NEW COMPOUNDS
The present invention relates to the compounds of general formula I wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 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.
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The present invention relates to the compounds of general formula I
wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 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 INVENTIONIn the above general formula I in one embodiment 1
- n denotes one of the numbers 0, 1 or 2,
- R1 denotes
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (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,
- (c) a substituted C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2— unit may be replaced by a —C(O)— group,
- (d) an aryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.3,
- (e) a five-membered heteroaryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.4, 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-C0-2-alkylene group optionally substituted by 1 or 2 groups R1.4, 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 R1.4 substituted, which contains one, two or three N-atoms,
- (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
- (i) —O—R1.1.1,
- (j) —NR1.1.3R1.1.4 or
- (k) —C(═NR1.5)—CN,
- R1.1 denotes halogen, —NO2, —CN, C3-6-cycloalkyl, —OR1.1.1, —SR1.1.1, —C(O)R1.1.1, —S(O)2—R1.1.2, —O—S(O)2—R1.1.1, —CO2R1.1.1, —O—C(O)—R1.1.1, NR1.1.3R1.1.4, —NR1.1,3−C(O)—R1.1.1, —NR1.1,3−C(O)—R1.1.1, —NR1.1,3−CO2—R1.1.1 or —C(O)—NR1.1.3R1.1.4,
- R1.1.1 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) 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,
- (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
- (e) C3-6-cycloalkyl or
- (f) a pyridyl group optionally substituted by 1, 2 or 3 groups R1.1.1.2,
- R1.1.1.1 independently of one another denote
- (a) halogen, —NO2, —CN, —OH, —O—C1-4-alkyl, C3-6-cycloalkyl, C1-4-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,
- R1.1.1.2 independently of one another denote halogen or C1-4-alkyl,
- R1.1.2 denotes
- (a) C1-4-alkyl,
- (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,
- (c) —O—C1-4-alkyl or
- (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1 substituted,
- R1.1.3,
- R1.1.4 independently of one another denote
- (a) H,
- (b) a C1-4-alkyl group optionally substituted by 1, 2 or 3 groups R1.1.4.1,
- (c) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
- (d) C3-6-cycloalkyl, or
- R1.1.3 and R1.1.4 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
- R1.1.3 and R1.1.4 together with the N atom to which they are attached, form a cyclic imide,
- R1.1.4.1 independently of one another halogen denote —NH2, —NH(C1-4-alkyl), —N(C1-4-alkyl)2 or —SO2—R1.1.2,
- R1.2 denotes halogen, —NO2, —CN, OH, —O—CH3 or phenyl,
- R1.3 denotes
- (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —CO2R1.1.1, C1-6-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,
- R1.4 independently of one another denote
- (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —S(O)—R1.1.2, —S(O)2—R1.1.2, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl,
- (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, or
- (c) an oxo group,
- R1.4.1 denotes H or C1-4-alkyl,
- R1.5 denotes —OH or —O—C1-3-alkyl,
- R2 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) C1-4-alkyl-C(O)—,
- R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
- R3.1 denotes H, —OH,
- R5 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) 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,
- R6 independently of one another denote
- (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-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,
- R7 denotes
- (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R7.1,
- (i) —S—C1-4-alkyl, —SO2—R7.2,
- (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
- R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
- R8 denotes H, halogen, C1-4-alkyl,
- R9 denotes
- (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) C2-4-alkynyl,
- (f) —O—C1-6-alkyl,
- (g) —O—C3-7-cycloalkyl,
- (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (i) —C(O)—R9.1,
- (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
- R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R10 denotes H, halogen, C1-4-alkyl,
- R11 denotes
- (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R11.1,
- (i) —S—C1-3-alkyl, —SO2—R11.2,
- (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
- R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R11.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
- X independently of one another denote C—R6 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.
One embodiment 2 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
- R1 denotes
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (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,
- (c) a C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2-unit may be replaced by a —C(O)— group,
- (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (e) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms,
- (g) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
- (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
- (i) —O—R1.1.1 or
- (j) —NR1.1.3R1.1.4,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OR1.1.1, —NR1.1.3R1.1.4,
- R1.1.1 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) 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,
- R1.1.3,
- R1.1.4 independently of one another denote
- (a) H,
- (b) C1-4-alkyl,
- (c) C3-6-cycloalkyl, or
- R1.1.3 and R1.1.4 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
- R1.2 denotes halogen, —NO2, —CN, —OH, —O—CH3 or phenyl,
- R1.3 independently of one another denote
- (a) halogen, —NO2, —CN, —OR1.1.1, C1-6-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,
- R1.4 independently of one another denote
- (a) halogen, —NO2, —CN, —OR1.1.1, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-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, and
- R1.4.1 denotes H or C1-4-alkyl,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 3 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
- R1 denotes
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms,
- (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 independently of one another denote
- (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
- R1.4 independently of one another denote
- (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, NHC2-3-alkyl, —N(C2-3-alkyl)2—NH—C(O)—C1-4-Alkyl, C1-6-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,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 4 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
- R1 denotes
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is selected from among
-
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 which is selected from among
-
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
- R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 independently of one another denotes
- (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
- R1.4 independently of one another denotes
- (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 5 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
- R1 is selected from among
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 6 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
- R1 is selected from among
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 7 of the present invention consists of the compounds of the above general formula I, wherein R1 is defined as mentioned hereinbefore under embodiment 2, 3, 4, 5 or 6 and
n denotes one of the numbers 0, 1 or 2,
R2 denotes
-
- (a) H,
- (b) C1-4-alkyl,
R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2 unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
R3.1 denotes H, —OH,
R5 denotes - (a) H,
- (b) C1-4-alkyl,
- (c) 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,
R6 independently of one another denotes - (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-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,
R7 denotes - (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R7.1,
- (i) —S—C1-4-alkyl,
R7.1 denotes —NH2, —OH, —O—C1-8-alkyl,
R8 denotes H, halogen, C1-4-alkyl,
R9 denotes - (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) C2-4-alkynyl,
- (f) —O—C1-6-alkyl,
- (g) —O—C3-7-cycloalkyl,
- (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (i) —C(O)—R9.1,
- (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
R9.1 denotes —NH2, —OH, —O—C1-8-alkyl,
R10 denotes H, halogen, C1-4-alkyl,
R11 denotes - (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R11.1,
- (i) —S—C1-3-alkyl,
R11.1 denotes —NH2, —OH, —O—C1-8-alkyl, and
X independently of one another represent C—R6 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.
An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5 or 6 and
R2 denotes H or CH3,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
R2 denotes H or CH3,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 9 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
R2 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.
An embodiment 10 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2— 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.
An embodiment 11 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
R3 and R4 together with the carbon atom to which they are bonded denote a group selected from
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 12 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 and
R5 denotes H or CH3,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 13 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 and
R6 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.
An embodiment 14 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R3, R4, R5, R6, 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
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R8 denotes H,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R10 denotes H and
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 15 of the present invention comprises the compounds of general formula Ia
wherein
R1 denotes
-
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms,
- (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 independently of one another denotes - (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
R1.4 independently of one another denotes - (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or C1-4-alkyl,
R6 denotes H, F, Cl, Br or C1-4-alkyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 16 of the present invention comprises the compounds of general formula Ia, wherein
R1 denotes
-
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is selected from among
-
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 denotes independently of one another
-
- (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
R1.4 denotes independently of one another - (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 17 of the present invention comprises the compounds of general formula Ia, wherein
R1 denotes a group selected from
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 18 of the present invention comprises the compounds of general formula Ia wherein
R1 denotes a group selected from
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 19 of the present invention comprises the compounds of general formula Ib
wherein
R1 denotes
-
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms,
- (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 denotes independently of one another - (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
R1.4 denotes independently of one another - (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
R2 denotes H or CH3,
R5 denotes H or C1-4-alkyl,
R6 denotes H, F, Cl, Br or C1-4-alkyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 20 of the present invention comprises the compounds of general formula Ib, wherein
R1 denotes
-
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is selected from among
-
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 denotes independently of one another
-
- (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
R1.4 denotes independently of one another - (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 21 of the present invention comprises the compounds of general formula Ib, wherein
R1 denotes a group selected from
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 22 of the present invention comprises the compounds of general formula Ib, wherein
R1 denotes a group selected from
R2 denotes H,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 23 of the present invention comprises the compounds of general formula IC
wherein
R1 denotes
-
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms,
- (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 which contains one, two or three N-atoms,
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, wherein a —CH2— unit may be replaced by a —C(O)— group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 independently of one another denote - (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
R1.4 independently of one another denote - (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
R2 denotes H or CH3,
R5 denotes H or C1-4-alkyl,
R6 denotes H, F, Cl, Br or C1-4-alkyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 24 of the present invention comprises the compounds of general formula IC, wherein
R1 denotes
-
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
- (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is selected from among
-
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
-
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 independently of one another denotes
-
- (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
R1.4 independently of one another denote - (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 25 of the present invention comprises the compounds of general formula Ic, wherein
R1 denotes a group selected from
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 26 of the present invention comprises the compounds of general formula Ic, wherein
R1 denotes a group selected from
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, 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.
An embodiment 27 of the present invention comprises the compounds of general formula Id
wherein
R1 denotes a group selected from
R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes Cl or CH3,
R7 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.
An embodiment 28 of the present invention comprises the compounds of general formula I, Ia, Ib, Ic or Id, wherein n, R1, R3, R4, R5, R6, R7, R8, R9, R10, R11 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
R2 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.
The following are mentioned as examples of most particularly preferred compounds of the above general formula I:
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
A further embodiment of the present invention comprises the compounds of general formula II
wherein
n denotes one of the numbers 0, 1 or 2,
- R2 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) C1-4-alkyl-C(O)—,
- R5 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) 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,
- R6 independently of one another denotes
- (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-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,
- R7 denotes
- (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R7.1,
- (i) —S—C1-4-alkyl, —SO2—R7.2,
- (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
- R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
- R8 denotes H, halogen, C1-4-alkyl,
- R9 denotes
- (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) C2-4-alkynyl,
- (f) —O—C1-6-alkyl,
- (g) —O—C3-7-cycloalkyl,
- (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (i) —C(O)—R9.1,
- (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
- R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R10 denotes H, halogen, C1-4-alkyl,
- R11 denotes
- (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R11.1,
- (i) —S—C1-3-alkyl, —SO2—R11.2,
- (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
- R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R11.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
- X independently of one another denotes C—R6 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.
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,
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R8 denotes H,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R10 denotes H,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X independently of one another represent C—R6 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.
The following compounds are mentioned as examples of particularly preferred compounds of the above general formula II:
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
A further embodiment of the present application relates to the use of the compounds of general formula II, wherein R2, R5, R6, R7, R8, R9, R10 and R11 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.
A further embodiment of the present invention comprises the compounds of general formula III
wherein
- R1 denotes
- (a) a C1-6-alkyl group optionally substituted by a group R1.1,
- (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,
- (c) a C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2-unit may be replaced by a —C(O)— group,
- (d) an aryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.3,
- (e) a five-membered heteroaryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.4, 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-C0-2-alkylene group optionally substituted by 1 or 2 groups R1.4, 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 R1.4, which contains one, two or three N-atoms,
- (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, wherein a —CH2— unit may be replaced by a —C(O)— group,
- (i) —O—R1.1.1,
- (j) —NR1.1.3R1.1.4 or
- (k) —C(═NR1.5)—CN,
- R1.1 denotes halogen, —NO2, —CN, C3-6-cycloalkyl, —OR1.1.1, —SR1.1.1, —C(O)R1.1.1, —S(O)2—R1.1.2, —O—S(O)2—R1.1.1, —CO2R1.1.1, —O—C(O)—R1.1.1, —NR1.1.3R1.1.4, —NR1.1,3−C(O)—R1.1.1, —NR1.1,3−C(O)—R1.1.1, —NR1.1,3−CO2—R1.1.1 or —C(O)—NR1.1.3R1.1.4,
R1.1.1 denotes- (a) H,
- (b) C1-4-alkyl,
- (c) 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,
- (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
- (e) C3-6-cycloalkyl or
- (f) a pyridyl group optionally substituted by 1, 2 or 3 groups R1.1.1.2,
- R1.1.1.1 independently of one another denotes
- (a) halogen, —NO2, —CN, —OH, —O—C1-4-alkyl, C3-6-cycloalkyl, C1-4-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,
- R1.1.1.2 independently of one another denotes halogen or C1-4-alkyl,
- R1.1.2 denotes
- (a) C1-4-alkyl,
- (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,
- (c) —O—C1-4-alkyl or
- (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
- R1.1.3,
- R1.1.4 independently of one another denote
- (a) H,
- (b) a C1-4-alkyl group optionally substituted by 1, 2 or 3 groups R1.1.4.1,
- (c) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
- (d) C3-6-cycloalkyl, or
- R1.1.3 and R1.1.4 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
- R1.1.3 and R1.1.4 together with the N atom to which they are attached, form a cyclic imide,
- R1.1.4.1 independently of one another denote halogen, —NH2, —NH(C1-4-alkyl), —N(C1-4-alkyl)2 or —SO2—R1.1.2,
- R1.2 denotes halogen, —NO2, —CN, OH, —O—CH3 or phenyl,
- R1.3 denotes
- (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —CO2R1.1.1, C1-6-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,
- R1.4 independently of one another denotes
- (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —S(O)—R1.1.2, S(O)2—R1.1.2, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl,
- (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, or
- (c) a oxo group,
- R1.4.1 denotes H or C1-4-alkyl,
- R1.5 denotes —OH or —O—C1-3-alkyl,
- R2 denotes
- (a) H,
- (b) C1-4-alkyl,
- (c) C1-4-alkyl-C(O)—,
- R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2, and
- R3.1 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.
A further embodiment of the present invention comprises the compounds of the above general formula III, wherein
R1 is selected from among
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2, and
R3.1 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.
The following compounds are mentioned as examples of most particularly preferred compounds of the above general formula III:
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
A further embodiment of the present application relates to the use of the compounds of general formula III, wherein R2, R3, and R4 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.
A further embodiment of the present invention comprises the compounds of general formula IV
wherein
n denotes one of the numbers 0, 1 or 2,
R2 denotes
-
- (a) H,
- (b) C1-4-alkyl,
- (c) C1-4-alkyl-C(O)—,
R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
R3.1 denotes H, —OH,
R5 denotes - (a) H,
- (b) C1-4-alkyl,
- (c) 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,
R6 independently of one another denote - (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-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,
R7 denotes - (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R7.1,
- (i) —S—C1-4-alkyl, —SO2—R7.2,
- (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
R8 denotes H, halogen, C1-4-alkyl,
R9 denotes - (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) C2-4-alkynyl,
- (f) —O—C1-6-alkyl,
- (g) —O—C3-7-cycloalkyl,
- (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (i) —C(O)—R9.1,
- (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
R10 denotes H, halogen, C1-4-alkyl,
R11 denotes - (a) H, halogen, —CN, —OH,
- (b) C1-6-alkyl,
- (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl,
- (e) —O—C1-6-alkyl,
- (f) —O—C3-7-cycloalkyl,
- (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
- (h) —C(O)—R11.1,
- (i) —S—C1-3-alkyl, —SO2—R11.2,
- (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
R11.2—NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
X independently of one another denotes C—R6 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.
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,
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2 unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
R3.1 denotes H, —OH,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R8 denotes H,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R10 denotes H,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X independently of one another denotes C—R6 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.
The following compounds are mentioned as examples of most particularly preferred compounds of the above general formula IV:
the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
A further embodiment of the present application relates to the use of the compounds of general formula IV, wherein R2, R5, R6, R7, R8, R9, R10 and R11 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 USEDUnless otherwise stated, all the substituents are independent of one another. If for example there are a plurality of C1-6-alkyl groups as substituents in one group, in the case of three substituents C1-6-alkyl, one may represent methyl, one n-propyl and one tert-butyl.
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.
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.
By the term “C1-3-alkyl” (including those that are part of other groups) are meant alkyl groups with 1 to 3 carbon atoms, by the term “C1-4-alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms, by the term “C1-6-alkyl” are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, and by the term “C1-8-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.
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.
By the term “C0-2-alkylene” are meant branched and unbranched alkylene groups with 0 to 2 carbon atoms, while a C0-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.
By the term “C3-7-cycloalkyl” (including those that are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms and by the term “C3-6-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.
By the term “C3-6-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.
By the term “C2-4-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.
“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.
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:
“Cyclic imides” includes for example succinimides, maleimide and phthalimide.
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.
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.
The following are examples of five- or six-membered heteroaromatic groups:
The following are examples of nine- or ten-membered heteroaromatic groups:
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.
In addition, any nitrogen atom present in the heteroaryl group may be oxidised, thereby forming an N-oxide.
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 —CH2 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.
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.
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.
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.
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.
Compounds with a carbon double bond may be present in both the E and Z form.
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:
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: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.
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, Hünig base) is additionally used.
B) Amide Coupling: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.
The compounds of general formula V are either commercially obtainable or may be prepared by methods known from the literature
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:The reduction of a nitrile of general formula VI to an amine of general formula III, wherein the group R2 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.
Compounds of general formula III, wherein the group R2 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.
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: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, R6 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° C. to 160° C. If the aniline of general formula VIII is liquid, the reaction may also be carried out without a solvent and additional base.
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
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 μl of the homogenate (50 to 250 μg 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 μl. 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 μM 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 Ki value for the test substance.
Test results of the cynoBK1-receptor binding assay:
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.
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.
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.
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, Sjögren 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.
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.
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.
Preferably, the compounds of general formula I according to the invention are used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
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.
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.
The term “patient” preferably refers to a human being.
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.
CombinationsFor 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.
The following compounds may be used for combination therapy, for example:
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).
Opiate receptor agonists which may for example be selected from among morphine, Darvon, tramadol and buprenorphine;
Cannabinoid agonists such as for example GW-1000;
Sodium channel blockers which may for example be selected from among carbamazepine, mexiletin, pregabalin, tectin and ralfinamide.
N-type calcium channel blockers such as for example ziconotide.
Serotonergic and noradrenergic modulators which may be selected from among for example duloxetine and amitriptyline.
Corticosteroids which may be selected from among for example betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
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.
Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from among zafirlukast, montelukast, pranlukast and zileuton.
Local anaesthetics which may for example be selected from among ambroxol and lidocaine.
TRVP1 antagonists which may for example be selected from among AZD-1386, JTS-653 and PHE-377.
Nicotine receptor agonists such as for example A-366833.
P2X3-receptor antagonists such as e.g. A-317491.
anti-NGF antibodies and NGF antagonists which may for example be selected from among JNJ-42160443 and PPH 207.
NK1 and NK2 antagonists such as e.g. CP-728663.
NMDA antagonists which may for example be selected from among CNS-5161, AZ-756 and V-3381.
Potassium channel modulators such as e.g. CL-888.
GABA modulators such as e.g. baclofen.
Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan and eletriptan.
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.
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.
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
-
- betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,
- anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,
- PDE4-inhibitors, corticosteroids, EGFR-inhibitors and LTD4-antagonists,
- EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists,
- EGFR-inhibitors and LTD4-antagonists,
- 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),
- anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors and MRP4-inhibitors.
