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NZ624124B2 - Heterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10a - Google Patents

Heterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10a Download PDF

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Publication number
NZ624124B2
NZ624124B2 NZ624124A NZ62412412A NZ624124B2 NZ 624124 B2 NZ624124 B2 NZ 624124B2 NZ 624124 A NZ624124 A NZ 624124A NZ 62412412 A NZ62412412 A NZ 62412412A NZ 624124 B2 NZ624124 B2 NZ 624124B2
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New Zealand
Prior art keywords
ethyl
dihydro
dimethoxyoxo
alkyl
isoquinolinecarboxylic acid
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NZ624124A
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NZ624124A (en
Inventor
Jurgen Dinges
Karla Drescher
Herve Geneste
Clarissa Jakob
Michael Ochse
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Abbvie Deutschland Gmbh & Co Kg
Abbvie Inc
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Priority claimed from PCT/EP2012/072175 external-priority patent/WO2013068489A1/en
Publication of NZ624124A publication Critical patent/NZ624124A/en
Publication of NZ624124B2 publication Critical patent/NZ624124B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

Disclosed are fused heterocyclic carboxamide compounds of formula (I) that are inhibitors of phosphodiesterase type 10A, wherein the variables are as defined in the specification. These inhibitors of phosphodiesterase type 10A are used for the manufacture of a medicament 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. 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.

Description

/072175 HETEROCYCLIC CARBOXAMIDES USEFUL AS INHIBITORS 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 rating the symptoms associated with such disorders and for reducing the risk of such ers.
Background of the Invention Phosphodiesterase type 10A (hereinafter PDElOA) is a dual-substrate phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP. PDE10A is highly prominent in the mammalian brain. In the rat, as well as in other mammalian species, PDElOA and the mRNA of PDElOA are highly enriched in the GABAergic medium spiny projection neurons (MSNs) ofthe striatal x (caudate nucleus, nucleus accumbens, and olfactory tubercle) where the output is regulated by the effect ofPDE10A on cAMP and cGMP signalling cascades (see e.g. C. J. Schmidt et al, The Journal of cology and Experimental Therapeutics 325 (2008) 681-690, A. Nishi, The Journal ofNeuroscience 2008, 28, 10450-10471).
MSNs express two functional classes of neurons: the D1 class expressing D1 dopamine receptors and the D2 class expressing D2 ne receptors. The D1 class of neurons is part of the 'direct' striatal output pathway, which y functions to facilitate behavioral responses. The D2 class of neurons is part of the ect' striatal output pathway, which fianctions to suppress behavioral responses that e with those being facilitated by the 'direct' pathway. PDElOA regulation of cAMP and/or cGMP ing in the dendritic compartment of these neurons may be involved in filtering the cortico/thalamic input into the MSN. Furthermore, PDElOA may be involved in the tion of GABA release in the substantia nigra and globus pallidus (Seeger, T.F. et al. Brain ch, 2003, 985, 1 13-126). Inhibition ofPDElOA results in striatal activation and behavioral suppression such as dampened locomotion, inhibition of conditioned nce response (CAR), and activity in the rat auditory WO 68489 gating model, suggesting that inhibitors ofphosphodiesterase type 10A represent a novel class of antipsychotic agents.
The hypotheses around the physiological role ofPDE10A and the therapeutic utility ofPDE10A inhibitors derive in part from studies with papaverine (J. A. Siuciak et al. loc. cit.), the first extensively profiled pharmacological tool compound for this target. The PDE10A inhibitor papaverine was shown to be active in l antipsychotic models. Papaverine potentiated the cataleptic effect of the D2 receptor antagonist ridol in rats, but did not cause catalepsy on its own (WO 03/093499).
Papaverine reduced hyperactivity in rats induced by PCP, while reduction of amphetamine-induced hyperactivity was insignificant (WO 03/093499). These models suggest that PDE10A tion has the classic ychotic potential that would be expected from theoretical considerations. Papaverine, however has significant limitations in this regard with vely poor potency and selectivity and a very short exposure ife after systemic administration. It was found that tion of PDE10A reverses subchronic PCP-induced deficits in ional set-shifting in rats suggesting that PDE10A 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 PDE10A inhibitors with improved potency, selectivity, and pharmacokinetic properties, provided an opportunity to filrther explore the logy ofPDE10A and the potential therapeutic y of ting this enzyme. The new class of inhibitors are exemplified by MP-10 (PF-2545920: 2- {4-[1- methylpyridineylH-pyrazol-3 -3ly]phenoxymethyl} -quino line) and TP-10, i.e. 2- {4-[pyridineyl(2,2,2-trifiuoroethyl)H-pyrazol-3 -3ly]phenoxymethyl} - quino line. The compounds offer a eutic approach to the treatment of 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 ctivity caused by amphetamine-induced dopamine release or phencyclidine (PCP) mediated NMDA receptor blockade, attenuation of pharmaco logically 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 68489 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 gton's disease (S. H. Francis et al., l. Rev., 91 (2011) 651- 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 PDE10A inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes (see e.g. 14, , Cantin et al, Bioorganic & nal Chemistry Letters 17 (2007) 2869-2873).
In summary, tors of PDE10A offer a promising therapeutic ch to the ent or prevention of neurological and psychiatric disorders, in particular schizophrenia and related disorders, including symptoms linked to schizophrenia such as cognitive dysfiJnction.
Several classes of compounds which are inhibitors of PDE10A have been described in the art, the recent compound groups are: Pyrido[3,2-e]pyridazines - see , , WO 68246, , and ; 4-substiuted phthalazines and quinazolines , , , , , and WO 2009/036766; 4-substiuted cinnazolines - see , , WO 2007/098214, , and ; Isoquinolines and isoquinolinones - see and WO 29214; MP10 and MP10 like componds: US 2007/0155779, and WO 2008/004117; and Benzodiazepines - see .
For a fiarther review see also T. Chappie et al. Current Opinion in Drug ery & Development 12(4), (2009) 45 8-467) and the literature cited therein.
Although some of the compounds of prior art are known to inhibit PDE10A effectively having IC50 values of less than 50 nM, there is still an ongoing need for compounds which inhibit PDE10A. In ular, there is an ongoing need for compounds which have one of the following characteristics: i. Selective tion of PDElOA, 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 s (e.g. rat or human) in human cells, such as hepatocytes; iii. no or only low inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP) is the name for a superfamily ofheme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms. The principal representatives ofthe 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 on the enzyme, the degradation thereofmay 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 ; v. suitable cokinetics (time course of the concentration of the nd of the invention in plasma or in tissue, for example . The pharmacokinetics can be described by the following parameters: half-life, volume of distribution (in l-kg'l), plasma nce (in l-h'1 'kg'l), AUC (area under the curve, area under the concentration-time curve (in 'l), oral bioavailability, (the dose-normalized ratio ofAUC after oral administration and AUC after intravenous administration), the so-called brain-plasma ratio (the ratio ofAUC 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 al and thus lead to serious disturbances of cardiac rhythm (for example so-called de de pointes"). The potential of compounds to block the hERG channel can be determined by means of the displacement assay with radio labelled dofetilide which is described in the literature (G. J. Diaz et al., Journal of WO 68489 Pharmacological and logical Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide assay means a greater probability of potent hERG de. In addition, the blockade of the hERG channel can be measured by electrophysio logical experiments on cells which have been 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 on in brain, i.e. the fraction of the compound bound to proteins should be low.
Viii. low lipophilicity.
Brief Description of the Invention The present invention is thus based on the object of providing compounds which inhibit PDElOA at low concentrations.
The compounds are further ed to display at least one of the properties i. to Viii. mentioned above, in particular high selectiVity with regard to inhibition of , high selectivity vis-a-vis other phosphodiesterases such as enhanced lic ity, in particular microsomal and/or cytosolic stability, low affinity to 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: 4 1 R O \ N/R 2 '1 (I) X / /X O N wherein X1 is CH or N, X2 is OR5 or N, Y is O or S, R1 is selected from the group consisting of C2-Cg-alkyl, C2-Cg-alkenyl, C1-C4- fluoroalkyl, Cg-Cg-cycloalkyl, C5-Cg-cycloalkyl carrying a fused benzene ring, fluorinated Cg-Cg-cycloalkyl, C3-Cg-cycloalkyl-C1-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-Cl-C4-alkyl, alkyl-N(Rb)(R°) and a moiety Zl-Arl; R2 is a radical of the formula CRZIRZZR23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, Where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra, Where R21 is selected from the group consisting of en, C1-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, C1-C4-fluoroalkyl, Cg-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-Cg-cycloalkyl-C1-C4-alkyl, fluorinated cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-Cl-C4-alkyl, C1-C4-alkyl-N(Rb)(R°), (CH2)mC(O)O-Rd, (CH2)mC(O)N(Re)(Rf) and 22.1%, R22 is selected from the group consisting of hydrogen, fluorine, C1-C8- alkyl, C2-Cg-alkenyl, fluoroalkyl, Cg-Cg-cycloalkyl, ated C3-Cg-cycloalkyl, C3-Cg-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8- cycloalkyl-Cl-C4-alkyl, alkoxy-C1-C4-alkyl, hydroxy-Cl-C4- alkyl and C1-C4-alkyl-N(Rb)(R°), or 2012/072175 R21 and R22 together with the carbon atom, to which they are bound form a ted 5- to 7-membered yclic ring or a saturated 5- to 7- membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and S02 as ring members, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by l, 2 or 3 cal or different substituents Rg, 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 tituted or carry 1, 2 or 3 substituents Rh, R23 is selected from the group consisting of hydrogen, fluorine, C1-C8- alkyl and C1-C4-fluoroalkyl; R3 is selected from the group consisting of hydrogen, C1-Cg-alkyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, Cg-Cg-cycloalkyl, C3-Cg-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-Cl-C4-alkyl, C1-C4-alkyl-N(Rb)(R°), and trimethylsilyl, or 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 fiarther heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and S02 as ring members, where the heterocyclic ring may be unsubstituted or may be substituted by l, 2 or 3 identical or different substituents R31, and where the heterocyclic ring may carry a filSGd benzene ring or a fused 5- or 6- membered heteroaromatic ring, where the fused rings lves are unsubstituted or carry 1, 2 or 3 substituents R”, where R31 is selected from the group ting of halogen, CN, OH, C1-C4- alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4- alkoxy, N(Rb)(R°), C(O)O-Rd, C(O)N(Re)(Rf), where one radical R31 may also be a moiety Z3-Ar3, R32 is selected from the group consisting of halogen, CN, OH, C1-C4- alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4- alkoxy, N(Rb)(R°), C(O)O-Rd and C(O)N(Re)(Rf); R4 is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl, C3- C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl and Z4-Ar4; R5 is ed from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1- roalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, -Z5-Ar5, -O-Z5-Ar5, C3- C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy and C3-C6- cycloalkyl-Cl-C4-alkoxy, where the cyclic radical in the last four mentioned groups may be tituted, partially or completely fluorinated or s 1, 2, 3 or 4 methyl groups; Ar1 is selected from the group consisting of phenyl, monocyclic 5- or 6- membered l or bicyclic 9- or lO-membered hetaryl, where hetaryl has 1, 2 or 3 atoms as ring members which are selected from O, 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 heteroatoms as ring s which are selected from O, S and N, where phenyl and monocyclic l are tituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar3 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar4 and Ar5 are independently of each other selected from the group consisting ofphenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rk; Z1, Z4, Z5 are independently of each other C1-C4-alkylene; Z2 is a single bond or C1-C4-alkylene; z3 is a single bond, C1-C4-alkylene, o, N, s, so or $02; Ra is selected from the group consisting of halogen, CN, OH, N02, C1- C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4- alkoxy, (CH2)mN(Rb)(R°), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(Re)(Rf); Rb, RC, independently of each other are selected from the group consisting of hydrogen, C1-C4-alkyl, fluoroalkyl, C3-C6-cycloalkyl, C3-C6- cycloalkylmethyl and benzyl or Rb and Rc 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 ent or identical heteroatoms or heteroatom containing groups selected from the group ofO, N, S, SO and S02 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; Rd is selected from the group ting of C1-C4-alkyl, C1-C4- fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl; Re, Rf, independently of each other are selected from the group ting of en, C1-C4-alkyl, fluoroalkyl, C3-C6-cycloalkyl, C3-C6- lkylmethyl 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 ofO, N, S, SO and S02 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; Rg is selected from the group consisting of halogen, CN, OH, C1-C6- alkyl, alkenyl, C1-C4-fluoroalkyl, cycloalkyl, fluorinated lO cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, fluorinated C3-C6- cycloalkyl-Cl-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-Cl-C4- alkyl, C1-C4-alkyl-N(Rb)(R°), C1-C4-alkoxy, fluorinated C1-C4-alkoxy, one Rg together with a carbon atom to which Rg is attached may also form a carbonyl group, one Rg may also be phenyl or benzyl, where 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, C1-C4- alkyl, ated C1-C4-alkyl, C1-C6-alkoxy, fluorinated C1-C4- alkoxy, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkoxy, C3-C6- cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6-cycloalkoxy, C3-C6- cycloalkyl-Cl-C4-alkoxy, phenoxy, N(Rb)(R°), C1-C4-alkyl-N(Rb)(R°), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff), S(O)2N(Re)(Rf), 3— to 7— membered heterocyclyloxy, 3- to 7-membered heterocyclyl-Cl-C4- alkoxy, where heterocyclyl in the two last mentioned ls has 1, 2 or 3 heteroatoms as ring s which are selected from O, S and N, and 5- to ered hetaryl-Cl-C4-alkoxy, where hetaryl has 1, 2 or 3 atoms as ring members which are selected from O, S and Rk is selected from the group consisting of halogen, CN, OH, C1-C4- alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4- alkoxy, N(Rb)(R°), Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(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 members selected from O, N and S, where the fused e ring and the fiased heteroaromatic ring are unsubstituted or may carry 1, 2 or 3 radicals Rh; Ree is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4- fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and ; Rff is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl and phenyl, which is tituted or carries 1, 2 or 3 radicals Rh; m isO, 1,2, 3 or4.
The present invention therefore relates to the compounds of the general formula I, the N—oxides, the ers and the hydrates thereof, the pharmaceutically acceptable salts of the compounds of a I, the prodrugs of the compounds of formula I and the pharmaceutically acceptable salts of said N—oxides, prodrugs, tautomers or hydrates ofthe compounds of a 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 ofthe compounds of formula I, the prodrugs of the compounds of formula I and the 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 ogical and psychiatric disorders which can be d by modulation of phosphodiesterase type 10.
The compounds of the formula 1, their pharmaceutically acceptable salts, their N- oxides, their prodrugs, their hydrates and their tautomers and the pharmaceutically acceptable salts of said N—oxides, prodrugs, tautomers or hydrates effectively inhibit PDElOA even at low concentrations. They are additionally distinguished by a high selectivity in relation to the inhibition of the PDElOA 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- , their prodrugs, their es and their tautomers and the pharmaceutically acceptable salts of said es, 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 1 0A.
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 phodiesterase 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 ofphosphodiesterase type 10A. The ment comprises at least one compound of the formula I, as described herein, or an N—oxide, a er, or a e or a prodrug of said compound I, or a pharmaceutically acceptable salt of the compound ofthe formula I or a pharmaceutically acceptable salt of the N—oxide, the tautomer, the hydrate or the prodrug of compound ofthe formula I.
Detailed Description of the Invention The terms "compound of the formula I" and unds 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. h (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 5. These include for example phosphates, ates, amino acids, esters, amides, peptides, ureas and the like. Suitable gs in the present case may be for e tives of those compounds I carrying an OH or NHz-group, where the OH or NHz-group forms an ester/amide/peptide linkage, i.e. where one of the hydrogen atoms ofthe OH or NHz-group is substituted by a C1-C4-alkylcarbonyl group, e.g. by acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or tertbutylcarbonyl (pivaloyl), by benzoyl, or by an acyl group derived from an amino acid, e. g. glycine, alanine, , phenylalanine and the like, which is linked to the oxygen or nitrogen of the OH or NHz-group via the carbonyl group of the amino acid. r suitable prodrugs are alkylcarbonyloxyalkyl carbonates or carbamates of compounds I carrying an OH- or NHz-group in which one of the hydrogen atoms of the OH- or NH2- group has been replaced by a group of the formula -C(=O)-O-CHRp-O-C(=O)-Rq in which Rp and Rq are independently of one another 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), 2. These groups can then be eliminated under metabolic conditions and result in nds 1. Therefore, said prodrugs and their pharmaceutically acceptable salts are also part of the invention.
The term "pharmaceutically acceptable salts" refers to cationic or anionic salts nds, 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 a I or its prodrug, tautomer, hydrate or N—oxide is acidic, salts may be ed from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts, n 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 salts of primary, secondary, and ry amines, substituted amines including lly occurring tuted amines, cyclic amines, and basic ion ge resins, such as arginine, betaine, ne, choline, dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylamino ethanol, ethanolamine, ethylenediamine, N- ethyl-morpholine, N—ethylpiperidine, glucamine, glucosamine, ine, hydrabamine, isopropylamine, lysine, methylglucamine, morpho line, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of formula I or its prodrug, tautomer, hydrate or N—oxide is basic, salts may be prepared from ceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, trifluoroacetic acid, benzenesulfonic, c, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, enesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, SlllfilI'lC, fumaric, and tartaric acids. It will be tood that, as used herein, references to the compounds of formula I are meant to also e the ceutically 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 nds are preferably in the form of essentially diastereomerically pure compounds (diastereomeric excess de > 90%). The compounds I of the invention may furthermore be in the form of a mixture of omers (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 ntly prone to zation in relation to the stereochemistry of the carbon atom which carries the radical R1, so that es 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 red to employ the compounds enantiomerically pure or diastereomerically pure.
The present invention moreover relates to compounds as defined herein, wherein one or more ofthe atoms depicted in formula I have been replaced by its stable, preferably non-radioactive e (e.g., hydrogen by ium, 12C by 13C, 14N by 15N, 16O by 18O) and preferably wherein at least one hydrogen atom has been replaced by a 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 68489 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.
In the context of the present description, unless stated otherwise, the terms "alkyl", "alkenyl", "alkoxy , alkenyloxy", alkyl", "fluoroalkoxy , cycloalkyl", "fluorinated cycloalkyl", "alkylene , alkandiyl", "hetaryl" and radicals derived therefrom, such as "hydroxylalkyl", "alkoxylalkyl", "alkoxyalkoxy", alkylalkyl" and "fluorinated lkylalkyl" and "hetarylalkyl" represent groups of indiVidual radicals. The groups of noncyclic ls "alkyl", "alkenyl", "alkoxy , alkenyloxy", alkyl", "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.
The prefix Cn-Cm- indicates the respective number of carbons in the hydrocarbon unit. Unless ted ise, ated 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.
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. l to 10, l to 8, l to 6 or 1 to 4 carbon atoms. Examples of C1-C4-alkyl are methyl, ethyl, propyl, l- ethyl, n-butyl, l-methylpropyl, 2-methylpropyl and l,l-dimethylethyl. C1-C6- alkyl are, apart those mentioned for C1-C4-alkyl, n-pentyl, l-methylbutyl, 2—methylbutyl, 3-methylbutyl, methylpropyl, l-ethylpropyl, n-hexyl, l,l- dimethylpropyl, methylpropyl, l-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, l,l-dimethylbutyl, l,2-dimethylbutyl, l,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, methylbutyl, l-ethylbutyl, 2-ethylbutyl, l,l,2- trimethylpropyl, l,2,2-trimethylpropyl, l-ethyl-l-methylpropyl and l-ethyl propyl. Examples for C1-Cg-alkyl or C2-C9-alkyl are, apart those mentioned for C1-C6-alkyl, n-heptyl, l-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- methylhexyl, lpentyl, lpentyl, 3-ethylpentyl, n-octyl, l-methyloctyl, 2- methylheptyl, l-ethylhexyl, 2-ethylhexyl, l,2-dimethylhexyl and l-propylpentyl, 2- propylpentyl. alkyl and the fluoroalkyl moieties for example in fluoroalkylsulfonyl: an alkyl l having ordinarily l to 4 C atoms, in particular 1 or 2 C-atoms (C1-C2- 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-l- ethyl, 2,2-difluoro-l-methylethyl, 2,2-trifluoro-l-methylethyl, 2-fluoropropyl, 3- fluoropropyl, fluoropropyl, 2,3-difluoropropyl, 3,3,3-trifluoropropyl, 3- pentafluoropropyl, heptafluoropropyl, l-(fluoromethyl)fluoroethyl, 4-fluorobutyl, and nonafluorobutyl.
