DE102011082041A1 - New substituted fused pyrimidine compounds are guanylate cyclase stimulators useful to treat and/or prevent e.g. heart failure, hypertension, ischemia, vascular disease, renal failure, thromboembolic disorders and fibrotic diseases - Google Patents

Abstract

Substituted fused pyrimidine compounds (I) are new. Substituted fused pyrimidine compounds of formula (I) and their N-oxides, salts, solvates, salts of N-oxides, solvates of the N-oxides or salts are new. L : a1-CR7aR7b-(CR8aR8b) m-a2; a1 : connection point to carbonyl group; a2 : connection point to pyrimidine ring; m : 0-2; either R7a : H, F, (1-4C)alkyl (optionally substituted by 1-3 F, CF 3, OH, hydroxycarbonyl, (1-4C)alkoxycarbonyl or amino), OH or amino; and R7b : H, F, (1-4C)-alkyl (optionally substituted by 1-3 F, CF 3, OH, hydroxycarbonyl, (1-4C)alkoxycarbonyl or amino), CF 3, (1-4C)alkoxycarbonylamino or phenyl; or R7aR7b : 3-6-membered carbocyclic group, 4-7-membered heterocycle (both optionally substituted by 1 or 2 F or (1-4C)alkyl), (2-4C)alkenyl group or oxo; R8a : H, F, (1-4C)alkyl or OH; R8b : H, F, (1-4C)alkyl or CF 3; ring Q : 8-9-membered heteroaryl; R3 : -OR4 or -NR5R6; R4 : (1-6C)alkyl, (3-7C)cycloalkyl, 4-7-membered heterocyclyl or 5 or 6 membered heteroaryl (all optionally substituted by 1-3 F, difluoromethyl, trifluoromethyl, (3-6C)cycloalkyl, difluoromethoxy, trifluoromethoxy, -(C=O) p-OR9, -C(=O) p-NR9R10, -NR9-(C=O)-R10, -NR9-(C=O)-OR10, -NR9-(C=O)-NR10R11, -NR9-SO 2-R10, -S(O) q-R12 or -SO 2-NR9R10) or H; p : 0 or 1; q : 0-2; either R9-R11 : (1-6C)alkyl (optionally substituted by 1 or 2 F, difluoromethyl, trifluoromethyl, OH, (1-6C)alkoxy, difluoromethoxy, trifluoromethoxy, (1-6C)alkoxycarbonyl, amino, mono-(1-6C)alkylamino, di-(1-6C)alkylamino or 4-7-membered substituted heterocyclyl), H or (3-8C)cycloalkyl; or R9R10, R10R11 : 4-7 membered heterocycle optionally substituted by 1 or 2 F, CF 3, (1-6C)alkyl, OH, oxo, (1-6C)alkoxy, trifluoromethoxy, (1-6C)alkoxycarbonyl, amino, mono-(1-6C)alkylamino or di-(1-6C)alkylamino); R12 : (1-6C)alkyl or (3-7C)cycloalkyl; either R5 : H or (1-4C)alkyl; and R6 : (1-4C)alkyl, (3-7C)cycloalkyl, 4-7 membered heterocycle or 5 or 6 membered heteroaryl (all optionally substituted by F, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -(C=O) p-OR9, -C(=O) p-NR9R10, -NR9-(C=O)-R10, -NR9-(C=O)-OR10, -NR9-(C=O)-NR10R11, -NR9-SO 2-R10, -S(O) q-R12 or -SO 2-NR9R10); or R5R6N : 4-7 membered heterocycle (optionally substituted by 1 or 2 F, CF 3, (1-6C)alkyl, OH, oxo, (1-6C)alkoxy, trifluoromethoxy, (1-6C)alkoxycarbonyl, amino, mono-(1-6C) alkylamino or di-(1-6C)alkylamino); R1 : F, Cl or CH 3; n : 0-2; and R2 : (1-6C)alkyl ((substituted by CF 3and optionally substituted by 1-3 F), (3-8C)-cycloalkyl, phenyl (substituted by 1-3 F) or 5- or 6-membered heteroaryl (optionally substituted by 1 or 2 F or CH 3). Independent claims are included for: (1) the preparation of (I); and (2) a medicament comprising (I) in combination with an inert, non-toxic excipient. [Image] ACTIVITY : Cardiant; Antianginal; Hypotensive; Respiratory-Gen.; Vasotropic; Nephrotropic; Thrombolytic; Antiarteriosclerotic; Immunosuppressive; Antiinflammatory; Antibacterial; Cerebroprotective; Endocrine-Gen.; Antilipemic; Hemostatic; Anorectic; Cardiovascular-Gen.; Ophthalmological; Dermatological; Antirheumatic; Uropathic; Antiasthmatic; Anti-HIV; Antianemic; Antisickling; CNS-Gen.; Nootropic; Neuroprotective; Antiparkinsonian; Anticonvulsant; Tranquilizer; Antidepressant; Analgesic; Auditory; Gastrointestinal-Gen.; Hepatotropic; Vulnerary; Cytostatic; Virucide; Osteopathic. MECHANISM OF ACTION : Guanylate cyclase stimulator.

Description

The present application relates to novel substituted fused pyrimidines, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or Prophylaxis of cardiovascular diseases.

One of the most important cellular transmission systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Together with nitric oxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO / cGMP system. The guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO. The soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO.

Through the formation of cGMP and the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations. Under pathophysiological conditions, the NO / cGMP system may be suppressed, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.

A NO-independent treatment option for such diseases, which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.

For therapeutic stimulation of soluble guanylate cyclase, only compounds such as organic nitrates have been used, whose action is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attack on the central iron atom of the heme. In addition to the side effects, tolerance development is one of the decisive disadvantages of this treatment.

In recent years, some substances have been described which stimulate soluble guanylate cyclase directly, ie without prior release of NO, such as, for example, 3- (5'-hydroxymethyl-2'-furyl) -1-benzylindazole [ YC-1; Wu et al., Blood 84 (1994), 4226 ; Mülsch et al., Brit. J. Pharmacol. 120 (1997), 681 ], Fatty acids [ Goldberg et al., J. Biol. Chem. 252 (1977), 1279 ], Diphenyliodonium hexafluorophosphate [ Pettibone et al., Eur. J. Pharmacol. 116 (1985), 307 ], Isoliquiritigenin [ Yu et al., Brit. J. Pharmacol. 114 (1995), 1587 ] as well as various substituted pyrazole derivatives ( WO 98/16223 ).

As stimulators of soluble guanylate cyclase be in WO 00/06568 and WO 00/06569 fused pyrazole derivatives and in WO 03/095451 Carbamate-substituted 3-pyrimidinyl-pyrazolopyridines disclosed. 3-pyrimidinyl-pyrazolopyridines with phenylamide substituents are used in EM Becker et al., BMC Pharmacology 1 (13), 2001 described. WO 2004/009590 describes pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS disorders. WO 2010/065275 discloses substituted pyrrolo and dihydropyridopyrimidines as sGC activators.

The object of the present invention was to provide novel substances which act as stimulators of soluble guanylate cyclase and have a similar or improved therapeutic profile compared to the compounds known from the prior art, for example with regard to their in vivo properties and / or their pharmacokinetic behavior.