Combinations of three active substances of one of the above mentioned categories of compounds are also covered by the invention.
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
- 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
- 8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
- 8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
- 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
- 8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
- N-(5-{2-[3-(4.4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
- N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
- 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)-methanesulphonamide,
- 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,
- 8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
- 8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
- 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,
- 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,
- N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide,
- 8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one,
- 8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one,
- 5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,
- [3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea,
- 4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,
- 3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,
- 3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulphonamide,
- 4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,
- N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)propyl]phenyl}acetamide,
- (1R)-5-{2-[6-(2.2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinolin-2-one
- (R,S)-4-(2-{[6-(2.2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
- (R,S)-4-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
- (R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
- (R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
- (R,S)-5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one,
- (R,S)-[2-({6-[2.2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,
- 4-(1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxyl-methyl)phenol,
- (R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4.4.5l5-tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenol,
- (R,S)-[5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]formamide,
- (R,S)-4-[2-({6-[2-(3-bromophenyl)-2.2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,
- (R,S)—N-[3-(1.1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea,
- 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,
- (R,S)-4-[2-({6-[2.2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,
- 5-((1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one,
- 4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
- (R,S)-4-(2-{[6-(3.3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxylmethyl)phenol,
- (R,S)-(2-{[6-(2.2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,
- (R,S)-4-(2-{[6-(2.2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxyl-methyl)phenol,
- 3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl)-ethylamino]-ethyl}-propionamide,
- N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide,
- 7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)-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.
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]octane salts. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions X− 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.
Other anticholinergics may be selected from among
- tropenol 2,2-diphenylpropionate-methobromide,
- scopine 2,2-diphenylpropionate-methobromide,
- scopine 2-fluoro-2,2-diphenylacetate methobromide,
- tropenol 2-fluoro-2,2-diphenylacetate methobromide,
- tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,
- scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,
- tropenol 4,4′-difluorobenzilate methobromide,
- scopine 4,4′-difluorobenzilate methobromide,
- tropenol 3,3′-difluorobenzilate methobromide,
- scopine 3,3′-difluorobenzilate methobromide,
- tropenol 9-hydroxy-fluorene-9-carboxylate methobromide,
- tropenol 9-fluoro-fluorene-9-carboxylate methobromide,
- scopine 9-hydroxy-fluorene-9-carboxylate methobromide,
- scopine 9-fluoro-fluorene-9-carboxylate methobromide,
- tropenol 9-methyl-fluorene-9-carboxylate methobromide,
- scopine 9-methyl-fluorene-9-carboxylate methobromide,
- cyclopropyltropine benzilate methobromide,
- cyclopropyltropine 2,2-diphenylpropionate methobromide,
- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide,
- cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide,
- cyclopropyltropin 9-methyl-xanthene-9-carboxylate methobromide,
- cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide,
- cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide,
- tropenol 9-hydroxy-xanthene-9-carboxylate methobromide,
- scopine 9-hydroxy-xanthene-9-carboxylate methobromide,
- tropenol 9-methyl-xanthene-9-carboxylate methobromide,
- scopine 9-methyl-xanthene-9-carboxylate methobromide,
- tropenol 9-ethyl-xanthene-9-carboxylate methobromide,
- tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide, and
- scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.
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− hereinbefore.
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)
- 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one (RPR-106541),
- (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,
- (S)-(2-oxo-tetrahydrofuran-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, and
- 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-carboxylate,
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.
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
- 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamid]-8-methoxy-quinoline (D-4418),
- N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamid]-8-methoxy-2-(trifluoromethyl)-quinoline (D-4396 (Sch-351591)), N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylamide (AWD-12-281 (GW-842470)), 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine (NCS-613),
- 4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine (CDP-840),
- N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-pyridinecarboxamide (PD-168787),
- 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone (T-440),
- 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone (T-2585),
- (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V-11294A),
- beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801),
- imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888)
- 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenylmethyl], (3S,5S)-2-piperidinone (HT-0712),
- 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141),
- N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,
- (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s]-[1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,
- (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,
- 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]-benzyl)-2-pyrrolidone,
- cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid],
- 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-1-one,
- cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],
- (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,
- (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,
- 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo-[4.3-a]pyridine and
- 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo-[4.3-a]pyridine,
optionally in the form of their racemates, enantiomers, 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.
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
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
- 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
- 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
- 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,
- 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,
- 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)-amino]-quinazoline,
- 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,
- 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,
- 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,
- 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,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
- 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,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 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,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
- 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,
- 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline;
- [4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
- 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, and
- 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-cyclopropylmethoxy-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.
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),
- 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyric acid (MN-001),
- 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid,
- 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and
- [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid,
optionally in the form of their racemates, enantiomers, 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.
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.
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.
MAP Kinase inhibitors used according to the invention are preferably compounds selected from among:
- Bentamapimod (AS-602801)
- Doramapimod,
- 5-carbamoylindole (SD-169),
- 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide (VX-702),
- alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile (AS-601245),
- 9,12-epoxy-1H-diindolo[1,2,3-fg:3′.2′.1′-kl]pyrrolo[3,4-i][1.6]benzodiazocine-10-carboxylic acid (CEP-1347), and
- 4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazol-4-yl]-pyrimidine (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.
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.
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.
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-methylfuran-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.
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 SECTIONGenerally, there are mass spectra and 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.
Unless indicated otherwise, the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.
For chromatographic purification, silica gel from Millipore (MATREX™, 35 to 70 μm) or Alox (E. Merck, Darmstadt, Alumina 90 standardized, 63 to 200 μm, article No. 1.01097.9050) is used.
In the descriptions of the experiments, the following abbreviations are used:
- TLC thin layer chromatograph
- DIPEA diisopropylethylamine
- DMA N, N-dimethylacetamide
- DMAP 4-dimethylaminopyridine
- DMF N,N-dimethylformamide
- DMSO dimethylsulphoxide
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
- RP reverse phase
- Rt retention time
- tert tertiary
- TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
- TEA triethylamine
- THF tetrahydrofuran
The following analytical HPLC methods were used:
Method 1: Column: Interchim Strategy C18, 5 μM, 4.6×50 mm
-
- Detection: 220-320 nm
- Eluant A: water/0.1% acetic acid
- Eluant B: acetonitrile
- Gradient:
Method 2: Column: Merck Cromolith Flash RP18e, 4.6×25 mm
-
- Eluant A: water/0.1% formic acid
- Eluant B: acetonitrile/0.1% formic acid
- Gradient:
Method 3: Column: YMC-Pack ODS-AQ, 3 μM, 4.6×75 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
Method 4: Column: Zorbax Stable Bond C18, 1.8 μM, 3×30 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
Method 5: Column: Sunfire C18, 3.5 μM, 4.6×50 mm
Detection: 180-820 nm
-
- Eluant A: water/0.1% trifluoroacetic acid
- Eluant B: acetonitrile/0.1% trifluoroacetic acid
- Temperature: 40° C.
- Gradient:
Method 6: Column: Sunfire C18, 3.5 μM, 4.6×50 mm
-
- Detection: 180-820 nm
- Eluant A: water/0.1% trifluoroacetic acid
- Eluant B: acetonitrile/0.1% trifluoroacetic acid
- Temperature: 40° C.
- Gradient:
Method 7: Column: YMC-Pack ODS-AQ, 3 μM, 4.6×75 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
Method 8: Column: Zorbax Stable Bond C18, 1.8 μM, 3×30 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
Method 9: Column: Zorbax Stable Bond C18, 1.8 μM, 3×30 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
Method 10: Column: Zorbax Stable Bond C18, 3.5 μM, 4.6×75 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
Method 11: Column: X Terra C18, 3.5 μM, 4.6×50 mm
-
- Detection: 180-820 nm
- Eluant A: water/0.1% trifluoroacetic acid
- Eluant B: acetonitrile/0.1% trifluoroacetic acid
- Temperature: 40° C.
- Gradient:
Method 12: Column: Merck Cromolith Flash RP18e, 4.6×25 mm
-
- Eluant A: water/0.1% formic acid
- Eluant B: acetonitrile/0.1% formic acid
- Gradient:
Method 13: Column: Merck Cromolith SpeedROD RP-18e, 4.6×50 mm
-
- Eluant A: water/0.1% formic acid
- Eluant B: acetonitrile/0.1% formic acid
- Gradient:
Method 14: Column: Zorbax Stable Bond C18, 3.5 μM, 4.6×75 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
The following preparative methods were used for the reversed-phase chromatography:
Method 1: Column: Atlantis C18, 5 μM, 100×30 mm
-
- Detection: 210-500 nm
- Eluant A: water/0.1% trifluoroacetic acid
- Eluant B: acetonitrile
- Gradient:
Method 2: Column: Varian Pursuit 5 μM, 50×200 mm
-
- Eluant A: water/0.1% trifluoroacetic acid
- Eluant B: acetonitrile/0.1% trifluoroacetic acid
- Gradient:
Method 3: Column: YMC-Pack ODS-AQ 5 μM, 30×100 mm
-
- Eluant A: water/0.15% formic acid
- Eluant B: acetonitrile
- Gradient:
The compounds of general formula I may be prepared from the following intermediates A, B and C:
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 Hydrolysis2N 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 GroupA 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 AA 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° C. For working up the mixture was filtered through Alox and evaporated to dryness in vacuo.
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° 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° 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° C. and the alkylketone thus obtained was isolated and purified by chromatography in the usual way.
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.
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.
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° 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 AThe 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-phenyl)-amineHPLC: Rt=1.98 minutes (method 2)
Mass spectrum (ESI): [M+H]+=334
intermediate A2: (6-aminomethyl-pyridin-3-yl)-(4-isopropyl-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.95 minutes (method 2)
Mass spectrum (ESI): [M+H]+=310
intermediate A3: (6-aminomethyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.74 minutes (method 13)
Mass spectrum (ESI): [M+H]+=302
intermediate A4: 2-[6-(1-amino-ethyl)-5-fluoro-pyridin-3-ylamino]-5-fluoro-benzonitrileHPLC: Rt=1.39 minutes (method 2)
Mass spectrum (ESI): [M+H]+=275; [M−H]−=273
intermediate A5: [6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.92 minutes (method 2)
intermediate A6: (4-aminomethyl-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=285
thin layer chromatogram (silica gel, CH2Cl2/ethanol 19:1): Rt=0.16
intermediate A7: (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amineHPLC: Rt=2.06 minutes (method 3)
Mass spectrum (ESI): [M+H]+=286; [M−H]−=284
intermediate A8: (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=320; [M−H]−=320
intermediate A9: (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.97 minutes (method 2)
Mass spectrum (ESI): [M+H]+=346
intermediate A10: (6-aminomethyl-5-chloro-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-aminethin layer chromatogram (silica gel, CH2Cl2/ethanol/NH4OH 9:1:0.1): Rf=0.52
intermediate A11: (4-aminomethyl-3-fluoro-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=303
thin layer chromatogram (silica gel, CH2Cl2/ethanol 19:1): Rf=0.08
intermediate A12: (4-aminomethyl-3-fluoro-phenyl)-(2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M−H]−=283
thin layer chromatogram (silica gel, CH2Cl2/ethanol 19:1): Rf=0.09
intermediate A13: (6-aminomethyl-5-chloro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=320
thin layer chromatogram (silica gel, CH2Cl2/ethanol/NH4OH 9:1:0.1): Rf=0.58
intermediate A14: (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=304
thin layer chromatogram (silica gel, CH2Cl2/ethanol/NH4OH 9:1:0.1): Rf=0.56
intermediate A15: (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=320; [M−H]−=318
intermediate A16: (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amineHPLC: Rt=1.44 minutes (method 2)
intermediate A17: (4-aminomethyl-phenyl)-(2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.36 minutes (method 1)
Mass spectrum (ESI): [M+H-NH3]+=250
intermediate A18: (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amineHPLC: Rt=2.05 minutes (method 2)
intermediate A19: (4-aminomethyl-3-fluoro-phenyl)-(6-fluoro-2-trifluoromethyl-phenyl)-aminethin layer chromatogram (silica gel, CH2Cl2/ethanol 9:1): Rf=0.18
intermediate A20: 2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-benzonitrileHPLC: Rt=1.14 minutes (method 2)
Mass spectrum (ESI): [M+H]+=243
intermediate A21: (6-aminomethyl-5-methyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.79 minutes (method 2)
Mass spectrum (ESI): [M+H]+=300
intermediate A22: (4-aminomethyl-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H-NH3]+=284/286
intermediate A23: (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=286
intermediate A24: (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-6-fluorophenyl)-amineHPLC: Rt=1.87 minutes (method 2)
Mass spectrum (ESI): [M+H]+=330
intermediate A25: (6-aminomethyl-pyridin-3-yl)-(2-bromo-6-fluoro-phenyl)-amineHPLC: Rt=2.18 minutes (method 2)
Mass spectrum (ESI): [M+H]+=296
intermediate A26: (6-aminomethyl-5-methyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amineHPLC: Rt=2.33 minutes (method 2)
intermediate A27: (6-aminomethyl-5-methyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amineMass spectrum (ESI): [M+H]+=282
intermediate A28: (6-aminomethyl-pyridin-3-yl)-(4-chloro-2-difluoromethyl-phenyl)-amineHPLC: Rt=1.66 minutes (method 2)
Mass spectrum (ESI): [M+H]+=284
intermediate A29: (4-aminomethyl-3-fluoro-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.83 minutes (method 2)
intermediate A30: 2-(4-aminomethyl-3-fluoro-phenylamino)-benzonitrileHPLC: Rt=1.38 minutes (method 2)
intermediate A31: (4-aminomethyl-phenyl)-(4-bromo-2-trifluoromethyl-phenyl)-amineHPLC: Rt=1.81 minutes (method 2)
Preparation of the Intermediates BThe 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 acidMass spectrum (ESI): [M+H]+=208; [M−H]−=206
intermediate B2: (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acidHPLC: Rt=0.85 minutes (method 7)
Mass spectrum (ESI): [M+H]+=252
intermediate B3: (S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acidMass spectrum (ESI): [M+H]+=238; [M−H]−=236
intermediate B4: 1-[(5-amino-pyridine-3-carbonyl)-amino]cyclopropanecarboxylic acidMass spectrum (ESI): [M+H]+=222
intermediate B5: (S)-3-[(3H-imidazo[4,5-1D]pyridin-6-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acidHPLC: Rt=1.49 minutes (method 3)
Mass spectrum (ESI): [M−H]−=275
intermediate B6: (S)-3-[(2-methylamino-pyrimidine-5-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acidHPLC: Rt=0.47 minutes (method 2)
Mass spectrum (ESI): [M+H]+=267
intermediate B7: (S)-3-[(2-methyl-pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acidHPLC: Rt=0.43 minutes (method 2)
Mass spectrum (ESI): [M+H]+=252; [M−H]−=250
intermediate B8: (S)-3-[(5-hydroxy-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acidHPLC: Rt=0.48 minutes (method 2)
Mass spectrum (ESI): [M+H]+=253
intermediate B9: (S)-3-[(6-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acidHPLC: Rt=0.33 minutes (method 2)
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 acidHPLC: Rt=0.33 minutes (method 2)
Mass spectrum (ESI): [M+H]+=254
intermediate B11: 1-[(2-methyl-pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acidMass spectrum (ESI): [M+H]+=222; [M−H]−=220
The following Intermediates B12 to B15 may be prepared analogously:
Intermediate B12The 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]-amideHPLC: Rt=1.55 minutes (method 13)
Mass spectrum (ESI): [M−H]−=383
intermediate C2: 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideHPLC: Rt=2.33 minutes (method 7)
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-ylmethyl]-amideMass spectrum (ESI): [M+H]+=433
intermediate C4: 1-amino-cyclopropanecarboxylic acid-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideHPLC: Rt=1.65 minutes (method 2)
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-ylmethyl]-amideMass spectrum (ESI): [M+H]+=433
intermediate C6: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideMass spectrum (ESI): [M+H]+=417
intermediate C7: 1-amino-cyclopropanecarboxylic acid-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideHPLC: Rt=1.50 minutes (method 2)
intermediate C8: 3-amino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideA 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° 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.
C18H18N2O (278.35)
Mass spectrum (ESI): [M+H]+=279
(b) 3-dibenzylamino-oxetan-3-carboxylic acidA 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.
C18H19NO3 (297.35)
Mass spectrum (ESI): [M+H]+=298
(c) 3-dibenzylamino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamidePrepared from 3-dibenzylamino-oxetan-3-carboxylic acid and 4-(2-trifluoromethyl-phenyl-amino)-benzylamine by amide coupling according to general working method AAV1.
C32H30F3N3O2 (545.59)
Mass spectrum (ESI): [M+H]+=546
(d) 3-amino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide3-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.
C18H18F3N3O2 (365.35)
HPLC: Rt=1.93 minutes (method 5)
Mass spectrum (ESI): [M+H]+=366
intermediate C9: (S)-3-amino-tetrahydrofuran-3-carboxlic acid-2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamideMass spectrum (ESI): [M+H]+=416
intermediate C10:1-amino-cyclopropanecarboxylic acid-2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamideMass spectrum (ESI): [M+H]+=386
intermediate C11: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylamideMass spectrum (ESI): [M+H]+=416
intermediate C12: 1-amino-cyclopropanecarboxylic acid-2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylamideMass spectrum (ESI): [M+H]+=368
intermediate C13: 1-amino-cyclopropanecarboxylic acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideMass spectrum (ESI): [M+H]+=387
intermediate C14: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamideHPLC: Rt=1.99 minutes (method 2)
Mass spectrum (ESI): [M+H]+=398
intermediate C15: 1-amino-cyclopropanecarboxylic acid-[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideMass spectrum (ESI): [M+H]+=385
intermediate C16: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideHPLC: Rt=1.34 minutes (method 2)
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-ylmethyl]-amideHPLC: Rt=2.35 minutes (method 2)
intermediate C18: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylamideHPLC: Rt=2.41 minutes (method 2)
intermediate C19: 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-amideHPLC: Rt=1.24 minutes (method 2)
Mass spectrum (ESI): [M+H]+=383
intermediate C20:1-amino-cyclopropanecarboxylic acid-[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideHPLC: Rt=1.30 minutes (method 2)
Mass spectrum (ESI): [M+H]+=365
intermediate C21: 1-amino-cyclopropanecarboxylic acid-[5-(4-chloro-2-difluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideHPLC: Rt=1.48 minutes (method 2)
Mass spectrum (ESI): [M+H]+=367
intermediate C22: (S)-3-amino-tetrahydrofuran-3-carboxylic acid 2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylamideMass spectrum (ESI): [M+H]+=398
The following intermediates C23 to C25 may be prepared analogously:
Intermediate C23A 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).
Yield: 95% of theory
C11H13N3O3 (235.24)
Rt=1.23 min. method 1
1b) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid28.39 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).
