sub.3 (488.5)
[1528] R.sub.t=1.99 min. method 5
Example 89
(S)-thiazole-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydro-f-
uran-3-yl}-amide
##STR00691##
[1530] C.sub.23H.sub.21F.sub.3N.sub.4O.sub.3S (490.5)
[1531] R.sub.t=2.01 min. method 5
Example 90
(S)-2-hydroxy-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofu-
ran-3-yl}-amide
##STR00692##
[1533] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.4 (501.5)
[1534] R.sub.t=1.79 min. method 5
Example 91
(S)-3-(3,3,3-trifluoro-2-methyl-propionylamino)-tetrahydrofuran-3-carboxyl-
ic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00693##
[1536] C.sub.23H.sub.23F.sub.6N.sub.3O.sub.3 (503.4)
[1537] R.sub.t=2.18 min. method 5
Example 92
(S)-5-methoxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-nicotinamide
##STR00694##
[1539] C.sub.26H.sub.25F.sub.3N.sub.4O.sub.4 (514.5)
[1540] R.sub.t=1.85 min. method 5
Example 93
(S)-furan-3-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-
-yl}-amide
##STR00695##
[1542] C.sub.24H.sub.22F.sub.3N.sub.3O.sub.4 (473.4)
[1543] R.sub.t=2.09 min. method 5
Example 94
(S)-furan-2-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-
-yl}-amide
##STR00696##
[1545] C.sub.24H.sub.22F.sub.3N.sub.3O.sub.4 (473.4)
[1546] R.sub.t=2.08 min. method 5
Example 95
(S)--N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-f-
uran-3-yl}-isonicotinamide
##STR00697##
[1548] C.sub.25H.sub.23F.sub.3N.sub.4O.sub.3 (484.5)
[1549] R.sub.t=1.71 min. method 5
Example 96
(S)-pyrazine-2-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00698##
[1551] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.3 (485.5)
[1552] R.sub.t=2.06 min. method 5
Example 97
(S)-3-(3-hydroxy-benzoylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00699##
[1554] C.sub.26H.sub.24F.sub.3N.sub.3O.sub.4 (499.5)
[1555] R.sub.t=2.03 min. method 5
Example 98
(S)-6-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-nicotinamide
##STR00700##
[1557] C.sub.25H.sub.23F.sub.3N.sub.4O.sub.4 (500.5)
[1558] R.sub.t=1.84 min. method 5
Example 99
(S)-3-(4-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00701##
[1560] C.sub.27H.sub.26F.sub.3N.sub.3O.sub.4 (513.5)
[1561] R.sub.t=2.16 min. method 5
Example 100
(S)-3-(3-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00702##
[1563] C.sub.27H.sub.26F.sub.3N.sub.3O.sub.4 (513.5)
[1564] R.sub.t=2.18 min. method 5
Example 101
(S)-3-(2-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00703##
[1566] C.sub.27H.sub.26F.sub.3N.sub.3O.sub.4 (513.5)
[1567] R.sub.t=2.22 min. method 5
Example 102
(S)-3-(3,5-dihydroxy-benzoylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00704##
[1569] C.sub.26H.sub.24F.sub.3N.sub.3O.sub.5 (515.5)
[1570] R.sub.t=1.93 min. method 5
Example 103
(S)-3-(3,5-dimethoxy-benzoylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
##STR00705##
[1572] C.sub.28H.sub.28F.sub.3N.sub.3O.sub.5 (543.5)
[1573] R.sub.t=2.20 min. method 5
Example 104
(S)-3-(2-pyridin-3-yl-acetylamino)-tetrahydrofuran-3-carboxylic
acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
##STR00706##
[1575] C.sub.26H.sub.25F.sub.3N.sub.4O.sub.3 (498.5)
[1576] R.sub.t=1.64 min. method 5
Example 105
(S)-5-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetra-
hydrofuran-3-yl}-nicotinamide
##STR00707##
[1578] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.5)
[1579] R.sub.t=1.65 min. method 5
Example 106
(S)-1H-pyrazole-3-carboxylic acid
{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3--
yl}-amide
##STR00708##
[1581] C.sub.23H.sub.22F.sub.3N.sub.5O.sub.3 (473.5)
[1582] R.sub.t=1.96 min. method 5
Example 107
(S)-6-fluoro-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-nicotinamide
##STR00709##
[1584] C.sub.25H.sub.22F.sub.4N.sub.4O.sub.3 (502.5)
[1585] R.sub.t=2.10 min. method 5
Example 108
1-(3-ethylureido)-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropane-
carboxamide
##STR00710##
[1587] A solution of 55 mg (0.16 mmol)
1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)-cyclopropanecarboxam-
ide (from 5a) in 2 mL dichloromethane was combined with 68 .mu.L
(0.49 mmol) TEA and 16 .mu.L (0.2 mmol) ethylisocyanate and stirred
overnight at ambient temperature. Then ethylisocyanate was added
another three times and the mixture was stirred at ambient
temperature or at 60.degree. C. Then the reaction mixture was
evaporated to dryness in vacuo and purified by RP-HPLC-MS with an
eluant gradient (water/acetonitrile=1:1 to 1:20+0.1%
trifluoroacetic acid).
[1588] Yield: 79% of theory
[1589] C.sub.21H.sub.23F.sub.3N.sub.4O.sub.2 (420.43)
[1590] R.sub.t=2.27 min. method 5
Example 109
pyrimidine-5-carboxylic
acid-N-(1-(4-(methyl(phenyl)amino)benzylcarbamoyl)cyclopropyl)amide
##STR00711##
[1591] 109a) 4-(aminomethyl)-N-methyl-N-phenylaniline
[1592] Analogously to method (1c) the title compound was prepared
from N-methylaniline and 4-fluorobenzonitrile.
[1593] C.sub.14H.sub.16N.sub.2 (212.3)
109b) pyrimidine-5-carboxylic
acid-N-(1-(4-(methyl(phenyl)amino)benzylcarbamoyl)-cyclopropyl)amide
[1594] Analogously to method (1d) the title compound was prepared
starting from 4-(aminomethyl)-N-methyl-N-phenylaniline (from 109a)
and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid
(from 1b).
[1595] C.sub.23H.sub.23N.sub.5O.sub.2 (401.47)
[1596] R.sub.t=2.87 min. method 5
Example 110
pyrimidine-5-carboxylic
acid-N-(1-(4-((2-chlorophenyl)(methyl)amino)-benzylcarbamoyl)cyclopropyl)-
amide
##STR00712##
[1597] 110a) N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline
[1598] Analogously to Example (1c) the title compound was prepared
starting from 2-chloro-N-methylaniline and
4-fluorobenzonitrile.
[1599] C.sub.14H.sub.15ClN.sub.2 (246.74)
110b) pyrimidine-5-carboxylic
acid-N-(1-(4-((2-chlorophenyl)(methyl)amino)benzylcarbamoyl)cyclopropyl)a-
mide
[1600] Analogously to Example (1d) the title compound was prepared
starting from N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline
(from 110a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid
(from 1b).
[1601] C.sub.23H.sub.22ClN.sub.5O.sub.2 (435.91)
[1602] R.sub.t=2.23 min. method 11
Example 111
pyrimidine-5-carboxylic
acid-N-(1-(4-(ethyl(phenyl)amino)benzylcarbamoyl)cyclopropyl)amide
##STR00713##
[1603] 111a) 4-(aminomethyl)-N-ethyl-N-phenylaniline
[1604] Analogously to method (1c) the title compound was prepared
starting from N-ethylaniline and 4-fluorobenzonitrile.
[1605] C.sub.15H.sub.18N.sub.2 (226.32)
111b) pyrimidine-5-carboxylic
acid-N-(1-(4-(ethyl(phenyl)amino)benzylcarbamoyl)-cyclopropyl)amide
[1606] Analogously to method (1d) the title compound was prepared
from 4-(aminomethyl)-N-ethyl-N-phenylaniline (from 111a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid
(from 1b).
[1607] C.sub.24H.sub.25N.sub.5O.sub.2 (415.49)
[1608] R.sub.t=2.26 min. method 11
Example 112
pyrimidine-5-carboxylic
acid-N-(1-(4-((4-methoxyphenyl)(methyl)amino)benzylcarbamoyl)cyclopropyl)-
amide
##STR00714##
[1609] 111a)
4-(aminomethyl)-N-(4-methoxyphenyl)-N-methylaniline
[1610] Analogously to method (1c) the title compound was prepared
starting from 4-methoxy-N-methylaniline and 4-fluorobenzonitrile
using Raney nickel.
[1611] C.sub.15H.sub.18N.sub.2O (242.32)
112b) pyrimidine-5-carboxylic
acid-N-(1-(4-((4-methoxyphenyl)(methyl)amino)benzyl-carbamoyl)cyclopropyl-
)amide
[1612] Analogously to method (1d) the title compound was prepared
starting from 4-(aminomethyl)-N-(4-methoxyphenyl)-N-methylaniline
(from 112a) and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid
(from 1b).
[1613] C.sub.24H.sub.25N.sub.5O.sub.3 (431.49)
[1614] R.sub.t=2.13 min. method 11
Example 113
pyrimidine-5-carboxylic
acid-N-(1-(4-(methyl(o-tolyl)amino)benzylcarbamoyl)cyclopropyl)amide
##STR00715##
[1615] 113a) N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline
[1616] Analogously to method (1c) N-methyl-o-toluidine and
4-fluorobenzonitrile were reacted using Raney nickel to obtain the
title compound.
[1617] C.sub.15H.sub.18N.sub.2 (226.32)
113b) pyrimidine-5-carboxylic
acid-N-(1-(4-(methyl(o-tolyl)amino)benzylcarbamoyl)-cyclopropyl)amide
[1618] Analogously to method (1d) the title compound was prepared
from N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline (from 113a)
and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid
(from 1b).
[1619] C.sub.24H.sub.25N.sub.5O.sub.2 (415.49)
[1620] R.sub.t=2.26 min. method 11
Example 114
pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-5-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}--
amide
##STR00716##
[1621] 114a) tert-butyl
[4-(2-cyano-5-fluoro-phenylamino)-benzyl]-carbamate
[1622] Prepared analogously to the method in (55a) from
2-bromo-4-fluoro-benzonitrile and tea-butyl
(4-amino-benzyl)-carbamate.
[1623] Yield: 60% of theory
[1624] C.sub.19H.sub.20FN.sub.3O.sub.2 (341.38)
[1625] R.sub.t=2.65 min. method 12
114b) 2-(4-aminomethyl-phenylamino)-4-fluoro-benzonitrile
di-trifluoroacetate
[1626] 92 mg (0.27 mmol) tert-butyl
[4-(2-cyano-5-fluoro-phenylamino)-benzyl]-carbamate were stirred in
1 mL trifluoroacetic acid and 5 mL dichloromethane for 1 hour at
ambient temperature. Then the reaction mixture was evaporated to
dryness in vacuo.
[1627] Yield: 96% of theory
[1628] C.sub.14H.sub.12FN.sub.3*2C.sub.2HF.sub.3O.sub.2
(469.31)
[1629] R.sub.t=1.41 min. method 12
114c) pyrimidine-5-carboxylic acid
{1-[4-(2-cyano-5-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
[1630] 83 mg (0.21 mmol) TBTU, 146 .mu.L (1.0 mmol) triethylamine
and 122 mg (0.21 mmol)
2-(4-aminomethyl-phenylamino)-4-fluoro-benzonitrile
di-trifluoroacetate were added to a solution of 54 mg (0.26 mmol)
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid in 5
mL DMF. The mixture was stirred overnight at ambient temperature
and then the solvents were distilled off in vacuo. The residue was
purified by chromatography (RP with eluant gradient, acetonitrile
and water with 0.1% trifluoroacetic acid).
[1631] Yield: 69% of theory
[1632] C.sub.23H.sub.19FN.sub.6O.sub.2 (430.44)
[1633] R.sub.t=1.91 min. method 12
Example 115
pyrimidine-5-carboxylic acid
{1-[4-(2-cyano-3-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
##STR00717##
[1634] 115a) tert-butyl
4-(2-cyano-3-fluoro-phenylamino)-benzyl]-carbamate
[1635] The title compound was obtained from
2-bromo-6-fluoro-benzonitrile and tert-butyl
(4-amino-benzyl)-carbamate analogously to method (55a).
[1636] C.sub.19H.sub.20FN.sub.3O.sub.2 (341.38)
[1637] R.sub.t=2.65 min. method 12
115b) 2-(4-aminomethyl-phenylamino)-6-fluoro-benzonitrile
di-trifluoroacetate
[1638] The title compound was prepared from tert-butyl
[4-(2-cyano-3-fluoro-phenylamino)-benzyl]-carbamate analogously to
method (114b).
[1639] C.sub.14H.sub.12FN.sub.3*2C.sub.2HF.sub.3O.sub.2
(469.31)
[1640] R.sub.t=1.46 min. method 12
115c) pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-3-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-a-
mide
[1641] The title compound was obtained analogously to method (114c)
from 2-(4-aminomethyl-phenylamino)-6-fluoro-benzonitrile
di-trifluoroacetate and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
[1642] Yield: 44% of theory
[1643] C.sub.23H.sub.19FN.sub.6O.sub.2 (430.44)
[1644] R.sub.t=1.94 min. method 12
Example 116
pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-6-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}--
amide
##STR00718##
[1645] 116a) tert-butyl
[4-(2-cyano-6-fluoro-phenylamino)-benzyl]-carbamidate
[1646] The title compound was prepared from
2-bromo-3-fluoro-benzonitrile and tert-butyl
(4-amino-benzyl)-carbamate according to method (55a).
[1647] C.sub.13H.sub.20FN.sub.3O.sub.2 (341.38)
[1648] R.sub.t=2.50 min. method 12
116b) 2-(4-aminomethyl-phenylamino)-3-fluoro-benzonitrile
di-trifluoroacetate
[1649] Preparation of the title compound from tert-butyl
[4-(2-cyano-6-fluoro-phenylamino)-benzyl]-carbamate analogously to
method (114b).
[1650] C.sub.14H.sub.12FN.sub.3*2C.sub.2HF.sub.3O.sub.2
(469.31)
[1651] R.sub.t=1.27 min. method 12
116c) pyrimidine-5-carboxylic acid
{1-[4-(2-cyano-6-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
[1652] The title compound was prepared analogously to method (114c)
from 2-(4-aminomethyl-phenylamino)-3-fluoro-benzonitrile
di-trifluoroacetate and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
[1653] C.sub.23H.sub.19FN.sub.6O.sub.2 (430.44)
[1654] R.sub.t=1.78 min. method 12
Example 117
pyrimidine-5-carboxylic acid
{1-[4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cycloprop-
yl}-amide
##STR00719##
[1655] 117a)
4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzonitrile
[1656] 276 mg (2.28 mmol) 4-fluoro-benzonitrile and 550 mg (2.28
mmol) 4-ethoxy-2-trifluoromethyl-phenylamine-hydrochloride were
dissolved in 10 mL DMSO and combined with 639 mg (5.69 mmol)
potassium-tert-butoxide while cooling with ice. The reaction
mixture was stirred overnight at ambient temperature, diluted with
water and extracted with diethyl ether. The organic phase was dried
on sodium sulphate and evaporated down. The residue was purified by
chromatography on silica gel (petroleum ether/ethyl
acetate=9:1).
[1657] Yield: 20% of theory
[1658] C.sub.16H.sub.13F.sub.3N.sub.2O (306.28)
[1659] mass spectroscopy [M+H].sup.+=307
117b)
(4-aminomethyl-phenyl)-(4-ethoxy-2-trifluoromethyl-phenyl)-amine
[1660] 140 mg (0.46 mmol)
4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzonitrile in 10 mL
methanolic ammonia were hydrogenated with Raney nickel as catalyst
at 50 psi hydrogen pressure. The catalyst was filtered off and the
filtrate was freed from the solvent.
[1661] C.sub.16H.sub.17F.sub.3N.sub.2O (310.31)
117c) pyrimidine-5-carboxylic acid
{1-[4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-cyclopro-
pyl}-amide
[1662] 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid
and
(4-aminomethyl-phenyl)-(4-ethoxy-2-trifluoromethyl-phenyl)-amine
were refluxed analogously to method (1d). After the end of the
reaction the solvent was distilled off and the residue was combined
with ethyl acetate, extracted with sodium hydrogen carbonate
solution and dried on sodium sulphate. The solution was evaporated
down in vacuo and the residue was purified on a silica gel column
(dichloromethane/ethanol=19:1)
[1663] C.sub.25H.sub.24F.sub.3N.sub.5O.sub.3 (499.49)
[1664] mass spectroscopy [M+H].sup.+=500
Example 118
pyrimidine-5-carboxylic acid
(1-{4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzylcarba-
moyl}-cyclopropyl)-amide hydrochloride
##STR00720##
[1665] 118a)
4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzonitrile
[1666] The title compound was obtained analogously to method (117a)
from 4-fluoro-benzonitrile and
4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamine.
[1667] Yield: 32% of theory
[1668] C.sub.16H.sub.11F.sub.5N.sub.2O (342.26)
[1669] mass spectroscopy [M+H].sup.+=343
118b)
(4-aminomethyl-phenyl)-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-ph-
enyl]-amine
[1670] The title compound was prepared analogously to method (117b)
from
4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzonitrile.
[1671] C.sub.16H.sub.15F.sub.5N.sub.2O (346.30)
[1672] mass spectroscopy [M+H-NH.sub.3]+=330
118c) pyrimidine-5-carboxylic acid
(1-{4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethylphenylamino]-benzylcarbam-
oyl}-cyclopropyl)-amide hydrochloride
[1673]
(4-aminomethyl-phenyl)-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-p-
henyl]-amine and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were
refluxed analogously to method (1d). The reaction mixture was then
purified by chromatography (RP, acetonitrile/water+0.15% formic
acid). The fractions containing product were evaporated down, made
alkaline with aqueous ammonia solution and extracted with ethyl
acetate. Then the organic phases were evaporated down, the residue
was dissolved in ethyl acetate, an acid pH was created with
hydrochloric acid and the solvent was distilled off.
[1674] Yield: 56% of theory
[1675] C.sub.25H.sub.22F.sub.5N.sub.5O.sub.3*HCl (571.93)
[1676] R.sub.t=3.96 min method 10
Example 119
Pyrimidine-5-carboxylic
acid-{1-[4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]--
cyclopropyl}-amide
##STR00721##
[1677] 119a)
4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzonitrile
[1678] Prepared analogously to method (117a) from
4-fluoro-benzonitrile and
4-isopropoxy-2-trifluoromethyl-phenylamine.
[1679] Yield: 37% of theory
[1680] C.sub.17H.sub.15F.sub.3N.sub.2O (320.31)
[1681] mass spectroscopy [M+H].sup.+=321
119b)
(4-aminomethyl-phenyl)-(4-isopropoxy-2-trifluoromethyl-phenyl)-amine
[1682] The title compound was obtained according to method (117b)
from
4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzonitrile.
[1683] C.sub.17H.sub.19F.sub.3N.sub.2O (324.34)
[1684] mass spectroscopy [M+H-NH.sub.3]+=308
119c) pyrimidine-5-carboxylic acid
{1-[4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclo-
propyl}-amide
[1685]
(4-aminomethyl-phenyl)-(4-isopropoxy-2-trifluoromethyl-phenyl)-amin-
e and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid
were reacted analogously to method (1d). After the chromatographic
purification (RP, acetonitrile/water+0.15% formic acid) of the
reaction mixture the hydrochloride was prepared as described in
method (118c).
[1686] Yield: 28% of theory
[1687] C.sub.26H.sub.26F.sub.3N.sub.5O.sub.3*HCl (549.97)
[1688] R.sub.t=2.72 min method 14
Example 120
pyrimidine-5-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00722##
[1689] 120a)
3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carbonitri-
le
[1690] While cooling with ice 7.21 g (64.2 mmol)
potassium-tert-butoxide were added to a solution of 6.00 g (42.8
mmol) 3,5-difluoro-pyridine-2-carbonitrile and 7.67 g (42.8 mmol)
2-fluoro-6-trifluoromethyl-phenylamine in 240 mL DMSO. The reaction
mixture was stirred for 2 hours at ambient temperature, mixed with
water and extracted with diethyl ether. The organic phases were
dried on sodium sulphate and evaporated down. The residue was
purified by chromatography (silica gel, petroleum ether with 0-15%
ethyl acetate).