in welcher
L für eine Gruppe #¹-CR^7AR^7B-(CR^8AR^8B)_m-#² steht,
wobei
#¹ für die Anknüpfstelle an die Carbonylgruppe steht,
#² für die Anknüpfstelle an den Pyrimidinring steht,
m für eine Zahl 0, 1 oder 2 steht,
R^7A für Wasserstoff, Fluor, (C₁-C₄)-Alkyl, Hydroxy oder Amino steht,
worin (C₁-C₄)-Alkyl mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Hydroxy, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl und Amino substituiert sein kann,
R^7B für Wasserstoff, Fluor, (C₁-C₄)-Alkyl, Trifluormethyl, (C₁-C₄)-Alkoxycarbonylamino oder Phenyl steht,
worin (C₁-C₄)-Alkyl mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Hydroxy, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl und Amino substituiert sein kann,
oder
R^7A und R^7B zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, eine (C₂-C₄)-Alkenyl-Gruppe, eine Oxo-Gruppe, einen 3- bis 6-gliedrigen Carbocyclus oder einen 4- bis 7-gliedrigen Heterocyclus bilden,
worin der 3- bis 6-gliedrigen Carbocyclus und der 4- bis 7-gliedrigen Heterocyclus mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor und (C₁-C₄)-Alkyl substituiert sein können,
R^8A für Wasserstoff, Fluor, (C₁-C₄)-Alkyl oder Hydroxy steht,
R^8B für Wasserstoff, Fluor, (C₁-C₄)-Alkyl oder Trifluormethyl steht,
der Ring Q für 8- oder 9-gliedriges Heteroaryl steht,
R³ für -OR⁴ oder -NR⁵R⁶ steht,
wobei
R⁴ für Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocyclyl oder 5- oder 6-gliedriges Heteroaryl steht,
worin (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocyclyl und 5- oder 6-gliedriges Heteroaryl mit 1 bis 3 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, (C₃-C₆)-Cycloalkyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹, -C(=O)_p-NR⁹R¹⁰, -NR⁹-(C=O)-R¹⁰, -NR⁹-(C=O)-OR¹⁰, -NR⁹-(C=O)-NR¹⁰R¹¹, -NR⁹-SO₂-R¹⁰, -S(O)_q-R¹² und -SO₂-NR⁹R¹⁰ substituiert sein können,
worin
p die Zahl 0 oder 1 bedeutet,
q die Zahl 0, 1 oder 2 bedeutet,
R⁹, R¹⁰ und R¹¹ unabhängig voneinander jeweils für Wasserstoff, (C₁-C₆)-Alkyl oder (C₃-C₈)-Cycloalkyl stehen,
worin (C₁-C₆)-Alkyl seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Hydroxy, (C₁-C₆)-Alkoxy, Difluormethoxy, Trifluormethoxy, (C₁-C₆)-Alkoxycarbonyl, Amino, Mono-(C₁-C₆)-alkylamino, Di-(C₁-C₆)-alkylamino und 4- bis 7-gliedriges Heterocyclyl substituiert sein kann,
oder
R⁹ und R¹⁰ bilden zusammen mit dem/den Atom/-en, an die sie jeweils gebunden sind, einen 4- bis 7-gliedrigen Heterocyclus,
worin der 4- bis 7-gliedrigen Heterocyclus seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, (C₁-C₆)-Alkyl, Hydroxy, Oxo, (C₁-C₆)-Alkoxy, Trifluormethoxy, (C₁-C₆)-Alkoxycarbonyl, Amino, Mono-(C₁-C₆)-alkylamino und Di-(C₁-C₆)-alkylamino substituiert sein kann,
oder
R¹⁰ und R¹¹ bilden zusammen mit dem/den Atom/-en, an die sie jeweils gebunden sind, einen 4- bis 7-gliedrigen Heterocyclus,
worin der 4- bis 7-gliedrigen Heterocyclus seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, (C₁-C₆)-Alkyl, Hydroxy, Oxo, (C₁-C₆)-Alkoxy, Trifluormethoxy, (C₁-C₆)-Alkoxycarbonyl, Amino, Mono-(C₁-C₆)-alkylamino und Di-(C₁-C₆)-alkylamino substituiert sein kann,
und worin
R¹² für (C₁-C₆)-Alkyl oder (C₃-C₇)-Cycloalkyl steht,
R⁵ für Wasserstoff oder (C₁-C₄)-Alkyl steht,
R⁶ für (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocyclyl oder 5- oder 6-gliedriges Heteroaryl steht,
worin (C₁-C₆)-Alkyl (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocyclyl und 5- oder 6-gliedriges Heteroaryl mit 1 bis 3 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹, -C(=O)_p-NR⁹R¹⁰, -NR⁹-(C=O)-R¹⁰, -NR⁹-(C=O)-OR¹⁰, -NR⁹-(C=O)-NR¹⁰R¹¹, -NR⁹-SO₂-R¹⁰, -S(O)_q-R¹² und -SO₂-NR⁹R¹⁰ substituiert sein können,
worin
p die Zahl 0 oder 1 bedeutet,
q die Zahl 0, 1 oder 2 bedeutet,
R⁹, R¹⁰ und R¹¹ unabhängig voneinander jeweils für Wasserstoff, (C₁-C₆)-Alkyl oder (C₃-C₈)-Cycloalkyl stehen,
oder
R⁹ und R¹⁰ bilden zusammen mit dem/den Atom/-en, an die sie jeweils gebunden sind, einen 4- bis 7-gliedrigen Heterocyclus,
worin der 4- bis 7-gliedrigen Heterocyclus seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, Hydroxy, Oxo, (C₁-C₆)-Alkoxy, Trifluormethoxy, (C₁-C₆)-Alkoxycarbonyl, Amino, Mono-(C₁-C₆)-alkylamino und Di-(C₁-C₆)-alkylamino substituiert sein kann,
oder
R¹⁰ und R¹¹ bilden zusammen mit dem/den Atom/-en, an die sie jeweils gebunden sind, einen 4- bis 7-gliedrigen Heterocyclus,
worin der 4- bis 7-gliedrigen Heterocyclus seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, Hydroxy, Oxo, (C₁-C₆)-Alkoxy, Trifluormethoxy, (C₁-C₆)-Alkoxycarbonyl, Amino, Mono-(C₁-C₆)-alkylamino und Di-(C₁-C₆)-alkylamino substituiert sein kann,
und worin
R¹² für (C₁-C₆)-Alkyl oder (C₃-C₇)-Cycloalkyl steht,
oder
R⁵ und R⁶ bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen 4- bis 7-gliedrigen Heterocyclus,
worin der 4- bis 7-gliedrigen Heterocyclus mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, (C₁-C₆)-Alkyl, Hydroxy, Oxo, (C₁-C₆)-Alkoxy, Trifluormethoxy, (C₁-C₆)-Alkoxycarbonyl, Amino, Mono-(C₁-C₆)-alkylamino und Di-(C₁-C₆)-alkylamino substituiert sein kann,
R¹ für Fluor, Chlor oder Methyl steht,
n für eine Zahl 0, 1 oder 2 steht,
R² für (C₁-C₆)-Alkyl, (C₃-C₈)-Cycloalkyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei (C₁-C₆)-Alkyl mit einem Substituenten Trifluormethyl substituiert ist,
wobei (C₁-C₆)-Alkyl mit 1 bis 3 Substituenten Fluor substituiert sein kann,
wobei Phenyl mit 1 bis 3 Substituenten Fluor substituiert ist,
und
wobei 5- und 6-gliedriges Heteroaryl mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor und Methyl substituiert sein können,
sowie ihre N-Oxide, Salze, Solvate, Salze der N-Oxide und Solvate der N-Oxide und Salze.The present invention relates to compounds of the general formula (I)

in which
L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2,
in which
# ^{1 represents} the point of attachment to the carbonyl group,
# ^{2 represents} the point of attachment to the pyrimidine ring,
m is a number 0, 1 or 2,
R ^{7A is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, hydroxy or amino,
in which (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents independently of one another selected from the group of fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and amino may be substituted,
R ^{7B is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxycarbonylamino or phenyl,
in which (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents independently of one another selected from the group of fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and amino may be substituted,
or
R ^7A and R ^7B together with the carbon atom to which they are attached, a (C ₂ -C ₄ ) alkenyl group, an oxo group, a 3- to 6-membered carbocycle or a 4- to 7-membered Form heterocycle,
wherein the 3- to 6-membered carbocycle and the 4- to 7-membered heterocycle may be substituted with 1 or 2 substituents independently selected from the group fluorine and (C ₁ -C ₄ ) -alkyl,
R ^{8A is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or hydroxy,
R ^{8B is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl or trifluoromethyl,
the ring Q is 8- or 9-membered heteroaryl,
R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ ,
in which
R ^{4 is} hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
wherein (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl having 1 to 3 substituents independently selected from the group fluorine, difluoromethyl , Trifluoromethyl, (C ₃ -C ₆ ) -cycloalkyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ , -C (= O) _p -NR ⁹ R ¹⁰ , -NR ⁹ - (C = O) -R ¹⁰ , -NR ⁹ - (C = O) -OR ¹⁰ , -NR ⁹ - (C = O) -NR ¹⁰ R ¹¹ , -NR ⁹ -SO ₂ -R ¹⁰ , -S (O) _q -R ¹² and -SO ₂ -NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0 or 1,
q is the number 0, 1 or 2,
R ⁹ , R ¹⁰ and R ¹¹ independently of one another each represent hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl, in turn, having 1 or 2 substituents independently selected from the group fluorine, difluoromethyl, trifluoromethyl, hydroxy, (C ₁ -C ₆ ) alkoxy, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₆ ) Alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino and 4- to 7-membered heterocyclyl may be substituted,
or
R ⁹ and R ¹⁰ together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle,
wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, (C ₁ -C ₆ ) alkyl, hydroxy, oxo, (C ₁ -C ₆ ) alkoxy, trifluoromethoxy , (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino,
or
R ¹⁰ and R ¹¹ together with the atom (s) to which they are respectively bonded form a 4- to 7-membered heterocycle,
wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, (C ₁ -C ₆ ) alkyl, hydroxy, oxo, (C ₁ -C ₆ ) alkoxy, trifluoromethoxy , (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino,
and in which
R ^{12 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
R ^{5 is} hydrogen or (C ₁ -C ₄ ) -alkyl,
R ^{6 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which (C ₁ -C ₆ ) -alkyl (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl having 1 to 3 substituents independently of one another are selected from the group of fluorine, difluoromethyl, Trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C = O) _p -OR ⁹ , -C (= O) _p -NR ⁹ R ¹⁰ , -NR ⁹ - (C = O) -R ¹⁰ , -NR ⁹ - (C = O) -OR ¹⁰ , -NR ⁹ - (C = O) -NR ¹⁰ R ¹¹ , -NR ⁹ -SO ₂ -R ¹⁰ , -S (O) _q -R ¹² and -SO ₂ -NR ⁹ R ¹⁰ substituted could be,
wherein
p is the number 0 or 1,
q is the number 0, 1 or 2,
R ⁹ , R ¹⁰ and R ¹¹ independently of one another each represent hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl,
or
R ⁹ and R ¹⁰ together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle,
wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, hydroxy, oxo, (C ₁ -C ₆ ) alkoxy, trifluoromethoxy , (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino,
or
R ¹⁰ and R ¹¹ together with the atom (s) to which they are respectively bonded form a 4- to 7-membered heterocycle,
wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, hydroxy, oxo, (C ₁ -C ₆ ) alkoxy, trifluoromethoxy , (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino,
and in which
R ^{12 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
wherein the 4- to 7-membered heterocycle having 1 or 2 substituents selected independently of one another from the group fluorine, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, hydroxy, oxo, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino may be substituted,
R ^{1 is} fluorine, chlorine or methyl,
n is a number 0, 1 or 2,
R ^{2 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, phenyl or 5- or 6-membered heteroaryl,
where (C ₁ -C ₆ ) -alkyl is substituted by a substituent trifluoromethyl,
where (C ₁ -C ₆ ) -alkyl can be substituted by 1 to 3 substituents of fluorine,
wherein phenyl is substituted with 1 to 3 substituents fluorine,
and
wherein 5- and 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl,
and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic Citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
In the context of the invention, alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2 -methylbutyl, 3-methylbutyl, n -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.

Cycloalkyl or carbocycle in the context of the invention is a monocyclic, saturated alkyl radical having in each case the number of carbon atoms specified. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 4 carbon atoms and one double bond. By way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy , 3-methylbutoxy and n-hexoxy. Preference is given to a linear or branched alkoxy radical having 1 to 4 carbon atoms. By way of example and preferably mention may be made of: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy,

Alkoxycarbonyl in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. By way of example and preferably mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Alkoxycarbonylamino in the context of the invention represents an amino group having a linear or branched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the nitrogen atom. By way of example and preferably mention may be made of: methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, n-butoxycarbonylamino, isobutoxycarbonylamino and tert-butoxycarbonylamino.

Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. By way of example and preferably mention may be made of: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N -methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Heterocyclyl or heterocycle in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms which contains one or two ring heteroatoms from the series N, O, S, SO and / or SO ₂ and linked via a ring carbon atom is. Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and Dioxidothiomorpholinyl. Preferred are azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl and morpholinyl.

5- or 6-membered heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S. a ring carbon atom or optionally linked via a ring nitrogen atom. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preference is given to pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.

8- or 9-membered heteroaryl is in the context of the invention for a bicyclic aromatic or partially unsaturated heterocycle having a total of 8 or 9 ring atoms, the at least two nitrogen atoms and up to two identical or different ring heteroatoms from the series N, O and / or S, and is linked via a ring carbon atom or optionally via a ring nitrogen atom. Examples which may be mentioned are: dihydrothienopyrazolyl, thienopyrazolyl, pyrazolopyrazolyl, imidazothiazolyl, indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyridazinyl,

Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine. Preference is given to bromine and iodine.

An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.

