Heterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10A

专利摘要:
Novel inhibitor compounds of phosphodiesterase type 10A The present invention relates to compounds which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders.
公开号:AU2012334011A1
申请号:U2012334011
申请日:2012-11-08
公开日:2014-05-15
发明作者:Jurgen Dinges；Karla Drescher；Herve Geneste；Clarissa Jakob；Michael Ochse
申请人:AbbVie Deutschland GmbH and Co KG；AbbVie Inc；
IPC主号:C07D217-26

专利说明:
WO 2013/068489 PCT/EP2012/072175 1 HETEROCYCLIC CARBOXAMIDES USEFUL AS INHIBITORS OF PHOSPHODIESTERASE TYPE 10A The present invention relates to compounds which are inhibitors of phosphodiesterase type 10 A and to their use for the manufacture of a medicament and 5 which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders. Background of the Invention 10 Phosphodiesterase type 10 A (hereinafter PDE 10 A) is a dual-substrate phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP. PDE1OA is highly prominent in the mammalian brain. In the rat, as well as in other mammalian species, PDE1OA and the mRNA of PDE1OA are highly enriched in the GABAergic 15 medium spiny projection neurons (MSNs) of the striatal complex (caudate nucleus, nucleus accumbens, and olfactory tubercle) where the output is regulated by the effect of PDE1OA on cAMP and cGMP signalling cascades (see e.g. C. J. Schmidt et al, The Journal of Pharmacology and Experimental Therapeutics 325 (2008) 681-690, A. Nishi, The Journal of Neuroscience 2008, 28, 10450-10471). 20 MSNs express two functional classes of neurons: the Di class expressing D 1 dopamine receptors and the D 2 class expressing D 2 dopamine receptors. The Di class of neurons is part of the 'direct' striatal output pathway, which broadly functions to facilitate behavioral responses. The D 2 class of neurons is part of the 'indirect' striatal output pathway, which functions to suppress behavioral responses that compete with 25 those being facilitated by the 'direct' pathway. PDE 10 A regulation of cAMP and/or cGMP signaling in the dendritic compartment of these neurons may be involved in filtering the cortico/thalamic input into the MSN. Furthermore, PDE1OA may be involved in the regulation of GABA release in the substantia nigra and globus pallidus (Seeger, T.F. et al. Brain Research, 2003, 985, 1 13-126). Inhibition of PDE1OA results 30 in striatal activation and behavioral suppression such as dampened locomotion, inhibition of conditioned avoidance response (CAR), and activity in the rat auditory WO 2013/068489 PCT/EP2012/072175 2 gating model, suggesting that inhibitors of phosphodiesterase type I0A represent a novel class of antipsychotic agents. The hypotheses around the physiological role of PDE1OA and the therapeutic utility of PDE1OA inhibitors derive in part from studies with papaverine (J. A. Siuciak 5 et al. loc. cit.), the first extensively profiled pharmacological tool compound for this target. The PDE 10 A inhibitor papaverine was shown to be active in several antipsychotic models. Papaverine potentiated the cataleptic effect of the D 2 receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499). Papaverine reduced hyperactivity in rats induced by PCP, while reduction of 10 amphetamine-induced hyperactivity was insignificant (WO 03/093499). These models suggest that PDE1OA inhibition has the classic antipsychotic potential that would be expected from theoretical considerations. Papaverine, however has significant limitations in this regard with relatively poor potency and selectivity and a very short exposure half-life after systemic administration. It was found that inhibition of PDE 10 A 15 reverses subchronic PCP-induced deficits in attentional set-shifting in rats suggesting that PDE 10 A inhibitors might alleviate cognitive deficits associated with schizophrenia. (Rodefer et al., Eur. J. Neurosci., 4 (2005) 1070-1076). The discovery of a new class of PDE1OA inhibitors with improved potency, selectivity, and pharmacokinetic properties, provided an opportunity to further explore 20 the physiology of PDE1OA and the potential therapeutic utility of inhibiting this enzyme. The new class of inhibitors are exemplified by MP-10 (PF-2545920: 2-{4-[1 methylpyridine-4-yl- 1 -H-pyrazol-3 -3 ly]phenoxymethyl} -quino line) and TP-10, i.e. 2 {4-[yridine-4-yl-1-(2,2,2-trifluoroethyl)-1-H-pyrazol-3-31y]phenoxymethyl} quinoline. The compounds offer a therapeutic approach to the treatment of 25 schizophrenia (see C. J. Schmidt et al., loc cit.; S.M. Grauer et al., Journal of Pharmacology and Experimental Therapeutics, fast forward DOI 10.1124 JPET 109.155994). Positive signals in rodent models of schizophrenia include the: attenuation of conditioned avoidance response (CAR), inhibition of hyperactivity caused by amphetamine-induced dopamine release or phencyclidine (PCP) mediated NMDA 30 receptor blockade, attenuation of pharmacologically impaired social or object recognition, and antagonism of apomorphine-induced climbing. Taken together, these data suggest a broad suppression of all 3 symptoms clusters (positive symptoms, WO 2013/068489 PCT/EP2012/072175 3 negative symptoms & cognitive dysfunctions) linked to schizophrenia (see C. J. Schmidt et al., loc cit.; S.M. Grauer et al., loc. cit). Beyond schizophrenia, selective PDE10 inhibitiors may have the potential for the treatment of Huntington's disease (S. H. Francis et al., Physiol. Rev., 91 (2011) 651 5 690) and they may be an therapeutic option for substance abuse disorders (F. Sotty et al., J. Neurochem., 109 (2009) 766-775). Furthermore, it has been suggested that PDE1OA inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes (see e.g. WO 2005/120514, WO 2005/012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873). 10 In summary, inhibitors of PDE 10 A offer a promising therapeutic approach to the treatment or prevention of neurological and psychiatric disorders, in particular schizophrenia and related disorders, including symptoms linked to schizophrenia such as cognitive dysfunction. Several classes of compounds which are inhibitors of PDE1OA have been 15 described in the art, the recent compound groups are: Pyrido[3,2-e]pyridazines - see WO 2007/137819, WO 2007/137820, WO 2009/068246, WO 2009/068320, WO 2009/070583 and WO 2009/070584; 4-substiuted phthalazines and quinazolines WO 2007/085954, WO 2007/022280, WO 2007/096743, WO 2007/103370, WO 2008/020302, WO 2008/006372 and WO 20 2009/036766; 4-substiuted cinnazolines - see WO 2006/028957, WO 2007/098169, WO 2007/098214, WO 2007/103554, WO 2009/025823 and WO 2009/025839; Isoquinolines and isoquinolinones - see WO 2007/100880 and WO 2009/029214; MP1O and MP1O like componds: US 2007/0155779, WO 2008/001182 and WO 25 2008/004117; and Benzodiazepines - see WO 2007/082546. For a further review see also T. Chappie et al. Current Opinion in Drug Discovery & Development 12(4), (2009) 458-467) and the literature cited therein. Although some of the compounds of prior art are known to inhibit PDE1OA 30 effectively having IC 50 values of less than 50 nM, there is still an ongoing need for compounds which inhibit PDE 10 A. In particular, there is an ongoing need for compounds which have one of the following characteristics: WO 2013/068489 PCT/EP2012/072175 4 i. Selective inhibition of PDE 10 A, in particular vis-A-vis inhibition of other phosphodisesterases such as PDE3 or PDE4; ii. metabolic stability, in particular microsomal stability, e.g. measured in vitro, in liver microsomes from various species (e.g. rat or human) in human cells, 5 such as hepatocytes; iii. no or only low inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP) is the name for a superfamily of heme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics 10 in mammalian organisms. The principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site 15 on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced; iv. a suitable solubility in water (in mg/ml); v. suitable pharmacokinetics (time course of the concentration of the 20 compound of the invention in plasma or in tissue, for example brain). The pharmacokinetics can be described by the following parameters: half-life, volume of distribution (in 1-kg-1), plasma clearance (in 1-h-1-kg-1), AUC (area under the curve, area under the concentration-time curve (in ng -h-1-1), oral bioavailability, (the dose-normalized ratio of AUC after oral 25 administration and AUC after intravenous administration), the so-called brain-plasma ratio (the ratio of AUC in brain tissue and AUC in plasma); vi. no or only low blockade of the hERG channel: compounds which block the hERG channel may cause a prolongation of the QT interval and thus lead to serious disturbances of cardiac rhythm (for example so-called "torsade de 30 pointes"). The potential of compounds to block the hERG channel can be determined by means of the displacement assay with radiolabelled dofetilide which is described in the literature (G. J. Diaz et al., Journal of WO 2013/068489 PCT/EP2012/072175 5 Pharmacological and Toxicological Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide assay means a greater probability of potent hERG blockade. In addition, the blockade of the hERG channel can be measured by electrophysio logical experiments on cells which have been 5 transfected with the hERG channel, by so-called whole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199). vii. high free fraction in brain, i.e. the fraction of the compound bound to proteins should be low. 10 viii. low lipophilicity. Brief Description of the Invention The present invention is thus based on the object of providing compounds which 15 inhibit PDE 10 A at low concentrations. The compounds are further intended to display at least one of the properties i. to viii. mentioned above, in particular high selectivity with regard to inhibition of PDE1OA, high selectivity vis-A-vis other phosphodiesterases such as , enhanced metabolic stability, in particular microsomal and/or cytosolic stability, low affinity to 20 the HERG receptor, low inhibition of cytochrome P450 (CYP) enzymes, suitable solubility in water and suitable pharmacokinetics. This object and further objects are achieved by the compounds of the general formula I described below, the N-oxides, the prodrugs, the hydrates and the tautomers thereof and the pharmaceutically suitable salts thereof: 25 Y R4 1 " R-O R 2 1() X / X O R2 0 N 1 3
R
WO 2013/068489 PCT/EP2012/072175 6 wherein XI is CH or N, 5 X2 is C-R5 or N, Y is O or S, 10 RI is selected from the group consisting of C 2 -Cs-alkyl, C 2 -Cs-alkenyl, C 1
-C
4 fluoroalkyl, C 3 -Cs-cycloalkyl, Cs-Cs-cycloalkyl carrying a fused benzene ring, fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl, CI-C 4 -alkyl-N(Rb)(Rc) and a moiety Z-Arl; 15 R2 is a radical of the formula CR2 R R23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra, where 20 R2 is selected from the group consisting of hydrogen, CI-Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, 25 hydroxy-C1-C 4 -alkyl, CI-C 4 -alkyl-N(R)(Rc), (CH 2 )mC(O)O-Rd
(CH
2 )mC(O)N(Re)(R) and Z 2 -Ar 2 , R is selected from the group consisting of hydrogen, fluorine, C 1
-C
8 alkyl, C 2 -Cs-alkenyl, C 1
-C
4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated 30 C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-Ci-C 4 alkyl and CI-C 4 -alkyl-N(Rb)(Rc), or WO 2013/068489 PCT/EP2012/072175 7
R
2 ' and R 2 2 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a saturated 5- to 7 membered heterocyclic ring which has 1, 2 or 3 heteroatoms or 5 heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R9, and where the carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a 10 fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, R is selected from the group consisting of hydrogen, fluorine, C 1
-C
8 alkyl and C1-C 4 -fluoroalkyl; 15 R3 is selected from the group consisting of hydrogen, CI-Cs-alkyl, C 2
-C
8 alkenyl, C 1
-C
4 -fluoroalkyl, C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl,
CI-C
4 -alkoxy-CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl, CI-C 4 -alkyl-N(Rb)(Rc), and trimethylsilyl, or 20 R2 and R3 together with the nitrogen atom, to which they are bound form a saturated 5- to 7- membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring 25 members, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R 31 , and where the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6 membered heteroaromatic ring, where the fused rings themselves are 32 unsubstituted or carry 1, 2 or 3 substituents R , where 30 R31 is selected from the group consisting of halogen, CN, OH, C 1
-C
4 alkyl, fluorinated CI-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1
-C
4
-
WO 2013/068489 PCT/EP2012/072175 8 alkoxy, N(R)(R), C(O)O-Rd, C(O)N(R)(R), where one radical R" may also be a moiety Z 3 -Ar 3 , R is selected from the group consisting of halogen, CN, OH, C 1
-C
4 5 alkyl, fluorinated C1-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1
-C
4 alkoxy, N(R)(RC), C(O)O-Rd and C(O)N(Re)(R); R4 is selected from the group consisting of CI-C 4 -alkyl, CI-C 4 -fluoroalkyl, C 3 C 6 -cycloalkyl, C 3
-C
6 -cycloalkyl-C1-C 4 -alkyl and Z 4 -Ar 4 ; 10
R
5 is selected from the group consisting of hydrogen, halogen, CI-C 4 -alkyl, C1
C
4 -fluoroalkyl, C 1
-C
4 -alkoxy, C 1
-C
4 -fluoroalkoxy, -Z 5 -Ar 5 , -O-Z 5 -Ar 5 , C 3 C 6 -cycloalkyl, C 3
-C
6 -cycloalkyl-C1-C 4 -alkyl, C 3
-C
6 -cycloalkoxy and C 3
-C
6 cycloalkyl-C1-C 4 -alkoxy, where the cyclic radical in the last four mentioned 15 groups may be unsubstituted, partially or completely fluorinated or carries 1, 2, 3 or 4 methyl groups; Ar is selected from the group consisting of phenyl, monocyclic 5- or 6 membered hetaryl or bicyclic 9- or 1 0-membered hetaryl, where 20 hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar2 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 25 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar 3 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 30 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; WO 2013/068489 PCT/EP2012/072175 9 Ar 4 and Ar' are independently of each other selected from the group consisting of phenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S 5 and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R Z 1 , Z 4 , Z 5 are independently of each other CI-C 4 -alkylene; 10 Z 2 is a single bond or CI-C 4 -alkylene;
Z
3 is a single bond, CI-C 4 -alkylene, 0, N, S, SO or SO 2 ; Ra is selected from the group consisting of halogen, CN, OH, NO 2 , C1 15 C 4 -alkyl, fluorinated C1-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C1-C 4 alkoxy, (CH 2 )mN(R)(RC), C(O)O-Rd, C(O)N(R)(R), N(Ree)S(O) 2 (Rff) and S(O) 2 N(Re)(R); R , Rc, independently of each other are selected from the group consisting of 20 hydrogen, CI-C 4 -alkyl, C1-C 4 -fluoroalkyl, C 3
-C
6 -cycloalkyl, C 3
-C
6 cycloalkylmethyl and benzyl or R and R' form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group 25 of 0, N, S, SO and SO 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from CI-C 4 -alkyl; Rd is selected from the group consisting of CI-C 4 -alkyl, C 1
-C
4 fluoroalkyl, C 3
-C
6 -cycloalkyl, C 3
-C
6 -cycloalkylmethyl and benzyl; 30 Re, Rf, independently of each other are selected from the group consisting of hydrogen, CI-C 4 -alkyl, C1-C 4 -fluoroalkyl, C 3
-C
6 -cycloalkyl, C 3
-C
6
-
WO 2013/068489 PCT/EP2012/072175 10 cycloalkylmethyl and benzyl or Re and Rf form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group 5 of 0, N, S, SO and SO 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from CI-C 4 -alkyl; R9 is selected from the group consisting of halogen, CN, OH, C 1
-C
6 alkyl, C 2
-C
6 -alkenyl, C 1
-C
4 -fluoroalkyl, C 3
-C
6 -cycloalkyl, fluorinated 10 C 3
-C
6 -cycloalkyl, C 3
-C
6 -cycloalkyl-C1-C 4 -alkyl, fluorinated C 3
-C
6 cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-Ci-C 4 alkyl, CI-C 4 -alkyl-N(Rb)(Rc), CI-C 4 -alkoxy, fluorinated CI-C 4 -alkoxy, one R9 together with a carbon atom to which R9 is attached may also form a carbonyl group, one R9 may also be phenyl or benzyl, where 15 the phenyl ring in the last 2 mentioned radicals is unsubstituted or carries 1, 2 or 3 radicals Rh; Rh is selected from the group consisting of halogen, CN, OH, C 1
-C
4 alkyl, fluorinated CI-C 4 -alkyl, C1-C 6 -alkoxy, fluorinated C 1
-C
4 20 alkoxy, C1-C 4 -alkylsulfanyl, CI-C 4 -alkoxy-CI-C 4 -alkoxy, C 3
-C
6 cycloalkyl, fluorinated C 3
-C
6 -cycloalkyl, C 3
-C
6 -cycloalkoxy, C 3
-C
6 cycloalkyl-C1-C 4 -alkoxy, phenoxy, N(R)(Rc), C 1
-C
4 -alkyl-N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (Rff), S(O) 2 N(Re)(R), 3- to 7 membered heterocyclyloxy, 3- to 7-membered heterocyclyl-CI-C 4 25 alkoxy, where heterocyclyl in the two last mentioned radicals has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, and 5- to 6-membered hetaryl-C1-C 4 -alkoxy, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N; 30 R is selected from the group consisting of halogen, CN, OH, C 1
-C
4 alkyl, fluorinated CI-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1
-C
4
-
WO 2013/068489 PCT/EP2012/072175 11 alkoxy, N(R)(R*), C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (Rf) and
S(O)
2 N(Re)(R) or two radicals Rk that are bound to adjacent carbon atoms together with said carbon atoms may form fused benzene ring or a fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring 5 members selected from 0, N and S, where the fused benzene ring and the fused heteroaromatic ring are unsubstituted or may carry 1, 2 or 3 radicals Rh; Ree is selected from the group consisting of hydrogen, CI-C 4 -alkyl, CI-C 4 10 fluoroalkyl, C 3
-C
6 -cycloalkyl, C 3
-C
6 -cycloalkylmethyl and benzyl; Rf is selected from the group consisting of CI-C 4 -alkyl, C1-C 4 -fluoroalkyl and phenyl, which is unsubstituted or carries 1, 2 or 3 radicals Rh. 15 m is 0, 1, 2, 3 or 4. The present invention therefore relates to the compounds of the general formula I, the N-oxides, the tautomers and the hydrates thereof, the pharmaceutically acceptable salts of the compounds of formula I, the prodrugs of the compounds of formula I and 20 the pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates of the compounds of formula I. The present invention also relates to the compounds of the general formula I, the N-oxides, the tautomers and the hydrates thereof, the pharmaceutically acceptable salts of the compounds of formula I, the prodrugs of the compounds of formula I and the 25 pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates of the compounds of formula I for the use in the treatment of a medical disorder, selected from neurological and psychiatric disorders which can be treated by modulation of phosphodiesterase type 10. The compounds of the formula I, their pharmaceutically acceptable salts, their N 30 oxides, their prodrugs, their hydrates and their tautomers and the pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates effectively inhibit PDE1OA even at low concentrations. They are additionally distinguished by a high WO 2013/068489 PCT/EP2012/072175 12 selectivity in relation to the inhibition of the PDE1OA vis-A-vis inhibition of other phosphodiesterease, such as PDE3 or PDE4. The compounds of the invention may additionally have one or more of the properties ii. to viii. mentioned above. The compounds of the formula I, their pharmaceutically acceptable salts, their N 5 oxides, their prodrugs, their hydrates and their tautomers and the pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates are therefore particularly suitable for treating disorders and conditions in creatures, especially human creatures, which can be treated or controlled by inhibition of phosphodiesterase type 10 A. 10 The invention therefore also relates to the use of the compounds of the formula I, their N-oxides, their tautomers, their hydrates and their pharmaceutically acceptable salts and the pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates for the manufacture of a medicament, in particular of a medicament which is suitable for the treatment of a disorder or a condition which can be treated by inhibition 15 of phosphodiesterase type 10A. The invention further relates to a medicament, in particular a medicament which is suitable for the treatment of a disorder or a condition which can be treated by inhibition of phosphodiesterase type 10 A. The medicament comprises at least one compound of the formula I, as described herein, or an N-oxide, a tautomer, or a hydrate 20 or a prodrug of said compound I, or a pharmaceutically acceptable salt of the compound of the formula I or a pharmaceutically acceptable salt of the N-oxide, the tautomer, the hydrate or the prodrug of compound of the formula I. Detailed Description of the Invention 25 The terms "compound of the formula I" and "compounds I" are used as synonyms. The term "prodrugs" means compounds which are metabolized in vivo to the compounds I of the invention. Typical examples of prodrugs are described in C.G. Wermuth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 30 1996, pages 671-715. These include for example phosphates, carbamates, amino acids, esters, amides, peptides, ureas and the like. Suitable prodrugs in the present case may be for example derivatives of those compounds I carrying an OH or NH 2 -group, where the WO 2013/068489 PCT/EP2012/072175 13 OH or NH 2 -group forms an ester/amide/peptide linkage, i.e. where one of the hydrogen atoms of the OH or NH 2 -group is substituted by a CI-C 4 -alkylcarbonyl group, e.g. by acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or tert butylcarbonyl (pivaloyl), by benzoyl, or by an acyl group derived from an amino acid, 5 e.g. glycine, alanine, serine, phenylalanine and the like, which is linked to the oxygen or nitrogen of the OH or NH 2 -group via the carbonyl group of the amino acid. Further suitable prodrugs are alkylcarbonyloxyalkyl carbonates or carbamates of compounds I carrying an OH- or NH 2 -group in which one of the hydrogen atoms of the OH- or NH 2 group has been replaced by a group of the formula -C(=0)-O-CHRP-0-C(=0)-RI in 10 which RP and RI are independently of one another CI-C 4 -alkyl. Such carbonates and carbamates are described for example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322. These groups can then be eliminated under metabolic conditions and result in compounds I. Therefore, said prodrugs and their pharmaceutically acceptable salts are also part of the invention. 15 The term "pharmaceutically acceptable salts" refers to cationic or anionic salts compounds, wherein the counter ion is derived from pharmaceutically acceptable non toxic bases or acids including inorganic or organic bases and inorganic or organic acids. When the compound of formula I or its prodrug, tautomer, hydrate or N-oxide is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, 20 including inorganic and organic bases. Salts derived from inorganic bases include salts, wherein the counter ion is aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc ion and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium ions. Salts derived from pharmaceutically acceptable organic non-toxic bases include 25 salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, dibenzylethylene-diamine, diethylamine, 2 diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N ethyl-morpho line, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, 30 isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
WO 2013/068489 PCT/EP2012/072175 14 When the compound of formula I or its prodrug, tautomer, hydrate or N-oxide is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, trifluoroacetic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, 5 glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of formula I are 10 meant to also include the pharmaceutically acceptable salts. The compounds of the invention may be in the form of a mixture of diastereomers, or of a mixture of diastereomers in which one of the two diastereomers is enriched, or of essentially diastereomerically pure compounds (diastereomeric excess de > 90%). The compounds are preferably in the form of essentially diastereomerically 15 pure compounds (diastereomeric excess de > 90%). The compounds I of the invention may furthermore be in the form of a mixture of enantiomers (for example as racemate), of a mixture of enantiomers in which one of the two enantiomers is enriched, or essentially in enantiomerically pure compounds (enantiomeric excess ee > 90%). However, the compounds of the invention are frequently prone to racemization in 20 relation to the stereochemistry of the carbon atom which carries the radical R 1 , so that mixtures are frequently obtained in relation to this carbon atom, or compounds which exhibit a uniform stereochemistry in relation to this C atom form mixtures under physiological conditions. However, in relation to other stereocenters and the occurrence, associatied therewith, of enantiomers and diastereomers, it is preferred to employ the 25 compounds enantiomerically pure or diastereomerically pure. The present invention moreover relates to compounds as defined herein, wherein one or more of the atoms depicted in formula I have been replaced by its stable, preferably non-radioactive isotope (e.g., hydrogen by deuterium, 12 C by "C, 14 N by "N, 160 by 180) and preferably wherein at least one hydrogen atom has been replaced by a 30 deuterium atom. Of course, the compounds according to the invention contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds I.
WO 2013/068489 PCT/EP2012/072175 15 The compounds of the formula I and their salts in the solid form may exist in more than one crystal structure (polymorphism), and may also be in the form of hydrates or other solvates. The present invention includes any polymorph of the compound I or its salt as well as any hydrate or other solvate. 5 In the context of the present description, unless stated otherwise, the terms "alkyl", "alkenyl", "alkoxy", "alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "cycloalkyl", "fluorinated cycloalkyl", "alkylene", "alkandiyl", "hetaryl" and radicals derived therefrom, such as "hydroxylalkyl", "alkoxylalkyl", "alkoxyalkoxy", "cycloalkylalkyl" and "fluorinated cycloalkylalkyl" and "hetarylalkyl" represent groups of individual 10 radicals. The groups of noncyclic radicals "alkyl", "alkenyl", "alkoxy", "alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "alkylene", "alkandiyl", and the groups of radicals derived therefrom always include both unbranched and branched "alkyl", "alkenyl", "alkoxy", "alkenyloxy", "fluoroalkyl", "fluoroalkoxy", "alkylene" and "alkandiyl", respectively. 15 The prefix C-Cm- indicates the respective number of carbons in the hydrocarbon unit. Unless indicated otherwise, fluorinated substituents preferably have one to five identical or different fluorine atoms. The term "halogen" designates in each case, fluorine, bromine, chlorine or iodine, specifically fluorine, chlorine or bromine. 20 Examples of other meanings are: Alkyl, and the alkyl moieties for example in alkylcarbonyl, alkylsulfanyl, alkylsulfonyl, alkylsulfanylalkyl and alkylsulfanylalkoxy: saturated, straight-chain or branched hydrocarbon radicals having one or more C atoms, e.g. 1 to 10, 1 to 8, 1 to 6 or I to 4 carbon atoms. Examples of CI-C 4 -alkyl are methyl, ethyl, propyl, 1 25 methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. C1-C 6 alkyl are, apart those mentioned for CI-C 4 -alkyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1 dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2 30 dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2 trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-i -methylpropyl and 1 -ethyl-2 methylpropyl. Examples for C1-Cs-alkyl or C 2
-C
9 -alkyl are, apart those mentioned for WO 2013/068489 PCT/EP2012/072175 16
C
1
-C
6 -alkyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5 methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 1-methyloctyl, 2 methylheptyl, 1 -ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl and 1-propylpentyl, 2 propylpentyl. 5 Fluoroalkyl and the fluoroalkyl moieties for example in fluoroalkylsulfonyl: an alkyl radical having ordinarily 1 to 4 C atoms, in particular 1 or 2 C-atoms (C 1
-C
2 fluoroalkyl) as mentioned above, whose hydrogen atoms are partly or completely replaced by fluorine atoms such as fluoromethyl, difluoromethyl, trifluoromethyl, 2 fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoro-1 10 methylethyl, 2,2-difluoro-1-methylethyl, 2,2-trifluoro-1-methylethyl, 2-fluoropropyl, 3 fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,3,3,3 pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 4-fluorobutyl, and nonafluorobutyl. Cycloalkyl, and the cycloalkyl moieties for example in cycloalkoxy, cycloalkyl 15 C1-C 4 -alkyl or cycloalkyl-C1-C 4 -alkoxy: monocyclic, saturated hydrocarbon groups having three or more C atoms, e.g. 3, 4, 5, 6, 7 or 8 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Fluorinated cycloalkyl, and the flourinted cycloalkyl moieties for example in fluorinated cycloalkoxy or fluorinated cycloalkyl-C1-C 4 -alkyl: monocyclic, saturated 20 hydrocarbon groups having three or more C atoms, e.g. 3, 4, 5, 6, 7 or 8 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein at least one, e.g. 1, 2, 3, 4, 5 or 6 of the hydrogen atoms are replaced by fluorine atoms, examples including 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2 difluorocyclopropyl, 1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, etc.. 25 Cycloalkoxy: a cycloalkyl radical as defined above which is linked via an oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy. Cycloalkylalkyl: a cycloalkyl radical as defined above which is linked via an alkylene group, in particular via a methylene, 1,1-ethylene or 1,2-ethylene group, e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethy, cyclohexylmethyl, 1 30 cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2 cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl.
WO 2013/068489 PCT/EP2012/072175 17 Fluorinated cycloalkylalkyl: a fluorinated cycloalkyl radical as defined above which is linked via an alkylene group, in particular via a methylene, 1,1-ethylene or 1,2 ethylene group, e.g. 1-fluorocyclopropylmethyl, 2-fluorocyclopropylmethyl, 2,2 difluorocyclopropylmethyl, 1,2-difluorocyclopropylmethyl, 2,3 5 difluorocyclopropylmethyl, 1-(1-fluorocyclopropyl)ethyl, 1-(2-fluorocyclopropyl)ethyl, 1-(2,2-difluorocyclopropyl)ethyl, 1-(1,2-difluorocyclopropyl)ethyl, 1-(2,3 difluorocyclopropyl)ethyl, 2-(1-fluorocyclopropyl)ethyl, 2-(2-fluorocyclopropyl)ethyl, 2-(2,2-difluorocyclopropyl)ethyl, 2-(1,2-difluorocyclopropyl)ethyl or 2-(2,3 difluorocyclopropyl)ethyl. 10 Alkenyl, and alkenyl moieties for example in alkenyloxy: monounsaturated, straight-chain or branched hydrocarbon radicals having two or more C atoms, e.g. 2 to 4 carbon atoms and one C=C-double bond in any position, e.g. C 2
-C
4 -alkenyl such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 methyl-i -propenyl, 2-methyl-i -propenyl, 1 -methyl-2-propenyl and 2-methyl-2 15 propenyl. Alkoxy or alkoxy moieties for example in alkoxyalkyl and alkoxyalkoxy: an alkyl radical as defined above ordinarily having 1 to 6 C atoms, preferably 1 to 4 C atoms, which is connected to the remainder of the molecule via an 0 atom: e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 20 2-methylpropoxy or 1,1 -dimethylethoxy. Fluoroalkoxy: alkoxy as described above, in which the hydrogen atoms of these groups are partly or completely replaced by fluorine atoms, i.e. for example C 1
-C
4 fluoroalkoxy, in particular C1-C 2 -fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 25 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3,3-trifluoropropoxy, 2,2,3,3,3 pentafluoropropoxy, heptafluoropropoxy, 1-(fluoromethyl)-2-fluoroethoxy, specifically fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or 2,2,2 trifluoroethoxy. 30 Hydroxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by an OH radical. Examples thereof are CH 2 -OH, 1 hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1-methyl-1- WO 2013/068489 PCT/EP2012/072175 18 hydroxyethyl, 1-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 3 hydroxybutyl, 4-hydroxybutyl, 1 -methyl-2-hydroxypropyl, 1,1 -dimethyl-2-hydroxyetyl, 1-methyl-i -hydroxypropyl etc. Alkylsulfanyl: alkyl as defined above preferably having 1 to 4 C atoms, which is 5 connected via a sulfur atom to the remainder of the molecule, e.g. methylsulfanyl, ethylsulfanyl, n-propylsulfanyl and the like. Alkoxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by an alkoxy radical ordinarily having 1 to 4 C atoms. Examples thereof are CH 2
-OCH
3 , CH 2
-OC
2
H
5 , n-propoxymethyl, CH 2
-OCH(CH
3
)
2 , 10 n-butoxymethyl, (1-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH 2
-OC(CH
3
)
3 , 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl, 2-(1,1 -dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(1 15 methylpropoxy)propyl, 2-(2-methylpropoxy)propyl, 2-(1,1-dimethylethoxy)propyl, 3 (methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3 (n-butoxy)propyl, 3-(1-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl, 3-(1,1 dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl, 2-(n-propoxy)butyl, 2-(1 methylethoxy)butyl, 2-(n-butoxy)butyl, 2-(1-methylpropoxy)butyl, 2-(2 20 methylpropoxy)butyl, 2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl, 3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl, 3-(1 methylpropoxy)butyl, 3-(2-methylpropoxy)butyl, 3-(1,1-dimethylethoxy)butyl, 4 (methoxy)butyl, 4-(ethoxy)butyl, 4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n butoxy)butyl, 4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl, 4-(1,1 25 dimethylethoxy)butyl, etc. Alkoxyalkoxy: an alkoxyalkyl radical as defined above ordinarily having 1 to 4 C atoms both in the alkoxy and the alkyl moiety which is connected to the remainder of the molecule via an 0 atom: Examples thereof are OCH 2
-OCH
3 , OCH 2
-OC
2
H
5 , n propoxymethoxy, OCH 2
-OCH(CH
3
)
2 , n-butoxymethoxy, (1-methylpropoxy)methoxy, 30 (2-methylpropoxy)methoxy, OCH 2
-OC(CH
3
)
3 , 2-(methoxy)ethoxy, 2-(ethoxy)ethoxy, 2-(n-propoxy)ethoxy, 2-(1-methylethoxy)ethoxy, 2-(n-butoxy)ethoxy, WO 2013/068489 PCT/EP2012/072175 19 2-(1-methylpropoxy)ethoxy, 2-(2-methylpropoxy)ethoxy, 2-(1,1 -dimethyl ethoxy)ethoxy, etc. Cycloalkylalkoxy: an alkoxy radical ordinarily having 1 to 4 C atoms, preferably 1 to 2 C atoms, in which one hydrogen atom is replaced by a cycloalkyl radical 5 ordinarily having 3 to 6 C atoms as defined above. Examples thereof are cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, cyclobutylethoxy, cyclopentylethoxy, cyclohexylethoxy and the like. "Alkylen" or "alkanediyl": a saturated hydrocarbon chain having ordinarily from 1 10 to 4 carbon atoms, such as methylen (-CH 2 -), 1,2-ethylen (-CH 2
CH
2 -), 1,1-ethanediyl
(-CH(CH
3 )-), 1,2-propanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-butanediyl, 1,3 butanediyl, 1-methyl-1,2-propanediyl, 2-methyl-1,3-propanediyl, 1-methyl-1,1 ethanediyl, 1-methyl-1,2-propanediyl etc. Saturated or partially unsaturated 5- to 7-membered monocarbocyclic radicals 15 include cycloalkyl as defined above and cycloalkenyl having ordinarily from 4 to 7 carbon atoms as ring members, e.g. 1-cyclobuten-1-yl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2 cycloheptenyl, 3-cycloheptenyl. Heterocyclyl: a heterocyclic radical which may be saturated or partly unsaturated 20 and which may be a monocyclic heterocyclic radical ordinarily having 3, 4, 5, 6, 7 or 8 ring atoms or a heterobicyclic radical ordinarily having 7, 8, 9 or 10 ring atoms, where ordinarily 1, 2, 3 or 4, in particular 1, 2 or 3, of the ring atoms are heteroatoms such as N, S or 0, or heteroatom groups such as S(=0) or S(=0)2 besides carbon atoms as ring members. 25 Examples of saturated heteromonocycles are in particular: - Saturated heteromonocyclic radical which ordinarily has 3, 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as N, S or 0, besides carbon atoms as ring members. These include for example: 30 C-bonded, 3- or 4-membered saturated rings such as 2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl, 1-azetidinyl, 2-azetidinyl.