120b)
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-ph-
enyl)-amine
[1691]
3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carb-
onitrile was hydrogenated analogously to method (1c). The product
obtained was further reacted directly.
120c) pyrimidine-5-carboxylic acid
(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-amide
[1692]
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-p-
henyl)-amine and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were
reacted analogously to method (1d). For working up solvent was
distilled off. Then the residue was mixed with water, made alkaline
with potassium carbonate solution and extracted with ethyl acetate.
The organic phases were washed with water, dried on sodium sulphate
and evaporated down. The crude product remaining was purified by
chromatography.
[1693] C.sub.22H.sub.17F.sub.5N.sub.6O.sub.2 (492.40)
[1694] mass spectroscopy [M+H].sup.+=493
Example 121
pyrimidine-5-carboxylic
acid-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-
-yl]ethylcarbamoyl}-cyclopropyl)-amide
##STR00723##
[1695] 121a)
1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-etha-
none
[1696] At -25.degree. C. a solution of 2.70 g (9.02 mmol)
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-
-amine in 50 mL diethyl ether was added dropwise to 12 mL of a 3
molar methylmagnesium bromide solution in 50 mL diethyl ether. The
reaction mixture was heated to 5.degree. C. and then while being
cooled combined with 1 molar aqueous hydrochloric acid. Then the
organic phase was separated off, dried on sodium sulphate and
evaporated down. The residue was used in the next reaction without
any further purification.
[1697] C.sub.14H.sub.9F.sub.5N.sub.2O (316.23)
[1698] mass spectroscopy [M+H].sup.+=317
121b)
1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-
-ethanone-oxime
[1699]
1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl-
]-ethanone was reacted analogously to method (40c). For working up
the reaction mixture was evaporated down, mixed with water and
extracted with ethyl acetate. The organic phases were washed with
water and sodium chloride solution and dried on sodium sulphate.
After the solvent has been distilled off the residue was purified
by chromatography (silica gel, dichloromethane with 2-6%
methanol).
[1700] C.sub.14H.sub.10F.sub.5N.sub.3O (331.24)
[1701] mass spectroscopy [M+H].sup.+=332
121c)
6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-
-phenyl)-amine
[1702] The reaction of
1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-etha-
none-oxime was carried out analogously to method (40d). The crude
product was purified by chromatography (silica gel, ethyl acetate
with 0-10% methanol/ammonia=9:1).
[1703] C.sub.14H.sub.12F.sub.5N.sub.3 (317.26)
[1704] mass spectroscopy [M+H].sup.+=318
121d) pyrimidine-5-carboxylic
acid-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-
-yl]-ethylcarbamoyl}-cyclopropyl)-amide
[1705]
6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethy-
l-phenyl)-amine and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were
reacted analogously to method (1d). For working up the reaction
mixture was evaporated down and made alkaline with potassium
carbonate solution. The solid was filtered off, washed with water
and dried. Then the residue was purified by chromatography on a
silica gel column and the fractions containing product were freed
from the solvent. The hydrochloride was obtained by dissolving the
residue in an amount of ethyl acetate and combining it with
ethereal hydrochloric acid.
[1706] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.2*2HCl (579.35)
[1707] mass spectroscopy [M+H].sup.+=507
[1708] The (R)- and (S)-enantiomer of Example 121 were obtained by
chiral HPLC(SFC) from the racemic compound (column: Daicel AD-H,
250.times.20 mm, eluant: 80% supercritical carbon dioxide and 20%
isopropanol with 0.2% diethylamine, flow rate: 70 mL/min).
Example 122
5-amino-N-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyrid-
in-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide
##STR00724##
[1709] 122a) tert-butyl
(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]--
ethylcarbamoyl}-cyclopropyl)-carbamate
[1710] 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and
6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phen-
yl)-amine were reacted and worked up as described in method (121d).
In the final chromatographic purification a silica gel column was
used (petroleum ether with 30-50% ethyl acetate).
122b) 1-amino-cyclopropanecarboxylic
acid-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl-
]-ethyl}-amide
[1711] 400 mg (0.80 mmol) tert-butyl
(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]--
ethylcarbamoyl}-cyclopropyl)-carbamate in 10 mL dichloromethane
were combined with 3 mL of 4 molar hydrochloric acid in dioxane and
stirred for two hours at ambient temperature. Then the solvents
were distilled off. The residue was further reacted directly.
122c)
5-amino-N-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-
-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide
[1712] 1-amino-cyclopropanecarboxylic acid
{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]ethy-
l}-amide dihydrochloride and 5-amino-nicotinic acid were reacted
and worked up as described in method (121d). During the
chromatographic purification through silica gel dichloromethane
with 0-15% methanol was used as eluant.
[1713] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.2*2HCl (593.38)
[1714] mass spectroscopy [M+H].sup.+=521
Example 123
pyrimidine-5-carboxylic
acid-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethy-
lcarbamoyl}-cyclopropyl)-amide
##STR00725##
[1715] 123a)
1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
[1716] 39.7 mL of a 1.4 molar methylmagnesium bromide solution in
toluene/THF (3:1) and 200 mL diethyl ether were taken and cooled to
-30.degree. C. Then 3.90 g (13.9 mmol)
5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile
in 100 mL diethyl ether were added and the reaction mixture was
left overnight with heating to ambient temperature and with
stirring. The reaction mixture was mixed with 1 molar aqueous
hydrochloric acid and stirred for some time. The organic phase was
separated off, dried on sodium sulphate and evaporated down. The
crude product was used in the next reaction without any further
purification.
[1717] C.sub.14H.sub.10F.sub.4N.sub.2O.sub.2 (298.24)
[1718] mass spectroscopy [M+H].sup.+=299
123b)
1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-
-oxime
[1719]
1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanon-
e was reacted and worked up analogously to method (121b). During
the subsequent column chromatography on silica gel
dichloromethane/ethanol 50:1 was used as eluant.
[1720] C.sub.14H.sub.11F.sub.4N.sub.3O (313.25)
123c)
[6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-
-amine
[1721]
1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanon-
e-oxime was hydrogenated analogously to method (40d). The crude
product was purified by chromatography (silica gel, dichloromethane
with 2 to 5% methanol/ammonia 10:1).
[1722] C.sub.14H.sub.13F.sub.4N.sub.3 (299.27))
[1723] R.sub.t=2.76 min. method 7
123d) pyrimidine-5-carboxylic acid
(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarb-
amoyl}-cyclopropyl)-amide
[1724]
[6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl-
)-amine and
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were
reacted analogously to method (1d). For working up the reaction
mixture was evaporated down, combined with ethyl acetate and washed
with sodium hydrogen carbonate solution. The organic phase was
dried on sodium sulphate and the solvent was distilled off. The
residue was purified by chromatography (silica gel,
dichloromethane/ethanol=50:1).
[1725] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.2 (488.44)
[1726] mass spectroscopy [M+H].sup.+=489
Example 124
5-amino-N-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]--
ethylcarbamoyl}-cyclopropyl)-nicotinamide
##STR00726##
[1727] 124a) ten-butyl
(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarb-
amoyl}-cyclopropyl)-carbamate
[1728] 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and
[6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amin-
e were reacted and worked up as described in method (123d). The
crude product was used in the next reaction without being purified
by column chromatography.
[1729] C.sub.23H.sub.26F.sub.4N.sub.4O.sub.3 (482.47)
[1730] mass spectroscopy [M+H].sup.+=483
124b) 1-amino-cyclopropanecarboxylic acid
{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide
hydrochloride
[1731] Reaction of tert-butyl
(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-car-
bamoyl}-cyclopropyl)-carbamate analogously to method (122b).
[1732] C.sub.18H.sub.18F.sub.4N.sub.4O*HCl (418.82)
[1733] mass spectroscopy [M+H].sup.+=383
124c)
5-amino-N-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin--
2-yl]-ethyl-carbamoyl}-cyclopropyl)-nicotinamide
[1734] 1-amino-cyclopropanecarboxylic acid
{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide
hydrochloride and 5-aminonicotinic acid were reacted analogously to
method (1d). For working up the reaction mixture was evaporated
down, combined with ethyl acetate and washed with sodium hydrogen
carbonate solution. The organic phase was dried on sodium sulphate
and the solvent was distilled off. The residue was purified by
chromatography (silica gel, dichloromethane/ethanol=9:1).
[1735] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.2 (502.46)
[1736] mass spectroscopy [M+H].sup.+=503
Example 125
5-amino-N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-
-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00727##
[1737] 125a) tert-butyl
(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-carbamate
[1738] Reaction of
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-
-amine and 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid
analogously to method (1d). After the end of the reaction the
solution was evaporated down and made alkaline with potassium
carbonate solution. The precipitate was filtered off, washed with
water and dried.
[1739] C.sub.22H.sub.23F.sub.5N.sub.4O.sub.3 (486.44)
125b) 1-amino-cyclopropanecarboxylic
acid-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}--
amide
[1740] Tert-butyl
(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-carbamate was reacted analogously to
method (122b).
[1741] C.sub.17H.sub.15F.sub.5N.sub.4O*2HCl (459.24)
125c)
5-amino-N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-p-
yridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
[1742] 5-amino-nicotinic acid and 1-amino-cyclopropanecarboxylic
acid
{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide
were reacted as described in method (121d). During the
chromatographic purification through silica gel dichloromethane and
0 to 15% methanol were used as eluant.
[1743] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.2*2HCl (579.35)
[1744] mass spectroscopy [M+H].sup.+=507
Example 126
pyrimidine-5-carboxylic
acid-(1-{[5-(4-bromo-2-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-
-cyclopropyl)-amide
##STR00728##
[1745] 126a)
5-(4-bromo-2-chloro-phenylamino)-pyridine-2-carbonitrile
[1746] 250 mg (2.0 mmol) 5-fluoro-pyridine-2-carbonitrile were
added at ambient temperature to a solution of 423 mg (2.0 mmol)
4-bromo-2-chloroaniline and 459 mg (4.0 mmol)
potassium-tert-butoxide in 4 mL DMSO. The reaction mixture was
stirred overnight, then combined with sodium chloride solution and
extracted with tert-butyl-methylether. The organic phases were
dried on sodium sulphate and evaporated down.
[1747] C.sub.12H.sub.7BrClN.sub.3 (308.56)
[1748] mass spectroscopy [M+H].sup.+=308
126b)
(6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-phenyl)-amine
[1749] A solution of 250 mg
5-(4-bromo-2-chloro-phenylamino)-pyridine-2-carbonitrile in 4 mL
THF was added dropwise to 0.8 mL of a 2 molar solution of lithium
aluminium hydride in THF at ambient temperature. Then the reaction
mixture was refluxed for 20 minutes. It was carefully hydrolysed
with water and extracted with THF. The organic phases were washed
with sodium chloride solution, dried on sodium sulphate and
evaporated down. The residue was purified by chromatography (RP,
eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
[1750] C.sub.12H.sub.11BrClN.sub.3 (312.59)
[1751] mass spectroscopy [M+H].sup.+=311
126c) pyrimidine-5-carboxylic
acid-(1-{[5-(4-bromo-2-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-
-cyclopropyl)-amide
[1752] Prepared analogously to method (51b) from
(6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-phenyl)-amine and
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid.
[1753] C.sub.21H.sub.18BrClN.sub.6O.sub.2 (501.76)
[1754] mass spectroscopy [M+H].sup.+=501
Example 127
(S)-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-fu-
ran-3-yl}-amide
##STR00729##
[1756] (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic
acid and N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline were
reacted analogously to method (51b). The final purification was
carried out by chromatography (RP, eluant: acetonitrile and water
with 0.2% trifluoroacetic acid).
[1757] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.3 (485.46)
[1758] mass spectroscopy (ESI): [M+H].sup.+=486
Example 128
pyridazine-4-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00730##
[1759] 128a) tert-butyl
(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-carbamate
[1760] Reaction of tert-butyl (1-carbamoyl-cyclopropyl)-carbamate
and
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-
-amine analogously to method (1d). For working up the reaction
mixture was evaporated down and made alkaline with potassium
carbonate solution. The product precipitated was filtered off,
washed with water and dried.
[1761] C.sub.22H.sub.23F.sub.5N.sub.4O.sub.3 (486.44)
[1762] R.sub.t=2.30 min. method 12
128b) 1-amino-cyclopropanecarboxylic acid
[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
amide dihydrochloride
[1763] Tert-butyl
(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-carbamate was reacted as described in
method (122b).
[1764] C.sub.17H.sub.15F.sub.5N.sub.4O*2HCl (459.24)
[1765] R.sub.t=1.50 min. method 12
128c) pyridazine-4-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
[1766] 1-amino-cyclopropanecarboxylic acid
[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
amide dihydrochloride and pyridazine-4-carboxylic acid were reacted
analogously to method (1d) and then purified by chromatography (RP,
eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
[1767] Yield: 47% of theory
[1768] C.sub.22H.sub.17F.sub.5N.sub.6O.sub.2 (492.40)
[1769] mass spectroscopy (ESI): [M+H].sup.+=493
[1770] The following Examples 129 to 137 were prepared analogously
to method (128c) from 1-amino-cyclopropanecarboxylic acid
[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
amide dihydrochloride and the corresponding carboxylic acid.
Example 129
2-methoxy-pyrimidine-5-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00731##
[1772] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.3*C.sub.2HF.sub.3O.sub.2
(636.45)
[1773] mass spectroscopy (ESI): [M+H].sup.+=523
Example 130
N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamide
##STR00732##
[1775] C.sub.23H.sub.18F.sub.5N.sub.5O.sub.3 (507.41)
[1776] mass spectroscopy (ESI): [M+H].sup.+=508
Example 131
N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamide
##STR00733##
[1778] C.sub.24H.sub.20F.sub.5N.sub.5O.sub.2 (505.44)
[1779] mass spectroscopy (ESI): [M+H].sup.+=506
Example 132
1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00734##
[1781] C.sub.24H.sub.20F.sub.5N.sub.5O.sub.3 (521.44)
[1782] mass spectroscopy (ESI): [M+H].sup.+=522
Example 133
2-methylamino-pyrimidine-5-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00735##
[1784] C.sub.23H.sub.20F.sub.5N.sub.7O.sub.2 (521.44)
[1785] mass spectroscopy (ESI): [M+H].sup.+=522
Example 134
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00736##
[1787] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.2 (506.43)
[1788] mass spectroscopy (ESI): [M+H].sup.+=507
Example 135
thiazole-5-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00737##
[1790] C.sub.21H.sub.16F.sub.5N.sub.5O.sub.2S (497.44)
[1791] mass spectroscopy (ESI): [M+H].sup.+=498
Example 136
6-hydroxy-pyridine-2-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00738##
[1793] C.sub.23H.sub.18F.sub.5N.sub.5O.sub.3 (507.41)
[1794] mass spectroscopy (ESI): [M+H].sup.+=508
Example 137
isoxazole-5-carboxylic
acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00739##
[1796] C.sub.21H.sub.16F.sub.5N.sub.5O.sub.3 (481.38)
[1797] mass spectroscopy (ESI): [M+H].sup.+=482
Example 138
2-methoxy-pyrimidine-5-carboxylic acid
(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbam-
oyl}-cyclopropyl)-amide
##STR00740##
[1798] 138a) tert-butyl
(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbam-
oyl}-cyclopropyl)-carbamate
[1799] Reaction of
(6-aminomethyl-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine
and 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid
analogously to method (1d). Then the reaction mixture was
evaporated down and the residue was chromatographed (RP, eluant:
acetonitrile and water with 0.1% trifluoroacetic acid)
[1800] C.sub.22H.sub.24BrF.sub.3N.sub.4O.sub.3 (529.35)
[1801] mass spectroscopy (ESI): [M+H].sup.+=529
138b) 1-amino-cyclopropanecarboxylic acid
[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
trifluoroacetate
[1802] 150 mg (0.28 mmol) tert-butyl
(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbam-
oyl}-cyclopropyl)-carbamate in 2.5 mL dichloromethane were combined
with 1 mL trifluoroacetic acid and stirred for one hour at ambient
temperature. The solvent was distilled off and the residue was
further reacted directly.
[1803] Yield: 100% of theory
[1804] C.sub.17H.sub.16BrF.sub.3N.sub.4O*C.sub.2HF.sub.3O.sub.2
(543.26)
[1805] R.sub.t=1.59 min. method 12
138c) 2-methoxy-pyrimidine-5-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
[1806] The product was prepared according to method (1d) from
1-amino-cyclopropanecarboxylic acid
[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
trifluoroacetate and 2-methoxy-pyrimidine-5-carboxylic acid.
[1807] C.sub.23H.sub.20BrF.sub.3N.sub.6O.sub.3 (565.34)
[1808] mass spectroscopy (ESI): [M+H].sup.+=565
[1809] The following Examples 139 to 141 were prepared from
1-amino-cyclopropanecarboxylic acid
[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
trifluoroacetate and the corresponding carboxylic acid according to
method (1d).
Example 139
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00741##
[1811] C.sub.23H.sub.20BrF.sub.3N.sub.6O.sub.2 (549.34)
[1812] mass spectroscopy (ESI): [M+H].sup.+=549
Example 140
6-hydroxy-pyridine-2-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00742##
[1814] C.sub.23H.sub.19BrF.sub.3N.sub.5O.sub.3 (550.33)
[1815] mass spectroscopy (ESI): [M+H].sup.+=550
Example 141
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-5-hydroxy-nicotinamide
##STR00743##
[1817] C.sub.23H.sub.19BrF.sub.3N.sub.5O.sub.3 (550.33)
[1818] mass spectroscopy (ESI): [M+H].sup.+=550
Example 142
5-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00744##
[1819] 142a) benzyl
1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylate
[1820] 5-amino-nicotinic acid and benzyl
1-amino-cyclopropanecarboxylate hydrochloride were coupled
according to method (1d). For working up the reaction mixture was
evaporated down, combined with potassium carbonate solution and
extracted with ethyl acetate. The organic phases were washed with
water, dried on sodium sulphate and freed from the solvent in
vacuo. The residue was chromatographed on a silica gel column
(eluant: dichloromethane with 0-10% methanol).
142b)
1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylic
acid
[1821] 1.90 g (6.1 mmol) benzyl
1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylate
were dissolved in 70 mL methanol and hydrogenated with palladium on
charcoal (10%) as catalyst at 3 bar hydrogen pressure. The catalyst
was filtered off and the filtrate was evaporated down. For
purification the residue was stirred with diethyl ether, filtered
and dried.
[1822] Yield: 85% of theory
[1823] C.sub.10H.sub.11N.sub.3O.sub.3 (221.21)
[1824] mass spectroscopy (ESI): [M+H].sup.+=222
142c)
5-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2--
ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
[1825]
1-[(5-amino-pyridine-3-carbonyl)-amino]cyclopropanecarboxylic acid
and
(6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amin-
e were reacted analogously to method (1d). Following the
chromatographic purification (RP, eluant: acetonitrile and water
with 0.15% formic acid) the fractions containing product were made
alkaline with potassium carbonate solution. Then the acetonitrile
was distilled off and extracted with ethyl acetate. The organic
phases were dried on sodium sulphate, freed from the solvent and
triturated with diisopropylether.
[1826] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.2 (488.44)
[1827] mass spectroscopy (ESI): [M+H].sup.+=489
Example 143
3H-imidazo[4,5-b]pyridine-6-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00745##
[1828] 143a) benzyl
1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylate
[1829] Prepared from 3H-imidazo[4,5-b]pyridine-6-carboxylic acid
and benzyl 1-amino-cyclopropanecarboxylate hydrochloride
analogously to method (142a).
[1830] C.sub.18H.sub.16N.sub.4O.sub.3 (336.35)
[1831] mass spectroscopy (ESI): [M+H].sup.+=337
143b)
1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxy-
lic acid
[1832] Obtained from the reaction of benzyl
1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylate
according to method (142b).
[1833] C.sub.11H.sub.10N.sub.4O.sub.3 (246.22)
[1834] R.sub.t=1.64 min. method 10
143c) 3H-imidazo[4,5-b]pyridine-6-carboxylic acid
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
[1835] The compound was obtained by reacting
1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylic
acid and
(6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine analogously to (142c).
[1836] C.sub.24H.sub.19F.sub.4N.sub.7O.sub.2 (513.45)
[1837] mass spectroscopy (ESI): [M+H].sup.+=514
Example 144
6-amino-pyrazine-2-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00746##
[1838] 144a) tert-butyl
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-carbamate
[1839] 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and
(6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
were coupled with TBTU analogously to method (1d). The reaction
mixture was evaporated down, combined with ethyl acetate and washed
with sodium hydrogen carbonate solution. Then the organic phase was
dried on sodium sulphate and freed from the solvent. The residue
was purified on a silica gel column with dichloromethane/ethanol as
eluant in the ratio 1:50 to 1:20.