Cycloalkyl, and the cycloalkyl moieties for example in cycloalkoxy, cycloalkyl- C1-C4-alkyl or cycloalkyl—Cl-C4-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, entyl, cyclohexyl and cycloheptyl.
Fluorinated cycloalkyl, and the flourinted cycloalkyl moieties for example in fluorinated cycloalkoxy or fluorinated cycloalkyl-Cl-C4-alkyl: clic, saturated hydrocarbon groups having three or more C atoms, e. g. 3, 4, 5, 6, 7 or 8 carbon ring members, such as ropyl, utyl, cyclopentyl, cyclohexyl and cycloheptyl, n at least one, e.g. l, 2, 3, 4, 5 or 6 of the hydrogen atoms are replaced by fluorine atoms, examples including l-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, l,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, etc..
Cycloalkoxy: a cycloalkyl radical as defined above which is linked Via an oxygen atom, e. g. cyclopropyloxy, utyloxy, cyclopentyloxy or cyclohexyloxy.
Cycloalkylalkyl: a cycloalkyl radical as defined above which is linked Via an alkylene group, in particular Via a methylene, l,l-ethylene or l,2-ethylene group, e. g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethy, cyclohexylmethyl, l- cyclopropylethyl, l-cyclobutylethyl, l-cyclopentylethyl, l-cyclohexylethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl.
Fluorinated cycloalkylalkyl: a fluorinated cycloalkyl radical as defined above which is linked via an alkylene group, in particular via a methylene, hylene or 1,2- ethylene group, e.g. l-fluorocyclopropylmethyl, 2-fluorocyclopropylmethyl, 2,2- difluorocyclopropylmethyl, 1,2-difluorocyclopropylmethyl, 2,3- difiuorocyclopropylmethyl, l -( l cyclopropyl)ethyl, l -(2-fluorocyclopropyl)ethyl, l-(2,2-difluorocyclopropyl)ethyl, l-(l ,2-difluorocyclopropyl)ethyl, l-(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.
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. C2-C4-alkenyl such as ethenyl, l-propenyl, 2-propenyl, l-methylethenyl, l-butenyl, 2-butenyl, 3-butenyl, 1- methylpropenyl, 2-methyl- l -propenyl, l lpropenyl and 2-methyl yl.
Alkoxy or alkoxy moieties for example in alkoxyalkyl and alkoxyalkoxy: an alkyl radical as defined above rily having 1 to 6 C atoms, preferably 1 to 4 C atoms, which is connected to the remainder of the molecule via an O atom: e. g. methoxy, ethoxy, n-propoxy, ylethoxy, butoxy, ylpropoxy, 2-methylpropoxy or 1, l hylethoxy.
Fluoroalkoxy: alkoxy as described above, in which the hydrogen atoms of these groups are partly or tely replaced by fluorine atoms, i.e. for example C1-C4- fluoroalkoxy, in particular C1-C2-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 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, l-(fluoromethyl)fluoroethoxy, specifically fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, or 2,2,2- trifluoroethoxy.
Hydroxyalkyl: an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is ed by an OH radical. Examples thereof are CHz-OH, l- hydroxyethyl, 2-hydroxyethyl, l-hydroxypropyl, 2-hydroxypropyl, l-methyl- l - WO 68489 hydroxyethyl, l-methylhydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 3- ybutyl, 4-hydroxybutyl, l-methylhydroxypropyl, l,l-dimethylhydroxyetyl, 1 -methylhydroxypropyl etc.
Alkylsulfanyl: alkyl as defined above preferably having 1 to 4 C atoms, which is 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 rily having 1 to 4 C atoms. es thereof are CHz-OCHg, CH2-OC2H5, n-propoxymethyl, CH2-OCH(CH3)2, n-butoxymethyl, (l-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH2-OC(CH3)3, 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(l-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(l-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl, 2-(l,l-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n- propoxy)propyl, 2-(l-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(l- methylpropoxy)propyl, 2-(2-methylpropoxy)propyl, 2-(l,l-dimethylethoxy)propyl, 3- (methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl, 3-(l-methylethoxy)propyl, 3- (n-butoxy)propyl, 3-(l-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl, 3-(l,ldimethylethoxy )propyl, 2-(methoxy)butyl, oxy)butyl, 2-(n-propoxy)butyl, 2-(lmethylethoxy )butyl, 2-(n-butoxy)butyl, 2-(l-methylpropoxy)butyl, 2-(2- methylpropoxy)butyl, 2-(l,l-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl, ropoxy)butyl, 3-(l-methylethoxy)butyl, utoxy)butyl, 3-(lmethylpropoxy )butyl, 3-(2-methylpropoxy)butyl, 3-(l,l-dimethylethoxy)butyl, 4- (methoxy)butyl, 4-(ethoxy)butyl, 4-(n-propoxy)butyl, 4-(l-methylethoxy)butyl, 4-(nbutoxy )butyl, 4-(l-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl, 4-(l,l- 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 der of the molecule via an O atom: Examples thereof are OCHz-OCHg, OCHz-OCsz, n- propoxymethoxy, CH(CH3)2, n-butoxymethoxy, (l-methylpropoxy)methoxy, (2-methylpropoxy)methoxy, OCHg-OC(CH3)3, 2-(methoxy)ethoxy, 2-(ethoxy)ethoxy, 2-(n-propoxy)ethoxy, 2-(l-methylethoxy)ethoxy, 2-(n-butoxy)ethoxy, ethylpropoxy)ethoxy, ethylpropoxy)ethoxy, 2-(l , l -dimethylethoxy )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 ordinarily having 3 to 6 C atoms as defined above. Examples thereof are ropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, cyclobutylethoxy, cyclopentylethoxy, cyclohexylethoxy and the like.
"Alkylen" or "alkanediyl": a saturated hydrocarbon chain haVing ordinarily from 1 to 4 carbon atoms, such as methylen (-CH2-), l,2-ethylen (-CH2CH2-), l,l-ethanediyl (-CH(CH3)-), l,2-propanediyl, l,3-propanediyl, tanediyl, l,2-butanediyl, l,3- butanediyl, 1 -methyl- 1 ,2-propanediyl, 2-methyl- l ,3 -propanediyl, 1 l- 1 l - ethanediyl, 1 -methyl- 1 ,2-propanediyl etc.
Saturated or partially unsaturated 5- to 7-membered monocarbocyclic radicals e cycloalkyl as defined above and cycloalkenyl haVing ordinarily from 4 to 7 carbon atoms as ring members, e.g. l-cyclobuten—l-yl, 2-cyclobutenyl, l-cyclopentenyl, 2-cyclopentenyl, ohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, l-cycloheptenyl, 2- cycloheptenyl, 3-cycloheptenyl.
Heterocyclyl: a heterocyclic radical which may be saturated or partly unsaturated 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 l, 2, 3 or 4, in particular 1, 2 or 3, of the ring atoms are heteroatoms such as N, S or O, or heteroatom groups such as S(=O) or S(=O)2 besides carbon atoms as ring members. es of saturated monocycles are in particular: - Saturated heteromonocyclic radical which ordinarily has 3, 4, 5, 6 or 7 ring atoms, where ordinarily l, 2 or 3 of the ring atoms are heteroatoms such as N, S or O, besides carbon atoms as ring members. These e for example: C-bonded, 3- or 4-membered saturated rings such as 2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl, l-azetidinyl, 2-azetidinyl.
C-bonded, nbered saturated rings such as tetrahydrofilran-Z-yl, tetrahydrofiJrany1, tetrahydrothien—Z-yl, tetrahydrothien—3-y1, tetrahydropyrr01y1, tetrahydropyrr01yl, tetrahydropyraz01y1, tetrahydropyraz01y1, tetrahydroisoxaz01yl, tetrahydroisoxaz01yl, tetrahydroisoxazol—S-yl, 1,2-oxathi01anyl, 1,2- oxathiolanyl, 1,2-oxathi01anyl, tetrahydroisothiazo1y1, ydroisothiazo1y1, tetrahydroisothiazo1y1, thiolan—3-y1, 1,2- dithiolan—4-y1, tetrahydroirnidazo , tetrahydroirnidazol—4-yl, tetrahydrooxazo 1y1, tetrahydrooxaz01y1, tetrahydrooxazol—S-yl, tetrahydrothiazol—Z-yl, tetrahydrothiaz01y1, tetrahydrothiazo 1y1, 1,3- an—Z-yl, 1,3-di0x01an—4-y1, 1,3-oxathi01anyl, 1,3-oxathi01anyl, 1,3-oxathi01anyl, 1,3-dithiolan—2-y1, 1,3-dithiolan—4-y1, 1,3,2- hio 1any1.
C-bonded, 6-mernbered saturated rings such as: tetrahydropyran—Z-yl, tetrahydropyran—3-y1, tetrahydropyran—4-yl, piperidin- 2-y1, piperidiny1, piperidin—4-yl, tetrahydrothiopyran—Z-y1, tetrahydrothiopyran—3-y1, tetrahydrothiopyran—4-yl, 1,3-di0xan—2-y1, 1,3- dioxan—4-y1, 1,3-di0xan—5-y1, 1,4-di0xan—2-y1, 1,3-dithian—2-yl, 1,3-dithian— 4-y1, 1,3-dithian—5-y1, 1,4-dithian—2-y1, 1,3-oxathiany1, 1,3-oxathiany1, 1,3-oxathiany1, 1,3-oxathiany1, 1,4-oxathianyl, 1,4-oxathiany1, 1,2-dithian—3-y1, 1,2-dithian—4-yl, hexahydropyrirnidin—Z-yl, hexahydropyrirnidiny1, hexahydropyrirnidin—S-yl, hexahydropyrazin—Z-yl, hexahydropyridazin—3-yl, hexahydropyridazin—4-yl, tetrahydr0-1,3-oxazin- 2-y1, tetrahydro- 1 ,3 -oxazinyl, tetrahydro- 1 ,3-oxazin-5 -y1, tetrahydro- 1 ,3 - oxazin—6-yl, tetrahydro- 1 ,3-thiazin—2-y1, tetrahydro- 1 azinyl, tetrahydro- 1 ,3-thiazin-5 -y1, tetrahydro- 1 ,3 -thiazin—6-yl, tetrahydro- 1 ,4- thiazin-Z-yl, tetrahydro- 1 ,4-thiazin—3-y1, tetrahydro- 1 ,4-oxazinyl, tetrahydro- 1 ,4-oxazin-3 -y1, tetrahydro- 1 ,2-oxazin-3 -y1, tetrahydro- 1 ,2- oxazinyl, ydro- 1 ,2-oxaziny1, ydro- 1 ,2-oxazinyl.
N—bonded, 5-mernbered saturated rings such as: tetrahydropyrrol- l -yl, tetrahydropyrazo l- l -yl, tetrahydroisoxazo lyl, ydroisothiazo lyl, ydroimidazol- l -yl, tetrahydrooxazol—3 -yl, tetrahydrothiazolyl.
N—bonded, 6-membered saturated rings such as: piperidin— l -yl, hexahydropyrimidin- l -yl, hexahydropyrazin- l -yl, hexahydro-pyridazin- l -yl, tetrahydro- l ,3 n-3 -yl, tetrahydro- l ,3 - thiazinyl, tetrahydro- l ,4-thiazinyl, tetrahydro- l ,4-oxazinyl, tetrahydro- l zin—2-yl.
- Unsaturated heteromonocyclic radicals which ordinarily have 4, 5, 6 or 7 ring atoms, Where ordinarily l, 2 or 3 of the ring atoms are heteroatoms such as N, S or O, s carbon atoms as ring members. These include for example: C-bonded, 5-membered, partially unsaturated rings such as: 2,3-dihydrofiJranyl, 2,3-dihydrofuran—3-yl, 2,5-dihydrofi1ran—2-yl, 2,5-dihydrofuran—3-yl, 4,5-dihydrofi1ran—2-yl, 4,5-dihydrofiJranyl, 2,3- dihydrothienyl, hydrothienyl, 2,5-dihydrothien—2—yl, 2,5- othienyl, 4,5-dihydrothienyl, 4,5-dihydrothienyl, 2,3- dihydro- l H-pyrrolyl, 2,3-dihydro- l H-pyrrolyl, 2,5-dihydro- l H- pyrrolyl, 2,5-dihydro-lH-pyrrol—3-yl, 4,5-dihydro-lH-pyrrol—2-yl, 4,5- dihydro-lH-pyrrolyl, 3,4-dihydro-2H-pyrrol—2-yl, 3,4-dihydro-2H- pyrrolyl, 3,4-dihydro-5H-pyrrol—2-yl, hydro-5H-pyrrol—3-yl, 4,5- dihydro- l H-pyrazo l-3 -yl, 4,5 -dihydro- l H-pyrazo lyl, 4,5 -dihydro- l H- pyrazol—S-yl, 2,5-dihydro-lH-pyrazol—3-yl, 2,5-dihydro-lH-pyrazol—4-yl, 2,5-dihydro-lH-pyrazol—S-yl, 4,5-dihydroisoxazolyl, 4,5- dihydroisoxazol—4-yl, 4,5-dihydroisoxazol—5-yl, 2,5-dihydroisoxazolyl, 2,5-dihydroisoxazolyl, 2,5-dihydroisoxazol—5-yl, 2,3-dihydroisoxazol—3- yl, 2,3-dihydroisoxazolyl, 2,3-dihydroisoxazol—5-yl, 4,5- oisothiazolyl, hydroisothiazolyl, 4,5-dihydroisothiazol—5- yl, 2,5-dihydroisothiazol—3-yl, 2,5-dihydroisothiazolyl, 2,5- dihydroisothiazol-S-yl, 2,3-dihydroisothiazolyl, 2,3-dihydroisothiazol yl, 2,3-dihydroisothiazolyl, 4,5-dihydro-lH-imidazolyl, 4,5-dihydro- lH-imidazolyl, 4,5-dihydro-lH-imidazol-S-yl, 2,5-dihydro-lH-imidazol— 2-yl, 2,5-dihydr0-1H-irnidaz01—4-yl, 2,5-dihydr0-lH-imidazol-S-yl, 2,3- dihydro-1H-irnidaz01—2-yl, 2,3-dihydr0-1H-imidaz01—4-yl, 4,5- dihydrooxazol—Z-yl, 4,5-dihydr00xazol—4-yl, 4,5-dihydr00xazol—5-yl, 2,5- dihydrooxazol—Z-yl, hydr00xazol—4-yl, 2,5-dihydr00xazol—5-yl, 2,3- dihydrooxazol—Z-yl, 2,3-dihydr00xazol—4-yl, 2,3-dihydr00xazol—5-yl, 4,5- dihydrothiazol—2-yl, 4,5-dihydr0thiazol—4-yl, 4,5-dihydr0thiazol—5-yl, 2,5- dihydrothiazol—2-yl, 2,5-dihydr0thiazol—4-yl, 2,5-dihydr0thiazol—5-yl, 2,3- dihydrothiazol—2-yl, 2,3-dihydr0thiazol—4-yl, 2,3-dihydr0thiazol—5-yl, 1,3- dioxol—Z-yl, 1,3-dioxol—4-yl, 1,3-dithiol—2-yl, 1,3-dithiol—4-yl, 1,3-oxathiol- 2-yl, 1,3-0xathi01—4-yl, 1,3-oxathi01yl.
C-bonded, 6-mernbered, lly unsaturated rings such as: 2H-3,4-dihydr0pyran—6-y1, 2H-3,4-dihydr0pyran—5-yl, 2H-3,4- dihydropyran—4-yl, 2H-3 ,4-dihydr0pyran—3-yl, 2H-3 ,4-dihydr0pyran—2-yl, 2H-3 ,4-dihydrothiopyran—6-yl, 2H-3 ,4-dihydrothi0pyran—5 -y1, 2H-3 ,4- dihydrothiopyran—4-yl, 2H-3,4-dihydr0thi0pyran—3-yl, 2H-3,4- dihydrothiopyran—2-yl, 1 ,2,3 ,4-tetrahydropyridiny1, 1 ,2,3 ,4- tetrahydropyridin-S-yl, 1 ,2,3 ,4-tetrahydropyridiny1, 1 ,2,3 rahydropyridinyl , 1 ,2,3 rahydropyridiny1, 2H-5 ,6-dihydr0pyran—2- yl, 2H-5,6-dihydr0pyran—3-yl, 2H-5,6-dihydr0pyran—4-yl, 2H-5,6- dihydropyran—S-yl, 2H-5 ,6-dihydr0pyran—6-yl, 2H-5 ,6-dihydr0thiopyran—2- yl, 2H-5,6-dihydr0thi0pyran—3-yl, 2H-5,6-dihydr0thi0pyran—4-yl, 2H-5,6- dihydrothiopyran—S-yl, 2H-5 ,6-dihydr0thi0pyran—6-yl, 1 ,2,5 ,6- tetrahydropyridin-Z-yl, 1,2,5,6-tetrahydr0pyridiny1, 1,2,5,6- tetrahydropyridinyl, 6-tetrahydr0pyridiny1, 1,2,5,6-tetra- hydropyridinyl, 2,3,4,5-tetrahydropyridinyl, 2,3,4,5-tetrahydropyridin- 3-y1, 2,3,4,5-tetrahydr0pyridin—4-yl, 2,3,4,5-tetrahydropyridinyl, 2,3,4,5- tetrahydropyridinyl, 4H-pyran—2-yl, an—3-yl, 4H-pyran—4-yl, 4H- thiopyran—2-yl, 4H-thiopyran—3-y1, 4H-thiopyran—4-yl, 1,4-dihydropyridin—2- yl, 1,4-dihydropyridinyl, hydr0pyridinyl, an—2-yl, 2H- pyran—3-yl, 2H-pyran—4-yl, 2H-pyran—5-yl, 2H-pyran—6-yl, 2H-thi0pyran—2- yl, opyran—3-y1, 2H-thiopyran—4-yl, 2H-thiopyran—5-y1, 2H-thi0pyran— 6-y1, 1,2-dihydropyridin—2-yl, 1,2-dihydropyridinyl, 1,2-dihydr0pyridin— 4-y1, 1,2-dihydropyridin—5-yl, 1,2-dihydropyridinyl, 3,4-dihydropyridin— 2-y1, 3,4-dihydr0pyridin—3-yl, 3,4-dihydr0pyridiny1, 3,4-dihydropyridin— -y1, 3,4-dihydr0pyridin—6-yl, 2,5-dihydr0pyridinyl, 2,5-dihydropyridin— 3-y1, 2,5-dihydr0pyridin—4-yl, 2,5-dihydr0pyridinyl, 2,5-dihydropyridin— 6-y1, 2,3-dihydr0pyridin—2-yl, 2,3-dihydr0pyridinyl, 2,3-dihydropyridin— 4-y1, 2,3-dihydr0pyridin—5-yl, 2,3-dihydr0pyridinyl, 2H-5,6-dihydro-1,2- oxazin—3-yl, 2H-5,6-dihydr0-1 ,2-oxaziny1, -dihydr0-1,2-oxazin yl, 2H-5,6-dihydr0-1,2-oxazinyl, 2H-5,6-dihydr0-1,2-thiaziny1, -dihydro-1,2-thiazinyl, 2H-5,6-dihydro-1,2-thiazinyl, 2H-5,6- dihydro- 1 ,2-thiazinyl, 4H-5 ,6-dihydro-1 ,2-oxaziny1, 4H-5 ,6-dihydr0- 1 ,2-oxaziny1, 4H-5 ,6-dihydro-1 ,2-oxaziny1, 4H-5 ,6-dihydr0-1,2- oxazinyl, -dihydro-1,2-thiazin—3-yl, 4H-5,6-dihydro-1,2-thiazin—4- yl, 4H-5,6-dihydr0-1,2-thiaziny1, 4H-5,6-dihydr0-1,2-thiaziny1, 2H- 3,6-dihydr0-1,2-oxaziny1, 2H-3,6-dihydr0-1,2-oxazinyl, 2H-3,6- dihydro- 1 ,2-oxazinyl, 2H-3 ,6-dihydr0-1,2-oxazinyl, 2H-3 ,6-dihydr0- 1,2-thiaziny1, 2H-3,6-dihydro-1,2-thiazin—4-yl, -dihydr0-1,2- thiazin-S-yl, -dihydro-1,2-thiazin—6-yl, 2H-3,4-dihydr0-1,2-oxazin yl, 2H-3,4-dihydr0-1,2-oxazinyl, 2H-3,4-dihydr0-1,2-oxazinyl, 2H- 3,4-dihydr0-1,2-oxaziny1, 2H-3,4-dihydr0-1,2-thiaziny1, - dihydro- 1 ,2-thiazinyl, 2H-3,4-dihydro-1,2-thiaziny1, 2H-3,4-dihydr0- 1 ,2-thiazinyl, 2,3 etrahydr0pyridazin—3-y1, 2,3 ,4,5- tetrahydropyridazinyl, 5-tetrahydropyridazin—5-y1, 2,3,4,5- tetrahydropyridaziny1, 3 ,4,5 ,6-tetrahydropyridazin—3 -y1, 3 ,4,5 ,6- tetrahydropyridaziny1, 1 ,2,5 ,6-tetrahydropyridazin—3-y1, 1 ,2,5 ,6- tetrahydropyridaziny1, 1 ,2,5 ,6-tetrahydropyridazin—5-y1, 1 ,2,5 ,6- tetrahydropyridaziny1, 1 ,2,3 ,6-tetrahydropyridazin—3-y1, 1 ,2,3 ,6- tetrahydropyridaziny1, -dihydr0-1,3-oxazinyl, 4H-5,6-dihydr0- 1 ,3-oxaziny1, 4H-5 ,6-dihydro-1 ,3-oxaziny1, 4H-5 ,6-dihydr0-1,3- oxazin—6-yl, 4H-5,6-dihydro-1,3-thiazin—2-yl, 4H-5,6-dihydro-1,3-thiazin—4- yl, 4H-5,6-dihydr0-1,3-thiaziny1, 4H-5,6-dihydr0-1,3-thiaziny1, 3,4,5- 6-tetrahydr0pyrirnidiny1, 3 ,4,5 ,6-tetrahydropyrirnidin—4-y1, 3 ,4,5 ,6-tetra— hydropyrimidin—S -y1, 3 ,4,5 ,6-tetrahydropyrirnidin—6-y1, 1 ,2,3 ,4- tetrahydropyrazinyl, l ,2,3 ,4-tetrahydropyrazin-5 -yl, l ,2,3 ,4- ydropyrirnidin—2-yl, l ,2,3 ,4-tetrahydr0pyrirnidinyl, l ,2,3 ,4- tetrahydropyrirnidin—5 -yl, l ,2,3 ,4-tetrahydr0pyrirnidinyl, 2,3 -dihydr0- l ,4- thiazinyl, 2,3-dihydr0- l ,4-thiazin—3-yl, hydr0- l ,4-thiazin—5-yl, 2,3- dihydro- l ,4-thiazinyl, 2H- 1 ,3-oxazinyl, 2H- 1 ,3-oxazinyl, 2H- 1 ,3- oxazin—5 -yl, 2H- 1 ,3 -oxazinyl, 2H- 1 ,3 -thiazin—2-yl, 2H- 1 ,3 -thiazin—4-yl, 2H- 1 ,3 -thiazin-5 -yl, 2H- 1 ,3 inyl, 4H- 1 ,3 -oxazinyl, 4H- 1 ,3 - —4-yl, 4H- 1 ,3 -oxazin-5 -yl, 4H- 1 ,3 -0xazin—6-yl, 4H- 1 ,3 -thiazin—2-yl, 4H- 1 ,3 -thiazinyl, 4H- 1 ,3 -thiazin-5 -yl, 4H- 1 ,3 -thiazinyl, 6H- 1 ,3 - lO oxazin—2-yl, 6H- 1 ,3 -oxazinyl, 6H- 1 ,3 n-5 -yl, 6H- 1 ,3 -0xazin—6-yl, 6H- 1 ,3 -thiazinyl, 6H- 1 ,3 -oxazinyl, 6H- 1 ,3 n-5 -yl, 6H- 1 ,3 - thiazinyl, 2H- 1 ,4-oxazinyl, 2H- 1 ,4-oxazinyl, 2H- 1 ,4-oxazinyl, 2H- 1 ,4-oxazinyl, 2H- 1 ,4-thiazinyl, 2H- 1 ,4-thiazinyl, 2H- 1 ,4- thiazinyl, 2H- 1 ,4-thiazinyl, 4H- 1 ,4-oxazinyl, 4H- 1 ,4-oxazinyl, l5 4H- 1 ,4-thiazinyl, 4H- 1 ,4-thiazin-3 -yl, l,4-dihydr0pyridazin—3 -yl, 1,4- dihydropyridazinyl, l ,4-dihydr0pyridazin-5 -yl, l ,4-dihydr0pyridazin—6- yl, l ,4-dihydr0pyrazin—2-yl, l ,2-dihydr0pyrazinyl, l ,2-dihydropyrazin—3 - yl, l ,2-dihydropyrazin—5 -yl, l ,2-dihydr0pyrazinyl, l ,4-dihydr0pyrirnidin— 2-yl, l ,4-dihydr0pyrirnidin—4-yl, l ,4-dihydr0pyrirnidin—5 -yl, l ,4- dihydropyrirnidin—6-yl, 3,4-dihydropyrirnidin—2-yl, 3,4-dihydropyrirnidin yl, 3 ,4-dihydropyrirnidin—5 -yl or 3 ,4-dihydr0pyrirnidin—6-yl.