In the formula of the group which L and Q may stand respectively, the end point of the line where the symbol # ¹ , # ² , * and ** stands is not a carbon atom or a CH ₂ group, but is Part of the bond to the respective designated atom to which L or Q is bound.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.

steht, wobei
* für die Anknüpfungsstelle an -CH₂-R² steht,
** für die Anknüpfungsstelle an das Pyrimidin steht,
R¹ für Fluor, Chlor oder Methyl steht,
n für eine Zahl 0, 1 oder 2 steht,
A¹, A², A³ und A⁴ unabhängig voneinander jeweils für N, CH oder CR¹ stehen,
mit der Maßgabe, dass maximal zwei der Gruppen A¹, A², A³ und A⁴ für N stehen,
R³ für -OR⁴ oder -NR⁵R⁶ steht,
wobei
R⁴ für Wasserstoff, (C₁-C₆)-Alkyl oder (C₃-C₇)-Cycloalkyl steht,
worin (C₁-C₆)-Alkyl mit 1 oder 2 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹ und -C(=O)_p-NR⁹R¹⁰ substituiert sein kann,
worin
p die Zahl 0 bedeutet,
R⁹ und R¹⁰ unabhängig voneinander jeweils für Wasserstoff, Methyl oder Ethyl stehen,
oder
R⁹ und R¹⁰ bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Azetidinyl-, Pyrrolidinyl-, Piperidinyl-, Piperazinyl- oder Morpholinyl-Ring,
worin der Azetidinyl-, Pyrrolidinyl-, Piperidinyl-, Piperazinyl- und Morpholinyl-Ring seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Methyl, Ethyl, Hydroxy, Oxo, Methoxy, Ethoxy, Amino, Methylamino, Ethylamino, Dimethylamino und Diethylamino substituiert sein können,
R⁵ für Wasserstoff oder Methyl steht,
R⁶ für (C₁-C₆)-Alkyl oder (C₃-C₇)-Cycloalkyl steht,
worin (C₁-C₆)-Alkyl mit 1 oder 2 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹ und -C(=O)_p-NR⁹R¹⁰ substituiert sein kann,
worin
p die Zahl 0 bedeutet,
R⁹ und R¹⁰ unabhängig voneinander jeweils für Wasserstoff, Methyl oder Ethyl stehen,
oder
R⁹ und R¹⁰ bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Azetidinyl-, Pyrrolidinyl-, Piperidinyl-, Piperazinyl- oder Morpholinyl-Ring,
worin der Azetidinyl-, Pyrrolidinyl-, Piperidinyl-, Piperazinyl- und Morpholinyl-Ring seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Methyl, Ethyl, Hydroxy, Oxo, Methoxy, Ethoxy, Amino, Methylamino, Ethylamino, Dimethylamino und Diethylamino substituiert sein können,
oder
R⁵ und R⁶ bilden zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen Azetidinyl-, Pyrrolidinyl-, Piperidinyl-, Piperazinyl- oder Morpholinyl-Ring, worin der Azetidinyl-, Pyrrolidinyl-, Piperidinyl-, Piperazinyl- und Morpholinyl-Ring seinerseits mit 1 oder 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Trifluormethyl, Methyl, Ethyl, Hydroxy, Oxo, Methoxy, Ethoxy, Amino, Methylamino, Ethylamino, Dimethylamino und Diethylamino substituiert sein können,
R² für Trifluormethyl, 2,2,2-Trifluorethyl, 3,3,3-Trifluorprop-1-yl, 2,2,3,3,3-Pentafluorprop-1-yl, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Phenyl, Pyridyl, Pyrimidinyl, Pyrazinyl oder Pyridazinyl steht,
wobei Phenyl mit 1 bis 3 Substituenten Fluor substituiert ist,
und
wobei Pyridyl, Pyrimidinyl, Pyrazinyl und Pyridazinyl mit 1 oder 2 Substituenten Fluor substituiert sein können,
sowie ihre Salze, Solvate und Solvate der Salze.In the context of the present invention, preference is given to compounds of the formula (I) in which
L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2,
in which
# ^{1 represents} the point of attachment to the carbonyl group,
# ^{2 represents} the point of attachment to the pyrimidine ring,
m is a number 0 or 1,
R ^{7A is} hydrogen, fluorine, methyl, ethyl or hydroxy,
R ^{7B is} hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxycarbonylamino or phenyl,
wherein methyl and ethyl may be substituted with 1 to 3 substituents independently selected from the group fluorine, trifluoromethyl and hydroxy,
or
R ^7A and R ^7B together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring,
wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl ring may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine and methyl,
R ^{8A is} hydrogen, fluorine, methyl, ethyl or hydroxy,
R ^{8B is} hydrogen, fluorine, methyl, ethyl or trifluoromethyl,
the ring Q for a group of the formula

stands, where
* represents the point of attachment to -CH ₂ -R ² ,
** stands for the point of attachment to the pyrimidine,
R ^{1 is} fluorine, chlorine or methyl,
n is a number 0, 1 or 2,
A ¹ , A ² , A ³ and A ⁴ are each independently N, CH or CR ¹ ,
with the proviso that at most two of the groups A ¹ , A ² , A ³ and A ^{4 are} N,
R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ ,
in which
R ^{4 is} hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
R ^{5 is} hydrogen or methyl,
R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
or
R ⁵ and R ⁶ , together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl rings Ring in turn may be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino,
R ^{2 is} trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl , Pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,
wherein phenyl is substituted with 1 to 3 substituents fluorine,
and
where pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl can be substituted by 1 or 2 substituents fluorine,
and their salts, solvates and solvates of the salts.

steht, wobei
* für die Anknüpfungsstelle an -CH₂-R² steht,
** für die Anknüpfungsstelle an das Pyrimidin steht,
R^1a für Wasserstoff oder Fluor steht,
R^1b für Wasserstoff oder Methyl steht,
R³ für -OR⁴ oder -NR⁵R⁶ steht,
wobei
R⁴ für Wasserstoff oder (C₁-C₆)-Alkyl steht,
worin (C₁-C₆)-Alkyl mit 1 oder 2 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹ und -C(=O)_p-NR⁹R¹⁰ substituiert sein kann,
worin
p die Zahl 0 bedeutet,
R⁹ und R¹⁰ unabhängig voneinander jeweils für Wasserstoff stehen,
R⁵ für Wasserstoff steht,
R⁶ für (C₁-C₆)-Alkyl steht,
worin (C₁-C₆)-Alkyl mit 1 oder 2 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹ und -C(=O)_p-NR⁹R¹⁰ substituiert ist,
worin
p die Zahl 0 bedeutet,
R⁹ und R¹⁰ unabhängig voneinander jeweils für Wasserstoff stehen,
R² für 2,2,3,3,3-Pentafluorprop-1-yl, 2-Fluorphenyl oder 2,3,6-Trifluorbenzyl steht,
sowie ihre Salze, Solvate und Solvate der Salze.In the context of the present invention, particular preference is given to compounds of the formula (I) in which
L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2,
in which
# ^{1 represents} the point of attachment to the carbonyl group,
# ^{2 represents} the point of attachment to the pyrimidine ring,
m stands for a number 0,
R ^{7A is} hydrogen, fluorine, methyl or hydroxy,
R ^{7B is} hydrogen, fluorine, methyl or trifluoromethyl,
or
R ^7A and R ^7B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring,
wherein the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl,
the ring Q for a group of the formula

stands, where
* represents the point of attachment to -CH ₂ -R ² ,
** stands for the point of attachment to the pyrimidine,
R ^{1a is} hydrogen or fluorine,
R ^{1b is} hydrogen or methyl,
R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ ,
in which
R ^{4 is} hydrogen or (C ₁ -C ₆ ) -alkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ are each independently hydrogen,
R ^{5 is} hydrogen,
R ^{6 is} (C ₁ -C ₆ ) -alkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ^{10 is} substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ are each independently hydrogen,
R ^{2 is} 2,2,3,3,3-pentafluoroprop-1-yl, 2-fluorophenyl or 2,3,6-trifluorobenzyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ ,
in which
R ^{4 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, Oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino may be substituted,
R ^{5 is} hydrogen or methyl,
R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{3 is} -NR ⁵ R ⁶ ,
in which
R ^{5 is} hydrogen or methyl,
R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{3 is} -OR ⁴ ,
in which
R ^{4 is} hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{3 is} -OR ⁴ ,
in which
R ^{4 is} hydrogen,
and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} H, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} fluorine, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} methyl, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is also given to compounds of the formula (I) in which
R ^{2 is} 2,2,3,3,3-pentafluoroprop-1-yl, 2-fluorophenyl, 2,3,6-trifluorobenzyl, 3-fluoropyrid-2-yl or pyrimidin-2-yl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is also given to compounds of the formula (I) in which
R ^{2 is} 2-fluorophenyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is also given to compounds of the formula (I) in which
R ^{2 is} 3-fluoropyrid-2-yl or pyrimidin-2-yl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2,
in which
# ^{1 represents} the point of attachment to the carbonyl group,
# ^{2 represents} the point of attachment to the pyrimidine ring,
m stands for a number 0,
R ^{7A is} hydrogen, fluorine, methyl or hydroxy,
R ^{7B is} hydrogen, fluorine, methyl or trifluoromethyl,
or
R ^7A and R ^7B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring,
wherein the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2,
in which
# ^{1 represents} the point of attachment to the carbonyl group,
# ^{2 represents} the point of attachment to the pyrimidine ring,
m stands for a number 0,
R ^{7A is} hydrogen, fluorine, methyl or hydroxy,
R ^{7B is} hydrogen, fluorine, methyl or trifluoromethyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2,
in which
# ^{1 represents} the point of attachment to the carbonyl group,
# ^{2 represents} the point of attachment to the pyrimidine ring,
m stands for a number 0,
R ^{7A is} methyl,
R ^{7B is} methyl,
and their salts, solvates and solvates of the salts.

steht, wobei
* für die Anknüpfungsstelle an -CH₂-R² steht,
** für die Anknüpfungsstelle an das Pyrimidin steht,
A¹, A³ und A⁴ unabhängig voneinander jeweils für N, CH oder CR¹ stehen,
worin
R¹ für Fluor, Chlor oder Methyl steht,
n für eine Zahl 0, 1 oder 2 steht,
mit der Maßgabe, dass maximal zwei der Gruppen A¹, A³ und A⁴ für N stehen,
sowie ihre Salze, Solvate und Solvate der Salze.In the context of the present invention, compounds of the formula (I) in which
R ^{3 is} -NR ⁵ R ⁶ ,
in which
R ^{5 is} hydrogen or methyl,
R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ independently of one another each represent hydrogen, methyl or ethyl,
or
R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
or
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring,
wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, in turn, having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino , Dimethylamino and diethylamino,
the ring Q for a group of the formula

stands, where
* represents the point of attachment to -CH ₂ -R ² ,
** stands for the point of attachment to the pyrimidine,
A ¹ , A ³ and A ⁴ are each independently N, CH or CR ¹ ,
wherein
R ^{1 is} fluorine, chlorine or methyl,
n is a number 0, 1 or 2,
with the proviso that at most two of the groups A ¹ , A ³ and A ^{4 are} N,
and their salts, solvates and solvates of the salts.