Yield: 100% of theory
C9H9N3O3 (207.19)
Rt=1.23 min. method 1
1c) N-(4-aminomethyl)phenyl)-2,3-dichloraniline-trifluoroacetateA 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° 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 μL methanolic ammonia solution with 20 mg Raney nickel as catalyst at 55° 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).
Yield: 47% of theory
C13H12Cl2N2 (267.15)
1d) pyrimidine-5-carboxylic acid N-(1-(4-(2,3-dichlorophenylamino)benzylcarbamoyl)-cyclopropyl)amide0.5 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).
Yield: 16% of theory
C22H19Cl2N5O3 (456.32)
Rt=2.1 min. method 5
Example 2 pyrimidine-5-carboxylic acid-N-(1-(4-(2-chlorophenylamino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-chloroaniline, 4-fluorobenzonitrile and Raney nickel.
C13H9ClN2 (228.68)
2b) pyrimidine-5-carboxylic acid-N-(1-(4-(2-chlorophenylamino)benzylcarbamoyl)cyclo-propyl)amideAnalogously 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).
C22H20ClN5O2 (421.88)
Rt=2.13 min. method 6
Example 3 pyrimidine-5-carboxylic acid-N-(1-(4-(phenylamino)benzylcarbamoyl)cyclo-propyl)amideAnalogously to method (1c) the title compound was prepared starting from aniline, 4-fluorobenzonitrile and Raney nickel.
C13H14N2 (199.26)
3b) pyrimidine-5-carboxylic acid-N-(1-(4-(phenylamino)benzylcarbamoyl)cyclopropyl)-amideAnalogously 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).
C22H20ClN5O2 (421.88)
Rt=1.82 min. method 5
Example 4 pyrimidine-5-carboxylic acid-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-(trifluoromethyl)aniline, 4-fluorobenzonitrile and Raney nickel.
C14H13F3N2 (266.26)
4b) pyrimidine-5-carboxylic acid-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzyl-carbamoyl)cyclopropyl)amideAnalogously 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).
C23H20F3N5O2 (455.43)
Rt=2.27 min. method 6
Example 5 5-oxo-pyrrolidine-2-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideA 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).
Yield: 16% of theory
C22H19Cl2N5O3 (456.32)
5b) 5-oxo-pyrrolidine-2-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideAnalogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 5-oxopyrrolidine-2-carboxylic acid.
C23H23F3N4O3 (460.46)
Rt=1.89 min. method 5
Examples 6 to 22 that follow were prepared analogously to method (1d) from 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide and the corresponding acids:
Example 6 1-(4-dimethylamino-butyrylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC24H29F3N4O2 (462.5)
Rt=1.67 min. method 5
Example 7 1-(3,3,3-trifluoro-propionylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC21H19F6N3O2 (459.4)
Rt=2.21 min. method 5
Example 8 1-(3-dimethylamino-propionylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC23H27F3N4O2 (448.5)
Rt=1.67 min. method 5
Example 9 2,4-dihydroxy-pyrimidine-5-carboxylic acid-{1-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-cyclopropyl}-amideC23H20F3N5O4 (487.4)
Rt=1.93 min. method 5
Example 10 1-(5-dimethylamino-pentanoylamino)-cyclopropanecarboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamideC25H31F3N4O2 (476.5)
Rt=1.69 min. method 5
Example 11 N-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-nicotinamideC24H21F3N4O2 (454.4)
Rt=1.79 min. method 5
Example 12 1-(2-dimethylamino-acetylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC22H25F3N4O2 (434.5)
Rt=1.68 min. method 5
Example 13 1-propionylamino-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenyl-amino)-benzylamideC21H22F3N3O2 (405.4)
Rt=2.09 min. method 5
Example 14 1-(2-methoxy-acetylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC21H22F3N3O3 (421.4)
Rt=2.07 min. method 5
Example 15 1-(cyclopropanecarbonyl-amino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC22H22F3N3O2 (417.4)
Rt=2.13 min. method 5
Example 16 1-pentanoylamino-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenyl-amino)-benzylamideC23H26F3N3O2 (433.5)
Rt=2.24 min. method 5
Example 17 1-methyl-1H-imidazol-4-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideC23H22F3N5O2 (457.5)
Rt=1.73 min. method 5
Example 18 1-methyl-4H-imidazole-2-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideC23H22F3N5O2 (457.5)
Rt=1.88 min. method 5
Example 19 1-(2-cyclopropyl-acetylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC23H24F3N3O2 (431.5)
Rt=2.18 min. method 5
Example 20 N-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-benzamideC25H22F3N3O2 (453.5)
Rt=2.26 min. method 5
Example 21 pyridine-2-carboxylic acid {1-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amideC24H21F3N4O2 (454.4)
Rt=2.20 min. method 5
Example 22 1-methyl-piperidine-4-carboxylic acid {1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideC25H29F3N4O2 (474.5)
Rt=1.68 min. method 5
Example 23 1-(2,2,2-trifluoracetamido)-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)-cyclopropanecarboxamideAnalogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and trifluoroacetic acid.
C20H17F6N3O2 (445.37)
Rt=2.27 min. method 5
Example 24 N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-isoxazole-5-carboxamide20 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)cyclopropanecarboxamide (from 5a) and 70 μL (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).
Yield: 29% of theory
C22H19F3N4O3 (444.41)
Rt=2.42 min. method 6
Example 25 pyrimidine-5-carboxylic acid N-(1-(1-(4-(4-(difluoromethoxy)phenylamino)-phenyl)ethylcarbamoyl)cyclopropyl)amideThe 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° 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.
Yield: 33% of theory
C15H13F2NO2 (277.27)
Rt=1.98 min. method 1
25b) (Z)-1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone-oximeA 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° C. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC (method 2).
Yield: 19% of theory
C15H14F2N2O2 (292.28)
Rt=1.96 min. method 1
25c) 4-(1-aminoethyl)-N-(4-(difluoromethoxy)phenyl)aniline0.22 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° 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.
C15H16F2N2O (278.3)
Rt=1.37 min. method 1
25d) pyrimidine-5-carboxylic acid N-(1-(1-(4-(4-(difluoromethoxy)phenylamino)phenyl)-ethylcarbamoyl)cyclopropyl) amideAnalogously 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).
C24H23F2N5O3 (467.47)
Rt=1.78 min. method 1
Example 26 5-(trifluoromethyl)-N-(1-(4-(2-(trifluoromethyl)phenylamino)-benzylcarbamoyl)cyclopropyl)nicotinamideA solution of 1.5 g 3-bromo-5-(trifluoromethyl)pyridine in 50 ml of toluene was added dropwise at −75° 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° 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° C.
Yield: 9% of theory
C7H4F3NO2 (191.11)
26b) 5-(trifluoromethyl)-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropyl)nicotinamideAnalogously to method (1d) the title compound was prepared starting from 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 5-(trifluoromethyl)nicotinic acid (from 26a).
C22H20F3N5O3 (459.42)
Rt=2.41 min. method 6
Example 27 5-methyl-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropyl)-1,3,4-oxadiazole-2-carboxamideAnalogously to method (1d) the title compound was prepared starting from 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 5-methyl-1,3,4-oxadiazole-2-carboxylic acid.
C22H20F3N5O3 (459.42)
Rt=1.66 min. method 6
Example 28 pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 4-(methylthio)-2-(trifluoromethyl)aniline and 4-fluorobenzonitrile.
C15H15F3N2S (312.35)
Rt=1.88 min. method 2
28b) pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)amideAnalogously 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).
C24H22F3N5O2S (501.53)
Rt=2.33 min. method 2
Example 29 N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropyl)thiazole-5-carboxamideAnalogously to method (1c) the title compound was prepared starting from 2-trifluoromethyl-4-fluoraniline and 4-fluorobenzonitrile.
C14H8F4N2 (280.22)
Rt=0.38 min. method 4
29b) tea-butyl 1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropylcarbamate0.98 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.
Yield: 96% of theory
C23H25F4N3O3 (467.46)
Rt=1.50 min. method 4
29c) 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl-cyclopropanecarboxamide1.57 g (3.36 mmol) tert-butyl 1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl-carbamoyl)cyclopropylcarbamate 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.
Yield: 101% of theory
C18H17F4N3O (367.34)
Rt=1.33 min. method 4
29d) N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-thiazole-5-carboxamideAnalogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and thiazole-5-carboxylic acid.
C22H18F4N4O3S (478.46)
Rt=2.76 min. method 3
Example 30 N-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzyl)-1-(3,3,3-trifluoro-propanamido)cyclopropanecarboxamide44.0 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)cyclopropanecarboxamide (from 29c) and 80 μL (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.
Yield: 44% of theory
C21H18F7N3O2 (477.38)
Rt=2.85 min. method 3
Example 31 N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)-cyclopropyl)isoxazole-5-carboxamideAnalogously to method (30a) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and isoxazole-5-carbonyl chloride.
C22H18F4N4O3 (462.4)
Rt=2.79 min. method 3
Example 32 pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylsulphonyl)-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)cyclopropyl)amide34 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)benzylcarbamoyl)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.
Yield: 40% of theory
C24H22F3N5O4S (533.52)
Rt=1.84 min. method 2
Example 33 pyrimidine-5-carboxylic acid-N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and pyrimidine-5-carboxylic acid.
C23H19F4N5O2 (473.42)
Rt=2.09 min. method 2
Example 34 1-(2-(pyrimidin-5-yl)acetamido)-N-(4-(2-(trifluoromethyl)phenylamino)-benzyl)cyclopropanecarboxamideAnalogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and pyrimidine-5-carboxylic acid.
C24H22F3N5O2 (469.46)
Rt=2.21 min. method 6
Example 35 pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyanphenylamine)benzylcarbamoyl)cyclopropyl)amide92.65 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).
Yield: 66% of theory
C12H18N2O2 (222.28)
Rf=0.49 hexane:ethyl acetate (1/1)
35b) tert-butyl-4-(2-cyanophenylamino)benzylcarbamateThe 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° 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).
Yield: 82% of theory
C19H21N3O2 (323.39)
Rt=2.57 min. method 2
35c) 2-(4-(aminomethyl)phenylamino)benzonitrile-2,2,2-trifluoroacetate119 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.
Yield: 99% of theory
C14H13N3*C2HF3O2 (337.3)
Rt=1.30 min. method 2
35d) pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyanophenylamine)benzylcarbamoyl)cyclo-propyl)amideAnalogously 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).
C23H20N6O2 (412.44)
Rt=1.84 min. method 2
Example 36 pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyano-4-fluorophenylamine)benzyl-carbamoyl)cyclopropyl)amideAnalogously 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.
C19H20FN6O2 (341.38)
Rt=2.61 min. method 2
36b) 2-(4-(aminomethyl)phenylamino)-5-fluorobenzonitrile 2,2,2-trifluoroacetateAnalogously to method (35c) the title compound was prepared starting from tert-butyl-4-(2-cyano-4-fluorophenylamino)benzylcarbamate and trifluoroacetic acid.
C14H12FN3*C2HF3O2 (355.29)
Rt=1.39 min. method 2
36c) pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyano-4-fluorophenylamine)benzylcarbamoyl)cyclopropyl)amideAnalogously 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).
C23H19FN6O2 (430.43)
Rt=1.91 min. method 2
Example 37 pyrimidine-5-carboxylic acid-N-(1-(4-(4-fluorophenylamino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-bromo-4-fluoro-aniline, 4-fluorobenzonitrile and Raney nickel.
C13H13FN2 (216.25)
37b) pyrimidine-5-carboxylic acid-N-(1-(4-(4-fluorophenylamino)benzylcarbamoyl)cyclo-propyl)amideAnalogously 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).
C22H20FN5O2 (405.43)
mass spectroscopy [M+H]+=406
Example 38 pyrimidine-5-carboxylic acid-N-(1-((5-(2-chlorophenylamino)-3-fluoropyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-chloro-aniline, 2-cyano-3,5-difluoropyridine and Raney nickel.
C12H11FN3 (251.69)
Rt=1.295 min. method 1
38b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-chlorophenylamino)-3-fluoropyridin-2-yl)-methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C21H18FN6O2 (440.86)
Rt=1.73 min. method 1
Example 39 pyrimidine-5-carboxylic acid-N-(1-((5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-(trifluoromethyl)aniline, 5-fluoro-picolinic acid nitrile and Raney nickel.
C13H12F3N3 (267.25)
Rt=1.29 min. method 1
39b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)-methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C22H19F3N6O2 (456.42)
Rt=1.39 min. method 1
Example 40 pyrimidine-5-carboxylic acid-N-(1-(1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amide820 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).
Yield: 54% of theory
C13H8F3N3 (263.22)
40b) 1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-ylethanoneThe 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° 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° C. and extracted with tert-butylmethylether. The organic phase was evaporated to dryness in vacuo.
Yield: 96% of theory
C14H11F3N2O (280.25)
Rt=1.97 min. method 1
40c) (Z)-1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-ylethanone-oxime0.73 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° C. and then the solvents were distilled off.
Yield: 98% of theory
C14H12F3N3O (295.26)
Rt=1.75 min. method 1
40d) 6-(1-aminoethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine900 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.
Yield: 96% of theory
C14H14F3N3 (281.28)
Rt=1.33 min. method 1
40e) pyrimidine-5-carboxylic acid-N-(1-(1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amideAnalogously 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).
C23H21F3N6O2 (470.45)
Rt=1.46 min. method 1
Example 41 pyrimidine-5-carboxylic acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-trifluoromethyl-4-fluoro-aniline, 2-cyano-5-fluoropyridine and Raney nickel.
C13H11F4N3 (285.24)
Rt=1.50 min. method 9
41b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C22H18F4N6O2 (474.41)
Rt=2.96 min. method 7
Example 42 pyrimidine-5-carboxylic acid-N-(1-((5-(5-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-fluoro-6-(trifluoromethyl)aniline, 2-cyano-5-fluoropyridine and Raney nickel.
C13H11F4N3 (281.24)
Rt=1.95 min. method 8
42b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1d) the title compound was prepared starting from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
C22H18F4N6O2 (474.41)
Rt=3.10 min. method 7
Example 43 (S)-pyrimidine-5-carboxylic acid-N-(3-((5-(4-fluoro-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-yl)amide19.37 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.
Yield: 85% of theory
C13H17NO3 (235.28)
Rt=1.19 min. method 1
43b) (S)-phenethyl-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylate4.43 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).
Yield: 93% of theory
C18H19N3O4 (341.36)
Rt=1.60 min. method 1
43c) (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid60.24 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).
Yield: 93% of theory
C10H11N3O4 (237.21)
Rt=0.87 min. method 1
43d) pyrimidine-5-carboxylic acid-(S)—N-(3-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)-pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-0amideAnalogously 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).
C23H20F4N6O3 (504.44)
Rt=2.86 min. method 7
Example 44 pyrimidine-5-carboxylic acid-N-(1-((5-(2-fluoro-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-trifluoromethyl-5-fluoro-aniline, 2-cyano-5-fluoropyridine and Raney nickel.
C13H11F4N3 (285.24)
Rt=1.95 min. method 8
44b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-fluoro-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1d) the title compound was prepared starting from 6-(aminomethyl)-N-(2-fluoro-6-(trifluoromethyl)phenyl)pyridin-3-amine (from 44a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
C22H18F4N6O2 (474.41)
Rt=2.71 min. method 7
Example 45 pyrimidine-5-carboxylic acid-N-(1-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amideAnalogously 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.
C13H8F3N3 (281.21)
Rt=1.40 min. method 4
45b) 1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-ylethanoneAnalogously to method (40b) the title compound was prepared from methylmagnesium bromide and 5-(4-fluoro-2-(trifluoromethyl)phenylamino)picolinic acid nitrile.
C14H11F4N2O (298.24)
Rt=1.43 min. method 4
45c) (E)-1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-ylethanone-oximeAnalogously 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.
C14H11F4N3O (313.25)
Rt=1.31 min. method 4
45d) 6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amineAnalogously to method (40d) the title compound was prepared starting from (E)-1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-oxime and Raney nickel.
C14H14F4N3 (299.27)
Rt=1.65 min. method 9
45e) pyrimidine-5-carboxylic acid-N-(1-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amideAnalogously 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.
C23H20F4N6O2 (488.44)
Rt=3.01 min. method 7
Example 46 (S)-pyrimidine-5-carboxylic acid-N-(3-((5-(2-fluoro-6-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-yl)amideAnalogously 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).
C23H20F4N6O3 (504.44)
Rt=2.74 min. method 7
Example 47 (S)-pyrimidine-5-carboxylic acid-N-(−3-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)tetrahydrofuran-3-yl)amideAnalogously 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).
C24H22F4N6O3 (518.46)
Rt=3.00 min. method 7
Example 48 (S)-pyrimidine-5-carboxylic acid-N-(3-((5-(5-fluoro-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-yl)amideAnalogously 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).
C23H20F4N6O3 (504.44)
Rt=3.15 min. method 7
Example 49 pyrimidine-5-carboxylic acid-N-(1-((5-(2-methyl-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared from 2-methyl-6-(trifluoromethyl)-aniline and 2-cyano-5-fluoropyridine with Raney nickel as catalyst.
C14H14F3N3 (281.28)
Rt=1.52 min. method 2
49b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-methyl-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C22H18F4N6O2 (470.45)
Rt=1.57 min. method 2
Example 50 pyrimidine-5-carboxylic acid-N-(1-((5-(4-methoxy-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 2-amino-5-methoxybenzotrifluoride and 2-cyano-5-fluoropyridine with Raney nickel as catalyst.
C14H14F3N3O (297.28)
Rt=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)methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C23H21F3N6O3 (486.45)
Rt=2.82 min. method 7
Example 51 pyrimidine-5-carboxylic acid-N-(1-((5-(4-methyl-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared from 2-amino-5-methylbenzotrifluoride and 2-cyano-5-fluoropyridine using Raney nickel.
C14H14F3N3 (281.28)
Rt=1.63 min. method 2
51b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-methyl-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide0.1 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; 41.4×250 mm with acetonitrile/water/trifluoroacetic acid=10/90/0.1=>100/0/0.1).
Yield: 33% of theory
C23H21F3N6O2 (470.45)
Rt=1.63 min. method 2
Example 52 pyrimidine-5-carboxylic acid-N-(1-((5-(2,4-bis(trifluoromethyl)phenylamino)-pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared from 2,4-bis(trifluoromethyl)aniline and 2-cyano-5-fluoropyridine using Raney nickel.
C14H11F6N3 (335.25)
52b) pyrimidine-5-carboxylic acid-N-(1-((5-(2,4-bis(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C23H18F6N6O2 (524.42)
Rt=3.63 min. method 10
Example 53 pyrimidine-5-carboxylic acid-N-(1-((5-(4-bromo-2-methylphenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously 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.
C13H7BrF3N3 (342.11)
Rt=2.50 min. method 2
53b-1) 6-(aminomethyl)-N-(4-bromo-2-methylphenyl)pyridin-3-amine 2,2,2-trifluoroacetate1.65 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.