[1840] C.sub.22H.sub.24F.sub.4N.sub.4O.sub.3 (468.45)
[1841] mass spectroscopy (ESI): [M+H].sup.+=469
144b) 1-amino-cyclopropanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
hydrochloride
[1842] 1.00 g (2.14 mmol) tert-butyl
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-carbamate were dissolved in 30 mL dioxane and
after the addition of 3.2 mL 4 molar hydrochloride solution in
dioxane stirred overnight at ambient temperature. The solvent was
distilled off in vacuo and the residue was further reacted
directly.
[1843] C.sub.17H.sub.16F.sub.4N.sub.4O*HCl (404.79)
[1844] mass spectroscopy (ESI): [M+H].sup.+=369
144c) 6-amino-pyrazine-2-carboxylic acid
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
[1845] Obtained analogously to method (142c) from
1-amino-cyclopropanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
hydrochloride and 6-amino-pyrazine-2-carboxylic acid.
[1846] C.sub.22H.sub.19F.sub.4N.sub.7O.sub.2 (489.43)
[1847] mass spectroscopy (ESI): [M+H].sup.+=490
Example 145
2-methylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00747##
[1848] 145a) tert-butyl
(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-carbamate
[1849] 1-(tert-butoxycarbonyl-amino)-cyclopropanecarboxylic acid
and
(6-aminomethyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
were coupled as described in method (1d). For working up the
reaction mixture was mixed with water and extracted with
dichloromethane. The organic phases were dried on sodium sulphate
and evaporated down.
[1850] C.sub.22H.sub.24ClF.sub.3N.sub.4O.sub.3 (484.90)
[1851] R.sub.t=2.23 min. method 12
145b) 1-amino-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e trifluoroacetate
[1852] 906 mg (1.40 mmol) tert-butyl
(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-carbamate in 5 mL dichloromethane were combined
with 2 mL trifluoroacetic acid and stirred for one hour at ambient
temperature. Then the solvent was distilled off in vacuo and the
residue was reacted without any further purification.
[1853] C.sub.17H.sub.16ClF.sub.3N.sub.4O*C.sub.2HF.sub.3O.sub.2
(498.81)
[1854] R.sub.t=1.54 min. method 12
145c) 2-methylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
[1855] 1-amino-cyclopropanecarboxylic acid
[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
trifluoroacetate and 2-methylamino-pyrimidine-5-carboxylic acid
were reacted analogously to method (1d). Then the reaction mixture
was purified by chromatography (RP, eluant: acetonitrile and water
with 0.1% trifluoroacetic acid).
[1856] C.sub.23H.sub.21ClF.sub.3N.sub.7O.sub.2 (519.91)
[1857] mass spectroscopy (ESI): [M+H].sup.+=520
[1858] Examples 146 to 149 were prepared analogously from
1-amino-cyclopropanecarboxylic acid
[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
and the corresponding carboxylic acid.
Example 146
2-methoxy-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00748##
[1860] C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.3 (520.89)
[1861] mass spectroscopy (ESI): [M+H].sup.+=521
Example 147
2-methyl-pyrimidine-5-carboxylic acid
(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
##STR00749##
[1863] C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.2 (504.89)
[1864] mass spectroscopy (ESI): [M+H].sup.+=505
Example 148
1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid
(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
##STR00750##
[1866] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.3 (519.90)
[1867] mass spectroscopy (ESI): [M+H].sup.+=520
[1868] R.sub.t=1.74 min. method 13
Example 149
thiazole-5-carboxylic acid
(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
##STR00751##
[1870] C.sub.21H.sub.17ClF.sub.3N.sub.5O.sub.2S (495.91)
[1871] mass spectroscopy (ESI): [M+H].sup.+=496
[1872] R.sub.t=1.84 min. method 13
Example 150
3-amino-isoxazole-5-carboxylic acid
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
##STR00752##
[1874] Prepared according to method (142c) from
1-amino-cyclopropanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
hydrochloride and 3-amino-isoxazole-5-carboxylic acid.
[1875] C.sub.21H.sub.18F.sub.4N.sub.6O.sub.3 (478.40)
[1876] mass spectroscopy (ESI): [M+H].sup.+=479
Example 151
pyrimidine-5-carboxylic acid
(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-amide dihydrochloride
##STR00753##
[1878] 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid
and
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine were reacted analogously to method (1d). The reaction
mixture was evaporated down, combined with potassium carbonate
solution and extracted with ethyl acetate. The organic phases were
washed with water and sodium chloride solution, dried on sodium
sulphate and freed from the solvent. After the chromatographic
purification of the residue (RP, eluant: water and acetonitrile
with formic acid) the fractions containing product were made
alkaline with ammonia, the acetonitrile was distilled off and the
remainder was extracted with ethyl acetate. The product was
precipitated from the organic solution with ethereal hydrochloride
solution after drying with sodium sulphate.
[1879] C.sub.22H.sub.17F.sub.5N.sub.6O.sub.2*2HCl (565.32)
[1880] mass spectroscopy (ESI): [M+H].sup.+=493
Example 152
5-amino-N-(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-
-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
dihydrochloride
##STR00754##
[1882] Obtained analogously to the method of Example 147 from
5-amino-nicotinic acid and 1-amino-cyclopropanecarboxylic
acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide. In the chromatographic purification, however, a silica
gel column was used (eluant: dichloromethane with 5 to 12%
methanol).
[1883] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.2*2HCl (579.35)
[1884] mass spectroscopy (ESI): [M+H].sup.+=507
Example 153
(S)-pyrimidine-5-carboxylic acid
(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-tetrahydro-furan-3-yl)-amide dihydrochloride
##STR00755##
[1886] Prepared from
(S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid
and
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine analogously to Example 150. The column chromatographic
purification used a silica gel column and dichloromethane with 0 to
7% methanol as eluant.
[1887] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.3*2HCl (595.35)
[1888] mass spectroscopy (ESI): [M+H].sup.+=523
Example 154
(S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00756##
[1889] 154a) butyl
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate
[1890] 5-amino-nicotinic acid and butyl
(S)-3-amino-tetrahydrofuran-3-carboxylate were coupled with TBTU
analogously to method (1d). For working up the reaction mixture was
evaporated down, combined with potassium carbonate solution and
extracted with ethyl acetate. The organic phases were washed with
water and sodium chloride solution, dried on sodium sulphate and
freed from the solvent. The residue was chromatographed on a silica
gel column (eluant: dichloromethane with 5 to 10% methanol).
[1891] C.sub.15H.sub.21N.sub.3O.sub.4 (307.35)
[1892] mass spectroscopy (ESI): [M+H].sup.+=308
154b)
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydro-furan-3-carbo-
xylic acid
[1893] 2.45 g (7.97 mmol) butyl
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate
in 50 mL methanol were combined with 16 mL 1 molar sodium hydroxide
solution and stirred for one hour at ambient temperature. After the
addition of 16 mL of 1 molar hydrochloric acid the solvents were
distilled off in vacuo. The residue was dissolved in ethanol and
the inorganic salts were filtered off. Then the filtrate was
evaporated down.
[1894] Yield: 99% of theory
[1895] C.sub.11H.sub.13N.sub.3O.sub.4 (251.24)
[1896] mass spectroscopy (ESI): [M+H].sup.+=252
154c)
(S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamin-
o)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-O-nicotinamide-dihydr-
ochloride
[1897]
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carbo-
xylic acid and
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine were reacted and purified as described in method (154a).
Following the chromatographic purification the product was
dissolved in ethyl acetate and precipitated with ethereal
hydrochloride solution.
[1898] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.3*2HCl (609.38)
[1899] mass spectroscopy (ESI): [M+H].sup.+=537
Example 155
(S)-pyrimidine-5-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR00757##
[1901] A solution of 64 mg (0.27 mmol)
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetra-hydrofuran-3-carboxylic
acid, 93 mg (0.28 mmol)
0-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N',N'-tetramethyluronium-tet-
rafluoroborate (TOTU) and 139 .mu.L (0.81 mmol) DIPEA in 1 mL DMF
was stirred for 1 hour at ambient temperature, then combined with
144 mg (0.41 mmol)
N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline and left to
stand overnight. Then the mixture was purified by chromatography
(RP with gradient, eluant: acetonitrile and water with 0.2%
trifluoroacetic acid).
[1902] Yield: 18% of theory
[1903] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.3 (485.46)
[1904] mass spectroscopy (ESI): [M+H].sup.+=486
[1905] R.sub.t=2.15 min. method 12
Example 156
(S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
dihydrochloride
##STR00758##
[1907]
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carbo-
xylic acid and
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine were reacted and purified as described in method (154a).
Following the chromatographic purification the product was
dissolved in ethyl acetate and precipitated with ethereal
hydrochloride solution.
[1908] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.3*2HCl (609.38)
[1909] mass spectroscopy (ESI): [M+H].sup.+=537
Example 157
(S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00759##
[1911] Obtained from
(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid and
(6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine according to method (142c).
[1912] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.3 (518.46)
[1913] mass spectroscopy (ESI): [M+H].sup.+=519
Example 158
(S)-pyrimidine-5-carboxylic
acid-(3-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide dihydrochloride
##STR00760##
[1915] Prepared analogously to method (154a) from
(S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid and
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phe-
nyl)-amine.
[1916] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.3*2HCl (595.35)
[1917] mass spectroscopy (ESI): [M+H].sup.+=523
Example 159
(S)-3H-imidazo[4,5-b]pyridine-6-carboxylic
acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydro-furan-3-yl)-amide
##STR00761##
[1918] 159a) butyl
(S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydro-furan-3-c-
arboxylate
[1919] Prepared from 3H-imidazo[4,5-b]pyridine-6-carboxylic acid
and butyl (S)-3-amino-tetrahydrofuran-3-carboxylate as described in
method (154a), with no chromatographic purification.
[1920] C.sub.16H.sub.20N.sub.4O.sub.4 (332.36)
[1921] R.sub.t=1.99 min. method 13
159b)
(S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydro-fura-
n-3-carboxylic acid
[1922] 400 mg (1.20 mmol) butyl
(S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydrofuran-3-ca-
rboxylate were dissolved in 10 mL THF and 5 mL ethanol, combined
with 1.2 mL 2 molar lithium hydroxide solution and stirred
overnight at ambient temperature. Then the solvents were distilled
off and the residue was combined with 2.4 mL 1 molar aqueous
hydrochloric acid. The mixture was evaporated down in vacuo and
residual water was eliminated by repeated azeotropic distillation
with ethanol.
[1923] C.sub.12H.sub.12N.sub.4O.sub.4 (276.25)
[1924] mass spectroscopy (ESI): [M-H].sup.+=275
159c) (S)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid
(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-tetrahydrofuran-3-yl)-amide
[1925] Prepared from
(S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydrofuran-3-ca-
rboxylic acid and
(6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
analogously to method (154a).
[1926] C.sub.25H.sub.21F.sub.4N.sub.7O.sub.3 (543.47)
[1927] mass spectroscopy (ESI): [M+H].sup.+=544
Example 160
pyrimidine-5-carboxylic
acid-(1-{[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00762##
[1928] 160a) tert-butyl
(5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate
[1929] 581 mg (2.41 mmol)
C-(5-bromo-3-fluoro-pyridin-2-yl)-methylamine were dissolved in 5
mL triethylamine and 1.5 mL water and while the mixture was being
cooled with the ice bath 630 mg (2.89 mmol)
di-tert-butyl-dicarbonate were added. Then the reaction mixture was
stirred overnight. The solvent was distilled off and the residue
was purified by chromatography (RP with eluant gradient, eluant:
acetonitrile and water with 0.2 trifluoroacetic acid). The
fractions containing product were neutralised with triethylamine
and evaporated down.
[1930] Yield: 40% of theory
[1931] C.sub.11H.sub.14BrFN.sub.2O.sub.2 (305.14)
[1932] R.sub.t=2.29 min. method 12
160b) tert-butyl
[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate
[1933] 132 mg (0.97 mmol) 2-amino-5-fluorobenzonitrile and 295 mg
(0.97 mmol) tert-butyl
(5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate were reacted and
worked up analogously to method (55a).
[1934] Yield: 15% of theory
[1935] C.sub.18H.sub.18F.sub.2N.sub.4O.sub.2 (360.36)
[1936] R.sub.t=2.35 min. method 12
160c)
2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-5-fluoro-benzonitrile-t-
rifluoroacetate
[1937] 51 mg (0.14 mmol) tert-butyl
[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate
were stirred with 1.5 mL trifluoroacetic acid and 2.5 mL
dichloromethane for 3 hours at ambient temperature. Then the
reaction mixture was evaporated down in vacuo and further reacted
directly.
[1938] Yield: 94% of theory
[1939] C.sub.13H.sub.10F.sub.2N.sub.4*C.sub.2HF.sub.3O.sub.2
(374.27)
[1940] R.sub.t=1.17 min. method 12
160d) pyrimidine-5-carboxylic
acid-(1-{[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
[1941] 28 mg (0.13 mmol)
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid and 50
mg (0.13 mmol)
2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-5-fluoro-benzonitrile
were reacted with TBTU using DMF as solvent analogously to method
(1d).
[1942] Yield: 50% of theory
[1943] C.sub.22H.sub.17F.sub.2N.sub.7O.sub.2 (449.13)
[1944] mass spectroscopy (ESI): [M+H].sup.+=450
[1945] R.sub.t=1.67 min. method 12
Example 161
pyrimidine-5-carboxylic acid
{1-[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzylcarbamoyl]-cycloprop-
yl}-amide
##STR00763##
[1946] 161a) tert-butyl (4-bromo-benzyl)-carbamate
[1947] 2.35 g (11 mmol) di-tert-butyl-dicarbonate in 20 mL
dichloromethane were added dropwise to a solution of 2.00 g (8.99
mmol) 4-bromobenzylamine hydrochloride and 6.26 mL triethylamine in
30 mL dichloromethane while being cooled with the ice bath. Then
the mixture was stirred overnight and then evaporated down. The
residue was dissolved in ethyl acetate, acidified with citric acid
and then washed with water and sodium hydrogen carbonate solution.
The organic phase was dried on sodium sulphate and freed from the
solvent.
[1948] Yield: 96% of theory
[1949] C.sub.12H.sub.16BrNO.sub.2 (286.17)
[1950] mass spectroscopy (ESI): [M+H].sup.+=286
161b) tert-butyl
{4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzyl}-carbamate
[1951] Tert-butyl (4-bromo-benzyl)-carbamate and
2-amino-5-trifluoromethoxy-benzonitrile were reacted analogously to
method (55a).
[1952] C.sub.20H.sub.20F.sub.3N.sub.3O.sub.3 (407.39)
[1953] mass spectroscopy (ESI): [M+H].sup.+=408
[1954] R.sub.t=4.63 min. method 13
161c)
2-(4-aminomethyl-phenylamino)-5-trifluoromethoxy-benzonitrile-triflu-
oroacetate
[1955] To cleave the protective group tert-butyl
[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzyl]-carbamate was
treated with trifluoroacetic acid in dichloromethane. Then the
solvent was distilled off and the residue was chromatographed (RP
with eluant gradient, eluant: acetonitrile and water with 0.2%
trifluoroacetic acid).
[1956] C.sub.15H.sub.12F.sub.3N.sub.3O*C.sub.2HF.sub.3O.sub.2
(421.29)
[1957] mass spectroscopy (ESI): [M+H].sup.+=308
[1958] R.sub.t=2.45 min. method 13
161d) pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzylcarbamoyl]-cycl-
opropyl}-amide
[1959] 166 mg (0.39 mmol) of
2-(4-aminomethyl-phenylamino)-5-trifluoromethoxy-benzonitrile-trifluoroac-
etate and 82 mg (0.39 mmol)
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were
coupled analogously to method (1d).
[1960] Yield: 33% of theory
[1961] C.sub.24H.sub.19F.sub.3N.sub.6O.sub.3 (496.44)
[1962] mass spectroscopy (ESI): [M+H].sup.+=497
[1963] R.sub.t=2.24 min. method 13
Example 162
pyrimidine-5-carboxylic acid
{1-[4-(4-chloro-2-cyano-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
##STR00764##
[1965] Prepared by the same reaction sequence (Buchwald reaction,
cleaving of protective group, amide linking) as in Example 161
starting from tert-butyl (4-bromobenzyl)-carbamate.
[1966] C.sub.23H.sub.19ClN.sub.6O.sub.2 (446.89)
[1967] mass spectroscopy (ESI): [M+H].sup.+=447
[1968] R.sub.t=2.10 min. method 13
Example 163
(S)-pyrimidine-5-carboxylic acid
(3-{1-[5-(4-chloro-2-trifluoromethyl-phenyl-amino)-pyridin-2-yl]-ethylcar-
bamoyl}-tetrahydrofuran-3-yl)-amide
##STR00765##
[1969] 163a)
1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
[1970] 500 mg (1.68 mmol)
5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile
in 5 mL diethyl ether were added dropwise at -5.degree. C. to a
solution of 2.2 mL of 3 molar methylmagnesium bromide in diethyl
ether. The reaction mixture was hydrolysed with ammonium chloride
solution and combined with 1 molar hydrochloric acid and
tert-butylmethylether. The organic phase was separated off, dried
on sodium sulphate and evaporated down
[1971] Yield: 50% of theory
[1972] C.sub.14H.sub.10ClF.sub.3N.sub.2O (314.69)
[1973] mass spectroscopy (ESI): [M+H].sup.+=315
163b)
1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-
-oxime
[1974] 266 mg (0.85 mmol)
1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone,
73 mg (1.04 mmol) hydroxylamine-hydrochloride and 238 .mu.L (1.69
mmol) triethylamine were refluxed overnight in 15 mL acetonitrile
with stirring. Then the reaction mixture was mixed with water and
extracted with dichloromethane. The organic phase was dried on
sodium sulphate and evaporated down. The residue was used in the
next reaction without any further purification.
[1975] Yield: 79% of theory
[1976] C.sub.14H.sub.11ClF.sub.3N.sub.3O (329.71)
[1977] R.sub.t=2.27 min. method 12
163c)
[6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-
-amine
[1978] 220 mg (0.67 mmol)
1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxim-
e in 1 mL methanol were mixed batchwise with 50 mg zinc powder and
1.1 mL of 4 molar hydrochloric acid in methanol and then refluxed
for 3 hours with stirring. Then water was added to the mixture and
it was extracted with dichloromethane. The organic phases were
dried on sodium sulphate and evaporated down.
[1979] Yield: 62% of theory
[1980] C.sub.14H.sub.13ClF.sub.3N.sub.3 (315.72)
[1981] R.sub.t=1.76 min. method 12
163d) (S)-pyrimidine-5-carboxylic
acid-(3-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethy-
lcarbamoyl}-tetrahydrofuran-3-yl)-amide
[1982] The compound was obtained from
(S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid and
[6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)--
amine analogously to method (51b).
[1983] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.3 (534.93)
[1984] mass spectroscopy (ESI): [M+H].sup.+=535
[1985] R.sub.t=1.86 min. method 12
Example 164
pyrimidine-5-carboxylic acid
(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarb-
amoyl}-cyclopropyl)-amide trifluoroacetate
##STR00766##
[1987] Obtained analogously to method (1d) from
[6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amin-
e and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic
acid.
[1988]
C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.2*C.sub.2HF.sub.3O.sub.2
(618.92)
[1989] mass spectroscopy (ESI): [M+H].sup.+=505
[1990] R.sub.t=1.84 min. method 12
Example 165
tert-butyl
[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2--
ylmethyl]-carbamate
##STR00767##
[1991] 165a) tert-butyl
[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]--
carbamate
[1992] Prepared analogously to method (55a) from tert-butyl
(5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate and
4-chloro-2-trifluoromethyl-phenylamine.
[1993] C.sub.18H.sub.18ClF.sub.4N.sub.3O.sub.2 (419.80)
[1994] mass spectroscopy (ESI): [M+H].sup.+=420
165b)
(6-aminomethyl-5-fluoro-pyridin-3-O-(4-chloro-2-trifluoromethyl-phen-
yl)-amine hydrochloride
[1995] 50 mg (0.12 mmol) tert-butyl
[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]--
carbamate in 3 mL dioxane were combined with 2 mL of
semi-concentrated hydrochloric acid and stirred for two hours at
60.degree. C. After evaporation of the reaction mixture residual
water was eliminated by azeotropic distillation with toluene.