steht, wobei
* für die Anknüpfungsstelle an -CH₂-R² steht,
** für die Anknüpfungsstelle an das Pyrimidin steht,
A¹, A³ und A⁴ unabhängig voneinander jeweils für N, CH oder CR¹ stehen,
worin
R¹ für Fluor, Chlor oder Methyl steht,
n für eine Zahl 0, 1 oder 2 steht,
mit der Maßgabe, dass maximal zwei der Gruppen A¹, A³ und A⁴ für N stehen,
R³ für -OR⁴ oder -NR⁵R⁶ steht,
wobei
R⁴ für Wasserstoff oder (C₁-C₆)-Alkyl steht,
worin (C₁-C₆)-Alkyl mit 1 oder 2 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹ und -C(=O)_p-NR⁹R¹⁰ substituiert sein kann,
worin
p die Zahl 0 bedeutet,
R⁹ und R¹⁰ unabhängig voneinander jeweils für Wasserstoff stehen,
R⁵ für Wasserstoff steht,
R⁶ für (C₁-C₆)-Alkyl steht,
worin (C₁-C₆)-Alkyl mit 1 oder 2 Subsituenten unabhängig voneinander ausgewählt aus der Gruppe Fluor, Difluormethyl, Trifluormethyl, Difluormethoxy, Trifluormethoxy, -(C=O)_p-OR⁹ und -C(=O)_p-NR⁹R¹⁰ substituiert ist,
worin
p die Zahl 0 bedeutet,
R⁹ und R¹⁰ unabhängig voneinander jeweils für Wasserstoff stehen,
sowie ihre Salze, Solvate und Solvate der Salze.In the context of the present invention, compounds of the formula (I) in which
the ring Q for a group of the formula

stands, where
* represents the point of attachment to -CH ₂ -R ² ,
** stands for the point of attachment to the pyrimidine,
A ¹ , A ³ and A ⁴ are each independently N, CH or CR ¹ ,
wherein
R ^{1 is} fluorine, chlorine or methyl,
n is a number 0, 1 or 2,
with the proviso that at most two of the groups A ¹ , A ³ and A ^{4 are} N,
R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ ,
in which
R ^{4 is} hydrogen or (C ₁ -C ₆ ) -alkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ¹⁰ may be substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ are each independently hydrogen,
R ^{5 is} hydrogen,
R ^{6 is} (C ₁ -C ₆ ) -alkyl,
in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (OO) _p - NR ⁹ R ^{10 is} substituted,
wherein
p is the number 0,
R ⁹ and R ¹⁰ are each independently hydrogen,
and their salts, solvates and solvates of the salts.

steht, wobei
* für die Anknüpfungsstelle an -CH₂-R² steht,
** für die Anknüpfungsstelle an das Pyrimidin steht,
A¹, A³ und A⁴ unabhängig voneinander jeweils für N, CH oder CR¹ stehen,
worin
R¹ für Fluor, Chlor oder Methyl steht,
n für eine Zahl 0, 1 oder 2 steht,
mit der Maßgabe, dass maximal zwei der Gruppen A¹, A³ und A⁴ für N stehen,
sowie ihre Salze, Solvate und Solvate der Salze.In the context of the present invention, compounds of the formula (I) in which
the ring Q for a group of the formula

stands, where
* represents the point of attachment to -CH ₂ -R ² ,
** stands for the point of attachment to the pyrimidine,
A ¹ , A ³ and A ⁴ are each independently N, CH or CR ¹ ,
wherein
R ^{1 is} fluorine, chlorine or methyl,
n is a number 0, 1 or 2,
with the proviso that at most two of the groups A ¹ , A ³ and A ^{4 are} N,
and their salts, solvates and solvates of the salts.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Particularly preferred are combinations of two or more of the preferred ranges mentioned above.

in welcher n, L, Q, R¹ und R² jeweils die oben genannten Bedeutungen haben,
in einem inerten Lösungsmittel mit iso-Pentylnitrit und einem Iod-Äquivalent in eine Verbindung der Formel (III)

in welcher n, L, Q, R¹ und R² jeweils die oben angegebenen Bedeutungen haben,
überführt, und diese im Anschluss in einen inerten Lösungsmittel gegebenenfalls in Gegenwart einer geeigneten Base mit einer Verbindung der Formel (IV) R³-H (IV), in welcher R³ die oben angegebene Bedeutung hat,
zu einer Verbindung der Formel (I)

in welcher n, L, Q, R¹, R² und R³ jeweils die oben angegebenen Bedeutungen haben,
umsetzt,
und gegebenenfalls die resultierenden Verbindungen der Formel (I) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Säuren oder Basen in ihre Solvate, Salze und/oder Solvate der Salze überführt.The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)

in which n, L, Q, R ¹ and R ^{2 are} each as defined above,
in an inert solvent with iso-pentyl nitrite and an iodine equivalent in a compound of formula (III)

in which n, L, Q, R ¹ and R ^{2 are} each as defined above,
which is subsequently converted into an inert solvent, if appropriate in the presence of a suitable base, with a compound of the formula (IV) R ³ -H (IV), in which R ^{3 has} the meaning given above,
to a compound of the formula (I)

in which n, L, Q, R ¹ , R ² and R ^{3 are} each as defined above,
implements,
and optionally the resulting compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.

The process step (II) → (III) takes place with or without solvent. Suitable solvents are all organic solvents which are inert under the reaction conditions. Preferred solvent is dimethoxyethane.

The reaction (II) → (III) is generally carried out in a temperature range of + 20 ° C to + 100 ° C, preferably in the range of + 50 ° C to + 100 ° C, optionally in a microwave. The reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.

The process step (II) → (III) is generally carried out with a molar ratio of 10 to 30 mol Isopentylnitrit and 10 to 30 moles of the iodine equivalent based on 1 mol of the compound of formula (IV).

Suitable iodine sources in the reaction (II) → (III) are, for example, diiodomethane or a mixture of cesium iodide, iodine and copper (I) iodide.

Inert solvents for process step (III) + (IV) → (I) are, for example, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to NMP.

In the case of R ³ = -OR ⁴ , the reaction (III) + (IV) → (I) is preferably carried out without solvent.

In the case of R ³ = -OR ⁴ , the reaction takes place (III) + (IV) → (I) in the presence of a suitable copper catalyst such as copper (I) iodide, with the addition of 3,4,7,8 -Tetramethyl-1,10-phenanthroline, and a suitable base such as alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, preferably cesium carbonate.

The reaction (III) + (IV) → (I) is generally carried out in a temperature range from + 20 ° C to + 200 ° C, preferably at + 100 ° C to + 150 ° C, preferably in a microwave. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).

[a): Diiodmethan, iso-Pentylnitrit; b): NMP, Mikrowelle, 150°C].The described preparation process can be exemplified by the following synthesis scheme (Scheme 1): Scheme 1

[a): diiodomethane, iso-pentylnitrite; b): NMP, microwave, 150 ° C].

The compounds of formula (II) are known from the literature (see, for example WO 2010/065275 ) or can be prepared analogously to processes known from the literature.

in welcher n, Q¹, R¹ und R² jeweils die zuvor genannten Bedeutungen haben,
in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit einer Verbindung der Formel (VI)

in welcher L die oben genannte Bedeutung hat und
T¹ für (C₁-C₄)-Alkyl steht,
zu einer Verbindung der Formel (II-A)

in welcher n, L, Q¹, R¹ und R² jeweils die oben genannten Bedeutungen haben,
umsetzt.The compounds of the formula (II-A) in which Q ^{1 is} a group of the formula (a-1) or (c-1) can be prepared by reacting a compound of the formula (V)

in which n, Q ¹ , R ¹ and R ² each have the meanings given above,
in an inert solvent in the presence of a suitable base with a compound of formula (VI)

in which L has the abovementioned meaning and
T ^{1 is} (C ₁ -C ₄ ) -alkyl,
to a compound of the formula (II-A)

in which n, L, Q ¹ , R ¹ and R ² each have the meanings given above,
implements.

Inert solvents for process step (V) + (VI) → (II-A) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran , Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), Pyridine, acetonitrile, sulfolane or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to tert-butanol or methanol.

Suitable bases for process step (V) + (VI) → (II-A) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, Alkali alcoholates such as sodium or potassium, sodium or potassium or potassium tert-butoxide, or organic amines such Triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to potassium tert-butoxide or sodium methoxide.

The reaction (V) + (VI) → (II-A) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 75 ° C to + 100 ° C, optionally in a microwave , The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

[a): KOt-Bu, tert.-Butanol; b): Diiodmethan, iso-Pentylnitrit; c): Pd/C, Wasserstoff, DMF].The preparation process described above can be exemplified by the following synthesis scheme (Scheme 2): Scheme 2

[a): KOt-Bu, tert-butanol; b): diiodomethane, iso-pentylnitrite; c): Pd / C, hydrogen, DMF].

[a): Hydrazinhydrat, 1,2-Ethandiol; b): iso-Pentylnitrit, NaI, THF; b): 2-Fluorbenzylbromid, Cs₂CO₃, DMF; d): CuCN, DMSO, e): 1. NaOMe, MeOH, 2. NH₄Cl, Esssigsäure]. Schema 4

[a): TFA, Dioxan; b) NH₃; c) Trifluoressigsäureanhydrid]. Schema 5

[a): Hydrazinhydrat, Triethylamin, Ethanol, Rückfluss; b): (2-Fluorphenyl)acetylchlorid, Triethylamin, Acetonitril; c): Brom, Essigsäure, 50°C; d): Phosphoroxychlorid, Sulfolan, 100°C; e): Palladium auf Kohle (5%), Triethylamin, Wasserstoff, Essigsäureethylester; f): 1. N-Bromsuccinimid, Dichlormethan; 2. Kupfer-(I)-cyanid, DMSO, 170°C; g): 1. Natriummethanolat, Methanol, 2. NH₄Cl, Essigsäure, Rückfluss].The compounds of formula (V) are known from the literature (see, for example WO 03/095451 , Example 6A) or can be prepared as in the following synthesis schemes (Schemes 3 to 5)

[a): hydrazine hydrate, 1,2-ethanediol; b): iso-pentyl nitrite, NaI, THF; b): 2-fluorobenzyl bromide, Cs ₂ CO ₃ , DMF; d): CuCN, DMSO, e): 1. NaOMe, MeOH, 2.NH ₄ Cl, acetic acid]. Scheme 4

[a): TFA, dioxane; b) NH ₃ ; c) trifluoroacetic anhydride]. Scheme 5

[a): hydrazine hydrate, triethylamine, ethanol, reflux; b): (2-fluorophenyl) acetyl chloride, triethylamine, acetonitrile; c): bromine, acetic acid, 50 ° C; d): phosphorus oxychloride, sulfolane, 100 ° C; e): palladium on carbon (5%), triethylamine, hydrogen, ethyl acetate; f): 1. N-bromosuccinimide, dichloromethane; 2. copper (I) cyanide, DMSO, 170 ° C; g): 1. sodium methoxide, methanol, 2. NH ₄ Cl, acetic acid, reflux].