N—bonded, bered, partially unsaturated rings such as: 2,3 -dihydr0- l H-pyrrol— l -yl, 2,5 -dihydr0- l H-pyrrol- l -yl, 4,5 -dihydr0- l H- pyrazo l- l -yl, 2,5 -dihydr0- l H-pyrazo l- l -yl, 2,3 r0- l H-pyrazo l- l -yl, 2,5 -dihydr0isoxazo lyl, 2,3 -dihydr0isoxazo lyl, 2,5 r0isothiazo l yl, 2,3 -dihydr0is0xazo , 4,5 -dihydr0- l H-irnidazol— l -yl, 2,5 -dihydr0- lH-irnidazo l- l -yl, 2,3 -dihydro- l H-irnidazo l- l -yl, 2,3 -dihydr00xazol-3 -yl, 2,3 -dihydr0thiazo l-3 -yl.
N—bonded, 6-rnernbered, partially unsaturated rings such as: 3 0 l ,2,3 ,4-tetrahydr0pyridin- l -yl, l ,2,5 ,6-tetrahydr0pyridin— l -yl, l ,4- dihydropyridin- l -yl, l ,2-dihydr0pyridin- l -yl, 2H-5 ,6-dihydr0- l zin yl, 2H-5 ,6-dihydr0- l ,2-thiazinyl, 2H-3 ,6-dihydr0- l ,2-oxazinyl, 2H- 3,6-dihydro- l ,2-thiazinyl, 2H-3,4-dihydro- l ,2-oxazinyl, 2H-3,4- dihydro-l,2-thiazinyl, 2,3,4,5-tetrahydropyridazinyl, l,2,5,6- tetrahydropyridazin-l-yl, l,2,5,6-tetrahydropyridazinyl, l,2,3,6- tetrahydropyridazin- l -yl, 3,4,5,6-tetrahydropyrimidinyl, l,2,3,4- tetrahydropyrazin- l -yl, l ,2,3 ,4-tetrahydropyrimidin- l -yl, l ,2,3 rahydro- pyrimidinyl, 2,3-dihydro- l ,4-thiazinyl, 2H- 1 ,2-oxazin—2-yl, 2H- 1 ,2- thiazinyl, 4H-l,4-oxazinyl, 4H-l,4-thiazinyl, l,4-dihydropyridazin- l-yl, l ,4-dihydropyrazin- l -yl, l ydropyrazin- l -yl, l ,4- dihydropyrimidin- l -yl or 3 ydropyrimidin-3 -yl.
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 s carbon atoms as ring members ordinarily l, 2 or 3, in ular 1 or 2, of the ring atoms are heteroatoms such as N, S or O, in particular 5- to 7-membered heterocycloyloxy, where heterocyclyl has 1 or 2 heteroatoms ed from O, S and N as ring members, for example tetrahydrofuran—2- yloxy, tetrahydrofuranyloxy, tetrahydrothiophenyloxy or tetrahydrothiophen yloxy.
Heterocyclyl-C1-C4-alkoxy: a C1-C4-alkoxy group as defined above in which one hydrogen atom is replaced by a heterocyclyl radical as defined above. The heterocyclyl radical ordinarily has 3, 4, 5, 6 or 7 ring atoms, in which besides carbon atoms as ring s ordinarily l, 2 or 3, in particular 1 or 2, of the ring atoms are heteroatoms such as N, S or O. In particular, 5- to 7-membered heterocyclyl-C1-C2-alkoxy, where heterocyclyl has 1 or 2 heteroatoms selected from O, S and N as ring members, for example tetrahydrofilranyl-methoxy, tetrahydrofuranyl-ethoxy, tetrahydrofuran ylmethoxy, tetrahydrofuranylethoxy, tetrahydrothiophenylmethoxy, tetrahydrothiophenylethoxy, tetrahydrothiophenylmethoxy, tetrahydrothiophen ylethoxy.
Hetaryl: a 5- or 6-membered aromatic heteromonocyclic radical (also termed 5- or 6-membered clic hetaryl) which ordinarily has 1, 2, 3 or 4 heteroatoms as ring members, which are selected from O, S and N, and which has in particular 1, 2, 3 or 4 en atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1 or 2 nitrogen atoms as ring s s carbon atoms as ring members and a 8-, 9- or lO-membered aromatic heterobicyclic radical (also termed 8-, 9- or lO-membered bicyclic hetaryl) which ordinarily has 1, 2, 3 or 4 atoms as ring s, which are ed from O, 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: 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-fi1ryl, 3-fi1ryl, 2-thienyl, 3-thienyl, pyrrolyl, pyrrolyl, lyl, lO pyrazolyl, isoxazol—3-yl, isoxazol—4-yl, isoxazol-S-yl, isothiazol—3-yl, isothiazolyl, isothiazol-S-yl, imidazolyl, imidazolyl, oxazol—2-yl, oxazol- 4-yl, oxazol—S-yl, thiazolyl, thiazolyl, thiazol-S-yl, l,2,3-oxadiazolyl, l,2,3-oxadiazolyl, oxadiazolyl, l,2,4,-oxadiazolyl, l,3,4-oxadiazol- 2-yl, l,2,3-thiadiazolyl, l,2,3-thiadiazolyl, l,2,4-thiadiazolyl, 1,2,4- thiadiazol-S-yl, l,3,4-thiadiazolylyl, l,2,3-triazolyl, l,2,4-triazolyl, tetrazol-S-yl.
C-bonded, 6-membered monocyclic hetaryl having 1, 2 or 3 nitrogen atoms as ring members, such as: pyridinyl, pyridinyl, nyl, pyridazinyl, pyridazinyl, pyrimidin- 2-yl, pyrimidinyl, pyrimidinyl, pyrazinyl, l,3,5-triazinyl, l,2,4-triazin- 3-yl, l,2,4-triazinyl, l,2,4-triazinyl, l,2,4,5-tetrazinyl.
N—bonded, 5-membered heteroaromatic radicals having 1, 2, 3 or 4 nitrogen atoms as ring members, such as: pyrrol- l -yl, pyrazol- l -yl, imidazol— l -yl, l,2,3-triazol- l -yl, l,2,4-triazol- l -yl, tetrazol- l -yl. bicyclic 8-, 9- bered hetaryl, l which has one of the aforementioned - or 6-membered aromatic rings and a further aromatic carbocycle or 5- or 6-membered heterocycle fused thereto, for example a fused benzene, thiophene, , pyrrole, pyrazole, imidazole, pyridine or dine ring. These bicyclic hetaryl include for example inyl, nolinyl, cinnolinyl, indolyl, indolizynyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, imidazo[l,2-a]pyridineyl, thieno[3 ,2-b]pyridineyl, imidazo-[2, l -b]—thiazolyl and l ,2,4-triazo lo [ l ,5- a]pyridineyl.
Hetarylalkyl: a hetaryl radical as defined above which is linked Via an alkylene group, in particular Via a methylene, l,l-ethylene or l,2-ethylene group, to the remainder of the molecule. - to 6-membered hetaryl—Cl-C4-alkoxy: a C1-C4-alkoxy group as defined above which carries a 5-to 6-membered hetaryl l as defined above, where the hetaryl radical has ordinarily l, 2 or 3, in particular 1 or 2, heteroatoms as ring members which are selected from O, S and N. Examples are furanylmethoxy, furanylmethoxy, 2-ylethoxy, furanylethoxy, thiophenylmethoxy, thiophenylmethoxy, thiophenylethoxy and thiophenylethoxy.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, C1-C4-alkyl, haloalkyl, OH, SH, CN, CF3, O-CFg, COOH, O-CHz-COOH, alkoxy, C1- C4-haloalkoxy, C1-C6-alkylthio, C3-C7-cycloalkyl, COO-Cl-C6-alkyl, CONHZ, CONHC1-C6-alkyl , SOZNH-Cl-C6-alkyl, l-C6-alkyl)2, SOzN-(Cl-C6-alkyl)2, NH-SOZ- C1-C6-alkyl, NH-CO-Cl-C6-alkyl, SOz-Cl-C6-alkyl, O-phenyl, O-CHg-phenyl, CONH- phenyl, SOZNH-phenyl, CONH-hetaryl, SOZNH-hetaryl, SOg-phenyl, NH-SOz-phenyl, NH-CO-phenyl, NH-SOz-hetaryl and NH-CO-hetaryl, where phenyl and hetaryl in the last 11 radicals mentioned are unsubstituted or may have 1, 2 or 3 tuents which are selected from halogen, C1-C4-alkyl, haloalkyl, C1-C4-alkoxy and C1-C4- haloalkoxy.
In particular embodiments of the ion, Rh is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fiuorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, N(Rb)(R°), C1-C4-alkyl-N(Rb)(R°), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and (Re)(Rf).
In relation to their use as inhibitors of PDElOA, the variables X1, X2, Y, R1, R2, R3 and R4 in formula I preferably have the following meanings, where these represent, both considered on their own and in combination with at least one other or all, l embodiments ofthe compounds of the formula I: R1 is preferably C2-Cg-alkyl, Cg-Cg-cycloalkyl or C3-Cg-cycloalkylmethyl, in particular C3-Cg-cycloalkylmethyl or especially C2-Cg-alkyl. Particularly, R1 is alkyl of the formula CHRlaRlb, where R181 is selected from the group consisting of hydrogen and C1-C3-alkyl, in particular methyl, ethyl, n-propyl and where R1b is selected from the group consisting of C1-C4-alkyl, in particular methyl, ethyl, n-propyl or l.
Particular examples of R1 are selected from the group consisting of ethyl, isopropyl, l- methylpropyl and l-ethylpropyl.
Particular embodiments of the invention also relate to compounds, where R1 is a moiety Zl-Arl, where Z1 and Ar1 are as defined above and where Z1 is ably l,2- ethanediyl or l,3-propanediyl, wherein l, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z1 is l,2-ethanediyl which is unsubstituted or l,3-propanediyl which is unsubstituted. In these embodiments, Ar1 is ably monocyclic 6-membered hetaryl or bicyclic 9- or bered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where mono- and bicyclic l are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh.
Ar1 is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring s, and C-bound, filsed bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a fiarther heteroatom selected from O, S and N as ring member, where monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in ular 0, l or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C4-alkyl, fluoroalkyl, alkoxy, C1-C2-fluoralkoxy, C3-C6- cycloalkyl, and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, y, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
Ar1 is in particular selected from the group consisting of filsed bicyclic hetaryl, which has 1 or 2 en atoms as ring members and optionally a further heteroatom ed from O, S and N as ring member and which may be unsubstituted or may carry 1, 2 or 3 tuents Rh, in particular 0, l or 2 substituents Rh as defined above.
Amongst these, particular preference is given to those compounds, where the Ar1 l has at least one imino-nitrogen as ring member, which is located in the position nt to carbon atom bound to the group Z1. Amongst these, particular preference is given to those, where Ar1 is ed 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 ed from O, 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 , Rh is preferably selected from n, C1-C4-alkyl, C1- Cz-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoralkoxy, C3-C6-cycloalkyl and fluorinated C3- C6-cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
Particular examples of Ar1 are selected from the group consisting of 2-benzofilryl, 2-pyridyl, 2-pyrimidinyl, midinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3- isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, l,5-naphthyridinyl, l,8-naphthyridin- 2-yl, benzothiazo l- l -yl, benzoxazo l- l -yl, benzimidazolyl, l-methylbenzimidazo l yl, imidazo[l ,2-a]pyridineyl, thieno[3 ,2-b]pyridineyl, imidazo-[2, l -b]-thiazolyl and l,2,4-triazolo[l,5-a]pyridineyl, where the entioned 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, ne, , ethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
In particular embodiments, R2 is a radical of the formula CRZIRZZRB, where R21, R22 and R23 are as defined above and where R21 is in particular different from hydrogen.
In other particular embodiments, R2 is a phenyl or 5- or 6-membered l radical having 1, 2 or 3 heteroatoms as ring members which are selected from O, 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 R2 is a l of the formula CRZIRZZRB, where R21, R22 and R23 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 members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents R81 as defined above, the radical R3 is preferably selected from the group consisting of hydrogen and alkyl. In these embodiments, R3 is in particular hydrogen.
In the particular embodiments, where R2 is a radical of the formula CRZIRZZRB, a particular group of embodiments relates to compounds, where the radicals R21, R22 and R23 have the ing meanings: R21 is selected from the group consisting of C1-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, C1-C4-fluoroalkyl, C3-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy- C1-C4-alkyl, hydroxy-Cl-C4-alkyl, C1-C4-alkyl-N(Rb)(R°), (CH2)mC(O)O-Rd, (CH2)mC(O)N(Re)(Rf) and 224%, R22 is selected from the group ting of hydrogen, fluorine, alkyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, Cg-Cg-cycloalkyl, ated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy- C1-C4-alkyl, y-Cl-C4-alkyl and C1-C4-alkyl-N(Rb)(R°), or R23 is selected from the group consisting of en, fluorine, C1-Cg-alkyl and C1- C4-fluoroalkyl; In the particular embodiments, where R2 is a radical of the formula CRZIRZZRB, a particular group of embodiments relates to compounds, where the radicals R21, R22 and R23 preferably have the ing meanings, both considered on their own and in combination with at least one other or all: R21 is selected from the group consisting of C2-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, C1-C4-fluoroalkyl, C3-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- lkyl-Cl-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl and ZZ-Arz, where Z2 and Arz, where Z2 and Ar2 are as defined above and where Z2 is ably a single bond or CH2 and Ar2 is preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or different substituents Rh; R22 is selected from the group consisting of hydrogen, fluorine, C1-Cg-alkyl, in particular hydrogen; and R23 is hydrogen or C1-C4-alkyl, such as , or especially hydrogen.
In the particular embodiments, where R2 is a radical of the formula CRZIRZZRB, a particular group of embodiments relates to compounds, where the radicals R21, R22 and R23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R21 is selected from the group consisting of C2-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, C1-C4-fluoroalkyl, C3-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl, and where R21 is in particular C2-C4-alkyl; R22 is selected from the group consisting of hydrogen, fluorine, C1-Cg-alkyl, in particular methyl or hydrogen; and R23 is hydrogen or C1-C4-alkyl, such as , or especially hydrogen.
In the particular ments, where R2 is a radical of the a CRZIRZZRB, another particular group of embodiments relates to compounds, where the ls R21, R22 and R23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R21 is a l ZZ-Arz, where Z2 and Ar2 are as defined above and where Z2 is preferably a single bond or CH2 and Ar2 is preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or ent substituents Rh, particular examples of R21 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, thiazolyl, thiazolyl, l,3,4-thiadiazolyl, 2-(l-morpholinosulfonyl)phenyl, 3 -( l -morpholino sulfonyl)phenyl, 2-(4-methylpiperazin— l -ylsulfonyl)phenyl or 3- (4-methylpiperazin- l -ylsulfonyl)phenyl.
R22 is ed from the group ting of hydrogen, fluorine, C1-Cg-alkyl, in particular methyl or hydrogen; and R23 is hydrogen or C1-C4-alkyl, such as methyl, or especially hydrogen.
In the particular embodiments, where R2 is a radical of the formula ZRB, a r group of embodiments relates to compounds, where the radicals R21 and R22 er 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 cyclopentyl, or a saturated 5-, 6- or ered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and $02 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 l, 2 or 3 identical or different substituents Rg, and where the yclic ring and the heterocyclic ring may carry a fiased 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 Rg, Rh and R23 are as defined above and where R23 is in particular hydrogen or C1-C4-alkyl, such as methyl, or especially hydrogen.