WO 2013/068489 PCT/EP2012/072175 20 C-bonded, 5-membered saturated rings such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, tetrahydropyrazol-3-yl, tetrahydropyrazol-4-yl, tetrahydroisoxazol-3-yl, 5 tetrahydroisoxazol-4-yl, tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2 oxathiolan-4-yl, 1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl, tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl, 1,2-dithiolan-3-yl, 1,2 dithiolan-4-yl, tetrahydroimidazol-2-yl, tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl, tetrahydrooxazol-5-yl, 10 tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl, tetrahydrothiazol-5-yl, 1,3 dioxolan-2-yl, 1,3-dioxolan-4-yl, 1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl, 1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2 dioxathiolan-4-yl. C-bonded, 6-membered saturated rings such as: 15 tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidin 2-yl, piperidin-3-yl, piperidin-4-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3 dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian 4-yl, 1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl, 1,3-oxathian-4-yl, 20 1,3-oxathian-5-yl, 1,3-oxathian-6-yl, 1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl, 1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin 2-yl, tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl, tetrahydro-1,3 25 oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl, tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl, tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4 thiazin-2-yl, tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl, tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl, tetrahydro-1,2 oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl, tetrahydro-1,2-oxazin-6-yl. 30 N-bonded, 5-membered saturated rings such as: WO 2013/068489 PCT/EP2012/072175 21 tetrahydropyrrol-1-yl, tetrahydropyrazol-1-yl, tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl, tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl. N-bonded, 6-membered saturated rings such as: 5 piperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl, hexahydro-pyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl, tetrahydro-1,3 thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl, tetrahydro- 1,2-oxazin-2-yl. Unsaturated heteromonocyclic radicals which ordinarily have 4, 5, 6 or 7 10 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as N, S or 0, besides carbon atoms as ring members. These include for example: C-bonded, 5-membered, partially unsaturated rings such as: 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl, 15 2,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl, 2,3 dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl, 2,5 dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl, 2,3 dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 4,5 20 dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H pyrrol-3-yl, 3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl, 4,5 dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl, 4,5-dihydro-1H pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl, 2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl, 4,5-dihydroisoxazol-3-yl, 4,5 25 dihydroisoxazol-4-yl, 4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl, 2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl, 2,3-dihydroisoxazol-3 yl, 2,3-dihydroisoxazol-4-yl, 2,3-dihydroisoxazol-5-yl, 4,5 dihydroisothiazol-3-yl, 4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5 yl, 2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl, 2,5 30 dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl, 2,3-dihydroisothiazol-4 yl, 2,3-dihydroisothiazol-5-yl, 4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro 1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol- WO 2013/068489 PCT/EP2012/072175 22 2-yl, 2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl, 2,3 dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl, 4,5 dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl, 2,5 dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl, 2,3 5 dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 4,5 dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl, 4,5-dihydrothiazol-5-yl, 2,5 dihydrothiazol-2-yl, 2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl, 2,3 dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl, 1,3 dioxol-2-yl, 1,3-dioxol-4-yl, 1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol 10 2-yl, 1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl. C-bonded, 6-membered, partially unsaturated rings such as: 2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl, 2H-3,4 dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl, 2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl, 2H-3,4-dihydrothiopyran-5-yl, 2H-3,4 15 dihydrothiopyran-4-yl, 2H-3,4-dihydrothiopyran-3-yl, 2H-3,4 dihydrothiopyran-2-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4 tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra hydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2 yl, 2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl, 2H-5,6 20 dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl, 2H-5,6-dihydrothiopyran-2 yl, 2H-5,6-dihydrothiopyran-3-yl, 2H-5,6-dihydrothiopyran-4-yl, 2H-5,6 dihydrothiopyran-5-yl, 2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6 tetrahydropyridin-2-yl, 1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6 tetrahydropyridin-4-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetra 25 hydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin 3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl, 2,3,4,5 tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl, 4H-pyran-4-yl, 4H thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl, 1,4-dihydropyridin-2 yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H 30 pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2 yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran 6-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin- WO 2013/068489 PCT/EP2012/072175 23 4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 3,4-dihydropyridin 2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin 5-yl, 3,4-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin 3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin 5 6-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin 4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2H-5,6-dihydro-1,2 oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl, 2H-5,6-dihydro-1,2-oxazin-5 yl, 2H-5,6-dihydro-1,2-oxazin-6-yl, 2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl, 2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6 10 dihydro-1,2-thiazin-6-yl, 4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro 1,2-oxazin-4-yl, 4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2 oxazin-6-yl, 4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4 yl, 4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl, 2H 3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl, 2H-3,6 15 dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl, 2H-3,6-dihydro 1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl, 2H-3,6-dihydro-1,2 thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl, 2H-3,4-dihydro-1,2-oxazin-3 yl, 2H-3,4-dihydro-1,2-oxazin-4-yl, 2H-3,4-dihydro-1,2-oxazin-5-yl, 2H 3,4-dihydro-1,2-oxazin-6-yl, 2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4 20 dihydro-1,2-thiazin-4-yl, 2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro 1,2-thiazin-6-yl, 2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5 tetrahydropyridazin-4-yl, 2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5 tetrahydropyridazin-6-yl, 3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6 tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6 25 tetrahydropyridazin-4-yl, 1,2,5,6-tetrahydropyridazin-5-yl, 1,2,5,6 tetrahydropyridazin-6-yl, 1,2,3,6-tetrahydropyridazin-3-yl, 1,2,3,6 tetrahydropyridazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro 1,3-oxazin-4-yl, 4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3 oxazin-6-yl, 4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4 30 yl, 4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl, 3,4,5 6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl, 3,4,5,6-tetra hydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl, 1,2,3,4- WO 2013/068489 PCT/EP2012/072175 24 tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl, 1,2,3,4 tetrahydropyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl, 1,2,3,4 tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl, 2,3-dihydro-1,4 thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl, 2,3-dihydro-1,4-thiazin-5-yl, 2,3 5 dihydro-1,4-thiazin-6-yl, 2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3 oxazin-5-yl, 2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl, 2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3 oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl, 4H-1,3-thiazin-6-yl, 6H-1,3 10 oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3 thiazin-6-yl, 2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl, 2H-1,4 thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl, 15 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl, 1,4-dihydropyridazin-3-yl, 1,4 dihydropyridazin-4-yl, 1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6 yl, 1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl, 1,2-dihydropyrazin-3 yl, 1,2-dihydropyrazin-5-yl, 1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin 2-yl, 1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl, 1,4 20 dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl, 3,4-dihydropyrimidin-4 yl, 3,4-dihydropyrimidin-5-yl or 3,4-dihydropyrimidin-6-yl. N-bonded, 5-membered, partially unsaturated rings such as: 2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl, 25 2,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2 yl, 2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl, 2,5-dihydro 1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl. N-bonded, 6-membered, partially unsaturated rings such as: 30 1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 1,4 dihydropyridin- l-yl, 1,2-dihydropyridin- l-yl, 2H-5,6-dihydro- 1,2-oxazin-2 yl, 2H-5,6-dihydro-1,2-thiazin-2-yl, 2H-3,6-dihydro-1,2-oxazin-2-yl, 2H- WO 2013/068489 PCT/EP2012/072175 25 3,6-dihydro-1,2-thiazin-2-yl, 2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4 dihydro-1,2-thiazin-2-yl, 2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6 tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6 tetrahydropyridazin-1-yl, 3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4 5 tetrahydropyrazin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydro pyrimidin-3-yl, 2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2 thiazin-2-yl, 4H- 1,4-oxazin-4-yl, 4H- 1,4-thiazin-4-yl, 1,4-dihydropyridazin 1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl, 1,4 dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl. 10 Heterocyclyloxy: a heterocyclyl radical as defined above which is attached to the remainder of the molecule via an oxygen atom. The heterocyclyl radical ordinarily has 3, 4, 5, 6 or 7 ring atoms, in which besides carbon atoms as ring members ordinarily 1, 2 or 3, in particular 1 or 2, of the ring atoms are heteroatoms such as N, S or 0, in particular 5- to 7-membered heterocycloyloxy, where heterocyclyl has 1 or 2 15 heteroatoms selected from 0, S and N as ring members, for example tetrahydrofuran-2 yloxy, tetrahydrofuran-3-yloxy, tetrahydrothiophen-2-yloxy or tetrahydrothiophen-3 yloxy. Heterocyclyl-C1-C 4 -alkoxy: a CI-C 4 -alkoxy group as defined above in which one hydrogen atom is replaced by a heterocyclyl radical as defined above. The heterocyclyl 20 radical ordinarily has 3, 4, 5, 6 or 7 ring atoms, in which besides carbon atoms as ring members ordinarily 1, 2 or 3, in particular 1 or 2, of the ring atoms are heteroatoms such as N, S or 0. In particular, 5- to 7-membered heterocyclyl-C1-C 2 -alkoxy, where heterocyclyl has 1 or 2 heteroatoms selected from 0, S and N as ring members, for example tetrahydrofuran-2-yl-methoxy, tetrahydrofuran-2-yl-ethoxy, tetrahydrofuran-3 25 ylmethoxy, tetrahydrofuran-3-ylethoxy, tetrahydrothiophen-2-ylmethoxy, tetrahydrothiophen-2-ylethoxy, tetrahydrothiophen-3-ylmethoxy, tetrahydrothiophen-3 ylethoxy. Hetaryl: a 5- or 6-membered aromatic heteromonocyclic radical (also termed 5- or 6-membered monocyclic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring 30 members, which are selected from 0, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as ring members besides carbon atoms as ring members and a 8-, 9- or WO 2013/068489 PCT/EP2012/072175 26 10-membered aromatic heterobicyclic radical (also termed 8-, 9- or 10-membered bicyclic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are selected from 0, S and N, and which has in particular 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms 5 as ring members besides carbon atoms as ring members: for example C-bonded, 5-membered monocyclic hetaryl having 1, 2 or 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, having 1, 2 or 3 nitrogen atoms as ring members, such as: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, 10 pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl, oxazol 4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol 2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4 15 thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, tetrazol-5-yl. C-bonded, 6-membered monocyclic hetaryl having 1, 2 or 3 nitrogen atoms as ring members, such as: pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin 20 2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin 3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl. N-bonded, 5-membered heteroaromatic radicals having 1, 2, 3 or 4 nitrogen atoms as ring members, such as: pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 25 tetrazol-1-yl. bicyclic 8-, 9- 10-membered hetaryl, hetaryl which has one of the aforementioned 5- or 6-membered heteroaromatic rings and a further aromatic carbocycle or 5- or 6-membered heterocycle fused thereto, for example a fused benzene, thiophene, furane, pyrrole, pyrazole, imidazole, pyridine or pyrimidine ring. These bicyclic 30 hetaryl include for example quinolinyl, isoquinolinyl, cinnolinyl, indolyl, indolizynyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[1,2-a]pyridine-2-yl, WO 2013/068489 PCT/EP2012/072175 27 thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5 a]pyridine-2-yl. Hetarylalkyl: a hetaryl radical as defined above which is linked via an alkylene group, in particular via a methylene, 1,1-ethylene or 1,2-ethylene group, to the 5 remainder of the molecule. 5- to 6-membered hetaryl-C1-C 4 -alkoxy: a C1-C 4 -alkoxy group as defined above which carries a 5-to 6-membered hetaryl radical as defined above, where the hetaryl radical has ordinarily 1, 2 or 3, in particular 1 or 2, heteroatoms as ring members which are selected from 0, S and N. Examples are furan-2-ylmethoxy, furan-3-ylmethoxy, 10 furan-2-ylethoxy, furan-3-ylethoxy, thiophen-2-ylmethoxy, thiophen-3-ylmethoxy, thiophen-2-ylethoxy and thiophen-3-ylethoxy.The expression "optionally substituted" in the context of the present invention means that the respective moiety is unsubstituted or has 1, 2 or 3, in particular 1, substituents which are selected from halogen, CI-C 4 -alkyl, C1-C 4 -haloalkyl, OH, SH, CN, CF 3 , O-CF 3 , COOH, O-CH 2 -COOH, C1-C 6 -alkoxy, C 1 15 C 4 -haloalkoxy, CI-C-alkylthio, C 3
-C
7 -cycloalkyl, COO-CI-C-alkyl, CONH 2 , CONH
C
1
-C
6 -alkyl, SO 2
NH-C
1
-C
6 -alkyl, CON-(C 1
-C
6 -alkyl) 2 , SO 2
N-(C
1
-C
6 -alkyl) 2 , NH-SO 2 CI-C-alkyl, NH-CO-C1-C 6 -alkyl, S0 2 -CI-C-alkyl, 0-phenyl, O-CH 2 -phenyl, CONH phenyl, SO 2 NH-phenyl, CONH-hetaryl, SO 2 NH-hetaryl, S0 2 -phenyl, NH-S0 2 -phenyl, NH-CO-phenyl, NH-S0 2 -hetaryl and NH-CO-hetaryl, where phenyl and hetaryl in the 20 last 11 radicals mentioned are unsubstituted or may have 1, 2 or 3 substituents which are selected from halogen, CI-C 4 -alkyl, C1-C 4 -haloalkyl, C1-C 4 -alkoxy and C 1
-C
4 haloalkoxy. In particular embodiments of the invention, Rh is selected from the group consisting of halogen, CN, OH, C 1
-C
4 -alkyl, fluorinated C 1
-C
4 -alkyl, C 1
-C
4 -alkoxy, 25 fluorinated C 1
-C
4 -alkoxy, C 3
-C
6 -cycloalkyl, fluorinated C 3
-C
6 -cycloalkyl, N(R)(Rc), C1-C 4 -alkyl-N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (R) and
S(O)
2 N(Re)(R). 1 2 1 2 In relation to their use as inhibitors of PDE1OA, the variables X1, X , Y, R1, R, R3 and R4 in formula I preferably have the following meanings, where these represent, 30 both considered on their own and in combination with at least one other or all, special embodiments of the compounds of the formula I: WO 2013/068489 PCT/EP2012/072175 28 R' is preferably C 2 -Cs-alkyl, C 3 -Cs-cycloalkyl or C 3 -Cs-cycloalkylmethyl, in particular C 3 -Cs-cycloalkylmethyl or especially C 2 -Cs-alkyl. Particularly, R 1 is alkyl of the formula CHRiaRi", where Ria is selected from the group consisting of hydrogen and
CI-C
3 -alkyl, in particular methyl, ethyl, n-propyl and where Rlb is selected from the 5 group consisting of CI-C 4 -alkyl, in particular methyl, ethyl, n-propyl or n-butyl. Particular examples of R 1 are selected from the group consisting of ethyl, isopropyl, 1 methylpropyl and 1-ethylpropyl. Particular embodiments of the invention also relate to compounds, where R1 is a moiety Z 1 -Ar 1 , where Z' and Ar are as defined above and where Z' is preferably 1,2 10 ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z' is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted. In these embodiments, Ar is preferably monocyclic 6-membered hetaryl or bicyclic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S 15 and N, where mono- and bicyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh Ar is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally 20 a further heteroatom selected from 0, S and N as ring member, where monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents R, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 cycloalkyl, and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected 25 from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. Ar1 is in particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom 30 selected from 0, S and N as ring member and which may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar WO 2013/068489 PCT/EP2012/072175 29 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z'. Amongst these, particular preference is given to those, where Ar is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a 5 further heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, CI-C 4 -alkyl, C1
C
2 -fluoroalkyl, C 1
-C
4 -alkoxy, C 1
-C
2 -fluoralkoxy, C 3
-C
6 -cycloalkyl and fluorinated C 3 C 6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, 10 fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. Particular examples of Ar are selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3 isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin 15 2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2 yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rh as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, 20 difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl. In particular embodiments, R 2 is a radical of the formula CR 21 R R , where R 21 ,
R
2 2 and R 23 are as defined above and where R 21 is in particular different from hydrogen. In other particular embodiments, R 2 is a phenyl or 5- or 6-membered hetaryl 25 radical having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra as defined above. In the particular embodiments, where R 2 is a radical of the formula CR 2 1
R
22
R
23 , where R 21 , R 22 and R 23 are as defined above or where R 2 is a phenyl or 5- or 6 30 membered hetaryl radical having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra as defined above, the radical R 3 WO 2013/068489 PCT/EP2012/072175 30 is preferably selected from the group consisting of hydrogen and C1-C 4 -alkyl. In these embodiments, R3 is in particular hydrogen. In the particular embodiments, where R 2 is a radical of the formula CR 21
R
22
R
23 , a particular group of embodiments relates to compounds, where the radicals R 2 , R 2 and 5 R2 3 have the following meanings: R2 is selected from the group consisting of C1-Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, C 1
-C
4 -alkoxy
CI-C
4 -alkyl, hydroxy-C1-C 4 -alkyl, C 1
-C
4 -alkyl-N(Rb)(Rc), (CH 2 )mC(O)O-Rd 10 (CH 2 )mC(O)N(Re)(R) and Z 2 -Ar 2 , R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, C 2
-C
8 alkenyl, C 1
-C
4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, C 1
-C
4 -alkoxy
CI-C
4 -alkyl, hydroxy-C1-C 4 -alkyl and C 1
-C
4 -alkyl-N(Rb)(Rc), or 15 R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl and C 1 C 4 -fluoroalkyl; In the particular embodiments, where R 2 is a radical of the formula CR RR 2 , a particular group of embodiments relates to compounds, where the radicals R 2 , R 2 and
R
2 3 preferably have the following meanings, both considered on their own and in 20 combination with at least one other or all: R2 is selected from the group consisting of C 2 -Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl and Z 2 -Ar 2 , where Z 2 and Ar 2 , where Z 2 and Ar 2 are as defined above and where Z 2 is 25 preferably a single bond or CH 2 and Ar 2 is preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or different substituents Rh. R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, in particular hydrogen; and 30 R 2 3 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In the particular embodiments, where R 2 is a radical of the formula CR R
R
2 , a particular group of embodiments relates to compounds, where the radicals R 21 , R 22 and WO 2013/068489 PCT/EP2012/072175 31
R
2 3 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R2 is selected from the group consisting of C 2 -Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 5 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, and where R 21 is in particular C 2
-C
4 -alkyl; R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, in particular methyl or hydrogen; and
R
2 3 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. 10 In the particular embodiments, where R 2 is a radical of the formula CR R R, another particular group of embodiments relates to compounds, where the radicals R 21 ,
R
2 2 and R 23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R2 is a radical Z 2 -Ar 2 , where Z 2 and Ar 2 are as defined above and where Z 2 is 15 preferably a single bond or CH 2 and Ar 2 is preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or different substituents Rh, particular examples of R 21 being 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4 methoxyphenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 20 thiazol-2-yl, thiazol-4-yl, 1,3,4-thiadiazol-2-yl, 2-(1-morpholinosulfonyl)phenyl, 3-(1-morpholinosulfonyl)phenyl, 2-(4-methylpiperazin-1-ylsulfonyl)phenyl or 3 (4-methylpiperazin- 1 -ylsulfonyl)phenyl. R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, in particular methyl or hydrogen; and 25 R 23 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In the particular embodiments, where R 2 is a radical of the formula CR 2 R 22
R
2 3 , a further group of embodiments relates to compounds, where the radicals R 21 and R2 together with the carbon atom, to which they are bound form a saturated 5-, 6- or 7 membered carbocyclic ring, such as cyclopentyl, cyclohexyl or cycloheptyl, especially 30 cyclopentyl, or a saturated 5-, 6- or 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, especially 2- or 3-tetrahydrofuryl or 2- or 3- WO 2013/068489 PCT/EP2012/072175 32 tetrahydrothienyl, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R9, and where the carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are 5 unsubstituted or carry 1, 2 or 3 substituents Rh, and where R9, Rh and R 2 3 are as defined above and where R is in particular hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In the particular embodiments, where R 2 is a radical of the formula CR 2 1
R
22
R
23 , a further particular group of embodiments relates to compounds, where the radicals R 2 1 , 10 R 22 and R 23 preferably have the following meanings, both considered on their own and in combination with at least one other or all:
R
2 1 and R 22 together with the carbon atom, to which they are bound form a saturated 5-, 6- or 7-membered carbocyclic radical, namely a cyclopentyl, cyclohexyl or cycloheptyl radical or a 3-tetrahydrofuryl or 3-tetrahydrothienyl, where the 5- to 15 7-membered carbocyclic ring and the 3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, such as a fused thiophene or pyridine ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, and where R 21 and R 22 in particular form a bicyclic radical selected from the group consisting of 5-indanyl, 20 6-indanyl, 5,6,7,8-tetrahydronaphthalin-5-yl, 5,6,7,8-tetrahydronaphthalin-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl, 6,7,8,9-tetrahydro-5H benzocycloheptene-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophene-4-yl, 6,7 dihydro-5H-[1]-pyrindin-6-yl, 3,4-dihydrobenzofuran-3-yl, 2,3 dihydrobenzothiophen-3-yl or where these bicyclic radicals are in particular 25 unsubstituted or where the aromatic moiety of these rings carry 1, 2 or 3 substituents Rh;
R
2 3 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In further particular embodiments of the invention R 2 and R 3 together with the nitrogen atom, to which they are bound form a saturated 4-, 5-, 6- or 7-membered 30 heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, e.g. a pyrrolidine, piperidine, morpholine, thiomorpholine or WO 2013/068489 PCT/EP2012/072175 33 piperazine ring, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R3, and where the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, such as a thiophene or pyridine ring, where the fused rings themselves are unsubstituted or carry 5 1, 2 or 3 substituents R , where R 31 and R are as defined defined above. R3 is in particular selected from the group consisting of CI-C 4 -alkyl, C 1
-C
4 alkoxy, halogen, phenyl and phenoxy, where the phenylring in the last two mentioned radicals itself is unsubstituted or carries 1 or 2 radicals selected from the group consisting of CI-C 4 -alkyl, C 1
-C
4 -alkoxy, halogen. 10 R is in particular selected from the group consisting of CI-C 4 -alkyl, C 1
-C
4 alkoxy and halogen. R4 is preferably C1-C 4 -alkyl and especially methyl. Y is preferably 0. A particular group of embodiments of the invention relates to compounds of the 15 formula I, to their salts, N-oxides, tautomers, hydrates and prodrugs and to the salts of said N-oxides, tautomers, hydrates and prodrugs, where X 2 is C-R 5 . In this particular group of embodiments R 5 is preferably selected from the group consisting of hydrogen, fluorine, CI-C 4 -alkoxy or a radical O-Z 5 -Ar 5 , especially hydrogen, fluorine, methoxy or a radical O-Z 5 -Ar 5 . Amongst these compounds a first embodiment relates to compounds 20 of the formula I, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R 5 is hydrogen, fluorine, OH or CI-C 4 -alkoxy, especially hydrogen, fluorine, OH or methoxy, with methoxy being particularly preferred. Amongst these compounds a second embodiment relates to compounds of the 25 formula I, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R 5 is a radical O-Z 5 -Ar 5 . In this second embodiment R4 is in particular CI-C 4 -alkyl, especially methyl. In the second embodiment, Z 5 is preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a 30 specific embodiment, Z 5 is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted.
WO 2013/068489 PCT/EP2012/072175 34 In the second embodiment, Ar' is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, 5 where monocyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 identical or different substituents Rk, in particular 0, 1 or 2 substituents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent R , and 0, 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 10 cycloalkyl, and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. Ar 5 is in particular selected from the group consisting of fused bicyclic hetaryl, 15 which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member and which may be unsubstituted or may carry 1 substituent R and/or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar 5 radical has at least one imino-nitrogen as ring member, 20 which is located in the position adjacent to carbon atom bound to the group Z 5 . Amongst these, particular preference is given to those, where Ar 5 is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1 substituent R 25 and/or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C 1
-C
4 alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 -cycloalkyl and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, 30 trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. Particular examples of Ar 5 are selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3- WO 2013/068489 PCT/EP2012/072175 35 isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin 2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2 yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are 5 unsubstituted or may carry 1, 2 or 3 radicals Rh as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl. Amongst these compounds a third embodiment relates to compounds of the 10 formula I, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R4 is a radical Z 4 -Ar 4 . In this third embodiment R 5 is in particular hydrogen, fluorine or C1-C 4 -alkoxy, especially methoxy. In the third embodiment, Z 4 is preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a 15 specific embodiment, Z 4 is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted. In the third embodiment, Ar 4 is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring 20 members and optionally a further heteroatom selected from 0, S and N as ring member, where monocyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 identical or different substituents Rk, in particular 0, 1 or 2 substituents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent R , and 0, 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from 25 halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 cycloalkyl, and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. 30 Ar 4 is in particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member and which may be unsubstituted or may carry WO 2013/068489 PCT/EP2012/072175 36 1 substituent R and/or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar 4 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z 4 . 5 Amongst these, particular preference is given to those, where Ar 4 is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1 substituent R and/or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this 10 regard, Rh is preferably selected from halogen, CI-C 4 -alkyl, C1-C 2 -fluoroalkyl, C 1
-C
4 alkoxy, CI-C 2 -fluoralkoxy, C 3
-C
6 -cycloalkyl and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. 15 Particular examples of Ar 4 are selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3 isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5-naphthyridin-2-yl, 1,8-naphthyridin 2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2 yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2-b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl 20 and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rh as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl. 25 A first group of embodiments of the invention relates to compounds of the formula I, to their salts, N-oxides, tautomers, hydrates and prodrugs and to the salts of said N-oxides, tautomers, hydrates and prodrugs, where X 1 is C-H and X 2 is C-R 5 . In this first group, Y, R1, R2, R3, R 4 and R 5 are as defined above and preferably have the preferred or particular or special meanings given above. Amongst these compounds, a 30 particular group of embodiments is represented by the following formula Ia WO 2013/068489 PCT/EP2012/072175 37 0 R4 1 R-O
N
5 (la) R5 S N'2 1 3 R where R 1 , R 2 , R3, R4 and R 5 are as defined above. A second group of embodiments of the invention relates to compounds of the formula I, to their salts, N-oxides, tautomers, hydrates and prodrugs and to the salts of 5 said N-oxides, tautomers, hydrates and prodrugs, where X 1 is N and X 2 is C-R 5 . In this second group, Y, R1, R2, R3, R4 and R 5 are as defined above and preferably have the preferred or particular or special meanings given above. Amongst these compounds, a particular group of embodiments is represented by the following formula Ib 0 R4 1 "R1 R-O N' 5 (Ib) R5N S N'2 1 3 R 10 where R 1 , R 2 , R3, R4 and R 5 are as defined above. A particular group of embodiments of the invention relates to compounds of the formulae Ta and Tb, to their salts, N-oxides, tautomers, hydrates and prodrugs and to the salts of said N-oxides, tautomers, hydrates and prodrugs, where R 5 is preferably selected from the group consisting of hydrogen, fluorine, C1-C 4 -alkoxy or a radical O-Z 5 -Ar5, 15 especially hydrogen, fluorine, methoxy or a radical O-Z 5 -Ar 5 . Amongst these compounds a first embodiment relates to compounds of the formulae Ta and Ib, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R 5 is hydrogen, fluorine, OH or C1-C 4 -alkoxy, especially hydrogen, fluorine, OH or methoxy, with methoxy being particularly preferred. 20 Amongst these compounds a second embodiment relates to compounds of the formula Ta and Tb, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R is a radical O-Z 5 -Ar 5 , where Z 5 and Ar are WO 2013/068489 PCT/EP2012/072175 38 as defined above and having in particular the preferred, particular or special meanings given above. In this second embodiment R4 is in particular CI-C 4 -alkyl, especially methyl. In the second embodiment of formulae Ta and Tb, Z 5 is preferably 1,2-ethanediyl 5 or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z 5 is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted. In the second embodiment of formulae Ta and Ib, Ar 5 is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 10 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where monocyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 identical or different substituents Rk, in particular 0, 1 or 2 substituents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent R , and 0, 1, 2 or 3 15 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, CI-C 4 -alkyl, CI-C 2 -fluoroalkyl, CI-C 4 -alkoxy, CI-C 2 fluoralkoxy, C 3
-C
6 -cycloalkyl, and fluorinated C 3
-C
6 -cycloalkyl. In this regard, R is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 20 cyclopropyl and fluorinated cyclopropyl. In the second embodiment of formulae Ta and Tb, Ar 5 is in particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member and which may be unsubstituted, or may carry 1 substituent Rk and/or may carry 1, 2 or 25 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar 5 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z 5 . Amongst these, particular preference is given to those, where Ar5 is selected from the group consisting of C-bound, fused bicyclic 30 hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted, or may carry 1 substituent Rk and/or may carry 1, 2 or 3 substituents R, WO 2013/068489 PCT/EP2012/072175 39 in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, CI-C 4 -alkyl, Ci-C 2 -fluoroalkyl, Ci-C 4 -alkoxy, CI-C 2 -fluoralkoxy, C 3
-C
6 cycloalkyl and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 5 methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. In the second embodiment of formulae Ta and Tb, Ar 5 is e.g. selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5 10 naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2 b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rh as defined above, which are in particular selected from the group consisting of fluorine, 15 chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl. Amongst these compounds a third embodiment relates to compounds of the formula Ta and Ib, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R4 is a radical Z 4 -Ar 4 , where Z 4 and Ar 4 are as 20 defined above and having in particular the preferred, particular or special meanings given above. In this third embodiment R 5 is in particular hydrogen, fluorine or in particular CI-C 4 -alkoxy, especially methoxy. In the third embodiment of formulae Ta and Tb, Z 4 is preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine 25 atom. According to a specific embodiment, Z 4 is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted. In the third embodiment of formulae Ta and Tb, Ar 4 is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen 30 atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where monocyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents R , in particular 0, 1 or 2 substituents Rk and bicyclic hetaryl may be WO 2013/068489 PCT/EP2012/072175 40 unsubstituted or may carry 1 substituent Rk, and 0, 1,2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, CI-C 4 alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 -cycloalkyl, and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, 5 chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. In the third embodiment of formulae Ta and Tb, Ar 4 is in particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring 10 members and optionally a further heteroatom selected from 0, S and N as ring member and which may be unsubstituted, or may carry 1 substituent Rk and/or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar 4 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to 15 carbon atom bound to the group Z 4 . Amongst these, particular preference is given to those, where Ar 4 is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted, or may carry 1 substituent Rk and/or may carry 1, 2 or 3 substituents R, 20 in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 cycloalkyl and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and 25 fluorinated cyclopropyl. In the third embodiment of formulae Ta and Ib, Ar 4 is e.g. selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3 pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5 naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, 30 benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2 b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rh WO 2013/068489 PCT/EP2012/072175 41 as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl. A third group of embodiments of the invention relates to compounds of the 5 formula I, to their salts, N-oxides, tautomers, hydrates and prodrugs and to the salts of said N-oxides, tautomers, hydrates and prodrugs, where X 1 is C-H and X 2 is N. In this third group, Y, R 1 , R 2 , R3 and R4 are as defined above and preferably have the preferred or particular or special meanings given above. Amongst these compounds, a particular group of embodiments is represented by the following formula Ic 0 R4 1 R-O N1 (Ic) N 2 0 N 13 10 R where R 1 , R 2 , R3 and R4 are as defined above. A fourth group of embodiments of the invention relates to compounds of the formula I, to their salts, N-oxides, tautomers, hydrates and prodrugs and to the salts of said N-oxides, tautomers, hydrates and prodrugs, where X 1 is N and X 2 is N. In this 15 second group, Y, R1, R2, R3 and R4 are as defined above and preferably have the preferred or particular or special meanings given above. Amongst these compounds, a particular group of embodiments is represented by the following formula Id 0 R4 1 R-O N N N I- (Id) 2 0 N 1 3 R where R 1 , R 2 , R3, R4 and R 5 are as defined above. 20 In relation to their use as inhibitors of PDE1OA, the variables R 1 , R 2 , R3 and R4 in formulae Ia, Ib, Ic and Id preferably have the following meanings, where these WO 2013/068489 PCT/EP2012/072175 42 represent, both considered on their own and in combination with at least one other or all, special embodiments of the compounds of the formula I: In formulae Ta, Tb, Ic and Id, R 1 is preferably C 2 -Cs-alkyl, C 3 -Cs-cycloalkyl or C 3 Cs-cycloalkylmethyl, in particular C 3 -Cs-cycloalkylmethyl or especially C 2 -Cs-alkyl. alb 5 Particularly, R 1 is alkyl of the formula CHRiR' , where Ria is selected from the group consisting of hydrogen and C1-C 3 -alkyl, in particular methyl, ethyl, n-propyl and where Rib is selected from the group consisting of CI-C 4 -alkyl, in particular methyl, ethyl, n propyl or n-butyl. Particular examples of R 1 are selected from the group consisting of ethyl, isopropyl, 1-methylpropyl and 1-ethylpropyl. 10 In formulae Ta, Ib, Ic and Id, R 1 is likewise preferably a moiety Z-Ar 1 , where Z and Ar are as defined above and where Z 1 is preferably 1,2-ethanediyl or 1,3 propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z 1 is 1,2-ethanediyl which is unsubstituted or 1,3 propanediyl which is unsubstituted. 15 In formulae Ta, Tb, Ic and Id, where R 1 is a moiety Z 1 -Ar 1 , Ar is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where monocyclic hetaryl and bicyclic hetaryl may be 20 unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents R. Ar is in particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member and which may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. 25 Amongst these, particular preference is given to those compounds, where the Ar radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z 1 . Amongst these, particular preference is given to those, where Ar is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a 30 further heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, CI-C 4 -alkyl, C 1
-
WO 2013/068489 PCT/EP2012/072175 43
C
2 -fluoroalkyl, C 1
-C
4 -alkoxy, C 1
-C
2 -fluoralkoxy, C 3
-C
6 -cycloalkyl and fluorinated C 3 C 6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. 5 In particular embodiments of formulae Ta, Tb, Ic and Id, R 2 is a radical of the formula C 2 1
R
22
R
2 3 , where R 21 , R 22 and R 23 are as defined above and where R 21 is in particular different from hydrogen. In other particular embodiments of formulae Ta, Ib, Ic and Id, R 2 is a phenyl or 5 or 6-membered hetaryl radical having 1, 2 or 3 heteroatoms as ring members which are 10 selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra as defined above. In the particular embodiments of formulae Ta, Tb, Ic and Id, where R2 is a radical of the formula CR 2 R R2, where R 21 , R 22 and R 23 are as defined above or where R2 is a phenyl or 5- or 6-membered hetaryl radical having 1, 2 or 3 heteroatoms as ring 15 members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra as defined above, the radical R3 is preferably selected from the group consisting of hydrogen and
CI-C
4 -alkyl. In these embodiments, R 3 is in particular hydrogen. In the particular embodiments of formulae Ta, Tb, Ic and Id, where R 2 is a radical 20 of the formula CR 2 R R , a particular group of embodiments relates to compounds, where the radicals R2, R2 and R 23 have the following meanings: R2 is selected from the group consisting of C1-Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, C1-C 4 -alkoxy 25 CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl, CI-C 4 -alkyl-N(Rb)(Rc), (CH 2 )mC(O)O-Rd
(CH
2 )mC(O)N(Re)(R) and Z 2 -Ar 2 , R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, C 2
-C
8 alkenyl, C 1
-C
4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, C1-C 4 -alkoxy 30 CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl and CI-C 4 -alkyl-N(Rb)(Rc), or R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl and C 1 C 4 -fluoroalkyl; WO 2013/068489 PCT/EP2012/072175 44 In the particular embodiments of formulae Ia, Ib, Ic and Id, where R 2 is a radical of the formula CR 2 R R , a particular group of embodiments relates to compounds, where the radicals R2, R2 and R 23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: 5 R2 is selected from the group consisting of C 2 -Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl,
C
1
-C
4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl and Z 2 -Ar 2 , where Z 2 and Ar 2 , where Z 2 and Ar 2 are as defined above and where Z 2 is preferably a single bond or CH 2 and Ar 2 is preferably phenyl, pyridyl, 10 pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or different substituents Rh. R is selected from the group consisting of hydrogen, fluorine, C 1 -Cs-alkyl, in particular hydrogen; and
R
2 3 is hydrogen or C 1
-C
4 -alkyl, such as methyl, or especially hydrogen. 15 In the particular embodiments of formulae Ta, Ib, Ic and Id, where R2 is a radical of the formula CR 2 R R , a particular group of embodiments relates to compounds, where the radicals R2, R2 and R 23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R2 is selected from the group consisting of C 2 -Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, 20 C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3
-C
8 cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, and where R2 is in particular C 2
-C
4 -alkyl; R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, in particular methyl or hydrogen; and 25 R 23 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In the particular embodiments of formulae Ta, Ib, Ic and Id, where R2 is a radical of the formula CR 2 R R , another particular group of embodiments relates to compounds, where the radicals R 21 , R 2 2 and R 23 preferably have the following meanings, both considered on their own and in combination with at least one other or 30 all: R2 is a radical Z 2 -Ar 2 , where Z 2 and Ar 2 , where Z 2 and Ar 2 are as defined above and where Z 2 is preferably a single bond or CH 2 and Ar 2 is preferably phenyl, pyridyl, WO 2013/068489 PCT/EP2012/072175 45 pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or different substituents Rh, particular examples of R 2 ' being 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4 methoxyphenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 5 thiazol-2-yl, thiazol-4-yl, 1,3,4-thiadiazol-2-yl, 2-(1-morpholinosulfonyl)phenyl, 3-(1-morpholinosulfonyl)phenyl, 2-(4-methylpiperazin-1-ylsulfonyl)phenyl or 3 (4-methylpiperazin- 1 -ylsulfonyl)phenyl. R is selected from the group consisting of hydrogen, fluorine, C1-Cs-alkyl, in particular methyl or hydrogen; and 10 R 2 3 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In the particular embodiments of formulae Ia, Ib, Ic and Id, where R is a radical of the formula CR 2 RR , a further group of embodiments relates to compounds, where the radicals R 21 and R 22 together with the carbon atom, to which they are bound form a saturated 5-, 6- or 7-membered carbocyclic ring, such as cyclopentyl, cyclohexyl 15 or cycloheptyl, especially cyclopentyl, or a saturated 5-, 6- or 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, especially 2- or 3-tetrahydrofuryl or 2 or 3-tetrahydrothienyl, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R9, 20 and where the carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, and where R9, Rh and R 23 are as defined above and where R is in particular hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. 25 In the particular embodiments of formulae Ia, Ib, Ic and Id, where R 2 is a radical of the formula CR 2 RR , a further particular group of embodiments relates to compounds, where the radicals R 21 , R 2 2 and R 23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: 30 R 2 1 and R 22 together with the carbon atom, to which they are bound form a saturated 5-, 6- or 7-membered carbocyclic radical, namely a cyclopentyl, cyclohexyl or cycloheptyl radical or a 3-tetrahydrofuryl or 3-tetrahydrothienyl, where the 5 to 7 WO 2013/068489 PCT/EP2012/072175 46 membered carbocyclic ring and the 3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, such as a fused thiophene or pyridine ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, and where R 2 1 and R 22 in 5 particular form a bicyclic radical selected from the group consisting of 5-indanyl, 6-indanyl, 5,6,7,8-tetrahydronaphthalin-5-yl, 5,6,7,8-tetrahydronaphthalin-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-yl, 6,7,8,9-tetrahydro-5H benzocycloheptene-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophene-4-yl, 6,7 dihydro-5H-[1]-pyrindin-6-yl, 3,4-dihydrobenzofuran-3-yl, 2,3 10 dihydrobenzothiophen-3-yl or where these bicyclic radicals are in particular unsubstituted or where the aromatic moiety of these rings carry 1, 2 or 3 substituents Rh;
R
2 3 is hydrogen or CI-C 4 -alkyl, such as methyl, or especially hydrogen. In further particular embodiments of the invention R2 and R 3 together with the 15 nitrogen atom, to which they are bound form a saturated 4-, 5-, 6- or 7-membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, e.g. a pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine ring, where the heterocyclic ring may be unsubstituted or may be substituted 20 by 1, 2 or 3 identical or different substituents R3, and where the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, such as a thiophene or pyridine ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents R , where R 31 and R are as defined defined above. R3 is in particular selected from the group consisting of CI-C 4 -alkyl, C 1
-C
4 25 alkoxy, halogen, phenyl and phenoxy, where the phenylring in the last two mentioned radicals itself is unsubstituted or carries 1 or 2 radicals selected from the group consisting of CI-C 4 -alkyl, C1-C 4 -alkoxy, halogen. R is in particular selected from the group consisting of CI-C 4 -alkyl, C 1
-C
4 alkoxy and halogen. 30 In formulae Ia, Ib, Ic and Id, a particular embodiment relates to compounds where
R
4 is CI-C 4 -alkyl and especially methyl.
WO 2013/068489 PCT/EP2012/072175 47 In formulae Ta, Tb, Ic and Id, another particular embodiment relates to compounds where R4 is a radical Z 4 -Ar 4 , where Z 4 and Ar 4 are as defined above and having in particular the preferred, particular or special meanings given above. In this embodiment in formulae Ta and Ib R 5 is in particular hydrogen, fluorine or in particular C 1
-C
4 5 alkoxy, especially methoxy. In this embodiment of formulae Ta, Ib, Ic and Id, Z 4 is preferably 1,2-ethanediyl or 1,3-propanediyl, wherein 1, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z 4 is 1,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted. 10 In this embodiment of formulae Ta, Tb, Ic and Id, Ar 4 is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from 0, S and N as ring member, where monocyclic hetaryl may be unsubstituted or may carry 1, 15 2 or 3 identical or different substituents Rk, in particular 0, 1 or 2 substituents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent R , and 0, 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, CI-C 2 fluoralkoxy, C 3
-C
6 -cycloalkyl, and fluorinated C 3
-C
6 -cycloalkyl. In this regard, R is in 20 particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. In this embodiment of formulae Ta, Tb, Ic and Id, Ar 4 is in particular selected from the group consisting of fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring 25 members and optionally a further heteroatom selected from 0, S and N as ring member and which may be unsubstituted, or may carry 1 substituent Rk and/or may carry 1, 2 or 3 substituents Rh, in particular 0, 1 or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar 4 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to 30 carbon atom bound to the group Z 4 . Amongst these, particular preference is given to those, where Ar 4 is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further WO 2013/068489 PCT/EP2012/072175 48 heteroatom selected from 0, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1 substituent Rk and/or may carry 1, 2 or 3 substituents R, in particular 0, 1 or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C 4 -alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 5 cycloalkyl and fluorinated C 3
-C
6 -cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. In this embodiment of formulae Ta, Tb, Ic and Id, Ar 4 is e.g. selected from the 10 group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5 naphthyridin-2-yl, 1,8-naphthyridin-2-yl, benzothiazol-1-yl, benzoxazol-1-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, imidazo[1,2-a]pyridine-2-yl, thieno[3,2 b]pyridine-5-yl, imidazo-[2,1-b]-thiazol-6-yl and 1,2,4-triazolo[1,5-a]pyridine-2-yl, 15 where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rh as defined above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl. Apart from that, the variables Ar 3 , Z 3 , Z 4 , Ra, Re R, Rd, R, Rf, Rg, Rh and Rk 20 preferably have, irrespectively of their occurrence and with regard to the formulae I, Ta, Tb, Ic and Id and with regard to each of the above mentioned embodiments groups of embodiments one of the following meanings: Ar 3 is preferably phenyl, which is unsubstituted or substituted by 1, 2 or 3 radicals Rh. 25 Z 3 is preferably a single bond, CH 2 or CH 2
CH
2 .