[a): Schwefelsäure; b): Zink, Methanol, Eisessig; c): Trifluoressigsäureanhydrid, Dichlormethan].The compound of the formula (VII) is known from the literature [cf. eg Winn M., J. Med. Chem. 1993, 36, 2676-7688 ; EP 634 413-A1 ; CN 1613849-A ; EP 1626045-A1 ; WO 2009/018415 ], can be prepared analogously to processes known from the literature or as shown in the following synthesis scheme (Scheme 6):

[a): sulfuric acid; b): zinc, methanol, glacial acetic acid; c): trifluoroacetic anhydride, dichloromethane].

The compounds of the formula (IV) and (VI) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

The compounds of the invention are potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties, and have an improved therapeutic profile, such as in their in vivo properties and / or their pharmacokinetic behavior. They are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated via direct stimulation of soluble guanylate cyclase and intracellular cGMP increase. In addition, the compounds of the invention potentiate the action of cGMP level enhancing substances such as endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.

The compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmia of the atria and the chambers and conduction disorders such for example atrio-ventricular blockades grade I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, premature ventricular contraction (PVC), for the treatment and / or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or heart failure-related edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal Angioplasties (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, as well as microvascular and macrovascular lesions (vasculitis), increased levels of fibrinogen and LDL low density and elevated levels of plasminogen activator inhibitor 1 (PAI-1), as well as for the treatment and / or prophylaxis of erectile dysfunction and female sexual dysfunction.

For the purposes of the present invention, the term cardiac insufficiency also encompasses more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valve insufficiency, Aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure.

In addition, the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias and the metabolic syndrome.

In addition, the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis , rheumatic diseases and to promote wound healing.

Furthermore, the compounds according to the invention are suitable for the treatment of urological diseases such as, for example, benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feline's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome abnormally reduced creatinine and / or water excretion, abnormally elevated blood levels of urinary ff, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, e.g. Glutamyl synthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF).

The compounds described in the present invention are also agents for controlling central nervous system diseases characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia,HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous conditional sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, consumption and addiction.

Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.

In addition, the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, UC) , Pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases.

Furthermore, the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye. For the purposes of the present invention, the term fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).

Furthermore, the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.

The compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.

In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.

The present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,

• • organische Nitrate und NO-Donatoren, wie beispielsweise Natriumnitroprussid, Nitroglycerin, Isosorbidmononitrat, Isosorbiddinitrat, Molsidomin oder SIN-1, sowie inhalatives NO;
• • Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil und Tadalafil;
• • antithrombotisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen;
• • den Blutdruck senkende Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Calcium-Antagonisten, Angiotensin AII-Antagonisten, ACE-Hemmer, Endothelin-Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-Blocker, beta-Rezeptoren-Blocker, Mineralocorticoid-Rezeptor-Antagonisten sowie der Diuretika; und/oder
• • den Fettstoffwechsel verändernde Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie beispielhaft und vorzugsweise HMG-CoA-Reduktase- oder Squalensynthese-Inhibitoren, der ACAT-Inhibitoren, CETP-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin-Absorptionshemmer, Lipase-Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer und Lipoprotein(a)-Antagonisten.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

• • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
• Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterases (PDE) 1, 2 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil;
• Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
• Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists and diuretics; and or
• Lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112 , YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds of the present invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor such as, by way of example and preferably, ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions , Ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odor remedies.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

A. Examples

Abbreviations and acronyms:

• aq.

  aqueous solution

  calc.

  Calculated

  DCI

  direct chemical ionization (in MS)

  DMF

  dimethylformamide

  DMSO

  dimethyl sulfoxide

  theory

  the theory (at yield)

  eq.

  Equivalent (s)

  IT I

  Electrospray ionization (in MS)

  et

  ethyl

  gef.

  Found

  H

  Hour (s)

  HPLC

  High pressure, high performance liquid chromatography

  HRMS

  high-resolution mass spectrometry

  conc.

  concentrated

  LC / MS

  Liquid chromatography-coupled mass spectrometry

  LiHMDS

  lithium

  me

  methyl

  min

  Minute (s)

  MS

  Mass spectrometry

  NMR

  nuclear magnetic resonance spectrometry

  Pd / C

  Palladium on charcoal (10%)

  Ph

  phenyl

  RT

  room temperature

  R _t

  Retention time (by HPLC)

  t-Bu

  tert-butyl

  TFA

  trifluoroacetic

  THF

  tetrahydrofuran

  UV

  Ultraviolet spectrometry

  v / v

  Volume to volume ratio (of a solution)

  XPhos

  Dicyclohexyl- (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine

LC / MS methods:

Method 1 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 × 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A Furnace: 50 ° C; Flow: 0.40 ml / min; UV detection: 210-400 nm.

Method 2 (LC-MS):

Device Type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3 μ 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A, oven: 55 ° C; Flow 2ml / min; UV detection: 210 nm.

Method 3 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 30 × 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A Furnace: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.

Starting compounds and intermediates:

Example 1A 1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidamide hydrochloride

The synthesis of this compound is described in WO 03/095451 Example 6A.

Example 2A 2,6-Dichloro-5-fluoronicotinamide

A suspension of 25 g (130.90 mmol) of 2,6-dichloro-5-fluoro-3-cyanopyridine in conc. Sulfuric acid (125 ml) was stirred at 60-65 ° C for 1 h. After cooling to RT, the contents of the flask were poured into ice-water and extracted three times with ethyl acetate (100 ml each time). The combined organic phases were washed with water (100 ml) and then with saturated aqueous sodium bicarbonate solution (100 ml), dried and concentrated on a rotary evaporator. The resulting material was dried under high vacuum.
Yield: 24.5 g (90% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.95 (br s, 1H), 8.11 (br s, 1H), 8.24 (d, 1H).

Example 3A 2-chloro-5-fluoronicotinamide

To a suspension of 21.9 g (335.35 mmol) of zinc in methanol (207 ml) was added at RT 44 g (210.58 mmol) of 2,6-dichloro-5-fluoronicotinamide. Acetic acid (18.5 ml) was then added and the mixture was heated to reflux with stirring for 24 h. The contents of the flask were then decanted from the zinc and ethyl acetate (414 ml) and saturated aqueous sodium bicarbonate solution (414 ml) were added and the mixture was stirred thoroughly. The mixture was then filtered off with suction through kieselguhr and washed three times with ethyl acetate (517 ml each time). The organic phase was separated and the aqueous phase washed with ethyl acetate (258 ml). The combined organic phases were washed once with saturated aqueous sodium bicarbonate solution (414 ml), dried and concentrated in vacuo. The resulting crystals were added with dichloromethane (388 ml) and stirred for 20 minutes. It was again filtered off with suction and washed with diethyl ether and sucked dry.
Yield: 20.2 g (53% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.87 (brs, 1H), 7.99 (dd, 1H), 8.10 (brs, 1H), 8.52 (d, 1H).

Example 4A 2-Chloro-5-fluoronicotinonitrile

A suspension of 46.2 g (264.66 mmol) of 2-chloro-5-fluoronicotinamide in dichloromethane (783 ml) was admixed with 81.2 ml (582.25 mmol) of triethylamine and cooled to 0 ° C. 41.12 ml (291.13 mmol) of trifluoroacetic anhydride were then slowly added dropwise with stirring and stirred at 0 ° C. for 1.5 h. The reaction solution was then washed twice with saturated aqueous sodium bicarbonate solution (each 391 ml), dried and concentrated in vacuo.
Yield: 42.1 g (90% of theory).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.66 (dd, 1H), 8.82 (d, 1H).

Example 5A 5-Fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine

A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1,2-ethanediol (380 ml), followed by addition of hydrazine hydrate (119.6 ml). It was heated to reflux with stirring for 4 h. Upon cooling, the product precipitated. The crystals were mixed with water (380 ml) and stirred at RT for 10 min. The suspension was then filtered off with suction through a frit, washed with water (200 ml) and with -10 ° C. cold THF (200 ml). Drying under high vacuum over phosphorus pentoxide.
Yield: 22.8 g (61% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).

Example 6A 5-Fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine

THF (329 ml) was charged with 10 g (65.75 mmol) of 5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine and cooled to 0 ° C. Subsequently, 16.65 ml (131.46 mmol) of boron trifluoride-diethyl ether complex were slowly added. The reaction mixture was further cooled to -10 ° C. Thereafter, a solution of 10.01 g (85.45 mmol) of isopentyl nitrite in THF (24.39 ml) was slowly added and stirred for a further 30 min. The mixture was diluted with cold diethyl ether (329 ml) and the resulting solid filtered off. The diazonium salt thus prepared was added in portions to a 0 ° C cold solution of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml) and the mixture stirred for 30 min at RT. The reaction mixture was added to ice-water (1.8 L) and extracted twice with ethyl acetate (487 mL each time). The combined organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. 12.1 g (86% purity, 60% of theory) of the title compound were obtained as a solid. The crude product was reacted without further purification.
LC-MS (Method 2): R _t = 1.68 min
MS (ESIpos): m / z = 264 (M + H) ⁺

Example 7A 5-Fluoro-1- (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine

In DMF (217 ml), 12.1 g (about 39.65 mmol) of the compound from Example 6A were initially charged and then 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of cesium carbonate were added. The mixture was stirred at RT for two hours. The reaction mixture was then added to water (1.17 L) and extracted twice with ethyl acetate (502 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: petroleum ether / ethyl acetate 97: 3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid is taken up in ethyl acetate and washed with 10% aqueous sodium thiosulfate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.
LC-MS (Method 2): R _t = 2.57 min
MS (ESIpos): m / z = 372 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d6): δ = 5.73 (s, 2H), 7.13-7.26 (m, 3H), 7.33-7.41 (m, 1H), 7.94 (dd, 1H), 8.69-8.73 (m, 1H).

