Substituted fused imidazoles and pyrazoles and use thereof
View Patent ↗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.