Z
4 is preferably CH 2 or CH 2
CH
2 . Ra is preferably halogen, in particular fluorine, CI-C 4 -alkyl, C1-C 4 -alkoxy, C1
C
4 -fluoroalkyl, C 1
-C
4 -fluoroalkoxy, N(R)(Rc), CH 2 N(R)(R), or S(0) 2 N(R)(R), Rb is preferably hydrogen or C1-C4-alkyl; 30 Rc is preferably hydrogen or CI-C 4 -alkyl; or R and Rc together with the nitrogen atom to which they are bound may also form a saturated N-bound heterocyclic radical, selected from the group consisting of WO 2013/068489 PCT/EP2012/072175 49 pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl and 4-methylpiperazin-1-yl, where the 6 aforementioned heterocyclic radicals may carry 1, 2, 3 or 4 substituents, selected from methyl and fluorine. Rd is preferably CI-C 4 -alkyl. 5 Re is preferably hydrogen or CI-C 4 -alkyl; Rf is preferably hydrogen or CI-C 4 -alkyl; or Re and Rf together with the nitrogen atom to which they are bound may also form a saturated N-bound heterocyclic radical, selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl and 10 4-methylpiperazin-1-yl, where the 6 aforementioned heterocyclic radicals may carry 1, 2, 3 or 4 substituents, selected from methyl and fluorine. R9 is preferably halogen, in particular fluorine, CI-C 4 -alkyl, C1-C 4 -alkoxy, C 1 C 4 -fluoroalkyl or C 1
-C
4 -fluoroalkoxy. Rh is preferably halogen, in particular fluorine, CI-C 4 -alkyl, C1-C 4 -alkoxy, C 1 15 C 4 -fluoroalkyl, C1-C 4 -fluoroalkoxy, C 3
-C
6 -cycloalkyl, fluorinated C 3
-C
6 -cycloalkyl, N(R)(R), CH 2 N(R)(R) or S(O) 2 N(Re)(Rf). In addition, Rh is preferably CI-C 2 alkylsulfanyl, C 1
-C
2 -alkoxy-C1-C 4 -alkoxy, C 3
-C
6 -cycloalkoxy, C 3
-C
6 -cycloalkyl-C1-C 2 alkoxy, phenoxy, 3- to 7-membered heterocyclyloxy, 3- to 7-membered heterocyclyl C1-C 2 -alkoxy, where heterocyclyl in the two last mentioned radicals has 1 or 2 20 heteroatoms as ring members which are selected from 0, S and N, and 5- to 6 membered hetaryl-C1-C 2 -alkoxy, where hetaryl has 1 or 2 heteroatoms as ring members which are selected from 0, S and N. Rh is in particular selected from halogen, C 1
-C
4 alkyl, C1-C 2 -fluoroalkyl, C1-C 4 -alkoxy, C1-C 2 -fluoralkoxy, C 3
-C
6 -cycloalkyl and fluorinated C 3
-C
6 -cycloalkyl. Rh is especially selected from fluorine, chlorine, methyl, 25 fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl. R is preferably halogen, in particular fluorine, CI-C 4 -alkyl, CI-C 4 -alkoxy, C 1 C 4 -fluoroalkyl or C 1
-C
4 -fluoroalkoxy. Particular embodiments of the invention relates to the compounds of formula I, to 30 the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the pharmaceutically suitable salts thereof, where the compounds of the formula I are selected from the group consisting of: WO 2013/068489 PCT/EP2012/072175 50 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methylamide, 5 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylmethyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl phenethyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 10 methoxy-benzyl)-methyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 methoxy-benzyl)-methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 methoxy-benzyl)-methyl-amide, 15 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl (3-trifluoromethyl-benzyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzyl (2-dimethylamino-ethyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 20 benzyl-piperidin-4-yl)-methyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid tert butylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid sec butylamide, 25 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isobutyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopentylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 30 methyl-butyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1,1 dimethyl-propyl)-amide, WO 2013/068489 PCT/EP2012/072175 51 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1,2 dimethyl-propyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2,2 dimethyl-propyl)-amide, 5 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1-ethyl propyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 10 methyl-butyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid pentylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexylamide, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1,3 dimethyl-butyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3,3 dimethyl-butyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2-ethyl 20 butyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid dicyclopropylmethyl-amide, 25 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 fluoro-ethyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexylmethyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 30 phenyl-ethyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 fluoro-benzylamide, WO 2013/068489 PCT/EP2012/072175 52 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3 fluoro-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 4 fluoro-benzylamide, 5 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2,3 difluoro-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2,4 difluoro-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2,6 10 difluoro-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3,4 difluoro-benzylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2,2,2 trifluoro-ethyl)-amide, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3,5 difluoro-benzylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid phenethyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid [1-(4 20 fluoro-phenyl)-ethyl]-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 ylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan-2 ylamide, 25 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid [1-(4 fluoro-phenyl)- 1-methyl-ethyl] -amide, 4-(azetidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin- 1-one, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylamide, 30 2-ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1 one, 2-ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin- 1-one, WO 2013/068489 PCT/EP2012/072175 53 2-ethyl-4-(3-fluoro-pyrrolidine- 1 -carbonyl)-6,7-dimethoxy-2H-isoquinolin- 1-one, 2-ethyl-6,7-dimethoxy-4-(4-methyl-piperazine- 1 -carbonyl)-2H-isoquinolin- 1-one, 4-(3,3-difluoro-pyrrolidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1 one, 5 4-(3-dimethylamino-pyrrolidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 2-ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine- 1 -carbonyl)-2H isoquinolin-1-one, 4-(1,3-dihydro-isoindo le-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquino lin- 10 one, 4-(4,4-difluoro-piperidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquino linone, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isopropylamide, 15 2-ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1 one, 4-(4-dimethylamino-piperidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 2-ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine- 1 -carbonyl)-2H 20 isoquinolin-1-one, 4-(4-cyclopropylmethyl-piperazine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 2-ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin- 1 -ylmethyl-pyrrolidine- 1 -carbonyl) 2H-isoquinolin- 1-one, 25 2-ethyl-6,7-dimethoxy-4-(4-pyrrolidin- 1 -yl-piperidine- 1 -carbonyl)-2H isoquinolin-1-one, 4-[4-(2-dimethylamino-ethyl)-piperazine- 1 -carbonyl]-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 4-([1,4']bipiperidinyl- l'-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin- 1-one, 30 4-[4-(3-dimethylamino-propyl)-piperazine- 1 -carbonyl]-2-ethyl-6,7-dimethoxy 2H-isoquinolin- 1-one, WO 2013/068489 PCT/EP2012/072175 54 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid propylamide, 2-ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-2H isoquinolin-1-one, 5 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid dimethylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 10 isopropyl-methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid diethylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl propyl-amide, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl isopropyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid tert butyl-methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 20 isobutyl-methyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butyl methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl propyl-amide, 25 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 dimethylamino-ethyl)-methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl-(2 methoxy-ethyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 cyclopentyl-methyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butyl ethyl-amide, WO 2013/068489 PCT/EP2012/072175 55 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl pentyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid diisopropylamide, 5 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isopropyl-propyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclobutylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 10 dipropylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 dimethylamino-propyl)-methyl-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexyl-methyl-amide, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylmethyl-propyl-amide 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid diisobutylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzyl 20 methyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 fluoro-benzyl)-methyl-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 fluoro-benzyl)-methyl-amide, 25 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 fluoro-benzyl)-methyl-amide, 2-tert-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-sec-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 butylamide, 2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, WO 2013/068489 PCT/EP2012/072175 56 2-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-cyclopropylmethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 5 2-(2-dimethylamino-ethyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 2-cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid butylamide, 6,7-dimethoxy- 1 -oxo-2-(2,2,2-trifluoro-ethyl)- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide 6,7-dimethoxy- 1 -oxo-2-(2-pyrrolidin- 1 -yl-ethyl)- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 15 2-(2-fluoro-ethyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-(2,4-difluoro-benzyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 20 carboxylic acid butylamide, 2-cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 6,7-dimethoxy-1-oxo-2-(2-piperidin-1-yl-ethyl)-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 25 6,7-dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 6,7-dimethoxy-2-(2-methoxy-benzyl)- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 2-indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 butylamide, 2-isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, WO 2013/068489 PCT/EP2012/072175 57 6,7-dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 6,7-dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 5 6,7-dimethoxy-2-(2-methoxy-ethyl)- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 10 butylamide, 2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide, 2-ethyl-7-methoxy- 1 -oxo-6-(2-quinolin-2-yl-ethoxy)- 1,2-dihydro-isoquinoline-4 15 carboxylic acid butylamide, 2-ethyl-7-methoxy- 1 -oxo-6-(3-quinolin-2-yl-propoxy)- 1,2-dihydro-isoquino line 4-carboxylic acid butylamide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7,8,9 tetrahydro-5H-benzocyclohepten-7-yl)-amide, 20 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (R) indan- 1 -ylamide, 2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid indan- 1 -ylamide, 2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid 25 butylamide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7,8,9 tetrahydro-5H-benzocyclohepten-5-yl)-amide, 30 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (1,2,3,4 tetrahydro-naphthalen-2-yl)-amide, WO 2013/068489 PCT/EP2012/072175 58 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (1,2,3,4 tetrahydro-naphthalen- 1 -yl)-amide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (4 bromo-indan- 1 -yl)-amide, 5 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (5 bromo-indan- 1 -yl)-amide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 2 dimethylaminomethyl-benzylamide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7 10 dihydro-5H-[1]pyrindin-5-yl)-amide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7 dihydro-5H-[1]pyrindin-7-yl)-amide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 3 dimethylaminomethyl-benzylamide, 15 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 4 dimethylaminomethyl-benzylamide, 7-methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 7-methoxy- 1 -oxo-2-(2-quinolin-2-yl-ethyl)- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid indan- 1 -ylamide, 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (S) indan- 1 -ylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, 25 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-dimethylaminomethyl-benzylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3,5-difluoro-benzylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid 3,4-difluoro-benzylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexylmethyl-amide, WO 2013/068489 PCT/EP2012/072175 59 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (R)-indan-1-ylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (S)-indan-1-ylamide, 5 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1,2,3,4 tetrahydro-naphthalen- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid pyridin 3-ylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 10 (pyrimidin-4-ylmethyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 methoxy-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 morpholin-4-yl-phenyl)-amide, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3 chloro-benzylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (pyridin-4-ylmethyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid o 20 tolylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid m tolylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 methoxy-phenyl)-amide, 25 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 methoxy-phenyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (pyridin-3-ylmethyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 (pyridin-2-ylmethyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 dimethylamino-propyl)-amide, WO 2013/068489 PCT/EP2012/072175 60 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid phenylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 4 methoxy-benzylamide, 5 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3 methyl-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 methyl-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 10 methoxy-ethyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 fluoro-phenyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 methoxy-phenyl)-amide, 15 2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid p tolylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 fluoro-phenyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 20 fluoro-phenyl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 4 methyl-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 chloro-benzylamide, 25 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid [(R)-1 (4-fluoro-phenyl)-ethyl]-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid pyridin 4-ylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-1 30 (4-fluoro-phenyl)-ethyl]-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (6 methyl-indan- 1 -yl)-amide, WO 2013/068489 PCT/EP2012/072175 61 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 morpholin-4-ylmethyl-benzylamide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (5 chloro-indan- 1 -yl)-amide, 5 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (6 chloro-indan- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (6 fluoro-indan- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (5,6 10 dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 fluoro-indan- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 methyl-indan- 1 -yl)-amide, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (5 methyl-indan- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (6 methoxy-indan- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (5 20 fluoro-indan- 1 -yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 diethylaminomethyl-benzylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 pyrrolidin- 1 -ylmethyl-benzylamide, 25 2-ethyl-6,7-dimethoxy-4-(4-methyl-piperidine- 1 -carbonyl)-2H-isoquino lin- 1-one, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 methoxy-propyl)-amide, 30 4-(3,5-dimethyl-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1 one, 2-ethyl-4-(4-ethyl-piperazine- 1 -carbonyl)-6,7-dimethoxy-2H-isoquinolin- 1-one, WO 2013/068489 PCT/EP2012/072175 62 2-isobutyl-6,7-dimethoxy-4-(4-methyl-piperazine- 1 -carbonyl)-2H-isoquinolin-1 one, 2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 dimethylamino-ethyl)-amide, 5 2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butyl-methyl-amide, [(2-isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonyl)-amino] acetic acid methyl ester, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 10 isopropoxy-propyl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide, 15 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide, 2-sec-butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 20 indan- 1 -ylamide, 2-isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy-4-(3 -phenyl-piperidine- 1 -carbonyl)-2H isoquinolin-1-one, 25 2-(1 -ethyl-propyl)-6,7-dimethoxy-4-(3 -phenoxy-piperidine- 1 -carbonyl)-2H isoquinolin-1-one, 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (S)indan- 1 -ylamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 (R)indan-1-ylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy-4- [3 -(3 -methoxy-phenyl)-piperazine- 1 carbonyl]-2H-isoquinolin- 1-one, WO 2013/068489 PCT/EP2012/072175 63 2-(1 -ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine- 1 -sulfonyl)-3,4 dihydro- 1 H-isoquinoline-2-carbonyl]-2H-isoquinolin- 1-one, 2-(1 -ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro- 1 H isoquinoline-2-carbonyl]-2H-isoquinolin- 1-one, 5 2-(1 -ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperazine 1 -carbonyl]-2H-isoquinolin- 1-one, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid ([1,3,4]thiadiazol-2-ylmethyl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid 2-(morpholine-4-sulfonyl)-benzylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (thiazol-4-ylmethyl)-amide, 2-(1-ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidine-1 carbonyl]-2H-isoquinolin- 1-one, 15 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (S)(5,6 dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (R)(5,6 dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (thiophen-3-ylmethyl)-amide, 4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7 dimethoxy-2H-isoquino lin- 1-one, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3-(4-chloro-benzenesulfonylamino)-benzylamide, 25 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic 30 acid (S)-indan-1-ylamide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide, WO 2013/068489 PCT/EP2012/072175 64 2-(1 -ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid 2-(morpholine-4-sulfonyl)-benzylamide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, 5 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid 3,5-difluoro-benzylamide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic 10 acid 4-methyl-benzylamide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid cyclohexylmethyl-amide, 2-(1-ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid butylamide, 15 2-(1 -ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (thiazol-2-ylmethyl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (thiophen-2-ylmethyl)-amide, 2-ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (5,6 dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 25 3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide, 3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid indan- 1 -ylamide, 3-(1-ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic 30 acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, 2-(1 -ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin- 1-one, and WO 2013/068489 PCT/EP2012/072175 65 2-ethyl-6,7-dimethoxy-N-(4-nitrophenyl)- 1 -oxo- 1,2-dihydroisoquino line-4 carboxamide. Particular embodiments of the invention also relates to the compounds of formula I, to the N-oxides, the prodrugs, the hydrates and the tautomers thereof and to the 5 pharmaceutically suitable salts thereof, where the compounds of the formula I are selected from the group consisting of: 6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 10 dihydroisoquinoline-4-carboxamide, N-((3,5-dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 15 6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, N-((2,5-dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 20 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 25 (R)-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, (S)-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 30 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 66 6,7-dimethoxy-N-((4-methylthiazol-5-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy- 1 -oxo-2-(pentan-3 -yl)-N-((5 -(trifluoromethyl)furan-2-yl)methyl) 1,2-dihydroisoquinoline-4-carboxamide, 5 6,7-dimethoxy-N-((5-methylfuran-2-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, N-(5-fluoro-2,3-dihydro- 1 H-inden- 1 -yl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl) 1,2-dihydroiso-quinoline-4-carboxamide, 6,7-dimethoxy-N-(5-methyl-2,3-dihydro- 1 H-inden- 1-yl)-1 -oxo-2-(pentan-3-yl) 10 1,2-dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-(4-methyl-2,3-dihydro- 1 H-inden- 1-yl)-1 -oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide, N-((2-ethylthiazol-4-yl)methyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 15 6,7-dimethoxy-N-(6-methoxy-2,3-dihydro- 1 H-inden- 1-yl)-1 -oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((4-methylthiophen-2-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((3-methylthiophen-2-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 20 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((5-methyloxazol-2-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-(6-methyl-2,3-dihydro- 1 H-inden- 1-yl)-1 -oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide, 25 6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)- 1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-(4-methylbenzyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)- 1,2 30 dihydroisoquinoline-4-carboxamide, N-((5-cyanofuran-2-yl)methyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 67 N-(4-chloro-2,3-dihydro- 1 H-inden- 1 -yl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide, N-((5-ethylthiophen-2-yl)methyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 5 6,7-dimethoxy-N-((3-methylfuran-2-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((2-methylfuran-3-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-dimethoxy-N-((1-methyl-i H-pyrazol-3-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 10 dihydroisoquinoline-4-carboxamide, N- [(3,4-dimethylphenyl)methyl] -2-ethyl-6,7-dimethoxy- 1 -oxo-isoquino line-4 carboxamide, N-[(2-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 15 N-[[2-(dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 2-ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl] -1 -oxo 20 isoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl] -1 -oxo isoquinoline-4-carboxamide, N-[(2-tert-butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 25 N-[[2-( 1,1 -dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 oxo-isoquinoline-4-carboxamide, N-[(2,3-difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 2-ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy- 1 -oxo 30 isoquinoline-4-carboxamide, N-[(3-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 68 2-ethyl-6,7-dimethoxy- 1 -oxo-N- [(2,4,6-trimethylphenyl)methyl]isoquino line-4 carboxamide, N-[(2,4-dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo-isoquinoline-4 carboxamide, 5 2-ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1 oxo-isoquinoline-4-carboxamide, N-[[2-(2-ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, N-[[2-(cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo 10 isoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl] -1 -oxo isoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-[[2-(2-methoxy- 1 -methyl-ethoxy)-4-methyl phenyl]methyl]- 1 -oxo-isoquinoline-4-carboxamide, 15 2-ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl]-1 oxo-isoquinoline-4-carboxamide, N-[[2-(cyclohexoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, N-[[2-(cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 20 oxo-isoquinoline-4-carboxamide, 2-ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3 ylmethoxy)phenyl]methyl] -1 -oxo-isoquinoline-4-carboxamide, 25 2-ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1 oxo-isoquinoline-4-carboxamide, 2-ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 30 dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 69 N-(2-ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, N-(2-sec-butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 5 2-ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)- 1 -oxo- 1,2 10 dihydroisoquinoline-4-carboxamide, 2-ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)- 1 -oxo 1,2-dihydroisoquinoline-4-carboxamide, 15 2-ethyl-6,7-dimethoxy- 1 -oxo-N-(2,4,5-trimethylbenzyl)- 1,2-dihydroisoquino line 4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl)- 1 oxo- 1,2-dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)- 1 -oxo 20 1,2-dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 25 2-ethyl-6,7-dimethoxy- 1 -oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-N- [ [4-(trifluoromethyl)phenyl]methyl]isoquino line 4-carboxamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-N-[(l S)- 1 -(p-tolyl)ethyl]isoquinoline-4 carboxamide, 30 2-ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy- 1 -oxo-isoquinoline-4 carboxamide, WO 2013/068489 PCT/EP2012/072175 70 2-ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy- 1 -oxo-isoquinoline-4 carboxamide, 2-ethyl-6,7-dimethoxy- 1 -oxo-N-[(1 R)- 1 -(p-tolyl)ethyl]isoquinoline-4 carboxamide, 5 N-[[4-(difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo-isoquino line 4-carboxamide, 2-ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl] -1 -oxo-isoquinoline-4 carboxamide, 2-ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl] -1 -oxo-isoquinoline-4 10 carboxamide, N-[(4-cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo-isoquinoline-4 carboxamide, N-indan- 1 -yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl] -1 -oxo-isoquino line 4-carboxamide, 15 N-butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl] -1 -oxo-isoquinoline-4 carboxamide, 2-ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl] -1 -oxo-isoquinoline-4 carboxamide, N-butyl-6,7-dimethoxy- 1 -oxo-2-[2-(2-quino,1yl)ethyl]isoquinoline-4 20 carboxamide, and N-indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quino,1yl)ethyl]iso'quinoline-4 carboxamide. In particular embodiments, the compounds of the present invention are distinct from the group of the following compounds: 25 1-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl]-(3 ethoxycarbonyl)piperidine, 1-[(2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl) carbonyl]-(3-ethoxycarbonyl)piperidine, 2- { [(2-ethyl-1,2-dihydro-6,7-dimethoxy- 1 -oxo-4-isoquino linyl)carbonyl] amino} 30 benzoic acid ethyl ester, N-cycloheptyl-2-ethyl-1,2-dihydro-6,7-dimethoxy- 1 -oxo-4-isoquino line carboxamide, WO 2013/068489 PCT/EP2012/072175 71 N-(3-ethoxypropyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4-isoquino line carboxamide, N-(3-(1 -methylethoxy)propyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinoline carboxamide, 5 N-(3-(1-methylethoxy)propyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1 oxo-4-isoquinoline carboxamide, N-(3-ethoxypropyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4 isoquinoline carboxamide, N- [3 -(4-methyl-i -piperidinyl)propyl] -2-ethyl-1,2-dihydro-6,7-dimethoxy- 1 -oxo 10 4-isoquinoline carboxamide, N- [3 -(2-ethyl-i -piperidinyl)propyl] -2-(2-methylpropyl)- 1,2-dihydro-6,7 dimethoxy- 1 -oxo-4-isoquino line carboxamide, N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-1 oxo-4-isoquinoline carboxamide, 15 N-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2-(2-methylpropyl)-1,2-dihydro-6,7 dimethoxy- 1 -oxo-4-isoquino line carboxamide, N-(3-acetylaminophenyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4 isoquinoline carboxamide, N,N-diethyl-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4-isoquinoline 20 carboxamide, N-(5-methyl-2-furanylmethyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinoline carboxamide, N-(5-methyl-2-furanylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1 oxo-4-isoquinoline carboxamide, 25 N-(2-furanylmethyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4-isoquino line carboxamide, N-(tetrahydro-2-furanylmethyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinoline carboxamide, N-(2-pyridylmethyl)-2-(2-methylpropyl)- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 30 isoquinoline carboxamide, N-(3 -pyridylmethyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4-isoquino line carboxamide, WO 2013/068489 PCT/EP2012/072175 72 N-(1,3-benzodioxol-5-ylmethyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinoline carboxamide, N-(1,3-benzodioxol-5-ylmethyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy 1 -oxo-4-isoquino line carboxamide, 5 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-ethyl-1,2-dihydro-6,7-dimethoxy 1 -oxo-4-isoquino line carboxamide, N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo 4-isoquinoline carboxamide, N-ethyl-N-(2-methylphenyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 10 isoquinoline carboxamide, N-ethyl-N-(2-ethylphenyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinoline carboxamide, N-(3,4-dimethoxyphenyl)-2-ethyl- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinoline carboxamide, 15 N-(3-chlorophenyl)-2-(2-methylpropyl)-1,2-dihydro-6,7-dimethoxy-1-oxo-4 isoquinoline carboxamide, 4-[(4-propyl-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7 dimethoxy-4-isoquinolin- 1-one, 4-[(4-cyclohexyl-1-piperazinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-4 20 isoquinolin-1-one, 4-[(4-cyclohexyl-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7 dimethoxy-4-isoquinolin- 1-one, 4-[(4-(2-pyridyl)-1-piperazinyl)carbonyl]-2-(2-methylpropyl)-1,2-dihydro-6,7 dimethoxy-4-isoquinolin- 1-one, 25 4-[(4-(3-chlorophenyl)-1-piperazinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7 dimethoxy-4-isoquinolin- 1-one, 4-{[4-(2-furanylcarbonyl)-1-piperazinyl]carbonyl}-2-ethyl-1,2-dihydro-6,7 dimethoxy-4-isoquinolin- 1-one, 4-[(3,4-dihydro-1(2H)quinolinyl)carbonyl]-2-ethyl-1,2-dihydro-6,7-dimethoxy-4 30 isoquinolin-1-one, N-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl] glycine methyl ester, WO 2013/068489 PCT/EP2012/072175 73 N-[(2-(2-methylpropyl)- 1,2-dihydro-6,7-dimethoxy- 1 -oxo-4 isoquinolinyl)carbonyl] glycine methyl ester, N-[(2-ethyl-1,2-dihydro-6,7-dimethoxy-1-oxo-4-isoquinolinyl)carbonyl] glycine ethyl ester, 5 the pharmaceutically acceptable salts thereof, the N-oxides thereof, the prodrugs thereof, the hydrates thereof, the tautomers the and the pharmaceutically acceptable salts of said N-oxides, prodrugs, tautomers or hydrates. The compounds of the invention of the general formulae I, Ia, Ib, Ic and Id and the starting materials used to prepare them can be prepared in analogy to known processes 10 of organic chemistry as are described in standard works of organic chemistry, e.g. Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March "Advanced Organic Chemistry", 5 th edition, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2 nd edition, Weinheim, 1999 and the literature cited therein. The compounds of the invention of the 15 general formula I are advantageously prepared by the methods described below and/or in the experimental section. Compounds of the formula I, wherein Y is oxygen, can be prepared e.g. by reacting a compound of the formula II with an amine of the formula III, as depicted in scheme 1. 20 Scheme 1: 0 0 R40N H R 4N 2 113- , 2 2 11~ SX +R3 R X 2 R2 0 Q0 N~ 13 (1): Y = 0 R3 where X , X2, R1, R2, R3 and R4 are as defined above. Q is a suitable leaving group such as chlorine, bromine or OH or a radical of an activated ester such as para 25 nitrophenoxy, pentafluorophenoxy, N-hydroxysuccinimide or hydroxybenzotriazol-1-yl. suitable reaction conditions have been described e.g. in Houben-Weyl: "Methoden der organ. Chemie" [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, New York 1985, Volume E5, pp. 941-1045).
WO 2013/068489 PCT/EP2012/072175 74 The reaction of II with III may be performed in the presence of a base. Suitable base include but are not limited to If Q is OH, the reaction may be performed in the presence of a coupling agent. Suitable coupling agents are, for example: 5 - coupling agents based on carbodiimides, for example N,N'-dicyclohexylcarbodiimide [J.C. Sheehan, G.P. Hess, J. Am. Chem. Soc. 1955, 77, 1067], N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; - coupling agents which form mixed anhydrides with carbonic esters, for example 2-ethoxy- 1 -ethoxycarbonyl- 1,2-dihydroquino line [B. Belleau, G. Malek, J. Amer. 10 Chem. Soc. 1968, 90, 1651], 2-isobutyloxy-1-isobutyloxycarbonyl-1,2 dihydroquinoline [Y. Kiso, H. Yajima, J. Chem. Soc., Chem. Commun. 1972, 942]; - coupling agents based on phosphonium salts, for example (benzotriazol-1 yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [B. Castro, J.R. 15 Domoy, G. Evin, C. Selve, Tetrahedron Lett. 1975, 14, 1219], (benzotriazol-1-yl oxy)tripyrrolidinophosphonium hexafluorophosphate [J. Coste et al., Tetrahedron Lett. 1990, 31, 205]; - coupling agents based on uronium salts or having a guanidinium N-oxide structure, for example N,N,N',N'-tetramethyl-O-(1 H-benzotriazo l-1 -yl)uronium 20 hexafluorophosphate [R. Knorr, A. Trzeciak, W. Bannwarth, D. Gillessen, Tetrahedron Lett. 1989, 30, 1927], N,N,N',N'-tetramethyl-O-(benzotriazol-1 yl)uronium tetrafluoroborate, (benzotriazol- 1 -yloxy)dipiperidinocarbenium hexafluorophosphate [S. Chen, J. Xu, Tetrahedron Lett. 1992, 33, 647]; - coupling agents which form acid chlorides, for example bis-(2-oxo 25 oxazolidinyl)phosphinic chloride [J. Diago-Mesequer, Synthesis 1980, 547]. Apart from that, compounds of the formula I and likewise compounds of the formula II, where Q is S can be prepared by successively reacting compounds of the formulae I and II, where Q is 0 with a suitable sulfurizing agent, such as Lawenson's reagent or P 2 S5. 30 The N-oxides of compound I may be prepared from the compounds of formula I according to conventional oxidation methods, for example by treating said compounds with an organic peracid; such as metachloroperbenzoic acid or 3-chloroperbenzoic acid WO 2013/068489 PCT/EP2012/072175 75 [Journal of Medicinal Chemistry 38(11), 1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents; such as hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7), 1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society 123(25), 5962-5973 (2001)]. The oxidation may lead to pure mono-N-oxides or 5 to a mixture of different N-oxides, which can be separated by conventional methods; such as chromatography. The compounds of the formulae II and III are well known in the art or can be prepared by anology to well established reactions of organic synthetic chemistry or by analogy to the methods as described in standard works of organic chemistry, e.g. 10 Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March "Advanced Organic Chemistry", 5 th edition, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2 nd edition, Weinheim, 1999 and the literature cited therein. The compounds of the formula II, where Q is OH can be easily transformed into 15 compounds of the formula II, where Q is halogen, in particular chlorine by a suitable chlorination agent such as thionylchloride or oxalyl chloride. Compounds of the formula II, where X 2 is C-R 5 , where R 5 is a radical O-Z 5 -Ar5 can be prepared e.g. by reacting compounds of the formula II, where X2 is C-OH with a compound of formula HO-Z 5 -Ar 5 (formula IV) in terms of a Mitsunobu reaction, i.e. in 20 the presence of dialkyl azodicarboxylate and triphenylphosphine (for suitable reaction conditions see e.g. A.J. Reynolds et al. Curr. Org. Chem. 13(16) (2009) pp.1610-16-32; K.C. Swamy et al., Chem. Rev. 109(6) (2009), pp. 2551-2651; D.L. Hughes, Organic Preparations and Procedures International 28(2) (1996), pp. 127-164. Compounds of the formula II, where X 1 is CH and Q is OH (compounds Ila), can 25 be prepared e.g. according to the following reaction scheme 2: Scheme 2: 0 0 0 R'--O OR a) Ri-O OR b) H 2 NR1 R4-O NR X X- x ~ -~ N c) hydrolysis X! (V) RO 0 (VI) RO 0 (Ila) HO 0 In scheme 2, X 2 , R 1 and R 4 are as defined above. R is C1-C 4 -alkyl, in particular methyl.
WO 2013/068489 PCT/EP2012/072175 76 Step a) is performed by reacting a compound of the formula V with dimethoxymethyl dimethylamine (also termed dimethylformamide dimethylacetal). Thereby the compound of formula VI is obtained, which can be cyclised in step b) to the compound of formula II, where Q is methoxy, by reaction with a primary amine of 5 the formula H 2
N-R
1 (compound VII). Subsequent hydrolysis of the primarily obtained ester in step c) yields the compound of the formula II, where X 1 is CH and Q is OH. Compounds of the formula II, where X 1 is N and Q is OH (compounds Ib), can be prepared e.g. according to the following reaction scheme 3: Scheme 3: 0 0 d) 0 OH e) H 2
NNH
2 R N R 2- ---- 2 21 X2 0 X / 0 f)R 1 -Q' X N 10 (Vill) (IX) HO 0 (1Ib) HO 0 In scheme 3, X 2 , R 1 and R4 are as defined above. Step d) is performed by reacting a compound of the formula VIII with an excess of a suitable oxidising agent in the presence of water, e.g. aqueous potassium permanganate. Thereby the compound of formula IX is obtained, which can be cyclised 15 in step e) to a phthalazinone or phthalazinone analogue by reaction with hydrazine. Subsequent alkylation with an alkylating agent of formula R 1 -Q' in step f) yields the compound of the formula II, where X 1 is CH and Q is OH. The reactions are usually performed in an organic solvent, including aprotic organic solvent, e.g. substituted amides, lactames and ureas; such as 20 dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethyl urea, cyclic ethers; such as dioxane, tetrahydrofurane, halogenated hydrocarbons; such as dichloromethane, and mixtures thereof as well as mixtures thereof with C 1
-C
6 -alkanols and/or water. The reactions described above will be usually performed at temperatures ranging 25 from -10 C to 100 0 C, depending on the reactivity of the used compounds. The reaction mixtures are worked up in a conventional way, e.g. by mixing with water, separating the phases and, where appropriate, purifying the crude products by chromatography. The intermediates and final products in some cases result in the form of colorless or pale brownish, viscous oils which are freed of volatiles or purified under WO 2013/068489 PCT/EP2012/072175 77 reduced pressure and at moderately elevated temperature. If the intermediates and final products are obtained as solids, the purification can also take place by recrystallization or digestion. Due to their capability of inhibiting PDE 10 A at low concentrations, the 5 compounds of the formula I, their N-oxides, their hydrates, their tautomers and their prodrugs and the pharmaceutically acceptable salts thereof, are particularly suitable for treating disorders or conditions, which can be treated by inhibition of phosphodiesterase type 10A. The terms "treating" and "treatment" in terms of the present invention have to be understood to include both curative treatment of the cause of a disease or disorder, 10 the treatment of the symptoms associated with a disease or disorder, i.e. controlling the disease or disorder or ameliorating the conditions or symptoms associated with a disease or disorder, and prophylactic treatment, i.e. a treatment for reducing the risk of a disease or disorder. Neurological and psychiatric disorders or conditions which can be treated by 15 inhibition of PDE 10 A, including curative treatment, control or amelioration and prophylaxis, include CNS disorders, in particular schizophrenia, depression, bipolar disorders, cognitive dysfunctions associated with schizophrenia, cognitive dysfunctions associated with Alzheimer's disease, Huntington's disease (Huntington chorea), anxiety and substance-related disorders, especially substance use disorder, substance tolerance 20 conditions associated with substance withdrawal. Disorders or conditions which can be treated by inhibition of PDE 10 A, including curative treatment, control or amelioration and prophylaxis, also include treatment of diet induced obesity. Thus, the invention relates to the use of compounds of formula I, their N-oxides, their hydrates, their tautomers and their prodrugs and the pharmaceutically acceptable 25 salts thereof, for treatment of disorders or conditions, which can be treated by inhibition of phosphodiesterase type 10A, i.e. the invention relates to the use of such compounds for curative treatment of such a disease or disorder, controlling such a disease or disorder, ameliorating the symptoms associated with such a disease or disorder and reducing the risk for such a disease or disorder. 30 The present invention also relates to a method for the treatment of a medical disorder, selected from neurological and psychiatric disorders which can be treated by inhibition of phosphodiesterase type 10 A, said method comprising administering an WO 2013/068489 PCT/EP2012/072175 78 effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof, to a mammal in need thereof. The present invention in particular relates to: 5 * a method for treating, controlling, ameliorating or reducing the risk of schizophrenia in a mammalian; * a method for treating, controlling, ameliorating or reducing the risk of cognitive disturbances associated with schizophrenia in a mammalian; * a method for treating, controlling, ameliorating or reducing the risk of 10 depression in a mammalian; * a method for treating, controlling, ameliorating or reducing the risk of bipolar disorders in a mammalian; * a method for treating or ameliorating the symptoms associated with substance use disorders in a mammalian; 15 * a method for treating or ameliorating the symptoms associated with diet induced obesity in a mammalian; * a method for treating, controlling, ameliorating or reducing the risk of cognitive disturbances associated with Alzheimer's disease in a mammalian; * a method for treating, controlling, ameliorating or reducing the risk of 20 behavioral symptoms in Alzheimer's disease; * a method for treating, controlling, ameliorating or reducing the risk of anxiety in a mammalian; * a method for treating, controlling, ameliorating or reducing the risk of Huntington's disease in a mammalian; 25 which methods comprising administering an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof, to a mammal in need thereof. The subject treated in the present methods is generally a mammal, preferably a 30 human being, male or female, in whom inhibition of PDE1OA is desired. The terms "effective amount" and "therapeutically effective amount" mean the amount of the subject compound that will elicit the biological or medical response of a tissue, system, WO 2013/068489 PCT/EP2012/072175 79 animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective 5 amount of the compound of the present invention. As used herein, the terms "treatment" and "treating" refer to all processes, wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is 10 predisposed to such disease or disorder. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active 15 ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention 20 encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of and or "administering a" compound should be 25 understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment. A preferred embodiment of the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, 30 their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
WO 2013/068489 PCT/EP2012/072175 80 In another preferred embodiment, the present invention provides a method for treating cognitive disturbances associated with schizophrenia, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their 5 tautomers, their prodrugs and the pharmaceutically acceptable salts thereof At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including schizophrenia and other psychotic disorders. These include: disorders having psychotic symptoms as the defining feature. The term 10 psychotic refers to delusions, prominent hallucinations, disorganized speech, disorganized or catatonic behavior. The disorder includes: paranoid, disorganized, catatonic, undifferentiated, and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced 15 psychotic disorder, and psychotic disorder not otherwise specified. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular schizophrenia, and that these systems evolve with medical scientific progress. Thus, the term "schizophrenia" is intended to include like disorders that are described in other 20 diagnostic sources. In another preferred embodiment, the present invention provides a method for treating substance-related disorders, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs 25 and the pharmaceutically acceptable salts thereof In another preferred embodiment, the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically 30 acceptable salts thereof At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including anxiety and related disorders.
WO 2013/068489 PCT/EP2012/072175 81 These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and 5 anxiety disorder not otherwise specified. As used herein the term "anxiety" includes treatment of those anxiety disorders and related disorder as described in the DSM-IV. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress. Thus, the term 10 "anxiety" is intended to include like disorders that are described in other diagnostic sources. In another preferred embodiment, the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of at least one compound, selected from the group of compounds of formula I, 15 their N-oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including depression and related disorders. Depressive disorders include, for example, single episodic or recurrent major 20 depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or 25 manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder. As used herein the term "depression" includes treatment of those depression disorders and related disorder as described in the DSM-1V. In another preferred embodiment, the present invention provides a method for treating substance-related disorders, especially substance dependence, substance abuse, 30 substance tolerance, and substance withdrawal, comprising: administering to a patient in need thereof an effective amount at least one compound, selected from the group of compounds of formula I, their N-oxides, their hydrates, their tautomers, their prodrugs WO 2013/068489 PCT/EP2012/072175 82 and the pharmaceutically acceptable salts thereof At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including disorders related to taking a drug of abuse (including alcohol), to the side effects of a 5 medication, and to toxin exposure. Substances include alcohol, amphetamine and similarly acting sympathomimetics, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (PCP) or similarly acting arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also, polysubstance dependence and other unknown substance-related disorders are included. The skilled 10 artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular substance-related disorders, and that these systems evolve with medical scientific progress. Thus, the term "substance-related disorder" is intended to include like disorders that are described in other diagnostic sources. 15 In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require inhibition of PDE 10 A an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A 20 suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 25 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. When treating, preventing, controlling, ameliorating, or reducing the risk of neurological and psychiatric disorders or other diseases for which 30 compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body WO 2013/068489 PCT/EP2012/072175 83 weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams, in the case of a 70 kg adult human, the total daily dose will 5 generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that 10 compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The compounds of the present invention may be administered by conventional routes of administration, including parenteral (e.g., intramuscular, intrapentoneal, 15 intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), oral, by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration. The compounds according to the present invention are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the 20 aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective 25 than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula I. When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula I is preferred. However, the combination 30 therapy may also include therapies in which the compound of formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the WO 2013/068489 PCT/EP2012/072175 84 compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of formula I. The above combinations 5 include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are 10 useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the 15 pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each 20 ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be 25 within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). 30 The present invention also relates to pharmaceutical compositions (i.e. medicaments) which comprise at least one compound of the present invention and, where appropriate, one or more suitable excipients.
WO 2013/068489 PCT/EP2012/072175 85 These excipients/drug carriers are chosen according to the pharmaceutical form and the desired mode of administration. The compounds of the present invention can be used to manufacture pharmaceutical compositions for parenteral (e.g., intramuscular, intrapentoneal, 5 intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), oral, sublingual, intratracheal, intranasal, topical, transdermal, vaginal or rectal administration, and be administered to animals or humans in unit dose forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above impairments or diseases. 10 In the pharmaceutical compositions, the at least one compound of the present invention may be formulated alone or together with further active compounds, in suitable dosage unit formulations containing conventional excipients, which generally are non-toxic and/or pharmaceutically acceptable. Carriers or excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active 15 compound. Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste 20 corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; 25 thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fdr Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4 th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996. 30 Suitable unit dose forms include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, WO 2013/068489 PCT/EP2012/072175 86 forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration. The compounds of the invention can be used in creams, ointments or lotions for topical administration. 5 If a solid composition is prepared in the form of tablets, the main ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like. The tablets may be coated with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a prolonged or delayed activity and 10 in order to release a predetermined amount of the active basic ingredient continuously. A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with an extender and taking up the resulting mixture in soft or hard gelatin capsules. A preparation in the form of a syrup or elixir or for administration in the form of 15 drops may comprise active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavoring and a suitable coloring. The water-dispersible powders or granules may comprise the active ingredients mixed with dispersants, wetting agents or suspending agents such as 20 polyvinylpyrrolidones, and sweeteners or taste improvers. Rectal administration is achieved by the use of suppositories which are prepared with binders which melt at the rectal temperature, for example cocobutter or polyethylene glycols. Parenteral administration is effected by using aqueous suspensions, isotonic salt solutions or sterile and injectable solutions which comprise 25 pharmacologically suitable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol. The active basic ingredient may also be formulated as microcapsules or liposomes/centrosomes, if suitable with one or more carriers or additives. In addition to the compounds of the general formula I, their prodrugs, their N 30 oxides, their tautomers, their hydrates or their pharmaceutically suitable salts, the compositions of the invention may comprise further active basic ingredients which may be beneficial for the treatment of the impairments or diseases indicated above.
WO 2013/068489 PCT/EP2012/072175 87 The present invention thus further relates to pharmaceutical compositions in which a plurality of active basic ingredients are present together, where at least one thereof is a compound of the invention. When producing the pharmaceutical compositions, the compounds according to 5 the invention are optionally mixed or diluted with one or more carriers. The following examples are intended for further illustration of the present invention. Examples 10 The compounds were either characterized via proton-NMR in d 6 -dimethylsulfoxide or d-chloroform on a 400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C1 8-material (electrospray-ionisation (ESI) mode), or melting point. 15 The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (6) expressed in parts per million (ppm). The relative area of the shifts in the 'H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad 20 triplet (t br.), quartet (q), quintet (quint.) and multiplet (m). Abbreviations: DMSO dimethylsulfoxide DMF dimethylformamide 25 DMA dimethylacetamide MeOH methanol EtOH ethanol AcOH acetic acid EtOAc ethyl acetate 30 DCM dichloromethane DIPEA or DIEA diisoproylethyl amine TFA trifluoroacetic acid WO 2013/068489 PCT/EP2012/072175 88 HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium PS-TFP 4-hydroxy-2,3,5,6-tetrafluorobenzamidomethyl polystyrene r.t. room temperature 5 RT retention time Prep-TLC preperative thin layer chromatography I. Preparation Examples 10 Example 1: 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide 15 1.1 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid dimethyl ester To rapidly stirred cold (0 0 C) dimethyl malonate (20 mL) was added sodium (423 mg, 18.38 mmol) in portions. After the addition was complete, the mixture was stirred until the sodium disappeared and the mixture turned to a white colloidal suspension. Cuprous bromide (110 mg, 0.7660 mmol) and 2-bromo-4, 5-dimethoxybenzoic acid 20 (2.00 g, 7.760 mmol) were added. The mixture was heated at 70 'C for 6 h. The reaction mixture was dissolved in water and extracted with toluene and EtOAc. The aqueous layer was acidified with HCl (2 N). The mixture was then extracted with EtOAc, dried over Na 2
SO
4 , filtered and concentrated in vacuo to give the product as an oil. After standing overnight the title compound was obtained as a solid (1.3 g, yield 54%). 25 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.58 (s, 1H, ArH), 6.92 (s, 1H, ArH), 5.98 (s, 1H, CH), 3.87 (s, 3H, CH 3 ), 3.72 (s, 3H, CH 3 ). LCMS (ESI+): m/z 313 (M+H)*, RT: 1.29 min. 1.2 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid 30 A solution of sodium hydroxide (1.92 g, 48.03 mmol) in water (20 mL) was added over 30 min to a solution of the compound obtained in step 1.1 (3.0 g, 9.6 mmol) in methanol (30 mL) at room temperature. After stirred for 3 h, methanol was removed WO 2013/068489 PCT/EP2012/072175 89 under reduced pressure, and the contents were acidified with HCl (conc.) at r.t. to pH 3. The resulting white aqueous suspension was extracted twice with EtOAc (100 mL), and the organic layer was dried over Na 2
SO
4 . After filtration and concentration in vacuo the title product was obtained as a white solid (1.8 g, 67%). 5 IH NMR (DMSO-d 6 /TMS, 400MHz) 6:12.67 (s, 3H, COOH), 7.48 (s, 1H, ArH), 6.88 (s, 1H, ArH), 5.76 (s, 1H, CH), 3.81 (s, 3H, CH 3 ), 3.78 (s, 3H, CH 3 ). LCMS (ESI+): m/z 307 (M+Na)*, RT: 0.71 min. 1.3 2-Carboxymethyl-4,5-dimethoxy-benzoic acid 10 The product obtained in step 1.2 (1.8 g, 6.4 mmol) was suspended in toluene (40 mL), and the suspension was heated at 105 'C overnight. The precipitates were removed by filtration. The filtrate was concentrated to afford the title product as a white solid. This was used in the next step without further purification. LCMS (ESI+): m/z 263 (M+Na)*, RT: 1.32 min. 15 1.4 4,5-Dimethoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester Thionyl chloride (0.74 g, 6.245 mmol) was added dropwise to a solution of the compound obtained in step 1.3 (0.50 g, 2.082 mmol) in methanol (5 mL) at ambient temperature. After the addition was completed, the mixture was then heated at 65 'C 20 overnight. The solvent was concentrated in vacuo. The concentrate was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO 3 (10 mL), water (10 mL) and brine (1OmL). The organic layer was dried over Na 2
SO
4 , filtered and concentrated. The residue was purified on silica gel column (petrol ether : EtOAc = 5:1) to afford the title product as a white solid (0.5 g, 60%). 25 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.56 (s, 1H, ArH), 6.72 (s, 1H, ArH), 3.97 (s, 2H, CH 2 ), 3.93 (s, 3H, CH 3 ), 3.92 (s, 3H, CH 3 ), 3.86 (s, 3H, CH 3 ), 3.71 (s, 3H, CH 3 ). LCMS (ESI+): m/z 269 (M+H)*, RT: 1.69 min. 1.5 2-(2-Dimethylamino-1-methoxycarbonylvinyl)-4,5-dimethoxy-benzoic acid 30 methyl ester A mixture of the compound obtained in step 1.4 (2.05 g, 7.641 mmol) in DMF DMA (20 mL) was heated at 90 'C overnight. The reaction mixture was concentrated in WO 2013/068489 PCT/EP2012/072175 90 vacuo. The residue was diluted with EtOAc and washed with brine. The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified on silica gel column (petrol ether : EtOAc = 3:1) to afford the title product as a white solid (0.78 g, 32%). 5 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.43 (s, 1H, ArH), 7.38 (s, 1H, ArH), 6.59 (s, 1H, CH), 3.86 (s, 3H, CH 3 ), 3.84 (s, 3H, CH 3 ), 3.73 (s, 3H, CH 3 ), 3.53 (s, 3H, CH 3 ), 2.61 (s, 6H, N(CH 3
)
2 ). LCMS (ESI+): m/z 265 (M+H)*, RT: 1.52 min. 10 1.6 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid methyl ester A mixture of the compound obtained in step 1.5 (80 mg, 0.2474 mmol), ethylamine hydrochloride (61 mg, 0.7423 mmol) and DIPEA (1 mL) in methanol (5 mL) was heated at reflux overnight. The solvent was removed under reduced pressure. 15 The residue was diluted with EtOAc (50 mL) and washed with HCl (2 N, 10 mL) and brine (10 ML). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo to afford the title product as a white solid (68 mg, yield 95%). The product was pure enough to be used in the next step without further purification. IH NMR (CDCl 3 /TMS, 400MHz) 6: 8.40 (s, 1H, ArH), 8.13 (s, 1H, ArH), 7.83 (s, 20 1H, ArH), 4.12 (q, J= 6.8 Hz, J= 7.2 Hz, 2H, CH 2 ), 4.05 (s, 3H, CH 3 ), 4.01 (s, 3H,
CH
3 ), 3.91 (s, 3H, CH 3 ), 1.43 (t, J= 7.6 Hz, 3H, CH 3 ). LCMS (ESI+): m/z 292 (M+H)*, RT: 1.75 min. 1.7 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid 25 A mixture of the compound obtained in step 1.6 (254 mg, 0.8720 mmol) and sodium hydroxide (42 mg, 1.046 mmol) in methanol (6 mL) and water (2 mL) was heated at 40 'C for 6 h. The reaction mixture was concentrated in vacuo. The concentrate was acidified with HCl (conc.) to pH=2-3. The resulting precipitates were collected by filtration. The solid was dried in vacuo and used in the next step without 30 further purification (200 mg, yield 83%). LCMS (ESI+): m/z 278 (M+H)*, RT: 1.50 min.