Yield: 65% of theory
C13H14BrN3*C2HF3O2 (406.2)
Rt=1.63 min. method 2
53b-2) 6-(aminomethyl)-N-(4-bromo-2-(trifluoromethyl)phenyl)pyridin-3-amineYield: 11% of theory
C13H11BrFF3N3 (346.15)
Rt=1.72 min. method 2
53c) pyrimidine-5-carboxylic acid-N-(1-((5-(4-bromo-2-methylphenylamino)pyridin-2-yl)-methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C22H21BrN6O2 (481.35)
Rt=1.61 min. method 2
Example 54 pyrimidine-5-carboxylic acid-N-(1-((5-(4-bromo-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C22H18BrF3N6O2 (535.32)
Rt=1.82 min. method 2
Example 55 pyrimidine-5-carboxylic acid-N-(1-((5-(4-chloro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideThe 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 μL (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° 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).
Yield: 68% of theory
C13H7ClF3N3 (297.66)
Rt=2.53 min. method 2
55b) 6-(aminomethyl)-N-(4-chloro-2-(trifluoromethyl)phenyl)pyridin-3-amineAnalogously 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.
C13H11ClF3N3 (301.69)
Rt=1.72 min. method 2
55c) pyrimidine-5-carboxylic acid-N-(1-((5-(4-chloro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amideAnalogously 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).
C22H18ClF3N6O2 (490.87)
Rt=1.76 min. method 2
Example 56 5-oxo-N—((S)-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide2 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° 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.
Yield: 63% of theory
C18H25NO5 (335.39)
Rt=2.05 min. method 1
56b) (S)-3-tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid8.94 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.
Yield: 100% of theory
C10H17NO5 (231.25)
Rt=1.53 min. method 1
56c) (S)-tert-butyl-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrahydrofuran-3-ylcarbamateAnalogously 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).
C24H28F3N3O4 (479.49)
56d) (S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofuran-3-carboxamide2 g (4.17 mmol) (S)-tert-butyl-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrahydrofuran-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.
Yield: 77% of theory
C19H20F3N3O2 (379.38)
Rt=1.97 min. method 6
56e) (S)-5-oxo-N-(−3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)tetrahydro-furan-3-yl)pyrrolidine-2-carboxamideAnalogously to method (1d) the title compound was prepared starting from (S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofuran-3-carboxamide (from 56d) and 5-oxopyrrolidine-2-carboxylic acid.
C24H25F3N4O4 (490.49)
Rt=1.84 min. method 5
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]-tetrahydro-furan-3-yl}-nicotinamideC25H24F3N5O3 (499.5)
Rt=1.66 min. method 5
Example 58 (S)-6-methyl-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-nicotinamideC26H25F3N4O3 (498.5)
Rt=1.69 min. method 5
Example 59 3-(2-pyridin-2-yl-acetylamino)-tetrahydro-furan-3-carboxylic acid 4-(2-tri-fluoromethyl-phenylamino)-benzylamideC26H25F3N4O3 (498.5)
Rt=1.64 min. method 5
Example 60 (S)-3-[(tetrahydro-furan-3-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC24H26F3N3O4 (477.5)
Rt=1.96 min. method 5
Example 61 (S)-2-chloro-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-isonicotinamideC25H22ClF3N4O3 (518.9)
Rt=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}-amideC24H22F3N5O4 (501.5)
Rt=1.91 min. method 5
Example 63 (S)-2-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-isonicotinamideC25H24F3N5O3 (499.5)
Rt=1.64 min. method 5
Example 64 (S)-pyridazine-4-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amideC24H22F3N5O3 (485.5)
Rt=1.92 min. method 5
Example 65 (S)-tetrahydropyran-4-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H28F3N3O4 (491.5)
Rt=1.97 min. method 5
Example 66 (S)-3-(2-cyano-2-hydroxyimino-acetylamino)-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC22H20F3N5O4 (475.4)
Rt=2.07 min. method 5
Example 67 (S)-6-chloro-pyridine-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amideC25H22ClF3N4O3 (518.9)
Rt=2.25 min. method 5
Example 68 (S)-5-methoxy-furan-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H24F3N3O5 (503.5)
Rt=2.12 min. method 5
Example 69 (S)-3-[(3-oxo-cyclohexanecarbonyl)-amino]-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC26H28F3N3O4 (503.5)
Rt=2.00 min. method 5
Example 70 (S)-6-hydroxy-pyridine-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H23F3N4O4 (500.5)
Rt=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}-amideC25H27F3N4O4 (504.5)
Rt=1.85 min. method 5
Example 72 (S)-6-amino-pyridine-2-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H24F3N5O3 (499.5)
Rt=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}-amideC23H22F3N5O4 (489.5)
Rt=1.89 min. method 5
Example 74 (S)-pyridazine-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC24H22F3N5O3 (485.5)
Rt=2.02 min. method 5
Example 75 (S)-3-[(3-methoxy-cyclobutanecarbonyl)-amino]-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC25H28F3N3O4 (491.5)
Rt=2.02 min. method 5
Example 76 (S)-6-oxo-piperidine-3-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H27F3N4O4 (504.5)
Rt=1.81 min. method 5
Example 77 (S)-4-methyl-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H24F3N5O3 (499.5)
Rt=1.96 min. method 5
Example 78 (S)-3-[(3-oxo-cyclopentanecarbonyl)-amino]-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC25H26F3N3O4 (489.5)
Rt=1.97 min. method 5
Example 79 (S)-2-methoxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-isonicotinamideC26H25F3N4O4 (514.5)
Rt=2.11 min. method 5
Example 80 (S)-2,4-dimethyl-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC26H26F3N5O3 (513.5)
Rt=1.95 min. method 5
Example 81 (S)-2-methoxy-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H24F3N5O4 (515.5)
Rt=2.04 min. method 5
Example 82 (S)-2-methylamino-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H25F3N6O3 (514.5)
Rt=1.91 min. method 5
Example 83 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC25H24F3N5O3 (499.5)
Rt=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]-tetrahydrofuran-3-yl}-amideC26H25F3N4O4 (514.5)
Rt=1.90 min. method 5
Example 85 (S)-oxazole-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-amideC23H21F3N4O4 (474.4)
Rt=1.97 min. method 5
Example 86 (S)-2-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-isonicotinamideC25H23F3N4O4 (500.5)
Rt=1.85 min. method 5
Example 87 (S)-5-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamideC25H23F3N4O4 (500.5)
Rt=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}-amideC23H23F3N6O3 (488.5)
Rt=1.99 min. method 5
Example 89 (S)-thiazole-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydro-furan-3-yl}-amideC23H21F3N4O3S (490.5)
Rt=2.01 min. method 5
Example 90 (S)-2-hydroxy-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC24H22F3N5O4 (501.5)
Rt=1.79 min. method 5
Example 91 (S)-3-(3,3,3-trifluoro-2-methyl-propionylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC23H23F6N3O3 (503.4)
Rt=2.18 min. method 5
Example 92 (S)-5-methoxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamideC26H25F3N4O4 (514.5)
Rt=1.85 min. method 5
Example 93 (S)-furan-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-amideC24H22F3N3O4 (473.4)
Rt=2.09 min. method 5
Example 94 (S)-furan-2-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-amideC24H22F3N3O4 (473.4)
Rt=2.08 min. method 5
Example 95 (S)—N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-isonicotinamideC25H23F3N4O3 (484.5)
Rt=1.71 min. method 5
Example 96 (S)-pyrazine-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC24H22F3N5O3 (485.5)
Rt=2.06 min. method 5
Example 97 (S)-3-(3-hydroxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamideC26H24F3N3O4 (499.5)
Rt=2.03 min. method 5
Example 98 (S)-6-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamideC25H23F3N4O4 (500.5)
Rt=1.84 min. method 5
Example 99 (S)-3-(4-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamideC27H26F3N3O4 (513.5)
Rt=2.16 min. method 5
Example 100 (S)-3-(3-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamideC27H26F3N3O4 (513.5)
Rt=2.18 min. method 5
Example 101 (S)-3-(2-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamideC27H26F3N3O4 (513.5)
Rt=2.22 min. method 5
Example 102 (S)-3-(3,5-dihydroxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC26H24F3N3O5 (515.5)
Rt=1.93 min. method 5
Example 103 (S)-3-(3,5-dimethoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamideC28H28F3N3O5 (543.5)
Rt=2.20 min. method 5
Example 104 (S)-3-(2-pyridin-3-yl-acetylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamideC26H25F3N4O3 (498.5)
Rt=1.64 min. method 5
Example 105 (S)-5-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamideC25H24F3N5O3 (499.5)
Rt=1.65 min. method 5
Example 106 (S)-1H-pyrazole-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideC23H22F3N5O3 (473.5)
Rt=1.96 min. method 5
Example 107 (S)-6-fluoro-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamideC25H22F4N4O3 (502.5)
Rt=2.10 min. method 5
Example 108 1-(3-ethylureido)-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamideA solution of 55 mg (0.16 mmol) 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)-cyclopropanecarboxamide (from 5a) in 2 mL dichloromethane was combined with 68 μL (0.49 mmol) TEA and 16 μL (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° 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).
Yield: 79% of theory
C21H23F3N4O2 (420.43)
Rt=2.27 min. method 5
Example 109 pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(phenyl)amino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared from N-methylaniline and 4-fluorobenzonitrile.
C14H16N2 (212.3)
109b) pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(phenyl)amino)benzylcarbamoyl)-cyclopropyl)amideAnalogously 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).
C23H23N5O2 (401.47)
Rt=2.87 min. method 5
Example 110 pyrimidine-5-carboxylic acid-N-(1-(4-((2-chlorophenyl)(methyl)amino)-benzylcarbamoyl)cyclopropyl)amideAnalogously to Example (1c) the title compound was prepared starting from 2-chloro-N-methylaniline and 4-fluorobenzonitrile.
C14H15ClN2 (246.74)
110b) pyrimidine-5-carboxylic acid-N-(1-(4-((2-chlorophenyl)(methyl)amino)benzylcarbamoyl)cyclopropyl)amideAnalogously 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).
C23H22ClN5O2 (435.91)
Rt=2.23 min. method 11
Example 111 pyrimidine-5-carboxylic acid-N-(1-(4-(ethyl(phenyl)amino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from N-ethylaniline and 4-fluorobenzonitrile.
C15H18N2 (226.32)
111b) pyrimidine-5-carboxylic acid-N-(1-(4-(ethyl(phenyl)amino)benzylcarbamoyl)-cyclopropyl)amideAnalogously 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).
C24H25N5O2 (415.49)
Rt=2.26 min. method 11
Example 112 pyrimidine-5-carboxylic acid-N-(1-(4-((4-methoxyphenyl)(methyl)amino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) the title compound was prepared starting from 4-methoxy-N-methylaniline and 4-fluorobenzonitrile using Raney nickel.
C15H18N2O (242.32)
112b) pyrimidine-5-carboxylic acid-N-(1-(4-((4-methoxyphenyl)(methyl)amino)benzyl-carbamoyl)cyclopropyl)amideAnalogously 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).
C24H25N5O3 (431.49)
Rt=2.13 min. method 11
Example 113 pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(o-tolyl)amino)benzylcarbamoyl)cyclopropyl)amideAnalogously to method (1c) N-methyl-o-toluidine and 4-fluorobenzonitrile were reacted using Raney nickel to obtain the title compound.
C15H18N2 (226.32)
113b) pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(o-tolyl)amino)benzylcarbamoyl)-cyclopropyl)amideAnalogously 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).
C24H25N5O2 (415.49)
Rt=2.26 min. method 11
Example 114 pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-5-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amidePrepared analogously to the method in (55a) from 2-bromo-4-fluoro-benzonitrile and tea-butyl (4-amino-benzyl)-carbamate.
Yield: 60% of theory
C19H20FN3O2 (341.38)
Rt=2.65 min. method 12
114b) 2-(4-aminomethyl-phenylamino)-4-fluoro-benzonitrile di-trifluoroacetate92 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.
Yield: 96% of theory
C14H12FN3*2C2HF3O2 (469.31)
Rt=1.41 min. method 12
114c) pyrimidine-5-carboxylic acid {1-[4-(2-cyano-5-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide83 mg (0.21 mmol) TBTU, 146 μL (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).
Yield: 69% of theory
C23H19FN6O2 (430.44)
Rt=1.91 min. method 12
Example 115 pyrimidine-5-carboxylic acid {1-[4-(2-cyano-3-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amideThe title compound was obtained from 2-bromo-6-fluoro-benzonitrile and tert-butyl (4-amino-benzyl)-carbamate analogously to method (55a).
C19H20FN3O2 (341.38)
Rt=2.65 min. method 12
115b) 2-(4-aminomethyl-phenylamino)-6-fluoro-benzonitrile di-trifluoroacetateThe title compound was prepared from tert-butyl [4-(2-cyano-3-fluoro-phenylamino)-benzyl]-carbamate analogously to method (114b).
C14H12FN3*2C2HF3O2 (469.31)
Rt=1.46 min. method 12
115c) pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-3-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideThe 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.
Yield: 44% of theory
C23H19FN6O2 (430.44)
Rt=1.94 min. method 12
Example 116 pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-6-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amideThe title compound was prepared from 2-bromo-3-fluoro-benzonitrile and tert-butyl (4-amino-benzyl)-carbamate according to method (55a).
C13H20FN3O2 (341.38)
Rt=2.50 min. method 12
116b) 2-(4-aminomethyl-phenylamino)-3-fluoro-benzonitrile di-trifluoroacetatePreparation of the title compound from tert-butyl [4-(2-cyano-6-fluoro-phenylamino)-benzyl]-carbamate analogously to method (114b).
C14H12FN3*2C2HF3O2 (469.31)
Rt=1.27 min. method 12
116c) pyrimidine-5-carboxylic acid {1-[4-(2-cyano-6-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amideThe 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.
C23H19FN6O2 (430.44)
Rt=1.78 min. method 12
Example 117 pyrimidine-5-carboxylic acid {1-[4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide276 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).
Yield: 20% of theory
C16H13F3N2O (306.28)
mass spectroscopy [M+H]+=307
117b) (4-aminomethyl-phenyl)-(4-ethoxy-2-trifluoromethyl-phenyl)-amine140 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.
C16H17F3N2O (310.31)
117c) pyrimidine-5-carboxylic acid {1-[4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide1-[(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)
C25H24F3N5O3 (499.49)
mass spectroscopy [M+H]+=500
Example 118 pyrimidine-5-carboxylic acid (1-{4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzylcarbamoyl}-cyclopropyl)-amide hydrochlorideThe title compound was obtained analogously to method (117a) from 4-fluoro-benzonitrile and 4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamine.
Yield: 32% of theory
C16H11F5N2O (342.26)
mass spectroscopy [M+H]+=343
118b) (4-aminomethyl-phenyl)-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenyl]-amineThe title compound was prepared analogously to method (117b) from 4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzonitrile.
C16H15F5N2O (346.30)
mass spectroscopy [M+H-NH3]+=330
118c) pyrimidine-5-carboxylic acid (1-{4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethylphenylamino]-benzylcarbamoyl}-cyclopropyl)-amide hydrochloride(4-aminomethyl-phenyl)-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenyl]-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.
Yield: 56% of theory
C25H22F5N5O3*HCl (571.93)
Rt=3.96 min method 10
Example 119 Pyrimidine-5-carboxylic acid-{1-[4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amidePrepared analogously to method (117a) from 4-fluoro-benzonitrile and 4-isopropoxy-2-trifluoromethyl-phenylamine.
Yield: 37% of theory
C17H15F3N2O (320.31)
mass spectroscopy [M+H]+=321
119b) (4-aminomethyl-phenyl)-(4-isopropoxy-2-trifluoromethyl-phenyl)-amineThe title compound was obtained according to method (117b) from 4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzonitrile.
C17H19F3N2O (324.34)
mass spectroscopy [M+H-NH3]+=308
119c) pyrimidine-5-carboxylic acid {1-[4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide(4-aminomethyl-phenyl)-(4-isopropoxy-2-trifluoromethyl-phenyl)-amine 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).
Yield: 28% of theory
C26H26F3N5O3*HCl (549.97)
Rt=2.72 min method 14
Example 120 pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideWhile 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-phenyl)-amine3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile 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-ylmethyl]-carbamoyl}-cyclopropyl)-amide(6-aminomethyl-5-fluoro-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 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.
C22H17F5N6O2 (492.40)
mass spectroscopy [M+H]+=493
Example 121 pyrimidine-5-carboxylic acid-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]ethylcarbamoyl}-cyclopropyl)-amideAt −25° 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° 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.
C14H9F5N2O (316.23)
mass spectroscopy [M+H]+=317
121b) 1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime1-[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).
C14H10F5N3O (331.24)
mass spectroscopy [M+H]+=332
121c) 6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amineThe reaction of 1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-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).
C14H12F5N3 (317.26)
mass spectroscopy [M+H]+=318
121d) pyrimidine-5-carboxylic acid-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide6-(1-amino-ethyl)-5-fluoro-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 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.
C23H19F5N6O2*2HCl (579.35)
mass spectroscopy [M+H]+=507
The (R)- and (S)-enantiomer of Example 121 were obtained by chiral HPLC(SFC) from the racemic compound (column: Daicel AD-H, 250×20 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)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and 6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-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}-amide400 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)-nicotinamide1-amino-cyclopropanecarboxylic acid {1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]ethyl}-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.
C24H21F5N6O2*2HCl (593.38)
mass spectroscopy [M+H]+=521
Example 123 pyrimidine-5-carboxylic acid-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide39.7 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° 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.
C14H10F4N2O2 (298.24)
mass spectroscopy [M+H]+=299
123b) 1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone 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.
C14H11F4N3O (313.25)
123c) [6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-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).
C14H13F4N3 (299.27))
Rt=2.76 min. method 7
123d) pyrimidine-5-carboxylic acid (1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide[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).
C23H20F4N6O2 (488.44)
mass spectroscopy [M+H]+=489
Example 124 5-amino-N-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and [6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine 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.
C23H26F4N4O3 (482.47)
mass spectroscopy [M+H]+=483
124b) 1-amino-cyclopropanecarboxylic acid {1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide hydrochlorideReaction of tert-butyl (1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-carbamoyl}-cyclopropyl)-carbamate analogously to method (122b).
C18H18F4N4O*HCl (418.82)
mass spectroscopy [M+H]+=383
124c) 5-amino-N-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-carbamoyl}-cyclopropyl)-nicotinamide1-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).
C24H22F4N6O2 (502.46)
mass spectroscopy [M+H]+=503
Example 125 5-amino-N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamideReaction 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.
C22H23F5N4O3 (486.44)
125b) 1-amino-cyclopropanecarboxylic acid-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amideTert-butyl (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate was reacted analogously to method (122b).
C17H15F5N4O*2HCl (459.24)
125c) 5-amino-N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide5-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.
C23H19F5N6O2*2HCl (579.35)
mass spectroscopy [M+H]+=507
Example 126 pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide250 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.