In the particular embodiments, where R2 is a radical of the formula CRZIRZZRB, a further particular group of embodiments relates to compounds, where the radicals R21, R22 and R23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R21 and R22 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 ahydrofuryl or 3-tetrahydrothienyl, where the 5- to 7-membered carbocyclic ring and the 3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a filSGd 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 tituted or carry 1, 2 or 3 substituents Rh, and where R21 and R22 in particular form a bicyclic radical selected from the group consisting of 5-indanyl, 6-indanyl, 5,6,7,8-tetrahydronaphthalinyl, 5,6,7,8-tetrahydronaphthalinyl, 6,7,8,9-tetrahydro-5H-benzocyclohepteneyl, 6,7,8,9-tetrahydro-5H- benzocyclohepteneyl, 5,6-dihydro-4H-cyclopenta[b]thiopheneyl, 6,7- dihydro-SH- [ l ]-pyrindinyl, 3 ,4-dihydrobenzo filran-3 -yl, 2,3 - dihydrobenzothiophenyl or where these bicyclic radicals are in particular unsubstituted or where the aromatic moiety ofthese rings carry 1, 2 or 3 tuents Rh; R23 is hydrogen or alkyl, such as methyl, or especially hydrogen.
In further particular ments of the invention R2 and R3 together with the nitrogen atom, to which they are bound form a saturated 4-, 5-, 6- or ered heterocyclic ring which, in addition to the en atom, may have 1 or 2 fiarther heteroatoms or heteroatom containing groups ed from the group of O, N, S, SO and $02 as ring members, e. g. a pyrrolidine, piperidine, line, thiomorpholine or zine ring, where the heterocyclic ring may be unsubstituted or may be substituted by l, 2 or 3 cal or different substituents R31, and where the heterocyclic ring may carry a filSGd 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 R31 and R32 are as defined defined above.
R31 is in particular selected from the group consisting of C1-C4-alkyl, C1-C4- , n, 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 alkyl, C1-C4-alkoxy, halogen.
R32 is in particular selected from the group consisting of C1-C4-alkyl, C1-C4- alkoxy and halogen.
R4 is preferably C1-C4-alkyl and especially methyl.
Y is preferably 0.
A particular group of embodiments of the invention s to nds 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 X2 is C-R5 . In this particular group of embodiments R5 is ably selected from the group ting of hydrogen, fluorine, C1-C4-alkoxy or a radical O-ZS-Ars, especially hydrogen, fluorine, methoxy or a radical O-ZS-Ar5 . Amongst these compounds a first embodiment relates to compounds ofthe formula I, to their salts, ers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R5 is hydrogen, fluorine, OH or C1-C4-alkoxy, ally hydrogen, fluorine, OH or methoxy, with methoxy being particularly preferred.
Amongst these compounds a second embodiment relates to compounds of the formula I, to their salts, ers, es and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R5 is a radical O-ZS-Ars. In this second embodiment R4 is in particular C1-C4-alkyl, especially methyl.
In the second embodiment, Z5 is preferably l,2-ethanediyl or l,3-propanediyl, wherein l, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z5 is l,2-ethanediyl which is unsubstituted or l,3-propanediyl which is unsubstituted.
In the second embodiment, Ar5 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 en atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where clic hetaryl may be unsubstituted or may carry 1, 2 or 3 identical or different substituents Rk, in particular 0, l or 2 substituents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent Rk, and 0, l, 2 or 3 tuents Rh, in particular 0, l or 2 tuents Rh. In this , Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, fluoralkoxy, C3-C6- cycloalkyl, and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, omethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and ated cyclopropyl.
Ar5 is in particular selected from the group consisting of filsed bicyclic hetaryl, which has I or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, 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, l or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar5 radical has at least one imino-nitrogen as ring member, which is d in the position adjacent to carbon atom bound to the group Z5.
Amongst these, particular preference is given to those, where Ar5 is selected from the group consisting of C-bound, fused ic hetaryl, which has 1 or 2 en atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member, where ic hetaryl may be unsubstituted or may carry 1 substituent Rk and/or may carry 1, 2 or 3 substituents Rh, in particular 0, l or 2 tuents Rh. In this regard, Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4- , C1-C2-fluoralkoxy, C3-C6-cycloalkyl and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from e, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
Particular examples of Ar5 are selected from the group consisting of 2-benzofi1ryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3- nolinyl, 2-quinazolinyl, 2-quinoxalinyl, l,5-naphthyridinyl, l,8-naphthyridin- 2-yl, benzothiazo l- l -yl, benzoxazo l- l -yl, idazolyl, l-methylbenzimidazo l yl, imidazo[l ,2-a]pyridineyl, thieno[3 ,2-b]pyridineyl, o-[2, l -b]-thiazolyl and l,2,4-triazolo[l,5-a]pyridineyl, 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 ting of fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
Amongst these compounds a third embodiment relates to compounds of the formula I, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R4 is a radical Z4-Ar4. In this third embodiment R5 is in particular hydrogen, fluorine or C1-C4-alkoxy, especially methoxy.
In the third embodiment, Z4 is preferably l,2-ethanediyl or l,3-propanediyl, n l, 2, 3 or 4 en atoms may be replaced by a fluorine atom. According to a specific embodiment, Z4 is l,2-ethanediyl which is tituted or l,3-propanediyl which is unsubstituted.
In the third embodiment, Ar4 is preferably selected from the group consisting of C-bound 6-membered monocyclic l, which has 1 or 2 nitrogen atoms as ring s, and C-bound, fused bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring s and optionally a further heteroatom selected from O, 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, l or 2 substituents Rk and bicyclic hetaryl may be tituted or may carry 1 substituent Rk, and 0, l, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, alkoxy, C1-C2-fluoralkoxy, C3-C6- cycloalkyl, and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
Ar4 is in ular selected from the group consisting of filsed bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member and which may be unsubstituted or may carry l tuent Rk and/or may carry 1, 2 or 3 tuents Rh, in particular 0, l or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar4 radical has at least one nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z4.
Amongst these, particular preference is given to those, where Ar4 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 O, 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 Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is ably selected from n, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4- alkoxy, C1-C2-fluoralkoxy, C3-C6-cycloalkyl and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular ed from fluorine, chlorine, methyl, fluoromethyl, omethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
Particular examples of Ar4 are selected from the group consisting of 2-benzofi1ryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3- isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, l,5-naphthyridinyl, l,8-naphthyridin- 2-yl, benzothiazo l- l -yl, benzoxazo l- l -yl, benzimidazolyl, l-methylbenzimidazo l yl, imidazo[l ,2-a]pyridineyl, thieno[3 ,2-b]pyridineyl, imidazo-[2, l -b]-thiazolyl and l,2,4-triazolo[l,5-a]pyridineyl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 radicals Rh as defined above, which are in particular ed from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluorinated cyclopropyl.
A first group of embodiments of the invention relates to compounds of the formula I, to their salts, es, tautomers, es and gs and to the salts of said N—oxides, tautomers, hydrates and gs, where X1 is C-H and X2 is C-RS. In this first group, Y, R1, R2, R3, R4 and R5 are as defined above and preferably have the red or particular or special meanings given above. Amongst these compounds, a particular group of embodiments is represented by the following formula Ia R4—O ,R1 (l a ) / 0 w where R1, R2, R3, R4 and R5 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, es and prodrugs and to the salts of said N—oxides, tautomers, hydrates and prodrugs, where X1 is N and X2 is C-RS. In this second group, Y, R1, R2, R3, R4 and R5 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 a 1b R4—O N,R1 | ( lb ) 0 w where R1, R2, R3, R4 and R5 are as defined above.
A particular group of embodiments of the invention relates to compounds of the formulae Ia and 1b, to their salts, es, tautomers, hydrates and gs and to the salts of said N—oxides, tautomers, hydrates and prodrugs, where R5 is preferably selected from the group consisting of hydrogen, fluorine, C1-C4-alkoxy or a radical rs, especially hydrogen, fluorine, methoxy or a radical rs. Amongst these nds a first ment relates to compounds of the formulae Ia and 1b, to their salts, tautomers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R5 is hydrogen, fluorine, OH or C1-C4-alkoxy, especially hydrogen, fluorine, OH or methoxy, with methoxy being particularly preferred.
Amongst these compounds a second embodiment relates to compounds of the formula Ia and 1b, to their salts, ers, hydrates and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R5 is a radical O-ZS-Ars, where Z5 and Ar5 are as defined above and having in ular the preferred, particular or special meanings given above. In this second embodiment R4 is in particular C1-C4-alkyl, especially methyl.
In the second embodiment of formulae Ia and Ib, Z5 is preferably l,2-ethanediyl or l,3-propanediyl, wherein l, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z5 is l,2-ethanediyl which is unsubstituted or 1,3-propanediyl which is unsubstituted.
In the second embodiment of formulae Ia and Ib, Ar5 is preferably selected from the group consisting of C-bound 6-membered monocyclic hetaryl, which has 1 or 2 nitrogen atoms as ring s, and C-bound, fiJsed bicyclic hetaryl, which has I or 2 nitrogen atoms as ring members and optionally a fiarther heteroatom selected from O, 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, l or 2 substituents Rk and ic l may be unsubstituted or may carry 1 substituent Rk, and 0, l, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh. In this , Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2- fluoralkoxy, cycloalkyl, and ated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from e, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, romethoxy, cyclopropyl and fluorinated cyclopropyl.
In the second embodiment of ae Ia and Ib, Ar5 is in particular selected from the group consisting of fiJsed bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, S and N as ring member and which may be unsubstituted, or may carry 1 tuent Rk and/or may carry 1, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar5 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z5. t these, particular preference is given to those, where Ar5 is selected from the group consisting of C-bound, fused bicyclic hetaryl, which has I or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, 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 Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoralkoxy, C3-C6- cycloalkyl and fluorinated C3-C6-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 the second ment of formulae Ia and Ib, Ar5 is e. g. ed from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, oxalinyl, 1,5- naphthyridinyl, l ,8-naphthyridinyl, benzothiazol— l -yl, benzoxazo l- l -yl, benzimidazolyl, ylbenzimidazolyl, imidazo[ l ,2-a]pyridineyl, thieno[3 ,2- b]pyridineyl, imidazo-[2, l -b]—thiazolyl and l ,2,4-triazo lo [ l ,5-a]pyridineyl, where the aforementioned radicals are unsubstituted or may carry 1, 2 or 3 ls Rh as defined above, which are in ular 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 formula Ia and Ib, to their salts, tautomers, es and prodrugs and to the salts of said tautomers, hydrates and prodrugs, where R4 is a radical Z4-Ar4, where Z4 and Ar4 are as defined above and having in particular the preferred, particular or l gs given above. In this third embodiment R5 is in particular hydrogen, fluorine or in particular C1-C4-alkoxy, ally methoxy.
In the third embodiment of formulae Ia and Ib, Z4 is preferably l,2-ethanediyl or l,3-propanediyl, wherein l, 2, 3 or 4 hydrogen atoms may be replaced by a e atom. According to a ic embodiment, Z4 is l,2-ethanediyl which is unsubstituted or opanediyl which is unsubstituted.
In the third embodiment of formulae Ia and Ib, Ar4 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 l, which has 1 or 2 nitrogen atoms as ring members and optionally a further atom selected from O, S and N as ring member, where monocyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents Rk, in particular 0, l or 2 substituents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent Rk, and 0, 1,2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C4- alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoralkoxy, C3-C6-cycloalkyl, and fluorinated C3-C6-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 the third embodiment of formulae Ia and lb, Ar4 is in particular ed from the group consisting of fiJsed ic hetaryl, which has 1 or 2 nitrogen atoms as ring s and optionally a further atom selected from O, 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 tuents Rh, in particular 0, l or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar4 l has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z4. Amongst these, particular preference is given to those, where Ar4 is ed 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 O, S and N as ring member, where bicyclic hetaryl may be tituted, or may carry 1 substituent Rk and/or may carry 1, 2 or 3 tuents Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoralkoxy, C3-C6- cycloalkyl and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from fluorine, ne, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
In the third embodiment of formulae Ia and 1b, Ar4 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, azolinyl, 2-quinoxalinyl, 1,5- naphthyridinyl, l ,8-naphthyridinyl, benzothiazol— l -yl, benzoxazo l- l -yl, idazolyl, l-methylbenzimidazolyl, imidazo[ l ,2-a]pyridineyl, thieno[3 ,2- b]pyridineyl, o-[2, l -b]—thiazolyl and l ,2,4-triazo lo [ l ,5-a]pyridineyl, 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 ting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and ated ropyl.
A third 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 X1 is C-H and X2 is N. In this third group, Y, R1, R2, R3 and R4 are as defined above and preferably have the preferred or particular or l meanings given above. Amongst these compounds, a particular group of embodiments is represented by the following formula lo 4 1 R o \ N,R I (IO) N / / 0 w where R1, R2, 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 X1 is N and X2 is N. In this 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 ing a Id 4 1 R o \ N,R | | (Id) N / /N o N where R1, R2, R3, R4 and R5 are as defined above.
In relation to their use as tors of PDElOA, the variables R1, R2, R3 and R4 in formulae Ia, Ib, lo and Id preferably have the following meanings, where these 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 Ia, Ib, Ic and Id, R1 is preferably C2-Cg-alkyl, Cg-Cg-cycloalkyl or C3- Cg-cycloalkylmethyl, in particular C3-Cg-cycloalkylmethyl or especially C2-Cg-alkyl.
Particularly, R1 is alkyl of the formula CHRlaRlb, where R181 is selected from the group consisting of hydrogen and C1-C3-alkyl, in ular methyl, ethyl, yl and where R1b is selected from the group consisting of C1-C4-alkyl, in particular methyl, ethyl, n- propyl or n-butyl. Particular examples of R1 are ed from the group consisting of ethyl, isopropyl, ylpropyl and l-ethylpropyl.
In formulae Ia, Ib, Ic and Id, R1 is se preferably a moiety Zl-Arl, where Z1 and Ar1 are as defined above and where Z1 is preferably l,2-ethanediyl or l,3- propanediyl, wherein l, 2, 3 or 4 hydrogen atoms may be replaced by a e atom.
According to a specific embodiment, Z1 is l,2-ethanediyl which is unsubstituted or l,3- propanediyl which is unsubstituted.
In formulae Ia, Ib, Ic and Id, where R1 is a moiety Zl-Arl, Ar1 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 fiarther heteroatom selected from O, S and N as ring member, where monocyclic hetaryl and bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh. Ar1 is in particular selected from the group ting of filsed bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a fiarther heteroatom selected from O, S and N as ring member and which may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh as defined above.
Amongst these, particular preference is given to those compounds, where the Ar1 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z1. Amongst these, particular ence is given to those, where Ar1 is selected from the group consisting of C-bound, fused bicyclic l, which has 1 or 2 en atoms as ring members and ally a further heteroatom selected from O, S and N as ring member, where bicyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh. In this , Rh is preferably selected from halogen, C1-C4-alkyl, C1- Cz-fluoroalkyl, C1-C4-alkoxy, fluoralkoxy, C3-C6-cycloalkyl and fluorinated C3- C6-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 particular ments of formulae Ia, Ib, Ic and Id, R2 is a radical of the formula ZRB, where R21, R22 and R23 are as defined above and where R21 is in particular different from hydrogen.
In other particular embodiments of ae Ia, Ib, Ic and Id, R2 is a phenyl or 5- or 6-membered hetaryl radical having 1, 2 or 3 heteroatoms as ring members which are selected from O, 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 Ia, Ib, Ic and Id, where R2 is a radical ofthe formula CRZIRZZRB, where R21, R22 and R23 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 members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or ent substituents R81 as defined above, the l R3 is preferably selected from the group consisting of hydrogen and C1-C4-alkyl. In these embodiments, R3 is in particular hydrogen.
In the particular embodiments of formulae Ia, Ib, Ic and Id, where R2 is a radical ofthe formula CRZIRZZRB, a particular group of embodiments relates to compounds, where the radicals R21, R22 and R23 have the following meanings: R21 is selected from the group consisting of C1-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, C1-C4-fluoroalkyl, C3-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, ated C3-Cg-cycloalkyl-C1-C4-alkyl, alkoxy- C1-C4-alkyl, hydroxy-Cl-C4-alkyl, C1-C4-alkyl-N(Rb)(R°), C(O)O-Rd, (CH2)mC(O)N(Re)(Rf) and 22.1%, R22 is selected from the group consisting of en, fluorine, C1-Cg-alkyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, Cg-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, fluorinated cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy- C1-C4-alkyl, hydroxy-Cl-C4-alkyl and C1-C4-alkyl-N(Rb)(R°), or R23 is selected from the group consisting of hydrogen, fluorine, C1-Cg-alkyl and C1- C4-fluoroalkyl; In the ular embodiments of formulae Ia, Ib, Ic and Id, where R2 is a radical ofthe formula CRZIRZZRB, a ular group of embodiments relates to compounds, where the radicals R21, R22 and R23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R21 is selected from the group ting of C2-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, C1-C4-fluoroalkyl, C3-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl and ZZ-Arz, where Z2 and Arz, where Z2 and Ar2 are as defined above and where Z2 is preferably a single bond or CH2 and Ar2 is preferably phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl or thiadiazolyl, which are unsubstituted or which carry 1, 2 or 3 identical or different substituents Rh; R22 is ed from the group consisting of hydrogen, fluorine, C1-Cg-alkyl, in particular en; and R23 is hydrogen or C1-C4-alkyl, such as methyl, or especially hydrogen.
In the particular embodiments of formulae Ia, Ib, Ic and Id, where R2 is a radical ofthe formula CRZIRZZRB, a ular group of embodiments relates to compounds, where the radicals R21, R22 and R23 preferably have the following meanings, both ered on their own and in combination with at least one other or all: R21 is selected from the group consisting of C2-Cg-alkyl, trimethylsilyl, C2-Cg-alkenyl, fluoroalkyl, C3-Cg-cycloalkyl, fluorinated Cg-Cg-cycloalkyl, C3-C8- cycloalkyl-Cl-C4-alkyl, fluorinated C3-Cg-cycloalkyl-C1-C4-alkyl, and where R21 is in particular C2-C4-alkyl; R22 is selected from the group consisting of hydrogen, fluorine, C1-Cg-alkyl, in particular methyl or hydrogen; and R23 is hydrogen or C1-C4-alkyl, such as methyl, or especially hydrogen.
In the particular embodiments of formulae Ia, Ib, Ic and Id, where R2 is a radical ofthe formula ZRB, another ular group of ments relates to compounds, where the radicals R21, R22 and R23 preferably have the following gs, both considered on their own and in combination with at least one other or all: R21 is a radical ZZ-Arz, where Z2 and Arz, where Z2 and Ar2 are as defined above and where Z2 is preferably a single bond or CH2 and Ar2 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 R21 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, thiazolyl, thiazolyl, l,3,4-thiadiazolyl, 2-(l-morpholinosulfonyl)phenyl, 3 -( l -morpholino sulfonyl)phenyl, 2-(4-methylpiperazin— l fonyl)phenyl or 3- (4-methylpiperazin- l -ylsulfonyl)phenyl.
R22 is selected from the group consisting of hydrogen, fluorine, C1-Cg-alkyl, in particular methyl or hydrogen; and R23 is hydrogen or alkyl, such as methyl, or especially hydrogen.
In the particular embodiments of formulae Ia, Ib, Ic and Id, where R2 is a radical ofthe formula CRZIRZZRB, a fiarther group of embodiments relates to compounds, where the radicals R21 and R22 together with the carbon atom, to which they are bound form a ted 5-, 6- or 7-membered yclic ring, such as cyclopentyl, cyclohexyl 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 O, N, S, SO and 802 as ring members, ally 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 l, 2 or 3 cal or different substituents Rg, and where the carbocyclic ring and the heterocyclic ring may carry a fiJsed benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 tuents Rh, and where Rg, Rh and R23 are as defined above and where R23 is in particular hydrogen or C1-C4-alkyl, such as methyl, or especially hydrogen.
In the ular embodiments of formulae Ia, Ib, Ic and Id, where R2 is a radical ofthe formula CRZIRZZRB, a fiarther particular group of embodiments relates to nds, where the radicals R21, R22 and R23 preferably have the following meanings, both considered on their own and in combination with at least one other or all: R21 and R22 together with the carbon atom, to which they are bound form a ted 5-, 6- or 7-membered carbocyclic l, namely a cyclopentyl, cyclohexyl or cycloheptyl radical or a 3-tetrahydrofuryl or 3-tetrahydrothienyl, where the 5 to 7 2012/072175 membered carbocyclic ring and the 3-tetrahydrofuryl or 3-tetrahydrothienyl ring carry a fiJsed benzene ring or a fused 5- or 6-membered heteroaromatic ring, such as a fused thiophene or ne ring, where the fused rings themselves are tituted or carry 1, 2 or 3 substituents Rh, and where R21 and R22 in particular form a bicyclic radical selected from the group consisting of 5-indanyl, 6-indanyl, 5,6,7,8-tetrahydronaphthalinyl, 5,6,7,8-tetrahydronaphthalinyl, 6,7,8,9-tetrahydro-5H-benzocyclohepteneyl, 6,7,8,9-tetrahydro-5H- yclohepteneyl, hydro-4H-cyclopenta[b]thiopheneyl, 6,7- dihydro-SH- [ l ]-pyrindinyl, 3 ,4-dihydrobenzo filran-3 -yl, 2,3 - dihydrobenzothiophen—3-yl or where these bicyclic radicals are in ular unsubstituted or where the aromatic moiety ofthese rings carry 1, 2 or 3 substituents Rh; R23 is en or C1-C4-alkyl, such as methyl, or especially hydrogen.
