Substituted imidazopyrimidines and triazolopyrimidines
The invention relates to substituted imidazo- and triazolopyrimidines and processes for their preparation, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, in particular of haematological disorders, preferably of leucopenias and neutropenias.
1. A compound of the formula
in which
A is CR 15 ,
where
R 15 is hydrogen, bromine or chlorine,
R 1 is hydrogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, trifluoromethyl, trifluoromethoxy, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, dihydroxypropyl-aminocarbonyl, dihydroxybutylaminocarbonyl, dihydroxypentylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylsulphonylamino, 5- or 6-membered heterocyclylcarbonyl, —CH 2 R 13 or —CH 2 CH 2 R 14 ,
where alkoxy, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino and alkylsulphonylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino and 5- or 6-membered heterocyclyl,
in which heterocyclyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl,
and
where heterocyclylcarbonyl may be substituted by 1 to 3 substituents,
where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl,
and
where
R 13 is hydroxy, amino, cyano, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl and alkylcarbonylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 1 -C 4 -alkylcarbonylamino,
and
in which heterocyclyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl,
and
where
R 14 is hydroxy, amino, cyano, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl and alkylcarbonylamino may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 1 -C 4 -alkylcarbonylamino,
and
in which heterocyclyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl,
R 2 is C 6 -C 10 -aryl or 5- to 10-membered heteroaryl,
where aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxy, hydroxymethyl, amino, halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxymethyl, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylaminomethyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphonylamino, C 1 -C 4 -alkylaminosulphonyl, phenyl, benzyloxy, 5-or 6-membered heterocyclyl, 5- or 6-membered heterocyclylcarbonyl, 5-or 6-membered heterocyclylmethyl and 5- or 6-membered heteroaryl,
in which phenyl, benzyloxy, heterocyclyl, heterocyclylcarbonyl, heterocyclylmethyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 1 -C 4 -alkylcarbonylamino,
or
two of the substituents on the aryl form together with the carbon atoms to which they are bonded a 1,3-dioxolane or 1,4-dioxane,
R 4 is hydrogen, halogen, cyano, trifluoromethyl, C 1 -C 3 -alkyl, methylthio or cyclopropyl,
R 16 is a group of the formula
where
* is the point of attachment to the heterocycle,
n is the number 0 or 1,
X is NR 11 , S or O,
where
R 11 is hydrogen, C 1 -C 3 -alkyl or cyclopropyl,
Y is NR 12 , S or O,
where
R 12 is hydrogen, C 1 -C 3 -alkyl or cyclopropyl,
R 3 is 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 2-cyclopropylaminopyrimid-4-yl, 2-methylaminopyrimid-4-yl, 2-ethylaminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl,
where 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 1,3-thiazol-5-yl are substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, nitro, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl, trifluoromethylcarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 3 -C 6 -cycloalkylcarbonyl,
in which alkyl, alkoxy, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and cycloalkylcarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of halogen, cyano, hydroxy, amino, trifluoromethyl and C 3 -C 6 -cycloalkyl,
or
R 3 is a group of the formula
where # is the point of attachment to Y,
R 5 is hydrogen, C 1 -C 3 -alkyl or cyclopropyl,
R 6 is hydrogen or C 1 -C 3 -alkyl,
R 7 is hydrogen, C 1 -C 3 -alkyl or cyclopropyl,
R 8 is hydrogen or C 1 -C 3 -alkyl,
R 9 is hydrogen, C 1 -C 3 -alkyl or cyclopropyl,
R 10 is hydrogen or C 1 -C 3 -alkyl,
or a salt thereof.