C12H7BrClN3 (308.56)
mass spectroscopy [M+H]+=308
126b) (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-phenyl)-amineA 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).
C12H11BrClN3 (312.59)
mass spectroscopy [M+H]+=311
126c) pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared analogously to method (51b) from (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid.
C21H18BrClN6O2 (501.76)
mass spectroscopy [M+H]+=501
Example 127 (S)-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amide(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).
C24H22F3N5O3 (485.46)
mass spectroscopy (ESI): [M+H]+=486
Example 128 pyridazine-4-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideReaction 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.
C22H23F5N4O3 (486.44)
Rt=2.30 min. method 12
128b) 1-amino-cyclopropanecarboxylic acid [3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide dihydrochlorideTert-butyl (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate was reacted as described in method (122b).
C17H15F5N4O*2HCl (459.24)
Rt=1.50 min. method 12
128c) pyridazine-4-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide1-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).
Yield: 47% of theory
C22H17F5N6O2 (492.40)
mass spectroscopy (ESI): [M+H]+=493
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-ylmethyl]-carbamoyl}-cyclopropyl)-amideC23H19F5N6O3*C2HF3O2 (636.45)
mass spectroscopy (ESI): [M+H]+=523
Example 130 N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamideC23H18F5N5O3 (507.41)
mass spectroscopy (ESI): [M+H]+=508
Example 131 N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamideC24H20F5N5O2 (505.44)
mass spectroscopy (ESI): [M+H]+=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-ylmethyl]-carbamoyl}-cyclopropyl)-amideC24H20F5N5O3 (521.44)
mass spectroscopy (ESI): [M+H]+=522
Example 133 2-methylamino-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC23H20F5N7O2 (521.44)
mass spectroscopy (ESI): [M+H]+=522
Example 134 2-methyl-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC23H19F5N6O2 (506.43)
mass spectroscopy (ESI): [M+H]+=507
Example 135 thiazole-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC21H16F5N5O2S (497.44)
mass spectroscopy (ESI): [M+H]+=498
Example 136 6-hydroxy-pyridine-2-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC23H18F5N5O3 (507.41)
mass spectroscopy (ESI): [M+H]+=508
Example 137 isoxazole-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC21H16F5N5O3 (481.38)
mass spectroscopy (ESI): [M+H]+=482
Example 138 2-methoxy-pyrimidine-5-carboxylic acid (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideReaction 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)
C22H24BrF3N4O3 (529.35)
mass spectroscopy (ESI): [M+H]+=529
138b) 1-amino-cyclopropanecarboxylic acid [5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate150 mg (0.28 mmol) tert-butyl (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-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.
Yield: 100% of theory
C17H16BrF3N4O*C2HF3O2 (543.26)
Rt=1.59 min. method 12
138c) 2-methoxy-pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideThe 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.
C23H20BrF3N6O3 (565.34)
mass spectroscopy (ESI): [M+H]+=565
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]-carbamoyl}-cyclopropyl)-amideC23H20BrF3N6O2 (549.34)
mass spectroscopy (ESI): [M+H]+=549
Example 140 6-hydroxy-pyridine-2-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC23H19BrF3N5O3 (550.33)
mass spectroscopy (ESI): [M+H]+=550
Example 141 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-hydroxy-nicotinamideC23H19BrF3N5O3 (550.33)
mass spectroscopy (ESI): [M+H]+=550
Example 142 5-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide5-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 acid1.90 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.
Yield: 85% of theory
C10H11N3O3 (221.21)
mass spectroscopy (ESI): [M+H]+=222
142c) 5-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide1-[(5-amino-pyridine-3-carbonyl)-amino]cyclopropanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine 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.
C23H20F4N6O2 (488.44)
mass spectroscopy (ESI): [M+H]+=489
Example 143 3H-imidazo[4,5-b]pyridine-6-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from 3H-imidazo[4,5-b]pyridine-6-carboxylic acid and benzyl 1-amino-cyclopropanecarboxylate hydrochloride analogously to method (142a).
C18H16N4O3 (336.35)
mass spectroscopy (ESI): [M+H]+=337
143b) 1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acidObtained from the reaction of benzyl 1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylate according to method (142b).
C11H10N4O3 (246.22)
Rt=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]-carbamoyl}-cyclopropyl)-amideThe 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).
C24H19F4N7O2 (513.45)
mass spectroscopy (ESI): [M+H]+=514
Example 144 6-amino-pyrazine-2-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide1-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.
C22H24F4N4O3 (468.45)
mass spectroscopy (ESI): [M+H]+=469
144b) 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride1.00 g (2.14 mmol) tert-butyl (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-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.
C17H16F4N4O*HCl (404.79)
mass spectroscopy (ESI): [M+H]+=369
144c) 6-amino-pyrazine-2-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideObtained 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.
C22H19F4N7O2 (489.43)
mass spectroscopy (ESI): [M+H]+=490
Example 145 2-methylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide1-(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.
C22H24ClF3N4O3 (484.90)
Rt=2.23 min. method 12
145b) 1-amino-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate906 mg (1.40 mmol) tert-butyl (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-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.
C17H16ClF3N4O*C2HF3O2 (498.81)
Rt=1.54 min. method 12
145c) 2-methylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide1-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).
C23H21ClF3N7O2 (519.91)
mass spectroscopy (ESI): [M+H]+=520
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)-amideC23H20ClF3N6O3 (520.89)
mass spectroscopy (ESI): [M+H]+=521
Example 147 2-methyl-pyrimidine-5-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC23H20ClF3N6O2 (504.89)
mass spectroscopy (ESI): [M+H]+=505
Example 148 1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC24H21ClF3N5O3 (519.90)
mass spectroscopy (ESI): [M+H]+=520
Rt=1.74 min. method 13
Example 149 thiazole-5-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideC21H17ClF3N5O2S (495.91)
mass spectroscopy (ESI): [M+H]+=496
Rt=1.84 min. method 13
Example 150 3-amino-isoxazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared 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.
C21H18F4N6O3 (478.40)
mass spectroscopy (ESI): [M+H]+=479
Example 151 pyrimidine-5-carboxylic acid (1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide dihydrochloride1-[(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.
C22H17F5N6O2*2HCl (565.32)
mass spectroscopy (ESI): [M+H]+=493
Example 152 5-amino-N-(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide dihydrochlorideObtained 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-ylmethyl]-amide. In the chromatographic purification, however, a silica gel column was used (eluant: dichloromethane with 5 to 12% methanol).
C23H19F5N6O2*2HCl (579.35)
mass spectroscopy (ESI): [M+H]+=507
Example 153 (S)-pyrimidine-5-carboxylic acid (3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-furan-3-yl)-amide dihydrochloridePrepared 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.
C23H19F5N6O3*2HCl (595.35)
mass spectroscopy (ESI): [M+H]+=523
Example 154 (S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide5-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).
C15H21N3O4 (307.35)
mass spectroscopy (ESI): [M+H]+=308
154b) (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid2.45 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.
Yield: 99% of theory
C11H13N3O4 (251.24)
mass spectroscopy (ESI): [M+H]+=252
154c) (S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-O-nicotinamide-dihydrochloride(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic 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.
C24H21F5N6O3*2HCl (609.38)
mass spectroscopy (ESI): [M+H]+=537
Example 155 (S)-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amideA 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-tetrafluoroborate (TOTU) and 139 μL (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).
Yield: 18% of theory
C24H22F3N5O3 (485.46)
mass spectroscopy (ESI): [M+H]+=486
Rt=2.15 min. method 12
Example 156 (S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide dihydrochloride(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic 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.
C24H21F5N6O3*2HCl (609.38)
mass spectroscopy (ESI): [M+H]+=537
Example 157 (S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamideObtained 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).
C24H22F4N6O3 (518.46)
mass spectroscopy (ESI): [M+H]+=519
Example 158 (S)-pyrimidine-5-carboxylic acid-(3-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide dihydrochloridePrepared 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-phenyl)-amine.
C23H19F5N6O3*2HCl (595.35)
mass spectroscopy (ESI): [M+H]+=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)-amidePrepared 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.
C16H20N4O4 (332.36)
Rt=1.99 min. method 13
159b) (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid400 mg (1.20 mmol) butyl (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydrofuran-3-carboxylate 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.
C12H12N4O4 (276.25)
mass spectroscopy (ESI): [M−H]+=275
159c) (S)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine analogously to method (154a).
C25H21F4N7O3 (543.47)
mass spectroscopy (ESI): [M+H]+=544
Example 160 pyrimidine-5-carboxylic acid-(1-{[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide581 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.
Yield: 40% of theory
C11H14BrFN2O2 (305.14)
Rt=2.29 min. method 12
160b) tert-butyl [5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate132 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).
Yield: 15% of theory
C18H18F2N4O2 (360.36)
Rt=2.35 min. method 12
160c) 2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-5-fluoro-benzonitrile-trifluoroacetate51 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.
Yield: 94% of theory
C13H10F2N4*C2HF3O2 (374.27)
Rt=1.17 min. method 12
160d) pyrimidine-5-carboxylic acid-(1-{[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide28 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).
Yield: 50% of theory
C22H17F2N7O2 (449.13)
mass spectroscopy (ESI): [M+H]+=450
Rt=1.67 min. method 12
Example 161 pyrimidine-5-carboxylic acid {1-[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide2.35 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.
Yield: 96% of theory
C12H16BrNO2 (286.17)
mass spectroscopy (ESI): [M+H]+=286
161b) tert-butyl {4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzyl}-carbamateTert-butyl (4-bromo-benzyl)-carbamate and 2-amino-5-trifluoromethoxy-benzonitrile were reacted analogously to method (55a).
C20H20F3N3O3 (407.39)
mass spectroscopy (ESI): [M+H]+=408
Rt=4.63 min. method 13
161c) 2-(4-aminomethyl-phenylamino)-5-trifluoromethoxy-benzonitrile-trifluoroacetateTo 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).
C15H12F3N3O*C2HF3O2 (421.29)
mass spectroscopy (ESI): [M+H]+=308
Rt=2.45 min. method 13
161d) pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide166 mg (0.39 mmol) of 2-(4-aminomethyl-phenylamino)-5-trifluoromethoxy-benzonitrile-trifluoroacetate and 82 mg (0.39 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were coupled analogously to method (1d).
Yield: 33% of theory
C24H19F3N6O3 (496.44)
mass spectroscopy (ESI): [M+H]+=497
Rt=2.24 min. method 13
Example 162 pyrimidine-5-carboxylic acid {1-[4-(4-chloro-2-cyano-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amidePrepared by the same reaction sequence (Buchwald reaction, cleaving of protective group, amide linking) as in Example 161 starting from tert-butyl (4-bromobenzyl)-carbamate.
C23H19ClN6O2 (446.89)
mass spectroscopy (ESI): [M+H]+=447
Rt=2.10 min. method 13
Example 163 (S)-pyrimidine-5-carboxylic acid (3-{1-[5-(4-chloro-2-trifluoromethyl-phenyl-amino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amide500 mg (1.68 mmol) 5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile in 5 mL diethyl ether were added dropwise at −5° 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
Yield: 50% of theory
C14H10ClF3N2O (314.69)
mass spectroscopy (ESI): [M+H]+=315
163b) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime266 mg (0.85 mmol) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone, 73 mg (1.04 mmol) hydroxylamine-hydrochloride and 238 μL (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.
Yield: 79% of theory
C14H11ClF3N3O (329.71)
Rt=2.27 min. method 12
163c) [6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amine220 mg (0.67 mmol) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime 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.
Yield: 62% of theory
C14H13ClF3N3 (315.72)
Rt=1.76 min. method 12
163d) (S)-pyrimidine-5-carboxylic acid-(3-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amideThe 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).
C24H22ClF3N6O3 (534.93)
mass spectroscopy (ESI): [M+H]+=535
Rt=1.86 min. method 12
Example 164 pyrimidine-5-carboxylic acid (1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide trifluoroacetateObtained analogously to method (1d) from [6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
C23H20ClF3N6O2*C2HF3O2 (618.92)
mass spectroscopy (ESI): [M+H]+=505
Rt=1.84 min. method 12
Example 165 tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamatePrepared analogously to method (55a) from tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate and 4-chloro-2-trifluoromethyl-phenylamine.
C18H18ClF4N3O2 (419.80)
mass spectroscopy (ESI): [M+H]+=420
165b) (6-aminomethyl-5-fluoro-pyridin-3-O-(4-chloro-2-trifluoromethyl-phenyl)-amine hydrochloride50 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° C. After evaporation of the reaction mixture residual water was eliminated by azeotropic distillation with toluene.
Rt=1.73 min. method 12
165c) tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamatePrepared 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).
C22H7ClF4N6O2 (508.86)
mass spectroscopy (ESI): [M+H]+=509
Rt=2.12 min. method 12
Example 166 pyrimidine-5-carboxylic acid-(1-{[5-(2,4-dichloro-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-cyclopropyl)-amide1.33 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).
Yield: 44% of theory
C12H7Cl2N3 (264.11)
Rt=2.46 min. method 12
166b) (6-aminomethyl-pyridin-3-yl)-(2,4-dichloro-phenyl)-amine3.56 mL of a 2 molar solution of lithium aluminium hydride in THF were added at −10° 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.
C12H11Cl2N3 (268.14)
mass spectroscopy (ESI): [M+H]+=268
166c) pyrimidine-5-carboxylic acid-(1-{[5-(2,4-dichloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideObtained from (6-aminomethyl-pyridin-3-yl)-(2,4-dichloro-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid analogously to method (1d).
C21H18Cl2N6O2 (457.31)
mass spectroscopy (ESI): [M+H]+=457
Example 167 pyrimidine-5-carboxylic acid (1-{[5-(2-bromo-4-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from 2-bromo-4-chloroaniline and 2-cyano-5-fluoropyridine analogously to (166a).
C12H7BrClN3 (308.56)
mass spectroscopy (ESI): [M+H]+=308
167b) (6-aminomethyl-pyridin-3-yl)-(2-bromo-4-chloro-phenyl)-amine-trifluoroacetate5-(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).
C12H11BrClN3 (312.59)
mass spectroscopy (ESI): [M+H]+=312
167c) pyrimidine-5-carboxylic acid-(1-{[5-(2-bromo-4-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared analogously to method (1d) from (6-aminomethyl-pyridin-3-yl)-(2-bromo-4-chloro-phenyl)-amine-trifluoroacetate and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
C21H18BrClN6O2 (501.76)
mass spectroscopy (ESI): [M+H]+=501
Example 168 6-methylamino-pyrazine-2-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide61 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 μL (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.
Yield: 34% of theory
C23H21F4N7O2 (503.45)
mass spectroscopy (ESI): [M+H]+=504
Example 169 2-amino-oxazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideObtained 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.
C26H26F4N6O5 (578.52)
Rt=3.19 min. method 14
169b) 2-amino-oxazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideThe protective group of the compound tert-butyl [5-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropylcarbamoyl)-oxazol-2-yl]-carbamate was cleaved using the method described for intermediate step (144b).
C21H18F4N6O3 (478.40)
mass spectroscopy (ESI): [M+H]+=479
Rt=2.71 min. method 7
Example 170 1-(2-cyano-2-methyl-acetylamino)-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amideReaction of 40 mg (0.40 mmol) cyanomethyl-acetic acid and 162 mg (0.40 mmol)
- 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride analogously to the method for Example 168.
Yield: 28% of theory
C21H19F4N5O2 (449.40)
mass spectroscopy (ESI): [M+H]+=450
Rt=3.03 min. method 7
Example 171 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamide150 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 μL (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).
Yield: 69% of theory
C23H19BrF3N6O3 (550.33)
mass spectroscopy (ESI): [M+H]+=550
Rt=1.73 min. method 12
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]-carbamoyl}-cyclopropyl)-amideYield: 94% of theory
C21H17BrF3N6O2S (540.36)
mass spectroscopy (ESI): [M+H]+=540
Rt=1.88 min. method 12
Example 173 6-amino-N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide trifluoroacetateYield: 89% of theory
C23H20BrF3N6O2*C2HF3O2 (663.37)
mass spectroscopy (ESI): [M+H]+=549
Example 174 pyridazine-4-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideYield: 71% of theory
C22H18BrF3N6O2 (535.32)
mass spectroscopy (ESI): [M+H]+=535
Rt=1.80 min. method 12
Example 175 2-dimethylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideYield: 67% of theory
C24H23BrF3N7O2 (578.39)
mass spectroscopy (ESI): [M+H]+=578
Rt=1.99 min. method 12
Example 176 2,6-dihydroxy-pyrimidine-4-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideYield: 46% of theory
C22H18BrF3N6O4 (567.32)
mass spectroscopy (ESI): [M+H]+=567
Rt=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]-carbamoyl}-cyclopropyl)-amideYield: 71% of theory
C24H21BrF3N5O3 (564.36)
mass spectroscopy (ESI): [M+H]+=564
Rt=1.78 min. method 12
Example 178 5-amino-N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamideYield: 99% of theory
C23H20BrF3N6O2*C2HF3O2 (663.37)
mass spectroscopy (ESI): [M+H]+=549
Rt=1.68 min. method 12
Example 179 pyrimidine-5-carboxylic acid (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideObtained from 2-cyano-3,5-difluoropyridine and 4-bromo-2-trifluoromethyl-phenylamine analogously to method (40a).
C13H6BrF4N3 (360.11)
mass spectroscopy (ESI): [M+H]+=360
Rt=2.68 min. method 12
179b) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine171 mg (0.48 mmol) 5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridine-2-carbonitrile 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° 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).
C13H10BrF4N3 (364.14)
mass spectroscopy (ESI): [M+H]+=364
Rt=1.79 min. method 13
179c) pyrimidine-5-carboxylic acid (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide54 mg (0.26 mmol) 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid, 36 μL 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 μL 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).
C22H17BrF4N6O2 (553.31)
mass spectroscopy (ESI): [M+H]+=553
Rt=2.20 min. method 13
Example 180 pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amideA 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).
C14H10BrF3N2O (359.14)
Rt=2.57 min. method 12
180b) 1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime702 mg (1.96 mmol) 1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone, 182 mg hydroxylamine-hydrochloride and 549 μl (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 trifluoroacetateA solution of 870 mg (approx. 85%, 2.0 mmol) 1-[5-(4-bromo-2-trifluoromethyl-phenyl-amino)-pyridin-2-yl]-ethanone-oxime 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).
Yield: 78% over two steps
C14H13BrF3N3 (360.17)
mass spectroscopy (ESI): [M+H]+=360
Rt=1.83 min. method 12
180d) pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amideAnalogously 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.
Yield: 55% of theory
C23H20BrF3N6O2*C2HF3O2 (663.37)
mass spectroscopy (ESI): [M+H]+=549
Rt=1.92 min. method 12
The (R)- and (S)-enantiomer of Example 180 were obtained by chiral HPLC(SFC) from the racemic compound (column: Daicel ASH, 250 mm×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}-amide877 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).