Example 8A Ethyl 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxylate

13,487 g (51,228 mmol) of ethyl 5-amino-1- (2-fluorobenzyl) -1H-pyrazole-3-carboxylate (preparation described for Example 20A in WO 00/06569 ) were initially charged in 300 ml of dioxane and at RT with 6 g (51.228 mmol) of 3- (dimethylamino) -2-fluoroacrylaldehyde (described in Justus Liebig's Annalen der Chemie 1970; 99-107 ). Subsequently, 4,736 ml (61,473 mmol) of trifluoroacetic acid were added and the mixture was heated to reflux for 3 days with stirring. After cooling, the mixture was concentrated under reduced pressure and the residue was combined with water and ethyl acetate. The phases were separated and the organic phase was washed twice with water. The combined aqueous phases were then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue (22 g) was then purified by chromatography on silica gel (eluent: dichloromethane). 5.67 g (35% of theory) of the title compound were obtained.
LC-MS (Method 1): R _t = 1.17 min
MS (ESIpos): m / z = 318 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H), 7.15-7.27 (m, 3H), 7.36-7.41 ( m, 1H), 8.25 (d, 1H), 8.78 (s br., 1H).

Example 9A 5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxamide

1.00 g (3.152 mmol) of the compound obtained in Example 8A were stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. It was then concentrated in vacuo. 908 mg (99% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 0.85 min
MS (ESIpos): m / z = 289 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.87 (s, 2H), 7.12-7.26 (m, 3H), 7.34-7.40 (m, 1H), 7.60 (s br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd, 1H).

Example 10A 5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carbonitrile

Option A:

A suspension of 16.03 g (43.19 mmol) of 5-fluoro-1- (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b] pyridine (Example 7A) and 4.25 g (47.51 mmol) of copper cyanide were added DMSO (120 ml) and stirred at 150 ° C for 2 h. After cooling, the flask contents were cooled to about 40 ° C, to a solution of conc. Ammonia water (90 ml) and water (500 ml) were poured, mixed with ethyl acetate (200 ml) and stirred briefly. The aqueous phase was separated and extracted twice more with ethyl acetate (200 ml each time). The combined organic phases were washed twice with 10% aqueous sodium chloride solution (100 ml each), dried and concentrated in vacuo. The crude product was reacted without further purification.
Yield: 11.1 g (91% of theory)

Variant B:

900 mg (3.122 mmol) of the compound obtained under Example 9A were dissolved in THF (14 ml) and treated with 0.646 ml (7.993 mmol) of pyridine. Then, with stirring, 1.129 ml (7.993 mmol) of trifluoroacetic anhydride were slowly added dropwise and then stirred at RT overnight. Thereafter, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were extracted with saturated aqueous sodium bicarbonate solution and 1N hydrochloric acid and then washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. 850 mg (99% of theory) of the title compound were obtained.
LC-MS (Method 1): R _t = 1.06 min
MS (ESIpos): m / z = 271 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.87 (s, 2H), 7.17-7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H).

Example 11A 5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboximidamide acetate

To 2.22 g (41.07 mmol) of sodium methoxide in methanol (270 ml) were added 11.1 g (41.07 mmol) of 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carbonitrile (Example 10A) and stirred for 2 h at RT. Thereafter, 2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml) were added and heated to reflux overnight. Thereafter, the reaction mixture was concentrated to dryness and the residue was taken up in water (100 ml) and ethyl acetate (100 ml) and adjusted to pH 10 with 2N sodium hydroxide solution. It was stirred vigorously for about 1 h at RT. The resulting suspension was filtered off with suction and washed with ethyl acetate (100 ml), water (100 ml) and again ethyl acetate (100 ml). The residue is dried over phosphorus pentoxide in a high vacuum. Yield: 9.6 g (78% of theory)
MS (ESIpos): m / z = 288 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.85 (s, 3H), 5.80 (s, 2H), 7.14-7.25 (m, 3H), 7.36 (m, 1H), 8.42 (dd, 1H), 8.72 (dd, 1H).

Example 12A Methyl 3,3-dicyano-2,2-dimethylpropanoate

In THF (91 ml), 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil) were slowly added with 3 g (45.411 mmol) of malononitrile. Subsequently, 5,876 ml (45,411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was stirred at RT overnight. Thereafter, another 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and it was heated to 50 ° C overnight. Then again 1762 ml (13,623) mmol) of methyl 2-bromo-2-methylpropanoate was added and it was heated to 50 ° C for a further 4 h. The reaction mixture was then treated with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, filtered and concentrated to dryness. This gave 8.9 g of crude product, which was purified by chromatography on silica gel (cyclohexane-ethyl acetate 4: 1).
Yield: 6.47 g (85% of theory)
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.40 (s, 6H), 3.74 (s, 3H), 5.27 (s, 1H).

Example 13A 4-Amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dimethyl-5,7-dihydro-6H-pyrrolo [ 2,3-d] pyrimidin-6-one

5,887 g (19,256 mmol) of Example 1A were initially charged in tert-butanol (50 ml) and treated with 2,593 g (23.107 mmol) of potassium tert-butoxide. Subsequently, 3.2 g (19.256 mmol) of Example 12A in tert-butanol (25 ml) were added dropwise and the mixture was heated to reflux overnight. The next day, another 0.64 g (3.851 mmol) of Example 12A was added and heated to reflux for a further day. After cooling, a precipitate was filtered off, which was washed with diethyl ether. It was then slurried in water and filtered once more and washed with diethyl ether. After drying under high vacuum, it was possible to obtain 6.65 g of the title compound (85% of theory).
LC-MS (Method 1): R _t = 0.90 min; MS (ESIpos): m / z = 404 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s, 6H), 5.82 (s, 2H), 6.82 (br s, 2H), 7.14-7.25 (m, 3H), 7.33-7.40 (m, 2H), 8.63 (dd, 1H), 9.03 (dd, 1H), 10.98 (s br, 1H).

Example 14A 4-Amino-2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dimethyl-5,7-dihydro- 6H-pyrrolo [2,3-d] pyrimidin-6-one

In analogy to the preparation of Example 13A, 4.18 g (12.035 mmol) of Example 11A were reacted with 2.20 g (13.239 mmol) of Example 12A. 3.72 g of the title compound were obtained (73% of theory).
LC-MS (Method 1): R _t = 0.98 min; MS (ESIpos): m / z = 422 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (s, 6H), 5.81 (s, 2H), 6.85 (br s, 2H), 7.13-7.25 (m, 3H), 7.36 (m, 1H), 8.69 (dd, 1H), 8.84 (dd, 1H), 10.96 (s br, 1H).

Example 15A 2- [1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo [ 2,3-d] pyrimidin-6-one

5.00 g (12.394 mmol) of Example 13A were initially charged in iso-pentyl nitrite (35.87 ml) and diiodomethane (1.16 mol, 93.71 ml) and heated to 85 ° C. for 12 h. After cooling, it was filtered off from solids, concentrated and then purified by chromatography on silica gel (mobile phase: first cyclohexane-dichloromethane gradient, then dichloromethane-methanol gradient). There were obtained 5.50 g of the title compound (67% of theory).
LC-MS (method 1): R _t = 1.19 min; MS (ESIpos): m / z = 515 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.42 (s, 6H), 5.88 (s, 2H), 7.13-7.26 (m, 3H), 7.34-7.38 (m, 1H) , 7.48 (dd, 1H), 8.69 (dd, 1H), 8.79 (dd, 1H), 11.78 (s br, 1H).

Example 16A 2- [5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4-iodo-5,5-dimethyl-5,7-dihydro- 6H-pyrrolo [2,3-d] pyrimidin-6-one

3,325 g (7,890 mmol) of Example 14A were reacted in analogy to Example 15A. This gave 3.65 g of the title compound (87% of theory, about 61% purity according to LC / MS).
LC-MS (Method 1): R _t = 1.26 min; MS (ESIpos): m / z = 533 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.42 (s, 6H), 5.87 (s, 2H), 7.14-7.26 (m, 3H), 7.37 (m, 1H), 8.48 (dd, 1H), 8.77 (dd, 1H), 11.76 (s br, 1H).

EXAMPLES

Example 1 2- [1- (2-Fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4-methoxy-5,5-dimethyl-5,7-dihydro-6H-pyrrolo [ 2,3-d] pyrimidin-6-one

100 mg (0.194 mmol) of the compound obtained in Example 15A were dissolved in a microwaveable flask with methanol (3 ml), 126 mg (0.389 mmol) cesium carbonate, 3.7 mg (0.019 mmol) copper (I) iodide and 9 mg (0.039 mmol) 3,4,7,8-tetramethyl-1,10-phenanthroline. It was flushed with argon for 5 min under ultrasound treatment and then closed with a corresponding septum. Thereafter, it was heated in 3 cycles for 2 hours each at 140 ° C in the microwave. After cooling, the reaction mixture was filtered, concentrated and the residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). There were obtained 32 mg of the title compound (39% of theory).
LC-MS (Method 1): R _t = 1.08 min; MS (EIpos): m / z = 419 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s, 6H), 4.15 (s, 3H), 5.87 (s, 2H), 7.13-7.26 (m, 3H), 7.34 -7.38 (m, 1H), 7.45 (dd, 1H), 8.68 (dd, 1H), 8.91 (dd, 1H), 11.44 (s br, 1H).

Example 2 2- [5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4 - [(2-hydroxyethyl) amino] -5,5-dimethyl -5,7-dihydro-6H-pyrrolo pyrimidin-6-one [2,3-d]

100 mg (0.115 mmol, about 61% purity) of the compound obtained in Example 16A were dissolved in a microwaveable flask in 1-methyl-2-pyrrolidone (2 ml) and treated with 0.75 ml of aminoethanol. It was then closed with a suitable septum and heated for 5 h at 150 ° C in the microwave. After cooling, the reaction mixture was purified by preparative HPLC (Acetonitrile: water (+0.05% formic acid) gradient). There was obtained 68 mg of the title compound (100% of theory, 94% purity by LC / MS).
LC-MS (Method 3): R _t = 0.94 min; MS (EIpos): m / z = 466 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (s, 6H), 3.29 (s, 2H), 3.64 (s, 2H), 4.82 (t, 1H), 5.83 (s , 2H), 6.65 (tbr, 1H), 7.13-7.25 (m, 3H), 7.33-7.39 (m, 1H), 8.55 (dd, 1H), 8.71 (dd, 1H), 11.00 (s br, 1H ).