WO 2013/068489 PCT/EP2012/072175 91 1.8 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide A suspension of the compound obtained in step 1.7 (50 mg, 0.1803 mmol) and thionyl chloride (64 mg, 0.5409 mmol) in DCM (3 mL) was refluxed for 3 h. The 5 mixture was concentrated in vacuo and diluted in DCM (3 mL). The solution was added dropwise to a mixture of n-butylamine (26 mg, 0.3606 mmol) and triethylamine (55 mg, 0.5409 mmol) in DCM (4 mL) at ambient temperature. The reaction mixture was stirred at r.t. for another 3 h. Then the solvent was removed under reduced pressure, the residue was diluted with EtOAc and washed with HCl (2 N), NaOH (2 N) and brine 10 successively. The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified on silica gel column (eluted with DCM/EtOAc=4: 1, v/v) to afford the title product as a white solid (53 mg, yield 88%). LCMS: 1.70 min; M+H: 333.1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.80 (s, 1H, ArH), 7.57 (s, 1H, ArH), 7.35 (s, 15 1H, ArH), 5.96 (s, 1H, NH), 4.05 (q, J= 7.6 Hz, 2H, CH 2 ), 4.01 (s, 3H, OCH 3 ), 3.99 (s, 3H, OCH 3 ), 3.48 (q, J= 5.6 Hz, 2H, CH 2 ), 1.59-1.69 (m, 2H, CH 2 ), 1.41-1.51 (m, 2H,
CH
2 ), 1.39 (t, J= 6.8 Hz, 3H, CH 3 ), 0.99 (t, J= 7.2 Hz, 3H, CH 3 ). The following compounds were synthesized analogously, using in the last reaction 20 step the respective amine. Example 2 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methylamide 25 LCMS: 1.54 min; M+H: 291 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.72 (s, 1H), 7.52 (s, 1H), 7.29 (s, 1H), 5.97 (s, 1H), 3.96 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.97 (d, J= 4.8 Hz, 2H), 1.31 (t, J= 7.2 Hz, 3H). 30 Example 3 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethylamide WO 2013/068489 PCT/EP2012/072175 92 LCMS: 1.62 min; M+H: 305 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.80 (s, 1H), 7.59 (s, 1H), 7.35 (s, 1H), 5.94 (s, 1H), 4.04 (m, 2H), 4.00 (s, 3H), 3.99 (s, 3H), 3.52 (m, 2H), 1.39 (t, J= 7.2 Hz, 3H), 1.30 (t, J= 7.4 Hz, 3H). 5 Example 4 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 fluoro-ethyl)-amide LCMS: 1.56 min; M+H: 323 10 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 6.26 (s, 1H), 4.66 (t, J= 4.6 Hz, 1H), 4.54 (t, J= 4.8 Hz, 1H), 3.99 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.77 (m, 1H), 3.70 (m, 1H), 1.33 (t, J= 7.2 Hz). Example 5 15 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2,2,2 trifluoro-ethyl)-amide LCMS: 1.77 min; M+H: 359 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.81 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 6.21 (s, 1H), 4.13-4.18 (m, 2H), 4.06 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 1.41 (t, J= 5.6 Hz, 20 3H). Example 6 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylamide 25 LCMS: 1.50 min; M+H: 317 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.71 (s, 1H), 7.56 (s, 1H), 7.24 (s, 1H), 6.06 (s, 1H), 3.96 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.85-2.88 (m, 1H), 1.31 (t, J= 7.4 Hz, 3H), 0.83-0.86 (m, 2H), 0.57-0.62 (m, 2H). 30 Example 7 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isopropylamide WO 2013/068489 PCT/EP2012/072175 93 LCMS: 1.58 min; M+H: 319 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.51 (s, 1H), 7.27 (s, 1H), 5.65 (s, 1H), 4.20-4.29 (m, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H), 1.24 (d, J= 6.4 Hz, 6H). 5 Example 8 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid propylamide LCMS: 1.59 min; M+H: 319 10 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H), 5.85 (s, 1H), 3.97-4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.38 (br, 2H), 1.59-1.65 (m, 2H), 1.33 (t, J= 6.8 Hz, 3H), 0.97 (t, J= 7.4 Hz, 3H). Example 9 15 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclobutylamide LCMS: 1.74 min; M+H: 331 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.60 (s, 1H), 7.40 (s, 1H), 6.02 (s, 1H), 4.63 (br, 1H), 4.10 (br, 2H), 4.01 (s, 3H), 4.00 (s, 3H), 2.48 (br, 2H), 1.99 (m, 20 2H), 1.80 (br, 2H), 1.41 (br, 3H). Example 10 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylmethyl-amide 25 LCMS: 1.72 min; M+H: 331 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.54 (s, 1H), 7.34 (s, 1H), 5.94 (s, 1H), 3.99-4.04 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.26-3.29 (m, 2H), 1.34 (t, J= 7.2 Hz, 3H), 0.98-1.07 (m, 1H), 0.51-0.55 (m, 2H), 0.23-0.27 (m, 2H). 30 Example 11 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid tert butylamide WO 2013/068489 PCT/EP2012/072175 94 LCMS: 1.72 min; M+H: 333 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 5.66 (s, 1H), 3.97-4.01 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.44 (s, 9H), 1.33 (t, J= 7.0 Hz, 3H). 5 Example 12 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid see butylamide LCMS: 1.67 min; M+H: 333 10 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 5.63 (s, 1H), 4.08 (m, 1H), 3.98-4.01 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.49-1.55 (m, 2H), 1.33 (t, J= 7.0 Hz, 3H), 1.21 (d, J= 6.8 Hz, 3H), 0.95 (t, J= 7.4 Hz, 3H). Example 13 15 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isobutyl-amide LCMS: 1.69 min; M+H: 333 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 5.88 (s, 1H), 3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.25 (t, J= 6.4 Hz, 2H), 1.84-1.90 20 (m, 1H), 1.33 (t, J= 7.2 Hz, 3H), 0.96 (d, J= 6.4 Hz, 6H). Example 14 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopentylamide 25 LCMS: 1.71 min; M+H: 345 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.50 (s, 1H), 7.27 (s, 1H), 5.77 (s, 1H), 4.34-4.39 (m, 1H), 3.97-4.02 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 2.05-2.10 (m, 2H), 1.61-1.69 (m, 4H), 1.43-1.46 (m, 2H), 1.33 (t, J= 7.2 Hz, 3H). 30 Example 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 methyl-butyl)-amide WO 2013/068489 PCT/EP2012/072175 95 LCMS: 1.88 min; M+H: 347 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 5.67 (s, 1H), 4.21-4.27 (m, 1H), 4.05-4.09 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 1.52-1.59 (m, 2H), 1.43-1.48 (m, 2H), 1.40 (t, J= 5.4 Hz, 3H), 1.28 (d, J= 5.2 Hz, 3H), 0.98 (t, J= 5 5.6 Hz, 3H). Example 16 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1,1 dimethyl-propyl)-amide 10 LCMS: 1.91 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.86 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 5.63 (s, 1H), 4.13 (m, 2H), 4.03 (s, 3H), 4.00 (s, 3H), 1.88-1.93 (m, 2H), 1.46 (s, 6H), 1.41 (br, 3H), 0.97 (t, J= 5.8 Hz, 3H). 15 Example 17 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1,2 dimethyl-propyl)-amide LCMS: 1.86 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 5.61 20 (s, 1H), 3.96-4.03 (m, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 1.77 (m, 1H), 1.34 (t, J= 7.2 Hz, 3H), 1.16 (d, J= 6.8 Hz, 3H), 0.94 (d, J= 4.0 Hz, 3H), 0.93 (d, J= 4.0 Hz, 3H). Example 18 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2,2 25 dimethyl-propyl)-amide LCMS: 1.89 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.55 (s, 1H), 7.37 (s, 1H), 5.99 (s, 1H), 4.07 (br, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.31 (s, 2H), 1.40 (s, 3H), 1.03 (s, 9H). 30 Example 19 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 ethyl-propyl)-amide WO 2013/068489 PCT/EP2012/072175 96 LCMS: 1.86 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 5.55 (s, 1H), 4.03-4.09 (m, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 1.64-1.70 (m, 2H), 1.51-1.55 (m, 2H), 1.41 (t, J= 7.0 Hz, 3H), 1.02 (t, J= 7.4 Hz, 6H). 5 Example 20 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 methyl-butyl)-amide LCMS: 1.89 min; M+H: 347 10 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 5.83 (s, 1H), 3.98-4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.33-3.39 (m, 1H), 3.21-3.27 (m, 1H), 1.61-1.68 (m, 1H), 1.41-1.47 (m, 1H), 1.33 (t, J= 5.6 Hz, 3H), 1.16-1.22 (m, 1H), 0.94 (d, J= 5.6 Hz, 3H), 0.90 (t, J= 6.0 Hz, 3H). 15 Example 21 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid pentylamide LCMS: 1.91 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 5.92 20 (s, 1H), 4.08-4.11 (m, 2H), 4.03 (s, 3H), 4.01 (s, 3H), 3.47-3.51 (s, 2H), 1.68 (m, 2H), 1.42 (m, 7H), 0.96 (t, J= 7.2 Hz, 3H). Example 22 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 25 cyclohexylamide LCMS: 1.90 min; M+H: 359 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 5.69 (s, 1H), 3.98-4.02 (m, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 2.01-2.03 (m, 2H), 1.71-1.73 (m, 2H), 1.38-1.42 (m, 2H), 1.33 (t, J= 4.8 Hz, 3H), 1.16-1.22 (m, 4H). 30 Example 23 WO 2013/068489 PCT/EP2012/072175 97 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (1,3 dimethyl-butyl)-amide LCMS: 1.97 min; M+H: 361 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.74 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 5.62 5 (s, 1H), 4.23-4.27 (m, 1H), 3.96-4.02 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.65 (m, 1H), 1.41 (m, 1H), 1.33 (m, 4H), 1.21 (d, J= 6.4 Hz, 3H), 0.93 (d, J= 6.4 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H). Example 24 10 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3,3 dimethyl-butyl)-amide LCMS: 1.98 min; M+H: 361 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.54 (s, 1H), 7.28 (s, 1H), 5.71 (s, 1H), 3.98-4.02 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.42 (s, 2H), 1.48 (m, 2H), 1.33 (t, 15 J= 5.4 Hz, 3H), 0.93 (s, 9H). Example 25 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 ethyl-butyl)-amide 20 LCMS: 1.98 min; M+H: 361 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 5.87 (s, 1H), 4.06-4.10 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.44-3.46 (m, 2H), 1.52-1.55 (m, 1H), 1.40-1.45 (m, 7H), 0.96 (t, J= 6.4 Hz, 3H). 25 Example 26 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzylamide LCMS: 1.84 min; M+H: 367 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.56 (s, 1H), 7.33-7.42 (m, 6H), 30 6.16 (s, 1H), 4.67 (s, 2H), 4.03-4.07 (m, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 1.39 (m, 3H). Example 27 WO 2013/068489 PCT/EP2012/072175 98 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid dicyclopropylmethyl-amide LCMS: 1.91 min; M+H: 371 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 5.85 5 (s, 1H), 4.00-4.04 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.26 (m, 1H), 1.34 (t, J= 7.0 Hz, 3H), 0.93 (m, 2H), 0.54 (m, 2H), 0.37-0.45 (m, 6H). Example 28 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 10 cyclohexylmethyl-amide LCMS: 2.00 min; M+H: 373 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 5.95 (s, 1H), 4.04-4.08 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.33 (s, 2H), 1.76-1.84 (m, 4H), 1.68-1.72 (m, 2H), 1.40 (s, 3H), 1.21-1.29 (m, 3H), 1.02-1.06 (m, 2H). 15 Example 29 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 phenyl-ethyl)-amide LCMS: 1.89 min; M+H: 381 20 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.69 (s, 1H), 7.38-7.40 (m, 2H), 7.31-7.35 (m, 4H), 7.22-7.25 (m, 1H), 6.25 (s, 1H), 5.33 (s, 1H), 3.92-3.96 (m, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 1.59 (d, J= 5.2 Hz, 3H), 1.31 (s, 3H). Example 30 25 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2 fluoro-benzylamide LCMS: 1.86 min; M+H: 385 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.81 (s, 1H), 7.53 (s, 1H), 7.46-7.49 (m, 1H), 7.41 (s, 1H), 7.30.7.33 (m, 1H), 7.15-7.18 (m, 1H), 7.08-7.12 (m, 1H), 6.28 (s, 1H), 30 4.72 (d, J = 4.4 Hz, 2H), 4.03-4.08 (m, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 1.38 (d, J= 5.8 Hz, 3H).
WO 2013/068489 PCT/EP2012/072175 99 Example 31 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3 fluoro-benzylamide LCMS: 1.87 min; M+H: 385 5 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.33 7.37 (m, 1H), 7.18 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.00-7.04 (m, 1H), 6.22 (s, 1H), 4.67 (d, J = 4.8 Hz, 2H), 4.04-4.08 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 1.39 (d, J = 5.2 Hz, 3H). 10 Example 32 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 4 fluoro-benzylamide LCMS: 1.86 min; M+H: 385 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.78 (s, 1H), 7.55 (s, 1H), 7.38-7.41 (m, 3H), 15 7.05-7.09 (m, 2H), 6.32 (s, 1H), 4.63 (d, J = 4.4 Hz, 2H), 4.00-4.04 (m, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 1.37 (d, J= 5.6 Hz, 3H). Example 33 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2,3 20 difluoro-benzylamide LCMS: 1.90 min; M+H: 403 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.81 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.24 (m, 1H), 7.08-7.16 (m, 2H), 6.29 (s, 1H), 4.73 (d, J= 5.6 Hz, 2H), 4.04-4.07 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 1.39 (t, J= 7.2 Hz, 3H). 25 Example 34 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2,4 difluoro-benzylamide LCMS: 1.90 min; M+H: 403 30 IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.74 (s, 1H), 7.47 (s, 1H), 7.36-7.43 (m, 1H), 7.32 (s, 1H), 6.76-6.85 (m, 2H), 6.17 (s, 1H), 4.59 (d, J= 5.6 Hz, 2H), 3.96-4.01 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H).
WO 2013/068489 PCT/EP2012/072175 100 Example 35 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2,6 difluoro-benzylamide 5 LCMS: 1.86 min; M+H: 403 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.19 (m, 1H), 6.88 (m, 2H), 6.16 (s, 1H), 4.71 (d, J= 5.2 Hz, 2H), 3.96-4.01 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H). 10 Example 36 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3,4 difluoro-benzylamide LCMS: 1.91 min; M+H: 403 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.74 (s, 1H), 7.51 (s, 1H), 7.33 (s, 1H), 7.06 15 7.17 (m, 3H), 6.17 (s, 1H), 4.55 (d, J= 5.6 Hz, 2H), 3.96-4.02 (m, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H). Example 37 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 3,5 20 difluoro-benzylamide LCMS: 1.92 min; M+H: 403 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.74 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 6.85 6.89 (m, 2H), 6.67-6.72 (m, 1H), 6.24 (s, 1H), 4.58 (d, J= 6.0 Hz, 2H), 3.97-4.02 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.33 (t, J= 7.0 Hz, 3H). 25 Example 38 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid phenethyl-amide LCMS: 1.88 min; M+H: 381 30 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.79 (s, 1H), 7.55 (s, 1H), 7.33-7.36 (s, 2H), 7.25-7.28 (m, 3H), 7.16 (s, 1H), 5.88 (s, 1H), 3.93-4.01 (m, 8H), 3.76 (s, 2H), 3.00 (t, J = 5.2 Hz, 3H), 1.36 (t, J= 4.8 Hz, 3H).
WO 2013/068489 PCT/EP2012/072175 101 Example 39 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid [1-(4 fluoro-phenyl)-ethyl]-amide 5 LCMS: 1.92 min; M+H: 399 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.41-7.44 (m, 3H), 7.35 (s, 1H), 7.07 (m, 2H), 6.23 (s, 1H), 5.37 (s, 1H), 4.01-4.04 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 1.64 (d, J= 5.6 Hz, 2H), 1.38 (t, J= 5.2 Hz, 3H). 10 Example 40 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan 1-ylamide LCMS: 1.94 min; M+H: 393 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.58 (s, 1H), 7.34-7.38 (m, 2H), 15 7.17-7.23 (m, 3H), 6.05 (m, 1H), 5.66 (s, 1H), 3.96-4.00 (m, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.97-3.03 (m, 1H), 2.86-2.71 (m, 1H), 2.64-2.71 (m, 1H), 1.89-1.95 (m, 1H), 1.32 (t, J= 5.2 Hz, 3H). Example 41 20 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan 2-ylamide LCMS: 1.93 min; M+H: 393 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.80 (s, 1H), 7.47 (s, 1H), 7.39 (s, 1H), 7.28 7.30 (m, 2H), 7.20-7.22 (m, 2H), 6.15 (s, 1H), 4.96 (s, 1H), 3.98-4.05 (m, 5H), 3.83 (s, 25 3H), 3.43-3.48 (m, 2H), 2.96-3.01 (m, 2H), 1.37 (s, 3H). Example 42 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid [1-(4 fluoro-phenyl)- 1-methyl-ethyl] -amide 30 LCMS: 1.98 min; M+H: 413 WO 2013/068489 PCT/EP2012/072175 102 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.44-7.47 (m, 3H), 7.39 (s, 1H), 7.03-7.07 (m, 2H), 6.18 (s, 1H), 4.06-4.10 (m, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 1.84 (s, 6H), 1.42 (s, 3H). 5 Example 43 4-(Azetidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin- 1-one LCMS: 1.58 min; M+H: 317 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 4.13 (t, J= 7.6 Hz, 4H), 3.98-4.03 (m, 2H), 3.94 (s, 6H), 2.24-2.32 (m, 2H), 1.32 (t, J= 7.2 10 Hz, 3H). Example 44 2-Ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine-1-carbonyl)-2H-isoquinolin-1 one 15 LCMS: 1.74 min; M+H: 345 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.18 (s, 1H), 7.03 (br, 1H), 4.41 (br, 1H), 4.03-4.07 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.38 (br, 2H), 1.63-2.13 (m, 4H), 1.39 (t, J= 5.6 Hz, 3H), 1.15-1.41 (br, 3H). 20 Example 45 2-Ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquinolin- 1-one LCMS: 1.54 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.78 (s, 1H), 7.10 (s, 1H), 6.87 (s, 1H), 3.97 4.03 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.48-3.64 (br, 8H), 1.33 (t, J= 7.4 Hz, 3H). 25 Example 46 2-Ethyl-4-(3-fluoro-pyrrolidine- 1 -carbonyl)-6,7-dimethoxy-2H-isoquinolin- 1-one LCMS: 1.61 min; M+H: 349 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 5.22 30 5.34 (br, 1H), 3.98-4.03 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.44-3.76 (br, 4H), 2.25 (br, 1H), 1.95-2.06 (br, 1H), 1.33 (t, J= 7.0 Hz, 3H).
WO 2013/068489 PCT/EP2012/072175 103 Example 47 2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperazine- 1 -carbonyl)-2H-isoquinolin- 1-one LCMS: 1.52 min; M+H: 360 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 3.97 5 4.01 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.61 (br, 4H), 2.41 (br, 4H), 2.30 (s, 3H), 1.33 (t, J= 7.2 Hz, 3H). Example 48 4-(3,3-Difluoro-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1 10 one LCMS: 1.74 min; M+H: 367 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 4.06 4.10 (m, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.86 (br, 4H), 2.43 (s, 2H), 1.40 (t, J= 6.0 Hz, 3H). 15 Example 49 4-(3-Dimethylamino-pyrrolidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one LCMS: 1.55 min; M+H: 374 20 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.22 (s, 1H), 7.03 (s, 1H), 4.04 4.09 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 2.81-3.57 (br, 4H), 1.61-2.33 (m, 9H), 1.39 (t, J = 5.6 Hz, 3H). Example 50 25 2-Ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine- 1 -carbonyl)-2H isoquinolin-1-one LCMS: 1.72 min; M+H: 375 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 4.45 (br, 1H), 4.06-4.10 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.37-3.49 (m, 5H), 1.76-2.08 (m, 30 4H), 1.41 (s, 3H). Example 51 WO 2013/068489 PCT/EP2012/072175 104 4-(1,3-Dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1 one LCMS: 1.86 min; M+H: 379 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.87 (s, 1H), 7.27-7.37 (m, 4H), 7.16 (s, 1H), 5 7.01 (s, 1H), 5.07 (s, 2H), 4.75 (s, 2H), 4.07-4.11 (m, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 1.42 (t, J = 5.2 Hz, 3H). Example 52 4-(4,4-Difluoro-piperidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1 10 one LCMS: 1.80 min; M+H: 381 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.19 (s, 1H), 6.90 (s, 1H), 5.07 (s, 2H), 4.75 (s, 2H), 4.04-4.07 (m, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.73 (br, 4H), 2.02 (br, 4H), 1.40 (t, J = 5.4 Hz, 3H). 15 Example 53 2-Ethyl-4-(4-isopropyl-piperazine-1-carbonyl)-6,7-dimethoxy-2H-isoquinolin-1 one LCMS: 1.70 min; M+H: 388 20 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.16 (s, 1H), 6.93 (s, 1H), 4.03 4.08 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.29-3.79 (br, 4H), 2.73 (s, 1H), 2.51 (br, 4H), 1.40 (t, J = 5.6 Hz, 3H), 1.05 (d, J = 4.8 Hz, 6H). Example 54 25 4-(4-Dimethylamino-piperidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one LCMS: 1.50 min; M+H: 388 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.14 (s, 1H), 6.92 (s, 1H), 4.08 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 2.96 (s, 2H), 2.35-2.43 (br, 7H), 1.97 (br, 2H), 1.53 30 (br, 4H), 1.39 (t, J= 7.0 Hz, 3H). Example 55 WO 2013/068489 PCT/EP2012/072175 105 2-Ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine- 1 -carbonyl)-2H isoquinolin-1-one LCMS: 1.89 min; M+H: 399 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.32 (s, 1H), 7.09 (s, 1H), 5.16 5 (s, 1H), 4.02-4.12 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.47 (t, J = 5.6 Hz, 2H), 2.15-2.25 (m, 2H), 2.04-2.09 (m, 1H), 1.88-1.93 (m, 1H), 1.41 (t, J= 5.8 Hz, 3H). Example 56 4-(4-Cyclopropylmethyl-piperazine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H 10 isoquinolin-1-one LCMS: 1.74 min; M+H: 400 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.16 (s, 1H), 6.93 (s, 1H), 4.02 4.08 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.63 (br, 4H), 2.55 (br, 4H), 2.31 (s, 2H), 1.40 (t, J= 6.4 Hz, 3H), 0.87 (s, 1H), 0.54 (s, 2H), 0.12 (s, 2H). 15 Example 57 2-Ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin- 1 -ylmethyl-pyrrolidine- 1 -carbonyl) 2H-isoquinolin-1-one LCMS: 1.65 min; M+H: 414 20 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 4.59 (br, 1H), 4.04-4.42 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.45 (br, 2H), 2.76 (br, 6H), 1.38-2.05 (m, 8H), 1.40 (t, J= 5.8 Hz, 3H). Example 58 25 2-Ethyl-6,7-dimethoxy-4-(4-pyrrolidin- 1 -yl-piperidine- 1 -carbonyl)-2H isoquinolin-1-one LCMS: 1.58 min; M+H: 414 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.13 (s, 1H), 6.92 (s, 1H), 4.66 (br, 1H), 4.05 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.02 (br, 4H), 2.64 (br, 4H), 2.36 (br, 30 2H), 2.00 (br, 2H), 1.85 (br, 4H), 1.38 (t, J= 6.0 Hz, 3H). Example 59 WO 2013/068489 PCT/EP2012/072175 106 4-[4-(2-Dimethylamino-ethyl)-piperazine- 1 -carbonyl]-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one LCMS: 1.46 min; M+H: 417 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.15 (s, 1H), 6.92 (s, 1H), 4.07 5 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.67 (br, 4H), 2.53-2.68 (m, 14H), 1.39 (t, J= 5.6 Hz, 3H). Example 60 4-([1,4']Bipiperidinyl- l'-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin- 1-one 10 LCMS: 1.66 min; M+H: 428 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.14 (br, 1H), 6.89 (br, 1H), 3.79-4.83 (b, IH), 2.93 (br, 4H), 2.55 (br, 4H), 1.97 (br, 4H), 1.63 (br, 5H), 1.39 (t, J= 5.6 Hz, 3H). 15 Example 61 4-[4-(3-Dimethylamino-propyl)-piperazine-1-carbonyl]-2-ethyl-6,7-dimethoxy 2H-isoquinolin-1-one LCMS: 1.45 min; M+H: 431 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.14 (s, 1H), 6.92 (s, 1H), 4.06 20 (br, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.63 (br, 4H), 2.80 (br, 2H), 2.59 (br, 6H), 2.46 (br, 6H), 1.92 (br, 2H), 1.39 (t, J= 6.0 Hz, 3H). Example 62 2-Ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carbonyl]-2H 25 isoquinolin-1-one LCMS: 1.48 min; M+H: 443 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 3.99 (m, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.56 (br, 4H), 2.45-2.67 (br, 11H), 1.81 (br, 5H), 1.32 (t, J= 7.2 Hz, 3H). 30 Example 63 WO 2013/068489 PCT/EP2012/072175 107 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid dimethylamide LCMS: 1.55 min; M+H: 305 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.15 (s, 1H), 6.90 (s, 1H), 4.07 5 (br, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.10 (br, 6H), 1.39 (t, J= 4.8 Hz, 3H). Example 64 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl methyl-amide 10 LCMS: 1.63 min; M+H: 319 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.04 4.09 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.50 (br, 2H), 3.04 (br, 3H), 1.39 (t, J= 7.2 Hz, 3H), 1.21 (br, 3H). 15 Example 65 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isopropyl-methyl-amide LCMS: 1.73 min; M+H: 333 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.78 (s, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 3.99 20 (m, 3H), 3.94 (s, 3H), 3.87 (s, 3H), 2.85 (br, 3H), 1.32 (t, J= 7.2 Hz, 3H), 1.14 (s, 6H). Example 66 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid diethylamide 25 LCMS: 1.72 min; M+H: 333 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.10 (s, 1H), 6.85 (s, 1H), 4.08 (br, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.56 (br, 4H), 3.04 (br, 3H), 1.40 (br, 3H), 1.21 (br, 6H). 30 Example 67 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl propyl-amide WO 2013/068489 PCT/EP2012/072175 108 LCMS: 1.73 min; M+H: 333 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.11 (s, 1H), 6.88 (s, 1H), 4.07 (br, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.42 (br, 2H), 3.02 (br, 3H), 1.63 (br, 2H), 1.39 (br, 3H), 0.89 (br, 3H). 5 Example 68 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl isopropyl-amide LCMS: 1.81 min; M+H: 347 10 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.06 (s, 1H), 6.85 (s, 1H), 4.07 (br, 3H), 4.01 (s, 3H), 3.93 (s, 3H), 3.34-3.60 (br, 2H), 1.39 (t, J= 5.6 Hz, 3H), 1.19 (br, 9H). Example 69 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid tert butyl-methyl-amide LCMS: 1.87 min; M+H: 347 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.13 (s, 1H), 6.98 (s, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 2.80 (s, 3H), 1.51 (s, 9H), 1.33 (t, J= 6.8 Hz, 3H). 20 Example 70 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isobutyl-methyl-amide LCMS: 1.83 min; M+H: 347 25 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.78 (s, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.36 (br, 2H), 2.95 (br, 3H), 1.95 (br, 1H), 1.32 (t, J = 6.8 Hz, 3H), 0.78-0.91 (br, 6H). Example 71 30 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butyl methyl-amide LCMS: 1.84 min; M+H: 347 WO 2013/068489 PCT/EP2012/072175 109 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 4.04 4.09 (m, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.44 (br, 2H), 3.03 (br, 3H), 1.65 (br, 2H), 1.39 (t, J= 5.8 Hz, 3H), 1.19 (br, 2H), 0.82 (br, 3H). 5 Example 72 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl propyl-amide LCMS: 1.82 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 4.01 10 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.26-3.43 (br, 4H), 1.61 (br, 2H), 1.32 (t, J= 7.2 Hz, 3H), 1.10 (br, 3H), 0.81 (br, 3H). Example 73 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 15 dimethylamino-ethyl)-methyl-amide LCMS: 1.56 min; M+H: 362 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.20 (s, 1H), 7.00 (s, 1H), 4.04 4.10 (m, 2H), 4.01 (s, 3H), 3.96 (s, 3H), 3.47-3.71 (br, 2H), 3.01 (s, 3H), 2.58 (br, 2H), 2.28 (br, 6H), 1.40 (t, J= 7.2 Hz, 3H). 20 Example 74 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl (2-methoxy-ethyl)-amide LCMS: 1.70 min; M+H: 363 25 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.10 (s, 1H), 6.87 (s, 1H), 3.96 4.02 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.29-3.52 (br, 9H), 1.32 (t, J= 7.2 Hz, 3H), 1.07 (br, 3H). Example 75 30 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopentyl-methyl-amide LCMS: 1.86 min; M+H: 359 WO 2013/068489 PCT/EP2012/072175 110 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 4.07 (br, 3H), 4.02 (s, 3H), 3.94 (s, 3H), 2.95 (br, 3H), 1.59-1.72 (m, 6H), 1.56 (br, 2H), 1.40 (br, 3H). 5 Example 76 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ethyl butyl-amide LCMS: 1.93 min; M+H: 361 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.78 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 3.97 10 4.02 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.20-3.48 (br, 4H), 1.44 (br, 4H), 1.32 (t, J= 5.4 Hz, 3H), 0.78-1.11 (br, 6H). Example 77 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl 15 pentyl-amide LCMS: 1.94 min; M+H: 361 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.07 (br, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 2.97-3.59 (br, 5H), 1.60 (br, 4H), 1.39 (br, 3H), 1.23 (br, 2H), 0.87 (br, 3H). 20 Example 78 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid diisopropylamide LCMS: 1.92 min; M+H: 361 25 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 6.99 (s, 1H), 6.86 (s, 1H), 4.02 4.08 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.74 (br, 2H), 1.38 (t, J= 7.2 Hz, 3H), 1.36 (br, 12H). Example 79 30 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid isopropyl-propyl-amide LCMS: 1.91 min; M+H: 361 WO 2013/068489 PCT/EP2012/072175 111 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 4.06 (br, 3H), 4.01 (s, 3H), 3.93 (s, 3H), 3.18-3.44 (br, 2H), 1.69 (br, 2H), 1.38 (t, J= 5.8 Hz, 3H), 0.98-1.17 (br, 9H). 5 Example 80 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid dipropylamide LCMS: 1.92 min; M+H: 361 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.65 (s, 1H), 7.51 (s, 1H), 6.75 (s, 1H), 3.97 10 4.03 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.42 (s, 2H), 3.13 (s, 2H), 1.47-1.67 (br, 4H), 1.23 (t, J= 7.0 Hz, 3H), 0.66-0.95 (br, 6H). Example 81 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 15 dimethylamino-propyl)-methyl-amide LCMS: 1.48 min; M+H: 376 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.09 (s, 1H), 6.81 (s, 1H), 3.97 4.03 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.44 (br, 3H), 3.00 (s, 3H), 1.84-2.17 (br, 9H), 1.32 (t, J= 7.2 Hz, 3H). 20 Example 82 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexyl-methyl-amide LCMS: 1.93 min; M+H: 373 25 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.78 (s, 1H), 7.02 (s, 1H), 6.78 (s, 1H), 3.97 4.03 (m, 3H), 3.94 (s, 3H), 3.87 (s, 3H), 2.73-2.95 (br, 3H), 1.51-1.74 (br, 8H), 1.32 (t, J = 5.8 Hz, 3H), 1.01 (br, 2H). Example 83 30 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylmethyl-propyl-amide LCMS: 1.94 min; M+H: 373 WO 2013/068489 PCT/EP2012/072175 112 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.77 (s, 1H), 7.03 (s, 1H), 6.83 (s, 1H), 3.97 4.03 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.28 (br, 4H), 1.52 (br, 1H), 1.32 (t, J= 7.2 Hz, 3H), 0.81 (br, 4H), 0.48 (s, 2H). 5 Example 84 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid diisobutylamide LCMS: 2.08 min; M+H: 389 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.85 (s, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 4.04 10 4.09 (m, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 3.07-3.42 (br, 4H), 1.88-2.15 (br, 2H), 1.39 (t, J = 5.6 Hz, 3H), 1.05 (br, 6H), 0.77 (br, 6H). Example 85 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzyl 15 methyl-amide LCMS: 1.88 min; M+H: 381 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.24-7.32 (m, 4H), 7.08 (s, 2H), 6.70 (br, 1H), 4.65 (br, 2H), 3.65-3.93 (br, 8H), 2.86 (br, 3H), 1.26 (s, 3H). 20 Example 86 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 fluoro-benzyl)-methyl-amide LCMS: 1.89 min; M+H: 399 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.40 (br, 1H), 7.29-7.34 (m, 25 1H), 7.15-7.18 (m, 2H), 7.06-7.10 (m, 1H), 6.79 (br, 1H), 4.79 (br, 2H), 4.02-4.06 (m, 2H), 4.00 (s, 3H), 3.79 (br, 3H), 2.97 (br, 3H), 1.36 (br, 3H). Example 87 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 30 fluoro-benzyl)-methyl-amide LCMS: 1.90 min; M+H: 399 WO 2013/068489 PCT/EP2012/072175 113 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.40 (br, 1H), 7.15 (br, 2H), 7.06 (m, 2H), 6.73 (br, 1H), 4.70 (br, 2H), 4.04 (br, 2H), 4.00 (s, 3H), 3.79 (br, 3H), 2.93 (br, 3H), 1.35 (br, 3H). 5 Example 88 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 fluoro-benzyl)-methyl-amide LCMS: 1.90 min; M+H: 399 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.32-7.36 (m, 1H), 6.82-7.16 10 (m, 5H), 4.74 (br, 2H), 4.04 (br, 2H), 4.00 (s, 3H), 3.80 (br, 3H), 2.93 (br, 3H), 1.36 (br, 3H). Example 89 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl 15 phenethyl-amide LCMS: 1.89 min; M+H: 395 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.19 (br, 5H), 7.02 (br, 1H), 6.72 (br, 1H), 3.93 (s, 3H), 3.87 (br, 2H), 3.82 (s, 3H), 3.44 (br, 2H), 2.86-3.08 (br, 5H), 1.26 (t, J = 7.0 Hz, 3H). 20 Example 90 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (2 methoxy-benzyl)-methyl-amide LCMS: 1.89 min; M+H: 411 25 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.24 (s, 1H), 6.80-7.06 (m, 5H), 4.45-4.75 (br, 2H), 3.65-3.93 (m, 11H), 2.83-3.06 (m, 3H), 1.18 (br, 3H). Example 91 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (4 30 methoxy-benzyl)-methyl-amide LCMS: 1.86 min; M+H: 411 WO 2013/068489 PCT/EP2012/072175 114 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.38 (br, 1H), 6.72-7.15 (m, 5H), 3.72-4.69 (m, 13H), 2.88 (br, 3H), 1.35 (br, 3H). Example 92 5 2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (3 methoxy-benzyl)-methyl-amide LCMS: 1.88 min; M+H: 411 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.22 (m, 2H), 6.76-7.09 (m, 4H), 4.60 (br, 2H), 3.73-3.93 (m, 11H), 2.85 (br, 3H), 1.27 (br, 3H). 10 Example 93 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl (3-trifluoromethyl-benzyl)-amide LCMS: 202 min; M+H: 449 15 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.52 (m, 3H), 7.45 (m, 1H), 7.09 (s, 1H), 6.75 (s, 1H), 4.71 (s, 2H), 3.96 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 2.91 (s, 3H), 1.27 (s, 3H). Example 94 20 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydro-isoquinoline-4-carboxylic acid benzyl (2-dimethylamino-ethyl)-amide LCMS: 1.88 min; M+H: 438 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.75 (s, 1H), 7.23-7.27 (m, 4H), 7.08 (br, 3H), 4.47 (br, 2H), 3.17-3.93 (m, IH), 1.98-2.53 (m, 8H), 1.22 (s, 3H). 25 Example 95 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 benzyl-piperidin-4-yl)-methyl-amide LCMS: 1.94 min; M+H: 464 30 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.29 (br, 4H), 7.25 (br, 1H), 7.10 (s, 1H), 6.81 (s, 1H), 4.02-4.08 (m, 3H), 4.01 (s, 3H), 3.91 (s, 3H), 3.50 (br, 2H), 2.96 (br, 5H), 1.72-2.17 (m, 6H), 1.38 (t, J= 5.8 Hz, 3H).
WO 2013/068489 PCT/EP2012/072175 115 The compounds of the following examples 96 to 118 were prepared in analogy to example 1, where however, in step 1.6, ethylamine was replaced by the respective amine and in step 1.8 butylamine was used instead of methylamine. 5 Example 96 6,7-Dimethoxy-1-oxo-2-(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide LCMS: 1.94 min; M+H: 387 10 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 5.85 (s, 1H), 4.68 (q, J= 7.6 Hz, 2H), 4.01 (s, 3H), 4.00(s, 3H), 3.48 (q, J= 5.6 Hz, 2H), 1.64 (m, 2H), 1.45 (m, 2H), 0.99 (t, J= 7.2 Hz, 3H). Example 97 15 2-(2-Fluoro-ethyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 1.77 min; M+H: 351 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.80 (s, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 5.84 (s, 1H), 4.84 (s, 1H), 4.71 (s, 1H), 4.37 (s, 1H), 4.28 (s, 1H), 4.01 (s, 6H), 3.46 (d, J= 20 5.2 Hz, 2H), 1.61-1.65 (m, 2H), 1.41-1.48 (m, 2H), 0.99 (t, J= 7.6 Hz, 3H). Example 98 2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide 25 LCMS: 1.81 min; M+H: 345 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.79 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 6.10 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.47-3.53 (m, 2H), 3.32-3.36 (m, 1H), 1.64-1.71 (m, 2H), 1.45-1.53 (m, 2H), 1.14-1.20 (m, 2H), 0.99 (t, J= 7.2 Hz, 3H), 0.89-0.94 (m, 2H). 30 Example 99 2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide WO 2013/068489 PCT/EP2012/072175 116 LCMS: 1.85 min; M+H: 347 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 5.83 (br, 1H), 5.31-5.40 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.46-3.53 (m, 2H), 1.60-1.69 (m, 2H), 1.41-1.49 (m, 2H), 1.41 (d, J= 6.8 Hz, 6H), 0.99 (t, J = 7.2 Hz, 3H). 5 Example 100 6,7-Dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 1.86 min; M+H: 347 10 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.61 (s, 1H), 7.36 (s, 1H), 5.83 (br, 1H), 3.98-4.03 (m, 8H), 3.45-3.52 (m, 2H), 1.82 (br, 2H), 1.60-1.68 (m, 2H), 1.41 1.50 (m, 2H), 0.99 (t, J= 7.2 Hz, 3H). Example 101 15 6,7-Dimethoxy-1-oxo-2-(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide LCMS: 1.94 min; M+H: 401 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.79 (s, 1H), 7.61 (s, 1H), 7.32 (s, 1H), 5.81 (br, 1H), 4.22 (t, J= 6.6 Hz, 2H), 4.01 (s, 6H), 3.45-3.51 (m, 2H), 2.60-73 (m, 2H), 20 1.60-1.68 (m, 2H), 1.41-1.49 (m, 2H), 0.99 (t, J= 7.4 Hz, 3H). Example 102 6,7-Dimethoxy-2-(2-methoxy-ethyl)- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide 25 LCMS: 1.76 min; M+H: 363 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.81 (s, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 5.88 (br, 1H), 4.20 (t, J= 4.8 Hz, 2H), 4.00 (s, 6H), 3.72 (t, J= 4.8 Hz, 2H), 3.43-3.51 (m, 2H), 3.33 (s, 3H), 1.58-1.67 (m, 2H), 1.41-1.49 (m, 2H), 0.99 (t, J= 7.4 Hz, 3H). 30 Example 103 2-Cyclobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide WO 2013/068489 PCT/EP2012/072175 117 LCMS: 1.90 min; M+H: 359 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.81 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 5.85 (br, 1H), 5.16-5.23 (m, 1H), 4.00 (s, 6H), 3.46-3.53 (m, 2H), 2.53 (br, 2H), 2.25-2.29 (m, 2H), 1.88-1.92 (m, 2H), 1.60-1.69 (m, 2H), 1.43-1.51 (m, 2H), 1.00 (t, J= 7.2 Hz, 5 3H). Example 104 2-tert-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide 10 LCMS: 1.97 min; M+H: 361 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.76 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 5.75 (br, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.38-3.42 (m, 2H), 1.53-1.59 (m, 2H), 1.35-1.41 (m, 2H), 1.18 (s, 9H), 0.92 (t, J= 7.4 Hz, 3H). 15 Example 105 2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 1.93 min; M+H: 361 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.57 (s, 1H), 7.33 (s, 1H), 5.85 20 (br, 1H), 5.14-5.20 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.46-3.51 (m, 2H), 1.73-1.78 (m, 2H), 1.61-1.67 (m, 2H), 1.43-1.49 (m, 2H), 1.39 (d, J = 7.2, 3H), 0.99 (t, J= 7.4 Hz, 3H), 0.89 (t, J= 7.4 Hz, 3H). Example 106 25 2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 1.94 min; M+H: 361 1 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 5.85 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.82 (d, J= 7.6 Hz, 2H), 3.45-3.50 (m, 2H), 2.17 30 2.23 (m, 1H), 1.61-1.67 (m, 2H), 1.42-1.49 (m, 2H), 0.96-1.01 (m, 9H). Example 107 WO 2013/068489 PCT/EP2012/072175 118 2-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 1.98 min; M+H: 361 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.82 (s, 1H), 7.60 (s, 1H), 7.34 (s, 1H), 5.83 5 (br, 1H), 3.99-4.03 (m, 8H), 3.45-3.50 (m, 2H), 1.73-1.78 (m, 2H), 1.61-1.67 (m, 2H), 1.39-1.49 (m, 4H), 0.95-1.01 (m, 6H). Example 108 2-Cyclopropylmethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 10 carboxylic acid butylamide LCMS: 1.88 min; M+H: 359 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 5.83 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.90 (d, J= 6.8 Hz, 2H), 3.45-3.51 (m, 2H), 1.60 1.66 (m, 2H), 1.42-1.50 (m, 2H), 1.23-1.29 (m, 1H), 0.99 (t, J= 7.4 Hz, 3H), 0.60-0.64 15 (m, 2H), 0.41-0.46 (m, 2H). Example 109 2-Cyclopentyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide 20 LCMS: 1.97 min; M+H: 373 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.83 (s, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 5.79 (br, 1H), 5.34-5.38 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.46-3.52 (m, 2H), 2.18-2.22 (m, 2H), 1.89 (br, 2H), 1.73-1.78 (m, 4H), 1.61-1.67 (m, 2H), 1.42-1.50 (m, 2H), 0.99 (t, J= 7.4 Hz, 3H). 25 Example 110 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 1.99 min; M+H: 375 30 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.86 (s, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 5.78 (br, 1H), 5.03 (br, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.45-3.51 (m, 2H), 1.81-1.87 (m, 2H), 1.61-1.67 (m, 4H), 1.43-1.49 (m, 2H), 0.99 (t, J= 7.2 Hz, 3H), 0.86 (t, J= 7.2 Hz, 6H).