In further particular embodiments of the invention R2 and R3 together with the 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 fiarther heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and $02 as ring members, e. g. a idine, piperidine, morpholine, thiomorpholine or piperazine ring, where the heterocyclic ring may be unsubstituted or may be substituted by l, 2 or 3 identical or different substituents R31, and where the heterocyclic ring may carry a fiJsed 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 R31 and R32 are as defined defined above.
R31 is in particular selected from the group consisting of C1-C4-alkyl, C1-C4- alkoxy, halogen, phenyl and phenoxy, where the ring in the last two mentioned radicals itself is unsubstituted or carries 1 or 2 radicals ed from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, halogen.
R32 is in particular selected from the group consisting of C1-C4-alkyl, C1-C4- alkoxy and halogen.
In formulae Ia, Ib, Ic and Id, a particular embodiment s to compounds where R4 is C1-C4-alkyl and especially methyl.
In formulae Ia, Ib, Ic and Id, another particular embodiment relates to compounds where R4 is a radical Z4-Ar4, where Z4 and Ar4 are as defined above and having in particular the preferred, particular or special meanings given above. In this embodiment in formulae Ia and lb R5 is in particular hydrogen, fluorine or in particular C1-C4- alkoxy, especially methoxy.
In this ment of formulae Ia, Ib, Ic and Id, Z4 is preferably l,2-ethanediyl or l,3-propanediyl, wherein l, 2, 3 or 4 hydrogen atoms may be replaced by a fluorine atom. According to a specific embodiment, Z4 is l,2-ethanediyl which is unsubstituted or l,3-propanediyl which is tituted.
In this ment of formulae Ia, Ib, Ic and Id, Ar4 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, fiJsed bicyclic l, which has 1 or 2 nitrogen atoms as ring members and ally a further heteroatom selected from O, S and N as ring member, where monocyclic hetaryl may be unsubstituted or may carry 1, 2 or 3 identical or different tuents Rk, in particular 0, l or 2 tuents Rk and bicyclic hetaryl may be unsubstituted or may carry 1 substituent Rk, and 0, l, 2 or 3 substituents Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is preferably ed from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2- fluoralkoxy, C3-C6-cycloalkyl, and fluorinated C3-C6-cycloalkyl. In this regard, Rh is in particular selected from e, chlorine, methyl, fluoromethyl, difluoromethyl, romethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
In this ment of formulae Ia, Ib, Ic and Id, Ar4 is in particular ed from the group consisting of fiased bicyclic hetaryl, which has 1 or 2 nitrogen atoms as ring members and optionally a fiarther heteroatom selected from O, 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 tuents Rh, in particular 0, l or 2 substituents Rh as defined above. Amongst these, particular preference is given to those compounds, where the Ar4 radical has at least one imino-nitrogen as ring member, which is located in the position adjacent to carbon atom bound to the group Z4. Amongst these, particular preference is given to those, where Ar4 is selected from the group consisting of C-bound, fused bicyclic l, which has 1 or 2 nitrogen atoms as ring members and optionally a further heteroatom selected from O, 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 Rh, in particular 0, l or 2 substituents Rh. In this regard, Rh is preferably selected from halogen, C1-C4-alkyl, C1-C2-fluoroalkyl, alkoxy, C1-C2-fluoralkoxy, C3-C6- lkyl and fluorinated C3-C6-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 ment of formulae Ia, Ib, Ic and Id, Ar4 is e. g. selected from the group consisting of 2-benzofuryl, 2-pyridyl, 2-pyrimidinyl, midinyl, 2-pyrazinyl, 3-pyridazinyl, 2-quinolinyl, 3-isoquinolinyl, 2-quinazolinyl, 2-quinoxalinyl, 1,5- naphthyridinyl, l hthyridinyl, benzothiazol— l -yl, benzoxazo l- l -yl, benzimidazolyl, l-methylbenzimidazolyl, imidazo[ l ,2-a]pyridineyl, thieno[3 ,2- dineyl, imidazo-[2, l -b]—thiazolyl and l ,2,4-triazo lo [ l ,5-a]pyridineyl, where the aforementioned radicals are tituted or may carry 1, 2 or 3 radicals Rh as d above, which are in particular selected from the group consisting of fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and ated cyclopropyl.
Apart from that, the variables Ar3, Z3, Z4, Ra, Rb, RC, Rd, Re, Rf, Rg, Rh and Rk preferably have, irrespectively of their occurrence and with regard to the formulae I, Ia, Ib, Ic and Id and with regard to each of the above mentioned embodiments groups of embodiments one of the following meanings: Ar3 is preferably phenyl, which is tituted or substituted by l, 2 or 3 radicals Rh.
Z3 is preferably a single bond, CH2 or CHZCHZ.
Z4 is preferably CH2 or CHZCHZ.
R81 is preferably halogen, in particular fluorine, C1-C4-alkyl, C1-C4-alkoxy, C1- roalkyl, C1-C4-fluoroalkoxy, N(Rb)(R°), CH2N(Rb)(R°), or S(O)2N(Re)(Rf), Rb is preferably hydrogen or C1-C4-alkyl; Rc is ably hydrogen or C1-C4-alkyl; or Rb and Rc together with the nitrogen atom to which they are bound may also form a saturated N—bound heterocyclic radical, ed from the group consisting of WO 68489 pyrrolidin- l -yl, piperidin- l -yl, morpho linyl, thiomorpholinyl, piperazin- l -yl and 4-methylpiperazin-l-yl, where the 6 aforementioned heterocyclic radicals may carry 1, 2, 3 or 4 substituents, selected from methyl and fluorine.
Rd is preferably C1-C4-alkyl.
Re is preferably hydrogen or C1-C4-alkyl; Rf is preferably hydrogen or C1-C4-alkyl; or Re and Rf together with the en atom to which they are bound may also form a saturated N—bound heterocyclic l, selected from the group consisting of pyrrolidin- l -yl, piperidin- l -yl, morpho linyl, thiomorpholinyl, piperazin- l -yl and 4-methylpiperazin-l-yl, where the 6 aforementioned heterocyclic radicals may carry 1, 2, 3 or 4 substituents, selected from methyl and fluorine.
Rg is preferably halogen, in particular fluorine, C1-C4-alkyl, C1-C4-alkoxy, C1- C4-fluoroalkyl or C1-C4-fluoroalkoxy.
Rh is preferably halogen, in ular e, C1-C4-alkyl, C1-C4-alkoxy, C1- roalkyl, C1-C4-fluoroalkoxy, cycloalkyl, fluorinated C3-C6-cycloalkyl, N(Rb)(R°), CH2N(Rb)(R°) or S(O)2N(Re)(Rf). In addition, Rh is preferably cl—cz— alkylsulfanyl, C1-C2-alkoxy-C1-C4-alkoxy, C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C2- alkoxy, phenoxy, 3- to 7-membered heterocyclyloxy, 3- to 7-membered heterocyclyl- C1-C2-alkoxy, where heterocyclyl in the two last ned radicals has 1 or 2 heteroatoms as ring members which are selected from O, S and N, and 5- to 6- membered hetaryl-Cl-Cz-alkoxy, where hetaryl has 1 or 2 heteroatoms as ring members which are ed from O, S and N. Rh is in particular selected from halogen, C1-C4- alkyl, C1-C2-fluoroalkyl, C1-C4-alkoxy, C1-C2-fluoralkoxy, C3-C6-cycloalkyl and fluorinated C3-C6-cycloalkyl. Rh is especially selected from fluorine, chlorine, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl and fluorinated cyclopropyl.
Rk is preferably n, in ular fluorine, C1-C4-alkyl, C1-C4-alkoxy, C1- C4-fluoroalkyl or C1-C4-fluoroalkoxy.
Particular embodiments of the invention relates to the compounds of formula I, to the N—oxides, the prodrugs, the hydrates and the tautomers thereof and to the ceutically suitable salts thereof, where the nds of the formula I are selected from the group consisting of: 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cyclopropylrncthyl—amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid methyl- phcncthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydro-isoquin01inccarboxylic acid (2- methoxy-bcnzyl)-mcthyl-amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- methoxy-bcnzyl)-mcthyl-amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - methoxy-bcnzyl)-mcthyl-amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid methyl- (3 -triflu0r0rncthy1—bcnzy1)-amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid benzyl— (2-dirncthylarnino-cthy1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1 - bcnzyl-pipcridin—4-yl)-rncthy1—amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid tertbutylarnidc 2-cthy1—6,7-dirncthoxyoxo- 1 ,2-dihydro-isoquinolinccarboxy1ic acid secbutylarnidc 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid isobutyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cntylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1 butyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1,1- dimcthyl-propyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1,2- dimcthyl-propyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2,2- dimcthyl-propyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1 -cthy1— propyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cthylarnidc, 2-cthy1—6,7-dirncth0xyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- methyl-butyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid pcntylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cyclohcxylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1,3 - yl-butyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid (3 ,3 - dimcthyl-butyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2-cthy1— buty1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid benzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid dicyclopropylrncthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- cthyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cxylrncthyl-amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (1 - phcnyl-cthy1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid 2- fluoro-bcnzy1arnidc, WO 68489 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 - fluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 4- fluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid 2,3 - difluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid 2,4- difluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2,6- difluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 ,4- difluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid (2,2,2- trifluoro-cthy1)-amidc, 2-cthy1—6,7-dimcthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 ,5 - difluoro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid phcncthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid [1-(4- fluoro-phcnyl)-cthyl] -arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid indan— 1 - ylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid indan—2- ylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid [1-(4- fluoro-phcny1)rncthy1—ethyl] -arnidc, 4-(azctidinccarb0ny1)cthy1—6,7-dirncthoxy-2H-isoquinolin-l-onc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquin01inccarboxylic acid cyclopropylarnidc, 2-cthy1—6,7-dirncthoxy(2-mcthy1—pyrrolidinccarb0ny1)-2H-isoquino lin one, 2-cthy1—6,7-dirncthoxy(morpho1inccarb0ny1)-2H-isoquinolinonc, 1—4-(3-fluoro-pyrrolidine- 1 ny1)-6,7-din1ethoxy-2H-isoquinolinone, 2-ethy1—6,7-din1ethoxy(4-n1ethy1—piperazinecarbony1)-2H-isoquino linone, 4-(3 ,3-difluoro-pyrrolidinecarbony1)ethyl-6 ,7-din1ethoxy-2H-isoquinolin one, 4-(3 -din1ethylan1ino-pyrrolidine- 1 ny1)ethy1—6,7-din1ethoxy-2H- isoquino linone, 2-ethy1—6,7-din1ethoxy((R)n1ethoxyn1ethy1—pyrrolidinecarbony1)-2H- isoquino linone, 4-(1 ,3-dihydro-isoindo1ecarbony1)ethyl-6,7-din1ethoxy-2H-isoquinolin one, 4-(4,4-difluoro-piperidinecarbony1)ethy1—6,7-din1ethoxy-2H-isoquinolin one, 2-ethy1—6,7-din1ethoxy0X0- 1 ,2-dihydro-isoquinolinecarboxylic acid isopropylamide, 2-ethy1—4-(4-isopropyl-piperazinecarbony1)-6,7-din1ethoxy-2H-isoquinolin one, 4-(4-din1ethylan1ino-piperidinecarbony1)ethy1—6,7-din1ethoxy-2H- isoquino linone, 2-ethy1—6,7-dimethoxy(2-trifluoron1ethy1—pyrrolidinecarbony1)-2H- isoquino linone, 4-(4-cyclopropylmethyl-piperazinecarbony1)ethy1—6,7-din1ethoxy-2H- isoquino linone, 2-ethy1—6,7-din1ethoxy((S)pyrrolidin— 1 thy1—pyrrolidinecarbony1)- 2H-isoquinolin—1-one, 2-ethy1—6,7-din1ethoxy(4-pyrrolidin— 1 -y1-piperidinecarbony1)-2H- isoquino linone, 4- [4-(2-din1ethy1an1ino-ethy1)-piperazinecarbony1] ethy1—6,7-din1ethoxy-2H- isoquino linone, 4-([1,4']bipiperidiny1—1'-carbony1)ethy1—6,7-din1ethoxy-2H-isoquinolin-l-one, 4-[4-(3-din1ethy1an1ino-propy1)-piperazinecarbony1] ethy1—6,7-din1ethoxy- 2H-isoquinolin—1-one, 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid propylamidc, 2-cthy1—6,7-dirncthoxy[4-(2-pyrr01idiny1-cthy1)-pipcrazinccarb0ny1]—2H- isoquino lin0nc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid dimcthylamidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid ethyl- methyl-amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid isopropyl-mcthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid dicthylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid methyl- propyl—amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid ethylisopropyl-arnidc 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid tertbutyl —rncthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid isobutyl-mcthyl—arnidc, 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid butylmethyl-amide 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid ethylpropyl —amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- dirncthylarnino-cthy1)-rncthy1—amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid ethyl-(2- methoxy-cthyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cntyl-mcthyl—amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid butyl- ethyl-amide, 2012/072175 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid pcntyl-arnidc 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid diisopropylamidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ydr0-isoquin01inccarboxylic acid isopropyl-propyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cyclobutylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid dipropylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - dimcthylarnino-pr0py1)-mcthy1—amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cyclohcxyl-mcthyl-amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid cyclopropylmcthyl—propyl-amide 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid diisobutylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid benzyl— methyl-amide, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- fluoro-bcnzy1)-rncthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- fluoro-bcnzy1)-rncthyl-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - fluoro-bcnzy1)-rncthyl-arnidc, 2-tcrt-buty1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-scc-buty1—6,7-dirncth0xy-l-oxo-l ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-isobuty1—6,7-dirncth0xyOXO- 1 ,2-dihydr0-isoquino 1inccarb0xylic acid butylarnidc, 2-buty1—6,7-dirncthoxy0X0-1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-cyclopropylmcthyl-6,7-dirncthoxy0X0-1 ,2-dihydr0-isoquinolinccarboxylic acid butylarnidc, 2-(2-dirncthylarnino-cthy1)-6,7-dirncthoxy— 1 -OXO- 1 ,2-dihydro-isoquinolinc carboxylic acid butylamidc, 2-cyc10pcnty1—6,7-dirncthoxy— 1 -OXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid rnidc, 6,7-dirncthoxy0X0(2,2,2-trifluor0-cthyl)-1 ,2-dihydr0-isoquin0 line carboxylic acid butylamidc 6,7-dirncth0xy0X0(2-pyrrolidiny1—cthy1)-1 ,2-dihydro-isoquinolinc carboxylic acid butylarnidc, u0ro-cthyl)-6,7-dirncthoxyoxo-1 ,2-dihydr0-isoquinolinccarboxylic acid butylarnidc, 2-bcnzy1—6,7-dimcthoxy0x0- 1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-(2,4-diflu0ro-bcnzy1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin0 line carboxylic acid butylarnidc, 2-cyclopropyl—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquino linecarb0xylic acid butylarnidc, 6,7-dimcth0xyox0(2-pipcridiny1—cthy1)-1 ,2-dihydr0-isoquino line carboxylic acid butylarnidc, 6,7-dirncth0xyphcncthy1- 1 ,2-dihydr0-isoquino linecarb0xylic acid butylarnidc, 6,7-dirncthoxy-Z-(2-mcthoxy-bcnzyl)OXO- 1 ,2-dihydro-isoquin01inc carboxylic acid rnidc, 2-indan—1-y1-6,7-dirncth0xy—1-0X0-1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 2-isopr0py1—6,7-dirncth0xyOXO- 1 ydr0-isoquin01inccarboxylic acid butylarnidc, 6,7-dirncthoxy0xopr0py1—1 ,2-dihydr0-isoquin01inccarboxylic acid rnidc, 6,7-dirncth0xy0X0(3 ,3 ,3 -trifluor0-pr0py1)- 1 ,2-dihydr0-isoquino line carboxylic acid butylarnidc, 6,7-dimcthoxy-Z-(2-rncth0xy—cthyl)OXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid butylarnidc, 2-Cyc10buty1—6,7-dirncthoxy—1-oxo-1 ,2-dihydr0-isoquin01inccarboxylic acid butylarnidc, 3 -Ethy1—6,7-dirncthoxy0X0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid rnidc, 2-cthy1—7-rncthoxy0X0-1 ,2-dihydr0-isoquino 1inccarb0xylic acid rnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid indan— 1 -y1arnidc, 2-cthy1—7-rncthoxyox0(2-quin01iny1—cthoxy)- 1 ,2-dihydr0-isoquin0 line carboxylic acid butylarnidc, 2-cthy1—7-rncthoxy0X0(3-quin01in—2-y1—pr0poxy)- 1 ,2-dihydr0-isoquin01inc- 4-carb0xy1ic acid butylarnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (6,7,8 ,9- tctrahydro-SH-bcnzocycloheptcn—7-yl)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinc- 1 xy1ic acid (R)- indan— 1 -y1arnidc, 2-cthy1—7-rncthoxy0X0-1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid indan— 1 -y1arnidc, 2-cthy1—7-rncthoxy0X0-1 ydr0-[2,6]naphthyridinccarboxy1ic acid butylarnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-isoquino linecarb0xylic acid indan— 1 -y1arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinc- 1 xy1ic acid (6,7,8 ,9- tctrahydro-SH-bcnzocycloheptcn—S -y1)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (1,2,3 ,4- tctrahydro-naphthalcnyl)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (1,2,3 ,4- tctrahydro-naphthalcny1)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (4- -indan— 1 -y1)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (5 - bromo-indan— 1 -y1)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid 2- dirncthylarninomethyl-benzylamidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (6,7- dihydro-SH-[1]pyrindin-5 -y1)-arnidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid (6,7- dihydro-SH-[l]pyrindin—7-y1)-arnidc, 3 —6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid 3 - dimcthylarninomethyl-benzylamidc, 3 -cthy1—6,7-dirncth0xyox0-3 ,4-dihydro-phtha1azinccarb0xy1ic acid 4- dirncthylarninomethyl-benzylamidc, 7-mcthoxy0X0(2-quino1in-2—y1—cthyl)-1 ,2-dihydr0-isoquinolinccarboxylic acid butylarnidc, oxy0X0(2-quino1in-2—y1—cthyl)-1 ,2-dihydr0-isoquinolinccarboxylic acid indan— 1 -y1arnidc, 3 -cthy1—6,7-dimcth0xyoxo-3 ydro-phtha1azinccarb0xy1ic acid (S)- indan— 1 -y1arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (6,7-dihydr0-5H-[1]pyrindin-5 -y1)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid 2-dirncthylarninomethyl-benzylarnidc, 2-(1 —pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 ,5 -difluoro-bcnzy1arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 ,4-diflu0ro-bcnzylarnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid cyclohcxylrncthyl-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (R)-indan— 1 -y1arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ydr0-isoquinolinccarboxylic acid (S)-indan— 1 -y1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid (1,2,3 ,4- tctrahydro-naphthalcny1)-arnidc, 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid pyridiny1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid (pyrirnidiny1rncthy1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2- methoxy-bcnzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- morpholiny1-phcny1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 - chloro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid (pyridiny1mcthyl)-arnidc, 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 0- tolylamidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid amidc 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- methoxy-phcny1)-amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - methoxy-phcnyl)-amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid (pyridin-3 -y1rncthyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid (pyridinylmcthyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - dimcthylarnino-pr0py1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquin01inccarboxylic acid phcnylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 4- methoxy-bcnzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 - -benzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2- methyl-benzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- methoxy-cthyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- fluoro-phcnyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- methoxy-phcnyl)-amidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid ptolylamidc 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - fluoro-phcnyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2- fluoro-phcnyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 4- methyl-benzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2- chloro-bcnzy1arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid [(R) (4-flu0r0-phcny1)-cthyl]—arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid pyridin- nidc, 1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid - r0-phcny1)-cthyl]—arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (6- rncthyl-indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2- morpholiny1rncthy1—bcnzylarnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (5 - chloro-indan- 1 rnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (6- chloro-indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (6- fluoro-indan— 1 rnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (5 ,6- dihydro-4H-cyclopcnta[b]thi0phcn—4-y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- fluoro-indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (4- rncthyl-indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (5 - -indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (6- rncthoxy-indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (5 - indan— 1 -y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2- dicthylarninomethyl-benzylamidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2- pyrrolidiny1rncthyl-bcnzylarnidc, 2-cthy1—6,7-dirncthoxy(4-mcthy1—pipcridinccarb0ny1)-2H-isoquino lin0nc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid hydro-furan—2-y1rncthyl)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (3 - methoxy-propyl)-arnidc, 4-(3 ,5-dimcthy1—pipcridinccarb0ny1)cthy1—6,7-dimcthoxy-2H-isoquinolin one, 2-cthy1—4-(4-cthy1—pipcrazinccarb0ny1)-6,7-dimcth0xy—2H-isoquinolin-l-onc, 2-isobuty1—6,7-dimethoxy(4-rnethyl-piperazinecarb0ny1)-2H-isoquino lin one, 2-isobutyl—6,7-dirneth0xyOXO- 1 ,2-dihydr0-isoquino1inecarb0xy1ic acid (2- dirnethylarnino-ethy1)-arnide, 2-isobuty1—6,7-dirneth0xyOXO- 1 ,2-dihydr0-isoquino 1inecarb0xy1ic acid butyl—rnethyl-arnide, obutyl-6,7-dirneth0xy— 1 -OXO- 1 ,2-dihydr0-isoquino1inecarb0ny1)-arnin0]— acetic acid methyl ester, 2-ethy1—6,7-dirneth0xyOXO- 1 ,2-dihydr0-isoquinolinecarboxylic acid (3 - isopropoxy-propyl)-arnide, 2-(1 -ethy1-pr0py1)-6,7-dirnethoxyOXO- 1 ,2-dihydr0-isoquinolinecarboxylic acid (5 ,6-dihydr0-4H-cyc10penta[b]thiophen—4-y1)-arnide, 2-(1 -ethy1-pr0py1)-6,7-dirnethoxyOXO- 1 ,2-dihydr0-isoquinolinecarboxylic acid (2,3 -dihydr0-benz0 filran-3 rnide, 2-(1 -ethy1-pr0py1)-6,7-dirnethoxyOXO- 1 ,2-dihydr0-isoquinolinecarboxylic acid (6-0X0-5 ,6-dihydr0-4H-cyclopenta[b]thiophen—4-y1)-arnide, 2-cyclopropyl—6,7-dirnethoxyOXO- 1 ydr0-isoquino linecarb0xy1ic acid indan— 1 -y1arnide, 2—sec-buty1—6,7-dirneth0xy-l-oxo-l ydr0-isoquino linecarb0xy1ic acid indan— 1 -y1arnide, 2-isopr0py1—6,7-dirneth0xyOXO- 1 ,2-dihydr0-isoquin0 linecarb0xy1ic acid indan— 1 -y1arnide, 2-(1-ethy1-propy1)-6,7-dirnethoxy(3-pheny1—piperidinecarb0ny1)-2H- no lin0ne, 2-(1-ethy1-propy1)-6,7-dirnethoxy(3-phenoxy-piperidinecarb0ny1)-2H- isoquino lin0ne, 2-ethy1—6,7-dirneth0xyOXO- 1 ,2-dihydr0-isoquin01inecarboxylic acid (S)indan—1-y1arnide, 2-ethy1—6,7-dirneth0xyOXO- 1 ,2-dihydr0-isoquinolinecarboxylic acid (R)indan— 1 -y1arnide, 2-(1 -ethy1-propy1)-6,7-dirnethoxy [3 -(3 -rnethoxy-phenyl)-piperazine carbonyl]-2H-isoquino lin0ne, 2—(1-cthy1—pr0pyl)-6,7-dirncth0xy[8-(4-mcthy1—pipcrazincsu1f0nyl)-3 ,4- dihydro-1H-isoquino1inccarb0ny1]-2H-isoquin01in—l-onc, 2-(1-cthy1—pr0pyl)-6,7-dirncthoxy[8-(rn0rpholinesulf0ny1)-3 ,4-dihydr0-1H- isoquino1inccarb0ny1]-2H-isoquinolin— 1 -0nc, 2-(1 -cthy1—propy1)-6,7-dirncthoxy [3 -(3 oxy-phcnyl)rncthy1—pipcrazinccarb0ny1]-2H-isoquinolin— 1 -0nc, 2-(1-cthy1—pr0py1)-6,7-dirncthoxy-l-oxo-1 ,2-dihydr0-isoquinolinccarboxylic acid ([1 ,3 ,4]thiadiazol—Z-ylmcthyl)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2-(rn0rpholinesu1fony1)-bcnzylarnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncth0xyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (thiazo1y1rncthy1)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dimcthoxy[(R)-3 -(quin0xa1iny10xy)-pyrr01idinc carbonyl]-2H-isoquino lin0nc, 2-cthy1—6,7-dirncthoxyoxo- 1 ,2-dihydro-isoquinolinccarboxylic acid (S)(5 ,6- dihydro-4H-cyclopcnta[b]thi0phcn—4-y1)-arnidc, 2-cthy1—6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (R)(5 ,6- dihydro-4H-cyclopcnta[b]thi0phcn—4-y1)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxy1ic acid (thiophcn—3-y1rncthy1)-arnidc, 4-(7-Amin0-3 ydr0- 1H-isoquino1inccarbonyl)(1 —pr0py1)-6,7- dimcthoxy-ZH-isoquino lin0nc, 2-(1 —pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3 -(4-ch10r0-bcnzcncsulfonylarnino)-bcnzylarnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (2,3 -dihydr0-bcnz0 [b]thi0phcn—3 -y1)-arnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ydr0-[2,6]naphthyridinccarboxy1ic acid (5 ,6-dihydr0-4H-cyc10pcnta[b]thiophcn—4-y1)-arnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid (S)-indan— 1 -y1arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 2-(4-rncthyl—pipcrazincsu1f0ny1)-bcnzylamidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid 2-(rn0rpholinesu1fony1)-bcnzylarnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid (6,7-dihydr0-5H-[1]pyrindin-5 -y1)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid 3-(4-rncthoxy—bcnzcncsulfonylarnino)-bcnzylarnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid 3 ,5 -difluoro-bcnzy1arnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid 4-mcthyl-bcnzylarnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ydr0-[2,6]naphthyridinccarboxy1ic acid cxylrncthyl-arnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid butylarnidc, 2-(1 -cthy1—pr0pyl)mcth0xyOXO- 1 ,2-dihydr0-[2,6]naphthyridinccarboxy1ic acid (2,3 -dihydr0-bcnz0 furan—3 -y1)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (thiazo1y1rncthy1)-arnidc, 2-(1 -cthy1—pr0py1)-6,7-dirncthoxyOXO- 1 ,2-dihydr0-isoquinolinccarboxylic acid (thiophcn—2-y1mcthy1)-arnidc, 2-cthy1—7-rncthoxy0X0-1 ,2-dihydr0-[2,6]naphthyridinccarboxylic acid (5 ,6- dihydro-4H-cyclopcnta[b]thi0phcn—4-y1)-arnidc, 3 hy1—pr0py1)-6,7-dirncth0xyoxo-3 ,4-dihydr0-phthalazinccarb0xy1ic acid (5 ,6-dihydr0-4H-cyc10pcnta[b]thiophcn—4-y1)-arnidc, 3 -(1-cthy1—pr0pyl)-6,7-dirncth0xyoxo-3 ,4-dihydr0-phthalazinccarb0xy1ic acid (2,3 -dihydr0-bcnz0 furan—3 -y1)-arnidc, 3 -(1-cthy1—pr0pyl)-6,7-dirncth0xyoxo-3 ydr0-phthalazinccarb0xy1ic acid indan— 1 -y1arnidc, 3 -(1-cthy1—pr0pyl)-6,7-dirncth0xyoxo-3 ,4-dihydr0-phthalazinccarb0xy1ic acid (6,7-dihydr0-5H-[1]pyrindin-5 -y1)-arnidc, 2-(1-cthy1—propy1)-6,7-dirncthoxy(3-phcny1—pr0piony1)-2H-isoquinolin0nc, 2-ethyl-6,7-dimethoxy-N—(4-nitrophenyl)0X0- 1 ,2-dihydroisoquino line amide.
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 pharmaceutically suitable salts thereof, Where the compounds of the formula I are selected from the group consisting of: 6,7-dimethoxy- l -oxo(pentan—3 -yl)-N-(pyridin—3 -ylmethyl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N—((5-methylthiophen—2-yl)methyl)- l -oxo(pentan—3 -yl)- l ,2- oisoquinolinecarboxamide, N—((3 ,S-dimethylisoxazolyl)methyl)-6,7-dimethoxy— l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N—((5-methylthiazolyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy- l -(pentan—3-yl)-N-(pyrimidinylmethyl)- l ,2- oisoquinolinecarboxamide, 6,7-dimethoxy-N—((3-methylisoxazo lyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, N—((2,5-dimethylthiophen—3-yl)methyl)-6,7-dimethoxy— l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N—((2-methylthiazo lyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- oisoquinolinecarboxamide, 6,7-dimethoxy-N—((5-methylisoxazo lyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, (R)-N-( l orophenyl)ethyl)-6,7-dimethoxy- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, ( l -(4-fluorophenyl)ethyl)-6,7-dimethoxy- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N—((4-methylthiazolyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N—((2-methylthiazolyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N—((4-rnethy1thiazo 1-5 -y1)rnethy1)0X0(pentan-3 -y1)-1 ,2- oisoquino1inecarboxamide, 6,7-dirnethoxy0X0(pentan-3 -y1)-N-((5 u0rornethyl)filranyl)rnethy1)- 1 ,2-dihydroisoquino linecarboxarnide, 6,7-dirneth0xy-N—((5-rnethy1fi1ran—2-y1)rnethy1)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, N—(S-flu0r0-2,3-dihydr0-lH-indeny1)-6,7-dirnethoxy0X0(pentan-3 -y1)- 1 ,2-dihydroiso-quin01inecarb0xamide, 6,7-dimethoxy-N—(5-rnethy1—2,3-dihydro-lH-indeny1)0X0(pentan-3 -y1)- 1 0 1 ,2-dihydroisoquino linecarboxarnide, 6,7-dimethoxy-N—(4-methyl—2,3-dihydro-lH-indeny1)0X0(pentan-3 -y1)- 1 ,2-dihydroisoquino -carboxarnide, N—((2-ethy1thiaz01y1)rnethyl)-6,7-dimethoxy0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, 6,7-dirnethoxy-N—(6-rneth0xy-2,3-dihydro-lH-inden-l-y1)0X0(pentan-3 -y1)- 1 ,2-dihydroisoquino linecarboxarnide, 6,7-dirnethoxy-N—((4-rnethy1thi0phen—2-y1)rnethy1)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, 6,7-dirnethoxy-N—((3-rnethy1thiophen—2-y1)rnethy1)-l-oxo-Z-(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, 6,7-dirnethoxy-N—((5-methy10xazol-Z-yl)rnethyl)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, 6,7-dimethoxy-N—(6-methyl—2,3-dihydro-lH-indeny1)0X0(pentan-3 -y1)- 1 ,2-dihydroisoquino linecarboxarnide, rnethoxy0X0(pentan-3 -y1)-N-(pyridin—4-y1rnethy1)-1 ,2- dihydroisoquino1inecarboxamide, 6,7-dirnethoxy-N—(4-methy1benzyl)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, 6,7-dirneth0xy0X0(pentan-3 -y1)-N-(pyridin—2-y1rnethy1)-1 ,2- dihydroisoquino1inecarboxamide, N—((5-cyan0furan—Z-yl)rnethyl)-6,7-dirnethoxy—1-0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, N—(4-chlor0-2,3-dihydr0-lH-indeny1)-6,7-dirnethoxy0X0(pentan-3 -y1)- 1 ,2-dihydroisoquino linecarboxarnide, ethylthiophen—Z-y1)rnethy1)-6,7-dirnethoxy— 1 -0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, rnethoxy-N—((3-methy1furan—2-y1)rnethy1)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxarnide, 6,7-dirnethoxy-N—((2-rnethylfuran-3 -y1)rnethyl)0X0(pentan-3 -y1)- 1 ,2- dihydroisoquino1inecarboxamide, 6,7-dirnethoxy-N—((1-rnethy1—1H-pyraz01—3 -y1)rnethy1)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino1inecarboxamide, N—[(3 ,4-dirnethylpheny1)rnethy1]ethy1—6,7-dimethoxy0X0-isoquino line carboxarnide, N—[(2-ch10r0methy1—phenyl)methyl]ethy1—6,7-dirnethoxy— 1 -OXO- isoquino1inecarboxamide, N— [ [2-(dirnethy1arnino)rnethyl-pheny1]methyl] ethy1—6,7-dirnethoxyOXO- isoquino1inecarboxamide, 2-ethy1-N-[(2-fluoromethy1—pheny1)methyl]-6,7-dirnethoxyOXO- isoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxy-N- [(3 -rneth0xy—4-rnethy1—phenyl)rnethyl]OXO- isoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxy-N-[(4-methy1—2-rnorpho lino-pheny1)rnethyl] OXO- isoquino1inecarboxamide, N—[(2-tert-butoxyrnethy1—pheny1)rnethy1]ethy1—6,7-dirnethoxy— 1 -OXO- isoquino1inecarboxamide, N— [ [2-(1 1 - , 1-dirnethy1propoxy)methy1—phenyl]methyl] ethy1—6,7-dirnethoxy- oquino1inecarboxamide, N—[(2,3-difluor0rnethy1—pheny1)rnethyl]ethy1—6,7-dirnethoxyOXO- isoquino1inecarboxamide, 2-ethy1-N- [(3 rnethy1—phenyl)methyl] -6,7-dirnethoxyOXO- isoquino1inecarboxamide, N—[(3-ch10r0methy1—phenyl)rnethy1]ethy1—6,7-dirnethoxyOXO- isoquino1inecarboxarnide, 2-ethy1-6,7-dirnethoxy [(2,4,6-trirnethy1phenyl)rnethyl]isoquino line carboxarnide, N—[(2,4-dimethylpheny1)methyl]ethy1—6,7-dirnethoxy0X0-isoquino line carboxarnide, 1-6,7-dirnethoxy-N- [ [2-(3 -rneth0xypropoxy)rnethy1—phenyl]rnethy1] oxo-isoquino1inecarboxamide, N— [ [2-(2-ethoxyethoxy)rnethy1—phenyl]methyl] ethy1—6,7-dirnethoxyOXO- isoquino1inecarboxamide, N— [ [2-(cyc10pentoxy)rnethy1—phenyl]rnethyl] ethy1—6,7-dirnethoxy— 1 -OXO- isoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxy-N-[(4-rnethy1—2-phen0xy-phenyl)methyl] OXO- isoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxy-N- [ [2-(2-rnethoxyrnethy1—ethoxy)rnethyl- pheny1]methyl]0X0-isoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxy-N- [[4-methyl(2,2,2-triflu0roethoxy)phenyl]methyl] oxo-isoquino1inecarboxamide, N—[[2-(cyc10hexoxy)rnethy1—phenyl]rnethy1]ethy1—6,7-dirnethoxyOXO- isoquino1inecarboxamide, N— [ [2-(cyclopropylmethoxy)methy1—pheny1]methyl]ethy1—6,7-dirnethoxy oxo-isoquino1inecarboxamide, 2-ethy1-N-[(2-hexoxyrnethy1—phenyl)rnethy1] -6,7-dirnethoxyOXO- isoquino1inecarboxamide, 2-ethy1-6,7-dimethoxy-N-[[4-methy1—2-(tetrahydrofuran—3 - ylrnethoxy)phenyl]rnethyl] 0X0-isoquin01inecarboxarnide, 2-ethy1-6,7-dirnethoxy-N- -rnethoxyethoxy)methy1—phenyl]methyl] oquino1inecarboxamide, 2-ethy1—N—(2-isobutoxyrnethy1benzyl)-6,7-dirnethoxyOXO- 1 ,2- dihydroisoquino1inecarboxamide, 2-ethyl-N-(2-(fi1ran—2-ylrnethoxy)rnethylbenzyl)-6,7-dirnethoxyOXO- 1 ,2- dihydroisoquino1inecarboxamide, 2-ethy1-6,7-dimethoxy-N—(4-rnethyl—2-(pentyloxy)benzyl)OXO- 1 ,2- dihydroisoquino1inecarboxamide, N—(2-ethoxy—4-methylbenzyl)ethyl-6,7-dirnethoxyOXO- 1 ,2- dihydroisoquino1inecarboxamide, N—(2-sec-but0xyrnethy1benzyl)ethyl—6,7-dimethoxy— 1 -OXO- 1 ,2- oisoquino1inecarboxamide, 2-ethy1-N-(2-(isopentyloxy)rnethy1benzyl)-6,7-dirnethoxyoxo-1 ,2- dihydroisoquino1inecarboxamide, 2-ethy1-6,7-dimethoxy-N—(4-rnethy1—2-propoxybenzyl)OXO- 1 ,2- dihydroisoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxy-N—(4-rnethy1—2-(rnethy1thio)benzy1)OXO- 1 ,2- oisoquino1inecarboxamide, 2-ethy1—N—(2-isopropoxy—4-rnethylbenzyl)-6,7-dirnethoxyOXO- 1 ,2- dihydroisoquino1inecarboxamide, 2-ethy1-6,7-dimethoxy-N—(4-rnethy1—2-(tetrahydr0furan—3 -y10xy)benzy1)OXO- 1 ,2-dihydroisoquino linecarboxarnide, 1-6,7-dirnethoxyOXO-N-(2,4,5-trimethy1benzyl)- 1 ,2-dihydroisoquino line- 4-carboxarnide, 2-ethy1-6,7-dirneth0xy-N—(4-methy1—2-((tetrahydrofuran—Z-y1)rnethoxy)benzy1) oxo-l,2-dihydroisoquino1inecarboxamide, 2-ethy1-6,7-dimethoxy-N—(4-methy1—2-(4-methylpentanyloxy)benzy1)OXO- 1 ,2-dihydroisoquino linecarboxarnide, 2-ethy1-6,7-dimethoxy-N—(4-methy1—2-(4-methy1pentyloxy)benzy1)OXO- 1 ,2- oisoquino1inecarboxamide, 2-ethy1-6,7-dimethoxy-N—(2-methoxyrnethylbenzyl)OXO- 1 ,2- dihydroisoquino1inecarboxamide, 2-ethy1-6,7-dirnethoxyoxo-N—(thiazo1y1rnethyl)isoquino1inecarboxarnide, 2-ethy1-6,7-dirnethoxy0X0-N—[[4-(trifluoromethyl)pheny1]rnethy1]isoquinoline- 4-carboxarnide, 2-ethy1-6,7-dirnethoxy0X0-N—[(1S)—1-(p-t01y1)ethyl]isoquinoline carboxarnide, 2-ethy1-N-[(4-isopropylpheny1)rnethyl]-6,7-dirneth0xy— 1 -0X0-isoquino line carboxarnide, 2-ethyl-N—[(4-ethylphenyl)methyl]-6,7-dimethoxy- l -oxo-isoquinoline carboxamide, l-6,7-dimethoxy [( l R)- l -(p-tolyl)ethyl]isoquino line carboxamide, N— [ [4-(difluoromethyl)phenyl]methyl]ethyl-6,7-dimethoxy- l soquino line- 4-carboxamide, 2-ethyl-6,7-dimethoxy-N—[(2-methylthiazolyl)methyl] - l -oxo-isoquino line carboxamide, 2-ethyl-6,7-dimethoxy-N—[(4-methylthienyl)methyl] - l -oxo-isoquino - carboxamide, N—[(4-cyclopropylphenyl)methyl]ethyl-6,7-dimethoxy— l -oxo-isoquino line carboxamide, N-indan- l -yl-6,7-dimethoxy [2-(5 -methylpyridyl)ethyl] - l -oxo-isoquino line- 4-carboxamide, N—butyl—6,7-dimethoxy-2— [2-(5-methylpyridyl)ethyl] - l -oxo-isoquinoline carboxamide, l-6,7-dimethoxy-N—[2-(6-methoxypyridyl)ethyl] - l -oxo-isoquino line carboxamide, N—butyl—6,7-dimethoxy- l -oxo[2-(2-quinonlyl)ethyl]isoquino line amide, and N-indan- l -yl-6,7-dimethoxy- l -oxo [2-(2-quinonlyl)ethyl]isomquino line carboxamide.