Example 3 4 - [(2-Amino-2-methylpropyl) amino] -2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5 , 5-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

100 mg (0.115 mmol, about 61% purity) of the compound obtained in Example 16A were dissolved in a microwaveable flask in 1-methyl-2-pyrrolidone (2 ml) and treated with 0.75 ml of 2-methylpropane-1,2-diamine , It was then closed with a suitable septum and heated for 3 h at 150 ° C in the microwave. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 57 mg of the title compound were obtained (100% of theory).
LC-MS (Method 3): R _t = 0.82 min; MS (EIpos): m / z = 493 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (s, 6H), 1.41 (s, 6H), 3.67 (signal probably superimposed with water signal 2H), 5.84 (s, 2H ), 6.98 (mbr, 1H), 7.15 (t, 1H), 7.20-7.26 (m, 2H), 7.34-7.39 (m, 1H), 8.56 (dd, 1H), 8.73 (dd, 1H), signals for -N H -C = O and -N H ₂ not observed.

Example 4 2- [5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -4 - [(2-hydroxy-2-methylpropyl) amino] -5 , 5-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

100 mg (0.115 mmol, about 61% purity) of the compound obtained under Example 16A were dissolved in 1-methyl-2-pyrrolidone (2 ml) in a microwell-suitable flask and treated with 0.5 ml of 1-amino-2-methylpropan-2-one. ol. It was then closed with a suitable septum and heated for 3 h at 150 ° C in the microwave. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 56 mg of the title compound were obtained (100% of theory).
LC-MS (Method 1): R _t = 1.06 min; MS (EIpos): m / z = 494 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.15 (s, 6H), 1.39 (s, 6H), 3.60 (d, 2H), 4.76 (s, 1H), 5.82 (s , 2H), 6.41 (t, 1H), 7.15 (t, 1H), 7.20-7.26 (m, 2H), 7.34-7.39 (m, 1H), 8.64 (dd, 1H), 8.72 (dd, 1H), 11.06 (s br, 1H).

Example 5 2- [5-Fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5,5-dimethyl-4 - [(3,3,3-) trifluoropropyl) amino] -5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one

100 mg (0.115 mmol, about 61% purity) of the compound obtained in Example 16A were dissolved in a microwaveable flask in 1-methyl-2-pyrrolidone (2 ml) and treated with 0.5 ml of 3,3-trifluoropropyl-1-amine , It was then closed with a suitable septum and for 3 h at 150 ° C in the microwave heated. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). There was obtained 60 mg of the title compound (100% of theory).
LC-MS (Method 1): R _t = 1.21 min; MS (EIpos): m / z = 518 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35 (s, 6H), 2.64-2.71 (m, 2H), 3.82 (q, 2H), 5.83 (s, 2H), 6.88 (t, 1H), 7.15 (t, 1H), 7.20-7.25 (m, 2H), 7.34-7.40 (m, 1H), 8.48 (dd, 1H), 8.72 (dd, 1H), 11.10 (s, 1H ).

Example 6 4 - [(2-Amino-3,3,3-trifluoropropyl) amino] -2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3 yl] -5,5-dimethyl-5,7-dihydro-6H-pyrrolo [pyrimidin-6-one 2,3-d]

100 mg (0.115 mmol, about 61% purity) of the compound obtained in Example 16A were suspended in 1-methyl-2-pyrrolidone (2 ml) in a microwave-suitable flask, with 1 ml of diisopropylethylamine and then with 300 mg (1492 mmol). Added 1- (trifluoromethyl) ethylene-1,2-diamine dihydrochloride. It was then closed with a suitable septum and heated for 3 h at 150 ° C in the microwave. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 5.7 mg of the title compound were obtained (9% of theory).
LC-MS (Method 1): R _t = 0.98 min; MS (EIpos): m / z = 534 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37 (d, 6H), 3.47-3.45 (m, 1H), 3.62-3.73 (m, 1H), 3.94-4.00 (m, 1H), 5.83 (s, 2H), 6.82 (t, 1H), 7.15 (t, 1H), 7.20-7.26 (m, 2H), 7.34-7.39 (m, 1H), 8.56 (dd, 1H), 8.72 (br d, 1H), 11.11 (br s, 1H), -N H ₂ not observed.

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

B-1. Vaso-relaxant effect in vitro

Rabbits are stunned and bled by a stroke of the neck. The aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC ₅₀ value). The standard application volume is 5 μl, the DMSO content in the bath solution corresponds to 0.1%.

Representative IC ₅₀ values for the compounds of the invention are given in the table below (Table 1): TABLE 1 Example no. IC ₅₀ [nM] 1 114 4 62

B-2. Effect on recombinant guanylate cyclase reporter cell line

The cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line, as in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005) described, determined.

Representative values (MEC = minimum effective concentration) for the compounds of the invention are given in the table below (Table 2): TABLE 2 Example no. MEC [μM] 1 0.1 2 0.3 3 3.0 4 0.1 5 0.3 6 0.1

B-3. Radiotelemetric blood pressure measurement on awake, spontaneously hypertensive rats

A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.

• – Implantierbare Sender (Physiotel^® Telemetrietransmitter)
• – Empfänger (Physiotel^® Receiver), die über einen Multiplexer (DSI Data Exchange Matrix) mit einem
• – Datenakquisitionscomputer

verbunden sind.The system consists of 3 main components:

• - Implantable Transmitters (Physiotel ^® Telemetry Transmitter)
• - Receiver (Physiotel ^® Receiver), which is connected via a multiplexer (DSI Data Exchange Matrix) with a
• - Data acquisition computer

are connected.

The telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.

animal material

The investigations are carried out on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of> 200 g. SHR / NCrl of Okamoto Kyoto School of Medicine, 1963 were crossed out of male Wistar Kyoto rats with high blood pressure and female with slightly elevated blood pressure and reported in F13 to U.S. Pat. National Institutes of Health.

The experimental animals are kept individually in Makrolon cages type 3 after transmitter implantation. You have free access to standard food and water.

The day-night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.

transmitter implantation

The TA11 PA-C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.

For implantation, the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side. After opening the abdominal cavity along the alba line, the system's liquid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD ™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.

Postoperatively, an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)

Substances and solutions

Unless otherwise described, the substances to be tested are each administered orally to a group of animals (n = 6) by gavage. According to an application volume of 5 ml / kg body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% Tylose.

A solvent-treated group of animals is used as a control.

experimental procedure

The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).

The instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).

The implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run. The emitted signals can be recorded online by a data acquisition system (Dataquest ™ ART for WINDOWS, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.

• – Systolischer Blutdruck (SBP)
• – Diastolischer Blutdruck (DBP)
• – Arterieller Mitteldruck (MAP)
• – Herzfrequenz (HR)
• – Aktivität (ACT).

In the standard procedure, duration is measured over 10 seconds:

• - Systolic blood pressure (SBP)
• - Diastolic blood pressure (DBP)
• - Mean Arterial Pressure (MAP)
• - heart rate (HR)
• - Activity (ACT).

The measured value acquisition is repeated computer-controlled in 5-minute intervals. The absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).

Unless otherwise stated, the administration of the test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.

evaluation

After the end of the test, the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS). The blank value is assumed here 2 hours before application, so that the selected data set covers the period from 7:00 am on the day of the experiment to 9:00 am on the following day.

The data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk. The presorted and compressed measured values are transferred to Excel templates and displayed in tabular form. The filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.

literature

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Muessig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000 ; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev. Exp Pathol 7: 227-270, 1969 ; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured with Radio Telemetry. Physiology & Behavior 55 (4): 783-787, 1994

B-4. Determination of pharmacokinetic parameters after intravenous and oral administration

The pharmacokinetic parameters of the compounds of the formula (I) according to the invention are determined in male CD-1 mice, male Wister rat and / or female beagle dogs. The application volume in mice is 5 mL / kg, in rats 5 mL / kg and in dogs 0.5 mL / kg. Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation (99/1) and in dogs by water / PEG400 / ethanol (50/40/10 or 30/60/10). Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration. The operation is carried out one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.). Substance administration is i.v. in mice and rats. bolus and in dogs by means of a 15-minute infusion. The blood is taken in rats after 0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7 and 24 hours, in mice after 0.033, 0.083, 0.17, 0.5, 1, 2, 3, 4, 6, 7, 24, 48 and 72 hours and in dogs 0.083, 0.25, 0.28 0.33, 0.42, 0.75, 1, 2, 3, 4, 6, 7 and 24 hours. Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation (50/40/10). The blood take in rats takes place after 0.083, 0.17, 0.5, 0.75, 1, 2, 3, 4, 6, 7 and 24 hours and in dogs after 0.083, 0.17, 0.5, 0.75, 1, 2, 3, 4, 6 , 7, 24, 30 and 48 hours. The blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.

An internal standard (ZK 228859) is added to the samples of the compounds of the formula (I) according to the invention, calibration samples and QCs, and protein precipitation by means of acetonitrile follows in excess. After addition of an ammonium acetate buffer (0.01 M, pH 6.8) and subsequent vortexing, the mixture is centrifuged at 1000 g and the supernatant is measured by means of LC-MS / MS (API 4000, AB Sciex). Chromatographic separation is performed on an 1100 HPLC from Agilent. The injection volume is 10 μL. The column used is a tempered at 40 ° C Luna 5μ C8 (2) 100A 50 × 2mm from. Phenomenex. A binary mobile phase gradient is run at 500 μL / min (A: 0.01M ammonium acetate buffer pH 6.8, B: 0.1% formic acid in acetonitrile): 0 min. (90% A), 1 min. (90% A), 3 Min. (15% A), 4 minutes (15% A), 4.50 minutes (90% A), 6 minutes (90% A). The temperature of the Turbo V ion source is 500 ° C. The following MS instrument parameters are used: curtain gas 15 units, ion spray volume 4.8 kV, gas 1 45 units, gas 2 35 units, CAD gas 40 units. The quantification of the substances takes place on the basis of the peak heights or areas from extracted ion chromatograms of specific MRM experiments.

The pharmacokinetic parameters such as AUC, C _max , t _1/2 (terminal half-life), MRI (Mean Residence Time) and CL (clearance) are determined from the plasma concentration-time profiles determined using the validated pharmacokinetic calculation program KinEx (verses 2.5 and 3 ).

Since the substance quantification is carried out in plasma, the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly. For this purpose, a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. After centrifugation at 1000 g, the concentration in the plasma is measured (see above) and by quotient of the C _blood / C _plasma value.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.

Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.

iv solution:

The compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 98/16223 [0006]
• WO 00/06568 [0007]
• WO 00/06569 [0007, 0152]
• WO 03/095451 [0007, 0070, 0145]
• WO 2004/009590 [0007]
• WO 2010/065275 [0007, 0064]
• EP 634413 A1 [0071]
• CN 1613849 A [0071]
• EP 1626045 A1 [0071]
• WO 2009/018415 [0071]

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Claims (9)

Compound of the formula (I)

in which L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2, where # ¹ is the linkage site to the carbonyl group, # ² represents the point of attachment to the pyrimidine ring, m represents an Number 0, 1 or 2, R ^{7A is} hydrogen, fluoro, (C ₁ -C ₄ ) alkyl, hydroxy or amino wherein (C ₁ -C ₄ ) alkyl having 1 to 3 substituents independently selected from Fluorine, trifluoromethyl, hydroxy, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and amino may be substituted, R ^{7B is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) Alkoxycarbonylamino or phenyl in which (C ₁ -C ₄ ) -alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and amino, or R ^7A and R ^7B together with the carbon atom to which they are attached, a (C ₂ -C ₄ ) alkenyl group, an oxo group, a 3- to 6-membered Ca rbocyclus or form a 4- to 7-membered heterocycle, wherein the 3- to 6-membered carbocycle and the 4- to 7-membered heterocycle having 1 or 2 substituents independently selected from the group fluorine and (C ₁ -C ₄ ) -Alkyl, R ^{8A is} hydrogen, fluorine, (C ₁ -C ₄ ) alkyl or hydroxy, R ^{8B is} hydrogen, fluoro, (C ₁ -C ₄ ) alkyl or trifluoromethyl, the ring Q is 8- or 9-membered heteroaryl, R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ , where R ^{4 is} hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4 - is up to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6- heteroaryl-containing heteroaryl having 1 to 3 substituents selected independently of one another from the group fluorine, difluoromethyl, trifluoromethyl, (C ₃ -C ₆ ) -cycloalkyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ , -C (= O) _p -NR ⁹ R ¹⁰ , -NR ⁹ - (C = O ) -R ¹⁰ , -NR ⁹ - (C = O) -OR ¹⁰ , -NR ⁹ - (C = O) -NR ¹⁰ R ¹¹ , -NR ⁹ -SO ₂ -R ¹⁰ , -S (O) _q - R ¹² and -SO ₂ -NR ⁹ R ¹⁰ may be substituted, wherein p is the number 0 or 1, q is the number 0, 1 or 2, R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, (C C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl, in which (C ₁ -C ₆ ) -alkyl in turn contains 1 or 2 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, hydroxy, C ₁ -C ₆ ) alkoxy, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₆ ) alkoxycarbonyl, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino and 4 - can be substituted to 7-membered heterocyclyl, or R ⁹ and R ¹⁰ together with the atom (s) to which they are respectively bonded form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, (C ₁ -C ₆ ) alkyl, hydroxy, oxo, (C ₁ -C ₆ ) alkoxy, trifluoromethoxy , (C ₁ -C ₆ ) alkoxycarbonyl, amino, mono (C ₁ -C ₆ ) alkylamino and di (C ₁ -C ₆ ) alkylamino, or R ¹⁰ and R ¹¹ form together with the / the atoms to which they are respectively attached, a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, (C C ₁ -C ₆ ) -alkyl, hydroxy, oxo, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino, and wherein R ^{12 is} (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, R ^{5 is} hydrogen or (C ₁ -C ₄ ) -Alkyl, R ^{6 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4-bis 7-membered heterocyclyl or 5- or 6-membered heteroaryl, wherein (C ₁ -C ₆ ) -alkyl (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl with 1 to 3 substituents independently selected from the group fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C = O) _p -OR ⁹ , -C (= O) _p -NR ⁹ R ¹⁰ , -NR ⁹ - (C = O) -R ¹⁰ , -NR ⁹ - (C = O) -OR ¹⁰ , -NR ⁹ - (C = O) -NR ¹⁰ R ¹¹ , -NR ⁹ -SO ₂ -R ¹⁰ , -S (O) _q -R ¹² and -SO ₂ -NR ⁹ R ¹⁰ may be substituted, wherein p is the number 0 or 1, q is the number 0, 1 or 2, R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl, or R ⁹ and R ¹⁰ together with the atom (s) to which they are respectively bonded form a 4-7 heterocycle in which the 4- to 7-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group cyano, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, hydroxy, oxo, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and May be di (C ₁ -C ₆ ) alkylamino, or R ¹⁰ and R ¹¹ together with the atom (s) to which they are each bonded form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, hydroxy, oxo, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, ( C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino, and wherein R ^{12 is} (C ₁ -C ₆ ) -Alkyl or (C ₃ -C ₇ ) -cycloalkyl, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl , (C ₁ -C ₆ ) -alkyl, hydroxy, oxo, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, amino, mono- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₆ ) -alkylamino, R ^{1 is} fluorine, chlorine or methyl, n is a number 0, 1, or 2, R ^{2 is} (C ₁ -C ₆ ) -alkyl , (C ₃ -C ₈ ) -cycloalkyl, phenyl or 5- or 6-membered heteroaryl wherein (C ₁ -C ₆ ) -alkyl is substituted with a substituent trifluoromethyl, wherein (C ₁ -C ₆ ) -alkyl with 1 to 3 substituents fluorine may be substituted, wherein phenyl is substituted by 1 to 3 substituents fluorine, and wherein 5- and 6-membered heteroaryl may be substituted with 1 or 2 substituents independently selected from the group fluorine and methyl, and their N Oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. Compound of the formula (I) according to claim 1, wherein L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2, where # ¹ is the linkage site to the carbonyl group, # ² for the point of attachment is to the pyrimidine ring, m is a number 0 or 1, R ^{7A is} hydrogen, fluorine, methyl, ethyl or hydroxyl, R ^{7B is} hydrogen, fluorine, methyl, ethyl, trifluoromethyl, methoxycarbonylamino or phenyl, wherein methyl and ethyl may be substituted with 1 to 3 substituents independently selected from the group fluorine, trifluoromethyl and hydroxy, or R ^7A and R ^7B together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl ring, in which the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, Pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl ring having 1 or 2 substituents independently selected from the group consisting of fluorine and methyl, R ^{8A is} hydrogen, fluorine, methyl, ethyl or hydroxy, R ^{8B is} hydrogen, fluorine Is methyl, ethyl or trifluoromethyl, the ring Q is a group of the formula

where * is the point of attachment to -CH ₂ -R ² , ** is the point of attachment to the pyrimidine, R ^{1 is} fluorine, chlorine or methyl, n is a number 0, 1 or 2, A ¹ , A ² , A ³ and A ⁴ are each independently N, CH or CR ¹ , with the proviso that at most two of the groups A ¹ , A ² , A ³ and A ^{4 are} N, R ^{3 is} -OR ⁴ or -NR ⁵ R ⁶ , wherein R ^{4 is} hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, wherein (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C = O) _p -OR ⁹ and -C (= O) _p -NR ⁹ R ¹⁰ , where p is the number 0 is, R ⁹ and R ¹⁰ are each independently hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or Morpholinyl ring in which the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring in turn with 1 or 2 substituents independently selected from the group fluorine, trifluoro or methyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino, R ^{5 is} hydrogen or methyl, R ^{6 is} (C ₁ -C ₆ ) -alkyl or (C C ₃ -C ₇ ) -cycloalkyl in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently of one another is selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, - (C =O) _p -OR ⁹ and -C (= O) _p -NR ⁹ R ¹⁰ may be substituted, wherein p is the number 0, R ⁹ and R ¹⁰ are each independently hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form together with the Nitrogen atom to which they are attached, an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring in turn having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, met hoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl Ring, wherein the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring in turn with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy, ethoxy, amino, methylamino , Ethylamino, dimethylamino and diethylamino, R ^{2 is} trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl, 2,2,3,3,3-pentafluoroprop-1-yl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein phenyl is substituted with 1 to 3 fluorine substituents, and wherein pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl may be substituted with 1 or 2 substituents fluorine n, and their salts, solvates and solvates of the salts. Compound of the formula (I) according to claim 1 or 2, in which L is a group # ¹ -CR ^7A R ^7B - (CR ^8A R ^8B) _m - # ^2, where # ¹ is the linkage site to the carbonyl group, # ^{2 is} the point of attachment to the pyrimidine ring, m is a number 0, R ^{7A is} hydrogen, fluoro, methyl or hydroxy, R ^{7B is} hydrogen, fluoro, methyl or trifluoromethyl, or R ^7A and R ^7B together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring in which the cyclopropyl and the cyclobutyl ring may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine and methyl, the ring Q is a group of formula

where * is the attachment site to -CH ₂ -R ² , ** is the point of attachment to the pyrimidine, R ^{1a is} hydrogen or fluorine, R ^{1b is} hydrogen or methyl, R ^{3 is} -OR ⁴ or - NR ⁵ R ⁶ , where R ^{4 is} hydrogen or (C ₁ -C ₆ ) -alkyl, in which (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents selected independently of one another from the group of fluorine, difluoromethyl, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, - (C = O) _p -OR ⁹ and -C (= O) _p -NR ⁹ R ¹⁰ may be substituted, wherein p is the number 0, R ⁹ and R ¹⁰ are each independently hydrogen, R ^{5 is} hydrogen, R ^{6 is} (C ₁ -C ₆ ) -alkyl, wherein (C ₁ -C ₆ ) -alkyl having 1 or 2 substituents independently selected from the group fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy , - (C = O) _p -OR ⁹ and -C (= O) _p -NR ⁹ R ¹⁰ where p is 0, R ⁹ and R ¹⁰ are each independently Wa R ^{2 is} 2,2,3,3,3-pentafluoroprop-1-yl, 2-fluorophenyl or 2,3,6-trifluorobenzyl, and their salts, solvates and solvates of the salts. Process for the preparation of compounds of the formula (I) as defined in claims 1 to 3, characterized in that a compound of the formula (II)

in which n, L, Q, R ¹ and R ^{2 are} each as defined in claims 1 to 3, in an inert solvent with iso-pentyl nitrite and an iodine equivalent in a compound of formula (III)

in which n, L, Q, R ¹ and R ^{2 in} each case have the meanings given in claims 1 to 3, and these are subsequently converted into an inert solvent, if appropriate in the presence of a suitable base, with a compound of the formula (IV) R ³ -H (IV), in which R ^{3 has} the meaning given in claims 1 to 3, to give a compound of formula (I)

in which n, L, Q, R ¹ , R ² and R ^{3 in} each case have the meanings given in claims 1 to 3, and if appropriate the resulting compounds of the formula (I), if appropriate with the corresponding (i) solvents and / or (ii) converting acids or bases into their solvates, salts and / or solvates of the salts. A compound of the formula (I) as defined in any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases. Use of a compound of the formula (I) as defined in any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic Diseases and arteriosclerosis. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 3, in combination with an inert, non-toxic, pharmaceutically-acceptable excipient. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 3 in combination with another active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, the Antihypertensive agents and lipid metabolizing agents. Medicament according to claim 7 or 8 for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic diseases, fibrotic diseases and arteriosclerosis.