Yield: 30% of theory
C23H25FN4O3 (424.47)
mass spectroscopy (ESI): [M−H]+=423
Rt=2.39 min. method 13
181b) 1-amino-cyclopropanecarboxylic acid 4-(2-cyano-4-fluoro-phenylamino)-benzylamide trifluoroacetate560 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).
C18H17FN4O*C2HF3O2 (438.38)
mass spectroscopy (ESI): [M−H]+=325
Rt=1.56 min. method 13
181c) 2-methyl-pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amidePrepared 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.
Yield: 83% of theory
C24H21FN6O2 (444.46)
mass spectroscopy (ESI): [M+H]+=445
Rt=1.92 min. method 13
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}-amideYield: 28% of theory
C24H21FN6O3 (460.46)
mass spectroscopy (ESI): [M+H]+=461
Rt=2.03 min. method 13
Example 183 2-methylamino-pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-fluoro-phenyl-amino)-benzylcarbamoyl]-cyclopropyl}-amideYield: 58% of theory
C24H22FN7O2 (459.48)
mass spectroscopy (ESI): [M+H]+=460
Rt=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)-amidePrepared from 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride and 2-acetylamino-thiazole-5-carboxylic acid analogously to method (142c).
Yield: 51% of theory
C23H20F4N6O3S (536.50)
Rt=2.96 min. method 7
184b) 2-amino-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide110 mg (0.21 mmol) 2-acetylamino-thiazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide were stirred overnight at 80° 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.
Yield: 43% of theory
C21H18F4N6O2S (494.47)
mass spectroscopy (ESI): [M+H]+=495
Rt=2.73 min. method 7
Examples 185 and 186 were prepared analogously from 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide 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)-amideC21H19F4N7O2 (477.42)
mass spectroscopy (ESI): [M+H]+=478
Rt=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)-amideC22H20F4N6O2S (508.49)
mass spectroscopy (ESI): [M+H]+=509
Rt=2.67 min. method 7
Example 187 pyrimidine-5-carboxylic acid (1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide dihydrochlorideA 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).
Yield: 45% of theory
187b) (6-aminomethyl-5-chloro-pyridin-3-O-(4-fluoro-2-trifluoromethyl-phenyl)-amineA solution of 100 mg (0.32 mmol) 3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile in 3 mL THF was combined at ambient temperature with 31 μL 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-ylmethyl]-carbamoyl}-cyclopropyl)-amide dihydrochloridePrepared 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.
C22H17ClF4N6O2*2HCl (581.78)
mass spectroscopy (ESI): [M+H]+=509
Rt=3.68 min. method 10
Example 188 pyrimidine-5-carboxylic acid-(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-(S)-tetrahydro-furan-3-yl)-amideA 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° 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 μL (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).
Yield: 41% of theory
C24H22BrF3N6O3 (579.37)
mass spectroscopy (ESI): [M+H]+=579
Rt=1.93 min. method 12
Example 188a: pyrimidine-5-carboxylic acid-(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amideSeparation of diastereomers by chiral HPLC (column: Daicel ASH; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/(isopropanol+0.2% diethylamine) 80:20; flow: 10 mL/min)
Rt=5.32-7.15 minutes
Example 188b pyrimidine-5-carboxylic acid (3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amideSeparation of diastereomers by chiral HPLC (column: Daicel ASH; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/(isopropanol+0.2% diethylamine) 80:20; flow: 10 mL/min)
Rt=8.23-10.51 minutes
Example 189 pyrimidine-5-carboxylic acid (1-{[5-(2-chloro-4-methyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideAnalogously 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.
C22H21ClN6O2 (436.90)
Mass spectrum (ESI): [M+H]+=437
-
- M−H]−=435
Rt=1.59 min (method 2)
Example 190 pyrimidine-5-carboxylic acid (1-{[5-(2-chloro-4-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideAnalogously 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.
C21H16ClFN6O2 (440.86)
Mass spectrum (ESI): [M+H]+=441
Rt=1.50 min (method 2)
Example 191 pyrimidine-5-carboxylic acid (1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclohexyl)-amide61 mg (0.25 mmol) 1-tert-butoxycarbonylamino-cyclohexanecarboxylic acid, 80 mg (0.25 mmol) TBTU and 53 μL (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).
Yield: 68% of theory (as trifluoroacetate)
mass spectroscopy [M+H]+=393
Rt=1.70 min method 6
191b) pyrimidine-5-carboxylic acid-(1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclohexyl)-amidePrepared from 1-amino-cyclohexanecarboxylic acid [5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and pyrimidine-5-carboxylic acid analogously to method 191a).
Yield: 37% of theory
C25H25F3N6O2 (498.51)
Mass spectrum (ESI): [M+H]+=499
-
- [M−H]−=497
Rt=1.84 min (method 5)
Example 192 pyrimidine-5-carboxylic acid (3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentyl)-amide1-tert-butoxycarbonylamino-3-hydroxy-cyclopentanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine were reacted analogously to method 191a).
Yield: 49% of theory (as trifluoroacetate)
mass spectroscopy [M+H]+=395
Rt=1.62 min method 6
192b) pyrimidine-5-carboxylic acid (3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentyl)-amideThe 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).
Yield: 55% of theory
C24H23F3N6O3 (500.48)
Mass spectrum (ESI): [M+H]+=501
Rt=1.66 min (method 5)
Example 193 pyrimidine-5-carboxylic acid (3-oxo-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentyl)-amide10 mg pyrimidine-5-carboxylic acid (3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-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).
Yield: 90% of theory
C24H21F3N6O3 (498.46)
Mass spectrum (ESI): [M+H]+=499
-
- [M−H]−=497
Rt=1.73 min (method 5)
Example 194 pyrimidine-5-carboxylic acid (1-oxo-3-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-1lambda*4*-thiophen-3-yl)-amideThe 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).
Yield: 96% of theory (as trifluoroacetate)
mass spectroscopy [M+H]+=413
Rt=1.62 min method 6
194b) pyrimidine-5-carboxylic acid (1-oxo-3-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-thiophen-3-yl)-amidePrepared 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).
Yield: 58% of theory
C23H21F3N6O3S (518.52)
Mass spectrum (ESI): [M+H]+=519
-
- [M+H]+=517
Rt=1.66 min (method 5)
Example 195 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoic acid469 (0.91 mmol) methyl 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]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).
Yield: 69% of theory
C23H19F3N6O4 (500.44)
Mass spectrum (ESI): [M+H]+=501
-
- [M−H]−=499
1190 mg (3.48 mmol) 5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile, 221 μL (1.6 mmol) triethylamine and 97 mg (0.13 mmol) Pd(ddpf)Cl2 in 10 mL methanol and 2 mL DMF were heated to 50° 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).
Yield: 78% of theory
mass spectroscopy [M+H]+=322
196b) methyl 4-(6-aminomethyl-pyridin-3-ylamino)-3-trifluoromethyl-benzoate860 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.
Yield: 76% of theory
mass spectroscopy [M+H]+=326
196c) methyl 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoate191 mg (0.92 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid, 305 mg (0.95 mmol) TBTU and 203 μL (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).
Yield: 62% of theory
C24H21F3N6O4 (514.46)
Mass spectrum (ESI): [M+H]+=515
Rt=1.73 min (method 12)
Example 197 pyrimidine-5-carboxylic acid (1-{[5-(4-cyano-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide55 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° 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).
Yield: 23% of theory
C23H18F3N7O2 (481.44)
Mass spectrum (ESI): [M+H]+=482
-
- [M−H]−=480
Rt=1.69 min (method 12)
Example 198 pyrimidine-5-carboxylic acid (1-{[5-(4-carbamoyl-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideA solution of 50 mg (0.10 mmol) 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoic acid, 33 mg (0.10 mmol) TBTU and 12 μL (0.11 mmol) N-methylmorpholine in 0.5 mL DMF was stirred for 3 minutes at ambient temperature, then combined with 17 μL (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).
Yield: 6% of theory
C23H20F3N7O3 (499.45)
Mass spectrum (ESI): [M+H]+=500
-
- [M−H]−=498
Obtained from 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid and (4-aminomethyl-phenyl)-(4-methoxy-phenyl)-amine analogously to method 191a).
Yield: 37% of theory
C23H23N5O3 (417.47)
Mass spectrum (ESI): [M+H]+=418
[M−H]−=416
Rt=1.83 min (method 12)
Example 200 pyrimidine-5-carboxylic acid (1-{[5-(2-chloro-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amideCoupling 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).
C21H18ClFN6O2 (440.86)
Mass spectrum (ESI): [M+H]+=441
-
- [M−H]−=439
Rt=1.38 min (method 2)
Example 201 pyrimidine-5-carboxylic acid {1-[4-(4-methoxy-2-methyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amidePrepared from 1-[(pyrimidine-5-carbonyl)-amino]cyclopropanecarboxylic acid and (4-aminomethyl-phenyl)-(4-methoxy-2-methyl-phenyl)-amine according to method 191a).
C24H25N5O3 (431.49)
Mass spectrum (ESI): [M+H]+=432
-
- [M+H]+=430
Rt=1.97 min (method 12)
Example 202 pyrimidine-5-carboxylic acid (1-{4-[(4-methoxy-2-methyl-phenyl)-methyl-amino]-benzylcarbamoyl}-cyclopropyl)-amide73 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° C. in 5 mL DMF. 90 mg (0.35 mmol) (4-aminomethyl-phenyl)-(4-methoxy-2-methyl-phenyl)-methyl-amine and 101 μL 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).
Yield: 19% of theory
C25H27N5O3 (445.52)
Mass spectrum (ESI): [M+H]+=446
Rt=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)-amidePrepared from intermediates A1 and B1 according to AAV1
C23H19ClF4N6O2 (522.89)
Rt=2.30 minutes method 2
The racemate was separated into the enantiomers by chiral HPLC (column: Daicel AD-H 250×20 mm; 5 μm; 25° C.; eluant CO2/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)-amideAnalytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
Rt=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)-amideAnalytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
Rt=2.29 minutes
Example 204 pyrimidine-5-carboxylic acid(1-{[5-(4-isopropyl-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates A2 and B1 according to AAV1
C25H25F3N6O2 (498.51)
Rt=1.95 minutes (method 2)
Example 205 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-hydroxy-nicotinamidePrepared from intermediate C1 and 5-hydroxynicotinic acid according to AAV1
C23H19ClF3N5O3 (505.88)
Rt=1.74 minutes (method 13)
Example 206 6-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C1 and 6-aminonicotinic acid according to AAV1
C23H20ClF3N6O2 (504.90)
Rt=1.60 minutes (method 13)
Example 207 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamidePrepared from intermediate C1 and 2-hydroxy-isonicotinic acid according to AAV1
C23H19ClF3N6O3 (505.88)
Rt=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)-amidePrepared from intermediate C1 and 2,6-dihydroxy-pyrimidine-4-carboxylic acid according to AAV1
C22H18ClF3N6O4 (522.87)
Rt=1.70 minutes (method 13)
Example 209 pyridazine-4-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediate C1 and pyridazine-4-carboxylic acid according to AAV1
C22H18ClF3N6O2 (522.87)
Rt=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)-amidePrepared from intermediate C1 and 2-dimethylamino-pyrimidine-5-carboxylic acid according to AAV1
C24H23ClF3N7O2 (533.94)
Rt=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)-amidePrepared from intermediate C1 and 6-hydroxy-pyridine-2-carboxylic acid according to AAV1
C23H19ClF3N5O3 (505.88)
Rt=1.75 minutes method 13
Example 212 pyrimidine-5-carboxylic acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amidePrepared from intermediates A4 and B1 according to AAV1
C23H19F2N7O2 (463.45)
Rt=1.81 minutes method 2
The racemate was separated into the enantiomers by chiral HPLC (column: Daicel AD-H 250×20 mm; 5 μm; 25° C.; eluant CO2/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]-ethylcarbamoyl}-cyclopropyl)-amideRt=2.75 minutes
Example 212b (S)-pyrimidine-5-carboxylic acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amideRt=5.12 minutes
Example 213 pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amidePrepared from intermediates A5 and B1 according to AAV1
C23H19BrF4N6O2 (567.34)
Rt=2.34 minutes (method 2)
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)-amideAnalytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
Rt=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)-amideAnalytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
Rt=2.55 minutes
Example 214 (S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A6 and B2 according to AAV1
C25H23F4N5O3 (517.48)
Rt=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)-amidePrepared from intermediate C2 and 6-oxo-5,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
C22H18F4N6O3 (490.42)
Rt=2.80 minutes (method 7)
Example 216 (S)-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-Pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A8 and B3 according to AAV1
C23H19ClF4N6O3 (538.89)
Rt=3.86 minutes (method 7)
Example 217 5-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C1 and 5-aminonicotinic acid according to AAV1.
C23H20ClF3N6O2 (504.90)
Rt=2.01 minutes (method 2)
Example 218 5-amino-N-(1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediates A8 and B4 according to AAV1
C23H19ClF4N6O2 (522.89)
Rt=3.21 minutes (method 7)
Example 219 (S)-5-amino-N-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A8 and B2 according to AAV1
C24H21ClF4N6O3 (552.91)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A8 and B5 according to AAV1
C25H20ClF4N7O3 (577.92)
Rt=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)-amidePrepared from intermediate C2 and 1-methyl-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
C23H20F4N6O3 (504.44)
Rt=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)-nicotinamidePrepared from intermediates A9 and B2 according to AAV1
C24H22BrF3N6O3 (579.37)
Rt=1.88 minutes (method 2)
Example 223 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A9 and B3 according to AAV1
C23H20BrF3N6O3 (565.35)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediate C3 and 2-methylamino-pyrimidine-5-carboxylic acid according to AAV1
C24H22ClF4N7O3 (567.93)
Rt=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-ylmethyl]-amidePrepared from intermediate C3 and 3,3,3-trifluoro-propionic acid according to AAV1
C21H18ClF7N4O3 (542.84)
Rt=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)-nicotinamidePrepared from intermediates A3 and B2 according to AAV1
C24H22ClF3N6O3 (534.92)
Rt=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)-amidePrepared from intermediate C2 and 6-methylamino-pyridazine-4-carboxylic acid according to AAV1
C23H21F4N7O2 (503.46)
Rt=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)-amidePrepared from intermediates A3 and B3 according to AAV1
C23H20ClF3N6O3 (520.90)
Rt=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)-nicotinamidePrepared from intermediates A10 and B2 according to AAV1
C24H22ClF3N6O3 (534.92)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediate C3 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
C24H21ClF4N6O4 (568.91)
Rt=4.01 minutes (method 7)
Example 231 (S)-5-amino-N-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamidePrepared from intermediates A11 and B2 according to AAV1
C25H22F5N5O3 (535.47)
Rt=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)-amidePrepared from intermediate C2 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C23H20F4N6O2 (488.44)
Rt=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)-amidePrepared from intermediate C2 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
C23H20F4N6O3 (504.44)
Rt=2.00 minutes (method 2)
Example 234 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-hydroxy-nicotinamidePrepared from intermediate C4 and 6-hydroxy-nicotinic acid according to AAV1
C23H19BrF3N5O3 (550.33)
Rt=1.79 minutes (method 2)
Example 235 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methoxy-nicotinamidePrepared from intermediate C4 and 6-methoxy-nicotinic acid according to AAV1
C24H21BrF3N5O3 (564.36)
Rt=1.84 minutes (method 2)
Example 236 (S)-5-amino-N-{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamidePrepared from intermediates A12 and B2 according to AAV1
C25H23F4N5O3 (517.48)
Rt=3.07 minutes (method 3)
Example 237 (S)-5-amino-N-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediate C5 and 5-aminonicotinic acid according to AAV1
C24H21ClF4N6O3 (552.91)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediate C6 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
C24H21F5N6O4 (552.46)
Rt=3.62 minutes (method 3)
Example 239 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-hydroxy-nicotinamidePrepared from intermediate C1 and 6-hydroxy-nicotinic acid according to AAV1
C23H19ClF3N5O3 (505.88)
Rt=1.71 minutes (method 2)
Example 240 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methoxy-nicotinamidePrepared from intermediate C1 and 6-methoxy-nicotinic acid according to AAV1
C24H21ClF3N5O3 (519.91)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediate C5 and 2-methylamino-pyrimidine-5-carboxylic acid according to AAV1
C24H22ClF4N7O3 (567.93)
Rt=4.64 minutes (method 3)
Example 242 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A15 and B3 according to AAV1
C23H19ClF4N6O3 (538.89)
Rt=2.15 minutes (method 2)
Example 243 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-hydroxy-nicotinamidePrepared from intermediate C2 and 5-hydroxynicotinic acid according to AAV1
C23H19F4N5O3 (489.43)
mass spectroscopy (ESI): [M+H]+=490
-
- [M−H]−=488
Prepared from intermediate C2 and 6-aminonicotinic acid according to AAV1
C23H20F4N6O2 (488.44)
mass spectroscopy (ESI): [M+H]+=489
-
- [M−H]−=487
Prepared from intermediate C2 and 2-isopropyl-pyrimidine-5-carboxylic acid according to AAV1
C25H24F4N6O2 (516.50)
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)-amidePrepared from intermediate C2 and 2-trifluoromethyl-pyrimidine-5-carboxylic acid according to AAV1
C23H17F7N6O2 (542.41)
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)-amidePrepared from intermediate C2 and 2-ethylamino-pyrimidine-5-carboxylic acid according to AAV1
C24H23F4N7O2 (517.48)
mass spectroscopy (ESI): [M+H]+=518
Rt=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)-amidePrepared from intermediate C2 and 2-piperidin-1-yl-pyrimidine-5-carboxylic acid according to AAV1
C27H27F4N7O2 (557.55)
mass spectroscopy (ESI): [M+H]+=558
Example 249 5-acetylamino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C2 and 5-acetylaminonicotinic acid according to AAV1
C25H22F4N6O3 (530.48)
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)-amidePrepared from intermediate C2 and 2-pyrrolidin-1-yl-pyrimidine-5-carboxylic acid according to AAV1
C26H25F4N7O2 (543.52)
mass spectroscopy (ESI): [M+H]+=544
Example 251 6-acetylamino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C2 and 6-acetylamino-nicotinic acid according to AAV1
C25H22F4N6O3 (530.48)
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)-amidePrepared from intermediate C2 and 6-dimethylamino-pyridazine-4-carboxylic acid according to AAV1
C24H23F4N7O2 (517.48)
mass spectroscopy (ESI): [M+H]+=518
Example 253 6-chloro-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C2 and 6-chloro-nicotinic acid according to AAV1
C23H18ClF4N5O2 (507.87)
mass spectroscopy (ESI): [M+H]+=508
Example 254 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-trifluoromethyl-nicotinamidePrepared from intermediate C2 and 6-trifluoromethyl-nicotinic acid according to AAV1
C24H18F7N5O2 (541.43)
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)-amidePrepared from intermediate C2 and 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid according to AAV1
C25H20F4N6O2 (512.47)
mass spectroscopy (ESI): [M+H]+=513
Example 256 6-cyano-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C2 and 6-cyano-nicotinic acid according to AAV1
C24H18F4N6O2 (498.44)