[1996] R.sub.t=1.73 min. method 12
165c) tert-butyl
[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]--
carbamate
[1997] Prepared from
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-
-amine hydrochloride and
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid
analogously to method (1d).
[1998] C.sub.22H.sub.7ClF.sub.4N.sub.6O.sub.2 (508.86)
[1999] mass spectroscopy (ESI): [M+H].sup.+=509
[2000] R.sub.t=2.12 min. method 12
Example 166
pyrimidine-5-carboxylic
acid-(1-{[5-(2,4-dichloro-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-cy-
clopropyl)-amide
##STR00768##
[2001] 166a)
5-(2,4-dichloro-phenylamino)-pyridine-2-carbonitrile
[2002] 1.33 g (8.2 mmol) 2,4-dichloroaniline in 30 mL DMSO were
combined with 1.38 g (12.3 mmol) potassium-tert-butoxide and
stirred for one hour at ambient temperature. Then 1.00 g (8.2 mmol)
of 2-cyano-5-fluoropyridine in 20 mL DMSO was added and the mixture
was stirred for a further six hours. It was diluted with
dichloromethane, washed with sodium chloride solution, dried on
sodium sulphate and evaporated down. The residue was
chromatographed on a silica gel column (eluant: petroleum
ether/ethyl acetate=4:1).
[2003] Yield: 44% of theory
[2004] C.sub.12H.sub.7Cl.sub.2N.sub.3 (264.11)
[2005] R.sub.t=2.46 min. method 12
166b) (6-aminomethyl-pyridin-3-yl)-(2,4-dichloro-phenyl)-amine
[2006] 3.56 mL of a 2 molar solution of lithium aluminium hydride
in THF were added at -10.degree. C. to 0.94 g (3.6 mmol)
5-(2,4-dichloro-phenylamino)-pyridine-2-carbonitrile in 60 mL THF.
The mixture was stirred for 30 minutes at ambient temperature, then
mixed with water and filtered. The solid was washed with THF and
the filtrate was evaporated to dryness.
[2007] C.sub.12H.sub.11Cl.sub.2N.sub.3 (268.14)
[2008] mass spectroscopy (ESI): [M+H].sup.+=268
166c) pyrimidine-5-carboxylic
acid-(1-{[5-(2,4-dichloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyc-
lopropyl)-amide
[2009] Obtained from
(6-aminomethyl-pyridin-3-yl)-(2,4-dichloro-phenyl)-amine and
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid
analogously to method (1d).
[2010] C.sub.21H.sub.18Cl.sub.2N.sub.6O.sub.2 (457.31)
[2011] mass spectroscopy (ESI): [M+H].sup.+=457
Example 167
pyrimidine-5-carboxylic acid
(1-{[5-(2-bromo-4-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cycl-
opropyl)-amide
##STR00769##
[2012] 167a)
5-(2-bromo-4-chloro-phenylamino)-pyridine-2-carbonitrile
[2013] Prepared from 2-bromo-4-chloroaniline and
2-cyano-5-fluoropyridine analogously to (166a).
[2014] C.sub.12H.sub.7BrClN.sub.3 (308.56)
[2015] mass spectroscopy (ESI): [M+H].sup.+=308
167b)
(6-aminomethyl-pyridin-3-yl)-(2-bromo-4-chloro-phenyl)-amine-trifluo-
roacetate
[2016] 5-(2-bromo-4-chloro-phenylamino)-pyridine-2-carbonitrile was
reduced analogously to method (166b) with lithium aluminium
hydride. The subsequent purification, however, was carried out by
chromatography (RP with eluant gradient, eluant: acetonitrile and
water with 0.1% trifluoroacetic acid).
[2017] C.sub.12H.sub.11BrClN.sub.3 (312.59)
[2018] mass spectroscopy (ESI): [M+H].sup.+=312
167c) pyrimidine-5-carboxylic
acid-(1-{[5-(2-bromo-4-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-
-cyclopropyl)-amide
[2019] Prepared analogously to method (1d) from
(6-aminomethyl-pyridin-3-yl)-(2-bromo-4-chloro-phenyl)-amine-trifluoroace-
tate and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic
acid.
[2020] C.sub.21H.sub.18BrClN.sub.6O.sub.2 (501.76)
[2021] mass spectroscopy (ESI): [M+H].sup.+=501
Example 168
6-methylamino-pyrazine-2-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00770##
[2023] 61 mg (0.40 mmol) 6-methylamino-pyrazine-2-carboxylic acid,
162 mg (0.40 mmol) 1-amino-cyclopropanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
hydrochloride and 167 .mu.L (1.20 mmol) triethylamine were placed
in 7 mL THF and 1 mL DMF, combined with 154 mg (0.48 mmol) TBTU and
then stirred for 4 days at ambient temperature. The THF was
distilled off and the residue was purified by chromatography (RP
with eluant gradient, eluant: water and acetonitrile with formic
acid). Then the fractions containing product were made alkaline
with potassium carbonate solution. The acetonitrile was distilled
off and the residue was extracted with ethyl acetate. The organic
phases were dried on sodium sulphate, freed from the solvent and
triturated with diisopropylether.
[2024] Yield: 34% of theory
[2025] C.sub.23H.sub.21F.sub.4N.sub.7O.sub.2 (503.45)
[2026] mass spectroscopy (ESI): [M+H].sup.+=504
Example 169
2-amino-oxazole-5-carboxylic acid
(1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-amide
##STR00771##
[2027] 169a) tert-butyl
[5-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-ca-
rbamoyl}-cyclopropylcarbamoyl)-oxazol-2-yl]-carbamate
[2028] Obtained from
2-tert-butoxycarbonylamino-oxazole-5-carboxylic acid and
1-amino-cyclo-propanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
hydrochloride analogously to the method for Example 168. However,
in the working up, no chromatographic purification was carried
out.
[2029] C.sub.26H.sub.26F.sub.4N.sub.6O.sub.5 (578.52)
[2030] R.sub.t=3.19 min. method 14
169b) 2-amino-oxazole-5-carboxylic acid
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
[2031] The protective group of the compound tert-butyl
[5-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-ca-
rbamoyl}-cyclopropylcarbamoyl)-oxazol-2-yl]-carbamate was cleaved
using the method described for intermediate step (144b).
[2032] C.sub.21H.sub.18F.sub.4N.sub.6O.sub.3 (478.40)
[2033] mass spectroscopy (ESI): [M+H].sup.+=479
[2034] R.sub.t=2.71 min. method 7
Example 170
1-(2-cyano-2-methyl-acetylamino)-cyclopropanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
##STR00772##
[2036] Reaction of 40 mg (0.40 mmol) cyanomethyl-acetic acid and
162 mg (0.40 mmol) [2037] 1-amino-cyclopropanecarboxylic acid
[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
hydrochloride analogously to the method for Example 168.
[2038] Yield: 28% of theory
[2039] C.sub.21H.sub.19F.sub.4N.sub.5O.sub.2 (449.40)
[2040] mass spectroscopy (ESI): [M+H].sup.+=450
[2041] R.sub.t=3.03 min. method 7
Example 171
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-2-hydroxy-isonicotinamide
##STR00773##
[2043] 150 mg (0.165 mmol) of 1-amino-cyclopropanecarboxylic acid
[5-(4-bromo-2-tri-fluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
tri-trifluoroacetate were added to a solution of 23 mg (0.165 mmol)
2-hydroxyisonicotinic acid, 56 mg (0.174 mmol) TBTU and 114 .mu.L
(0.661 mol) DIPEA in 0.5 mL DMF after 5 minutes stirring at ambient
temperature. Then the reaction mixture was left to stand overnight
and then chromatographed (RP with gradient, eluant: acetonitrile
and water with 0.2% trifluoroacetic acid).
[2044] Yield: 69% of theory
[2045] C.sub.23H.sub.19BrF.sub.3N.sub.6O.sub.3 (550.33)
[2046] mass spectroscopy (ESI): [M+H].sup.+=550
[2047] R.sub.t=1.73 min. method 12
[2048] The following Examples 172 to 179 were prepared analogously
from 1-amino-cyclopropanecarboxylic
acid-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
tri-trifluoroacetate and the corresponding acids.
Example 172
thiazole-5-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00774##
[2050] Yield: 94% of theory
[2051] C.sub.21H.sub.17BrF.sub.3N.sub.6O.sub.2S (540.36)
[2052] mass spectroscopy (ESI): [M+H].sup.+=540
[2053] R.sub.t=1.88 min. method 12
Example 173
6-amino-N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethy-
l]-carbamoyl}-cyclopropyl)-nicotinamide trifluoroacetate
##STR00775##
[2055] Yield: 89% of theory
[2056]
C.sub.23H.sub.20BrF.sub.3N.sub.6O.sub.2*C.sub.2HF.sub.3O.sub.2
(663.37)
[2057] mass spectroscopy (ESI): [M+H].sup.+=549
Example 174
pyridazine-4-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00776##
[2059] Yield: 71% of theory
[2060] C.sub.22H.sub.18BrF.sub.3N.sub.6O.sub.2 (535.32)
[2061] mass spectroscopy (ESI): [M+H].sup.+=535
[2062] R.sub.t=1.80 min. method 12
Example 175
2-dimethylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00777##
[2064] Yield: 67% of theory
[2065] C.sub.24H.sub.23BrF.sub.3N.sub.7O.sub.2 (578.39)
[2066] mass spectroscopy (ESI): [M+H].sup.+=578
[2067] R.sub.t=1.99 min. method 12
Example 176
2,6-dihydroxy-pyrimidine-4-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00778##
[2069] Yield: 46% of theory
[2070] C.sub.22H.sub.18BrF.sub.3N.sub.6O.sub.4 (567.32)
[2071] mass spectroscopy (ESI): [M+H].sup.+=567
[2072] R.sub.t=1.74 min. method 12
Example 177
1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic
acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00779##
[2074] Yield: 71% of theory
[2075] C.sub.24H.sub.21BrF.sub.3N.sub.5O.sub.3 (564.36)
[2076] mass spectroscopy (ESI): [M+H].sup.+=564
[2077] R.sub.t=1.78 min. method 12
Example 178
5-amino-N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethy-
l]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00780##
[2079] Yield: 99% of theory
[2080]
C.sub.23H.sub.20BrF.sub.3N.sub.6O.sub.2*C.sub.2HF.sub.3O.sub.2
(663.37)
[2081] mass spectroscopy (ESI): [M+H].sup.+=549
[2082] R.sub.t=1.68 min. method 12
Example 179
pyrimidine-5-carboxylic acid
(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethy-
l]-carbamoyl}-cyclopropyl)-amide
##STR00781##
[2083] 179a)
5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridine-2-carbonitril-
e
[2084] Obtained from 2-cyano-3,5-difluoropyridine and
4-bromo-2-trifluoromethyl-phenylamine analogously to method
(40a).
[2085] C.sub.13H.sub.6BrF.sub.4N.sub.3 (360.11)
[2086] mass spectroscopy (ESI): [M+H].sup.+=360
[2087] R.sub.t=2.68 min. method 12
179b)
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phe-
nyl)-amine
[2088] 171 mg (0.48 mmol)
5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridine-2-carbonitril-
e were dissolved in 3 mL pyridine, 1.5 mL glacial acetic acid and
1.5 mL water and combined with 459 mg (5.22 mmol) sodium
hypophosphite and Raney nickel. Then the mixture was hydrogenated
for three hours at 55.degree. C. and 3 bar hydrogen pressure. The
catalyst was filtered off, the filtrate was evaporated to dryness
and the residue was purified by chromatography (RP with gradient,
eluant: acetonitrile and water with 0.2 trifluoroacetic acid).
[2089] C.sub.13H.sub.10BrF.sub.4N.sub.3 (364.14)
[2090] mass spectroscopy (ESI): [M+H].sup.+=364
[2091] R.sub.t=1.79 min. method 13
179c) pyrimidine-5-carboxylic acid
(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethy-
l]-carbamoyl}-cyclopropyl)-amide
[2092] 54 mg (0.26 mmol)
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid, 36
.mu.L triethylamine and 105 mg (0.31 mmol) TBTU in 4 mL DMF were
stirred for 5 minutes at ambient temperature and then combined with
another 144 .mu.L triethylamine and 95 mg (0.26 mmol)
(6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)--
amine. The reaction mixture was stirred overnight and then
evaporated to dryness. The residue was purified by chromatography
(RP with gradient, eluant: acetonitrile and water with 0.2%
trifluoroacetic acid).
[2093] C.sub.22H.sub.17BrF.sub.4N.sub.6O.sub.2 (553.31)
[2094] mass spectroscopy (ESI): [M+H].sup.+=553
[2095] R.sub.t=2.20 min. method 13
Example 180
pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-
carbamoyl}-cyclopropyl)-amide
##STR00782##
[2096] 180a)
1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
[2097] A solution of 3.27 g (9.56 mmol)
5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile
in 100 mL diethyl ether was added dropwise to 5.42 mL 3 molar
methylmagnesium bromide in diethyl ether while being cooled with
the ice bath. Then the reaction mixture was allowed to come up to
ambient temperature and stirred for another hour. The mixture was
combined with 2.5 mL 1 molar hydrochloric acid and then evaporated
to dryness. The residue was purified by chromatography (RP with
gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic
acid).
[2098] C.sub.14H.sub.10BrF.sub.3N.sub.2O (359.14)
[2099] R.sub.t=2.57 min. method 12
180b)
1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone--
oxime
[2100] 702 mg (1.96 mmol)
1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone,
182 mg hydroxylamine-hydrochloride and 549 .mu.l (3.91 mmol)
triethylamine in 25 mL acetonitrile were refluxed for 1.5 hours.
The solvent was distilled off and the residue was combined with
dichloromethane and triethylamine and filtered through silica gel.
The filtrate was freed from the solvent and used directly in the
next reaction. 870 mg product.
180c)
[6-(1-amino-ethyl)-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)--
amine trifluoroacetate
[2101] A solution of 870 mg (approx. 85%, 2.0 mmol)
1-[5-(4-bromo-2-trifluoromethyl-phenyl-amino)-pyridin-2-yl]-ethanone-oxim-
e in 20 mL methanol was combined with 6 mL 10 molar hydrochloric
acid in methanol and 567 mg zinc and refluxed for 3 hours. Then the
mixture was filtered and the filtrate was freed from the solvent.
The residue was purified by chromatography (RP with gradient,
eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
[2102] Yield: 78% over two steps
[2103] C.sub.14H.sub.13BrF.sub.3N.sub.3 (360.17)
[2104] mass spectroscopy (ESI): [M+H].sup.+=360
[2105] R.sub.t=1.83 min. method 12
180d) pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-
carbamoyl}-cyclopropyl)-amide
[2106] Analogously to method (179c) from 190 mg (0.92 mmol)
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and
330 mg (0.69 mmol)
[6-(1-amino-ethyl)-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amine
trifluoroacetate.
[2107] Yield: 55% of theory
[2108]
C.sub.23H.sub.20BrF.sub.3N.sub.6O.sub.2*C.sub.2HF.sub.3O.sub.2
(663.37)
[2109] mass spectroscopy (ESI): [M+H].sup.+=549
[2110] R.sub.t=1.92 min. method 12
[2111] The (R)- and (S)-enantiomer of Example 180 were obtained by
chiral HPLC(SFC) from the racemic compound (column: Daicel ASH, 250
mm.times.10 mm, flow rate: 10 mL/min, eluant: 70% supercritical
carbon dioxide and 30% isopropanol with 0.2% triethylamine).
Example 181
2-methyl-pyrimidine-5-carboxylic acid
{1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
##STR00783##
[2112] 181a) tert-butyl
{144-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-carbama-
te
[2113] 877 mg (4.36 mmol)
1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and 2.58
(60%, 4.36 mmol)
2-(4-aminomethyl-phenylamino)-5-fluoro-benzonitrile
trifluoroacetate were coupled analogously to method (179c).
[2114] Yield: 30% of theory
[2115] C.sub.23H.sub.25FN.sub.4O.sub.3 (424.47)
[2116] mass spectroscopy (ESI): [M-H].sup.+=423
[2117] R.sub.t=2.39 min. method 13
181b) 1-amino-cyclopropanecarboxylic acid
4-(2-cyano-4-fluoro-phenylamino)-benzylamide trifluoroacetate
[2118] 560 mg (1.32 mmol)
2-(4-aminomethyl-phenylamino)-5-fluoro-benzonitrile
trifluoroacetate in 15 mL dichloromethane were combined with 15 mL
trifluoroacetic acid and stirred at ambient temperature. Then the
reaction mixture was evaporated to dryness and purified by
chromatography (RP with gradient, eluant: acetonitrile and water
with 0.2% trifluoroacetic acid).
[2119] C.sub.18H.sub.17FN.sub.4O*C.sub.2HF.sub.3O.sub.2
(438.38)
[2120] mass spectroscopy (ESI): [M-H].sup.+=325
[2121] R.sub.t=1.56 min. method 13
181c) 2-methyl-pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-a-
mide
[2122] Prepared analogously to method (179c) from 42 mg (0.29 mmol)
2-methyl-pyrimidine-5-carboxylic acid and 167 mg (75%, 0.29 mmol)
1-amino-cyclopropanecarboxylic
acid-4-(2-cyano-4-fluoro-phenylamino)-benzylamide
trifluoroacetate.
[2123] Yield: 83% of theory
[2124] C.sub.24H.sub.21FN.sub.6O.sub.2 (444.46)
[2125] mass spectroscopy (ESI): [M+H].sup.+=445
[2126] R.sub.t=1.92 min. method 13
[2127] Examples 182 and 183 were prepared analogously from
1-amino-cyclopropanecarboxylic
acid-4-(2-cyano-4-fluoro-phenylamino)-benzylamide trifluoroacetate
and the corresponding carboxylic acids.
Example 182
2-methoxy-pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-a-
mide
##STR00784##
[2129] Yield: 28% of theory
[2130] C.sub.24H.sub.21FN.sub.6O.sub.3 (460.46)
[2131] mass spectroscopy (ESI): [M+H].sup.+=461
[2132] R.sub.t=2.03 min. method 13
Example 183
2-methylamino-pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-4-fluoro-phenyl-amino)-benzylcarbamoyl]-cyclopropyl}--
amide
##STR00785##
[2134] Yield: 58% of theory
[2135] C.sub.24H.sub.22FN.sub.7O.sub.2 (459.48)
[2136] mass spectroscopy (ESI): [M+H].sup.+=460
[2137] R.sub.t=1.91 min. method 13
Example 184
2-amino-thiazole-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-
-carbamoyl}-cyclopropyl)-amide
##STR00786##
[2138] 184a) 2-acetylamino-thiazole-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
[2139] Prepared from 1-amino-cyclopropanecarboxylic
acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e hydrochloride and 2-acetylamino-thiazole-5-carboxylic acid
analogously to method (142c).
[2140] Yield: 51% of theory
[2141] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3S (536.50)
[2142] R.sub.t=2.96 min. method 7
184b) 2-amino-thiazole-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
[2143] 110 mg (0.21 mmol) 2-acetylamino-thiazole-5-carboxylic acid
(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide were stirred overnight at 80.degree. C. in
5 mL 4 molar hydrochloric acid. Then the reaction mixture was made
alkaline with potassium carbonate solution and the precipitated
solid was filtered off, washed with water and dried.
[2144] Yield: 43% of theory
[2145] C.sub.21H.sub.18F.sub.4N.sub.6O.sub.2S (494.47)
[2146] mass spectroscopy (ESI): [M+H].sup.+=495
[2147] R.sub.t=2.73 min. method 7
[2148] Examples 185 and 186 were prepared analogously from
1-amino-cyclopropanecarboxylic
acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e hydrochloride and the corresponding acetylamino-carboxylic
acid.