WO 2013/068489 PCT/EP2012/072175 119 Example 111 6,7-Dimethoxy-2-(2-methoxy-benzyl)- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide 5 LCMS: 2.00 min; M+H: 425 H NMR (CDCl 3 /TMS, 400MHz) 6: 7.84 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.33 7.36 (m, 1H), 7.25 (br, 1H), 6.89-6.95 (m, 2H), 5.77 (br, 1H), 5.22 (s, 2H), 3.99 (s, 6H), 3.88 (s, 3H), 3.43-3.47 (m, 2H), 1.58-1.62 (m, 2H), 1.41-1.47 (m, 2H), 0.98 (t, J= 7.4 Hz, 3H). 10 Example 112 2-Indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide LCMS: 2.05 min; M+H: 421 15 1H NMR (CDCl 3 /TMS, 400MHz) 6: 7.89 (s, 1H), 7.61 (s, 1H), 7.30-7.38 (m, 2H), 7.11 (s, 1H), 7.00 (s, 1H), 6.68 (br, 1H), 5.53 (br, 1H), 4.03 (s, 4H), 3.99 (s, 3H), 3.36 (br, 2H), 3.05-3.14 (m, 2H), 2.82 (br, 1H), 2.05 (br, 1H), 1.41-1.51 (m, 2H), 1.25-1.33 (m, 2H), 0.91 (t, J= 6.8 Hz, 3H). 20 Example 113 2-(2-Dimethylamino-ethyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide Example 114 25 6,7-Dimethoxy- 1 -oxo-2-(2-pyrrolidin- 1 -yl-ethyl)- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide Example 115 2-Benzyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 butylamide Example 116 WO 2013/068489 PCT/EP2012/072175 120 2-(2,4-Difluoro-benzyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide Example 117 5 6,7-Dimethoxy- 1 -oxo-2-(2-piperidin- 1 -yl-ethyl)- 1,2-dihydro-isoquino line-4 carboxylic acid butylamide Example 118 6,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic acid 10 butylamide Example 119 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid butylamide 15 119.1 1-(4,5-Dimethoxy-2-methyl-phenyl)-ethanone A solution of 1,2-dimethoxy-4-methylbenzene in CS 2 (20 mL) was added dropwise to a mixture of acetyl chloride (2.063 g, 26.3 mmol) and aluminium trichloride (3.50 g, 26.3 mmol) in CS 2 (80 mL). The reaction mixture was stirred for 12 h at 25 'C, then poured into ice-water and extracted with DCM. The organic layer was 20 separated and concentrated. The obtained residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1) to give the title compound (3.2 g, 62%) as a yellow oil. LCMS (ESI+): m/z 195 (M+H)*, RT: 0.776 min. 119.2 4,5-Dimethoxy-2-oxalyl-benzoic acid 25 A solution of potassium permanganate (11.39 g, 72.1 mmol) in water (45 mL) was added dropwise to a mixture of 1-(4,5-dimethoxy-2-methyl-phenyl)-ethanone obtained in step 119.1 (2 g, 10.30 mmol) and potassium carbonate (2.135 g, 15.45 mmol) in H 2 0 (5 mL), and the reaction mixture was stirred for 3 hat 50 'C. Then ethanol was added and the resulting mixture was stirred for 30min. The solid was filtered off, the filtrate 30 was adjusted to pH = 2 with conc. HCl, EtOAc was added, and the organic layer was separated and concentrated to give the title compound (1.7 g, 64.9 % ) as a white solid. LCMS (ESI+): m/z 255 (M+H)*, RT: 0.524 min.
WO 2013/068489 PCT/EP2012/072175 121 119.3 6,7-Dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid A solution of 4,5-dimethoxy-2-oxalyl-benzoic acid obtained in step 119.2 (1.15 g, 4.52 mmol) and hydrazine hydrate (254 mg, 4.98 mmol) in ethanol (20 mL) was stirred for 2 h at 75 'C. The solid was filtered to give the title compound (910 mg, 80 % ) as a 5 white solid. LCMS (ESI+): m/z 251 (M+H)*, RT: 0.587 min. 119.4 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid ethyl ester A mixture of 6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 10 obtained in step 119.3 (500 mg, 1.998 mmol), cesium carbonate (1954 mg, 6.00 mmol) and iodoethane (768 mg, 4.92 mmol) in DMF (8 mL) was stirred at 65 'C for 12 h. Water was added, and the solid was filtered to give the title compound (300 mg, 49.0 %) as a white solid. LCMS (ESI+): m/z 307 (M+H)*, RT: 0.839 min. 15 119.5 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid A solution of 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid ethyl ester obtained in step 119.4 (400 mg, 1.306 mmol) and lithium hydroxide (46.9 mg, 1.959 mmol) in ethanol and water (2 mL) was stirred at 35 'C for 3 h. The 20 reaction solution was adjusted to pH = 4 with dilute HCl, and the solid was filtered and washed with water to give the title compound (280 mg, 77 % ) as a white solid. LCMS (ESI+): m/z 279 (M+H)*, RT: 0.862 min. 119.6 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid butylamide 25 A solution of 3-ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid obtained in step 119.5 (200 mg, 0.719 mmol) in SOCl 2 (2 mL) was stirred at 76 'C for 2h. Then SOCl 2 was removed and the residue was dissolved in DCM (5 mL). Butan-1-amine (79 mg, 1.078 mmol) and triethylamine (109 mg, 1.078 mmol) were added dropwise and the resulting reaction was stirred at r.t. for 3 h. The solvent 30 was removed and the obtained residue was washed with EtOAc to give the title compound (140 mg, 58.4 % ) as a white solid. LCMS (ESI+): m/z 334 (M+H)*, RT: 1.910 min.
WO 2013/068489 PCT/EP2012/072175 122 H-NMR (400 MHz , CDCl 3 ): 6 8.75 (s, 1H), 7.78 (s, 1H), 7.37 (br, 1H), 4.33 (t, J = 7.2Hz, 2H), 4.06 (s, 6H), 3.47 (t, J = 7.2 Hz, 2H), 1.65 (t,J=7.2Hz, 2H), 1.47-1.42 (m, 5H), 0.98 (t, J = 7.2 Hz, 3H). 5 The compounds of the following examples 120 to 132 were prepared in analogy to example 119. Example 120 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7,8,9 10 tetrahydro-5H-benzocyclohepten-7-yl)-amide ESI-MS: [M+Na] = 444.20, [M+H*] = 422.20; Example 121 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (R) 15 indan- 1 -ylamide ESI-MS: [M+Na] = 416.10, [M+H*] = 394.10; Example 122 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (1,2,3,4 20 tetrahydro-naphthalen- 1 -yl)-amide ESI-MS: [M+Na] = 430.10, [M+H*] = 408.10; Example 123 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (R) 25 (1,2,3,4-tetrahydro-naphthalen- 1 -yl)-amide ESI-MS: [M+Na] = 430.10, [M+H*] = 408.10; Example 124 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7,8,9 30 tetrahydro-5H-benzocyclohepten-5-yl)-amide ESI-MS: [M+Na] = 444.10, [M+H*] = 422.10; WO 2013/068489 PCT/EP2012/072175 123 Example 125 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (1,2,3,4 tetrahydro-naphthalen-2-yl)-amide ESI-MS: [M+Na] = 430.10, [M+H] = 408.10; 5 Example 126 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (4 bromo-indan- 1 -yl)-amide ESI-MS: 495.10, [M+Na] = 494.10, 474.10, [M] = 472.10; 10 Example 127 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (5 bromo-indan- 1 -yl)-amide ESI-MS: 496.00, [M+Na] = 494.00, 474.00, [M] = 472.00; 15 Example 128 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 2 dimethylaminomethyl-benzylamide ESI-MS: [M+H] = 425.20; 20 Example 129 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7 dihydro-5H-[1]pyrindin-5-yl)-amide ESI-MS: [M+Na] = 417.10, [M+H] = 395.10; 25 Example 130 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7 dihydro-5H-[1]pyrindin-7-yl)-amide ESI-MS: [M+H] = 395.10; 30 Example 131 WO 2013/068489 PCT/EP2012/072175 124 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 3 dimethylaminomethyl-benzylamide ESI-MS: [M+Na] = 447.20, [M+H] = 425.20; 5 Example 132 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 4 dimethylaminomethyl-benzylamide ESI-MS: [M+Na] = 447.20, [M+H] = 425.20; 10 Example 133 2-Ethyl-7-methoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide 133.1 2-(2-Carboxy-4-methoxy-phenyl)-malonic acid dimethyl ester To a solution of dimethyl malonate (45 mL) was added sodium (0.915 g, 39.8 mmol), and the resulting mixture was stirred until sodium had disappeared. Then 15 copper(I) bromide (0.248 g, 1.731 mmol) and 2-bromo-5-methoxy-benzoic acid (4 g, 17.31 mmol) were added and the resulting reaction was stirred at 70 'C for 12 h. Water and EtOAc were added and the organic layer was separated off. The aqueous layer was acidified with conc. HCl, then EtOAc was added and the organic layer was separated and concentrated to give the title compound (3.2 g, 65.5 % ) as a yellow solid. 20 LCMS (ESI+): m/z 283 (M+H)*, RT: 0.724 min. 133.2 2-(2-Carboxy-4-methoxy-phenyl)-malonic acid A solution of 2-(2-carboxy-4-methoxy-phenyl)-malonic acid dimethyl ester obtained in step 133.1 (2.5g, 8.86 mmol) and lithium hydroxide (1.061 g, 44.3 mmol) in
CH
3 0H (30mL) and water (8 mL) was stirred for 12 h at 40 'C. The solvent was 25 removed, the residue was adjusted pH = 4 with dilute HCl, EtOAc was added, and the organic layer was separated and concentrated to give the title compound (1.67 g, 74.2 %) as a white solid. LCMS (ESI+): m/z 255 (M+H)*, RT: 0.453 min. 133.3 2-Carboxymethyl-5-methoxy-benzoic acid 30 A suspension of 2-(2-carboxy-4-methoxy-phenyl)-malonic acid obtained in step 133.2 (200 mg, 0.787 mmol) in toluene (8 mL) was stirred for 12 h at 105 'C. The solid was filtered to give the title compound (100 mg, 60.5 % ) as a white solid.
WO 2013/068489 PCT/EP2012/072175 125 LCMS (ESI+): m/z 211 (M+H)*, RT: 0.630 min. 133.4 5-Methoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester A mixture of 2-carboxymethyl-5-methoxy-benzoic acid obtained in step 133.3 (100 mg, 0.476 mmol) and sulfurous dichloride (170 mg, 1.427 mmol) in CH 3 0H (10 5 mL) was stirred at 65 'C for 12 h. The solvent was removed to give the crude title compound (100 mg, 88 % ) as a yellow oil. LCMS (ESI+): m/z 239 (M+H)*, RT: 0.820 min. 133.5 2-(2-Dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-benzoic acid methyl ester 10 A solution of 5-methoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester obtained in step 133.4 (700 mg, 2.94 mmol) and HOAc (0.5 mL ) in DMF-DMA (15 mL) was stirred 12 h at 90'C, then poured to water and extracted with EtOAc. The organic layer was separated and concentrated to give a residue which was purified by Prep-TLC (PE: EtOAc=1:1) to give the title compound (600 mg, 69.6 % ) as a yellow 15 oil. LCMS (ESI+): m/z 267 (M-27)-, RT: 0.735 min. 133.6 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester A solution of 2-(2-dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-benzoic 20 acid methyl ester obtained in step 133.5 (500mg, 1.705 mmol), ethanamine (231 mg, 5.11 mmol) and DIPEA (1.5ml) in MeOH (15 mL) was stirred at 65'C for 12 h. The solvent was removed, water and EtOAc were added to the residue, the organic layer was separated and concentrated to give the crude title compound (420 mg, 94 % ) as a white solid. 25 LCMS (ESI+): m/z 262 (M+H)*, RT: 0.867 min. 133.7 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 2-Ethyl-7-methoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl ester obtained in step 133.6 and lithium hydroxide (77 mg, 3.22 mmol) in CH 3 0H (15 mL) and water (2mL) were stirred at 35 'C for 5 h. The reaction solution was 30 concentrated and the obtained residue was dissolved in water and adjusted pH=4 with dilute HCl. The solid was filtered to give the title compound (362 mg, 91 % ) as white solid.
WO 2013/068489 PCT/EP2012/072175 126 LCMS (ESI+): m/z 248 (M+H)*, RT: 0.737 min. 133.8 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide A solution of 2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic 5 acid obtained in step 133.7 (300mg, 1.209 mmol) in SOCl 2 (4 mL) was stirred at 76 'C for 2h; then SOCl 2 was removed. The obtained residue was dissolved in DCM (6mL) and butan-1-amine (133 mg, 1.813 mmol) and triethylamine (183 mg, 1.813 mmol) were added dropwise. The resulting reaction was stirred at RT for 3 h. The solvent was removed and the obtained residue was washed with EtOAc to give the title compound 10 (200 mg, 0.659 mmol, 54.6 % yield). IH-NMR (400 MHz , MeOD) :7.93 (d, J= 8.8 Hz, 1H), 7.68 (d, J= 2.8 Hz, 1H),7.44 (s, 1H), 7.25 (dd, 9.2 Hz, 2.8 Hz, 1H), 4.01 (t, J= 7.2 Hz, 2H), 3.81 (s, 3H), 3.28 (t, J= 7.6 Hz, 2H), 1.56-1.51 (m, 2H), 1.39-1.32 (m, 2H), 1.28 (t, J= 7.6 Hz, 3H), 0.89 (t, J= 7.6 Hz, 3H). 15 The compounds of the following examples 134 to 136 were prepared in analogy to example 133. Example 134 20 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide ESI-MS: [M+Na] = 427.10, [M] = 405.10; Example 135 25 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide 135.1 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester A solution of 2-(2-dimethylamino-1-methoxycarbonylvinyl)-4,5-dimethoxy 30 benzoic acid methyl ester obtained in step 1.5 (800 mg, 2.474 mmol), pentan-3-amine (323 mg, 3.71 mmol) and HOAc (1.5mL) in MeOH (15 mL) was stirred at 65'C for 12 h. The solvent was removed and water and EtOAc were added to the obtained residue.
WO 2013/068489 PCT/EP2012/072175 127 The organic layer was separated and concentrated to give the title compound (750 mg, 91 %) as a white solid. LCMS (ESI+): m/z 334 (M+H)*, RT: 0.941 min. 135.2 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 5 carboxylic acid A mixture of 2-(1-ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester obtained in step 135.1 (750 mg, 2.250 mmol) and lithium hydroxide (108 mg, 4.50 mmol) in CH 3 0H (8 mL) and water (2 mL) was stirred at 35 'C for 5 h. The reaction solution was concentrated and the obtained residue was 10 dissolved in water and adjusted pH = 4 with dilute HCl. The solid was filtered to give the title compound (700 mg, 97 % ) as a white solid. LCMS (ESI+): m/z 320 (M+H)*, RT: 0.804 min. 135.3 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide 15 A solution of 2-(1 -ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquino line 4-carboxylic acid obtained in step 135.2 (300 mg, 0.939 mmol) in SOCl 2 (5 mL) was stirred at 76 'C for 2 h. SOCl 2 was removed. The obtained residue was dissolved in DCM (5mL), 2,3-dihydro-1H-inden-1-amine (188 mg, 1.409 mmol) was added dropwise and the resulting reaction was stirred at RT for 3 h. The solvent was removed 20 and the obtained residue was washed with EtOAc to give the title compound (200 mg, 49%) as a yellow solid. LCMS (ESI+): m/z 435 (M+H)*, RT: 2.084 min. IH-NMR (400 MHz ,MeOD) : 6 7.61 (s, 1H), 7.49 (s, 1H), 7.43 (m, 1H), 7.28 7.22 (m, 3H), 5.67 (t, J = 7.6Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.09-3.05 (m, 1H), 25 2.97-2.91 (m, 1H), 2.65-2.60 (m, 1H), 2.08-2.01 (m, 1H), 1.88-1.77 (m, 4H), 1.29 (m, 1H), 0.84 (t, J=1.6 Hz, 6H). Example 136 2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4 30 carboxylic acid butylamide 136.1 1 -Bromo-4-methoxy-2-methyl-benzene WO 2013/068489 PCT/EP2012/072175 128 To a solution of 1-methoxy-3-methylbenzene (51.6 ml, 405 mmol) in DCM (300 mL), 1-bromopyrrolidine-2,5-dione (72.1 g, 405 mmol) was added. The resulting reaction was stirred at about 20 'C overnight. The reaction mixture was diluted with 30 60 'C petroleum ether (200 mL). The mixture was stirred for 30 min. The reaction 5 mixture was filtered. The filtrate was concentrated under reduced pressure to provide the desired product (80 g, 98%) as a yellow oil, which was used in next step without further purification. 136.2 1 -Bromo-4-methoxy-2-methyl-5 -nitro-benzene 1-Bromo-4-methoxy-2-methylbenzene obtained in step 136.1 (60 g, 298 mmol) 10 was dissolved in acetic acid (150 ml) and TFA (150 ml). The mixture was cooled to -5 'C in an ice bath. Fuming nitric acid (14.56 ml, 328 mmol) was added slowly to the reaction. The resulting mixture was stirred at -5 'C for about 2 h. The reaction mixture was diluted with water (100 ml). The aqueous layer was extracted with ethyl acetate (3 x 1OOmL) and washed with sat. NaCl (100 mL), sat. NaHCO 3 (100 mL) and sat. NaCl 15 (100 mL). The organic layer was dried with Na 2
SO
4 , filtered and concentrated. The resulting solid was purified with silica gel column chromatography (hexane/EtOAc = 50:1). The proper fractions were collected and concentrated to give the title compound (20 g, 27%). 136.3 1 -Bromo-4-methoxy-5 -nitro-benzoic acid 20 In a 1 L round-bottomed flask, 1-bromo-4-methoxy-2-methyl-5-nitro-benzene obtained in step 136.2 (70 g, 0.28 mol) and KMnO 4 (270 g, 1.707mol) were dissolved in water (500 ml) and pyridine (250 ml) and the mixture was stirred and heated to about 110 'C over night. The reaction was cooled to ambient temperature and filtered through a sintered glass funnel. The aqueous layer was adjusted to pH = 2 and extracted with 25 ethyl acetate (2 x 750 mL). The organic layer was washed with sat. NaCl (300 mL), dried with Na 2
SO
4 , filtered and concentrated to afford the crude title compound (60 g). This was recrystallized in ethanol to afford the pure title compound (38 g, 48.4 %). LCMS (ESI+): m/z 263 (M+Na)*, RT: 1.32 min. IH NMR (MeOD/TMS, 400MHz) 6: 8.09 (s, 1H), 7.64 (s, 1H), 4.00 (s, 3H). 30 136.4 2-(2-Carboxy-4-methoxy-5 -nitro-phenyl)-malonic acid diethyl ester To rapidly stirred diethyl malonate (58.0 g, 362 mmol) was added sodium (0.999 g, 43.5 mmol) in portions at r.t. After the addition was complete, the mixture was stirred WO 2013/068489 PCT/EP2012/072175 129 at 50 C until the sodium had disappeared. Copper(I) bromide (0.260 g, 1.811 mmol) and then 2-bromo-5-methoxy-4-nitro-benzoic acid obtained in step 136.3 (5.0 g, 18.11 mmol) were added. The mixture was heated at 70 'C overnight. The reaction mixture was dissolved in water and extracted with toluene and EtOAc. The aqueous layer was 5 acidified with HCl (2 N). The mixture was then extracted with EtOAc and dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified on a silica gel column (DCM/MeOH= 10:1, v/v) to afford the title compound as a yellow solid (5.02 g, 78%). LCMS (ESI+): m/z 356 (M+H)*, RT: 1.56 min. 10 1H NMR (CDCl 3 /TMS, 400 MHz) 6: 7.95 (s, 1H), 7.80 (s, 1H), 5.62 (s, 1H), 4.25 4.28 (m, 4H), 4.03 (s, 3H), 1.27-1.33 (m, 6H). 136.5 2-Carboxymethyl-5-methoxy-4-nitro-benzoic acid NaOH (3.05 g, 76 mmol) in water (15 mL) was added over 30 min to a solution of 2-(2-carboxy-4-methoxy-5-nitro-phenyl)-malonic acid diethyl ester obtained in step 15 136.4 (5.42 g, 15.25 mmol) in EtOH (40 mL) at room temperature. The mixture was then stirred at 50 'C overnight, the solvent was removed under reduced pressure, the contents were acidified with HCl (conc.) at r.t. to pH = 3 and the resulting white aqueous suspension was extracted twice with EtOAc (100 mL). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was dissolved in 20 toluene (50 mL), and the mixture was heated at 105 0 C. The mixture was concentrated under reduced pressure and the concentrate was used in the next step without further purification. 136.6 5-Methoxy-2-methoxycarbonylmethyl-4-nitro-benzoic acid methyl ester 25 SOCl 2 (17.16 mL, 235 mmol) was added dropwise to a solution of 2 carboxymethyl-5-methoxy-4-nitrobenzoic acid obtained in step 136.5 (20.0 g, 78 mmol) in MeOH (150 mL) at ambient temperature. After the addition was completed, the mixture was heated at 65 'C overnight. The mixture was concentrated in vacuo. The residue was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO 3 30 (60 mL), water (60 mL) and brine (60 mL). The organic layer was dried over Na 2
SO
4 , filtered and concentrated. The residue was purified on a silica gel column (PE/EtOAc=5:1, v/v) to afford the title compound (20.7 g, 93 %) as a yellow solid.
WO 2013/068489 PCT/EP2012/072175 130 LCMS (ESI+): m/z 284 (M+H)*, RT: 1.95 min. H NMR(CDCl 3 /TMS, 400 MHz) 6: 7.72 (s, 2H), 4.01 (s, 3H), 3.97 (s, 2H), 3.92 (s, 3H), 3.71 (s, 3H). 136.7 2-((Z)-2-Dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-4 5 nitro-benzoic acid methyl ester A mixture of methyl 5-methoxy-2-methoxycarbonylmethyl-4-nitro-benzoic acid methyl ester obtained in step 136.6 (250 mg, 0.883 mmol) in DMF-DMA (5.909 ml, 44.1 mmol) was heated at 90 0 C overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL) and washed with 10 brine (6 mL*3). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The crude oil was pure enough for next step. LCMS (ESI+): m/z 339 (M+H)*, RT: 1.93 min. 136.8 2-Ethyl-7-methoxy-6-nitro-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester 15 A mixture of 2-((Z)-2-dimethylamino-1-methoxycarbonyl-vinyl)-5-methoxy-4 nitro-benzoic acid methyl ester obtained in step 136.7 (237 mg, 0.701 mmol), ethanamine (95 mg, 2.102 mmol) and DIPEA (0.734 mL, 4.20 mmol) in MeOH (5 mL) was heated at reflux overnight. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with HCl (2 N, 10 mL) and brine 20 (10 mL). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified on a silica column (PE/EtOAc=5:1, v/v) to afford the title compound (200 mg, 93 %) as a yellow solid. LCMS (ESI+): m/z 207 (M+H)*, RT: 2.05 min. H NMR(CDCl 3 /TMS, 400 MHz) 6: 9.24 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 4.14 25 (q, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 1.45 (t, J= 7.2 Hz, 3H). 136.9 6-Amino-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester To a suspension of 2-ethyl-7-methoxy-6-nitro-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester obtained in step 136.8 (200 mg, 0.653 mmol) in ethanol 30 (10 mL) and saturated NH 4 Cl solution (2 mL) was added zinc (427 mg, 6.53 mmol) in one portion. The mixture was stirred at r.t. for 30 min, then filtered. The filtrate was concentrated in vacuo. The residue was diluted with EtOAc (20 mL) and washed with WO 2013/068489 PCT/EP2012/072175 131 brine (6*2 mL). The organic layer was dried over Na 2
SO
4 , filtered and concentrated to afford the title compound (163 mg, 90 %) as a white solid. LCMS (ESI+): m/z 277 (M+H)*, RT: 1.83 min. H NMR(DMSO-d6/TMS, 400 MHz) 6: 8.22 (s, 1H), 7.87 (s, 1H), 7.50 (s, 1H), 5 5.86 (br, 2H), 4.00-4.04 (q, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 1.24 (t, J= 7.2 Hz, 3H). 136.10 6-Bromo-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester To a suspension of 6-amino-2-ethyl-7-methoxy- 1 -oxo- 1,2-dihydro-isoquino line 4-carboxylic acid methyl ester obtained in step 136.9 (1.20 g, 4.34 mmol) in 2 NH 2
SO
4 10 solution (25 mL) was added a solution of sodium nitrite (0.899 g, 13.03 mmol) in water (5 mL) dropwise at 0 'C. The mixture was stirred at 0 'C for 2 h, then it was added dropwise to a solution of copper(I) bromide (2.492 g, 17.37 mmol) in HBr (48%, 5 mL). The mixture was stirred for another 1 h at 0 'C, diluted with EtOAc (100 mL) and washed with brine (30 mL*3). The organic layer was dried over Na 2
SO
4 , filtered and 15 concentrated in vacuo. The residue was purified on a silica column (PE/EtOAc=5:1, v/v) to afford the title compound (1.31 g, 89 %). LCMS (ESI+): m/z 340 (M+H)*, RT: 2.04 min. IH NMR(CDCl 3 /TMS, 400 MHz) 6: 9.02 (s, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 4.01 4.07 (q, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H). 20 136.11 2-Ethyl-7-methoxy-4-(methoxycarbonyl)- 1 -oxo- 1,2 dihydroisoquinolin-6-yl-boronic acid A mixture of 6-bromo-2-ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester obtained in step 136.10 (1.31 g, 3.85 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.174 g, 4.62 mmol), 25 potassium acetate (1.134 g, 11.55 mmol) and PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.314 g, 0.385 mmol) in DMF (100 mL) was stirred at 90 'C overnight. The mixture was diluted with EtOAc (200 mL) and washed with brine (60 mLx4). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was used in the next step directly without further purification. 30 LCMS (ESI+): m/z 306 (M+H)*, RT: 1.82 min. 136.12 2-Ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester WO 2013/068489 PCT/EP2012/072175 132 A mixture of 2-ethyl-7-methoxy-4-(methoxycarbonyl)- 1 -oxo- 1,2 dihydroisoquinolin-6-yl-boronic acid obtained in step 136.11 (838 mg, 2.75 mmol), water (32 mL), acetone (4 mL), NaOH (110 mg, 2.75 mmol) and sodium bicarbonate (231 mg, 2.75 mmol) was warmed to 50 'C for 1 h. After cooling to r.t., 30% H202 5 (0.337 mL, 10.99 mmol) was added dropwise. The reaction was stirred at r.t. overnight, then it was acidified to pH=4 by dropwise addition of 2 N HCl, and extracted with DCM (50 mL*3). The DCM layer was washed with brine (50 mL), dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified on a silica column (PE/EtOAc=2: 1, v/v) to afford the title compound (220 mg, 28.9 %) as a white solid. 10 LCMS (ESI+): m/z 278 (M+H)*, RT: 1.87 min. H NMR(DMSO-d6/TMS, 400 MHz) 6: 10.27 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 4.04-4.08 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 1.26 (t, J= 7.2 Hz, 3H). 136.13 2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro isoquinoline-4-carboxylic acid methyl ester 15 To a solution of 2-ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid methyl ester of step 136.12 (50 mg, 0.180 mmol), 2-(quinolin-2 yl)ethanol (31.2 mg, 0.180 mmol) and Ph 3 P (142 mg, 0.541 mmol) in anhydrous THF (3 mL) was added DEAD (0.086 mL, 0.541 mmol) dropwise at 0 0 C. The mixture was stirred at 0 0 C for 30 min. Then it was allowed to warm to ambient temperature and 20 stirred overnight. The mixture was diluted with EtOAc (20 mL) and washed with 2 N HCl (10 mL*3). The aqueous layer was basified with 2 NNaOH to pH=10, then extracted with EtOAc (15 mL*3). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE/EtOAc=1:1, v/v) to afford the title compound (55 mg, 47.3 %). 25 LCMS (ESI+): m/z 433 (M+H)*, RT: 1.91 min. 1H NMR(CDCl 3 /TMS, 400 MHz) 6: 8.43 (s, 1H), 8.09-8.13 (m, 3H), 7.80 (s, 1H), 7.65-7.70 (m, 2H), 7.47-7.51 (m, 2H), 4.69 (t, J= 6.8 Hz, 2H), 4.08-4.12 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.62 (t, J= 6.8 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H). 136.14 2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro 30 isoquinoline-4-carboxylic acid A mixture of methyl 2-ethyl-7-methoxy- 1 -oxo-6-(2-quinolin-2-yl-ethoxy)-1,2 dihydro-isoquinoline-4-carboxylic acid ethyl ester obtained in step 136.13 (55 mg, WO 2013/068489 PCT/EP2012/072175 133 0.085 mmol) and NaOH (10.22 mg, 0.256 mmol) in MeOH (3 mL) and water (1 mL) was heated at 50 'C for 3h. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (5 mL) and acidified with HCl (2 N) to pH=5~6. The aqueous solution was extracted with EtOAc (15 mL*3). The organic layer was dried 5 over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was used in the next step without further purification. LCMS (ESI+): m/z 419 (M+H)*, RT: 2.08 min. 136.15 2-Ethyl-7-methoxy- 1 -oxo-6-(2-quinolin-2-yl-ethoxy)- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide 10 A suspension of 2-ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2 dihydro-isoquinoline-4-carboxylic acid obtained in step 136.14 (80 mg, 0.080 mmol), DMF (6.22 gL, 0.080 mmol) and SOCl 2 (0.0 18 mL, 0.241 mmol) in DCM (2 mL) was refluxed for 3h. The mixture was concentrated in vacuo. The residue was dissolved in DCM (2 mL). The solution was added dropwise to a mixture of butan-1-amine (11.75 15 mg, 0.161 mmol) and Et 3 N (0.034 mL, 0.241 mmol) in DCM (2 mL) at ambient temperature. The reaction mixture was stirred at r.t. for another 3h. Then the solvent was removed under reduced pressure, the residue was diluted with EtOAc (15 mL) and washed with brine (5 mL*3). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified on a silica column (PE/EtOAc=1:1, 20 v/v) to afford the title compound as a white solid (50 mg), (purity 94. 6% by LCMS). Further purification pre-HPLC afford the title compound (12 mg, 31.6 %) as a white solid. IH NMR (CDCl 3 /TMS, 400MHz) 6: 7.35-8.17 (m, 9H), 5.88 (s, 1H), 4.65 (m, 2H), 4.03-4.08 (m, 2H), 3.95 (s, 3H), 3.41-3.66 (m, 4H), 1.60-1.63 (m, 2H), 1.37-1.44 25 (m, 5H), 0.93 (t, J= 7.2 Hz, 3H). LCMS (ESI+): m/z 474 (M+H)*, RT: 2.05 min. Example 137 2-Ethyl-7-methoxy- 1 -oxo-6-(3 -quino lin-2-yl-propoxy)- 1,2-dihydro-isoquino line 30 4-carboxylic acid butyl amide 137.1 (E)-3-Quinolin-2-yl-acrylic acid ethyl ester WO 2013/068489 PCT/EP2012/072175 134 (2-Ethoxy-2-oxoethyl) triphenylphosphonium bromide (16.8 g, 39.1 mmol) and quinoline-2-carbaldehyde (5.8 g, 36.9 mmol) were dissolved in EtOH (100 ml). The mixture was heated at about 80 'C over night. The solvent was removed under reduced pressure, and the residue was purified with silica column (eluted with 5:1 5 hexane/EtOAc). The proper fractions were collected and concentrated to give the title compound (6.8 g, 76 %) as yellow oil. LCMS (ESI+): m/z 228 (M+H)*, RT: 1.871min 137.2 3-Quinolin-2-yl-propan-1-ol To a suspension of LiAlH 4 (0.534 g, 14.05 mmol) in THF (10 ml), at -78 'C was 10 added (E)-3-quinolin-2-yl-acrylic acid ethyl ester obtained in step 137.1 (1.6 g, 7.04 mmol) slowly. The mixture was allowed to warm to room temperature and stirred for 3 h. Water (0.1 ml) was added slowly. The reaction mixture was filtered through a pad of celite. The solvent was removed under reduced pressure to provide the desired crude product as an off-white solid. The crude product was purified with plate TLC (eluted 15 with 1:1 hexane/EtOAc) to give the title compound (55 mg, 4.2 %). LCMS (ESI+): m/z 188 (M+H)*, RT: 1.074 min. 137.3 2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro isoquinoline-4-carboxylic acid methyl ester To a solution of 2-ethyl-6-hydroxy-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 20 carboxylic acid methyl ester obtained in step 136.12 (148 mg, 0.534 mmol) and Ph 3 P (420 mg, 1.602 mmol) in anhydrous THF (3 mL) was added DEAD (0.254 mL, 1.602 mmol) dropwise at -30 'C. The mixture was stirred at -30 'C for 30 min. Then a solution of 3-quinolin-2-yl-propan-1-ol obtained in step 137.2 (100 mg, 0.534 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was allowed to warm to 25 ambient temperature and stirred overnight. The mixture was diluted with EtOAc (10 mL) and washed with 2 N HCl (5 mL*3). The aqueous layer was basified with 2 N NaOH to pH=10, then extracted with EtOAc (10 mL*3). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified by pre-TLC (PE/EtOAc= 1:1, v/v) to afford the title compound (43 mg, 11.36 %). 30 LCMS (ESI+): m/z 447 (M+H)*, RT: 2.08 min. 137.4 2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro isoquinoline-4-carboxylic acid WO 2013/068489 PCT/EP2012/072175 135 A mixture of 2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro isoquinoline-4-carboxylic acid methyl ester obtained in step 137.3 (43 mg, 0.061 mmol) and sodium hydroxide (7.28 mg, 0.182 mmol) in MeOH (3 mL) and water (1 mL) was heated at 50 'C for 3h. The reaction mixture was acidified with HCl (2 N) to pH=4~5. 5 The aqueous solution was concentrated in vacuo. and re-evaporated with MeOH (5 mL*3). The residue was used in the next step without further purification. LCMS (ESI+): m/z 433 (M+H)*, RT: 1.39 min. 137.5 2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro isoquinoline-4-carboxylic acid butylamide 10 A suspension of 2-ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2 dihydro-isoquinoline-4-carboxylic acid obtained in step 137.4 (23 mg, 0.023 mmol), DMF (3.54 gL, 0.046 mmol) and sulfurous dichloride (8.16 mg, 0.069 mmol) in DCM (2 mL) was refluxed for 3h. The mixture was concentrated in vacuo. The residue was dissolved in DCM (2 mL). The solution was added dropwise to a mixture of butan-1 15 amine (1.673 mg, 0.023 mmol) and Et 3 N (9.56 gL, 0.069 mmol) in DCM (2 mL) at ambient temperature. The reaction mixture was stirred at r.t. for another 3h. Then the solvent was removed under reduced pressure, the residue was diluted with EtOAc (15 mL) and washed with brine (5 mL*3). The organic layer was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to afford the 20 title compound (3 mg, 26.9 %) as a white solid. IH NMR (MeOD/TMS, 400MHz) 6: 8.15 (d, J= 8.0 Hz, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.61-7.64 (m, 2H), 7.52 (s, 1H), 7.49 (s, 1H), 7.41-7.45 (m, 1H), 7.40 (d, J= 8.4 Hz, 1H), 4.12 (t, J= 5.8 Hz, 2H), 3.99-4.02 (m, 2H), 3.76 (s, 3H), 3.25-3.29 (m, 2H), 3.12 (t, J= 7.6 Hz, 2H), 2.30 (m, 2H), 1.49-1.53 (m, 2H), 1.26 25 1.34 (m, 5H), 0.86 (t, J= 7.4 Hz, 3H). LCMS (ESI+): m/z 488 (M+H)*, RT: 2.08 min. The compounds of the following examples 138 to 166 were prepared according to following general procedure: 30 A 4 ml scintillation vial was charged with a stir bar, a solution of 2-ethyl-6,7 dimethoxy-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as prepared in step 1.7 WO 2013/068489 PCT/EP2012/072175 136 (16.57 mg, 0.059 mmol) in 1.0 mL of N,N-dimethylacetamide (DMA), a solution of the respective amine (1.2 eq, 0.0717 mmol) in DMA, a solution of HATU (27.26 mg, 0.0717 mmol, 1.2 eq) in DMA, and DIEA (3 eq, 0.179 mmol, 18.27mg) neat. The mixture was capped and placed in the Anton Paar Synthos 3000 optimizer at 150'C for 5 30 minutes. The vial was decapped and placed to concentrate to dryness. An additional 1.4 mL of DMSO/MeOH (1:1 v/v) was added for dissolution and submission for reverse phase HPLC purification. Example 138 10 2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-3-yl)-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 353.9 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, 3 H) 3.85 - 3.87 (m, 3 H) 3.89 3.91 (m, 3 H) 4.07 (q, 1 H) 7.50 (dd, J=8.39, 4.73 Hz, 1 H) 7.69 (s, 1 H) 7.74 (s, 1 H) 15 8.06 (s, 1 H) 8.21 (d, 1 H) 8.35 (s, 1 H) 8.90 (s, 1 H). Example 139 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-(pyrimidin-4-ylmethyl)- 1,2-dihydroisoquino line 4-carboxamide 20 ESI-MS [M+H*] = 368.15 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.32 (t, J=7.17 Hz, 3 H) 3.84 (s, 3 H) 3.88 (s, 3 H) 4.05 (q, J=7.02 Hz, 3 H) 4.57 (s, 2 H) 7.56 (dd, J=5.19, 1.22 Hz, 1 H) 7.67 (s, 1 H) 7.77 (s, 1 H) 7.92 (s, 1 H) 8.77 (d, J=5.19 Hz, 1 H) 9.13 (d, J=1.22 Hz, 1 H). 25 Example 140 2-Ethyl-6,7-dimethoxy-4-(2-methoxybenzylamino)carbonyl)isoquinolin-1(2H) one ESI-MS [M+H] = 397.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.30 (t, J=7.02 Hz, 3 H) 3.83 (d, 30 J=10.07 Hz, 6 H) 3.88 (s, 3 H) 4.03 (d, J=7.02 Hz, 2 H) 4.46 (s, 2 H) 6.96 (t, 1 H) 7.03 (d, 1 H) 7.30 (q, 2 H) 7.66 (s, 1 H) 7.71 (s, 1 H) 7.80 (s, 1 H) WO 2013/068489 PCT/EP2012/072175 137 Example 141 2-Ethyl-6,7-dimethoxy-N-(4-morpho linophenyl)- 1 -oxo- 1,2-dihydroisoquino line 4-carboxamide ESI-MS [M+H*] = 438.0 m/z. 5 1 H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.11 - 3.14 (m, 4 H) 3.76 - 3.79 (m, 4 H) 3.85 (s, 3 H) 3.89 (s, 3 H) 4.06 (q, J=7.12 Hz, 2 H) 7.03 (d, J=8.85 Hz, 2 H) 7.61 (d, J=8.85 Hz, 2 H) 7.68 (s, 1 H) 7.71 (s, 1 H) 7.92 (s, 1 H) Example 142 10 N-(3-Chlorobenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 400.9 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.30 (t, J=7.02 Hz, 3 H) 3.83 (s, 3 H) 3.88 (s, 3 H) 4.03 (q, J=7.12 Hz, 2 H) 4.49 (s, 2 H) 7.32 - 7.44 (m, 4 H) 7.66 (s, 1 H) 15 7.70 (s, 1 H) 7.82 (s, 1 H). Example 143 2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-4-ylmethyl)-1,2-dihydroisoquinoline-4 carboxamide 20 ESI-MS [M+H*] =368.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.83 (s, 3 H) 3.88 (s, 3 H) 4.03 - 4.10 (m, 2 H) 4.69 (s, 2 H) 7.67 (s, 1 H) 7.75 (s, 1 H) 7.88 (d, J=5.80 Hz, 2 H) 7.97 (s, 1 H) 8.76 (s, 2 H). 25 Example 144 2-Ethyl-6,7-dimethoxy-1-oxo-N-o-tolyl-1,2-dihydroisoquinoline-4-carboxamide ESI-MS [M+H] = 367.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 2.29 (s, 3 H) 3.85 (s, 3 H) 3.89 (s, 3 H) 4.07 (q, J=7.12 Hz, 2 H) 7.17 - 7.22 (m, 1 H) 7.23 - 7.28 (m, 30 1 H) 7.30 (d, J=7.63 Hz, 1 H) 7.37 - 7.41 (m, 1 H) 7.69 (s, 1 H) 7.76 (s, 1 H) 8.00 (s, 1
H)
WO 2013/068489 PCT/EP2012/072175 138 Example 145 2-Ethyl-6,7-dimethoxy-1-oxo-N-m-tolyl-1,2-dihydroisoquinoline-4-carboxamide ESI-MS [M+H*] = 367.0 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 2.33 (s, 3 H) 5 3.87 (d, 6 H) 4.06 (q, J=7.02 Hz, 2 H) 6.96 (d, J=7.63 Hz, 1 H) 7.26 (t, J=7.93 Hz, 1 H) 7.50 (d, J=8.24 Hz, 1 H) 7.55 (s, 1 H) 7.70 (d, J=14.34 Hz, 2 H) 7.95 (s, 1 H) Example 146 2-Ethyl-6,7-dimethoxy-N-(2-methoxyphenyl)- 1 -oxo- 1,2-dihydroisoquinoline-4 10 carboxamide ESI-MS [M+H*] =383.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.32 (t, J=7.17 Hz, 3 H) 3.84 (d, J=10.68 Hz, 6 H) 3.89 (s, 3 H) 4.06 (q, J=7.02 Hz, 2 H) 6.97 - 7.02 (m, 1 H) 7.11 (d, J=7.32 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 7.68 (s, 1 H) 7.73 - 7.79 (m, 2 H) 7.96 (s, 1 H) 15 Example 147 2-Ethyl-6,7-dimethoxy-N-(3-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] =383.0 m/z. 20 IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.77 (s, 3 H) 3.86 (s, 3 H) 3.89 (s, 3 H) 4.06 (q, J=7.22 Hz, 2 H) 6.70 - 6.75 (m, 1 H) 7.28 - 7.30 (m, 2 H) 7.38 (d, J=1.83 Hz, 1 H) 7.69 (d, J=6.41 Hz, 2 H) 7.95 (s, 1 H) Example 148 25 2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-3-ylmethyl)-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H] = 368.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.31 (t, J=7.02 Hz, 3 H) 3.83 (s, 3 H) 3.88 (s, 3 H) 4.04 (q, J=7.02 Hz, 2 H) 4.63 (s, 2 H) 7.66 (s, 1 H) 7.73 (s, 1 H) 7.88 30 7.94 (m, 2 H) 8.40 (d, J=7.93 Hz, 1 H) 8.73 (d, J=5.19 Hz, 1 H) 8.83 (s, 1 H) Example 149 WO 2013/068489 PCT/EP2012/072175 139 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-(pyridin-2-ylmethyl)- 1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 368.0 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.31 (t, J=7.02 Hz, 3 H) 3.83 (s, 3 H) 5 3.88 (s, 3 H) 4.04 (q, J=7.02 Hz, 2 H) 4.63 (s, 2 H) 7.66 (s, 1 H) 7.73 (s, 1 H) 7.88 7.94 (m, 2 H) 8.40 (d, J=7.93 Hz, 1 H) 8.73 (d, J=5.19 Hz, 1 H) 8.83 (s, 1 H) Example 150 N-(3-(Dimethylamino)propyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2 10 dihydroisoquinoline-4-carboxamide ESI-MS [M+H*] = 362.0 IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.30 (t, J=7.17 Hz, 3 H) 1.87 - 1.96 (m, 2 H) 2.81 (s, 6 H) 3.11 - 3.18 (m, 2 H) 3.34 (t, J=6.56 Hz, 2 H) 3.87 (d, J=7.93 Hz, 6 H) 4.02 (q, J=7.22 Hz, 2 H) 7.66 (s, 1 H) 7.74 (s, 1 H) 7.77 (s, 1 H) 15 Example 151 2-Ethyl-6,7-dimethoxy-1-oxo-N-phenyl-1,2-dihydroisoquinoline-4-carboxamide ESI-MS [M+H*] = 353.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.86 (s, 3 H) 20 3.89 (s, 3 H) 4.06 (q, J=7.02 Hz, 2 H) 7.14 (t, J=7.48 Hz, 1 H) 7.37 - 7.41 (m, 2 H) 7.68 - 7.73 (m, 4 H) 7.97 (s, 1 H) Example 152 2-Ethyl-6,7-dimethoxy-N-(4-methoxybenzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4 25 carboxamide ESI-MS [M+H] = 397.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.29 (t, J=7.17 Hz, 3 H) 3.74 (s, 3 H) 3.82 (s, 3 H) 3.88 (s, 3 H) 4.01 (q, J=7.02 Hz, 2 H) 4.42 (d, J=5.80 Hz, 2 H) 6.91 - 6.95 (m, 2 H) 7.31 - 7.34 (m, 2 H) 7.65 (s, 1 H) 7.70 (s, 1 H) 7.75 (s, 1 H) 8.86 (t, J=5.80 Hz, 30 1 H) Example 153 WO 2013/068489 PCT/EP2012/072175 140 2-Ethyl-6,7-dimethoxy-N-(4-methylbenzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 381.0 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.29 (t, J=7.17 Hz, 3 H) 2.31 (s, 3 H) 5 3.82 (s, 3 H) 3.88 (s, 3 H) 4.02 (q, J=7.22 Hz, 2 H) 4.45 (d, J=5.80 Hz, 2 H) 7.09 (d, J=7.63 Hz, 1 H) 7.16 - 7.21 (m, 2 H) 7.23 - 7.28 (m, 1 H) 7.66 (s, 1 H) 7.71 (s, 1 H) 7.78 (s, 1 H) 8.90 (t, J=5.95 Hz, 1 H) Example 154 10 2-Ethyl-6,7-dimethoxy-N-(2-methylbenzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 381.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.29 (t, J=7.17 Hz, 3 H) 2.35 (s, 3 H) 3.81 (s, 3 H) 3.88 (s, 3 H) 4.02 (q, J=7.22 Hz, 2 H) 4.47 (s, 2 H) 7.18 - 7.22 (m, 3 H) 15 7.33 (t, J=3.51 Hz, 1 H) 7.66 (s, 1 H) 7.70 (s, 1 H) 7.78 (s, 1 H) Example 155 2-Ethyl-6,7-dimethoxy-N-(2-methoxyethyl)- 1 -oxo- 1,2-dihydroisoquinoline-4 carboxamide 20 ESI-MS [M+H*] =335.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.29 (t, J=7.02 Hz, 3 H) 3.30 (s, 3 H) 3.44 (t, J=5.49 Hz, 2 H) 3.51 (t, J=5.80 Hz, 2 H) 3.87 (d, J=7.63 Hz, 6 H) 4.01 (q, J=7.02 Hz, 2 H) 7.65 (s, 1 H) 7.72 (d, J=2.75 Hz, 2 H) 25 Example 156 2-Ethyl-N-(4-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H] =371.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.02 Hz, 3 H) 3.86 (s, 3 H) 30 3.89 (s, 3 H) 4.06 (q, J=7.22 Hz, 2 H) 7.19 - 7.27 (m, 2 H) 7.68 (s, 1 H) 7.71 - 7.75 (m, 3 H) 7.97 (s, 1 H) WO 2013/068489 PCT/EP2012/072175 141 Example 157 2-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] =383.0 m/z. 5 1H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.76 (s, 3 H) 3.85 (s, 3 H) 3.89 (s, 3 H) 4.06 (q, J=7.22 Hz, 2 H) 6.96 (tt, 2 H) 7.62 (dt, 2 H) 7.68 (s, 1 H) 7.71 (s, 1 H) 7.93 (s, 1 H) Example 158 10 2-Ethyl-6,7-dimethoxy-1-oxo-N-p-tolyl-1,2-dihydroisoquinoline-4-carboxamide ESI-MS [M+H*] = 367.0 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 2.30 (s, 3 H) 3.85 (s, 3 H) 3.89 (s, 3 H) 4.06 (q, J=7.22 Hz, 2 H) 7.19 (d, J=8.24 Hz, 2 H) 7.59 (dd, J=8.39, 2.59 Hz, 2 H) 7.68 (s, 1 H) 7.71 (s, 1 H) 7.94 (s, 1 H) 15 Example 159 2-Ethyl-N-(3-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 371.0 m/z. 20 1H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.02 Hz, 3 H) 3.86 (s, 3 H) 3.89 (s, 3 H) 4.06 (q, J=7.02 Hz, 2 H) 6.93 - 6.99 (m, 1 H) 7.39 - 7.45 (m, 1 H) 7.46 7.50 (m, 1 H) 7.66 - 7.72 (m, 3 H) 8.00 (s, 1 H) Example 160 25 2-Ethyl-N-(2-fluorophenyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H] = 371.0 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.85 (s, 3 H) 3.89 (s, 3 H) 4.07 (d, J=7.32 Hz, 2 H) 7.22 - 7.35 (m, 3 H) 7.66 - 7.72 (m, 2 H) 7.78 (s, 30 1 H) 8.01 (s, 1 H) Example 161 WO 2013/068489 PCT/EP2012/072175 142 2-Ethyl-6,7-dimethoxy-N-(4-methylbenzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H*] = 381.0 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.29 (t, J=7.02 Hz, 3 H) 2.29 (s, 3 H) 5 3.81 (s, 3 H) 3.88 (s, 3 H) 4.02 (q, J=7.22 Hz, 2 H) 4.44 (d, J=5.19 Hz, 2 H) 7.17 (d, J=7.63 Hz, 2 H) 7.28 (d, J=7.93 Hz, 2 H) 7.65 (s, 1 H) 7.70 (s, 1 H) 7.77 (s, 1 H) Example 162 N-(2-Chlorobenzyl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4 10 carboxamide ESI-MS [M+H*] = 401.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.31 (t, J=7.17 Hz, 3 H) 3.82 (s, 3 H) 3.88 (s, 3 H) 4.04 (q, J=7.22 Hz, 2 H) 4.56 (d, J=5.49 Hz, 2 H) 7.31 - 7.41 (m, 2 H) 7.49 (dd, J=7.78, 1.37 Hz, 2 H) 7.66 (s, 1 H) 7.71 (s, 1 H) 7.85 (s, 1 H) 8.93 (t, J=5.80 Hz, 1 15 H) Example 163 (R)-2-Ethyl-N-(1 -(4-fluorophenyl)ethyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide 20 ESI-MS [M+H*] = 399.0 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm (t, J=7.17 Hz, 3 H) 1.48 (d, J=7.32 Hz, 3 H) 3.79 (s, 3 H) 3.87 (s, 3 H) 4.04 (q, J=7.02 Hz, 2 H) 5.14 (q, J=6.92 Hz, 1 H) 7.14 7.21 (m, 2 H) 7.44 - 7.50 (m, 2 H) 7.60 (s, 1 H) 7.65 (s, 1 H) 7.78 (s, 1 H) 25 Example 164 2-Ethyl-6,7-dimethoxy-1-oxo-N-(pyridin-4-yl)-1,2-dihydroisoquinoline-4 carboxamide ESI-MS [M+H] = 353.9 m/z. IH NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.35 (t, J=7.17 Hz, 3 H) 3.88 (s, 3 H) 30 3.90 (s, 3 H) 4.09 (q, J=7.02 Hz, 2 H) 7.70 (s, 1 H) 7.79 (s, 1 H) 8.17 (d, J=7.32 Hz, 2 H) 8.24 (s, 1 H) 8.70 (d, J=7.32 Hz, 2 H).