2. The compound according to claim 1 , wherein
A is CR 15 ,
where
R 15 is hydrogen,
R 1 is hydrogen, trifluoromethyl, cyano, C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonyl, dihydroxypropylaminocarbonyl, dihydroxybutylaminocarbonyl, dihydroxypentylaminocarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, —CH 2 R 13 or —CH 2 CH 2 R 14 ,
where alkylaminocarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl,
in which pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,
and
where pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and piperazinyl-carbonyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,
and
where
R 13 is hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl or pyridyl,
in which alkoxy, alkylamino and alkylaminocarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 1 -C 4 -alkylcarbonylamino,
and
in which pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,
and
where
R 14 is hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl or pyridyl, in which alkoxy, alkylamino and alkylaminocarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 1 -C 4 -alkylcarbonylamino,
and
in which pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, hydroxy, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,
R 2 is phenyl,
where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxymethyl, C 1 -C 4 -alkylaminomethyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkylsulphonylamino, C 1 -C 4 -alkylaminosulphonyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl and piperazinylmethyl,
in which phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl and piperazinylmethyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl,
R 4 is hydrogen or chlorine,
R 16 is a group of the formula
where
* is the point of attachment to the heterocycle,
n is the number 0,
X is NR 11 , S or O,
where
R 11 is hydrogen or methyl,
Y is NR 12 , S or O,
where
R 12 is hydrogen or methyl,
R 3 is 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 2-cyclopropylaminopyrimid-4-yl, 2-methylaminopyrimid-4-yl, 2-ethylaminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl,
where 2-pyridyl, pyrimid-2-yl, 2-aminopyrimid-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl and 1,3-thiazol-5-yl are substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, cyano, nitro, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl, trifluoromethylcarbonyl, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and C 3 -C 6 -cycloalkylcarbonyl,
in which alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and cycloalkylcarbonyl may be substituted by a substituent, where the substituent is selected from the group consisting of halogen, cyano, hydroxy, amino, trifluoromethyl and C 3 -C 6 -cycloalkyl,
R 5 is hydrogen or methyl,
R 6 is hydrogen,
R 7 is hydrogen or methyl,
R 8 is hydrogen,
R 9 is hydrogen,
R 10 is hydrogen,
or a salt thereof.
3. The compound according to claim 1 , wherein
A is CR 15 ,
where
R 15 is hydrogen,
R 1 is hydrogen, methyl or —CH 2 R 13 ,
where
R 13 is morpholinyl,
R 2 is phenyl,
where phenyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of chlorine, fluorine, trifluoromethyl, trifluoromethoxy and methyl,
R 4 is hydrogen,
R 16 is a group of the formula
where
* is the point of attachment to the heterocycle,
n is the number 0,
X is NR 11 ,
where
R 11 is hydrogen,
Y is NR 12 ,
where
R 12 is hydrogen,
R 3 is 2-pyridyl or 1,3-thiazol-2-yl,
where 2-pyridyl and 1,3-thiazol-2-yl are substituted by 1 to 2 substituents, where the substituents are selected independently of one another from the group consisting of cyano, nitro, amino, trifluoromethylcarbonyl and methylcarbonyl,
R 5 is hydrogen or methyl,
R 6 is hydrogen,
R 7 is hydrogen or methyl,
R 8 is hydrogen,
R 9 is hydrogen,
R 10 is hydrogen,
or a salt thereof.
4. A pharmaceutical composition comprising a compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
5. A method for preparing a compound of the formula (I) or one of its salts, its solvates or solvates of its salts according to claim 1 , comprising reacting
[A] a compound of the formula
in which
A, n, X, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the meaning indicated in claim 1 ,
with a compound of the formula
R 3 —X 1 (III),
in which
R 3 has the meaning indicated in claim 1 , and
X 1 is halogen, preferably chlorine or fluorine,
or reacting
[B] a compound of the formula
in which
A, R 1 , R 4 and R 16 have the meaning indicated in claim 1 , and
X 2 is iodine, bromine, chlorine or trifluoromethanesulphonyl, preferably iodine or bromine,
with a compound of the formula
Q-R 2 (V),
in which
R 2 has the meaning indicated in claim 1 , and
Q is —B(OH) 2 , a boronic acid ester, preferably boronic acid pinacol ester, or —BF 3 − K + ,
under Suzuki coupling conditions,
or reacting
[C] a compound of the formula
in which
A, R 1 , R 2 and R 4 have the meaning indicated in claim 1 , with a compound of the formula
H—R 16 (IX),
in which
R 16 has the meaning indicated in claim 1 .