Example 185
5-amino-2H-pyrazole-3-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00787##
[2150] C.sub.21H.sub.19F.sub.4N.sub.7O.sub.2 (477.42)
[2151] mass spectroscopy (ESI): [M+H].sup.+=478
[2152] R.sub.t=2.69 min. method 7
Example 186
2-amino-4-methyl-thiazole-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00788##
[2154] C.sub.22H.sub.20F.sub.4N.sub.6O.sub.2S (508.49)
[2155] mass spectroscopy (ESI): [M+H].sup.+=509
[2156] R.sub.t=2.67 min. method 7
Example 187
pyrimidine-5-carboxylic acid
(1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-amide dihydrochloride
##STR00789##
[2157] 187a)
3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitri-
le
[2158] A solution of 5.00 g (28.9 mmol)
3,5-dichloro-pyridine-2-carbonitrile and 5.18 g (28.9 mmol)
4-fluoro-2-trifluoromethyl-phenylamine in 75 mL DMSO was combined
with 5.05 g (45.0 mmol) potassium-tert-butoxide while being cooled
and then stirred for 30 minutes at ambient temperature. The
reaction mixture was stirred into water and then extracted with
diethyl ether. The organic phases were washed with water and sodium
chloride solution, dried on sodium sulphate and evaporated down.
The residue was purified by chromatography through a silica gel
column (petroleum ether with 5 to 15% ethyl acetate).
[2159] Yield: 45% of theory
187b)
(6-aminomethyl-5-chloro-pyridin-3-O-(4-fluoro-2-trifluoromethyl-phen-
yl)-amine
[2160] A solution of 100 mg (0.32 mmol)
3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitri-
le in 3 mL THF was combined at ambient temperature with 31 .mu.L
borane-dimethylsulphide complex and then stirred overnight.
Methanol was then added carefully and the mixture was evaporated to
dryness. The residue was used in the next reaction without any
further purification.
187c) pyrimidine-5-carboxylic acid
(1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-amide dihydrochloride
[2161] Prepared from
(6-aminomethyl-5-chloro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-
-amine and 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic
acid analogously to the method for Example 151.
[2162] C.sub.22H.sub.17ClF.sub.4N.sub.6O.sub.2*2HCl (581.78)
[2163] mass spectroscopy (ESI): [M+H].sup.+=509
[2164] R.sub.t=3.68 min. method 10
Example 188
pyrimidine-5-carboxylic
acid-(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-
carbamoyl}-(S)-tetrahydro-furan-3-yl)-amide
##STR00790##
[2166] A solution of 59 mg (0.25 mmol)
(S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic
acid and 48 mg (0.30 mmol) N,N'-carbonyldiimidazole in 5 mL DMF was
stirred for one hour at 50.degree. C. and then combined with 89 mg
(0.25 mmol)
[6-(1-amino-ethyl)-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amine
and 45 .mu.L (0.26 mmol) DIPEA. It was then stirred for another
hour at ambient temperature. The reaction mixture was purified by
chromatography (RP with eluant gradient, eluant: acetonitrile and
water with 0.2% trifluoroacetic acid).
[2167] Yield: 41% of theory
[2168] C.sub.24H.sub.22BrF.sub.3N.sub.6O.sub.3 (579.37)
[2169] mass spectroscopy (ESI): [M+H].sup.+=579
[2170] R.sub.t=1.93 min. method 12
Example 188a: pyrimidine-5-carboxylic
acid-(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00791##
[2172] Separation of diastereomers by chiral HPLC (column: Daicel
ASH; 250.times.4.6 mm; 5 .mu.m; 25.degree. C.; eluant
CO.sub.2/(isopropanol+0.2% diethylamine) 80:20; flow: 10
mL/min)
[2173] R.sub.t=5.32-7.15 minutes
Example 188b
pyrimidine-5-carboxylic acid
(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarba-
moyl}-tetrahydrofuran-3-yl)-amide
##STR00792##
[2175] Separation of diastereomers by chiral HPLC (column: Daicel
ASH; 250.times.4.6 mm; 5 .mu.m; 25.degree. C.; eluant
CO.sub.2/(isopropanol+0.2% diethylamine) 80:20; flow: 10
mL/min)
[2176] R.sub.t=8.23-10.51 minutes
Example 189
pyrimidine-5-carboxylic acid
(1-{[5-(2-chloro-4-methyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyc-
lopropyl)-amide
##STR00793##
[2178] Analogously to Example 1d) the product was prepared by amide
coupling from
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and
(6-aminomethyl-pyridin-3-yl)-(2-chloro-4-methyl-phenyl)-amine using
TBTU as coupling reagent and diisoproylethylamine as base.
[2179] C.sub.22H.sub.21ClN.sub.6O.sub.2 (436.90)
[2180] Mass spectrum (ESI): [M+H].sup.+=437 [2181]
M-H].sup.-=435
[2182] R.sub.t=1.59 min (method 2)
Example 190
pyrimidine-5-carboxylic acid
(1-{[5-(2-chloro-4-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyc-
lopropyl)-amide
##STR00794##
[2184] Analogously to Example 1d) the product was prepared by amide
coupling from
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid and
(6-aminomethyl-pyridin-3-yl)-(2-chloro-4-fluoro-phenyl)-amine,
using TBTU as coupling reagent and diisoproylethylamine as
base.
[2185] C.sub.21H.sub.16ClFN.sub.6O.sub.2 (440.86)
[2186] Mass spectrum (ESI): [M+H].sup.+=441
[2187] R.sub.t=1.50 min (method 2)
Example 191
pyrimidine-5-carboxylic acid
(1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyc-
lohexyl)-amide
##STR00795##
[2188] 191a) 1-amino-cyclohexanecarboxylic acid
[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
[2189] 61 mg (0.25 mmol)
1-tert-butoxycarbonylamino-cyclohexanecarboxylic acid, 80 mg (0.25
mmol) TBTU and 53 .mu.L (0.38 mmol) triethylamine in 2 mL DMF were
stirred for 5 minutes at ambient temperature and then mixed with 67
mg (0.25 mmol)
(6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine. The
reaction mixture was then stirred overnight and purified by
chromatography (RP with eluting gradient, eluant: acetonitrile and
water with 0.1% trifluoroacetic acid). 93 mg of the isolated
Boc-protected amine were stirred for 2 hours at ambient temperature
in 5 mL of a 1:1 mixture of dichloromethane and trifluoroacetic
acid. The reaction mixture was evaporated to dryness and then
purified by chromatography (RP with eluting gradient, eluant:
acetonitrile and water with 0.1% trifluoroacetic acid).
[2190] Yield: 68% of theory (as trifluoroacetate)
[2191] mass spectroscopy [M+H].sup.+=393
[2192] R.sub.t=1.70 min method 6
191b) pyrimidine-5-carboxylic
acid-(1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl-
}-cyclohexyl)-amide
[2193] Prepared from 1-amino-cyclohexanecarboxylic acid
[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and
pyrimidine-5-carboxylic acid analogously to method 191a).
[2194] Yield: 37% of theory
[2195] C.sub.25H.sub.25F.sub.3N.sub.6O.sub.2 (498.51)
[2196] Mass spectrum (ESI): [M+H].sup.+=499 [2197]
[M-H].sup.-=497
[2198] R.sub.t=1.84 min (method 5)
Example 192
pyrimidine-5-carboxylic acid
(3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopentyl)-amide
##STR00796##
[2199] 192a) 1-amino-3-hydroxy-cyclopentanecarboxylic acid
[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
[2200] 1-tert-butoxycarbonylamino-3-hydroxy-cyclopentanecarboxylic
acid and
(6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine were
reacted analogously to method 191a).
[2201] Yield: 49% of theory (as trifluoroacetate)
[2202] mass spectroscopy [M+H].sup.+=395
[2203] R.sub.t=1.62 min method 6
192b) pyrimidine-5-carboxylic acid
(3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopentyl)-amide
[2204] The target compound was prepared from
1-amino-3-hydroxy-cyclopentanecarboxylic acid
[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and
pyrimidine-5-carboxylic acid analogously to method 191a).
[2205] Yield: 55% of theory
[2206] C.sub.24H.sub.23F.sub.3N.sub.6O.sub.3 (500.48)
[2207] Mass spectrum (ESI): [M+H].sup.+=501
[2208] R.sub.t=1.66 min (method 5)
Example 193
pyrimidine-5-carboxylic acid
(3-oxo-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoy-
l}-cyclopentyl)-amide
##STR00797##
[2210] 10 mg pyrimidine-5-carboxylic acid
(3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopentyl)-amide in 1 mL acetonitrile were mixed with 8 mg
Dess-Martin-Periodinane reagent and stirred for 1 hour at ambient
temperature. Then the reaction mixture was purified by
chromatography (RP with eluting gradient, eluant: acetonitrile and
water with 0.1% trifluoroacetic acid).
[2211] Yield: 90% of theory
[2212] C.sub.24H.sub.21F.sub.3N.sub.6O.sub.3 (498.46)
[2213] Mass spectrum (ESI): [M+H].sup.+=499 [2214]
[M-H].sup.-=497
[2215] R.sub.t=1.73 min (method 5)
Example 194
pyrimidine-5-carboxylic acid
(1-oxo-3-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoy-
l}-tetrahydro-1lambda*4*-thiophen-3-yl)-amide
##STR00798##
[2216] 194a) 3-amino-1-oxo-tetrahydrothiophene-3-carboxylic acid
[5-(2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-amide
[2217] The product was obtained from
3-tert-butoxycarbonylamino-1-oxo-tetrahydro-thiophene-3-carboxylic
acid and
(6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
analogously to method 191a).
[2218] Yield: 96% of theory (as trifluoroacetate)
[2219] mass spectroscopy [M+H].sup.+=413
[2220] R.sub.t=1.62 min method 6
194b) pyrimidine-5-carboxylic acid
(1-oxo-3-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoy-
l}-tetrahydro-thiophen-3-yl)-amide
[2221] Prepared from
3-amino-1-oxo-tetrahydro-thiophene-3-carboxylic
acid-[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
and pyrimidine-5-carboxylic acid analogously to method 191a).
[2222] Yield: 58% of theory
[2223] C.sub.23H.sub.21F.sub.3N.sub.6O.sub.3S (518.52)
[2224] Mass spectrum (ESI): [M+H].sup.+=519 [2225]
[M+H].sup.+=517
[2226] R.sub.t=1.66 min (method 5)
Example 195
4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-met-
hyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoic acid
##STR00799##
[2228] 469 (0.91 mmol) methyl
4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-me-
thyl]pyridin-3-ylamino}-3-trifluoromethyl-benzoate were stirred
overnight in 5 mL of 1N aqueous sodium hydroxide solution and 20 mL
ethanol at ambient temperature. Then the reaction mixture was
neutralised with 1N aqueous hydrochloric acid and evaporated to
dryness. The residue was dissolved in methanol and DMF, filtered
and then chromatographed (RP with eluting gradient, eluant:
acetonitrile and water with 0.2 trifluoroacetic acid).
[2229] Yield: 69% of theory
[2230] C.sub.23H.sub.19F.sub.3N.sub.6O.sub.4 (500.44)
[2231] Mass spectrum (ESI): [M+H]+=501 [2232] [M-H].sup.-=499
Example 196
methyl
4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-ami-
no)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoate
##STR00800##
[2233] 196a) methyl
4-(6-cyano-pyridin-3-ylamino)-3-trifluoromethyl-benzoate
[2234] 1190 mg (3.48 mmol)
5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile,
221 .mu.L (1.6 mmol) triethylamine and 97 mg (0.13 mmol)
Pd(ddpf)Cl.sub.2 in 10 mL methanol and 2 mL DMF were heated to
50.degree. C. in an autoclave under a carbon monoxide pressure of 5
bar for 60 hours. After removal of the solvents by distillation the
residue was dissolved in acetonitrile and methanol and filtered.
The filtrate was then evaporated down and purified by
chromatography (1st column: RP with eluting gradient, eluant:
acetonitrile and water with 0.1% trifluoroacetic acid; 2nd column:
silica gel, eluant: dichloromethane).
[2235] Yield: 78% of theory
[2236] mass spectroscopy [M+H].sup.+=322
196b) methyl
4-(6-aminomethyl-pyridin-3-ylamino)-3-trifluoromethyl-benzoate
[2237] 860 mg (2.7 mmol) methyl
4-(6-cyano-pyridin-3-ylamino)-3-trifluoromethyl-benzoate in 30 mL
methanolic ammonia were hydrogenated at ambient temperature under a
hydrogen pressure of 50 psi in the presence of 100 mg Raney nickel.
The catalyst was filtered off and the filtrate was freed from
solvent.
[2238] Yield: 76% of theory
[2239] mass spectroscopy [M+H].sup.+=326
196c) methyl
4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-me-
thyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoate
[2240] 191 mg (0.92 mmol)
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid, 305
mg (0.95 mmol) TBTU and 203 .mu.L (1.85 mmol) N-methylmorpholine in
3 mL DMF were stirred for 5 minutes at ambient temperature. The
solution was combined with 300 mg (0.92 mmol) methyl
4-(6-aminomethyl-pyridin-3-ylamino)-3-trifluoromethyl-benzoate and
left to stand over the weekend. Then the reaction mixture was
purified by chromatography (RP with eluting gradient, eluant:
acetonitrile and water with 0.2% trifluoroacetic acid).
[2241] Yield: 62% of theory
[2242] C.sub.24H.sub.21F.sub.3N.sub.6O.sub.4 (514.46)
[2243] Mass spectrum (ESI): [M+H].sup.+=515
[2244] R.sub.t=1.73 min (method 12)
Example 197
pyrimidine-5-carboxylic acid
(1-{[5-(4-cyano-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbam-
oyl}-cyclopropyl)-amide
##STR00801##
[2246] 55 mg (0.18 mmol) pyrimidine-5-carboxylic acid
{1-[(5-amino-pyridin-2-ylmethyl)-carbamoyl]-cyclopropyl}-amide, 33
mg (0.18 mmol) 4-fluoro-3-(trifluoromethyl)benzonitrile and 42 mg
(0.35 mg) potassium-tert-butoxide in 5 mL DMSO were stirred for 1 h
at 50.degree. C. The reaction mixture was filtered and the filtrate
was purified by chromatography (RP with eluting gradient, eluant:
acetonitrile and water with 0.2% trifluoroacetic acid).
[2247] Yield: 23% of theory
[2248] C.sub.23H.sub.18F.sub.3N.sub.7O.sub.2 (481.44)
[2249] Mass spectrum (ESI): [M+H].sup.+=482 [2250]
[M-H].sup.-=480
[2251] R.sub.t=1.69 min (method 12)
Example 198
pyrimidine-5-carboxylic acid
(1-{[5-(4-carbamoyl-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-ca-
rbamoyl}-cyclopropyl)-amide
##STR00802##
[2253] A solution of 50 mg (0.10 mmol)
4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-me-
thyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoic acid, 33 mg
(0.10 mmol) TBTU and 12 .mu.L (0.11 mmol) N-methylmorpholine in 0.5
mL DMF was stirred for 3 minutes at ambient temperature, then
combined with 17 .mu.L (0.11 mmol) 2,4-dimethoxybenzylamine,
stirred for a further 10 minutes and left to stand overnight. In
order to cleave the benzyl group the mixture was combined with 10
mL dichloromethane and 10 mL trifluoroacetic acid, left to stand
overnight and evaporated to dryness. The residue was filtered and
then purified by chromatography (RP with eluting gradient, eluant:
acetonitrile and water with 0.2% trifluoroacetic acid).
[2254] Yield: 6% of theory
[2255] C.sub.23H.sub.20F.sub.3N.sub.7O.sub.3 (499.45)
[2256] Mass spectrum (ESI): [M+H].sup.+=500 [2257]
[M-H].sup.-=498
Example 199
pyrimidine-5-carboxylic acid
{1-[4-(4-methoxy-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
##STR00803##
[2259] Obtained from
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid and
(4-aminomethyl-phenyl)-(4-methoxy-phenyl)-amine analogously to
method 191a).
[2260] Yield: 37% of theory
[2261] C.sub.23H.sub.23N.sub.5O.sub.3 (417.47)
[2262] Mass spectrum (ESI): [M+H].sup.+=418
[2263] [M-H].sup.-=416
[2264] R.sub.t=1.83 min (method 12)
Example 200
pyrimidine-5-carboxylic acid
(1-{[5-(2-chloro-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyc-
lopropyl)-amide
##STR00804##
[2266] Coupling of
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid and
(6-amino-methyl-pyridin-3-yl)-(2-chloro-6-fluoro-phenyl)-amine
trifluoroacetate with TBTU analogously to method 191a).
[2267] C.sub.21H.sub.18ClFN.sub.6O.sub.2 (440.86)
[2268] Mass spectrum (ESI): [M+H].sup.+=441 [2269]
[M-H].sup.-=439
[2270] R.sub.t=1.38 min (method 2)
Example 201
pyrimidine-5-carboxylic acid
{1-[4-(4-methoxy-2-methyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amid-
e
##STR00805##
[2272] Prepared from
1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid and
(4-aminomethyl-phenyl)-(4-methoxy-2-methyl-phenyl)-amine according
to method 191a).
[2273] C.sub.24H.sub.25N.sub.5O.sub.3 (431.49)
[2274] Mass spectrum (ESI): [M+H].sup.+=432 [2275]
[M+H].sup.+=430
[2276] R.sub.t=1.97 min (method 12)
Example 202
pyrimidine-5-carboxylic acid
(1-{4-[(4-methoxy-2-methyl-phenyl)-methyl-amino]-benzylcarbamoyl}-cyclopr-
opyl)-amide
##STR00806##
[2278] 73 mg (0.35 mmol) of
1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and
57 mg (0.35 mmol) CDI were stirred for 30 minutes at 50.degree. C.
in 5 mL DMF. 90 mg (0.35 mmol)
(4-aminomethyl-phenyl)-(4-methoxy-2-methyl-phenyl)-methyl-amine and
101 .mu.L diisopropylethylamine were added at ambient temperature
and the mixture was left overnight with stirring. The solvent was
distilled off and the residue was dissolved in methanol and
purified by chromatography (RP with eluting gradient, eluant:
acetonitrile and water with 0.2% trifluoroacetic acid).
[2279] Yield: 19% of theory
[2280] C.sub.25H.sub.27N.sub.5O.sub.3 (445.52)
[2281] Mass spectrum (ESI): [M+H].sup.+=446
[2282] R.sub.t=2.16 min (method 12)
Example 203
pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-
-yl]-ethylcarbamoyl}-cyclopropyl)-amide
##STR00807##
[2284] Prepared from intermediates A1 and B1 according to AAV1
[2285] C.sub.23H.sub.19ClF.sub.4N.sub.6O.sub.2 (522.89)
[2286] R.sub.t=2.30 minutes method 2
[2287] The racemate was separated into the enantiomers by chiral
HPLC (column: Daicel AD-H 250.times.20 mm; 5 .mu.m; 25.degree. C.;
eluant CO.sub.2/isopropanol (+0.2% diethylamine) 80:20; flow: 10
mL/min).