WO 2013/068489 PCT/EP2012/072175 143 Example 165 (S)-2-Ethyl-N-(1 -(4-fluorophenyl)ethyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS [M+H*] = 399.0 m/z. 5 1H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.31 (t, J=7.17 Hz, 3 H) 1.48 (d, J=7.32 Hz, 3 H) 3.79 (s, 3 H) 3.87 (s, 3 H) 4.00 - 4.07 (m, 2 H) 5.14 (q, J=7.12 Hz, 1 H) 7.15 7.21 (m, 2 H) 7.45 - 7.49 (m, 2 H) 7.60 (s, 1 H) 7.65 (s, 1 H) 7.78 (s, 1 H). Example 166 10 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-(1,2,3,4-tetrahydronaphthalen- 1-yl)-1,2,3,8a tetrahydroisoquinoline-4-carboxamide ESI-MS [M+H*] = 407.2 m/z. H NMR (500 MHz, DMSO/D 2 0) 6 ppm 1.28 (t, J=7.17 Hz, 3 H) 1.75 - 1.88 (m, 2 H) 1.93 - 2.00 (m, 1 H) 2.01 - 2.08 (m, 1 H) 2.72 - 2.85 (m, 2 H) 3.87 (s, 3 H) 3.89 (s, 15 3 H) 4.00 (q, J=7.12 Hz, 2 H) 5.24 (q, 1 H) 7.13 - 7.16 (m, 1 H) 7.17 - 7.21 (m, 2 H) 7.31 - 7.35 (m, 1 H) 7.67 (s, 1 H) 7.71 (s, 1 H) 7.74 (s, 1 H). The compounds of the following examples 167 to 179 were prepared according to following general procedure: 20 In a 4 ml microwave vial was added 2-ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydroiso quinoline-4-carboxylic acid as prepared in step 1.7 (25 mg, 0.09 mmol), followed by 2 (1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU; 42 mg, 0.10 mmol), triethylamine (37 gl, 0.27 mmol) and the 25 respective amine (0.11 mmol). This mixture was placed in Anton Par with stir bar and heated at 150 'C for 30 minutes. The crude mixture was checked via LCMS for completion and concentrated to dryness. The residue was then dissolved in 1.4 mL of DMSO:MeOH (1:1) and purified through reverse phase HPLC (TFA method using MeOH) to afford pure products. 30 Example 167 WO 2013/068489 PCT/EP2012/072175 144 2-Ethyl-6,7-dimethoxy-N-(6-methyl-2,3-dihydro- 1H-inden- 1-yl)-1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide H NMR (500 MHz) 6 ppm 1.28 (t, J=7.02 Hz, 3 H) 1.95 (dd, J=12.66, 8.09 Hz, 1 H) 2.29 (s, 3 H) 2.74 - 2.85 (m, 1 H) 2.90 - 3.02 (m, 1 H) 3.88 (d, J=3.97 Hz, 6 H) 4.01 5 (q, J=7.22 Hz, 2 H) 5.50 (t, J=7.78 Hz, 1 H) 7.06 (d, J=7.63 Hz, 1 H) 7.17 (d, 2 H) 7.66 (s, 1 H) 7.78 (d, J=1 1.90 Hz, 2 H). MS (ESI+) M/Z 407 [M+H]+. Example 168 10 2-Ethyl-6,7-dimethoxy-N-(2-(morpholinomethyl)benzyl)- 1 -oxo- 1,2-dihydroiso quinoline-4-carboxamide IH NMR (500 MHz6 ppm 1.24 - 1.33 (m, 4 H) 3.40 (d, 4 H) 3.81 (s, 3 H) 3.87 3.89 (m, 3 H) 4.04 (q, J=7.02 Hz, 4 H) 4.58 (d, J=1 1.60 Hz, 4 H) 7.43 (t, J=7.48, 1.37 Hz, 1 H) 7.50 - 7.57 (m, 2 H) 7.60 - 7.67 (m, 3 H) 7.84 (s, 1 H). 15 MS (ESI+) M/Z 466 [M+H]+. Example 169 N-(5-Chloro-2,3-dihydro-1H-inden-1-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2 dihydroisoquinoline-4-carboxamide 20 1H NMR (500 MHz) 6 ppm 1.28 (t, J=7.02 Hz, 3 H) 2.00 (dd, J=12.82, 7.93 Hz, 1 H) 2.88 (d, J=8.24 Hz, 1 H) 2.97 - 3.06 (m, 1 H) 3.87 (d, J=6.10 Hz, 6 H) 4.00 (q, J=7.02 Hz, 2 H) 5.50 (t, J=7.78 Hz, 1 H) 7.28 (dd, J=8.09, 1.98 Hz, 1 H) 7.37 (t, 2 H) 7.66 (s, 1 H) 7.77 (d, J=3.36 Hz, 2 H). MS (ESI+) M/Z 427 [M+H]+. 25 Example 170 N-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-2-ethyl-6,7-dimethoxy-1-oxo-1,2 dihydroisoquinoline-4-carboxamide IH NMR (500 MHz) 6 ppm 1.28 (t, J=7.17 Hz, 3 H) 2.01 (dd, J=12.66, 8.09 Hz, 1 30 H) 2.77 - 2.87 (m, 1 H) 2.92 - 3.06 (m, 1 H) 3.88 (d, J=1.22 Hz, 6 H) 4.01 (q, J=7.02 Hz, 2 H) 5.52 (t, J=7.78 Hz, 1 H) 7.27 - 7.34 (m, 2 H) 7.39 (s, 1 H) 7.66 (s, 1 H) 7.77 (d, J=18.92 Hz, 2 H).
WO 2013/068489 PCT/EP2012/072175 145 MS (ESI+) M/Z 427 [M+H]+. Example 171 2-Ethyl-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2 5 dihydroisoquinoline-4-carboxamide H NMR (500 MHz) 6 ppm 1.28 (t, J=7.02 Hz, 3 H) 1.96 - 2.06 (m, 1 H) 2.77 2.88 (m, 1 H) 2.93 - 3.01 (m, 1 H) 3.88 (d, J=4.88 Hz, 6 H) 4.01 (q, J=7.02 Hz, 2 H) 5.52 (t, J=7.78 Hz, 1 H) 7.06 (t, 1 H) 7.16 (dd, J=8.85, 2.14 Hz, 1 H) 7.30 (dd, J=8.24, 5.19 Hz, 1 H) 7.66 (s, 1 H) 7.78 (d, J=13.43 Hz, 2 H). 10 MS (ESI+) M/Z 411 [M+H]+. Example 172 N-(5,6-Dihydro-4H-cyclopenta[b]thiophen-4-yl)-2-ethyl-6,7-dimethoxy- 1 -oxo 1,2-dihydroisoquinoline-4-carboxamide 15 1 H NMR (500 MHz, Solvent) 6 ppm 1.27 (t, J=7.02 Hz, 3 H) 2.33 - 2.41 (m, 1 H) 2.82 - 2.95 (m, 2 H) 3.03 (d, 1 H) 3.87 (d, J=6.71 Hz, 6 H) 3.99 (q, J=7.02 Hz, 2 H) 5.37 (t, 1 H) 6.99 (d, J=5.19 Hz, 1 H) 7.39 (d, J=5.19 Hz, 1 H) 7.65 (s, 1 H) 7.73 (d, J=13.12 Hz, 2 H). MS (ESI+) M/Z 399 [M+H]+. 20 Example 173 2-Ethyl-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2 dihydroisoquinoline-4-carboxamide IH NMR (500 MHz) 6 ppm 1.28 (t, J=7.17 Hz, 3 H) 2.03 (dd, J=12.66, 8.39 Hz, 1 25 H) 2.79 - 2.96 (m, 1 H) 3.04 (d, J=5.19 Hz, 1 H) 3.87 (d, J=7.02 Hz, 6 H) 4.01 (q, J=7.02 Hz, 2 H) 5.58 (d, J=7.93 Hz, 1 H) 6.93 - 7.14 (m, 1 H) 7.16 - 7.36 (m, 2 H) 7.66 (s, 1 H) 7.77 (d, J=1.22 Hz, 2 H) 8.78 (d, J=8.24 Hz, 1 H). MS (ESI+) M/Z 411 [M+H]+. 30 Example 174 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-l-oxo-1,2 dihydroisoquinoline-4-carboxamide WO 2013/068489 PCT/EP2012/072175 146 1 H NMR (500 MHz) 6 ppm 1.28 (t, J=7.17 Hz, 3 H) 1.96 (dd, J=12.51, 8.54 Hz, 1 H) 2.25 (s, 3 H) 2.71 - 2.81 (m, 1 H) 2.94 (dd, J=8.85, 3.36 Hz, 1 H) 3.87 (d, J=7.93 Hz, 6 H) 4.00 (q, J=7.12 Hz, 2 H) 5.54 (t, J=7.78 Hz, 1 H) 7.07 (d, J=7.32 Hz, 1 H) 7.10 7.24 (m, 2 H) 7.66 (s, 1 H) 7.76 (d, J=14.34 Hz, 2 H). 5 MS (ESI+) M/Z 407 [M+H]+. Example 175 2-Ethyl-6,7-dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-l-oxo-1,2 dihydroisoquinoline-4-carboxamide 10 1 H NMR (500 MHz) 6 ppm 1.27 (t, J=7.17 Hz, 3 H) 1.89 - 2.02 (m, 1 H) 2.30 (s, 3 H) 2.76 - 2.87 (m, 1 H) 2.91 - 3.01 (m, 1 H) 3.87 (d, J=7.63 Hz, 6 H) 4.00 (q, J=7.12 Hz, 2 H) 5.48 (t, J=7.63 Hz, 1 H) 6.98 - 7.14 (m, 2 H) 7.25 (d, J=7.63 Hz, 1 H) 7.66 (s, 1 H) 7.76 (d, J=15.56 Hz, 2 H). MS (ESI+) M/Z 407 [M+H]+. 15 Example 176 2-Ethyl-6,7-dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-l-oxo-1,2 dihydroisoquinoline-4-carboxamide IH NMR (500 MHz) 6 ppm 1.28 (t, J=7.17 Hz, 3 H) 1.97 (dd, J=12.51, 7.93 Hz, 1 20 H) 2.70 - 2.85 (m, 1 H) 2.91 (dd, J=8.85, 3.36 Hz, 1 H) 3.72 (s, 3 H) 3.87 (d, J=9.76 Hz, 6 H) 4.01 (q, J=7.02 Hz, 2 H) 5.49 (t, J=7.93 Hz, 1 H) 6.82 (dd, J=7.93, 2.14 Hz, 1 H) 6.92 (d, J=2.14 Hz, 1 H) 7.19 (d, J=8.24 Hz, 1 H) 7.66 (s, 1 H) 7.78 (d, J=5.80 Hz, 2 H). MS (ESI+) M/Z 423 [M+H]+. 25 Example 177 2-Ethyl-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-1,2 dihydroisoquinoline-4-carboxamide IH NMR (500 MHz) 6 ppm 1.28 (t, J=7.17 Hz, 3 H) 2.01 (dd, J=12.51, 7.93 Hz, 1 30 H) 2.76 - 2.93 (m, 1 H) 2.96 - 3.13 (m, 1 H) 3.87 (d, J=6.10 Hz, 6 H) 4.00 (q, J=7.02 Hz, 2 H) 5.50 (d, J=7.63 Hz, 1 H) 6.95 - 7.19 (m, 2 H) 7.38 (dd, J=8.09, 5.34 Hz, 1 H) 7.66 (s, 1 H) 7.77 (d, J=6.10 Hz, 2 H) 8.73 (d, J=8.24 Hz, 1 H).
WO 2013/068489 PCT/EP2012/072175 147 MS (ESI+) M/Z 411 [M+H]+. Example 178 N-(2-((Diethylamino)methyl)benzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 5 dihydroisoquinoline-4-carboxamide H NMR (500 MHz) 6 ppm 1.18 - 1.45 (m, 9 H) 3.25 (q, 4 H) 3.79 (s, 3 H) 3.87 (s, 3 H) 4.04 (q, J=7.02 Hz, 2 H) 4.53 (d, J=14.04 Hz, 4 H) 7.43 (t, J=7.48, 1.37 Hz, 1 H) 7.50 - 7.57 (m, 2 H) 7.59 (t, 2 H) 7.65 (s, 1 H) 7.85 (s, 1 H). MS (ESI+) M/Z 452 [M+H]+. 10 Example 179 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-(2-(pyrrolidin- 1 -ylmethyl)benzyl)- 1,2 dihydroisoquinoline-4-carboxamide H NMR (500 MHz) 6 ppm 1.22 - 1.34 (m, 4 H) 1.89 - 1.97 (m, 2 H) 2.08 - 2.16 15 (m, 2 H) 3.19 - 3.26 (m, 2 H) 3.47 - 3.55 (m, 2 H) 3.80 (s, 3 H) 3.86 - 3.89 (m, 4 H) 3.97 - 4.07 (m, 2 H) 4.58 (d, J=3.36 Hz, 4 H) 7.41 (t, 1 H) 7.49 - 7.58 (m, 3 H) 7.65 (d, 2 H) 7.83 (s, 1 H). MS (ESI+) M/Z 450 [M+H]+. 20 The compounds of the following examples 180 and 181 were prepared by analogy to example 133 starting from 2-ethyl-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 2-carboxylic acid, which in turn was prepared by analogy to steps 133.1-133.7 of example 133 starting from commercially available 5-bromo-2-methoxy-isonicotinic acid. 25 Example 180 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid indan- 1 -ylamide ESI-MS: [M+Na] = 386.20, [M+H+] = 364.10. 30 Example 181 WO 2013/068489 PCT/EP2012/072175 148 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid butylamide ESI-MS: [2M+Na] = 629.20, [M+H] = 304.10. 5 The compound of the following example 182 was prepared according to example 133 starting from (Z)-methyl 2-(1 -(dimethylamino)-3 -methoxy-3 -oxoprop- 1 -en-2-yl)-5 methoxybenzoate, which in turn was prepared according to step 133.6 of example 133 starting from starting from 2-(quinolin-2-yl)ethanamine. 10 Example 182 7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide ESI-MS: [M+H -] = 430.20. 15 The following compounds were prepared in analogy to the above examples. Example 183 7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide 20 ESI-MS: [M+H ]=490.20. Example 184 (S)-3-ethyl-6,7-dimethoxy-4-oxo-N-(1,2,3,4-tetrahydronaphthalen- 1-yl)-3,4 dihydrophthalazine- 1 -carboxamide 25 ESI-MS: [M+Na] = 430.20, [M+H] = 408.20. Example 185 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (S) indan- 1 -ylamide 30 ESI-MS: [M+Na] = 416.20, [M+H] = 394.20. Example 186 WO 2013/068489 PCT/EP2012/072175 149 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide ESI-MS: [M+H ]=436.20. 5 Example 187 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-dimethylaminomethyl-benzylamide hydrochloride ESI-MS: [M+H = 466.30. 10 Example 188 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3,5-difluoro-benzylamide ESI-MS: [M+H = 445.20; 15 Example 189 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3,4-difluoro-benzylamide ESI-MS: [M+H = 445.20. 20 Example 190 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexylmethyl-amide ESI-MS: [M+H = 415.30; 25 Example 191 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (R)-indan-1-ylamide ESI-MS: [M+H = 435.30. 30 Example 192 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (S)-indan-1-ylamide WO 2013/068489 PCT/EP2012/072175 150 ESI-MS: [M+H ]=435.30. Example 193 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 5 acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide ESI-MS: 442.10, [M+H] = 441.10. Example 194 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid (2,3-dihydro-benzofuran-3-yl)-amide ESI-MS: [M+Na]= 459.15, 438.20, [M+H] = 437.15. Example 195 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 15 acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide ESI-MS: [M+Na]= 477.05, 456.10, [M+H] = 455.10. Example 196 2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 20 indan- 1 -ylamide ESI-MS: 406.10, [M+H] = 405.10. Example 197 2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 25 indan- 1 -ylamide ESI-MS: 422.15, [M+H] = 421.10. Example 198 2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid 30 indan- 1 -ylamide ESI-MS: 408.20, [M+H] = 407.15; WO 2013/068489 PCT/EP2012/072175 151 Example 199 (+)-2-(1-Ethyl-propyl)-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide ESI-MS: 437.20, [M+H] = 436.20. 5 Example 200 (-)-2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide ESI-MS: 437.20, [M+H] = 436.20. 10 Example 201 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid ([1,3,4]thiadiazol-2-ylmethyl)-amide ESI-MS: 418.20, [M+H] = 417.10. 15 Example 202 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-(morpholine-4-sulfonyl)-benzylamide ESI-MS: 560.20, 559.20, [M+H *] = 558.20; 20 Example 203 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (thiazol-4-ylmethyl)-amide ESI-MS: 417.10, [M+H] = 416.10. 25 Example 204 (+)-2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide ESI-MS: [M+H ]=399.10. 30 Example 205 WO 2013/068489 PCT/EP2012/072175 152 (-)-2-Ethyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid (5,6 dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide ESI-MS: [M+H ]=399.10. 5 Example 206 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (thiophen-3-ylmethyl)-amide ESI-MS: 416.10, [M+H] = 415.10. 10 Example 207 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine-1-carbonyl)-2H isoquinolin-1-one ESI-MS: [M+H ]=463.10. 15 Example 208 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine-1-carbonyl)-2H isoquinolin-1-one ESI-MS: [M+H ]=479.20. 20 Example 209 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-piperazine-1 carbonyl]-2H-isoquinolin- 1-one ESI-MS: [M+H ]=494.20. 25 Example 210 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine-1-sulfonyl)-3,4 dihydro- 1H-isoquinoline-2-carbonyl]-2H-isoquinolin- 1-one ESI-MS: [M+H] = 597.20. 30 Example 211 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4-dihydro-1H isoquinoline-2-carbonyl]-2H-isoquinolin- 1-one WO 2013/068489 PCT/EP2012/072175 153 ESI-MS: [M+H] = 584.20. Example 212 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl-piperazine 5 1 -carbonyl]-2H-isoquinolin- 1-one ESI-MS: [M+H] = 508.30. Example 213 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy)-pyrrolidine-1 10 carbonyl]-2H-isoquinolin- 1-one ESI-MS: [M+H ]= 517.20. Example 214 4-(7-Amino-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2-(1-ethyl-propyl)-6,7 15 dimethoxy-2H-isoquinolin- 1-one trifluoroacetate ESI-MS: [M+H] = 450.20. Example 215 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid 3-(4-chloro-benzenesulfonylamino)-benzylamide ESI-MS: [M]- = 598.20. Example 216 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 25 acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide ESI-MS: [M+Na] = 475.20, [M+H] = 453.20. Example 217 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic 30 acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide ESI-MS: [M+Na] = 434.10, [M+H -] = 412.10.
WO 2013/068489 PCT/EP2012/072175 154 Example 218 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (S)-indan-1-ylamide ESI-MS: [M +Na] = 428.10, [M +H *] = 406.20. 5 Example 219 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide ESI-MS: [M+H] = 571.30. 10 Example 220: 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid 2-(morpholine-4-sulfonyl)-benzylamide ESI-MS: [M +Na ]* = 551.20, [M +H] = 529.20. 15 Example 221: 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide ESI-MS: [M +Na ]* = 429.15, [M +H ]* = 407.20. 20 Example 222 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide ESI-MS: [M +Na ]* = 616.20, [M +H] = 594.30. 25 Example 223 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid 3,5-difluoro-benzylamide ESI-MS: [M+Na]* = 438.15, [M+H] = 416.10 30 Example 224 WO 2013/068489 PCT/EP2012/072175 155 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid 4-methyl-benzylamide ESI-MS: [M +Na ]* = 416.20, [M +H] = 394.20. 5 Example 225 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid cyclohexylmethyl-amide ESI-MS: [M+Na]* = 408.20, [M+H]* = 386.20. 10 Example 226 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid butylamide ESI-MS: [M+H] = 346.20. 15 Example 227: 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide ESI-MS: [M+Na]* = 430.20, [M+H] = 408.20. 20 Example 228 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (thiazol-2-ylmethyl)-amide ESI-MS: [M+Na]* = 438.10, [M+H]* = 416.10. 25 Example 229 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (thiophen-2-ylmethyl)-amide ESI-MS: [M+Na]* = 437.10, [M+H] = 415.10. 30 Example 230 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4-carboxylic acid (5,6 dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide WO 2013/068489 PCT/EP2012/072175 156 ESI-MS: [M+Na]* = 392.10, [M+H]* = 370.10. Example 231 3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic 5 acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide trifluoroacetate ESI-MS: [M+Na]* = 464.10, [M+H]* = 442.15. Example 232 3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic 10 acid (2,3-dihydro-benzofuran-3-yl)-amide trifluoroacetate ESI-MS: [M+Na]* = 460.20, [M+H]* = 438.20. Example 233 3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic 15 acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide ESI-MS: [M+Na] = 459.20, [M+H]* = 437.20. Example 234: 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H-isoquinolin- 1-one 20 ESI-MS: [M+Na]* = 430.20, [M+H] = 408.20 Example 235 3-(1-Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid indan- 1 -ylamide 25 ESI-MS: [M +Na ]* = 458.20, [M +H ]* = 436.20. Example 236 6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)-1,2 dihydroisoquinoline-4-carboxamide 30 A microwave vial was charged with a stir bar and 284 mg of PS-TFP (10 eq.). To the vessel were added 6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2-dihydroisoquinoline-4- WO 2013/068489 PCT/EP2012/072175 157 carboxylic acid (29 mg, 0.09 mmol) dissolved in dry THF(1.0 mL) and CCl 3 CN (36 gL, 0.36 mmol) dissolved in dry THF(O.5 mL). The reaction vessel was sealed and heated to 120'C for 1800 seconds. Then pyridin-3-ylmethanamine (15 mg, 0.135 mmol) dissolved in THF (0.5 mL) was added followed by DIEA (47 gL, 0.27 mmol). The 5 mixture was heated again to 150'C for 1800 seconds. After cooling the reaction mixture was filtered and products were collected and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH. Purification by reverse phase HPLC provided the title compound (14.7 mg, 310%). ESI-MS =410 [M+H]*; 10 1 H NMR (500 MHz, DMSO-D 2 0 ,T: 25 'C) 6 ppm 8.86 (s, 1 H) 8.76 (d, J=5.49 Hz, 1 H) 8.47 (d, J=7.93 Hz, 1 H) 7.97 (dd, J=7.93, 5.49 Hz, 1 H) 7.74 (s, 1 H) 7.67 (d, J=10.99 Hz, 2 H) 4.86 (s, 1 H) 4.65 (s, 2 H) 3.86 (d, J=28.08 Hz, 6 H) 1.69 - 1.90 (m, 4 H) 0.74 (t, J=7.32 Hz, 6 H). 15 The following compounds of examples 237 to 244 were prepared in an analogous manner to the process described in example 236. Example 237 6,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 20 dihydroisoquinoline-4-carboxamide ESI-MS = 429 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.72 (s, 1 H) 7.67 (s, 1 H) 7.50 (s, 1 H) 6.83 (d, J=3.36 Hz, 1 H) 6.65 (d, J=2.14 Hz, 1 H) 4.85 (s, 1 H) 4.55 (s, 2 H) 3.86 (d, J=21.36 Hz, 6 H) 2.39 (s, 3 H) 1.65 - 1.85 (m, 4 H) 0.72 (t, J=7.32 Hz, 6 H). 25 Example 238 N-((3,5-Dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS = 428[M+H]*; 30 1 H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.67 (s, 1 H) 7.63 (s, 1 H) 7.45 (s, 1 H) 4.83 (s, 1 H) 4.26 (s, 2 H) 3.85 (d, J=28.99 Hz, 6 H) 2.43 (s, 3 H) 2.26 (s, 3 H) 1.65 - 1.85 (m, 4 H) 0.72 (t, J=7.17 Hz, 6 H).
WO 2013/068489 PCT/EP2012/072175 158 Example 239 6,7-Dimethoxy-N-((5-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide 5 ESI-MS =430 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.80 (s, 1 H) 7.69 (s, 1 H) 7.60 (s, 1 H) 7.42 (s, 1 H) 4.87 (s, 1 H) 4.68 (s, 2 H) 3.88 (d, J=14.04 Hz, 6 H) 2.42 (s, 3 H) 1.68 - 1.88 (m, 4 H) 0.74 (t, J=7.32 Hz, 6 H). 10 Example 240 6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =411 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 9.13 (s, 1 H) 8.76 - 8.79 (m, 1 15 H) 7.77 - 7.81 (m, 1 H) 7.67 - 7.70 (m, 2 H) 7.55 (d, J=4.88 Hz, 1 H) 4.87 (s, 1 H) 4.56 4.61 (m, 2 H) 3.89 (s, 3 H) 3.84 (s, 3 H) 1.77 - 1.86 (m, 4 H) 0.75 (t, J=7.32 Hz, 6 H). Example 241 6,7-Dimethoxy-N-((3-methylisoxazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 20 dihydroisoquinoline-4-carboxamide ESI-MS =414 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.75 (s, 1 H) 7.68 (s, 1 H) 7.58 (s, 1 H) 6.30 (s, 1 H) 4.85 (s, 1 H) 4.57 (s, 2 H) 3.87 (d, J=16.48 Hz, 6 H) 2.22 (s, 3 H) 1.71 - 1.87 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). 25 Example 242: N-((2,5-dimethylthiophen-3-yl)methyl)-6,7-dimethoxy-1-oxo-2 (pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide ESI-MS =443 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.67 (s, 1 H) 7.63 (s, 1 H) 30 7.47 (s, 1 H) 6.69 (s, 1 H) 4.84 (s, 1 H) 4.30 (s, 2 H) 3.85 (d, J=30.21 Hz, 6 H) 2.31 2.39 (m, 6 H) 1.67 - 1.84 (m, 4 H) 0.72 (t, J=7.32 Hz, 6 H).
