Substituted fused imidazoles and pyrazoles and use thereof
The present application relates to novel substituted fused imidazoles and pyrazoles, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases and to the use thereof producing medicaments for the treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.
1. A compound of formula (I)
wherein
A is nitrogen or CR 3
where
R 3 is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl or cyclobutyl,
L is a #-CR 4A R 4B —(CR 5A R 5B ) m -## group
where
# is the attachment site to the carbonyl group,
## is the attachment site to the pyrimidine or triazine ring,
m is a number 0,
R 4A is hydrogen, fluorine, methyl, ethyl, hydroxyl or amino,
R 4B is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or a group of the formula -M-R 6 ,
in which methyl and ethyl may each be substituted by 1 to 3 substituents selected independently from the group of fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, difluoromethoxy and trifluoromethoxy,
where R 4B is hydrogen, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or a group of the formula -M-R 6 when R 4A is hydroxyl,
and in which
M is a bond,
R 6 is —(C═O) r —NR 7 R 8 , phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl or pyrimidinyl,
in which
r is the number 1,
R 7 and R 8 are each independently hydrogen, or cyclopropyl,
and
in which phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl may each in turn be substituted by 1 or 2 substituents selected independently from the group of fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl and cyclobutylmethyl,
or
R 4A and R 4B together with the carbon atom to which they are bonded form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl or tetrahydropyranyl ring,
in which the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl and tetrahydropyranyl ring may each be substituted by 1 or 2 substituents selected independently from the group of fluorine and methyl,
the ring Q is a group of the formula
where
* is the attachment site to —CH 2 —R 2 ,
** is the attachment site to the pyrimidine or triazine ring,
A 1 is N or CH,
R 1a is hydrogen or methyl,
R 1b is hydrogen, fluorine or chlorine when A 1 is CH,
R 1b is hydrogen when A 1 is N,
R 1c is hydrogen or fluorine,
R 1d is hydrogen or chlorine,
R 2 is 3,3,3-trifluoroprop-1-yl, 2,2,3,3-tetrafluoroprop-1-yl, pentafluoroprop-1-yl, phenyl or pyridyl,
where phenyl is substituted by 1 to 3 fluorine substituents,
and
where pyridyl may be substituted by 1 fluorine substituent,
or a salt thereof.
2. The compound of claim 1 , in which
A is nitrogen or CR 3
where
R 3 is hydrogen,
L is a #-CR 4A R 4B —(CR 5A R 5B ) m -## group
where
# is the attachment site to the carbonyl group,
## is the attachment site to the pyrimidine or triazine ring,
m is a number 0,
R 4A is hydrogen, fluorine, methyl or hydroxyl,
R 4B is hydrogen, fluorine, trifluoromethyl, 2,2,2-trifluoroethyl or methyl, provided that R 4B is not fluorine when R 4A is hydroxyl,
the ring Q is a group of the formula
where
* is the attachment site to —CH 2 —R 2 ,
** is the attachment site to the pyrimidine or triazine ring,
A 1 is N or CH,
R 1a is hydrogen or methyl,
R 1b is hydrogen, fluorine or chlorine when A 1 is CH,
R 1b is hydrogen when A 1 is N,
R 1c is hydrogen or fluorine,
R 1d is hydrogen or chlorine,
R 2 is 3,3,3-trifluoroprop-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl, phenyl or pyridyl,
where phenyl is substituted by 1 to 3 fluorine substituents,
and
where pyridyl may be substituted by 1 fluorine substituent,
or a salt thereof.
3. The compound of claim 1 , in which
A is nitrogen or CR 3
where
R 3 is hydrogen,
L is a #-CR 4A R 4B —(CR 5A R 5B ) m -## group
where
# is the attachment site to the carbonyl group,
## is the attachment site to the pyrimidine or triazine ring,
m is a number 0,
R 4A is methyl,
R 4B is methyl,
the ring Q is a group of the formula
where
* is the attachment site to —CH 2 —R 2 ,
** is the attachment site to the pyrimidine or triazine ring,
A 1 is N or CH,
R 1a is hydrogen or methyl,
R 1b is hydrogen, fluorine or chlorine when A 1 is CH,
R 1b is hydrogen when A 1 is N,
R 1c is hydrogen or fluorine,
R 1d is chlorine,
R 2 is 2,2,3,3,3-pentafluoroprop-1-yl, phenyl or pyridyl,
where phenyl is substituted by 1 or 2 fluorine substituents,
and
where pyridyl may be substituted by 1 fluorine substituent,
or a salt thereof.