In particular embodiments, the compounds of the present invention are distinct from the group of the following compounds: 1- [(2-ethyl— l ,2-dihydro-6,7-dimethoxy— l -oxoisoquino linyl)carbonyl] -(3 - carbonyl)piperidine, l - [(2-(2-methylpropyl)- l ,2-dihydro-6,7-dimethoxy- l -oxoisoquino linyl)- carbonyl] -(3 -ethoxycarbonyl)piperidine, 2- {[(2-ethyl— l ,2-dihydro-6,7-dimethoxy— l -oxoisoquino linyl)carbonyl]amino} - benzoic acid ethyl ester, N—cycloheptylethyl- l ,2-dihydro-6,7-dimethoxy- l -oxoisoquino line carboxamide, N—(3-ethoxypr0pyl)ethy1— 1 ,2-dihydr0-6,7-dirnethoxy0X0isoquino line arnide, N—(3-(1-rnethylethoxy)propy1)ethyl-1 ydr0-6,7-dirnethoxy0X0 isoquino line carboxamide, N—(3-(1-methylethoxy)propyl)(2-rnethy1propy1)- 1 ,2-dihydr0-6,7-dirnethoxy 0X0isoquinoline carboxamide, N—(3-ethoxypr0pyl)(2-methy1propy1)- 1 ,2-dihydr0-6,7-dirneth0xy—1-0X0 isoquinoline carboxarnide, N—[3-(4-methy1— 1 -piperidiny1)propy1]ethyl- 1 ,2-dihydr0-6,7-dirnethoxyOXO- 1 0 4-isoquino line carboxarnide, N—[3 hy1— 1 -piperidiny1)propyl](2-rnethylpr0pyl)- 1 ,2-dihydr0-6,7- dimethoxy0X0isoquin0 line carboxamide, N—[3 -(3 ,5 -dirnethy1— 1 -piperidiny1)propy1]ethyl- 1 ,2-dihydro-6,7-dirnethoxy 0X0isoquinoline carboxamide, N—[3 -(3 ,5 -dirnethy1—1-piperidinyl)propy1](2-rnethy1propyl)-1 ,2-dihydr0-6,7- dimethoxy0X0isoquin0 line carboxamide, N—(3-acetylarninophenyl)ethy1— 1 ,2-dihydr0-6,7-dirnethoxy0X0 isoquinoline carboxarnide, N,N—diethy1—2-ethyl-1 ,2-dihydr0-6,7-dirneth0xy—1-0X0isoquinoline carboxarnide, N—(5-rnethy1—2-fiJranylrnethyl)ethyl-1 ydr0-6,7-dirnethoxy0X0 isoquinoline carboxarnide, N—(5-rnethy1—2-filranylmethyl)(2-rnethy1propy1)- 1 ,2-dihydr0-6,7-dirnethoxy 0X0isoquinoline arnide, N—(2-fiJranylmethyl)ethyl- 1 ,2-dihydr0-6,7-dirnethoxy— 1 -isoquin0 line carboxarnide, N—(tetrahydrofiJranylmethyl)ethyl- 1 ,2-dihydro-6,7-dirnethoxy— 1 -ox0 isoquinoline arnide, N—(2-pyridylrnethyl)(2-methylpr0pyl)- 1 ,2-dihydro-6,7-dirnethoxyox0 isoquino line carboxarnide, N—(3-pyridylrnethyl)ethyl- 1 ,2-dihydr0-6,7-dirnethoxy— 1 -0X0isoquin0 line carboxarnide, N—(l z0di0x0 l-5 -ylrnethyl)ethyl— l ,2-dihydro-6,7-dirnethoxy- l - isoquinoline carboxarnide, N—(l ,3-benzodi0x0 l-5 -ylrnethyl)(2-methylpropyl)- l ,2-dihydr0-6,7-dirnethoxy— l-ox0isoquino line carboxarnide, N—(2,3-dihydr0- l zodioxin-Z-ylrnethyl)ethyl- l ydro-6,7-dirnethoxy— l-ox0isoquino line carboxarnide, N—(2,3-dihydr0- l ,4-benzodioxinyl)ethyl- l ,2-dihydr0-6,7-dirnethoxy- l -OXO- 4-isoquinoline carboxarnide, N—ethyl—N—(2-rnethylphenyl)ethyl- l ,2-dihydr0-6,7-dirnethoxy- l -ox0 lO isoquino line carboxarnide, N—ethyl-N—(2-ethylphenyl)ethyl- l ,2-dihydr0-6,7-dirnethoxy— l -ox0 noline carboxarnide, N—(3 ,4-dirnethoxyphenyl)ethyl- l ,2-dihydr0-6,7-dimethoxy- l -ox0 isoquinoline carboxarnide, N—(3-chlor0phenyl)(2-rnethylpr0pyl)- l ,2-dihydro-6,7-dirnethoxy— l -ox0 isoquinoline carboxarnide, 4- [(4-pr0pyl- l -piperazinyl)carbonyl] (2-rnethylpr0pyl)- l ,2-dihydr0-6,7- dimethoxyisoquino lin- l -0ne, 4- [(4-cyclohexyl- l -piperazinyl)carbonyl] ethyl- l ,2-dihydro-6,7-dirneth0xy isoquino lin- l -0ne, 4- [(4-cyclohexyl- l -piperazinyl)carbonyl] (2-rnethylpr0pyl)- l ,2-dihydr0-6,7- dimethoxyisoquino lin- l -0ne, 4- [(4-(2-pyridyl)- l -piperazinyl)carbonyl] (2-rnethylpr0pyl)- l ,2-dihydr0-6,7- dimethoxyisoquino lin- l -0ne, 4- [(4-(3 -chlorophenyl)- l -piperazinyl)carbonyl] yl- l ,2-dihydr0-6,7- oxyisoquino lin- l -0ne, 4- {[4-(2-fi1ranylcarbonyl)- l -piperazinyl] carbonyl} ethyl- l ,2-dihydr0-6,7- dimethoxyisoquino lin- l -0ne, 4- [(3 ,4-dihydr0- l (2H)quinolinyl)carbonyl] ethyl- l ,2-dihydro-6,7-dirneth0xy 3 0 isoquino linone, N—[(2-ethyl— l ,2-dihydr0-6,7-dirnethoxy— l -ox0isoquin0 linyl)carb0nyl] glycine methyl ester, N—[(2-(2-methylpropyl)- l ,2-dihydro-6,7-dimethoxy- l -oxo isoquinolinyl)carbonyl] glycine methyl ester, N—[(2-ethyl- l ydro-6,7-dimethoxy- l -oxoisoquino linyl)carbonyl] glycine ethyl ester, the pharmaceutically acceptable salts thereof, the N—oxides thereof, the prodrugs f, the hydrates thereof, the tautomers the and the pharmaceutically able salts of said N—oxides, prodrugs, tautomers or hydrates.
The compounds of the invention of the general formulae I, la, 1b, 1c and Id and the starting materials used to prepare them can be prepared in y to known processes of organic chemistry as are described in standard works of organic chemistry, e. g.
Houben—Weyl, den der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March "Advanced Organic Chemistry", 5th edition, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2Ild edition, Weinheim, 1999 and the literature cited therein. The compounds of the invention of the general formula I are advantageously ed 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 a II with an amine of the formula III, as depicted in scheme 1.
Scheme 1: O 0 R4— R1 R4—O R1 X2 / /X1 + R3/ \R2 _> X2 / /X1 0 Q o N’ ( H ) (|||) (I):Y=O F|<3 where X1, 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- nitrophenoxy, pentafluorophenoxy, N—hydroxysuccinimide or hydroxybenzotriazol—l-yl. suitable reaction conditions have been described e.g. in Houben—Weyl: den der organ. Chemie" ds of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, New York 1985, Volume E5, pp. 941-1045).
The reaction of II with 111 may be performed in the presence of a base. Suitable base include but are not d to If Q is OH, the reaction may be performed in the presence of a coupling agent.
Suitable coupling agents are, for example: - coupling agents based on carbodiimides, for example N,N'-dicyclohexylcarbodiimide [J.C. n, 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 xyethoxycarbonyl-1,2-dihydroquinoline [B. Belleau, G. Malek, J. Amer.
Chem. Soc. 1968, 90, 1651], 2-isobutyloxyisobutyloxycarbonyl-1,2- dihydroquinoline [Y. Kiso, H. Yajima, J. Chem. Soc., Chem. Commun. 1972, 942]; - coupling agents based on phosphonium salts, for example (benzotriazol-l- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [B. Castro, J.R.
Domoy, G. EVin, C. Selve, Tetrahedron Lett. 1975, 14, 1219], (benzotriazolyl- oxy)tripyrrolidinophosphonium hexafluorophosphate [J . Coste et al., Tetrahedron Lett. 1990, 31, 205]; - coupling agents based on uronium salts or haVing a inium N—oxide structure, for example N,N,N',N'-tetramethyl-O-(1H-benzotriazolyl)uronium hexafluorophosphate [R. Knorr, A. Trzeciak, W. Bannwarth, D. Gillessen, Tetrahedron Lett. 1989, 3 0, 1927], N,N,N',N'-tetramethyl-O-(benzotriazol 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- 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 1 and II, where Q is O with a suitable sulfilrizing agent, such as Lawenson's t or P2S5.
The N—oxides of nd I may be prepared from the compounds of formula 1 according to conventional oxidation methods, for example by treating said nds with an c peracid; such as metachloroperbenzoic acid or 3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(11), 903 (1995), WO 03/64572]; or with inorganic oxidizing agents; such as hydrogen peroxide [cf Journal of cyclic 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 to a mixture of different N—oxides, which can be separated by tional 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 c chemistry, e. g.
Houben-Weyl, "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, Jerry March "Advanced Organic Chemistry", 5th n, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2Ild edition, Weinheim, 1999 and the ture cited n.
The compounds of the formula II, where Q is OH can be easily transformed into compounds of the formula II, where Q is halogen, in particular chlorine by a suitable chlorination agent such as thionylchloride or oxalyl chloride.
Compounds ofthe formula II, where X2 is C-RS, where R5 is a radical O-ZS-Ar5 can be prepared e.g. by reacting compounds of the formula II, where X2 is C-OH with a compound of formula HO-ZS-Ar5 (formula IV) in terms of a Mitsunobu on, i.e. in the presence of dialkyl azodicarboxylate and triphenylphosphine (for suitable on conditions see e.g. A.J. Reynolds et al. Curr. Org. Chem. 13(16) (2009) 032; K.C. Swamy et al., Chem. ReV. 109(6) (2009), pp. 2551-2651; D.L. Hughes, c Preparations and Procedures International 28(2) (1996), pp. 127-164. nds of the formula II, where X1 is CH and Q is OH (compounds IIa), can be prepared e.g. according to the following reaction scheme 2: Scheme 2: o o o 4 4 4_ l R_O R—O b)H2NR1 R O /R \ OR a) \ OR \ N I I I 2 —> 2 2 X X / X / / N/ / / c) hydrolysis (V) R0 0 (VI) R0 0 (Ila) HO 0 In scheme 2, X2, R1 and R4 are as defined above. R is C1-C4-alkyl, in particular methyl.
Step a) is performed by reacting a compound of the formula V with dimethoxymethyl dimethylamine (also termed dimethylformamide dimethylacetal).
Thereby the compound of formula V1 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 the formula HzN-R1 (compound VII). Subsequent hydrolysis of the primarily obtained ester in step c) yields the compound of the formula II, where X1 is CH and Q is OH.
Compounds of the formula II, where X1 is N and Q is OH unds 11b), can be prepared e.g. according to the following reaction scheme 3: Scheme 3: o o RLO RLO R4—O \ d) \ OH e)H2NNH2 \ N/R1 le / I I o X2 / o f)R1—-Q'> X2 / /lil (”b) O (VIII) (IX) HO O HO In scheme 3, X2, R1 and R4 are as d 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. y the nd of formula IX is obtained, which can be cyclised in step e) to a phthalazinone or phthalazinone analogue by reaction with hydrazine.
Subsequent tion with an alkylating agent of formula Rl-Q' in step f) yields the compound of the formula II, where X1 is CH and Q is OH.
The reactions are usually performed in an organic solvent, including aprotic organic t, e.g. substituted , lactames and ureas; such as 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 C1-C6-alkanols and/or water.
The reactions described above will be usually performed at temperatures g from -lO°C to 100°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 ts in some cases result in the form of colorless or pale sh, viscous oils which are freed of volatiles or purified under reduced re and at moderately elevated temperature. If the intermediates and final products are obtained as , the purification can also take place by tallization or digestion.
Due to their capability of inhibiting PDElOA at low concentrations, the compounds of the formula 1, 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 ofphosphodiesterase 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 e or er, 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 er.
Neurological and psychiatric disorders or ions which can be treated by inhibition of PDElOA, including curative treatment, control or amelioration and prophylaxis, include CNS disorders, in particular schizophrenia, depression, bipolar disorders, cognitive dysfiJnctions associated with schizophrenia, cognitive dysfiJnctions associated with Alzheimer's disease, Huntington's disease (Huntington chorea), anxiety and nce-related ers, especially substance use disorder, substance tolerance conditions associated with substance withdrawal. Disorders or conditions which can be treated by tion of PDElOA, including curative treatment, control or amelioration and laxis, also include treatment of diet d obesity.
Thus, the invention relates to the use of compounds of formula 1, their N—oxides, their hydrates, their tautomers and their prodrugs and the pharmaceutically acceptable salts thereof, for treatment of disorders or conditions, which can be treated by inhibition ofphosphodiesterase 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.
The t invention also relates to a method for the treatment of a l disorder, selected from ogical and psychiatric disorders which can be treated by inhibition ofphosphodiesterase type 10A, said method comprising administering an effective amount of at least one compound, selected from the group of compounds of formula 1, 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 s to: o a method for treating, lling, ameliorating or reducing the risk of schizophrenia in a mammalian; o a method for treating, lling, rating or reducing the risk of cognitive disturbances associated with schizophrenia in a mammalian; o a method for treating, controlling, ameliorating or reducing the risk of depression in a mammalian; o a method for treating, controlling, ameliorating or reducing the risk of bipolar disorders in a mammalian; o a method for ng or ameliorating the symptoms ated with substance use ers in a ian; o a method for ng or ameliorating the symptoms associated with diet- induced obesity in a mammalian; o a method for treating, controlling, ameliorating or reducing the risk of cognitive disturbances associated with Alzheimer's disease in a mammalian; o a method for treating, controlling, ameliorating or reducing the risk of behavioral symptoms in mer's disease; 0 a method for treating, controlling, ameliorating or reducing the risk of anxiety in a mammalian; o a method for treating, controlling, ameliorating or reducing the risk of Huntington's disease in a mammalian; which methods comprising administering an ive amount of at least one compound, ed from the group of compounds of formula 1, 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, ably a human being, male or female, in whom inhibition of PDElOA is desired. The terms "effective amount" and "therapeutically effective amount" mean the amount ofthe subject compound that will elicit the biological or medical response of a tissue, system, 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 t presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present ion. 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 ers bed 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 predisposed to such e or disorder. The term "composition" as used herein is intended to encompass a t sing the specified ingredients in the specified amounts, as well as any t which results, directly or indirectly, from combination ofthe specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or ctly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by ng 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" nd should be understood to mean ing a compound of the invention or a prodrug of a compound ofthe invention to the individual in need of treatment.
A preferred ment of the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an ive amount of at least one compound, selected from the group of compounds of formula 1, their N—oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically acceptable salts thereof.
In r 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 1, 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 V) (1994, American Psychiatric Association, Washington, DC), provides a diagnostic tool including schizophrenia and other psychotic disorders. These include: disorders having psychotic symptoms as the defining feature. The term psychotic refers to delusions, prominent hallucinations, disorganized speech, anized or catatonic behavior. The disorder includes: paranoid, disorganized, catatonic, erentiated, and residual schizophrenia, schizophreniform disorder, affective er, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic er, 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 diagnostic sources.
In another preferred embodiment, the present invention provides a method for treating substance-related ers, comprising: stering to a patient in need thereof an effective amount of at least one nd, selected from the group of nds of formula 1, their N—oxides, their hydrates, their ers, their prodrugs and the pharmaceutically acceptable salts f 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 1, their N—oxides, their hydrates, their tautomers, their prodrugs and the pharmaceutically able salts thereof At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, an Psychiatric Association, Washington, DC), provides a diagnostic tool ing anxiety and related disorders.
These include: panic disorder with or without agoraphobia, agoraphobia t history c disorder, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder, lized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety er and anxiety disorder not otherwise specified. As used herein the term "anxiety" es 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 atric disorders, and particular anxiety, and that these systems evolve with medical scientific progress. Thus, the term "anxiety" is intended to e like disorders that are described in other diagnostic sources.
In another red 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, ed from the group of compounds of a 1, 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, DC), provides a diagnostic tool including depression and related disorders. Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early g waking, and psychomotor retardation; atypical depression (or reactive depression) ing increased appetite, hypersomnia, psychomotor agitation or bility, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I er, bipolar II disorder and cyclothymic disorder. As used herein the term "depression" includes treatment of those sion disorders and related disorder as described in the DSM-lV.
In r preferred embodiment, the present ion provides a method for treating substance-related disorders, ally substance dependence, substance abuse, substance nce, and substance withdrawal, comprising: administering to a patient in need thereof an effective amount at least one compound, selected fiom the group of compounds of formula 1, 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, DC), provides a diagnostic tool including disorders d to taking a drug of abuse (including l), to the side effects of a medication, and to toxin exposure. Substances include alcohol, amphetamine and similarly acting sympathomimetics, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (PCP) or rly acting arylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also, polysubstance dependence and other unknown substance-related disorders are included. The skilled 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 s evolve with medical scientific progress. Thus, the term "substance-related disorder" is intended to e like disorders that are described in other diagnostic sources.
In the treatment, tion, control, amelioration, or reduction of risk of conditions which require inhibition of PDE10A 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 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 ably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ient, ularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 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 matic adjustment of the dosage to the patient to be d. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. When treating, ting, controlling, ameliorating, or reducing the risk of neurological and psychiatric disorders or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds ofthe present invention are stered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body 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 10 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 generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic se. 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 nd employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of stration, rate of excretion, drug ation, the ty 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, intravenous, ICV, istemal injection or infiasion, subcutaneous injection, or implant), oral, by inhalation spray, nasal, vaginal, rectal, sublingual, or l routes of administration.
The compounds according to the present invention are further useful in a method for the prevention, treatment, control, ration, or reduction of risk of the aforementioned es, 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 ent, tion, 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 ofthe drugs together are safer or more effective than either drug alone. Such other drug(s) may be stered, by a route and in an amount commonly used therefore, contemporaneously or tially 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 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 compounds of the present ion and the other active ingredients may be used in lower doses than when each is used . Accordingly, the pharmaceutical compositions ofthe present invention include those that contain one or more other active ingredients, in addition to a compound of formula I. The above ations include combinations of a compound ofthe 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, ent, l, amelioration, or reduction ofrisk of the diseases or conditions for which compounds of the present invention are . 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 ofthe present invention is used poraneously 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 pharmaceutical compositions ofthe present invention e 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 ive dose of each 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 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 ion and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, rent to, or subsequent to the administration of other agent(s).
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.
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, intravenous, ICV, istemal injection or infiasion, subcutaneous injection, or implant), oral, sublingual, intratracheal, intranasal, topical, ermal, vaginal or rectal administration, and be stered to animals or humans in unit dose forms, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above impairments or diseases.
In the pharmaceutical compositions, the at least one compound of the present invention may be ated alone or together with fiarther active nds, 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 compound. Suitable excipients are listed in the specialist medicinal monographs. In addition, the ations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending ; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film s; gel s; odor masking agents; taste 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 tives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as s, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; ners; 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 fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related ], 4th edition, orf: ECV-Editio-Kantor-Verlag, 1996.
Suitable unit dose forms include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral , forms for sublingual, buccal, racheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal stration.
The compounds of the invention can be used in creams, ointments or s for topical administration.
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, n dioxide or the like.
The s may be coated with sucrose, a cellulose derivative or r suitable substance or be treated otherwise in order to y a prolonged or delayed activity and in order to e a predetermined amount of the active basic ingredient continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active ient with an extender and taking up the resulting mixture in soft or hard gelatin capsules.
A ation in the form of a syrup or elixir or for administration in the form of drops may comprise active ingredients together with a sweetener, which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a ng and a suitable coloring.
The water-dispersible powders or granules may comprise the active ingredients mixed with sants, wetting agents or suspending agents such as polyvinylpyrrolidones, and sweeteners or taste improvers.
Rectal administration is achieved by the use of itories which are prepared with binders which melt at the rectal temperature, for example cocobutter or polyethylene s. Parenteral administration is effected by using aqueous suspensions, isotonic salt solutions or sterile and injectable solutions which comprise 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 1, their prodrugs, their N- oxides, their tautomers, their hydrates or their pharmaceutically suitable salts, the compositions ofthe invention may comprise further active basic ingredients which may be beneficial for the treatment of the impairments or diseases indicated above.