Example 203a
(R)-pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-
-yl]-ethylcarbamoyl}-cyclopropyl)-amide
##STR00808##
[2289] Analytical chiral HPLC (column: Daicel AD-H; 250.times.4.6
mm; 5 .mu.m; 25.degree. C.; eluant CO.sub.2/isopropanol 80:20;
flow: 4 mL/min)
[2290] R.sub.t=1.62 minutes
Example 203b
(S)-pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-
-yl]-ethylcarbamoyl}-cyclopropyl)-amide
##STR00809##
[2292] Analytical chiral HPLC (column: Daicel AD-H; 250.times.4.6
mm; 5 .mu.m; 25.degree. C.; eluant CO.sub.2/isopropanol 80:20;
flow: 4 mL/min)
[2293] R.sub.t=2.29 minutes
Example 204
pyrimidine-5-carboxylic
acid(1-{[5-(4-isopropyl-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl-
]-carbamoyl}-cyclopropyl)-amide
##STR00810##
[2295] Prepared from intermediates A2 and B1 according to AAV1
[2296] C.sub.25H.sub.25F.sub.3N.sub.6O.sub.2 (498.51)
[2297] R.sub.t=1.95 minutes (method 2)
Example 205
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-hydroxy-nicotinamide
##STR00811##
[2299] Prepared from intermediate C1 and 5-hydroxynicotinic acid
according to AAV1
[2300] C.sub.23H.sub.19ClF.sub.3N.sub.5O.sub.3 (505.88)
[2301] R.sub.t=1.74 minutes (method 13)
Example 206
6-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00812##
[2303] Prepared from intermediate C1 and 6-aminonicotinic acid
according to AAV1
[2304] C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.2 (504.90)
[2305] R.sub.t=1.60 minutes (method 13)
Example 207
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-2-hydroxy-isonicotinamide
##STR00813##
[2307] Prepared from intermediate C1 and 2-hydroxy-isonicotinic
acid according to AAV1
[2308] C.sub.23H.sub.19ClF.sub.3N.sub.6O.sub.3 (505.88)
[2309] R.sub.t=1.69 minutes (method 13)
Example 208
2,6-dihydroxy-pyrimidine-4-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00814##
[2311] Prepared from intermediate C1 and
2,6-dihydroxy-pyrimidine-4-carboxylic acid according to AAV1
[2312] C.sub.22H.sub.18ClF.sub.3N.sub.6O.sub.4 (522.87)
[2313] R.sub.t=1.70 minutes (method 13)
Example 209
pyridazine-4-carboxylic acid
(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-amide
##STR00815##
[2315] Prepared from intermediate C1 and pyridazine-4-carboxylic
acid according to AAV1
[2316] C.sub.22H.sub.18ClF.sub.3N.sub.6O.sub.2 (522.87)
[2317] R.sub.t=1.76 minutes (method 13)
Example 210
2-dimethylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00816##
[2319] Prepared from intermediate C1 and
2-dimethylamino-pyrimidine-5-carboxylic acid according to AAV1
[2320] C.sub.24H.sub.23ClF.sub.3N.sub.7O.sub.2 (533.94)
[2321] R.sub.t=1.94 minutes (method 13)
Example 211
6-hydroxy-pyridine-2-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00817##
[2323] Prepared from intermediate C1 and
6-hydroxy-pyridine-2-carboxylic acid according to AAV1
[2324] C.sub.23H.sub.19ClF.sub.3N.sub.5O.sub.3 (505.88)
[2325] R.sub.t=1.75 minutes method 13
Example 212
pyrimidine-5-carboxylic
acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethyl-
carbamoyl}-cyclopropyl)-amide
##STR00818##
[2327] Prepared from intermediates A4 and B1 according to AAV1
[2328] C.sub.23H.sub.19F.sub.2N.sub.7O.sub.2 (463.45)
[2329] R.sub.t=1.81 minutes method 2
[2330] The racemate was separated into the enantiomers by chiral
HPLC (column: Daicel AD-H 250.times.20 mm; 5 .mu.m; 25.degree. C.;
eluant CO.sub.2/isopropanol (+0.2% diethylamine) 80:20; flow: 10
mL/min):
Example 212a
(R)-pyrimidine-5-carboxylic
acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethyl-
carbamoyl}-cyclopropyl)-amide
##STR00819##
[2332] R.sub.t=2.75 minutes
Example 212b
(S)-pyrimidine-5-carboxylic
acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethyl-
carbamoyl}-cyclopropyl)-amide
##STR00820##
[2334] R.sub.t=5.12 minutes
Example 213
pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2--
yl]-ethylcarbamoyl}-cyclopropyl)-amide
##STR00821##
[2336] Prepared from intermediates A5 and B1 according to AAV1
[2337] C.sub.23H.sub.19BrF.sub.4N.sub.6O.sub.2 (567.34)
[2338] R.sub.t=2.34 minutes (method 2)
[2339] The racemate was separated into the enantiomers by chiral
HPLC:
Example 213a
(R)-pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2--
yl]-ethylcarbamoyl}-cyclopropyl)-amide
##STR00822##
[2341] Analytical chiral HPLC (column: Daicel AD-H; 250.times.4.6
mm; 5 .mu.m; 25.degree. C.; eluant CO.sub.2/isopropanol 80:20;
flow: 4 mL/min)
[2342] R.sub.t=1.78 minutes
Example 213b
(S)-pyrimidine-5-carboxylic
acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2--
yl]-ethylcarbamoyl}-cyclopropyl)-amide
##STR00823##
[2344] Analytical chiral HPLC (column: Daicel AD-H; 250.times.4.6
mm; 5 .mu.m; 25.degree. C.; eluant CO.sub.2/isopropanol 80:20;
flow: 4 mL/min)
[2345] R.sub.t=2.55 minutes
Example 214
(S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00824##
[2347] Prepared from intermediates A6 and B2 according to AAV1
[2348] C.sub.25H.sub.23F.sub.4N.sub.5O.sub.3 (517.48)
[2349] R.sub.t=3.33 minutes (method 7)
Example 215
6-oxo-5,6-dihydro-pyridazine-4-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00825##
[2351] Prepared from intermediate C2 and
6-oxo-5,6-dihydro-pyridazine-4-carboxylic acid according to
AAV1
[2352] C.sub.22H.sub.18F.sub.4N.sub.6O.sub.3 (490.42)
[2353] R.sub.t=2.80 minutes (method 7)
Example 216
(S)-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-Pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00826##
[2355] Prepared from intermediates A8 and B3 according to AAV1
[2356] C.sub.23H.sub.19ClF.sub.4N.sub.6O.sub.3 (538.89)
[2357] R.sub.t=3.86 minutes (method 7)
Example 217
5-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00827##
[2359] Prepared from intermediate C1 and 5-aminonicotinic acid
according to AAV1.
[2360] C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.2 (504.90)
[2361] R.sub.t=2.01 minutes (method 2)
Example 218
5-amino-N-(1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-
-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00828##
[2363] Prepared from intermediates A8 and B4 according to AAV1
[2364] C.sub.23H.sub.19ClF.sub.4N.sub.6O.sub.2 (522.89)
[2365] R.sub.t=3.21 minutes (method 7)
Example 219
(S)-5-amino-N-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00829##
[2367] Prepared from intermediates A8 and B2 according to AAV1
[2368] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.3 (552.91)
[2369] R.sub.t=3.22 minutes (method 7)
Example 220
(S)-3H-imidazo[4,5-b]pyridine-6-carboxylic
acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00830##
[2371] Prepared from intermediates A8 and B5 according to AAV1
[2372] C.sub.25H.sub.20ClF.sub.4N.sub.7O.sub.3 (577.92)
[2373] R.sub.t=3.62 minutes (method 7)
Example 221
1-methyl-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00831##
[2375] Prepared from intermediate C2 and
1-methyl-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according
to AAV1
[2376] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3 (504.44)
[2377] R.sub.t=2.95 minutes (method 7)
Example 222
(S)-5-amino-N-(3-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl--
methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00832##
[2379] Prepared from intermediates A9 and B2 according to AAV1
[2380] C.sub.24H.sub.22BrF.sub.3N.sub.6O.sub.3 (579.37)
[2381] R.sub.t=1.88 minutes (method 2)
Example 223
(S)-pyrimidine-5-carboxylic
acid-(3-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00833##
[2383] Prepared from intermediates A9 and B3 according to AAV1
[2384] C.sub.23H.sub.20BrF.sub.3N.sub.6O.sub.3 (565.35)
[2385] R.sub.t=1.74 minutes (method 2)
Example 224
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00834##
[2387] Prepared from intermediate C3 and
2-methylamino-pyrimidine-5-carboxylic acid according to AAV1
[2388] C.sub.24H.sub.22ClF.sub.4N.sub.7O.sub.3 (567.93)
[2389] R.sub.t=3.89 minutes (method 7)
Example 225
(S)-3-(3,3,3-trifluoro-propionylamino)-tetrahydrofuran-3-carboxylic
acid-[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00835##
[2391] Prepared from intermediate C3 and 3,3,3-trifluoro-propionic
acid according to AAV1
[2392] C.sub.21H.sub.18ClF.sub.7N.sub.4O.sub.3 (542.84)
[2393] R.sub.t=4.18 minutes (method 7)
Example 226
(S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00836##
[2395] Prepared from intermediates A3 and B2 according to AAV1
[2396] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.3 (534.92)
[2397] R.sub.t=1.57 minutes (method 2)
Example 227
6-methylamino-pyridazine-4-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00837##
[2399] Prepared from intermediate C2 and
6-methylamino-pyridazine-4-carboxylic acid according to AAV1
[2400] C.sub.23H.sub.21F.sub.4N.sub.7O.sub.2 (503.46)
[2401] R.sub.t=1.55 minutes (method 5)
Example 228
(S)-pyrimidine-5-carboxylic
acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00838##
[2403] Prepared from intermediates A3 and B3 according to AAV1
[2404] C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.3 (520.90)
[2405] R.sub.t=1.74 minutes (method 2)
Example 229
(S)-5-amino-N-(3-{[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00839##
[2407] Prepared from intermediates A10 and B2 according to AAV1
[2408] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.3 (534.92)
[2409] R.sub.t=3.19 minutes (method 7)
Example 230
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00840##
[2411] Prepared from intermediate C3 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
[2412] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.4 (568.91)
[2413] R.sub.t=4.01 minutes (method 7)
Example 231
(S)-5-amino-N-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benz-
ylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
##STR00841##
[2415] Prepared from intermediates A11 and B2 according to AAV1
[2416] C.sub.25H.sub.22F.sub.5N.sub.5O.sub.3 (535.47)
[2417] R.sub.t=1.23 minutes (method 2)
Example 232
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00842##
[2419] Prepared from intermediate C2 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2420] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.2 (488.44)
[2421] R.sub.t=1.94 minutes (method 2)
Example 233
2-methoxy-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00843##
[2423] Prepared from intermediate C2 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
[2424] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3 (504.44)
[2425] R.sub.t=2.00 minutes (method 2)
Example 234
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-hydroxy-nicotinamide
##STR00844##
[2427] Prepared from intermediate C4 and 6-hydroxy-nicotinic acid
according to AAV1
[2428] C.sub.23H.sub.19BrF.sub.3N.sub.5O.sub.3 (550.33)
[2429] R.sub.t=1.79 minutes (method 2)
Example 235
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-methoxy-nicotinamide
##STR00845##
[2431] Prepared from intermediate C4 and 6-methoxy-nicotinic acid
according to AAV1
[2432] C.sub.24H.sub.21BrF.sub.3N.sub.5O.sub.3 (564.36)
[2433] R.sub.t=1.84 minutes (method 2)
Example 236
(S)-5-amino-N-{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzyl-carbam-
oyl]-tetrahydrofuran-3-yl}-nicotinamide
##STR00846##
[2435] Prepared from intermediates A12 and B2 according to AAV1
[2436] C.sub.25H.sub.23F.sub.4N.sub.5O.sub.3 (517.48)
[2437] R.sub.t=3.07 minutes (method 3)
Example 237
(S)-5-amino-N-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00847##
[2439] Prepared from intermediate C5 and 5-aminonicotinic acid
according to AAV1
[2440] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.3 (552.91)
[2441] R.sub.t=3.28 minutes (method 3)
Example 238
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00848##
[2443] Prepared from intermediate C6 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
[2444] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.4 (552.46)
[2445] R.sub.t=3.62 minutes (method 3)
Example 239
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-hydroxy-nicotinamide
##STR00849##
[2447] Prepared from intermediate C1 and 6-hydroxy-nicotinic acid
according to AAV1
[2448] C.sub.23H.sub.19ClF.sub.3N.sub.5O.sub.3 (505.88)
[2449] R.sub.t=1.71 minutes (method 2)
Example 240
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-methoxy-nicotinamide
##STR00850##
[2451] Prepared from intermediate C1 and 6-methoxy-nicotinic acid
according to AAV1
[2452] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.3 (519.91)
[2453] R.sub.t=1.75 minutes (method 2)
Example 241
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00851##
[2455] Prepared from intermediate C5 and
2-methylamino-pyrimidine-5-carboxylic acid according to AAV1
[2456] C.sub.24H.sub.22ClF.sub.4N.sub.7O.sub.3 (567.93)
[2457] R.sub.t=4.64 minutes (method 3)
Example 242
(S)-pyrimidine-5-carboxylic
acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00852##
[2459] Prepared from intermediates A15 and B3 according to AAV1
[2460] C.sub.23H.sub.19ClF.sub.4N.sub.6O.sub.3 (538.89)
[2461] R.sub.t=2.15 minutes (method 2)
Example 243
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-hydroxy-nicotinamide
##STR00853##
[2463] Prepared from intermediate C2 and 5-hydroxynicotinic acid
according to AAV1
[2464] C.sub.23H.sub.19F.sub.4N.sub.5O.sub.3 (489.43)
[2465] mass spectroscopy (ESI): [M+H]+=490 [2466] [M-H]-=488
Example 244
6-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00854##
[2468] Prepared from intermediate C2 and 6-aminonicotinic acid
according to AAV1
[2469] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.2 (488.44)
[2470] mass spectroscopy (ESI): [M+H]+=489 [2471] [M-H]-=487
Example 245
2-isopropyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00855##
[2473] Prepared from intermediate C2 and
2-isopropyl-pyrimidine-5-carboxylic acid according to AAV1
[2474] C.sub.25H.sub.24F.sub.4N.sub.6O.sub.2 (516.50)
[2475] mass spectroscopy (ESI): [M+H]+=517
Example 246
2-trifluoromethyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00856##
[2477] Prepared from intermediate C2 and
2-trifluoromethyl-pyrimidine-5-carboxylic acid according to
AAV1
[2478] C.sub.23H.sub.17F.sub.7N.sub.6O.sub.2 (542.41)
[2479] mass spectroscopy (ESI): [M+H]+=543
Example 247
2-ethylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00857##
[2481] Prepared from intermediate C2 and
2-ethylamino-pyrimidine-5-carboxylic acid according to AAV1
[2482] C.sub.24H.sub.23F.sub.4N.sub.7O.sub.2 (517.48)
[2483] mass spectroscopy (ESI): [M+H]+=518
[2484] R.sub.t=1.58 minutes (method 5)
Example 248
2-piperidin-1-yl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00858##
[2486] Prepared from intermediate C2 and
2-piperidin-1-yl-pyrimidine-5-carboxylic acid according to AAV1
[2487] C.sub.27H.sub.27F.sub.4N.sub.7O.sub.2 (557.55)
[2488] mass spectroscopy (ESI): [M+H]+=558
Example 249
5-acetylamino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2--
ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00859##
[2490] Prepared from intermediate C2 and 5-acetylaminonicotinic
acid according to AAV1
[2491] C.sub.25H.sub.22F.sub.4N.sub.6O.sub.3 (530.48)
[2492] mass spectroscopy (ESI): [M+H]+=531
Example 250
2-pyrrolidin-1-yl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00860##
[2494] Prepared from intermediate C2 and
2-pyrrolidin-1-yl-pyrimidine-5-carboxylic acid according to
AAV1
[2495] C.sub.26H.sub.25F.sub.4N.sub.7O.sub.2 (543.52)
[2496] mass spectroscopy (ESI): [M+H]+=544
Example 251
6-acetylamino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2--
ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00861##
[2498] Prepared from intermediate C2 and 6-acetylamino-nicotinic
acid according to AAV1
[2499] C.sub.25H.sub.22F.sub.4N.sub.6O.sub.3 (530.48)
[2500] mass spectroscopy (ESI): [M+H]+=531
Example 252
6-dimethylamino-pyridazine-4-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00862##
[2502] Prepared from intermediate C2 and
6-dimethylamino-pyridazine-4-carboxylic acid according to AAV1
[2503] C.sub.24H.sub.23F.sub.4N.sub.7O.sub.2 (517.48)
[2504] mass spectroscopy (ESI): [M+H]+=518
Example 253
6-chloro-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00863##
[2506] Prepared from intermediate C2 and 6-chloro-nicotinic acid
according to AAV1
[2507] C.sub.23H.sub.18ClF.sub.4N.sub.5O.sub.2 (507.87)
[2508] mass spectroscopy (ESI): [M+H]+=508
Example 254
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-trifluoromethyl-nicotinamide
##STR00864##
[2510] Prepared from intermediate C2 and
6-trifluoromethyl-nicotinic acid according to AAV1
[2511] C.sub.24H.sub.18F.sub.7N.sub.5O.sub.2 (541.43)
[2512] mass spectroscopy (ESI): [M+H]+=542
Example 255
1H-pyrrolo[3,2-b]pyridine-6-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00865##
[2514] Prepared from intermediate C2 and
1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid according to AAV1
[2515] C.sub.25H.sub.20F.sub.4N.sub.6O.sub.2 (512.47)
[2516] mass spectroscopy (ESI): [M+H]+=513
Example 256
6-cyano-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00866##
[2518] Prepared from intermediate C2 and 6-cyano-nicotinic acid
according to AAV1
[2519] C.sub.24H.sub.18F.sub.4N.sub.6O.sub.2 (498.44)
[2520] mass spectroscopy (ESI): [M+H]+=499
Example 257
2-acetylamino-thiazole-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00867##
[2522] Prepared from intermediate C2 and
2-acetylamino-thiazole-5-carboxylic acid according to AAV1
[2523] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.3S (536.51)
[2524] mass spectroscopy (ESI): [M+H]+=537
Example 258
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00868##
[2526] Prepared from intermediate C3 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
[2527] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.4 (568.91)
[2528] R.sub.t=3.99 minutes (method 3)
Example 259
(S)--N-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2--
yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
##STR00869##
[2530] Prepared from intermediate C3 and 5-methylamino-nicotinic
acid according to AAV1
[2531] C.sub.25H.sub.23ClF.sub.4N.sub.6O.sub.3 (566.94)
[2532] R.sub.t=3.59 minutes (method 3)
Example 260
(S)--N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2--
yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
##STR00870##
[2534] Prepared from intermediate C6 and 5-methylamino-nicotinic
acid according to AAV1
[2535] C.sub.25H.sub.23F.sub.5N.sub.6O.sub.3 (550.49)
[2536] R.sub.t=3.81 minutes (method 3)
Example 261
(S)-3-(3,3,3-trifluoro-propionylamino)-tetrahydrofuran-3-carboxylic
acid-[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-amide
##STR00871##
[2538] Prepared from intermediate C5 and 3,3,3-trifluorpropionic
acid according to AAV1
[2539] C.sub.21H.sub.18ClF.sub.7N.sub.4O.sub.3 (542.84)
[2540] R.sub.t=4.11 minutes (method 3)
Example 262
6-amino-pyridazine-4-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00872##
[2542] Prepared from intermediate C2 and
6-amino-pyridazine-4-carboxylic acid according to AAV1
[2543] C.sub.22H.sub.19F.sub.4N.sub.7O.sub.2 (489.43)
[2544] R.sub.t=1.81 minutes (method 6)
Example 263
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-dimethylamino-nicotinamide
##STR00873##
[2546] Prepared from intermediate C1 and 6-dimethylamino-nicotinic
acid according to AAV1
[2547] C.sub.25H.sub.24ClF.sub.3N.sub.6O.sub.2 (532.95)
[2548] R.sub.t=1.90 minutes (method 2)
Example 264
1-methyl-1H-benzimidazole-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00874##
[2550] Prepared from intermediate C1 and
1-methyl-1H-benzimidazole-5-carboxylic acid according to AAV1
[2551] C.sub.26H.sub.22ClF.sub.3N.sub.6O.sub.2 (542.95)
[2552] R.sub.t=1.72 minutes (method 2)
Example 265
2-amino-1H-benzimidazole-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00875##
[2554] Prepared from intermediate C1 and
2-amino-1H-benzimidazole-5-carboxylic acid according to AAV1
[2555] C.sub.25H.sub.21ClF.sub.3N.sub.7O.sub.2 (543.93)
[2556] mass spectroscopy (ESI): [M+H]+=544
Example 266
1H-benzimidazole-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00876##
[2558] Prepared from intermediate C1 and
1H-benzimidazole-5-carboxylic acid according to AAV1
[2559] C.sub.25H.sub.20ClF.sub.3N.sub.6O.sub.2 (528.92)
[2560] R.sub.t=1.79 minutes (method 2)
Example 267
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00877##
[2562] Prepared from intermediate C6 and
(S)-2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2563] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.3 (536.46)
[2564] R.sub.t=3.91 minutes (method 3)
Example 268
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-dimethylamino-nicotinamide
##STR00878##
[2566] Prepared from intermediate C4 and 6-dimethylamino-nicotinic
acid according to AAV1
[2567] C.sub.25H.sub.24BrF.sub.3N.sub.6O.sub.2 (577.40)