4. The compound of claim 1 , in which
A is nitrogen,
L is a #-CR 4A R 4B —(CR 5A R 5B ) m -## group
where
# is the attachment site to the carbonyl group,
## is the attachment site to the triazine ring,
m is a number 0,
R 4A is methyl,
R 4B is methyl,
the ring Q is a group of the formula
where
* is the attachment site to —CH 2 —R 2 ,
** is the attachment site to the triazine ring,
A 1 is N or CH,
R 1a is hydrogen or methyl,
R 1b is hydrogen, fluorine or chlorine when A 1 is CH,
R 1b is hydrogen when A 1 is N,
R 1c is hydrogen or fluorine,
R 1d is hydrogen or chlorine,
R 2 is phenyl,
where phenyl is substituted by 1 or 2 fluorine substituents,
or a salt thereof.
5. The compound of claim 1 , selected from the group consisting of:
or a salt thereof.
6. A process for preparing the compound of claim 1 , comprising
[A] reacting a compound of formula (II)
in which n, L, Q, le and R 2 are each as defined in claim 1
isopentyl nitrite, thereby producing a compound of formula (I-A)
in which n, L, Q, le and R 2 are each as defined in claim 1 , and
X 1 is bromine or iodine,
or
[B] reacting a compound of the formula (I-A) in an inert solvent in the presence of a suitable transition metal catalyst to give a compound of formula (I-B)
in which n, L, Q, le and R 2 are each as defined in claim 1 ,
or
[C] reacting a compound of formula (I-A) in an inert solvent in the presence of a suitable transition metal catalyst with a compound of the formula (III-A), (III-B) or (III-C)
in which
R 3A is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, cyclopropyl, cyclobutyl, phenyl or 5- or 6-membered heteroaryl,
in which (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, phenyl and 5- or 6-membered heteroaryl may each be substituted by 1 to 3 substituents selected independently from the group comprising fluorine, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxycarbonyl, cyclopropyl and cyclobutyl,
T 1 is hydrogen or (C 1 -C 4 )-alkyl, or both R 11 radicals together form a —C(CH 3 ) 2 —C(CH 3 ) 2 — bridge,
and
X 3 is bromine or iodine,
to give a compound of the formula (I-C)
in which n, L, Q, le, R 2 and R 3A are each as defined above,
or
[D] reacting the compound of formula (IA) in an inert solvent in the presence of a suitable base with hydrazine hydrate to give a compound of the formula (IV)
in which n, L, Q, le and R 2 are each as defined in claim 1 ,
reacting the compound of formula (IV) in an inert solvent with a compound of the formula (V)
in which L is as defined in claim 1 and
T 4 is (C 1 -C 4 )-alkyl
to give a compound of the formula (VI)
in which n, L, Q, R 1 , R 2 and T 4 are each as defined above,
converting the compound of formula (VI) using phosphoryl chloride into a compound of the formula (VII)
in which n, L, Q, R 1 , R 2 and T 4 are each as defined above,
and reacting the compound of formula (VII) with ammonia to give a compound of the formula (VIII)
in which n, L, Q, le, R 2 and T 4 are each as defined above,
and cyclizing the compound of formula (VIII) in an inert solvent, optionally in the presence of a suitable base, to give a compound of the formula (I-D)
in which n, L, Q, le and R 2 are each as defined in claim 1 ,
or
[E] reacting a compound of the formula (X)
in which n, R 1 and R 2 are each as defined in claim 1 and
the ring Q 2 is a group of the formula
where
* is the attachment site to —CH 2 —R 2 ,
** is the attachment site to the hydrogen atom, and
A 1 , R 1a , R 1b , R 1c , and R 1d are each defined in claim 1 ;
in an inert solvent, optionally in the presence of a suitable base, with a compound of the formula (XI)
in which L is as defined in claim 1 ,
X 2 is chlorine or bromine and
PG 1 is a suitable amino protecting group, especially p-methoxybenzyl,
to give a compound of the formula (XII)
in which n, L, Q 2 , R 1 , R 2 and PG 1 are each as defined above,
the protecting group PG 1 is subsequently detached therefrom to give a compound of the formula (I-E)
in which n, L, Q 2 , R 1 and R 2 are each as defined above,
and, optionally, reacting a compound of formula (I-A), (I-B), (I-C), (I-D) or (I-E) with the appropriate (i) solvent and/or (ii) acid or bases to produce a salt thereof.
7. A pharmaceutical composition, comprising a compound claim 1 and an inert, nontoxic, pharmaceutically suitable excipient.