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)-amidePrepared from intermediate C2 and 2-acetylamino-thiazole-5-carboxylic acid according to AAV1
C23H20F4N6O3S (536.51)
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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediate C3 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
C24H21ClF4N6O4 (568.91)
Rt=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-nicotinamidePrepared from intermediate C3 and 5-methylamino-nicotinic acid according to AAV1
C25H23ClF4N6O3 (566.94)
Rt=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-nicotinamidePrepared from intermediate C6 and 5-methylamino-nicotinic acid according to AAV1
C25H23F5N6O3 (550.49)
Rt=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-ylmethyl]-amidePrepared from intermediate C5 and 3,3,3-trifluorpropionic acid according to AAV1
C21H18ClF7N4O3 (542.84)
Rt=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)-amidePrepared from intermediate C2 and 6-amino-pyridazine-4-carboxylic acid according to AAV1
C22H19F4N7O2 (489.43)
Rt=1.81 minutes (method 6)
Example 263 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-dimethylamino-nicotinamidePrepared from intermediate C1 and 6-dimethylamino-nicotinic acid according to AAV1
C25H24ClF3N6O2 (532.95)
Rt=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)-amidePrepared from intermediate C1 and 1-methyl-1H-benzimidazole-5-carboxylic acid according to AAV1
C26H22ClF3N6O2 (542.95)
Rt=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)-amidePrepared from intermediate C1 and 2-amino-1H-benzimidazole-5-carboxylic acid according to AAV1
C25H21ClF3N7O2 (543.93)
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)-amidePrepared from intermediate C1 and 1H-benzimidazole-5-carboxylic acid according to AAV1
C25H20ClF3N6O2 (528.92)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediate C6 and (S)-2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C24H21F5N6O3 (536.46)
Rt=3.91 minutes (method 3)
Example 268 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-dimethylamino-nicotinamidePrepared from intermediate C4 and 6-dimethylamino-nicotinic acid according to AAV1
C25H24BrF3N6O2 (577.40)
Rt=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-nicotinamidePrepared from intermediate C3 and 5-methylaminonicotinic acid according to AAV1
C25H23ClF4N6O3 (566.94)
Rt=3.66 minutes (method 3)
Example 270 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamidePrepared from intermediate C2 and 5-methylaminonicotinic acid according to AAV1
C24H22F4N6O2 (502.47)
Rt=1.97 minutes (method 2)
Example 271 (S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A15 and B2 according to AAV1
C24H21ClF4N6O3 (552.91)
Rt=2.48 minutes (method 2)
Example 272 N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamidePrepared from intermediate C7 and 5-methylaminonicotinic acid according to AAV1
C24H21F5N6O3 (520.46)
Rt=1.87 minutes (method 2)
Example 273 5-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-oxetan-3-yl}-nicotinamidePrepared from intermediate C8 and 5-aminonicotinic acid according to AAV1
C24H22F3N5O3 (485.46)
Rt=2.17 minutes (method 6)
Example 274 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediate C9 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C25H22F5N5O3 (535.47)
Rt=3.61 minutes (method 3)
Example 275 5-acetylamino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediate C1 and 5-acetylamino-nicotinic acid according to AAV1
C25H22ClF3N6O3 (546.93)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A15 and B6 according to AAV1
C24H22ClF4N7O3 (567.93)
Rt=2.16 minutes (method 2)
Example 277 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethylphenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A15 and B7 according to AAV1
C24H21ClF4N6O3 (552.91)
Rt=2.50 minutes (method 2)
Example 278 (S)-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethylphenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A18 and B3 according to AAV1
C23H19Cl2F3N6O3 (555.34)
Rt=2.56 minutes (method 2)
Example 279 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediate C22 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C25H23F4N5O3 (517.48)
Rt=1.97 minutes (method 7)
Example 280 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamidePrepared from intermediate C1 and 5-methylaminonicotinic acid according to AAV1
C24H22ClF3N6O2 (518.92)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A18 and B6 according to AAV1
C24H22Cl2F3N7O3 (584.38)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A18 and B7 according to AAV1
C24H21Cl2F3N6O3 (569.37)
Rt=2.59 minutes (method 2)
Example 283 2-methyl-pyrimidine-5-carboxylic acid-{1-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amidePrepared from intermediate C10 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C24H20F5N5O2 (505.44)
Rt=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)-amidePrepared from intermediate C1 and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
C22H18ClF3N6O3 (506.87)
Rt=2.13 minutes (method 2)
Example 285 (S)-5-amino-N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A18 and B2 according to AAV1
C24H21Cl2F3N6O3 (569.37)
Rt=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-nicotinamidePrepared from intermediates A18 and B8 according to AAV 1
C24H20Cl2F3N5O4 (570.35)
Rt=2.52 minutes (method 2)
mass spectroscopy (ESI): [M+H]+=570; [M−H]−=568
Example 287 (S)-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A6 and B3 according to AAV1
C24H21F4N5O3 (503.45)
Rt=2.43 minutes (method 2)
Example 288 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A6 and B7 according to AAV1
C25H23F4N5O3 (517.48)
Rt=2.64 minutes (method 2)
Example 289 (S)-2-methylamino-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A6 and B6 according to AAV1
C25H24F4N6O3 (532.50)
Rt=2.44 minutes (method 2)
Example 290 (S)-5-amino-N-{3-[2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamidePrepared from intermediate C11 and 5-aminonicotinic acid according to AAV1
C25H22F5N5O3 (535.47)
Rt=1.63 minutes (method 7)
Example 291 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediate C11 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C25H22F5N5O3 (535.47)
Rt=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)-amidePrepared from intermediates A10 and B7 according to AAV1
C24H22ClF3N6O3 (534.92)
Rt=1.78 minutes (method 7)
Example 293 (S)-6-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A15 and B9 according to AAV1
C24H21ClF4N6O3 (552.91)
Rt=2.14 minutes (method 2)
Example 294 2-methyl-pyrimidine-5-carboxylic acid-{1-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amidePrepared from intermediate C12 and 2-methylpyrimidine-5-carboxylic acid according to AAV1
C24H21F4N5O2 (487.45)
Rt=1.91 minutes (method 7)
Example 295 pyrimidine-5-carboxylic acid-(1-{[5-(2-cyano-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates A20 and B1 according to AAV1
C22H8FN7O2 (431.43)
Rt=1.62 minutes (method 2)
Example 296 pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-phenylamino)-2-fluoro-benzyl-carbamoyl]-cyclopropyl}-amidePrepared from intermediates A30 and B1 according to AAV1
C23H19FN6O2 (430.44)
Rt=1.88 minutes (method 2)
Example 297 (S)-6-amino-N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A18 and B9 according to AAV1
C24H21Cl2F3N6O3 (569.37)
Rt=2.46 minutes (method 2)
Example 298 2-methyl-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediate C13 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C23H19F5N6O2 (506.43)
Rt=1.74 minutes (method 7)
Example 299 (S)-thiazole-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediate C14 and thiazole-5-carboxylic acid according to AAV1
C23H20F4N4O3S (508.49)
Rt=2.43 minutes (method 2)
Example 300 (S)-2-methoxy-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediate C14 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
C25H23F4N5O4 (533.48)
Rt=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)-amidePrepared from intermediate C15 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
C23H20ClF3N6O2 (504.90)
Rt=1.79 minutes (method 7)
Example 302 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamidePrepared from intermediate C2 and 5-methyl-nicotinic acid according to AAV1
C24H21F4N5O2 (487.45)
Rt=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)-amidePrepared from intermediate C2 and 2-methyl-thiazole-5-carboxylic acid according to AAV1
C22H19F4N5O2S (493.48)
Rt=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)-amidePrepared from intermediates A7 and B6 according to AAV1
C24H23F4N7O3 (533.48)
Rt=1.88 minutes (method 2)
Example 305 (S)—N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methylamino-nicotinamidePrepared from intermediate C14 and 5-methylaminonicotinic acid according to AAV1
C26H25F4N5O3 (531.51)
Rt=1.83 minutes (method 7)
Example 306 pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates A21 and B1 according to AAV1
C23H20F4N6O2 (488.44)
Rt=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)-amidePrepared from intermediates A7 and B7 according to AAV1
C24H22F4N6O3 (518.47)
Rt=2.32 minutes (method 2)
Example 308 (S)—N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methyl-nicotinamidePrepared from intermediates C14 and 5-methylnicotinic acid according to AAV1
C26H24F4N4O3 (516.49)
Rt=2.45 minutes (method 2)
Example 309 (S)-6-amino-N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamidePrepared from intermediates C14 and 6-aminonicotinic acid according to AAV1
C25H23F4N5O3 (517.48)
Rt=2.09 minutes (method 2)
Example 310 (S)-2-isopropyl-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C14 and 2-isopropyl-pyrimidine-5-carboxylic acid according to AAV1
C27H27F4N5O3 (545.53)
Rt=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-nicotinamidePrepared from intermediates C16 and 5-methylamino-nicotinic acid according to AAV1
C25H24F4N6O3 (532.50)
Rt=2.22 minutes (method 2)
Example 312 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methyl-nicotinamidePrepared from intermediates C1 and 6-methyl-nicotinic acid according to AAV1
C24H21ClF3N5O2 (503.91)
Rt=2.17 minutes (method 2)
Example 313 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methoxy-nicotinamidePrepared from intermediates C1 and 5-methoxy-nicotinic acid according to AAV1
C24H21ClF3N5O3 (519.91)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates C17 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
C24H21ClF4N6O4 (568.91)
Rt=2.53 minutes (method 2)
Example 315 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methyl-nicotinamidePrepared from intermediates C4 and 6-methyl-nicotinic acid according to AAV1
C24H21BrF3N5O2 (548.36)
Rt=2.24 minutes (method 2)
Example 316 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methoxy-nicotinamidePrepared from intermediates C4 and 5-methoxy-nicotinic acid according to AAV1
C24H21BrF3N5O3 (564.36)
Rt=2.34 minutes (method 2)
Example 317 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A22 and B7 according to AAV1
C25H23ClF3N5O3 (533.94)
Rt=2.60 minutes (method 2)
Example 318 (S)-6-amino-N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamidePrepared from intermediates A22 and B9 according to AAV1
C25H23ClF3N5O3 (533.94)
Rt=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-nicotinamidePrepared from intermediates C17 and 5-methylamino-nicotinic acid according to AAV1
C25H23ClF4N6O3 (566.94)
Rt=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)-nicotinamidePrepared from intermediates A23 and B2 according to AAV1
C24H22F4N6O3 (518.47)
Rt=1.52 minutes (method 7)
Example 321 (S)-5-amino-N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamidePrepared from intermediates A22 and B2 according to AAV1
C25H23ClF3N5O3 (533.94)
Rt=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]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C14 and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
C24H21F4N5O4 (519.45)
Rt=2.39 minutes (method 2)
Example 323 (S)-2-methylamino-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A22 and B6 according to AAV1
C25H24ClF3N6O3 (548.95)
Rt=2.57 minutes (method 2)
Example 324 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A21 and B3 according to AAV1.
C24H22F4N6O3 (518.47)
Rt=1.80 minutes (method 2)
mass spectroscopy (ESI): [M+H]+=519
-
- [M−H]−=517
Prepared from intermediates A24 and B1 according to AAV1.
C21H17BrClFN6O2 (519.76)
Rt=2.01 minutes (method 2)
Example 326 pyrimidine-5-carboxylic acid-(1-{[5-(2-bromo-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates A25 and B1 according to AAV1.
C21H18BrFN6O2 (485.32)
Rt=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)-amidePrepared from intermediates C16 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1.
C24H22F4N6O4 (534.47)
Rt=1.98 minutes (method 2)
Example 328 (S)-2-ethylamino-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C14 and 2-ethylamino-pyrimidine-5-carboxylic acid according to AAV1.
C26H26F4N6O3 (546.52)
Rt=2.62 minutes (method 2)
Example 329 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-ethylamino-nicotinamidePrepared from intermediates C1 and 6-ethylamino-nicotinic acid according to AAV1.
C25H24ClF3N6O2 (532.95)
Rt=2.32 minutes (method 2)
Example 330 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-propylamino-nicotinamidePrepared from intermediates C1 and 6-propylamino-nicotinic acid according to AAV1.
C26H26ClF3N6O2 (546.98)
Rt=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-nicotinamidePrepared from intermediates A15 and B8 according to AAV1.
C24H20ClF4N5O4 (553.90)
Rt=2.48 minutes (method 2)
Example 332 (S)-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C18 and pyrimidine-5-carboxylic acid according to AAV1.
C24H21ClF3N5O3 (519.91)
Rt=2.57 minutes (method 2)
Example 333 (S)-2-methoxy-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C18 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1.
C25H23ClF3N5O4 (549.93)
Rt=2.72 minutes (method 2)
Example 334 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-ethylamino-nicotinamidePrepared from intermediates C4 and 6-ethylamino-nicotinic acid according to AAV1.
C25H24CBrF3N6O2 (577.40)
Rt=2.01 minutes (method 2)
Example 335 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-propylamino-nicotinamidePrepared from intermediates C4 and 6-propylamino-nicotinic acid according to AAV1.
C26H26BrF3N6O2 (591.43)
Rt=2.12 minutes (method 2)
Example 336 (S)-thiazole-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C18 and thiazole-5-carboxylic acid according to AAV1.
C23H20ClF3N4O3S (524.95)
Rt=2.58 minutes (method 2)
Example 337 (S)—N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methoxy-nicotinamidePrepared from intermediates C18 and 5-methoxy-nicotinic acid according to AAV1.
C26H24ClF3N4O4 (548.95)
Rt=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]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A22 and B10 according to AAV1.
C24H21ClF3N5O4 (535.91)
Rt=2.28 minutes (method 2)
Example 339 5-chloro-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediates C2 and 5-chloro-nicotinic acid according to AAV1.
C23H18ClF4N5O2 (507.87)
Rt=2.18 minutes (method 2)
Example 340 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamidePrepared from intermediates C2 and 5-trifluoromethyl-nicotinic acid according to AAV1.
C24H18F7N5O2 (541.43)
Rt=2.32 minutes (method 2)
Example 341 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methyl-nicotinamidePrepared from intermediates C2 and 6-methyl-nicotinic acid according to AAV1.
C24H21F4N5O2 (487.45)
Rt=1.85 minutes (method 2)
Example 342 (S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A21 and B2 according to AAV1.
C25H24F4N6O3 (487.45)
Rt=1.85 minutes (method 2)
Example 343 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methylamino-nicotinamidePrepared from intermediates C4 and 6-methylamino-nicotinic acid according to AAV1.
C24H22BrF3N6O2 (563.38)
Rt=2.32 minutes (method 2)
Example 344 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates C19 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
C24H22F4N6O2 (502.47)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A26 and B7 according to AAV1.
C25H24ClF3N6O3 (548.95)
Rt=2.16 minutes (method 2)
Example 346 (S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A26 and B2 according to AAV1.
C25H24ClF3N6O3 (548.95)
Rt=2.23 minutes (method 2)
Example 347 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methylamino-nicotinamidePrepared from intermediates C1 and 6-methylamino-nicotinic acid according to AAV1.
C24H22ClF3N6O2 (518.92)
Rt=1.85 minutes (method 2)
Example 348 (S)-6-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamidePrepared from intermediates A14 and B9 according to AAV1.
C24H21F5N6O3 (536.46)
Rt=1.96 minutes (method 2)
mass spectroscopy (ESI): [M+H]+=537
-
- [M−H]−=535
Prepared from intermediates A7 and B9 according to AAV1.
C24H22F4N6O3 (518.47)
mass spectroscopy (ESI): [M+H]+=519
-
- [M−H]−=517
Prepared from intermediates C1 and 2-hydroxy-pyrimidine-5-carboxylic acid according to AAV1.
C22H18ClF3N6O3 (506.87)
Rt=2.42 minutes (method 2)
Example 351 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-fluoro-nicotinamidePrepared from intermediates C1 and 5-fluoro-nicotinic acid according to AAV1.
C23H18ClF4N5O2 (507.87)
Rt=1.96 minutes (method 2)
Example 352 5-chloro-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediates C1 and 5-chloro-nicotinic acid according to AAV1.
C23H18Cl2F3N5O2 (524.33)
Rt=2.10 minutes (method 2)
Example 353 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamidePrepared from intermediates C1 and 5-methyl-nicotinic acid according to AAV1.
C24H21ClF3N5O2 (503.91)
Rt=1.86 minutes (method 2)
Example 354 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamidePrepared from intermediates C1 and 5-trifluoromethyl-isonicotinic acid according to AAV1.
C24H18ClF6N5O2 (557.88)
Rt=2.22 minutes (method 2)
Example 355 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-fluoro-isonicotinamidePrepared from intermediates C1 and 2-fluoro-isonicotinic acid according to AAV1.
C23H18ClF4N5O2 (507.87)
Rt=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)-amidePrepared from intermediates C1 and 3-methoxy-isoxazole-5-carboxylic acid according to AAV1
C22H19ClF3N5O4 (509.87)
Rt=1.96 minutes (method 2)
Example 357 isothiazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates C1 and isothiazole-5-carboxylic acid according to AAV1.
C21H7ClF3N5O2S (495.91)
Rt=1.88 minutes (method 2)
Example 358 isothiazol-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates C1 and isothiazole-4-carboxylic acid according to AAV1.
C21H7ClF3N5O2S (495.91)
Rt=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)-nicotinamidePrepared from intermediates A27 and B2 according to AAV1.
C25H25F3N6O3 (514.51)
Rt=1.51 minutes (method 2)
Example 360 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates A26 and B11 according to AAV1.
C24H22ClF3N6O2 (518.92)
Rt=2.11 minutes (method 2)
Example 361 5-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediates A26 and B4 according to AAV1.
C24H22ClF3N6O2 (518.92)
Rt=1.83 minutes (method 2)
Example 362 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amidePrepared from intermediates C1 and trifluoroacetic acid according to AAV1
C19H15ClF6N4O2 (480.79)
Rt=2.15 minutes (method 2)
Example 363 1-(3,3,3-trifluoro-propionylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amidePrepared from intermediates C1 and 3,3,3-trifluoro-propionic acid according to AAV1
C20H17ClF6N4O2 (494.82)
Rt=2.07 minutes (method 2)
Example 364 1-(2-cyano-acetylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amidePrepared from intermediates C1 and 2-cyano-acetic acid according to AAV1.
C20H17ClF3N5O2 (451.83)
Rt=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]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C14 and 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid according to AAV1.
C27H23F4N5O3 (541.50)
Rt=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)-amidePrepared from intermediates A27 and B7 according to AAV1
C25H25F3N6O3 (514.51)
Rt=1.84 minutes (method 2)
Example 367 1-cyano-1-(cyclopropanecarbonyl-amino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amidePrepared from intermediates C1 and 1-cyano-1-cyclopropanecarboxylic acid according to AAV1.