[2568] R.sub.t=2.09 minutes (method 2)
Example 269
(S)--N-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2--
yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
##STR00879##
[2570] Prepared from intermediate C3 and 5-methylaminonicotinic
acid according to AAV1
[2571] C.sub.25H.sub.23ClF.sub.4N.sub.6O.sub.3 (566.94)
[2572] R.sub.t=3.66 minutes (method 3)
Example 270
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-methylamino-nicotinamide
##STR00880##
[2574] Prepared from intermediate C2 and 5-methylaminonicotinic
acid according to AAV1
[2575] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.2 (502.47)
[2576] R.sub.t=1.97 minutes (method 2)
Example 271
(S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00881##
[2578] Prepared from intermediates A15 and B2 according to AAV1
[2579] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.3 (552.91)
[2580] R.sub.t=2.48 minutes (method 2)
Example 272
N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamide
##STR00882##
[2582] Prepared from intermediate C7 and 5-methylaminonicotinic
acid according to AAV1
[2583] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.3 (520.46)
[2584] R.sub.t=1.87 minutes (method 2)
Example 273
5-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-oxetan-3--
yl}-nicotinamide
##STR00883##
[2586] Prepared from intermediate C8 and 5-aminonicotinic acid
according to AAV1
[2587] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.3 (485.46)
[2588] R.sub.t=2.17 minutes (method 6)
Example 274
(S)-2-methyl-pyrimidine-5-carboxylic
acid-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbam-
oyl]-tetrahydrofuran-3-yl}-amide
##STR00884##
[2590] Prepared from intermediate C9 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2591] C.sub.25H.sub.22F.sub.5N.sub.5O.sub.3 (535.47)
[2592] R.sub.t=3.61 minutes (method 3)
Example 275
5-acetylamino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2--
ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00885##
[2594] Prepared from intermediate C1 and 5-acetylamino-nicotinic
acid according to AAV1
[2595] C.sub.25H.sub.22ClF.sub.3N.sub.6O.sub.3 (546.93)
[2596] R.sub.t=1.78 minutes (method 2)
Example 276
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00886##
[2598] Prepared from intermediates A15 and B6 according to AAV1
[2599] C.sub.24H.sub.22ClF.sub.4N.sub.7O.sub.3 (567.93)
[2600] R.sub.t=2.16 minutes (method 2)
Example 277
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[5-(4-chloro-2-trifluoromethylphenylamino)-3-fluoro-pyridin-2-yl-
methyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00887##
[2602] Prepared from intermediates A15 and B7 according to AAV1
[2603] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.3 (552.91)
[2604] R.sub.t=2.50 minutes (method 2)
Example 278
(S)-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethylphenylamino)-pyridin-2-yl-
methyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00888##
[2606] Prepared from intermediates A18 and B3 according to AAV1
[2607] C.sub.23H.sub.19Cl.sub.2F.sub.3N.sub.6O.sub.3 (555.34)
[2608] R.sub.t=2.56 minutes (method 2)
Example 279
(S)-2-methyl-pyrimidine-5-carboxylic
acid-{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00889##
[2610] Prepared from intermediate C22 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2611] C.sub.25H.sub.23F.sub.4N.sub.5O.sub.3 (517.48)
[2612] R.sub.t=1.97 minutes (method 7)
Example 280
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-methylamino-nicotinamide
##STR00890##
[2614] Prepared from intermediate C1 and 5-methylaminonicotinic
acid according to AAV1
[2615] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.2 (518.92)
[2616] R.sub.t=1.96 minutes (method 2)
Example 281
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00891##
[2618] Prepared from intermediates A18 and B6 according to AAV1
[2619] C.sub.24H.sub.22Cl.sub.2F.sub.3N.sub.7O.sub.3 (584.38)
[2620] R.sub.t=2.56 minutes (method 2)
Example 282
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00892##
[2622] Prepared from intermediates A18 and B7 according to AAV1
[2623] C.sub.24H.sub.21Cl.sub.2F.sub.3N.sub.6O.sub.3 (569.37)
[2624] R.sub.t=2.59 minutes (method 2)
Example 283
2-methyl-pyrimidine-5-carboxylic
acid-{1-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbam-
oyl]-cyclopropyl}-amide
##STR00893##
[2626] Prepared from intermediate C10 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2627] C.sub.24H.sub.20F.sub.5N.sub.5O.sub.2 (505.44)
[2628] R.sub.t=1.33 minutes (method 7)
Example 284
6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00894##
[2630] Prepared from intermediate C1 and
6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to
AAV1
[2631] C.sub.22H.sub.18ClF.sub.3N.sub.6O.sub.3 (506.87)
[2632] R.sub.t=2.13 minutes (method 2)
Example 285
(S)-5-amino-N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00895##
[2634] Prepared from intermediates A18 and B2 according to AAV1
[2635] C.sub.24H.sub.21Cl.sub.2F.sub.3N.sub.6O.sub.3 (569.37)
[2636] R.sub.t=2.34 minutes (method 2)
Example 286
(S)--N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2--
yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-hydroxy-nicotinamide
##STR00896##
[2638] Prepared from intermediates A18 and B8 according to AAV
1
[2639] C.sub.24H.sub.20Cl.sub.2F.sub.3N.sub.5O.sub.4 (570.35)
[2640] R.sub.t=2.52 minutes (method 2)
[2641] mass spectroscopy (ESI): [M+H]+=570; [M-H]-=568
Example 287
(S)-pyrimidine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00897##
[2643] Prepared from intermediates A6 and B3 according to AAV1
[2644] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.3 (503.45)
[2645] R.sub.t=2.43 minutes (method 2)
Example 288
(S)-2-methyl-pyrimidine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00898##
[2647] Prepared from intermediates A6 and B7 according to AAV1
[2648] C.sub.25H.sub.23F.sub.4N.sub.5O.sub.3 (517.48)
[2649] R.sub.t=2.64 minutes (method 2)
Example 289
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00899##
[2651] Prepared from intermediates A6 and B6 according to AAV1
[2652] C.sub.25H.sub.24F.sub.4N.sub.6O.sub.3 (532.50)
[2653] R.sub.t=2.44 minutes (method 2)
Example 290
(S)-5-amino-N-{3-[2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benz-
ylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
##STR00900##
[2655] Prepared from intermediate C11 and 5-aminonicotinic acid
according to AAV1
[2656] C.sub.25H.sub.22F.sub.5N.sub.5O.sub.3 (535.47)
[2657] R.sub.t=1.63 minutes (method 7)
Example 291
(S)-2-methyl-pyrimidine-5-carboxylic
acid-{3-[2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylcarbam-
oyl]-tetrahydrofuran-3-yl}-amide
##STR00901##
[2659] Prepared from intermediate C11 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2660] C.sub.25H.sub.22F.sub.5N.sub.5O.sub.3 (535.47)
[2661] R.sub.t=1.83 minutes (method 7)
Example 292
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00902##
[2663] Prepared from intermediates A10 and B7 according to AAV1
[2664] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.3 (534.92)
[2665] R.sub.t=1.78 minutes (method 7)
Example 293
(S)-6-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00903##
[2667] Prepared from intermediates A15 and B9 according to AAV1
[2668] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.3 (552.91)
[2669] R.sub.t=2.14 minutes (method 2)
Example 294
2-methyl-pyrimidine-5-carboxylic
acid-{1-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cycl-
opropyl}-amide
##STR00904##
[2671] Prepared from intermediate C12 and
2-methylpyrimidine-5-carboxylic acid according to AAV1
[2672] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.2 (487.45)
[2673] R.sub.t=1.91 minutes (method 7)
Example 295
pyrimidine-5-carboxylic
acid-(1-{[5-(2-cyano-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-
-cyclopropyl)-amide
##STR00905##
[2675] Prepared from intermediates A20 and B1 according to AAV1
[2676] C.sub.22H.sub.8FN.sub.7O.sub.2 (431.43)
[2677] R.sub.t=1.62 minutes (method 2)
Example 296
pyrimidine-5-carboxylic
acid-{1-[4-(2-cyano-phenylamino)-2-fluoro-benzyl-carbamoyl]-cyclopropyl}--
amide
##STR00906##
[2679] Prepared from intermediates A30 and B1 according to AAV1
[2680] C.sub.23H.sub.19FN.sub.6O.sub.2 (430.44)
[2681] R.sub.t=1.88 minutes (method 2)
Example 297
(S)-6-amino-N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00907##
[2683] Prepared from intermediates A18 and B9 according to AAV1
[2684] C.sub.24H.sub.21Cl.sub.2F.sub.3N.sub.6O.sub.3 (569.37)
[2685] R.sub.t=2.46 minutes (method 2)
Example 298
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00908##
[2687] Prepared from intermediate C13 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2688] C.sub.23H.sub.19F.sub.5N.sub.6O.sub.2 (506.43)
[2689] R.sub.t=1.74 minutes (method 7)
Example 299
(S)-thiazole-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00909##
[2691] Prepared from intermediate C14 and thiazole-5-carboxylic
acid according to AAV1
[2692] C.sub.23H.sub.20F.sub.4N.sub.4O.sub.3S (508.49)
[2693] R.sub.t=2.43 minutes (method 2)
Example 300
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00910##
[2695] Prepared from intermediate C14 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
[2696] C.sub.25H.sub.23F.sub.4N.sub.5O.sub.4 (533.48)
[2697] R.sub.t=2.61 minutes (method 2)
Example 301
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00911##
[2699] Prepared from intermediate C15 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1
[2700] C.sub.23H.sub.20ClF.sub.3N.sub.6O.sub.2 (504.90)
[2701] R.sub.t=1.79 minutes (method 7)
Example 302
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-methyl-nicotinamide
##STR00912##
[2703] Prepared from intermediate C2 and 5-methyl-nicotinic acid
according to AAV1
[2704] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.2 (487.45)
[2705] R.sub.t=1.96 minutes (method 2)
Example 303
2-methyl-thiazole-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-
-carbamoyl}-cyclopropyl)-amide
##STR00913##
[2707] Prepared from intermediate C2 and
2-methyl-thiazole-5-carboxylic acid according to AAV1
[2708] C.sub.22H.sub.19F.sub.4N.sub.5O.sub.2S (493.48)
[2709] R.sub.t=2.07 minutes (method 2)
Example 304
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00914##
[2711] Prepared from intermediates A7 and B6 according to AAV1
[2712] C.sub.24H.sub.23F.sub.4N.sub.7O.sub.3 (533.48)
[2713] R.sub.t=1.88 minutes (method 2)
Example 305
(S)--N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-5-methylamino-nicotinamide
##STR00915##
[2715] Prepared from intermediate C14 and 5-methylaminonicotinic
acid according to AAV1
[2716] C.sub.26H.sub.25F.sub.4N.sub.5O.sub.3 (531.51)
[2717] R.sub.t=1.83 minutes (method 7)
Example 306
pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00916##
[2719] Prepared from intermediates A21 and B1 according to AAV1
[2720] C.sub.23H.sub.20F.sub.4N.sub.6O.sub.2 (488.44)
[2721] R.sub.t=1.81 minutes (method 2)
Example 307
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00917##
[2723] Prepared from intermediates A7 and B7 according to AAV1
[2724] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.3 (518.47)
[2725] R.sub.t=2.32 minutes (method 2)
Example 308
(S)--N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-5-methyl-nicotinamide
##STR00918##
[2727] Prepared from intermediates C14 and 5-methylnicotinic acid
according to AAV1
[2728] C.sub.26H.sub.24F.sub.4N.sub.4O.sub.3 (516.49)
[2729] R.sub.t=2.45 minutes (method 2)
Example 309
(S)-6-amino-N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzyl-carbam-
oyl]-tetrahydrofuran-3-yl}-nicotinamide
##STR00919##
[2731] Prepared from intermediates C14 and 6-aminonicotinic acid
according to AAV1
[2732] C.sub.25H.sub.23F.sub.4N.sub.5O.sub.3 (517.48)
[2733] R.sub.t=2.09 minutes (method 2)
Example 310
(S)-2-isopropyl-pyrimidine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00920##
[2735] Prepared from intermediates C14 and
2-isopropyl-pyrimidine-5-carboxylic acid according to AAV1
[2736] C.sub.27H.sub.27F.sub.4N.sub.5O.sub.3 (545.53)
[2737] R.sub.t=2.60 minutes (method 2)
Example 311
(S)--N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-
-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
##STR00921##
[2739] Prepared from intermediates C16 and 5-methylamino-nicotinic
acid according to AAV1
[2740] C.sub.25H.sub.24F.sub.4N.sub.6O.sub.3 (532.50)
[2741] R.sub.t=2.22 minutes (method 2)
Example 312
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-methyl-nicotinamide
##STR00922##
[2743] Prepared from intermediates C1 and 6-methyl-nicotinic acid
according to AAV1
[2744] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.2 (503.91)
[2745] R.sub.t=2.17 minutes (method 2)
Example 313
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-methoxy-nicotinamide
##STR00923##
[2747] Prepared from intermediates C1 and 5-methoxy-nicotinic acid
according to AAV1
[2748] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.3 (519.91)
[2749] R.sub.t=2.29 minutes (method 2)
Example 314
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00924##
[2751] Prepared from intermediates C17 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
[2752] C.sub.24H.sub.21ClF.sub.4N.sub.6O.sub.4 (568.91)
[2753] R.sub.t=2.53 minutes (method 2)
Example 315
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-methyl-nicotinamide
##STR00925##
[2755] Prepared from intermediates C4 and 6-methyl-nicotinic acid
according to AAV1
[2756] C.sub.24H.sub.21BrF.sub.3N.sub.5O.sub.2 (548.36)
[2757] R.sub.t=2.24 minutes (method 2)
Example 316
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-5-methoxy-nicotinamide
##STR00926##
[2759] Prepared from intermediates C4 and 5-methoxy-nicotinic acid
according to AAV1
[2760] C.sub.24H.sub.21BrF.sub.3N.sub.5O.sub.3 (564.36)
[2761] R.sub.t=2.34 minutes (method 2)
Example 317
(S)-2-methyl-pyrimidine-5-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00927##
[2763] Prepared from intermediates A22 and B7 according to AAV1
[2764] C.sub.25H.sub.23ClF.sub.3N.sub.5O.sub.3 (533.94)
[2765] R.sub.t=2.60 minutes (method 2)
Example 318
(S)-6-amino-N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzyl-carbam-
oyl]-tetrahydrofuran-3-yl}-nicotinamide
##STR00928##
[2767] Prepared from intermediates A22 and B9 according to AAV1
[2768] C.sub.25H.sub.23ClF.sub.3N.sub.5O.sub.3 (533.94)
[2769] R.sub.t=2.25 minutes (method 2)
Example 319
(S)--N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2--
yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
##STR00929##
[2771] Prepared from intermediates C17 and 5-methylamino-nicotinic
acid according to AAV1
[2772] C.sub.25H.sub.23ClF.sub.4N.sub.6O.sub.3 (566.94)
[2773] R.sub.t=2.21 minutes (method 2)
Example 320
(S)-5-amino-N-(3-{[3-fluoro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00930##
[2775] Prepared from intermediates A23 and B2 according to AAV1
[2776] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.3 (518.47)
[2777] R.sub.t=1.52 minutes (method 7)
Example 321
(S)-5-amino-N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzyl-carbam-
oyl]-tetrahydrofuran-3-yl}-nicotinamide
##STR00931##
[2779] Prepared from intermediates A22 and B2 according to AAV1
[2780] C.sub.25H.sub.23ClF.sub.3N.sub.5O.sub.3 (533.94)
[2781] R.sub.t=2.36 minutes (method 2)
Example 322
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00932##
[2783] Prepared from intermediates C14 and
6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to
AAV1
[2784] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.4 (519.45)
[2785] R.sub.t=2.39 minutes (method 2)
Example 323
(S)-2-methylamino-pyrimidine-5-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00933##
[2787] Prepared from intermediates A22 and B6 according to AAV1
[2788] C.sub.25H.sub.24ClF.sub.3N.sub.6O.sub.3 (548.95)
[2789] R.sub.t=2.57 minutes (method 2)
Example 324
(S)-pyrimidine-5-carboxylic
acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00934##
[2791] Prepared from intermediates A21 and B3 according to
AAV1.
[2792] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.3 (518.47)
[2793] R.sub.t=1.80 minutes (method 2)
[2794] mass spectroscopy (ESI): [M+H]+=519 [2795] [M-H]-=517
Example 325
pyrimidine-5-carboxylic
acid-(1-{[5-(4-bromo-2-chloro-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00935##
[2797] Prepared from intermediates A24 and B1 according to
AAV1.
[2798] C.sub.21H.sub.17BrClFN.sub.6O.sub.2 (519.76)
[2799] R.sub.t=2.01 minutes (method 2)
Example 326
pyrimidine-5-carboxylic
acid-(1-{[5-(2-bromo-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-
-cyclopropyl)-amide
##STR00936##
[2801] Prepared from intermediates A25 and B1 according to
AAV1.
[2802] C.sub.21H.sub.18BrFN.sub.6O.sub.2 (485.32)
[2803] R.sub.t=1.64 minutes (method 2)
Example 327
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00937##
[2805] Prepared from intermediates C16 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1.
[2806] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.4 (534.47)
[2807] R.sub.t=1.98 minutes (method 2)
Example 328
(S)-2-ethylamino-pyrimidine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00938##
[2809] Prepared from intermediates C14 and
2-ethylamino-pyrimidine-5-carboxylic acid according to AAV1.
[2810] C.sub.26H.sub.26F.sub.4N.sub.6O.sub.3 (546.52)
[2811] R.sub.t=2.62 minutes (method 2)
Example 329
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-ethylamino-nicotinamide
##STR00939##
[2813] Prepared from intermediates C1 and 6-ethylamino-nicotinic
acid according to AAV1.
[2814] C.sub.25H.sub.24ClF.sub.3N.sub.6O.sub.2 (532.95)
[2815] R.sub.t=2.32 minutes (method 2)
Example 330
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-propylamino-nicotinamide
##STR00940##
[2817] Prepared from intermediates C1 and 6-propylamino-nicotinic
acid according to AAV1.
[2818] C.sub.26H.sub.26ClF.sub.3N.sub.6O.sub.2 (546.98)
[2819] R.sub.t=2.04 minutes (method 2)
Example 331
(S)--N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2--
yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-hydroxy-nicotinamide
##STR00941##
[2821] Prepared from intermediates A15 and B8 according to
AAV1.
[2822] C.sub.24H.sub.20ClF.sub.4N.sub.5O.sub.4 (553.90)
[2823] R.sub.t=2.48 minutes (method 2)
Example 332
(S)-pyrimidine-5-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00942##
[2825] Prepared from intermediates C18 and pyrimidine-5-carboxylic
acid according to AAV1.
[2826] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.3 (519.91)
[2827] R.sub.t=2.57 minutes (method 2)
Example 333
(S)-2-methoxy-pyrimidine-5-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00943##
[2829] Prepared from intermediates C18 and
2-methoxy-pyrimidine-5-carboxylic acid according to AAV1.
[2830] C.sub.25H.sub.23ClF.sub.3N.sub.5O.sub.4 (549.93)
[2831] R.sub.t=2.72 minutes (method 2)
Example 334
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-ethylamino-nicotinamide
##STR00944##
[2833] Prepared from intermediates C4 and 6-ethylamino-nicotinic
acid according to AAV1.
[2834] C.sub.25H.sub.24CBrF.sub.3N.sub.6O.sub.2 (577.40)
[2835] R.sub.t=2.01 minutes (method 2)
Example 335
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-propylamino-nicotinamide
##STR00945##
[2837] Prepared from intermediates C4 and 6-propylamino-nicotinic
acid according to AAV1.
[2838] C.sub.26H.sub.26BrF.sub.3N.sub.6O.sub.2 (591.43)
[2839] R.sub.t=2.12 minutes (method 2)
Example 336
(S)-thiazole-5-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00946##
[2841] Prepared from intermediates C18 and thiazole-5-carboxylic
acid according to AAV1.
[2842] C.sub.23H.sub.20ClF.sub.3N.sub.4O.sub.3S (524.95)
[2843] R.sub.t=2.58 minutes (method 2)
Example 337
(S)--N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-5-methoxy-nicotinamide
##STR00947##
[2845] Prepared from intermediates C18 and 5-methoxy-nicotinic acid
according to AAV1.
[2846] C.sub.26H.sub.24ClF.sub.3N.sub.4O.sub.4 (548.95)
[2847] R.sub.t=2.62 minutes (method 2)
Example 338
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00948##
[2849] Prepared from intermediates A22 and B10 according to
AAV1.
[2850] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.4 (535.91)
[2851] R.sub.t=2.28 minutes (method 2)
Example 339
5-chloro-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00949##
[2853] Prepared from intermediates C2 and 5-chloro-nicotinic acid
according to AAV1.
[2854] C.sub.23H.sub.18ClF.sub.4N.sub.5O.sub.2 (507.87)
[2855] R.sub.t=2.18 minutes (method 2)
Example 340
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide
##STR00950##
[2857] Prepared from intermediates C2 and
5-trifluoromethyl-nicotinic acid according to AAV1.