WO 2013/068489 PCT/EP2012/072175 159 Example 243 6,7-Dimethoxy-N-((2-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =430 [M+H]*; 5 1H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.73 (s, 1 H) 7.67 (s, 1 H) 7.58 (s, 1 H) 7.51 (s, 1 H) 4.84 (s, 2 H) 4.60 (s, 2 H) 3.87 (d, 6 H) 2.62 (s, 3 H) 1.66 1.85 (m, 4 H) 0.72 (t, J=7.32 Hz, 6 H). Example 244 10 6,7-Dimethoxy-N-((5-methylisoxazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-l,2 dihydroisoquinoline-4-carboxamide ESI-MS =414 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.78 (s, 1 H) 7.68 (s, 1 H) 7.55 - 7.59 (m, 1 H) 6.25 (s, 1 H) 4.85 (s, 1 H) 4.48 (s, 2 H) 3.87 (d, J=10.38 Hz, 6 H) 15 2.39 (s, 3 H) 1.70 - 1.85 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 245 (R)-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide 20 The title compound was prepared in analogy to the process described in example 236 but using (R)- 1 -(4-fluorophenyl)ethanamine instead of pyridine-3 -ylmethanamine. ESI-MS =441 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.67 (s, 1 H) 7.43 - 7.53 (m, 4 H) 7.19 (t, J=8.85 Hz, 2 H) 5.17 (q, J=6.92 Hz, 1 H) 4.84 (s, 1 H) 3.83 (d, J=50.35 Hz, 6 25 H) 1.67 - 1.88 (m, 4 H) 1.50 (d, J=7.32 Hz, 3 H) 0.69 - 0.78 (m, 6 H). Example 246 (S)-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide 30 The title compound was prepared in analogy to the process described in example 236 but using (S)- 1 -(4-fluorophenyl)ethanamine instead of pyridine-3 -ylmethanamine. ESI-MS =441 [M+H]*; WO 2013/068489 PCT/EP2012/072175 160 1 H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.67 (s, 1 H) 7.42 - 7.55 (m, 4 H) 7.19 (t, J=8.85 Hz, 2 H) 5.17 (q, J=7.02 Hz, 1 H) 4.84 (s, 1 H) 3.83 (d, J=50.35 Hz, 6 H) 1.67 - 1.90 (m, 4 H) 1.50 (d, J=7.32 Hz, 3 H) 0.68 - 0.78 (m, 6 H). 5 The compounds of examples 247 to 269 were prepared in an analogous manner to the process described in example 236. Example 247 6,7-Dimethoxy-N-((4-methylthiazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 10 dihydroisoquinoline-4-carboxamide ESI-MS =430 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.78 (s, 1 H) 7.69 (s, 1 H) 7.62 (s, 1 H) 7.20 (s, 1 H) 4.81 - 4.94 (m, J=10.38 Hz, 1 H) 4.72 (s, 2 H) 3.87 (d, J=19.53 Hz, 6 H) 2.36 (s, 3 H) 1.68 - 1.87 (m, 4 H) 0.74 (t, J=7.32 Hz, 6 H). 15 Example 248 6,7-Dimethoxy-N-((2-methylthiazol-4-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =430 [M+H]*; 20 1 H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.75 (s, 1 H) 7.68 (s, 1 H) 7.60 (s, 1 H) 7.32 (s, 1 H) 4.85 (s, 1 H) 4.53 (s, 2 H) 3.86 (d, J=20.45 Hz, 6 H) 2.66 (s, 3 H) 1.67 - 1.87 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 249 25 6,7-Dimethoxy-N-((4-methylthiazol-5-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =430[M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 8.96 (s, 1 H) 7.68 (d, J=8.54 Hz, 2 H) 7.50 (s, 1 H) 4.85 (s, 1 H) 4.61 (s, 2 H) 3.86 (d, J=22.28 Hz, 6 H) 2.45 (s, 3 H) 30 1.67 - 1.89 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 250 WO 2013/068489 PCT/EP2012/072175 161 6,7-Dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2-yl)methyl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS =467 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.72 (s, 1 H) 7.68 (s, 1 H) 5 7.56 (s, 1 H) 7.17 (d, J=2.14 Hz, 1 H) 6.58 (d, J=3.05 Hz, 1 H) 4.85 (s, 1 H) 4.56 (s, 2 H) 3.86 (d, 6 H) 1.67 - 1.87 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 251 6,7-Dimethoxy-N-((5-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 10 dihydroisoquinoline-4-carboxamide ESI-MS =413 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.73 (s, 1 H) 7.67 (s, 1 H) 7.53 (s, 1 H) 6.21 (d, J=2.75 Hz, 1 H) 6.03 (d, J=2.14 Hz, 1 H) 4.85 (s, 1 H) 4.42 (s, 2 H) 3.86 (d, J=20.14 Hz, 6 H) 2.24 (s, 3 H) 1.66 - 1.87 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). 15 Example 252 N-(5-Fluoro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS [M+H]* = 453 [M+H]*; 20 1H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.73 (s, 1 H) 7.68 (s, 1 H) 7.52 (s, 1 H) 7.38 (dd, J=8.24, 5.49 Hz, 1 H) 7.10 - 7.13 (m, 1 H) 7.02 - 7.07 (m, 1 H) 5.53 (t, J=7.78 Hz, 1 H) 4.83 (s, 1 H) 3.87 (d, J=11.90 Hz, 6 H) 2.96 - 3.05 (m, 1 H) 2.81 - 2.92 (m, 1 H) 2.54 - 2.59 (m, 1 H) 1.96 - 2.10 (m, 1 H) 1.65 - 1.86 (m, 4 H) 0.73 (q, J=7.02 Hz, 6 H). 25 Example 253 6,7-Dimethoxy-N-(5-methyl-2,3-dihydro-1H-inden-1-yl)-l-oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS =449 [M+H]*; 30 1H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.73 (s, 1 H) 7.68 (s, 1 H) 7.50 (s, 1 H) 7.24 (d, J=7.63 Hz, 1 H) 7.10 (s, 1 H) 7.05 (d, J=7.63 Hz, 1 H) 5.52 (t, J=7.78 Hz, 1 H) 4.83 (s, 1 H) 3.87 (d, J=14.34 Hz, 6 H) 2.92 - 3.02 (m, 1 H) 2.77 - 2.89 WO 2013/068489 PCT/EP2012/072175 162 (I, 1 H) 2.46 - 2.51 (m, 1 H) 2.30 (s, 3 H) 1.91 - 2.03 (m, 1 H) 1.65 - 1.85 (m, 4 H) 0.73 (q, J=7.02 Hz, 6 H). Example 254 5 6,7-Dimethoxy-N-(4-methyl-2,3-dihydro-1H-inden-1-yl)-l-oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS =449 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.74 (s, 1 H) 7.68 (s, 1 H) 7.51 (s, 1 H) 7.12 - 7.21 (m, 2 H) 7.07 (d, J=7.32 Hz, 1 H) 5.57 (t, J=7.93 Hz, 1 H) 4.84 10 (s, 1 H) 3.87 (d, J=14.34 Hz, 6 H) 2.90 - 3.02 (m, 1 H) 2.72 - 2.83 (m, 1 H) 2.55 - 2.59 (m, 1 H) 2.25 (s, 3 H) 1.92 - 2.04 (m, 1 H) 1.66 - 1.83 (m, 4 H) 0.68 - 0.77 (m, 6 H). Example 255 N-((2-Ethylthiazol-4-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 15 dihydroisoquinoline-4-carboxamide ESI-MS =444 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.75 (s, 1 H) 7.68 (s, 1 H) 7.60 (s, 1 H) 7.33 (s, 1 H) 4.86 (s, 1 H) 4.54 (s, 2 H) 3.86 (d, J=21.06 Hz, 6 H) 2.98 (q, J=7.53 Hz, 2 H) 1.70 - 1.86 (m, 4 H) 1.30 (t, J=7.48 Hz, 3 H) 0.73 (t, J=7.32 Hz, 6 H). 20 Example 256 6,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-l-oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS =465 [M+H]*; 25 1H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.75 (s, 1 H) 7.68 (s, 1 H) 7.54 (s, 1 H) 7.20 (d, J=8.24 Hz, 1 H) 6.90 (d, J=1.83 Hz, 1 H) 6.83 (dd, J=8.24, 2.44 Hz, 1 H) 5.52 (t, J=7.93 Hz, 1 H) 4.84 (s, 1 H) 3.87 (d, J=16.17 Hz, 6 H) 3.72 (s, 3 H) 2.89 - 2.99 (m, 1 H) 2.74 - 2.83 (m, 1 H) 2.47 - 2.52 (m, 1 H) 1.95 - 2.04 (m, 1 H) 1.67 1.85 (m, 4 H) 0.73 (q, J=7.02 Hz, 6 H). 30 Example 257 WO 2013/068489 PCT/EP2012/072175 163 6,7-Dimethoxy-N-((4-methylthiophen-2-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS = 429 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.72 (s, 1 H) 7.67 (s, 1 H) 5 7.51 (s, 1 H) 6.97 (s, 1 H) 6.88 (s, 1 H) 4.85 (s, 1 H) 4.58 (s, 2 H) 3.80 - 3.90 (m, 6 H) 2.16 - 2.19 (m, 3 H) 1.66 - 1.87 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 258 6,7-Dimethoxy-N-((3-methylthiophen-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 10 dihydroisoquinoline-4-carboxamide ESI-MS =429 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.68 (d, J=6.10 Hz, 2 H) 7.46 - 7.51 (m, 1 H) 7.30 (d, J=4.88 Hz, 1 H) 6.86 (d, J=4.88 Hz, 1 H) 4.85 (s, 1 H) 4.57 (s, 2 H) 3.79 - 3.91 (m, 6 H) 2.24 (s, 3 H) 1.63 - 1.86 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). 15 Example 259 6,7-Dimethoxy-N-((5-methyloxazol-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =414 [M+H]*; 20 IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.81 (s, 1 H) 7.68 (s, 1 H) 7.60 (s, 1 H) 6.79 (d, J=1.22 Hz, 1 H) 4.86 (s, 1 H) 4.54 (s, 2 H) 3.88 (d, J=10.38 Hz, 6 H) 2.28 (s, 3 H) 1.66 - 1.88 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 260 25 6,7-Dimethoxy-N-(6-methyl-2,3-dihydro-1H-inden-1-yl)-l-oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS =449 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.74 (s, 1 H) 7.69 (s, 1 H) 7.52 (s, 1 H) 7.14 - 7.20 (m, 2 H) 7.06 (d, J=7.93 Hz, 1 H) 5.54 (t, J=7.93 Hz, 1 H) 4.84 30 (s, 1 H) 3.88 (d, J=11.29 Hz, 6 H) 2.88 - 3.01 (m, 1 H) 2.74 - 2.87 (m, 1 H) 2.46 - 2.51 (m, 1 H) 2.28 (s, 3 H) 1.92 - 2.01 (m, 1 H) 1.66 - 1.85 (m, 4 H) 0.73 (q, J=7.63 Hz, 6
H).
WO 2013/068489 PCT/EP2012/072175 164 Example 261 6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)-1,2 dihydroisoquinoline-4-carboxamide 5 ESI-MS = 410 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 8.81 (d, J=6.71 Hz, 2 H) 7.96 (d, J=6.41 Hz, 2 H) 7.77 (s, 1 H) 7.73 (s, 1 H) 7.69 (s, 1 H) 4.80 - 4.95 (m, J=6.10 Hz, 1 H) 4.73 (s, 2 H) 3.84 (d, 6 H) 1.70 - 1.89 (m, 4 H) 0.75 (t, J=7.32 Hz, 6 H). 10 Example 262 6,7-Dimethoxy-N-(4-methylbenzyl)-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =423 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.69 (d, J=10.99 Hz, 2 H) 15 7.54 (s, 1 H) 7.27 (d, J=7.93 Hz, 2 H) 7.18 (d, J=7.93 Hz, 2 H) 4.85 (s, 1 H) 4.45 (s, 2 H) 3.85 (d, 6 H) 2.29 (s, 3 H) 1.67 - 1.87 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H). Example 263 6,7-Dimethoxy-1-oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)-1,2 20 dihydroisoquinoline-4-carboxamide ESI-MS =410 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 8.73 (d, J=4.88 Hz, 1 H) 8.28 - 8.34 (m, 1 H) 7.85 (d, J=7.93 Hz, 1 H) 7.78 (s, 1 H) 7.72 - 7.76 (m, 2 H) 7.69 (s, 1 H) 4.88 (s, 1 H) 4.74 (s, 2 H) 3.85 (d, J=31.43 Hz, 6 H) 1.68 - 1.92 (m, 4 H) 0.75 (t, J=7.32 25 Hz, 6 H). Example 264 N-((5-Cyanofuran-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide 30 ESI-MS =424 [M+H]*; WO 2013/068489 PCT/EP2012/072175 165 H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.71 (s, 1 H) 7.68 (s, 1 H) 7.57 (s, 1 H) 7.54 (d, J=3.66 Hz, 1 H) 6.64 (d, J=3.66 Hz, 1 H) 4.84 (s, 1 H) 4.56 (s, 2 H) 3.87 (d, J=14.04 Hz, 6 H) 1.67 - 1.89 (m, J=12.82 Hz, 4 H) 0.73 (t, J=7.32 Hz, 6 H). 5 Example 265 N-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl) 1,2-dihydroisoquinoline-4-carboxamide ESI-MS =469 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 C) 6 ppm 7.67 - 7.74 (m, J=17.70 Hz, 2 10 H) 7.52 (s, 1 H) 7.25 - 7.37 (m, 3 H) 5.64 (q, J=7.93 Hz, 1 H) 4.83 (s, 1 H) 3.87 (d, J=10.68 Hz, 6 H) 3.00 - 3.10 (m, 1 H) 2.83 - 2.95 (m, 1 H) 2.55 - 2.62 (m, 1 H) 1.97 2.12 (m, 1 H) 1.64 - 1.86 (m, 4 H) 0.67 - 0.79 (m, 6 H). Example 266 15 N-((5-Ethylthiophen-2-yl)methyl)-6,7-dimethoxy-1-oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =443 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.72 (s, 1 H) 7.67 (s, 1 H) 7.51 (s, 1 H) 6.85 (d, J=3.36 Hz, 1 H) 6.68 (d, J=3.36 Hz, 1 H) 4.84 (s, 1 H) 4.57 (s, 2 20 H) 3.86 (d, J=16.78 Hz, 6 H) 2.76 (q, J=7.43 Hz, 2 H) 1.64 - 1.90 (m, 4 H) 1.21 (t, J=7.63 Hz, 3 H) 0.73 (t, J=7.32 Hz, 6 H). Example 267 6,7-Dimethoxy-N-((3-methylfuran-2-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 25 dihydroisoquinoline-4-carboxamide ESI-MS =413 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.68 (d, J=8.24 Hz, 2 H) 7.44 - 7.52 (m, 2 H) 6.32 (d, J=1.83 Hz, 1 H) 4.83 (s, 1 H) 4.45 (s, 2 H) 3.85 (d, J=18.62 Hz, 6 H) 2.06 (s, 3 H) 1.65 - 1.85 (m, 4 H) 0.72 (t, J=7.32 Hz, 6 H). 30 Example 268 WO 2013/068489 PCT/EP2012/072175 166 6,7-Dimethoxy-N-((2-methylfuran-3-yl)methyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide ESI-MS =413 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.67 (s, 2 H) 7.42 - 7.48 (m, 5 2 H) 6.44 (d, J=1.53 Hz, 1 H) 4.83 (s, 1 H) 4.25 (s, 2 H) 3.85 (d, J=19.84 Hz, 6 H) 2.30 (s, 3 H) 1.59 - 1.89 (m, 4 H) 0.72 (t, J=7.32 Hz, 6 H). Example 269 6,7-Dimethoxy-N-((1-methyl-iH-pyrazol-3-yl)methyl)-1-oxo-2-(pentan-3-yl)-1,2 10 dihydroisoquinoline-4-carboxamide ESI-MS =413 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.75 (s, 1 H) 7.68 (s, 1 H) 7.62 (d, J=2.14 Hz, 1 H) 7.55 (s, 1 H) 6.22 (d, J=2.14 Hz, 1 H) 4.84 (s, 1 H) 4.43 (s, 2 H) 3.87 (d, J=14.04 Hz, 6 H) 3.80 (s, 3 H) 1.65 - 1.86 (m, 4 H) 0.73 (t, J=7.17 Hz, 6 H). 15 Example 270 N-[(3,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4 carboxamide To a solution of 2-ethyl-6,7-dimethoxy-1-oxo-1,2-dihydroisoquinoline-4 20 carboxylic acid (25 mg, 0.09 mmol) in DMA (1.0 mL) was added a solution of HATU (41 mg, 0.1 mmol) in DMA (0.5 mL). The reaction mixture was placed to shake for 45 minutes at room temperature. Then a solution of (3,4-dimethylphenyl)methanamine (18 mg, 0.13mmol) dissolved in DMA (0.4 mL) was added followed by triethylamine neat (40ptL, 0.27mmol). The reaction was shaken at 65'C overnight. The reaction was 25 checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH. Purification by reverse phase HPLCprovided the titled compound (17.9 mg, 50 %) ESI-MS: m/z 395 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.75 (s, 1 H) 7.70 (s, 1 H) 30 7.65 (s, 1 H) 7.15 (s, 1 H) 7.11 (s, 2 H) 4.41 (s, 2 H) 4.02 (q, J=7.12 Hz, 2 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 2.21 (d, J=6.10 Hz, 6 H) 1.29 (t, J=7.17 Hz, 3 H).
WO 2013/068489 PCT/EP2012/072175 167 The compounds of examples 271 to 292 were prepared in analogy to the process described in example 270. Example 271 5 N-[(2-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 415 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.81 (s, 1 H) 7.71 (s, 1 H) 7.66 (s, 1 H) 7.36 (d, J=7.63 Hz, 1 H) 7.31 (s, 1 H) 7.18 (d, J=8.24 Hz, 1 H) 4.51 (s, 2 H) 10 4.03 (q, J=7.12 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.30 (s, 3 H) 1.30 (t, J=7.17 Hz, 3 H). Example 272 N-[[2-(Dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo 15 isoquinoline-4-carboxamide ESI-MS: m/z 424 [M+H]*. IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 8.75 (t, J=5.80 Hz, 1 H) 7.78 (s, 1 H) 7.75 (s, 1 H) 7.66 (s, 1 H) 7.22 (d, J=7.63 Hz, 1 H) 6.96 (s, 1 H) 6.87 (d, J=7.93 Hz, 1 H) 4.53 (d, J=5.49 Hz, 2 H) 4.02 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.81 - 3.85 (m, 20 3 H) 2.66 (s, 6 H) 2.28 (s, 3 H) 1.29 (t, J=7.17 Hz, 3 H); Example 273 2-Ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide 25 ESI-MS: m/z 399 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 8.86 (t, J=5.65 Hz, 1 H) 7.77 (s, 1 H) 7.69 (s, 1 H) 7.65 (s, 1 H) 7.34 (t, J=8.09 Hz, 1 H) 7.01 - 7.06 (m, 2 H) 4.43 4.50 (m, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.31 (s, 3 H) 1.29 (t, J=7.17 Hz, 3 H). 30 Example 274 WO 2013/068489 PCT/EP2012/072175 168 2-Ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl] -1 -oxo isoquinoline-4-carboxamide ESI-MS: m/z 411 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.77 (s, 1 H) 7.71 (s, 1 H) 7.66 5 (s, 1 H) 7.11 (d, J=7.93 Hz, 1 H) 6.95 (s, 1 H) 6.84 - 6.90 (m, 1 H) 4.45 (s, 2 H) 4.02 (q, J=7.12 Hz, 2 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.78 (s, 3 H) 2.13 (s, 3 H) 1.29 (t, J=7.17 Hz, 3 H). Example 275 10 2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl]-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 466 [M+H]*. H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.76 (d, J=7.02 Hz, 2 H) 7.65 - 7.68 (m, 1 H) 7.26 (d, J=7.63 Hz, 1 H) 6.97 (s, 1 H) 6.94 (d, J=7.93 Hz, 1 H) 4.55 (s, 2 15 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.84 (s, 3 H) 3.75 - 3.79 (m, J=4.27 Hz, 4 H) 2.83 - 2.90 (m, 4 H) 2.29 (s, 3 H) 1.29 (t, 3 H). Example 276 N-[(2-tert-Butoxy-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo 20 isoquinoline-4-carboxamide ESI-MS: m/z 453 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.76 (s, 1 H) 7.72 (s, 1 H) 7.66 (s, 1 H) 7.22 (d, J=7.93 Hz, 1 H) 6.91 (s, 1 H) 6.86 (d, J=7.63 Hz, 1 H) 4.45 (s, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.83 (s, 3 H) 2.28 (s, 3 H) 1.38 (s, 9 H) 1.29 (t, 25 J=7.17 Hz, 3 H). Example 277 N-[[2-(1,1-Dimethylpropoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1 oxo-isoquinoline-4-carboxamide 30 ESI-MS: m/z 467 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.77 (s, 1 H) 7.73 (s, 1 H) 7.66 (s, 1 H) 7.20 (d, J=7.93 Hz, 1 H) 6.88 (s, 1 H) 6.84 (d, J=7.63 Hz, 1 H) 4.44 (s, 2 H) WO 2013/068489 PCT/EP2012/072175 169 4.02 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.83 (s, 3 H) 2.28 (s, 3 H) 1.75 (q, J=7.63 Hz, 2 H) 1.32 (s, 6 H) 1.29 (t, J=7.17 Hz, 3 H) 0.97 (t, J=7.32 Hz, 3 H). Example 278 5 N-[(2,3-Difluoro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 417 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.78 (s, 1 H) 7.69 (s, 1 H) 7.65 (s, 1 H) 7.17 (t, J=7.93 Hz, 1 H) 7.11 (t, J=7.32 Hz, 1 H) 4.51 (s, 2 H) 3.98 - 4.07 10 (m, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.27 (d, J=1.83 Hz, 3 H) 1.30 (t, 3 H). Example 279 2-Ethyl-N-[(3-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide 15 ESI-MS: m/z 399 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.80 (s, 1 H) 7.70 (s, 1 H) 7.66 (s, 1 H) 7.27 (t, J=8.09 Hz, 1 H) 7.10 - 7.15 (m, 2 H) 4.45 (s, 2 H) 4.03 (q, J=7.12 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.22 (d, J=1.22 Hz, 3 H) 1.29 (t, J=7.02 Hz, 3 H). 20 Example 280 N-[(3-chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 413 [M+H] IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.79 (s, 1 H) 7.69 (s, 1 H) 25 7.66 (s, 1 H) 7.41 (d, J=1.53 Hz, 1 H) 7.32 - 7.36 (m, 1 H) 7.24 - 7.28 (m, 1 H) 4.44 (s, 2 H) 4.02 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.31 (s, 3 H) 1.30 (t, 3 H). Example 281 2-Ethyl-6,7-dimethoxy-1-oxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline-4 30 carboxamide ESI-MS: m/z 409 [M+H]*; WO 2013/068489 PCT/EP2012/072175 170 H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.64 (s, 2 H) 7.61 (s, 1 H) 6.87 (s, 2 H) 4.47 (s, 2 H) 3.97 (q, J=7.12 Hz, 2 H) 3.87 (s, 3 H) 3.80 (s, 3 H) 2.33 2.36 (m, 6 H) 2.22 (s, 3 H) 1.25 (t, J=7.02 Hz, 3 H). 5 Example 282 N-[(2,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4 carboxamide ESI-MS: m/z 395 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.74 (s, 1 H) 7.69 (s, 1 H) 10 7.65 (s, 1 H) 7.21 (d, J=7.63 Hz, 1 H) 6.98 - 7.03 (m, 2 H) 4.43 (s, 2 H) 3.95 - 4.06 (m, 2 H) 3.88 (s, 3 H) 3.80 - 3.82 (m, 3 H) 2.31 (s, 3 H) 2.26 (s, 3 H) 1.29 (t, J=7.17 Hz, 3 H). Example 283 2-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl-phenyl]methyl]-1 15 oxo-isoquinoline-4-carboxamide ESI-MS: m/z 469 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.76 (s, 1 H) 7.72 (s, 1 H) 7.66 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.83 (s, 1 H) 6.75 (d, J=7.63 Hz, 1 H) 4.42 (s, 2 H) 3.97 - 4.07 (m, 4 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.50 (t, J=6.26 Hz, 2 H) 3.20 (s, 3 H) 20 2.29 (s, 3 H) 1.93 - 2.03 (m, 2 H) 1.29 (t, J=7.17 Hz, 3 H). Example 284 N-[[2-(2-Ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide 25 ESI-MS: m/z 469 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.76 (s, 1 H) 7.69 (s, 1 H) 7.66 (s, 1 H) 7.18 (d, J=7.63 Hz, 1 H) 6.86 (s, 1 H) 6.77 (d, J=7.63 Hz, 1 H) 4.43 (s, 2 H) 4.10 - 4.15 (m, 2 H) 4.02 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.74 (s, 2 H) 3.48 (q, J=7.02 Hz, 2 H) 2.29 (s, 3 H) 1.29 (t, J=7.02 Hz, 3 H) 1.05 (t, J=7.02 Hz, 3 H). 30 Example 285 WO 2013/068489 PCT/EP2012/072175 171 N-[[2-(Cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide ESI-MS: m/z 465 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.74 (d, J=4.58 Hz, 2 H) 7.66 5 (s, 1 H) 7.15 (d, J=7.63 Hz, 1 H) 6.81 (s, 1 H) 6.73 (d, J=7.63 Hz, 1 H) 4.82 - 4.90 (m, 1 H) 4.38 (s, 2 H) 4.01 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.82 1.97 (m, 2 H) 1.64 - 1.81 (m, 4 H) 1.50 - 1.64 (m, 2 H) 1.29 (t, J=7.17 Hz, 3 H). Example 286 10 2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 473 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.70 (s, 1 H) 7.64 (d, J=3.36 Hz, 2 H) 7.35 - 7.42 (m, 3 H) 7.11 (t, J=7.32 Hz, 1 H) 6.95 - 7.05 (m, 3 H) 6.73 (s, 1 H) 15 4.45 (s, 2 H) 3.97 (q, J=7.12 Hz, 2 H) 3.87 (s, 3 H) 3.80 (s, 3 H) 2.26 (s, 3 H) 1.27 (t, J=7.02 Hz, 3 H). Example 287 2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxy-1-methyl-ethoxy)-4-methyl 20 phenyl]methyl]-1-oxo-isoquinoline-4-carboxamide ESI-MS: m/z 469 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.75 (s, 1 H) 7.70 (s, 1 H) 7.66 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.88 (s, 1 H) 6.75 (d, J=7.32 Hz, 1 H) 4.57 - 4.67 (m, 1 H) 4.33 - 4.49 (m, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.42 - 3.55 25 (m, 2 H) 3.23 (s, 3 H) 2.29 (s, 3 H) 1.22 - 1.34 (m, 6 H). Example 288 2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2-trifluoroethoxy)phenyl]methyl]-1 oxo-isoquinoline-4-carboxamide 30 ESI-MS: m/z 479 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.78 (s, 1 H) 7.73 (s, 1 H) 7.66 (s, 1 H) 7.23 (d, J=7.63 Hz, 1 H) 6.96 (s, 1 H) 6.88 (d, J=7.32 Hz, 1 H) 4.75 (q, J=8.65 WO 2013/068489 PCT/EP2012/072175 172 Hz, 2 H) 4.44 (s, 2 H) 4.02 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.83 (s, 3 H) 2.31 (s, 3 H) 1.29 (t, J=7.17 Hz, 3 H). Example 289 5 N-[[2-(Cyclohexyloxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 479 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.76 (d, J=6.10 Hz, 2 H) 7.66 (s, 1 H) 7.16 (d, J=7.93 Hz, 1 H) 6.84 (s, 1 H) 6.73 (d, J=7.63 Hz, 1 H) 4.37 - 4.46 (m, 3 10 H) 4.01 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.25 - 2.31 (m, 3 H) 1.83 - 1.93 (m, J=7.93, 3.97 Hz, 2 H) 1.64 - 1.76 (m, 2 H) 1.44 - 1.58 (m, 3 H) 1.32 - 1.45 (m, 2 H) 1.29 (t, J=7.17 Hz, 4 H). Example 290 15 N-[[2-(Cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7-dimethoxy-1 oxo-isoquinoline-4-carboxamide ESI-MS: m/z 451 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.79 (s, 1 H) 7.73 (s, 1 H) 7.66 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.81 (s, 1 H) 6.75 (d, J=7.02 Hz, 1 H) 4.44 (s, 2 H) 20 4.02 (q, J=7.02 Hz, 2 H) 3.85 - 3.90 (m, 5 H) 3.82 (s, 3 H) 2.28 (s, 3 H) 1.19 - 1.35 (m, 4 H) 0.51 - 0.61 (m, 2 H) 0.31 - 0.37 (m, 2 H). Example 291 2-Ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy-1-oxo 25 isoquinoline-4-carboxamide ESI-MS: m/z 481 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.77 (s, 1 H) 7.74 (s, 1 H) 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.82 (s, 1 H) 6.74 (d, J=7.63 Hz, 1 H) 4.41 (s, 2 H) 3.92 - 4.09 (m, 4 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 2.29 (s, 3 H) 1.66 - 1.76 (m, 2 H) 1.36 30 1.49 (m, 2 H) 1.15 - 1.34 (m, 7 H) 0.81 (t, 3 H). Example 292 WO 2013/068489 PCT/EP2012/072175 173 2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3 ylmethoxy)phenyl]methyl] -1 -oxo-isoquinoline-4-carboxamide ESI-MS: m/z 481 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 27 'C) 6 ppm 7.77 (s, 1 H) 7.73 (s, 1 H) 5 7.66 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.85 (s, 1 H) 6.76 (d, J=7.93 Hz, 1 H) 4.42 (s, 2 H) 3.96 - 4.08 (m, 3 H) 3.89 - 3.95 (m, 1 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.76 - 3.80 (m, 2 H) 3.62 - 3.69 (m, 1 H) 3.55 - 3.62 (m, J=8.54, 5.49 Hz, 1 H) 2.62 - 2.75 (m, 1 H) 2.29 (s, 3 H) 1.98 - 2.10 (m, 1 H) 1.66 - 1.76 (m, 1 H) 1.29 (t, J=7.17 Hz, 3 H). 10 Example 293 2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl-phenyl]methyl]-1 oxo-isoquinoline-4-carboxamide 2-Ethyl-6,7-dimethoxy- 1 -oxo-1,2-dihydroisoquinoline-4-carboxylic acid (22 mg, 0.08 mmol) dissolved in N,N-dimethylacetamide (1.0 mL) was added to a 4mL vial 15 charged with a stir bar followed by a solution of HATU (36 mg, 0.09 mmol) dissolved in N,N-dimethylacetamide (1.0 mL). This was placed to shake for one hour at room temperature. Then a solution of (2-(2-methoxyethoxy)-4-methylphenyl)methanamine (19.5 mg, 0.1 mmol) dissolved in N,N-dimethylacetamide (0.4 mL) was added followed by triethylamine neat (33gL, 0.24 mmol) and the mixture was stirred and heated at 65 0 C 20 overnight. The reaction was controlled by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 MeOH:DMSO. Purification by reverse phase HPLC gave 16.5 mg of the title compound (46%). ESI-MS: m/z 455 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.77 (s, 1 H) 7.70 (s, 1 H) 7.66 25 (s, 1 H) 7.18 (d, J=7.63 Hz, 1 H) 6.85 (s, 1 H) 6.77 (d, J=7.63 Hz, 1 H) 4.39 - 4.45 (m, 2 H) 4.11 - 4.17 (m, 2 H) 4.02 (q, J=7.12 Hz, 2 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.67 - 3.71 (m, 2 H) 3.27 (s, 3 H) 2.29 (s, 3 H) 1.29 (t, J=7.02 Hz, 3 H). The compounds of the following examples 294 to 323 were prepared in analogy 30 to the processes described in the examples above. Example 294 WO 2013/068489 PCT/EP2012/072175 174 2-Ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 453 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.78 (s, 1 H) 7.74 (s, 1 H) 5 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.81 (s, 1 H) 6.75 (d, J=7.63 Hz, 1 H) 4.42 - 4.46 (m, 2 H) 4.01 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 3.78 (d, J=6.41 Hz, 2 H) 2.29 (s, 3 H) 2.00 - 2.12 (m, 1 H) 1.29 (t, J=7.02 Hz, 3 H) 1.00 (d, J=6.71 Hz, 6 H). Example 295 10 2-Ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 477 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.77 (s, 1 H) 7.71 (s, 1 H) 7.65 (s, 2 H) 7.19 (d, J=7.63 Hz, 1 H) 7.01 (s, 1 H) 6.80 (d, J=7.63 Hz, 1 H) 6.60 (d, J=3.05 15 Hz, 1 H) 6.42 - 6.51 (m, 1 H) 5.11 (s, 2 H) 4.35 - 4.43 (m, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 2.31 (s, 3 H) 1.29 (t, J=7.02 Hz, 3 H). Example 296 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)- 1 -oxo- 1,2 20 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 467 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.78 (s, 1 H) 7.74 (s, 1 H) 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.82 (s, 1 H) 6.74 (d, J=7.63 Hz, 1 H) 4.40 - 4.44 (m, 2 H) 3.96 - 4.06 (m, 4 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.68 - 1.77 (m, 2 H) 1.36 25 - 1.46 (m, 2 H) 1.26 - 1.34 (m, 5 H) 0.83 (t, J=7.17 Hz, 3 H). Example 297 N-(2-Ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide 30 ESI-MS: m/z 425 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.77 (s, 1 H) 7.72 (s, 1 H) 7.66 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.82 (s, 1 H) 6.75 (d, J=7.32 Hz, 1 H) 4.39 - 4.45 (m, 2 WO 2013/068489 PCT/EP2012/072175 175 H) 3.98 - 4.10 (m, 4 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.35 (t, J=6.87 Hz, 3 H) 1.29 (t, J=7.17 Hz, 3 H). Example 298 5 N-(2-sec-Butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 453 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.76 (s, 1 H) 7.74 (s, 1 H) 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.83 (s, 1 H) 6.73 (d, J=7.63 Hz, 1 H) 4.38 - 4.47 (m, 3 10 H) 4.01 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.56 - 1.76 (m, 2 H) 1.29 (t, J=7.17 Hz, 3 H) 1.25 (d, J=6.10 Hz, 3 H) 0.93 (t, J=7.32 Hz, 3 H). Example 299 2-Ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 15 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 467 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.78 (s, 1 H) 7.74 (s, 1 H) 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.84 (s, 1 H) 6.75 (d, J=7.63 Hz, 1 H) 4.38 - 4.44 (m, 2 H) 4.01 (q, J=6.82 Hz, 4 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.75 - 1.86 (m, 1 H) 20 1.64 (q, J=6.41 Hz, 2 H) 1.29 (t, J=7.17 Hz, 3 H) 0.90 (d, J=6.71 Hz, 6 H). Example 300 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide 25 ESI-MS: m/z 439 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.77 (s, 1 H) 7.73 (s, 1 H) 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.82 (s, 1 H) 6.75 (d, J=7.63 Hz, 1 H) 4.43 (s, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.96 (t, J=6.26 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.69 - 1.84 (m, 2 H) 1.29 (t, J=7.02 Hz, 3 H) 1.00 (t, J=7.32 Hz, 3 H). 30 Example 301 WO 2013/068489 PCT/EP2012/072175 176 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 427 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.80 (s, 1 H) 7.73 (s, 1 H) 7.66 5 (s, 1 H) 7.23 (d, J=7.63 Hz, 1 H) 7.13 (s, 1 H) 7.00 (d, J=7.93 Hz, 1 H) 4.45 (s, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.49 (s, 3 H) 2.31 (s, 3 H) 1.30 (t, J=7.02 Hz, 3 H). Example 302 10 2-Ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 439 [M+H]* IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.76 (s, 1 H) 7.73 (s, 1 H) 7.66 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.84 (s, 1 H) 6.73 (d, J=7.93 Hz, 1 H) 4.56 - 4.68 (m, 1 15 H) 4.40 (s, 2 H) 4.02 (q, J=7.02 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.24 1.34 (m, 9 H). Example 303 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3-yloxy)benzyl)-1-oxo 20 1,2-dihydroisoquinoline-4-carboxamide ESI-MS: m/z 467 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.75 (s, 1 H) 7.73 (s, 1 H) 7.65 (s, 1 H) 7.19 (d, J=7.63 Hz, 1 H) 6.82 (s, 1 H) 6.77 (d, J=7.63 Hz, 1 H) 5.07 (dd, J=5.80, 4.58 Hz, 1 H) 4.39 (s, 2 H) 4.01 (q, J=7.02 Hz, 2 H) 3.73 - 3.95 (m, 10 H) 2.30 25 (s, 3 H) 2.16 - 2.27 (m, 1 H) 2.03 (dd, J=12.51, 6.10 Hz, 1 H) 1.29 (t, J=7.17 Hz, 3 H). Example 304 2-Ethyl-6,7-dimethoxy-1-oxo-N-(2,4,5-trimethylbenzyl)-1,2 dihydroisoquinoline-4-carboxamide 30 ESI-MS: m/z 409 [M+H]*; WO 2013/068489 PCT/EP2012/072175 177 H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.73 (s, 1 H) 7.69 (s, 1 H) 7.65 (s, 1 H) 7.07 (s, 1 H) 6.96 (s, 1 H) 4.40 (s, 2 H) 4.01 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.80 (s, 3 H) 2.27 (s, 3 H) 2.17 (s, 6 H) 1.28 (t, J=7.17 Hz, 3 H). 5 Example 305 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2-yl)methoxy)benzyl) 1-oxo-1,2-dihydroisoquinoline-4-carboxamide ESI-MS: m/z 481 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.77 (s, 1 H) 7.70 (s, 1 H) 10 7.65 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.85 (s, 1 H) 6.77 (d, J=7.32 Hz, 1 H) 4.42 (s, 2 H) 4.16 - 4.24 (m, 1 H) 3.98 - 4.06 (m, 3 H) 3.92 - 3.97 (m, 1 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 3.67 - 3.71 (m, 1 H) 3.59 - 3.67 (m, 1 H) 2.29 (s, 3 H) 1.95 - 2.05 (m, 1 H) 1.68 1.93 (m, 3 H) 1.29 (t, J=7.17 Hz, 3 H). 15 Example 306 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2-yloxy)benzyl)- 1 -oxo 1,2-dihydroisoquinoline-4-carboxamide ESI-MS: m/z 481 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.76 (s, 1 H) 7.75 (s, 1 H) 7.66 20 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.84 (s, 1 H) 6.72 (d, J=7.32 Hz, 1 H) 4.50 - 4.58 (m, 1 H) 4.39 (s, 2 H) 3.96 - 4.06 (m, 2 H) 3.88 (s, 3 H) 3.82 (s, 3 H) 2.29 (s, 3 H) 1.70 - 1.82 (m, 1 H) 1.61 - 1.70 (m, 1 H) 1.34 - 1.44 (m, 1 H) 1.29 (t, J=7.02 Hz, 3 H) 1.24 (d, J=5.80 Hz, 3 H) 0.87 (dd, J=8.54, 6.71 Hz, 6 H). 25 Example 307 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide ESI-MS: m/z 481 [M+H]*; IH NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.78 (s, 1 H) 7.75 (s, 1 H) 7.65 30 (s, 1 H) 7.16 (d, J=7.63 Hz, 1 H) 6.82 (s, 1 H) 6.74 (d, J=7.32 Hz, 1 H) 4.41 (s, 2 H) 3.94 - 4.06 (m, 4 H) 3.88 (s, 3 H) 3.81 (s, 3 H) 2.25 - 2.31 (m, 3 H) 1.66 - 1.80 (m, 2 H) 1.47 - 1.60 (m, 1 H) 1.26 - 1.34 (m, 5 H) 0.83 (d, J=6.71 Hz, 6 H).
WO 2013/068489 PCT/EP2012/072175 178 Example 308 2-Ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide 5 ESI-MS: m/z 411 [M+H]*; H NMR (500 MHz, DMSO-D 2 0, T: 25 'C) 6 ppm 7.77 (s, 1 H) 7.71 (s, 1 H) 7.66 (s, 1 H) 7.17 (d, J=7.63 Hz, 1 H) 6.84 (s, 1 H) 6.76 (d, J=7.32 Hz, 1 H) 4.40 (s, 2 H) 4.02 (q, J=7.22 Hz, 2 H) 3.88 (s, 3 H) 3.82 (s, 6 H) 2.30 (s, 3 H) 1.29 (t, J=7.17 Hz, 3 H). 10 Example 309 2-Ethyl-6,7-dimethoxy-1-oxo-N-(thiazol-4-ylmethyl)isoquinoline-4-carboxamide ESI-MS: m/z 374.1 [M+H]* 15 Example 310 2-Ethyl-6,7-dimethoxy-1-oxo-N-[[4-(trifluoromethyl)phenyl] methyl]isoquinoline-4-carboxamide IH NMR (DMSO-d 6 ,600MHz): 6= 8.99 (br. s., 1 H), 7.89 (s, 1 H), 7.78 (s, 1 H), 7.73 (m, 2 H), 7.63 (m, 3 H), 4.57 (br. S., 2 H), 4.03 (m, 2 H), 3.87 (s, 3 H), 3.81 (s, 3 20 H), 1.27 - 1.32 (m, 3 H). Example 311 2-Ethyl-6,7-dimethoxy-1-oxo-N-[(lS)-1-(p-tolyl)ethyl]isoquinoline-4 carboxamide 25 ESI-MS: m/z 395.2 [M+H]* Example 312 2-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy-1-oxo-isoquinoline-4 carboxamide 30 ESI-MS: m/z 409.2 [M+H]* Example 313 WO 2013/068489 PCT/EP2012/072175 179 2-Ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy- 1 -oxo-isoquinoline-4 carboxamide ESI-MS: m/z 395.2 [M+H]* 5 Example 314 2-Ethyl-6,7-dimethoxy-1-oxo-N-[(1R)-1-(p-tolyl)ethyl]isoquinoline-4 carboxamide ESI-MS: m/z 395.2 [M+H]* 10 Example 315 N-[[4-(Difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy-1-oxo isoquinoline-4-carboxamide ESI-MS: m/z 417.1 [M+H]* 15 Example 316 2-Ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl]-1-oxo-isoquinoline-4 carboxamide ESI-MS: m/z 388.1 [M+H]* 20 Example 317 2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl]-1-oxo-isoquinoline-4 carboxamide ESI-MS: m/z 387.1 [M+H]* 25 Example 318 N-[(4-Cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy-1-oxo-isoquinoline-4 carboxamide ESI-MS: m/z 407.2 [M+H]* 30 Example 319 N-Indan- 1 -yl-6,7-dimethoxy-2- [2-(5 -methyl-2-pyridyl)ethyl] -1 -oxo-isoquino line 4-carboxamide WO 2013/068489 PCT/EP2012/072175 180 ESI-MS: m/z 484.20 [M+H]* Example 320 N-Butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4 5 carboxamide ESI-MS: m/z 424.20 [M+H]* Example 321 2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl]-1-oxo-isoquinoline-4 10 carboxamide; 2,2,2-trifluoroacetic acid ESI-MS: m/z 412.10 [M+H]* Example 322 N-Butyl-6,7-dimethoxy- 1 -oxo-2-[2-(2-quino lyl)ethyl]isoquinoline-4 15 carboxamide; 2,2,2-trifluoroacetic acid ESI-MS: m/z 460.20 [M+H]* Example 323 N-Indan-1-yl-6,7-dimethoxy-1-oxo-2-[2-(2-quinolyl)ethyl]isoquinoline-4 20 carboxamide; 2,2,2-trifluoroacetic acid ESI-MS: m/z 520.20 [M+H]* Biological Tests 25 a) Measurement of PDE activity The recombinant PDE proteins are used in in vitro enzymatic reaction for measurement of PDE activity. These recombinant proteins, including PDE1OA (human, rat and mouse PDE 10) and isoforms of PDEs 1, 3, 4, and 5, were purchased from commercial vendor BPS Bioscience. The enzymatic activity of PDEs was determined 30 by cAMP measurement kit from CisBio (IBA) using HTRF technology. The PDE enzymatic reaction was carried out in assay buffer (20mM Tris-HCl pH7.5, 10mM MgCl 2 , 0.l1% bovine serum albumin) containing enzyme and substrate.