C22H19ClF3N5O2 (477.87)
Rt=1.96 minutes (method 2)
Example 368 1-(2-cyano-2-methyl-acetylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amidePrepared from intermediates C1 and 2-cyano-2-methyl-acetic acid according to AAV1.
C21H19ClF3N5O2 (465.86)
Rt=1.92 minutes (method 2)
Example 369 isoxazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates C1 and isoxazole-5-carboxylic acid according to AAV1.
C21H17ClF3N5O3 (479.84)
Rt=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)-amidePrepared from intermediates C1 and 2-amino-pyrimidine-5-carboxylic acid according to AAV1.
C22H19ClF3N7O2 (505.89)
Rt=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)-amidePrepared from intermediates C1 and 2-ethyl-pyrimidine-5-carboxylic acid according to AAV1.
C24H22ClF3N6O2 (518.92)
Rt=2.38 minutes (method 2)
Example 372 1H-pyrazole-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates C1 and 1H-pyrazole-4-carboxylic acid according to AAV1.
C21H18ClF3N6O2 (478.86)
Rt=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)-amidePrepared from intermediates C1 and 1-methyl-1H-pyrazole-4-carboxylic acid according to AAV1.
C22H20ClF3N6O2 (492.89)
Rt=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)-amidePrepared from intermediates C20 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
C24H23F3N6O2 (484.48)
Rt=1.81 minutes (method 2)
Example 375 5-amino-N-(1-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediates C20 and 5-amino-nicotinic acid according to AAV1.
C24H23F3N6O2 (484.48)
Rt=1.29 minutes (method 2)
Example 376 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methoxy-nicotinamidePrepared from intermediates C2 and 5-methoxy-nicotinic acid according to AAV1.
C24H21F4N5O3 (503.45)
Rt=2.02 minutes (method 2)
Example 377 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methylamino-nicotinamidePrepared from intermediates C2 and 6-methylamino-nicotinic acid according to AAV1.
C24H22F4N6O2 (502.47)
Rt=2.01 minutes (method 2)
Example 378 6-amino-5-bromo-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamidePrepared from intermediates C1 and 6-amino-5-bromo-nicotinic acid according to AAV1.
C23H19BrClF3N6O2 (583.79)
Rt=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)-amidePrepared from intermediates C1 and 2-cyclopropylamino-pyrimidine-5-carboxylic acid according to AAV1.
C25H23ClF3N7O2 (545.95)
Rt=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)-amidePrepared from intermediates C1 and 2-propylamino-pyrimidine-5-carboxylic acid according to AAV1.
C25H25ClF3N7O2 (547.97)
Rt=2.42 minutes (method 2)
Example 381 (S)—N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methoxy-nicotinamidePrepared from intermediates C14 and 5-methoxy-nicotinic acid according to AAV1.
C26H24F4N4O4 (532.49)
Rt=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)-amidePrepared from intermediates C1 and 2-isopropylamino-pyrimidine-5-carboxylic acid according to AAV1.
C25H25ClF3N7O2 (547.97)
Rt=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]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C14 and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
C27H23F4N5O3 (541.50)
Rt=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)-amidePrepared from intermediates C2 and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
C25H20F4N6O2 (512.47)
Rt=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)-amidePrepared from intermediates C1 and 2-cyano-pyrimidine-5-carboxylic acid according to AAV1
C23H17ClF3N7O2 (515.88)
Rt=2.39 minutes (method 2)
Example 386 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-difluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amidePrepared from intermediates C21 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
C23H21ClF2N6O2 (486.91)
Rt=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-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amidePrepared from intermediates A21 and B7 according to AAV1.
C25H24F4N6O3 (532.50)
Rt=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]-tetrahydrofuran-3-yl}-amidePrepared from intermediates C18 and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
C27H23ClF3N5O3 (557.96)
mass spectroscopy (ESI): [M+H]+=558
-
- [M−H]−=556
Prepared from intermediates C1 and 6-cyclopropylamino-nicotinic acid according to AAV1.
C26H24ClF3N6O2 (544.96)
Rt=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)-amidePrepared from intermediates C1 and 2-ethoxy-pyrimidine-5-carboxylic acid according to AAV1.
C24H22ClF3N6O3 (534.92)
Rt=1.99 minutes (method 2)
Example 391 6-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamidePrepared from intermediates C2 and 6-amino-5-methyl-nicotinic acid according to AAV1.
C24H22F4N6O2 (502.47)
Rt=1.38 minutes (method 2)
Example 392 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A17 and B10 according to AAV1.
C24H22F3N5O4 (501.46)
Rt=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)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A11 and B10 according to AAV1.
C24H20F5N5O4 (537.44)
Rt=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-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A29 and B10 according to AAV1.
C24H20ClF4N5O4 (553.90)
Rt=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]-tetrahydrofuran-3-yl}-amidePrepared from intermediates A31 and B10 according to AAV1.
C24H21BrF3N5O4 (580.35)
Rt=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]-tetrahydro-furan-3-yl}-amidePrepared from intermediates A12 and B10 according to AAV1.
C24H21F4N5O4 (519.45)
Rt=1.35 minutes (method 7)
mass spectroscopy (ESI): [M+H]+=520
-
- [M−H]−=518
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 mlComposition:
Composition:
Composition:
Composition:
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 CompoundComposition:
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 Compound1 suppository comprises:
Claims
1. A compound of the formula I
- wherein
- n denotes one of the numbers 0, 1 or 2,
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (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, (c) a substituted C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2— unit may be replaced by a —C(O)— group, (d) an aryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.3, (e) a five-membered heteroaryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.4, 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-C0-2-alkylene group optionally substituted by 1 or 2 groups R1.4, 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 R1.4 substituted, which contains one, two or three N-atoms, (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group, (i) —O—R1.1.1, (j) —NR1.1.3R1.1.4 or (k) —C(═NR1.5)—CN,
- R1.1 denotes halogen, —NO2, —CN, C3-6-cycloalkyl, —OR1.1.1, —SR1.1.1, —C(O)R1.1.1, —S(O)2—R1.1.2, —O—S(O)2—R1.1.1, —CO2R1.1.1, —O—C(O)—R1.1.1, —NR1.1.3R1.1.4, —NR1.1,3−C(O)—R1.1.1, —NR1.1,3−C(O)—R1.1.1, —NR1.1,3−CO2—R1.1.1 or —C(O)—NR1.1.3R1.1.4,
- R1.1.1 denotes (a) H, (b) C1-4-alkyl, (c) 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, (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1, (e) C3-6-cycloalkyl or (f) a pyridyl group optionally substituted by 1, 2 or 3 groups R1.1.1.2,
- R1.1.1.1 independently of one another denote (a) halogen, —NO2, —CN, —OH, —O—C1-4-alkyl, C3-6-cycloalkyl, C1-4-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,
- R1.1.1.2 independently of one another denote halogen or C1-4-alkyl,
- R1.1.2 denotes (a) C1-4-alkyl, (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, (c) —O—C1-4-alkyl or (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1 substituted,
- R1.1.3,
- R1.1.4 independently of one another denote (a) H, (b) a C1-4-alkyl group optionally substituted by 1, 2 or 3 groups R1.1.4.1, (c) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1, (d) C3-6-cycloalkyl, or
- R1.1.3 and R1.1.4 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
- R1.1.3 and R1.1.4 together with the N atom to which they are attached, form a cyclic imide,
- R1.1.4.1 independently of one another halogen denote —NH2, —NH(C1-4-alkyl), —N(C1-4-alkyl)2 or —SO2—R1.1.2,
- R1.2 denotes halogen, —NO2, —CN, OH, —O—CH3 or phenyl,
- R1.3 denotes (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —CO2R1.1.1, C1-6-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,
- R1.4 independently of one another denote (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —S(O)—R1.1.2, S(O)2—R1.1.2, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl, (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, or (c) an oxo group,
- R1.4.1 denotes H or C1-4-alkyl,
- R1.5 denotes —OH or —O—C1-3-alkyl,
- R2 denotes (a) H, (b) C1-4-alkyl, (c) C1-4-alkyl-C(O)—,
- R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
- R3.1 denotes H, —OH,
- R5 denotes (a) H, (b) C1-4-alkyl, (c) 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,
- R6 independently of one another denote (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-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,
- R7 denotes (a) H, halogen, —CN, —OH, (b) C1-6-alkyl, (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl, (e) —O—C1-6-alkyl, (f) —O—C3-7-cycloalkyl, (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, (h) —C(O)—R7.1, (i) —S—C1-4-alkyl, —SO2—R7.2, (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
- R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
- R8 denotes H, halogen, C1-4-alkyl,
- R9 denotes (a) H, halogen, —CN, —OH, (b) C1-6-alkyl, (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl, (e) C2-4-alkynyl, (f) —O—C1-6-alkyl, (g) —O—C3-7-cycloalkyl, (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, (i) —C(O)—R9.1, (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
- R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R10 denotes H, halogen, C1-4-alkyl,
- R11 denotes (a) H, halogen, —CN, —OH, (b) C1-6-alkyl, (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl, (e) —O—C1-6-alkyl, (f) —O—C3-7-cycloalkyl, (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, (h) —C(O)—R11.1, (i) —S—C1-3-alkyl, —SO2—R11.2, (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-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 C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
- R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
- R11.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
- X independently of one another denote C—R6 or N,
- or a salt thereof.
2. A compound of the formula I according to claim 1, wherein:
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (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, (c) a C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2-unit may be replaced by a —C(O)— group, (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (e) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms, (g) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms, (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group, (i) —O—R1.1.1 or (j) —NR1.1.3R1.1.4,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OR1.1.1, NR1.1.3R1.1.4,
- R1.1.1 denotes (a) H, (b) C1-4-alkyl, (c) 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,
- R1.1.3,
- R1.1.4 independently of one another denote (a) H, (b) C1-4-alkyl, (c) C3-6-cycloalkyl, or
- R1.1.3 and R1.1.4 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
- R1.2 denotes halogen, —NO2, —CN, —OH, —O—CH3 or phenyl,
- R1.3 independently of one another denote (a) halogen, —NO2, —CN, —OR1.1.1, C1-6-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,
- R1.4 independently of one another denote (a) halogen, —NO2, —CN, —OR1.1.1, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-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, and
- R4.1 denotes H or C1-4-alkyl,
- or a salt thereof.
3. A compound of the formula I according to claim 1, wherein:
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms, (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms, (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 independently of one another denote (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
- R1.4 independently of one another denote (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, NHC2-3-alkyl, —N(C2-3-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
- or a salt thereof.
4. A compound of the formula I according to claim 1, wherein:
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 which is
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
- R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 independently of one another denotes (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
- R1.4 independently of one another denotes (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
- or a salt thereof.
5. A compound of the formula I according to claim 1, wherein:
- R1 is
- or a salt thereof.
6. A compound of the formula I according to claim 1, wherein:
- R1 is
- 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,
- R2 denotes (a) H, (b) C1-4-alkyl,
- R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
- R3.1 denotes H, —OH,
- R5 denotes (a) H, (b) C1-4-alkyl, (c) 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,
- R6 independently of one another denotes (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or (a) 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,
- R7 denotes (a) H, halogen, —CN, —OH, (b) C1-6-alkyl, (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl, (e) —O—C1-6-alkyl, (f) —O—C3-7-cycloalkyl, (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, (h) —C(O)—R7.1, (i) —S—C1-4-alkyl,
- R7.1 denotes —NH2, —OH, —O—C1-8-alkyl,
- R8 denotes H, halogen, C1-4-alkyl,
- R9 denotes (a) H, halogen, —CN, —OH, (b) C1-6-alkyl, (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl, (e) C2-4-alkynyl, (f) —O—C1-6-alkyl, (g) —O—C3-7-cycloalkyl, (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, (i) —C(O)—R9.1, (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
- R9.1 denotes —NH2, —OH, —O—C1-8-alkyl,
- R10 denotes H, halogen, C1-4-alkyl,
- R11 denotes (a) H, halogen, —CN, —OH, (b) C1-6-alkyl, (c) C1-3-alkyl or —O—C1-3-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) C3-7-cycloalkyl, (e) —O—C1-6-alkyl, (f) —O—C3-7-cycloalkyl, (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, (h) —C(O)—R11.1, (i) —S—C1-3-alkyl,
- R11.1 denotes —NH2, —OH, —O—C1-8-alkyl, and
- X independently of one another represent C—R6 or N,
- or a salt thereof.
8. A compound of the formula I according to claim 1, wherein:
- R2 denotes H or CH3,
- or a salt thereof.
9. A compound of the formula I according to claim 1, wherein:
- R2 denotes H,
- or a salt thereof.
10. A compound of the formula I according to claim 1, wherein:
- R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
- or a salt thereof.
11. A compound of the formula I according to claim 1, wherein:
- R3 and R4 together with the carbon atom to which they are bonded denote
- or a salt thereof.
12. A compound of the formula I according to claim 1, wherein:
- R5 denotes H or CH3,
- or a salt thereof.
13. A compound of the formula I according to claim 1, wherein:
- R6 denotes H, F, Cl or methyl,
- or a salt thereof.
14. A compound of the formula I according to claim 1, wherein:
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3 or CHF2,
- R8 denotes H,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R10 denotes H and
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3 or CHF2,
- or a salt thereof.
15. A compound of the formula Ia,
- wherein
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms, (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms, (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2 unit may be replaced by a —C(O) group,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 independently of one another denotes (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
- R1.4 independently of one another denotes (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or (a) 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,
- R2 denotes H or CH3,
- R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
- R5 denotes H or C1-4-alkyl,
- R6 denotes H, F, Cl, Br or C1-4-alkyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
16. A compound of the formula Ia according to claim 14, wherein
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
- R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, or —N(CH3)2,
- R1.3 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —OCF3, or C1-4-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, and
- R1.4 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, or C1-6-alkyl, or (a) 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,
- R2 denotes H or CH3,
- R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
17. A compound of the formula Ia according to claim 14, wherein
- R1 denotes
- R2 denotes H or CH3,
- R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
18. A compound of the formula Ia according to claim 15, wherein
- R1 denotes
- R2 denotes H or CH3,
- R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
19. A compounds of the formula Ib
- wherein:
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms, (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms, (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
- R1.4 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or (a) 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,
- R2 denotes H or CH3,
- R5 denotes H or C1-4-alkyl,
- R6 denotes H, F, Cl, Br or C1-4-alkyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
20. A compound of the formula Ib according to claim 17, wherein
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
- R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, or —N(CH3)2,
- R1.3 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
- R1.4 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or (a) 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,
- R2 denotes H or CH3,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
21. A compound of the formula Ib according to claim 17, wherein
- R1 denotes
- R2 denotes H or CH3,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
22. A compound of the formula Ib according to claim 19, wherein
- R1 denotes
- R2 denotes H,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
23. A compound of the formula Ic,
- wherein
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, 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 R1.4, which contains one, two or three N-atoms, (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms, (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
- R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, C1-6-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, and
- R1.4 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-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,
- R2 denotes H or CH3,
- R5 denotes H or C1-4-alkyl,
- R6 denotes H, F, Cl, Br or C1-4-alkyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
24. A compound of the formula Ic according to claim 20, wherein
- R1 denotes (a) a C1-6-alkyl group optionally substituted by a group R1.1, (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3, (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
- (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
- (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
- R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
- R1.3 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-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, and
- R1.4 denotes independently of one another (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or (a) 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,
- R2 denotes H or CH3,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
25. A compound of the formula Ic according to claim 20, wherein
- R1 denotes
- R2 denotes H or CH3,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
26. A compound of the formula Ic according to claim 23, wherein
- R1 denotes
- R2 denotes H or CH3,
- R5 denotes H or CH3,
- R6 denotes H, F, Cl or methyl,
- R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
- R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
- R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
- X denotes CH or N,
- or a salt thereof.
27. A compound of the formula Id,
- wherein
- R1 denotes
- R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
- R5 denotes H or CH3,
- R6 denotes Cl or CH3,
- R7 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: No. Structure (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) (67) (68) (69) (70) (71) (72) (73) (74) (75) (76) (77) (78) (79) (80) (81) (82) (83) (84) (85) (86) (87) (88) (89) (90) (91) (92) (93) (94) (95) (96) (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) (107) (108) (109) (110) (111) (112) (113) (114) (115) (116) (117) (118) (119) (120) (121) (122) (123) (124) (125) (126) (127) (128) (129) (130) (131) (132) (133) (134) (135) (136) (137) (138) (139) (140) (141) (142) (143) (144) (145) (146) (147) (148) (149) (150) (151) (152) (153) (154) (155) (156) (157) (158) (159) (160) (161) (162) (163) (164) (165) (166) (167) (168) (169) (170) (171) (172) (173) (174) (175) (176) (177) (178) (179) (180) (181) (182) (183) (184) (185) (186) (187) (188) (189) (190) (191) (192) (193) (194) (195) (196) (197) (198) (199) (200) (201) (202) (203) (203a) (203b) (204) (205) (206) (207) (208) (209) (210) (211) (212) (212a) (212b) (213) (213a) (213b) (214) (215) (216) (217) (218) (219) (220) (221) (222) (223) (224) (225) (226) (227) (228) (229) (230) (231) (232) (233) (234) (235) (236) (237) (238) (239) (240) (241) (242) (243) (244) (245) (246) (247) (248) (249) (250) (251) (252) (253) (254) (255) (256) (257) (258) (258) (260) (261) (262) (263) (264) (265) (266) (267) (268) (269) (270) (271) (272) (273) (274) (275) (276) (277) (278) (279) (280) (281) (282) (283) (284) (285) (286) (287) (288) (289) (290) (291) (292) (293) (294) (295) (296) (297) (298) (299) (300) (301) (302) (303) (304) (305) (306) (307) (308) (309) (310) (311) (312) (313) (314) (315) (316) (317) (318) (319) (320) (321) (322) (323) (324) (325) (326) (327) (328) (329) (330) (331) (332) (333) (334) (335) (336) (337) (338) (339) (340) (341) (342) (343) (344) (345) (346) (347) (348) (349) (350) (351) (352) (353) (354) (355) (356) (357) (358) (359) (360) (361) (362) (363) (364) (365) (366) (367) (368) (369) (370) (371) (372) (373) (374) (375) (376) (377) (378) (379) (380) (381) (382) (383) (384) (385) (386) (387) (388) (389) (390) (391) (392) (393) (394) (395) (396)
- 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.
Type: Application
Filed: Jan 15, 2013
Publication Date: May 23, 2013
Applicant: Boehringer Ingelheim International GmbH (Ingelheim am Rhein)
Inventors: Norbert HAUEL (Schemmerhofen), Angelo CECI (Mittelbiberach), Henri DOODS (Warthausen), Ingo KONETZKI (Warthausen), Juergen MACK (Biberach), Henning PRIEPKE (Warthausen), Annette SCHULER-METZ (Ulm), Rainer WALTER (Biberach), Dieter WIEDENMAYER (Biberach)
Application Number: 13/742,175
International Classification: C07D 405/12 (20060101); C07D 239/557 (20060101); C07D 239/28 (20060101);