[2858] C.sub.24H.sub.18F.sub.7N.sub.5O.sub.2 (541.43)
[2859] R.sub.t=2.32 minutes (method 2)
Example 341
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-methyl-nicotinamide
##STR00951##
[2861] Prepared from intermediates C2 and 6-methyl-nicotinic acid
according to AAV1.
[2862] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.2 (487.45)
[2863] R.sub.t=1.85 minutes (method 2)
Example 342
(S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00952##
[2865] Prepared from intermediates A21 and B2 according to
AAV1.
[2866] C.sub.25H.sub.24F.sub.4N.sub.6O.sub.3 (487.45)
[2867] R.sub.t=1.85 minutes (method 2)
Example 343
N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carba-
moyl}-cyclopropyl)-6-methylamino-nicotinamide
##STR00953##
[2869] Prepared from intermediates C4 and 6-methylamino-nicotinic
acid according to AAV1.
[2870] C.sub.24H.sub.22BrF.sub.3N.sub.6O.sub.2 (563.38)
[2871] R.sub.t=2.32 minutes (method 2)
Example 344
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00954##
[2873] Prepared from intermediates C19 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
[2874] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.2 (502.47)
[2875] R.sub.t=1.84 minutes (method 2)
Example 345
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00955##
[2877] Prepared from intermediates A26 and B7 according to
AAV1.
[2878] C.sub.25H.sub.24ClF.sub.3N.sub.6O.sub.3 (548.95)
[2879] R.sub.t=2.16 minutes (method 2)
Example 346
(S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00956##
[2881] Prepared from intermediates A26 and B2 according to
AAV1.
[2882] C.sub.25H.sub.24ClF.sub.3N.sub.6O.sub.3 (548.95)
[2883] R.sub.t=2.23 minutes (method 2)
Example 347
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-methylamino-nicotinamide
##STR00957##
[2885] Prepared from intermediates C1 and 6-methylamino-nicotinic
acid according to AAV1.
[2886] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.2 (518.92)
[2887] R.sub.t=1.85 minutes (method 2)
Example 348
(S)-6-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyr-
idin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00958##
[2889] Prepared from intermediates A14 and B9 according to
AAV1.
[2890] C.sub.24H.sub.21F.sub.5N.sub.6O.sub.3 (536.46)
[2891] R.sub.t=1.96 minutes (method 2)
[2892] mass spectroscopy (ESI): [M+H]+=537 [2893] [M-H]-=535
Example 349
(S)-6-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00959##
[2895] Prepared from intermediates A7 and B9 according to AAV1.
[2896] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.3 (518.47)
[2897] mass spectroscopy (ESI): [M+H]+=519 [2898] [M-H]-=517
Example 350
2-hydroxy-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00960##
[2900] Prepared from intermediates C1 and
2-hydroxy-pyrimidine-5-carboxylic acid according to AAV1.
[2901] C.sub.22H.sub.18ClF.sub.3N.sub.6O.sub.3 (506.87)
[2902] R.sub.t=2.42 minutes (method 2)
Example 351
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-fluoro-nicotinamide
##STR00961##
[2904] Prepared from intermediates C1 and 5-fluoro-nicotinic acid
according to AAV1.
[2905] C.sub.23H.sub.18ClF.sub.4N.sub.5O.sub.2 (507.87)
[2906] R.sub.t=1.96 minutes (method 2)
Example 352
5-chloro-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmet-
hyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00962##
[2908] Prepared from intermediates C1 and 5-chloro-nicotinic acid
according to AAV1.
[2909] C.sub.23H.sub.18Cl.sub.2F.sub.3N.sub.5O.sub.2 (524.33)
[2910] R.sub.t=2.10 minutes (method 2)
Example 353
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-methyl-nicotinamide
##STR00963##
[2912] Prepared from intermediates C1 and 5-methyl-nicotinic acid
according to AAV1.
[2913] C.sub.24H.sub.21ClF.sub.3N.sub.5O.sub.2 (503.91)
[2914] R.sub.t=1.86 minutes (method 2)
Example 354
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide
##STR00964##
[2916] Prepared from intermediates C1 and
5-trifluoromethyl-isonicotinic acid according to AAV1.
[2917] C.sub.24H.sub.18ClF.sub.6N.sub.5O.sub.2 (557.88)
[2918] R.sub.t=2.22 minutes (method 2)
Example 355
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-2-fluoro-isonicotinamide
##STR00965##
[2920] Prepared from intermediates C1 and 2-fluoro-isonicotinic
acid according to AAV1.
[2921] C.sub.23H.sub.18ClF.sub.4N.sub.5O.sub.2 (507.87)
[2922] R.sub.t=2.02 minutes (method 2)
Example 356
3-methoxy-isoxazole-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00966##
[2924] Prepared from intermediates C1 and
3-methoxy-isoxazole-5-carboxylic acid according to AAV1
[2925] C.sub.22H.sub.19ClF.sub.3N.sub.5O.sub.4 (509.87)
[2926] R.sub.t=1.96 minutes (method 2)
Example 357
isothiazole-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00967##
[2928] Prepared from intermediates C1 and isothiazole-5-carboxylic
acid according to AAV1.
[2929] C.sub.21H.sub.7ClF.sub.3N.sub.5O.sub.2S (495.91)
[2930] R.sub.t=1.88 minutes (method 2)
Example 358
isothiazol-4-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00968##
[2932] Prepared from intermediates C1 and isothiazole-4-carboxylic
acid according to AAV1.
[2933] C.sub.21H.sub.7ClF.sub.3N.sub.5O.sub.2S (495.91)
[2934] R.sub.t=1.84 minutes (method 2)
Example 359
(S)-5-amino-N-(3-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-
-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
##STR00969##
[2936] Prepared from intermediates A27 and B2 according to
AAV1.
[2937] C.sub.25H.sub.25F.sub.3N.sub.6O.sub.3 (514.51)
[2938] R.sub.t=1.51 minutes (method 2)
Example 360
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-y-
lmethyl]-carbamoyl}-cyclopropyl)-amide
##STR00970##
[2940] Prepared from intermediates A26 and B11 according to
AAV1.
[2941] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.2 (518.92)
[2942] R.sub.t=2.11 minutes (method 2)
Example 361
5-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-
-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00971##
[2944] Prepared from intermediates A26 and B4 according to
AAV1.
[2945] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.2 (518.92)
[2946] R.sub.t=1.83 minutes (method 2)
Example 362
1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00972##
[2948] Prepared from intermediates C1 and trifluoroacetic acid
according to AAV1
[2949] C.sub.19H.sub.15ClF.sub.6N.sub.4O.sub.2 (480.79)
[2950] R.sub.t=2.15 minutes (method 2)
Example 363
1-(3,3,3-trifluoro-propionylamino)-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00973##
[2952] Prepared from intermediates C1 and 3,3,3-trifluoro-propionic
acid according to AAV1
[2953] C.sub.20H.sub.17ClF.sub.6N.sub.4O.sub.2 (494.82)
[2954] R.sub.t=2.07 minutes (method 2)
Example 364
1-(2-cyano-acetylamino)-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00974##
[2956] Prepared from intermediates C1 and 2-cyano-acetic acid
according to AAV1.
[2957] C.sub.20H.sub.17ClF.sub.3N.sub.5O.sub.2 (451.83)
[2958] R.sub.t=1.85 minutes (method 2)
Example 365
(S)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00975##
[2960] Prepared from intermediates C14 and
1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid according to AAV1.
[2961] C.sub.27H.sub.23F.sub.4N.sub.5O.sub.3 (541.50)
[2962] R.sub.t=2.14 minutes (method 2)
Example 366
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00976##
[2964] Prepared from intermediates A27 and B7 according to AAV1
[2965] C.sub.25H.sub.25F.sub.3N.sub.6O.sub.3 (514.51)
[2966] R.sub.t=1.84 minutes (method 2)
Example 367
1-cyano-1-(cyclopropanecarbonyl-amino)-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00977##
[2968] Prepared from intermediates C1 and
1-cyano-1-cyclopropanecarboxylic acid according to AAV1.
[2969] C.sub.22H.sub.19ClF.sub.3N.sub.5O.sub.2 (477.87)
[2970] R.sub.t=1.96 minutes (method 2)
Example 368
1-(2-cyano-2-methyl-acetylamino)-cyclopropanecarboxylic
acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amid-
e
##STR00978##
[2972] Prepared from intermediates C1 and 2-cyano-2-methyl-acetic
acid according to AAV1.
[2973] C.sub.21H.sub.19ClF.sub.3N.sub.5O.sub.2 (465.86)
[2974] R.sub.t=1.92 minutes (method 2)
Example 369
isoxazole-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00979##
[2976] Prepared from intermediates C1 and isoxazole-5-carboxylic
acid according to AAV1.
[2977] C.sub.21H.sub.17ClF.sub.3N.sub.5O.sub.3 (479.84)
[2978] R.sub.t=1.89 minutes (method 2)
Example 370
2-amino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00980##
[2980] Prepared from intermediates C1 and
2-amino-pyrimidine-5-carboxylic acid according to AAV1.
[2981] C.sub.22H.sub.19ClF.sub.3N.sub.7O.sub.2 (505.89)
[2982] R.sub.t=2.11 minutes (method 2)
Example 371
2-ethyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00981##
[2984] Prepared from intermediates C1 and
2-ethyl-pyrimidine-5-carboxylic acid according to AAV1.
[2985] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.2 (518.92)
[2986] R.sub.t=2.38 minutes (method 2)
Example 372
1H-pyrazole-4-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00982##
[2988] Prepared from intermediates C1 and 1H-pyrazole-4-carboxylic
acid according to AAV1.
[2989] C.sub.21H.sub.18ClF.sub.3N.sub.6O.sub.2 (478.86)
[2990] R.sub.t=1.69 minutes (method 2)
Example 373
1-methyl-1H-pyrazole-4-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00983##
[2992] Prepared from intermediates C1 and
1-methyl-1H-pyrazole-4-carboxylic acid according to AAV1.
[2993] C.sub.22H.sub.20ClF.sub.3N.sub.6O.sub.2 (492.89)
[2994] R.sub.t=1.74 minutes (method 2)
Example 374
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00984##
[2996] Prepared from intermediates C20 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
[2997] C.sub.24H.sub.23F.sub.3N.sub.6O.sub.2 (484.48)
[2998] R.sub.t=1.81 minutes (method 2)
Example 375
5-amino-N-(1-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-met-
hyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00985##
[3000] Prepared from intermediates C20 and 5-amino-nicotinic acid
according to AAV1.
[3001] C.sub.24H.sub.23F.sub.3N.sub.6O.sub.2 (484.48)
[3002] R.sub.t=1.29 minutes (method 2)
Example 376
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-5-methoxy-nicotinamide
##STR00986##
[3004] Prepared from intermediates C2 and 5-methoxy-nicotinic acid
according to AAV1.
[3005] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.3 (503.45)
[3006] R.sub.t=2.02 minutes (method 2)
Example 377
N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-methylamino-nicotinamide
##STR00987##
[3008] Prepared from intermediates C2 and 6-methylamino-nicotinic
acid according to AAV1.
[3009] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.2 (502.47)
[3010] R.sub.t=2.01 minutes (method 2)
Example 378
6-amino-5-bromo-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin--
2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
##STR00988##
[3012] Prepared from intermediates C1 and 6-amino-5-bromo-nicotinic
acid according to AAV1.
[3013] C.sub.23H.sub.19BrClF.sub.3N.sub.6O.sub.2 (583.79)
[3014] R.sub.t=1.91 minutes (method 2)
Example 379
2-cyclopropylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00989##
[3016] Prepared from intermediates C1 and
2-cyclopropylamino-pyrimidine-5-carboxylic acid according to
AAV1.
[3017] C.sub.25H.sub.23ClF.sub.3N.sub.7O.sub.2 (545.95)
[3018] R.sub.t=2.29 minutes (method 2)
Example 380
2-propylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00990##
[3020] Prepared from intermediates C1 and
2-propylamino-pyrimidine-5-carboxylic acid according to AAV1.
[3021] C.sub.25H.sub.25ClF.sub.3N.sub.7O.sub.2 (547.97)
[3022] R.sub.t=2.42 minutes (method 2)
Example 381
(S)--N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tet-
rahydrofuran-3-yl}-5-methoxy-nicotinamide
##STR00991##
[3024] Prepared from intermediates C14 and 5-methoxy-nicotinic acid
according to AAV1.
[3025] C.sub.26H.sub.24F.sub.4N.sub.4O.sub.4 (532.49)
[3026] R.sub.t=2.50 minutes (method 2)
Example 382
2-isopropylamino-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00992##
[3028] Prepared from intermediates C1 and
2-isopropylamino-pyrimidine-5-carboxylic acid according to
AAV1.
[3029] C.sub.25H.sub.25ClF.sub.3N.sub.7O.sub.2 (547.97)
[3030] R.sub.t=2.41 minutes (method 2)
Example 383
(S)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic
acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00993##
[3032] Prepared from intermediates C14 and
1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
[3033] C.sub.27H.sub.23F.sub.4N.sub.5O.sub.3 (541.50)
[3034] R.sub.t=2.48 minutes (method 2)
Example 384
1H-pyrrolo[2,3-b]pyridine-5-carboxylic
acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00994##
[3036] Prepared from intermediates C2 and
1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
[3037] C.sub.25H.sub.20F.sub.4N.sub.6O.sub.2 (512.47)
[3038] R.sub.t=2.27 minutes (method 2)
Example 385
2-cyano-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR00995##
[3040] Prepared from intermediates C1 and
2-cyano-pyrimidine-5-carboxylic acid according to AAV1
[3041] C.sub.23H.sub.17ClF.sub.3N.sub.7O.sub.2 (515.88)
[3042] R.sub.t=2.39 minutes (method 2)
Example 386
2-methyl-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-difluoromethyl-phenylamino)-pyridin-2-ylmethyl]-c-
arbamoyl}-cyclopropyl)-amide
##STR00996##
[3044] Prepared from intermediates C21 and
2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
[3045] C.sub.23H.sub.21ClF.sub.2N.sub.6O.sub.2 (486.91)
[3046] R.sub.t=1.68 minutes (method 2)
Example 387
(S)-2-methyl-pyrimidine-5-carboxylic
acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-y-
lmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
##STR00997##
[3048] Prepared from intermediates A21 and B7 according to
AAV1.
[3049] C.sub.25H.sub.24F.sub.4N.sub.6O.sub.3 (532.50)
[3050] R.sub.t=1.86 minutes (method 2)
Example 388
(S)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetr-
ahydrofuran-3-yl}-amide
##STR00998##
[3052] Prepared from intermediates C18 and
1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
[3053] C.sub.27H.sub.23ClF.sub.3N.sub.5O.sub.3 (557.96)
[3054] mass spectroscopy (ESI): [M+H]+=558 [3055] [M-H]-=556
Example 389
N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carb-
amoyl}-cyclopropyl)-6-cyclopropylamino-nicotinamide
##STR00999##
[3057] Prepared from intermediates C1 and
6-cyclopropylamino-nicotinic acid according to AAV1.
[3058] C.sub.26H.sub.24ClF.sub.3N.sub.6O.sub.2 (544.96)
[3059] R.sub.t=1.67 minutes (method 2)
Example 390
2-ethoxy-pyrimidine-5-carboxylic
acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]--
carbamoyl}-cyclopropyl)-amide
##STR01000##
[3061] Prepared from intermediates C1 and
2-ethoxy-pyrimidine-5-carboxylic acid according to AAV1.
[3062] C.sub.24H.sub.22ClF.sub.3N.sub.6O.sub.3 (534.92)
[3063] R.sub.t=1.99 minutes (method 2)
Example 391
6-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmeth-
yl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamide
##STR01001##
[3065] Prepared from intermediates C2 and
6-amino-5-methyl-nicotinic acid according to AAV1.
[3066] C.sub.24H.sub.22F.sub.4N.sub.6O.sub.2 (502.47)
[3067] R.sub.t=1.38 minutes (method 2)
Example 392
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofur-
an-3-yl}-amide
##STR01002##
[3069] Prepared from intermediates A17 and B10 according to
AAV1.
[3070] C.sub.24H.sub.22F.sub.3N.sub.5O.sub.4 (501.46)
[3071] R.sub.t=2.09 minutes (method 2)
Example 393
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbam-
oyl]-tetrahydrofuran-3-yl}-amide
##STR01003##
[3073] Prepared from intermediates A11 and B10 according to
AAV1.
[3074] C.sub.24H.sub.20F.sub.5N.sub.5O.sub.4 (537.44)
[3075] R.sub.t=2.15 minutes (method 2)
Example 394
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-2-fluoro-benzylcarbam-
oyl]-tetrahydrofuran-3-yl}-amide
##STR01004##
[3077] Prepared from intermediates A29 and B10 according to
AAV1.
[3078] C.sub.24H.sub.20ClF.sub.4N.sub.5O.sub.4 (553.90)
[3079] R.sub.t=2.31 minutes (method 2)
Example 395
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic
acid-{3-[4-(4-bromo-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetra-
hydrofuran-3-yl}-amide
##STR01005##
[3081] Prepared from intermediates A31 and B10 according to
AAV1.
[3082] C.sub.24H.sub.21BrF.sub.3N.sub.5O.sub.4 (580.35)
[3083] R.sub.t=2.32 minutes (method 2)
Example 396
(S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid
{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydr-
o-furan-3-yl}-amide
##STR01006##
[3085] Prepared from intermediates A12 and B10 according to
AAV1.
[3086] C.sub.24H.sub.21F.sub.4N.sub.5O.sub.4 (519.45)
[3087] R.sub.t=1.35 minutes (method 7)
[3088] mass spectroscopy (ESI): [M+H].sup.+=520 [3089]
[M-H].sup.-=518
[3090] The following Examples describe pharmaceutical formulations
which contain as active substance any desired compound of general
formula I, without restricting the scope of the present invention
thereto:
Example I
Dry Ampoule with 75 mg of Active Compound Per 10 ml
[3091] Composition:
TABLE-US-00023 Active compound 75.0 mg Mannitol 500 mg Water for
injection ad 10.0 ml Production: Active compound and mannitol are
dissolved in water. The charged ampoules are freeze dried. Water
for injection is used to dissolve to give the solution ready for
use.
Example II
Tablet with 50 mg of Active Compound
[3092] Composition:
TABLE-US-00024 (1) Active compound 50.0 mg (2) Lactose 98.0 mg (3)
Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium
stearate 2.0 mg 215.0 mg Production: (1), (2) and (3) are mixed and
granulated with an aqueous solution of (4). (5) is admixed to the
dry granules. Tablets are compressed from this mixture, biplanar
with a bevel on both sides and dividing groove on one side.
Diameter of the tablets: 9 mm.
Example III
Tablet with 350 mg of Active Compound
[3093] Composition:
TABLE-US-00025 (1) Active compound 350.0 mg (2) Lactose 136.0 mg
(3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5)
Magnesium stearate 4.0 mg 600.0 mg Production: (1), (2) and (3) are
mixed and granulated with an aqueous solution of (4). (5) is
admixed to the dry granules. Tablets are compressed from this
mixture, biplanar with a bevel on both sides and dividing groove on
one side. Diameter of the tablets: 12 mm.
Example IV
Capsule with 50 mg of Active Compound
[3094] Composition:
TABLE-US-00026 (1) Active compound 50.0 mg (2) Maize starch dried
58.0 mg (3) Lactose powdered 50.0 mg (4) Magnesium stearate 2.0 mg
160.0 mg Production: (1) is triturated with (3). This trituration
is added to the mixture of (2) and (4) with vigorous mixing.
[3095] This powder mixture is packed into hard gelatine two-piece
capsules of size 3 in a capsule-filling machine.
Example V
Capsules with 350 mg of Active Compound
[3096] Composition:
TABLE-US-00027 (1) Active compound 350.0 mg (2) Maize starch dried
46.0 mg (3) Lactose powdered 30.0 mg (4) Magnesium stearate 4.0 mg
430.0 mg Production: (1) is triturated with (3). This trituration
is added to the mixture of (2) and (4) with vigorous stirring.
[3097] This powder mixture is packed into hard gelatine two-piece
capsules of size 0 in a capsule-filling machine.
Example VI
Suppositories with 100 mg of Active Compound
[3098] 1 suppository comprises:
TABLE-US-00028 Active compound 100.0 mg Polyethylene glycol (M.W.
1500) 600.0 mg Polyethylene glycol (M.W. 6000) 460.0 mg
Polyethylene sorbitan monostearate 840.0 mg 2000.0 mg
* * * * *