WO 2013/068489 PCT/EP2012/072175 181 The PDE enzymes concentration ranged from 10pM - 250pM, depending on each enzyme's specific activity. The substrate cyclic nucleotide (cAMP or cGMP) concentration used in the assay was 20nM for PDE 10, and 1OOnM for other PDEs. The inhibitory effect of compound was determined by incubating various concentration of 5 inhibitor in the enzymatic assay. Typically, compound was serial diluted in DMSO then further diluted in assay buffer. Next, the compound at varying concentration was mixed with PDE enzyme. The reaction was initiated by addition of cyclic nucleotide substrate, and incubated for 60 minutes at 29C. The reaction was stopped by addition of lysis buffer from assay kit. The cAMP-d2 and anti-cAMP cryptate in the lysis buffer detected 10 the level of cAMP left from the PDE hydrolysis reaction. The PDE activity is reversely correlated with the amount of cAMP left in the reaction and can be converted to the percent activity of an uninhibited control (100%). Thus, IC 50 value of inhibitor can be obtained by plotting inhibitor concentration against PDE activity at that concentration. The results are shown in Table 1. 15 Table 1 Example IC 50 Example IC 5 0 Example IC 50 36 ++ 149 + 1 ++ 37 ++ 151 + 15 + 39 ++ 152 + 20 + 40 ++ 153 ++ 21 + 51 + 154 ++ 23 + 129 +++ 156 + 24 + 135 +++ 158 ++ 26 ++ 136 +++ 161 +++ 28 + 139 + 162 + 29 + 140 + 164 + 30 + 141 ++ 165 ++ 31 + 142 ++ 167 + 32 + 145 + 168 + 33 + 146 + 169 + 34 + 147 ++ 171 + 35 + 148 + 172 ++ WO 2013/068489 PCT/EP2012/072175 182 Example IC 5 0 Example IC 50 Example IC 50 173 + 233 ++ 266 + 174 + 236 ++ 267 ++ 175 + 237 ++ 268 + 176 + 238 ++ 269 + 177 + 239 ++ 273 + 182 ++ 241 ++ 276 + 186 ++ 242 + 277 + 187 + 244 + 278 + 188 ++ 246 ++ 288 + 189 ++ 247 ++ 290 + 190 ++ 248 ++ 293 + 191 + 249 + 298 + 192 +++ 251 ++ 302 + 193 +++ 252 ++ 303 + 194 +++ 253 +++ 305 + 195 ++ 254 +++ 308 + 197 ++ 255 + 309 + 198 + 256 +++ 311 + 199 + 257 ++ 313 + 200 + 258 ++ 316 + 201 + 259 + 317 ++ 202 +++ 260 ++ 318 + 205 + 261 + 322 +++ 216 +++ 262 ++ 323 + 219 +++ 263 ++ 228 ++ 264 + 230 ++ 265 + 1) +++:IC 5 < 100 nM ++: 100 nM < IC 5 0 < 200 nM 5 +: 200 nM < IC 5 0 < 500 nM WO 2013/068489 PCT/EP2012/072175 183 b) Determination of the microsomal half-life: The metabolic stability of the compounds of the invention was determined in the following assay. 5 The test substances were incubated in a concentration of 0.5 gM as follows: 0.5 gM test substance are preincubated together with liver microsomes from different species (from rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 in microtiter plates at 37 0 C for 5 min. The reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 10 50 gl aliquots are removed, and the reaction is immediately stopped and cooled with the same volume of acetonitrile. The samples are frozen until analyzed. The remaining concentration of undegraded test substance is determined by MSMS. The half-life (T1/2) is determined from the gradient of the signal of test substance/unit time plot, it being possible to calculate the half-life of the test substance, assuming first order 15 kinetics, from the decrease in the concentration of the compound with time. The microsomal clearance (mCl) is calculated from mCl = ln2/T1/2 / (content of microsomal protein in mg/ml) x 1000 [ml/min/mg] (modified from references: Di, The Society for Biomoleculur Screening, 2003, 453-462; Obach, DMD, 1999 vol 27. N 11, 1350-1359). The results are shown in Table 2. 20 Table 2 Ex. Rat mCl1 2 Human mCle Ex. Rat mCl1 2 Human mCle [l min-' mg-1] [gl min-' mg-1] [gl min-' mg-1] [gl min-' mg-1] 40 ++ ++ 186 ++ ++ 136 o + 190 + o 141 ++ ++ 192 + o 147 ++ ++ 195 + + 158 ++ ++ 196 ++ ++ 161 ++ ++ 197 + o 165 ++ ++ 198 ++ + 171 ++ ++ 199 ++ ++ 172 ++ ++ 200 ++ ++ WO 2013/068489 PCT/EP2012/072175 184 Ex. Rat mCl1 2 Human mCl Ex. Rat mCl1 2 Human mCl [gl min-i mg-1] [gl min-l' mg-] [gl min-l' mg-1] [gl min-l' mg-1] 201 ++ ++ 251 o + 202 + o 256 + o 203 ++ ++ 263 ++ ++ 204 ++ + 267 o + 205 ++ ++ 309 nd ++ 219 + + 310 ++ ++ 228 ++ ++ 311 nd ++ 236 ++ + 312 ++ + 238 + ++ 313 ++ ++ 239 + + 314 ++ ++ 241 + ++ 315 ++ ++ 244 ++ ++ 316 ++ ++ 246 + o 317 + ++ 247 ++ + 318 ++ ++ 248 ++ + Ex. Example mCl mikrosomal clearance 2) ++: < 100 gl min-' mg-1 5 +: 100 - 220 gl min-' mg o: > 220 gl min-l' mg-1 nd: not determined

权利要求:
Claims (41)
[1] 1. Compound of formula I Y R4 1 I R-O R 2 11(I) X / 22 O N'R 1 3 5 R where in formula I XI is CH or N, 10 X2 is C-R5 or N, Y is O or S, 15 RI is selected from the group consisting of C
[2] 2 -Cs-alkyl, C 2 -Cs-alkenyl, C 1 -C 4 fluoroalkyl, C 3 -Cs-cycloalkyl, Cs-Cs-cycloalkyl carrying a fused benzene ring, fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-CI-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-CI-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl, CI-C 4 -alkyl-N(Rb)(Rc) and a moiety Z-Arl; 20 R2 is a radical of the formula CR2 R R23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra, where 25 R2 is selected from the group consisting of hydrogen, C1-Cs-alkyl, trimethylsilyl, C 2 -Cs-alkenyl, C1-C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, WO 2013/068489 PCT/EP2012/072175 186 fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl, C 1 -C 4 -alkyl-N(Rb)(Rc), (CH 2 )mC(O)O-Rd (CH 2 )mC(O)N(Re)(R) and Z 2 -Ar 2 , 5 R is selected from the group consisting of hydrogen, fluorine, C 1 -C 8 alkyl, C 2 -Cs-alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -C 8 cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-Ci-C 4 10 alkyl and CI-C 4 -alkyl-N(Rb)(Rc), or R 2 1 and R 22 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a saturated 5- to 7 membered heterocyclic ring which has 1, 2 or 3 heteroatoms or 15 heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R9, and where the carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a 20 fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, R is selected from the group consisting of hydrogen, fluorine, C 1 -C 8 alkyl and C1-C 4 -fluoroalkyl; 25 R3 is selected from the group consisting of hydrogen, CI-Cs-alkyl, C 2 -C 8 alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-CI-C 4 -alkyl, hydroxy-C1-C 4 -alkyl, CI-C 4 -alkyl-N(Rb)(Rc), and trimethylsilyl, or 30 R2 and R3 together with the nitrogen atom, to which they are bound form a saturated 5- to 7-membered heterocyclic ring which, in addition to the WO 2013/068489 PCT/EP2012/072175 187 nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R 31 , and where the 5 heterocyclic ring may carry a fused benzene ring or a fused 5- or 6 membered heteroaromatic ring, where the fused rings themselves are 32 unsubstituted or carry 1, 2 or 3 substituents R , where R3 is selected from the group consisting of halogen, CN, OH, C 1 -C 4 10 alkyl, fluorinated CI-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1 -C 4 alkoxy, N(R)(RC), C(O)O-Rd, C(O)N(Re)(Rf), where one radical R 31 may also be a moiety Z 3 -Ar 3 , R is selected from the group consisting of halogen, CN, OH, C 1 -C 4 15 alkyl, fluorinated CI-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1 -C 4 alkoxy, N(R)(RC), C(O)O-Rd and C(O)N(Re)(R); R4 is selected from the group consisting of CI-C 4 -alkyl, C1-C 4 -fluoroalkyl, C 3 C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C1-C 4 -alkyl and Z 4 -Ar 4 ; 20 R 5 is selected from the group consisting of hydrogen, halogen, CI-C 4 -alkyl, CI C 4 -fluoroalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -fluoroalkoxy, -Z 5 -Ar 5 , -O-Z 5 -Ar 5 , C 3 C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C1-C 4 -alkyl, C 3 -C 6 -cycloalkoxy and C 3 -C 6 cycloalkyl-C1-C 4 -alkoxy, where the cyclic radical in the last four mentioned 25 groups may be unsubstituted, partially or completely fluorinated or carries 1, 2, 3 or 4 methyl groups; Ar is selected from the group consisting of phenyl, monocyclic 5- or 6 membered hetaryl or bicyclic 9- or 10-membered hetaryl, where 30 hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; WO 2013/068489 PCT/EP2012/072175 188 Ar2 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 5 1, 2 or 3 identical or different substituents Rh; Ar 3 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 10 1, 2 or 3 identical or different substituents Rh; Ar 4 and Ar 5 are independently of each other selected from the group consisting of phenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from 0, S 15 and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R Z 1 , Z 4 , Z 5 are independently of each other CI-C 4 -alkylene; 20 z 2 is a single bond or CI-C 4 -alkylene; Z 3 is a single bond, CI-C 4 -alkylene, 0, N, S, SO or SO 2 ; Ra is selected from the group consisting of halogen, CN, OH, NO 2 , C1 25 C 4 -alkyl, fluorinated C1-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1 -C 4 alkoxy, (CH 2 )mN(R)(RC), C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (Rff) and S(O) 2 N(Re)(R); R , Rc, independently of each other are selected from the group consisting of 30 hydrogen, CI-C 4 -alkyl, C1-C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 cycloalkylmethyl and benzyl or Rb and R' form together with the N atom to which they are attached a 3- to 7-membered, nitrogen WO 2013/068489 PCT/EP2012/072175 189 heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C 4 -alkyl; 5 Rd is selected from the group consisting of CI-C 4 -alkyl, CI-C 4 fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and benzyl; Re, Rf, independently of each other are selected from the group consisting of 10 hydrogen, CI-C 4 -alkyl, CI-C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 cycloalkylmethyl and benzyl or Re and Rf form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group 15 of 0, N, S, SO and S02 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C 4 -alkyl; R9 is selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkyl, C 2 -C 6 -alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -C 6 -cycloalkyl, fluorinated 20 C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -C 6 cycloalkyl-C1-C 4 -alkyl, CI-C 4 -alkoxy-C1-C 4 -alkyl, hydroxy-Ci-C 4 alkyl, CI-C 4 -alkyl-N(Rb)(Rc), CI-C 4 -alkoxy, fluorinated C1-C 4 -alkoxy, one R9 together with a carbon atom to which R9 is attached may also form a carbonyl group, one R9 may also be phenyl or benzyl, where 25 the phenyl ring in the last 2 mentioned radicals is unsubstituted or carries 1, 2 or 3 radicals Rh; Rh is selected from the group consisting of halogen, CN, OH, C 1 -C 4 alkyl, fluorinated C1-C 4 -alkyl, CI-C 6 -alkoxy, fluorinated C 1 -C 4 30 alkoxy, CI-C 4 -alkylsulfanyl, Ci-C 4 -alkoxy-C1-C 4 -alkoxy, C 3 -C 6 cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkoxy, C 3 -C 6 cycloalkyl-C1-C 4 -alkoxy, phenoxy, N(R)(Rc), CI-C 4 -alkyl-N(Rb)(Rc), WO 2013/068489 PCT/EP2012/072175 190 C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (R), S(O) 2 N(Re)(R), 3- to 7 membered heterocyclyloxy, 3- to 7-membered heterocyclyl-CI-C 4 alkoxy, where heterocyclyl in the two last mentioned radicals has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and 5 N, and 5- to 6-membered hetaryl-C1-C 4 -alkoxy, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from 0, S and N; R is selected from the group consisting of halogen, CN, OH, C 1 -C 4 10 alkyl, fluorinated CI-C 4 -alkyl, CI-C 4 -alkoxy, fluorinated C 1 -C 4 alkoxy, N(R)(R*), C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (Rff) and S(O) 2 N(Re)(Rf) or two radicals Rk that are bound to adjacent carbon atoms together with said carbon atoms may form fused benzene ring or a fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring 15 members selected from 0, N and S, where the fused benzene ring and the fused heteroaromatic ring are unsubstituted or may carry 1, 2 or 3 radicals Rh; Ree is selected from the group consisting of hydrogen, CI-C 4 -alkyl, CI-C 4 20 fluoroalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and benzyl; Rf is selected from the group consisting of CI-C 4 -alkyl, C1-C 4 -fluoroalkyl and phenyl, which is unsubstituted or carries 1, 2 or 3 radicals Rh. 25 m is 0, 1, 2, 3 or 4, the N-oxides, hydrates, tautomers, the prodrugs thereof and the pharmaceutically acceptable salts thereof. 30 2. The compound as claimed in claim 1, where Rh is selected from the group consisting of halogen, CN, OH, CI-C 4 -alkyl, fluorinated CI-C 4 -alkyl, CI-C 4 alkoxy, fluorinated CI-C 4 -alkoxy, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, WO 2013/068489 PCT/EP2012/072175 191 N(R)(R), C 1 -C 4 -alkyl-N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(R), N(Ree)S(O) 2 (R) and S(O) 2 N(Re)(R).
[3] 3. The compound as claimed in any of claims 1 or 2, where X 1 is C-H. 5
[4] 4. The compound as claimed in any of claims 1 or 2, where X 1 is N.
[5] 5. The compound as claimed in any of claims 1 to 4, where X2 is C-R5. 10
[6] 6. The compound as claimed in any of claims I to 4, where X2 is N.
[7] 7. The compound as claimed in any of the preceding claims, where Y is 0.
[8] 8. The compound as claimed in any of the preceding claims, where R 1 is C 2 -C 8 15 alkyl, C 3 -Cs-cycloalkyl or C 3 -Cs-cycloalkylmethyl.
[9] 9. The compound as claimed in claim 8, where R 1 is a radical of the formula CHRia R , where Ria is selected from the group consisting of hydrogen and C 1 C 3 -alkyl and where Rib is selected from the group consisting of CI-C 4 -alkyl. 20
[10] 10. The compound as claimed in any of claims I to 7, where R 1 is a moiety Z-Arl.
[11] 11. The compound as claimed in any of the preceding claims, where R2 is a radical of the formula CR2 R R2. 25
[12] 12. The compound as claimed in claim 11, where R2 and R 22 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a saturated 5- to 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups 30 selected from the group of 0, N, S, SO and SO 2 as ring members, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R9, and where the WO 2013/068489 PCT/EP2012/072175 192 carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, where Rh and R9 are as defined in claim 1, and where 5 R is hydrogen.
[13] 13. The compound as claimed in claim 11, where R2 and R 2 2 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a 3-tetrahydrofuryl or 3 10 tetrahydrothienyl, where the 5- to 7-membered carbocyclic ring and the 3 tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fused benzene ring or a fused 5 or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, where Rh are as defined in claim 1, and where 15 R 23 is hydrogen.
[14] 14. The compound as claimed in claim 11, where R2 is selected from the group consisting of CI-Cs-alkyl, trimethylsilyl, C 2 -C 8 20 alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl and Z -Ar 2, where Z2 and Ar2 are as defined in claim 1; R is selected from the group consisting of hydrogen, fluorine, CI-Cs-alkyl; and 25 R23 is hydrogen.
[15] 15. The compound as claimed in claim 14, where R2 is a moiety Z 2 -Ar 2 , where Z2 and Ar2 are as defined in claim 1. 30
[16] 16. The compound as claimed in any of the preceding claims, where R 3 is hydrogen or CI-C 4 -alkyl. WO 2013/068489 PCT/EP2012/072175 193
[17] 17. The compound as claimed in any of claims I to 10, where R 2 and R3 together with the nitrogen atom, to which they are bound form a saturated 5- to 7-membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further 5 heteroatoms or heteroatom containing groups selected from the group of 0, N, S, SO and SO 2 as ring members, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R 31 , and where the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 10 1, 2 or 3 substituents R , where R 31 and R are as defined in claim 1.
[18] 18. The compound as claimed in any of the preceding claims, where R4 is C 1 -C 4 alkyl. 15
[19] 19. The compound as claimed in any of the preceding claims, where X2 is C-R 5 and R 5 is hydrogen, fluorine, CI-C 4 -alkoxy or a radical O-Z 5 -Ar5.
[20] 20. The compound as claimed in claim 19, where R4 is methyl and R5 is hydrogen, fluorine or methoxy. 20
[21] 21. The compound as claimed in claim 19, where R4 is methyl and R5 is O-Z 5 -Ar5.
[22] 22. The compound as claimed in any of the preceding claims which is a compound of the formula Ta 0 R-O RN N 5 (la) RR 0 N 1 3 25 R where R1, R2, R3, R and R5 are as defined in any of the preceding claims. WO 2013/068489 PCT/EP2012/072175 194
[23] 23. The compound as claimed in any of claims 1 to 21 which is a compound of the formula Ib 0 R-O RN 5 ~ - .~-N(1b) 0 N 1 3 R 5 where R1, R2, R3, R4 and R5 are as defined in any of claims I to 23.
[24] 24. The compound as claimed in claim 22 or 23, where R is a radical of the formula CHRia Rl, where Ria is selected from the group consisting of hydrogen and CI-C 3 -alkyl and where Rlb is selected from the 10 group consisting of CI-C 4 -alkyl; R2 is a radical of the formula CR2 R R2; R3 is hydrogen or CI-C 4 -alkyl; R4 is CI-C 4 -alkyl, and R5 is hydrogen, fluorine, CI-C 4 -alkoxy or a radical O-Z 5 -Ar 5 . 15
[25] 25. The compound as claimed in claim 22 or 23, where RI is a moiety Z-Arl; R2 is a radical of the formula CR2 R R2; R 3 is hydrogen or CI-C 4 -alkyl; 20 R 4 is CI-C 4 -alkyl, and R 5 is hydrogen, fluorine or CI-C 4 -alkoxy.
[26] 26. The compound as claimed in claim 24 or 25, where R2 and R 22 together with the carbon atom, to which they are bound form a 25 saturated 5- to 7-membered carbocyclic ring, which carries a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, where Rh are as WO 2013/068489 PCT/EP2012/072175 195 defined in claim 1, and where R is hydrogen.
[27] 27. The compound as claimed in claim 24 or 25, where 5 R2 is selected from the group consisting of CI-Cs-alkyl, trimethylsilyl, C 2 -C 8 alkenyl, C 1 -C 4 -fluoroalkyl, C 3 -Cs-cycloalkyl, fluorinated C 3 -Cs-cycloalkyl, C 3 -Cs-cycloalkyl-C1-C 4 -alkyl, fluorinated C 3 -Cs-cycloalkyl-C1-C 4 -alkyl and Z 2-Ar 2, where Z2 and Ar2 are as defined in claim 1; 10 R is selected from the group consisting of hydrogen, fluorine, CI-Cs-alkyl; and R is hydrogen. 15
[28] 28. The compound as claimed in any of claims 22 to 27, where R4 is methyl and R 5 is hydrogen, fluorine or methoxy.
[29] 29. The compound as claimed in any of claims 22 to 27, where R4 is methyl and R 5 is O-Z 5 -Ar 5 . 20
[30] 30. The compound as claimed in claim 1, which is selected from the group consisting of 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclopropylmethyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid methyl-phenethyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-methoxy-benzyl)-methyl-amide, WO 2013/068489 PCT/EP2012/072175 196 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-methoxy-benzyl)-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3-methoxy-benzyl)-methyl-amide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl-(3-trifluoromethyl-benzyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid benzyl-(2-dimethylamino-ethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid (1-benzyl-piperidin-4-yl)-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid tert-butylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid sec-butylamide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid isobutyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclopentylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (1-methyl-butyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1,1 -dimethyl-propyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1,2-dimethyl-propyl)-amide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2,2-dimethyl-propyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1 -ethyl-propyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid ethylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-methyl-butyl)-amide, WO 2013/068489 PCT/EP2012/072175 197 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid pentylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexylamide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1,3-dimethyl-butyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3,3-dimethyl-butyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid (2-ethyl-butyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid dicyclopropylmethyl-amide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-fluoro-ethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexylmethyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (1-phenyl-ethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-fluoro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3-fluoro-benzylamide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 4-fluoro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2,3-difluoro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid 2,4-difluoro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2,6-difluoro-benzylamide, WO 2013/068489 PCT/EP2012/072175 198 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3,4-difluoro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2,2,2-trifluoro-ethyl)-amide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3,5-difluoro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid phenethyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid [1-(4-fluoro-phenyl)-ethyl]-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid indan- 1 -ylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid indan-2-ylamide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid [1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide, 4-(Azetidine-1-carbonyl)-2-ethyl-6,7-dimethoxy-2H-isoquinolin-1 one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid cyclopropylamide, 2-Ethyl-6,7-dimethoxy-4-(2-methyl-pyrrolidine- 1 -carbonyl)-2H isoquinolin-1-one, 2-Ethyl-6,7-dimethoxy-4-(morpholine-4-carbonyl)-2H-isoquino lin- one, 25 2-Ethyl-4-(3 -fluoro-pyrro lidine- 1 -carbonyl)-6,7-dimethoxy-2H isoquinolin-1-one, 2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperazine- 1 -carbonyl)-2H isoquinolin-1-one, 4-(3,3-Difluoro-pyrrolidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H 30 isoquinolin-1-one, 4-(3-Dimethylamino-pyrrolidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy 2H-isoquinolin- 1-one, WO 2013/068489 PCT/EP2012/072175 199 2-Ethyl-6,7-dimethoxy-4-((R)-2-methoxymethyl-pyrrolidine- 1 carbonyl)-2H-isoquino lin- 1-one, 4-(1,3-Dihydro-isoindole-2-carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 5 4-(4,4-Difluoro-piperidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid isopropylamide, 2-Ethyl-4-(4-isopropyl-piperazine- 1 -carbonyl)-6,7-dimethoxy-2H 10 isoquinolin-1-one, 4-(4-Dimethylamino-piperidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy 2H-isoquinolin- 1-one, 2-Ethyl-6,7-dimethoxy-4-(2-trifluoromethyl-pyrrolidine- 1 -carbonyl) 2H-isoquinolin- 1-one, 15 4-(4-Cyclopropylmethyl-piperazine- 1 -carbonyl)-2-ethyl-6,7 dimethoxy-2H-isoquino lin- 1-one, 2-Ethyl-6,7-dimethoxy-4-((S)-2-pyrrolidin- 1 -ylmethyl-pyrrolidine- 1 carbonyl)-2H-isoquino lin- 1-one, 2-Ethyl-6,7-dimethoxy-4-(4-pyrrolidin- 1 -yl-piperidine- 1 -carbonyl) 20 2H-isoquinolin- 1-one, 4- [4-(2-Dimethylamino-ethyl)-piperazine- 1 -carbonyl] -2-ethyl-6,7 dimethoxy-2H-isoquino lin- 1-one, 4-([1,4']Bipiperidinyl- l'-carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 25 4- [4-(3-Dimethylamino-propyl)-piperazine- 1 -carbonyl] -2-ethyl-6,7 dimethoxy-2H-isoquino lin- 1-one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid propylamide, 2-Ethyl-6,7-dimethoxy-4-[4-(2-pyrrolidin- 1 -yl-ethyl)-piperazine- 1 30 carbonyl]-2H-isoquinolin- 1-one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid dimethylamide, WO 2013/068489 PCT/EP2012/072175 200 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid ethyl-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid isopropyl-methyl-amide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid diethylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl-propyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid ethyl-isopropyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid tert-butyl-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid isobutyl-methyl-amide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butyl-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid ethyl-propyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (2-dimethylamino-ethyl)-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid ethyl-(2-methoxy-ethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclopentyl-methyl-amide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butyl-ethyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid methyl-pentyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid diisopropylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid isopropyl-propyl-amide, WO 2013/068489 PCT/EP2012/072175 201 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclobutylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid dipropylamide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3-dimethylamino-propyl)-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid cyclohexyl-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid cyclopropylmethyl-propyl-amide 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid diisobutylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid benzyl-methyl-amide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-fluoro-benzyl)-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-fluoro-benzyl)-methyl-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (3-fluoro-benzyl)-methyl-amide, 2-tert-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 2-sec-Butyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 25 2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 2-Butyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-Cyclopropylmethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline 30 4-carboxylic acid butylamide, 2-(2-Dimethylamino-ethyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide, WO 2013/068489 PCT/EP2012/072175 202 2-Cyclopentyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 5 6,7-Dimethoxy- 1 -oxo-2-(2,2,2-trifluoro-ethyl)- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide 6,7-Dimethoxy- 1 -oxo-2-(2-pyrrolidin- 1 -yl-ethyl)- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide, 2-(2-Fluoro-ethyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 10 carboxylic acid butylamide, 2-Benzyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-(2,4-Difluoro-benzyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide, 15 2-Cyclopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 6,7-Dimethoxy- 1 -oxo-2-(2-piperidin- 1 -yl-ethyl)- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide, 6,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4 20 carboxylic acid butylamide, 6,7-Dimethoxy-2-(2-methoxy-benzyl)- 1 -oxo- 1,2-dihydro isoquinoline-4-carboxylic acid butylamide, 2-Indan-1-yl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 25 2-Isopropyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 6,7-Dimethoxy-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 6,7-Dimethoxy- 1 -oxo-2-(3,3,3-trifluoro-propyl)- 1,2-dihydro 30 isoquinoline-4-carboxylic acid butylamide, 6,7-Dimethoxy-2-(2-methoxy-ethyl)- 1 -oxo- 1,2-dihydro-isoquinoline 4-carboxylic acid butylamide, WO 2013/068489 PCT/EP2012/072175 203 2-Cyclobutyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butylamide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine- 1 -carboxylic acid butylamide, 5 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide, 2-Ethyl-7-methoxy- 1 -oxo-6-(2-quinolin-2-yl-ethoxy)- 1,2-dihydro 10 isoquinoline-4-carboxylic acid butylamide, 2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro isoquinoline-4-carboxylic acid butylamide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amide, 15 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (R)-indan-1-ylamide, 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4 carboxylic acid indan- 1 -ylamide, 2-Ethyl-7-methoxy-1-oxo-1,2-dihydro-[2,6]naphthyridine-4 20 carboxylic acid butylamide, 2-(1-Ethyl-propyl)-7-methoxy-1-oxo-1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-amide, 25 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic 30 acid (4-bromo-indan-1-yl)-amide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (5-bromo-indan-1-yl)-amide, WO 2013/068489 PCT/EP2012/072175 204 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine- 1 -carboxylic acid 2-dimethylaminomethyl-benzylamide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, 5 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-7-yl)-amide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid 3-dimethylaminomethyl-benzylamide, 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic 10 acid 4-dimethylaminomethyl-benzylamide, 7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline 4-carboxylic acid butylamide, 7-Methoxy-1-oxo-2-(2-quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline 4-carboxylic acid indan- 1 -ylamide, 15 3-Ethyl-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine-1-carboxylic acid (S)-indan-1-ylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 20 carboxylic acid 2-dimethylaminomethyl-benzylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid 3,5-difluoro-benzylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid 3,4-difluoro-benzylamide, 25 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid cyclohexylmethyl-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (R)-indan-1-ylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 30 carboxylic acid (S)-indan-1-ylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, WO 2013/068489 PCT/EP2012/072175 205 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid pyridin-3-ylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (pyrimidin-4-ylmethyl)-amide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-methoxy-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-morpholin-4-yl-phenyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid 3-chloro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (pyridin-4-ylmethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid o-tolylamide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid m-tolylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-methoxy-phenyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid (3-methoxy-phenyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (pyridin-3-ylmethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (pyridin-2-ylmethyl)-amide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid phenylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid 4-methoxy-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 3-methyl-benzylamide, WO 2013/068489 PCT/EP2012/072175 206 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-methyl-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-methoxy-ethyl)-amide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-fluoro-phenyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-methoxy-phenyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid p-tolylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3-fluoro-phenyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (2-fluoro-phenyl)-amide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 4-methyl-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-chloro-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 20 acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid pyridin-4-ylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6-methyl-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-morpholin-4-ylmethyl-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 30 acid (5-chloro-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6-chloro-indan-1-yl)-amide, WO 2013/068489 PCT/EP2012/072175 207 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6-fluoro-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-fluoro-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (4-methyl-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic 10 acid (5-methyl-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (6-methoxy-indan-1-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (5-fluoro-indan-1-yl)-amide, 15 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-diethylaminomethyl-benzylamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid 2-pyrrolidin-1-ylmethyl-benzylamide, 2-Ethyl-6,7-dimethoxy-4-(4-methyl-piperidine- 1 -carbonyl)-2H 20 isoquinolin-1-one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3-methoxy-propyl)-amide, 25 4-(3,5-Dimethyl-piperidine- 1 -carbonyl)-2-ethyl-6,7-dimethoxy-2H isoquinolin-1-one, 2-Ethyl-4-(4-ethyl-piperazine- 1 -carbonyl)-6,7-dimethoxy-2H isoquinolin-1-one, 2-Isobutyl-6,7-dimethoxy-4-(4-methyl-piperazine- 1 -carbonyl)-2H 30 isoquinolin-1-one, 2-Isobutyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquino line-4 carboxylic acid (2-dimethylamino-ethyl)-amide, WO 2013/068489 PCT/EP2012/072175 208 2-Isobutyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid butyl-methyl-amide, [(2-Isobutyl-6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4 carbonyl)-amino]-acetic acid methyl ester, 5 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (3-isopropoxy-propyl)-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 10 carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (6-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-Cyclopropyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide, 15 2-sec-Butyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide, 2-Isopropyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid indan- 1 -ylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-piperidine- 1 20 carbonyl)-2H-isoquinolin- 1-one, 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-(3-phenoxy-piperidine- 1 carbonyl)-2H-isoquinolin- 1-one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (S)indan- 1 -ylamide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (R)indan-i -ylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl) piperazine- 1 -carbonyl]-2H-isoquinolin- 1-one, 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-[8-(4-methyl-piperazine- 1 30 sulfonyl)-3,4-dihydro- 1 H-isoquinoline-2-carbonyl] -2H-isoquinolin- 1-one, 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-[8-(morpholine-4-sulfonyl)-3,4 dihydro- 1 H-isoquinoline-2-carbonyl]-2H-isoquinolin- 1-one, WO 2013/068489 PCT/EP2012/072175 209 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-[3-(3-methoxy-phenyl)-4-methyl piperazine- 1 -carbonyl]-2H-isoquinolin- 1-one, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid ([1,3,4]thiadiazol-2-ylmethyl)-amide, 5 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid 2-(morpholine-4-sulfonyl)-benzylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (thiazol-4-ylmethyl)-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy-4-[(R)-3-(quinoxalin-2-yloxy) 10 pyrrolidine- 1 -carbonyl]-2H-isoquinolin- 1-one, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (S)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 2-Ethyl-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4-carboxylic acid (R)(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 15 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (thiophen-3-ylmethyl)-amide, 4-(7-Amino-3,4-dihydro- 1 H-isoquinoline-2-carbonyl)-2-(1-ethyl propyl)-6,7-dimethoxy-2H-isoquinolin- 1-one, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 20 carboxylic acid 3-(4-chloro-benzenesulfonylamino)-benzylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (2,3-dihydro-benzo[b]thiophen-3-yl)-amide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 25 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid (S)-indan-1-ylamide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid 2-(4-methyl-piperazine-1-sulfonyl)-benzylamide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 30 4-carboxylic acid 2-(morpholine-4-sulfonyl)-benzylamide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, WO 2013/068489 PCT/EP2012/072175 210 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid 3,5-difluoro-benzylamide, 5 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid 4-methyl-benzylamide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid cyclohexylmethyl-amide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 10 4-carboxylic acid butylamide, 2-(1 -Ethyl-propyl)-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine 4-carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide, 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (thiazol-2-ylmethyl)-amide, 15 2-(1 -Ethyl-propyl)-6,7-dimethoxy- 1 -oxo- 1,2-dihydro-isoquinoline-4 carboxylic acid (thiophen-2-ylmethyl)-amide, 2-Ethyl-7-methoxy- 1 -oxo- 1,2-dihydro-[2,6]naphthyridine-4 carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 3-(1 -Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine- 1 20 carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)-amide, 3-(1 -Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine- 1 carboxylic acid (2,3-dihydro-benzofuran-3-yl)-amide, 3-(1 -Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine- 1 carboxylic acid indan- 1 -ylamide, 25 3-(1 -Ethyl-propyl)-6,7-dimethoxy-4-oxo-3,4-dihydro-phthalazine- 1 carboxylic acid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxy-4-(3-phenyl-propionyl)-2H isoquinolin-1-one, 2-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)- 1 -oxo- 1,2 30 dihydroisoquinoline-4-carboxamide, and the N-oxides, the tautomers, the hydrates, the prodrugs and the pharmaceutically acceptable salts thereof. WO 2013/068489 PCT/EP2012/072175 211
[31] 31. The compound as claimed in claim 1, which is selected from the group consisting of 6,7-Dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-(pyridin-3-ylmethyl)- 1,2 5 dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((5-methylthiophen-2-yl)methyl)- 1 -oxo-2-(pentan 3-yl)-1,2-dihydroisoquinoline-4-carboxamide, N-((3,5-Dimethylisoxazol-4-yl)methyl)-6,7-dimethoxy- 1 -oxo-2 (pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide, 10 6,7-dimethoxy-N-((5-methylthiazol-2-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-(pyrimidin-4-ylmethyl)- 1,2 dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((3-methylisoxazol-5-yl)methyl)- 1 -oxo-2-(pentan 15 3-yl)-1,2-dihydroisoquinoline-4-carboxamide, N-((2,5-Dimethylthiophen-3-yl)methyl)-6,7-dimethoxy- 1 -oxo-2 (pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((2-methylthiazol-5-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 20 6,7-Dimethoxy-N-((5-methylisoxazol-3-yl)methyl)- 1 -oxo-2-(pentan 3-yl)-1,2-dihydroisoquinoline-4-carboxamide, (R)-N-(1 -(4-Fluorophenyl)ethyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, (S)-N-(1 -(4-Fluorophenyl)ethyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3 25 yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((4-methylthiazol-2-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((2-methylthiazol-4-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 30 6,7-Dimethoxy-N-((4-methylthiazol-5-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 212 6,7-Dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-((5-(trifluoromethyl)furan-2 yl)methyl)- 1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((5 -methylfuran-2-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquino line-4-carboxamide, 5 N-(5 -Fluoro-2,3 -dihydro- 1 H-inden- 1 -yl)-6,7-dimethoxy- 1 -oxo-2 (pentan-3 -yl)-1,2-dihydroiso-quino line-4-carboxamide, 6,7-Dimethoxy-N-(5 -methyl-2,3 -dihydro- 1 H-inden- 1-yl)-1 -oxo-2 (pentan-3 -yl)-1,2-dihydroisoquino line-4-carboxamide, 6,7-Dimethoxy-N-(4-methyl-2,3 -dihydro- 1 H-inden- 1-yl)-1 -oxo-2 10 (pentan-3 -yl)-1,2-dihydroisoquino line-4-carboxamide, N-((2-Ethylthiazo 1-4-yl)methyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquino line-4-carboxamide, 6,7-Dimethoxy-N-(6-methoxy-2,3 -dihydro- 1 H-inden- 1-yl)-1 -oxo-2 (pentan-3 -yl)-1,2-dihydroisoquino line-4-carboxamide, 15 6,7-Dimethoxy-N-((4-methylthiophen-2-yl)methyl)- 1 -oxo-2-(pentan 3-yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((3-methylthiophen-2-yl)methyl)- 1 -oxo-2-(pentan 3-yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((5-methyloxazol-2-yl)methyl)- 1 -oxo-2-(pentan-3 20 yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-(6-methyl-2,3-dihydro- 1 H-inden- 1-yl)-1 -oxo-2 (pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-(pyridin-4-ylmethyl)- 1,2 dihydroisoquinoline-4-carboxamide, 25 6,7-Dimethoxy-N-(4-methylbenzyl)- 1 -oxo-2-(pentan-3-yl)-1,2 dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy- 1 -oxo-2-(pentan-3-yl)-N-(pyridin-2-ylmethyl)- 1,2 dihydroisoquinoline-4-carboxamide, N-((5-Cyanofuran-2-yl)methyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3-yl) 30 1,2-dihydroisoquinoline-4-carboxamide, N-(4-Chloro-2,3-dihydro- 1 H-inden- 1 -yl)-6,7-dimethoxy- 1 -oxo-2 (pentan-3-yl)-1,2-dihydroisoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 213 N-((5-Ethylthiophen-2-yl)methyl)-6,7-dimethoxy- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((3-methylfuran-2-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 5 6,7-Dimethoxy-N-((2-methylfuran-3-yl)methyl)- 1 -oxo-2-(pentan-3 yl)-1,2-dihydroisoquinoline-4-carboxamide, 6,7-Dimethoxy-N-((1-methyl-i H-pyrazol-3-yl)methyl)- 1 -oxo-2 (pentan-3 -yl)-1,2-dihydroisoquino line-4-carboxamide, N-[(3,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo 10 isoquinoline-4-carboxamide, N-[(2-Chloro-4-methyl-phenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, N-[[2-(Dimethylamino)-4-methyl-phenyl]methyl]-2-ethyl-6,7 dimethoxy- 1 -oxo-isoquinoline-4-carboxamide, 15 2-Ethyl-N-[(2-fluoro-4-methyl-phenyl)methyl]-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(3-methoxy-4-methyl-phenyl)methyl]-1 oxo-isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-morpholino-phenyl)methyl] 20 1 -oxo-isoquinoline-4-carboxamide, N- [(2-tert-Butoxy-4-methyl-phenyl)methyl] -2-ethyl-6,7-dimethoxy- 1 oxo-isoquinoline-4-carboxamide, N- [ [2-(1,1 -Dimethylpropoxy)-4-methyl-phenyl]methyl] -2-ethyl-6,7 dimethoxy- 1 -oxo-isoquinoline-4-carboxamide, 25 N- [(2,3-Difluoro-4-methyl-phenyl)methyl] -2-ethyl-6,7-dimethoxy- 1 oxo-isoquinoline-4-carboxamide, 2-Ethyl-N- [(3 -fluoro-4-methyl-phenyl)methyl] -6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, N- [(3 -Chloro-4-methyl-phenyl)methyl] -2-ethyl-6,7-dimethoxy- 1 -oxo 30 isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo-N- [(2,4,6 trimethylphenyl)methyl]isoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 214 N-[(2,4-Dimethylphenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)-4-methyl phenyl]methyl]- 1 -oxo-isoquinoline-4-carboxamide, 5 N-[[2-(2-Ethoxyethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7 dimethoxy- 1 -oxo-isoquinoline-4-carboxamide, N-[[2-(Cyclopentoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7 dimethoxy- 1 -oxo-isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-phenoxy-phenyl)methyl]-1 10 oxo-isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxy- 1 -methyl-ethoxy)-4 methyl-phenyl]methyl] -1 -oxo-isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(2,2,2 trifluoroethoxy)phenyl]methyl] -1 -oxo-isoquinoline-4-carboxamide, 15 N-[[2-(Cyclohexoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7 dimethoxy- 1 -oxo-isoquinoline-4-carboxamide, N-[[2-(Cyclopropylmethoxy)-4-methyl-phenyl]methyl]-2-ethyl-6,7 dimethoxy- 1 -oxo-isoquinoline-4-carboxamide, 2-Ethyl-N-[(2-hexoxy-4-methyl-phenyl)methyl]-6,7-dimethoxy- 1 20 oxo-isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[4-methyl-2-(tetrahydrofuran-3 ylmethoxy)phenyl]methyl] -1 -oxo-isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)-4-methyl phenyl]methyl]- 1 -oxo-isoquinoline-4-carboxamide, 25 2-Ethyl-N-(2-isobutoxy-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-Ethyl-N-(2-(furan-2-ylmethoxy)-4-methylbenzyl)-6,7-dimethoxy- 1 oxo- 1,2-dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(pentyloxy)benzyl)- 1 -oxo- 1,2 30 dihydroisoquinoline-4-carboxamide, N-(2-Ethoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 215 N-(2-sec-Butoxy-4-methylbenzyl)-2-ethyl-6,7-dimethoxy- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-Ethyl-N-(2-(isopentyloxy)-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo 1,2-dihydroisoquinoline-4-carboxamide, 5 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-propoxybenzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(methylthio)benzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-Ethyl-N-(2-isopropoxy-4-methylbenzyl)-6,7-dimethoxy- 1 -oxo- 1,2 10 dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(tetrahydrofuran-3 yloxy)benzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-(2,4,5-trimethylbenzyl)- 1,2 dihydroisoquinoline-4-carboxamide, 15 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-((tetrahydrofuran-2 yl)methoxy)benzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentan-2 yloxy)benzyl)- 1 -oxo- 1,2-dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl-2-(4-methylpentyloxy)benzyl)- 1 20 oxo- 1,2-dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(2-methoxy-4-methylbenzyl)- 1 -oxo- 1,2 dihydroisoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-(thiazol-4-ylmethyl)isoquinoline-4 carboxamide, 25 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-[[4 (trifluoromethyl)phenyl]methyl]isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-[(l S)- 1 -(p-tolyl)ethyl]isoquinoline-4 carboxamide, 2-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxy- 1 -oxo 30 isoquinoline-4-carboxamide, 2-Ethyl-N-[(4-ethylphenyl)methyl]-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, WO 2013/068489 PCT/EP2012/072175 216 2-Ethyl-6,7-dimethoxy- 1 -oxo-N-[(1 R)- 1 -(p-tolyl)ethyl]isoquino line 4-carboxamide, N-[[4-(Difluoromethyl)phenyl]methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo isoquinoline-4-carboxamide, 5 2-Ethyl-6,7-dimethoxy-N-[(2-methylthiazol-4-yl)methyl] -1 -oxo isoquinoline-4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(4-methyl-2-thienyl)methyl] -1 -oxo isoquinoline-4-carboxamide, N-[(4-Cyclopropylphenyl)methyl]-2-ethyl-6,7-dimethoxy- 1 -oxo 10 isoquinoline-4-carboxamide, N-Indan- 1 -yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl] -1 -oxo isoquinoline-4-carboxamide, N-Butyl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl] -1 -oxo isoquinoline-4-carboxamide, 15 2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxy-2-pyridyl)ethyl] -1 -oxo isoquinoline-4-carboxamide, N-Butyl-6,7-dimethoxy- 1 -oxo-2-[2-(2-quino,1yl)ethyl]isoquinoline-4 carboxamide, N-Indan- 1 -yl-6,7-dimethoxy- 1 -oxo-2-[2-(2 20 quino,1yl)ethyl]iso-quinoline-4-carboxamide; and the N-oxides, the tautomers, the hydrates, the prodrugs and the pharmaceutically acceptable salts thereof. 25
[32] 32. The compound as claimed in any of claims 1 to 31 for the use in the treatment of a medical disorder, selected from neurological and psychiatric disorders which can be treated by modulation of phosphodiesterase type 10 in a mammalian.
[33] 33. The compounds as claimed in any of claims 1 to 31 for treating, controlling, 30 ameliorating or reducing the risk of CNS disorders in a mammalian. WO 2013/068489 PCT/EP2012/072175 217
[34] 34. The compounds as claimed in any of claims 1 to 31 for treating, controlling, ameliorating or reducing the risk of schizophrenia in a mammalian.
[35] 35. The compounds as claimed in any of claims I to 31 for treating, controlling, 5 ameliorating or reducing cognitive dysfunction associated with schizophrenia in a mammalian.
[36] 36. The compounds as claimed in any of claims I to 31 for treating, controlling, ameliorating or reducing the risk of bipolar disorders in a mammalian. 10
[37] 37. The compounds as claimed in any of claims I to 31 for treating, controlling, ameliorating or reducing the risk of depression in a mammalian.
[38] 38. The compounds as claimed in any of claims I to 31 for treating, controlling, 15 ameliorating or reducing cognitive dysfunction associated with Alzheimer's disease in a mammalian.
[39] 39. The compounds as claimed in any of claims 1 to 31 for treating, controlling, ameliorating or reducing the risk of diet-induced obesity in a mammalian. 20
[40] 40. A method for treating a medical disorder, selected from neurological and psychiatric disorders which can be treated by modulation of phosphodiesterase type 10, said method comprising administering an effective amount of at least one compound as claimed in any of claims 1 to 31 to a subject in need thereof. 25
[41] 41. Pharmaceutical composition which comprises a carrier and a compound as claimed in any one of claims I to 31.

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法律状态:
2017-06-01| MK4| Application lapsed section 142(2)(d) - no continuation fee paid for the application|

优先权:

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申请号 | 申请日 | 专利标题

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US201161557878P| true| 2011-11-09|2011-11-09||

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US61/557,878||2011-11-09||

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PCT/EP2012/072175|WO2013068489A1|2011-11-09|2012-11-08|Heterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10a|

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