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 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 The compounds were either characterized via -NMR in d6-dimethylsulfoxide or d-chloroform on a 400 MHz or 500 MHz NMR instrument r AVANCE), or by mass spectrometry, generally ed via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode), or melting point.
The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (8) sed in parts per n (ppm). The ve area of the shifts in the 1H- NMR um corresponds to the number of hydrogen atoms for a ular 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 triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).
Abbreviations: DMSO dimethylsulfoxide DMF dimethylformamide DMA dimethylacetamide MeOH methanol EtOH ethanol AcOH acetic acid EtOAc ethyl acetate DCM dichloromethane DIPEA or DIEA diisoproylethyl amine TFA trifluoroacetic acid HATU 2-( l Hazabenzotriazo l- l -yl)- l , l ,3 ,3 -tetramethyl uronium hexafluorophosphate methanaminium PS-TFP oxy-2,3 ,5 ,6-tetrafluorobenzamidomethyl polystyrene r.t. room temperature RT retention time Prep-TLC preperative thin layer chromatography 1. Preparation Examples Example 1: 2-Ethyl-6,7-dimethoxy- l -oxo- l ,2-dihydro-isoquinolinecarboxylic acid butylamide l.l 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid dimethyl ester To rapidly stirred cold (0°C) dimethyl malonate (20 mL) was added sodium (423 mg, 18.38 mmol) in portions. After the on 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 (2.00 g, 7.760 mmol) were added. The mixture was heated at 70 0C for 6 h. The reaction mixture was ved 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 Na2S04, 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%). 1H NMR(CDC13/TMS, ) 5: 7.58 (s, 1H, ArH), 6.92 (s, 1H, ArH), 5.98 (s, 1H, CH), 3.87 (s, 3H, CH3), 3.72 (s, 3H, CH3).
LCMS (ESI+): m/z 313 (M+H)+, RT: 1.29 min. 1.2 2-(2-Carboxy-4,5-dimethoxy-phenyl)-malonic acid A on of sodium hydroxide (l .92 g, 48.03 mmol) in water (20 mL) was added over 30 min to a on 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 68489 under reduced pressure, and the contents were acidified with HCl (conc.) at r.t. to pH 3.
The resulting white s suspension was extracted twice with EtOAc (100 mL), and the organic layer was dried over . After filtration and concentration in vacuo the title product was obtained as a white solid (1.8 g, 67%). 1H NMR (DMSO-d6/TMS, 400MHz) 5: 12.67 (s, 3H, COOH), 7.48 (s, 1H, ArH), 6.88 (s, 1H, ArH), 5.76 (s, 1H, CH), 3.81 (s, 3H, CH3), 3.78 (s, 3H, CH3).
LCMS (ESI+): m/z 307 (M+Na)+, RT: 0.71 min. 1.3 2-Carboxymethyl-4,5-dimethoxy-benzoic acid 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 oC 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 r purification.
LCMS (ESI+): m/z 263 (M+Na)+, RT: 1.32 min. 1.4 4,5-Dimethoxymethoxycarbonylmethyl-benzoic acid methyl ester l 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 CC overnight. The solvent was trated in vacuo. The concentrate was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHC03 (10 mL), water (10 mL) and brine (10mL). The c layer was dried over Na2S04, 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%). 1H NMR(CDC13/TMS, 400MHz) 5: 7.56 (s, 1H, ArH), 6.72 (s, 1H, ArH), 3.97 (s, 2H, CH2), 3.93 (s, 3H, CH3), 3.92 (s, 3H, CH3), 3.86 (s, 3H, CH3), 3.71 (s, 3H, CH3).
LCMS (ESI+): m/z 269 , RT: 1.69 min. 1.5 2-(2-Dimethylaminomethoxycarbonylvinyl)-4,5 -dimethoxy-benzoic acid 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 OC overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and washed with brine. The organic layer was dried over Na2S04, 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%). 1H NMR(CDC13/TMS, 400MHz) 8: 7.43 (s, 1H, ArH), 7.38 (s, 1H, ArH), 6.59 (s, 1H, CH), 3.86 (s, 3H, CH3), 3.84 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.53 (s, 3H, CH3), 2.61 (s, 6H, N(CH3)2).
LCMS (ESI+): m/z 265 (M+H)+, RT: 1.52 min. 1 .6 l-6,7-dimethoxyoxo-1 ,2-dihydroisoquinolinecarboxylic acid methyl ester A mixture of the nd obtained in step 1.5 (80 mg, 0.2474 mmol), mine 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.
The e was diluted with EtOAc (50 mL) and washed with HCl (2 N, 10 mL) and brine (10 ML). The organic layer was dried over Na2S04, 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. 1H NMR(CDC13/TMS, 400MHz) 5: 8.40 (s, 1H, ArH), 8.13 (s, 1H, ArH), 7.83 (s, 1H, ArH), 4.12 (q, J: 6.8 Hz, J: 7.2 Hz, 2H, CH2), 4.05 (s, 3H, CH3), 4.01 (s, 3H, CH3), 3.91 (s, 3H, CH3), 1.43 (t, J: 7.6 Hz, 3H, CH3).
LCMS (ESI+): m/z 292 (M+H)+, RT: 1.75 min. 1 .7 2-Ethyl-6,7-dimethoxyoxo-1 ydroisoquinolinecarboxylic acid 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 0C for 6 h. The reaction mixture was concentrated in vacuo. The concentrate was acidified with HCl (cone) to pH=2~3. The ing precipitates were collected by filtration. The solid was dried in vacuo and used in the next step without further purification (200 mg, yield 83%).
LCMS (ESI+): m/z 278 (M+H)+, RT: 1.50 min.
WO 68489 1 .8 2-Ethyl-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid mide 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 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 r 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 successively. The organic layer was dried over Na2S04, 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 t as a white solid (53 mg, yield 88%).
LCMS: 1.70 min; M+H: 333.1 1H NMR(CDC13/TMS, 400MHz) 5: 7.80 (s, 1H, ArH), 7.57 (s, 1H, ArH), 7.35 (s, 1H, ArH), 5.96 (s, 1H, NH), 4.05 (q, J: 7.6 Hz, 2H, CH2), 4.01 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 3.48 (q, J: 5.6 Hz, 2H, CH2), 1.59-1.69 (m, 2H, CH2), .51 (m, 2H, CH2), 1.39 (t, J: 6.8 Hz, 3H, CH3), 0.99 (t, J: 7.2 Hz, 3H, CH3).
The following compounds were synthesized analogously, using in the last reaction step the respective amine.
Example 2 l-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid methylamide LCMS: 1.54 min; M+H: 291 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 3 2-Ethyl-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid ethylamide WO 68489 LCMS: 1.62 min; M+H: 305 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 4 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (2- ethyl)-amide LCMS: 1.56 min; M+H: 323 1H C13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy—1-ox0-1,2-dihydro-isoquinolinecarb0xylic acid (2,2,2- trifluoro-ethyl)-amide LCMS: 1.77 min; M+H: 359 1H NMR(CDC13/TMS, 400MHz) 5: 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, 3H).
Example 6 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid cyclopropylamide LCMS: 1.50 min; M+H: 317 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 7 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid isopropylamide LCMS: 1.58 min; M+H: 319 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 8 l-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid propylamide LCMS: 1.59 min; M+H: 319 1H NMR(CDC13/TMS, 400MHz) 5: 7.75 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H), 5.85 (s, 1H), .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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid cyclobutylamide LCMS: 1.74 min; M+H: 331 1H NMR(CDC13/TMS, 400MHz) 5: 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, 2H), 1.80 (br, 2H), 1.41 (br, 3H).
Example 10 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid cyclopropylmethyl—amide LCMS: 1.72 min; M+H: 331 1H C13/TMS, 400MHz) 5: 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).
Example 11 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid tert- butylamide LCMS: 1.72 min; M+H: 333 1H NMR(CDC13/TMS, ) 5: 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).
Example 12 2-Ethyl-6,7-dimethoxy— 1 -oxo- 1 ,2-dihydro-isoquinolinecarboxylic acid sec- butylamide LCMS: 1.67 min; M+H: 333 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid isobutyl-amide LCMS: 1.69 min; M+H: 333 1H NMR(CDC13/TMS, ) 5: 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 (m, 1H), 1.33 (t, J: 7.2 Hz, 3H), 0.96 (d, J: 6.4 Hz, 6H).
Example 14 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarboxylic acid cyclopentylamide LCMS: 1.71 min; M+H: 345 1H NMR(CDC13/TMS, 400MHz) 5: 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), .46 (m, 2H), 1.33 (t, J: 7.2 Hz, 3H).
Example 1 5 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (1 - methyl-butyl)-amide LCMS: 1.88 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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), .48 (m, 2H), 1.40 (t, J: 5.4 Hz, 3H), 1.28 (d, J: 5.2 Hz, 3H), 0.98 (t, J: .6 Hz, 3H).
Example 16 2-Ethyl-6,7-dimeth0xy—1-ox0-1,2-dihydro-isoquinolinecarb0xylic acid (1 , 1 - dimethyl-propyl)-amide LCMS: 1.91 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 17 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (1 ,2- dimethyl-propyl)-amide LCMS: 1.86 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 7.76 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 5.61 (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-dimeth0xy0x0-1 ydr0-isoquinolinecarb0xylic acid (2,2- yl-propyl)-amide LCMS: 1.89 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 1 9 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (1 - ethyl-propyl)-amide LCMS: 1.86 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 7.83 (s, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 5.55 (s, 1H), .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).
Example 20 l-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (2- methyl-butyl)-amide LCMS: 1.89 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 21 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid pentylamide LCMS: 1.91 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 7.84 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 5.92 (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-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid cyclohexylamide LCMS: 1.90 min; M+H: 359 1H NMR(CDC13/TMS, 400MHz) 5: 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), .42 (m, 2H), 1.33 (t, J: 4.8 Hz, 3H), 1.16-1.22 (m, 4H).
Example 23 2-Ethyl-6,7-dimeth0xy—1-ox0-1,2-dihydro-isoquinolinecarb0xylic acid (1,3 - dimethyl-butyl)-amide LCMS: 1.97 min; M+H: 361 1H NMR(CDC13/TMS, ) 5: 7.74 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 5.62 (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 2-Ethyl-6,7-dimeth0xy—1-ox0-1,2-dihydro-isoquinolinecarb0xylic acid (3 ,3 - dimethyl-butyl)-amide LCMS: 1.98 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 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, J: 5.4 Hz, 3H), 0.93 (s, 9H).
Example 25 2-Ethyl-6,7-dimeth0xy0x0-1 ydr0-isoquinolinecarb0xylic acid (2- ethyl-butyl)-amide LCMS: 1.98 min; M+H: 361 1H NMR(CDC13/TMS, ) 5: 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).
Example 26 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid benzylamide LCMS: 1.84 min; M+H: 367 1H NMR(CDC13/TMS, 400MHz) 5: 7.82 (s, 1H), 7.56 (s, 1H), 7.33-7.42 (m, 6H), 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid dicyclopropylmethyl—amide LCMS: 1.91 min; M+H: 371 1H NMR(CDC13/TMS, ) 5: 7.77 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 5.85 (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-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid exylmethyl-amide LCMS: 2.00 min; M+H: 373 1H NMR(CDC13/TMS, 400MHz) 5: 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), .72 (m, 2H), 1.40 (s, 3H), 1.21-1.29 (m, 3H), 1.02-1.06 (m, 2H).
Example 29 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (1 - phenyl-ethyl)-amide LCMS: 1.89 min; M+H: 381 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 2- fluoro-benzylamide LCMS: 1.86 min; M+H: 385 1H NMR(CDC13/TMS, 400MHz) 5: 7.81 (s, 1H), 7.53 (s, 1H), 7.46-7.49 (m, 1H), 7.41 (s, 1H), 7.30.7.33 (m, 1H), .18 (m, 1H), 7.08-7.12 (m, 1H), 6.28 (s, 1H), 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).
Example 31 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 3 - fluoro-benzylamide LCMS: 1.87 min; M+H: 385 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 32 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 4- fluoro-benzylamide LCMS: 1.86 min; M+H: 385 1H NMR(CDC13/TMS, 400MHz) 5: 7.78 (s, 1H), 7.55 (s, 1H), 7.38-7.41 (m, 3H), 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-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 2,3 - difluoro-benzylamide LCMS: 1.90 min; M+H: 403 1H NMR(CDC13/TMS, 400MHz) 5: 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), .07 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 1.39 (t, J: 7.2 Hz, 3H).
Example 34 l-6,7-dimeth0xy—1-ox0-1,2-dihydro-isoquinolinecarb0xylic acid 2,4- difluoro-benzylamide LCMS: 1.90 min; M+H: 403 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 35 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 2,6- difluoro-benzylamide LCMS: 1.86 min; M+H: 403 1H NMR(CDC13/TMS, 400MHz) 5: 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), .01 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 1.32 (t, J: 7.2 Hz, 3H).
Example 36 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 3 ,4- difluoro-benzylamide LCMS: 1.91 min; M+H: 403 1H NMR(CDC13/TMS, 400MHz) 5: 7.74 (s, 1H), 7.51 (s, 1H), 7.33 (s, 1H), 7.06- 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-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid 3 ,5 - difluoro-benzylamide LCMS: 1.92 min; M+H: 403 1H C13/TMS, 400MHz) 5: 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).
Example 38 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid phenethyl-amide LCMS: 1.88 min; M+H: 381 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 39 2-Ethyl-6,7-dimeth0xy0x0-1 ydr0-isoquinolinecarb0xylic acid [1-(4- fluoro-phenyl)-ethyl]-amide LCMS: 1.92 min; M+H: 399 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 40 2-Ethyl-6,7-dimeth0xy0x0-1 ydr0-isoquinolinecarb0xylic acid indan— 1-ylamide LCMS: 1.94 min; M+H: 393 1H NMR(CDC13/TMS, 400MHz) 5: 7.75 (s, 1H), 7.58 (s, 1H), 7.34-7.38 (m, 2H), 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), .95 (m, 1H), 1.32 (t, J: 5.2 Hz, 3H).
Example 41 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid indan— 2-ylamide LCMS: 1.93 min; M+H: 393 1H NMR(CDC13/TMS, 400MHz) 5: 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, 3H), 3.43-3.48 (m, 2H), 2.96-3.01 (m, 2H), 1.37 (s, 3H).
Example 42 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid [1-(4- fluoro-phenyl)methyl-ethyl]-amide LCMS: 1.98 min; M+H: 413 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 43 4-(Azetidinecarbonyl)ethyl—6,7-dimeth0xy-2H-1soqu1nolin— 1 -0ne LCMS: 1.58 min; M+H: 317 1H NMR(CDC13/TMS, 400MHz) 5: 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), .32 (m, 2H), 1.32 (t, J: 7.2 Hz, 3H).
Example 44 2-Ethyl-6,7-dimeth0xy(2-methyl-pyrrolidinecarb0nyl)-2H-isoquino lin LCMS: 1.74 min; M+H: 345 1H C13/TMS, 400MHz) 5: 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). e 45 2-Ethyl-6,7-dimeth0xy—4-(morpholinecarbonyl)-2H-isoquinolinone LCMS: 1.54 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 46 2-Ethyl(3-fluoro-pyrrolidinecarb0nyl)-6,7-dimethoxy-2H-isoquinolin0ne LCMS: 1.61 min; M+H: 349 1H NMR(CDC13/TMS, 400MHz) 5: 7.77 (s, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 5.22- 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). 2012/072175 Example 47 2-Ethyl-6,7-dimethoxy(4-methyl-piperazinecarb0nyl)-2H-isoquino lin— 1 -0ne LCMS: 1.52 min; M+H: 360 1H NMR(CDC13/TMS, 400MHz) 5: 7.77 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 3.97- 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-Diflu0r0-pyrrolidinecarb0nyl)ethyl—6,7-dimeth0xy-2H-isoquinolin one LCMS: 1.74 min; M+H: 367 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 49 4-(3-Dimethylamin0-pyrrolidinecarb0nyl)ethyl-6,7-dimethoxy-2H- isoquino lin0ne LCMS: 1.55 min; M+H: 374 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy((R)meth0xymethyl-pyrrolidinecarb0nyl)-2H- no lin0ne LCMS: 1.72 min; M+H: 375 1H NMR(CDC13/TMS, 400MHz) 5: 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, 4H), 1.41 (s, 3H).
Example 51 4-(1 ,3-Dihydro-isoindolecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolin LCMS: 1.86 min; M+H: 379 1H NMR(CDC13/TMS, 400MHz) 5: 7.87 (s, 1H), 7.27-7.37 (m, 4H), 7.16 (s, 1H), 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-piperidinecarbonyl)ethyl-6,7-dimethoxy—2H-isoquino lin one LCMS: 1.80 min; M+H: 381 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 53 2-Ethyl(4-isopropyl—piperazinecarbonyl)-6,7-dimethoxy-2H-isoquino lin LCMS: 1.70 min; M+H: 388 1H NMR(CDC13/TMS, 400MHz) 5: 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 imethylamino-piperidine- 1 nyl)ethyl-6,7-dimethoxy-2H- isoquino linone LCMS: 1.50 min; M+H: 388 1H NMR(CDC13/TMS, 400MHz) 5: 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 (br, 4H), 1.39 (t, J: 7.0 Hz, 3H).
Example 55 WO 68489 2-Ethyl-6,7-dimeth0xy(2-triflu0romethyl—pyrrolidinecarb0nyl)-2H- isoquino lin0ne LCMS: 1.89 min; M+H: 399 1H C13/TMS, 400MHz) 5: 7.83 (s, 1H), 7.32 (s, 1H), 7.09 (s, 1H), 5.16 (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,.]= 5.8 Hz, 3H). e 56 4-(4-Cyclopropylmethyl—piperazinecarbonyl)ethyl-6,7-dimethoxy-2H- isoquino lin0ne LCMS: 1.74 min; M+H: 400 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 57 2-Ethyl-6,7-dimeth0xy—4-((S)pyrr0lidinylmethyl-pyrrolidinecarbonyl)- 2H-isoquino lin— 1 -0ne LCMS: 1.65 min; M+H: 414 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy—4-(4-pyrrolidinyl-piperidinecarbonyl)-2H- isoquino lin0ne LCMS: 1.58 min; M+H: 414 1H NMR(CDC13/TMS, 400MHz) 5: 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, 2H), 2.00 (br, 2H), 1.85 (br, 4H), 1.38 (t, J: 6.0 Hz, 3H).
Example 59 4- [4-(2-Dimethylamino-ethyl)-piperazinecarb0nyl]ethyl-6,7-dimeth0xy-2H- isoquino lin0ne LCMS: 1.46 min; M+H: 417 1H C13/TMS, 400MHz) 5: 7.84 (s, 1H), 7.15 (s, 1H), 6.92 (s, 1H), 4.07 (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—1'-carbonyl)ethyl-6,7-dimeth0xy—2H-isoquinolin0ne LCMS: 1.66 min; M+H: 428 1H NMR(CDC13/TMS, 400MHz) 5: 7.84 (s, 1H), 7.14 (br, 1H), 6.89 (br, 1H), 3.79-4.83 (b, 10H), 2.93 (br, 4H), 2.55 (br, 4H), 1.97 (br, 4H), 1.63 (br, 5H), 1.39 (t, J: .6 Hz, 3H).
Example 61 4-[4-(3-Dimethylamino-propyl)-piperazinecarb0nyl]ethyl-6,7-dimethoxy- 2H-isoquino lin— 1 -0ne LCMS: 1.45 min; M+H: 431 1H NMR(CDC13/TMS, 400MHz) 5: 7.84 (s, 1H), 7.14 (s, 1H), 6.92 (s, 1H), 4.06 (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-(2-pyrrolidin—1-yl—ethyl)-piperazinecarb0nyl]—2H- isoquino lin0ne LCMS: 1.48 min; M+H: 443 1H NMR(CDC13/TMS, 400MHz) 5: 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), .67 (br, 11H), 1.81 (br, 5H), 1.32 (t, J: 7.2 Hz, 3H).
Example 63 2-Ethyl-6,7-dimeth0xy0x0-1 ydr0-isoquinolinecarb0xylic acid dimethylamide LCMS: 1.55 min; M+H: 305 1H NMR(CDC13/TMS, 400MHz) 5: 7.85 (s, 1H), 7.15 (s, 1H), 6.90 (s, 1H), 4.07 (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-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid ethyl- methyl-amide LCMS: 1.63 min; M+H: 319 1H NMR(CDC13/TMS, 400MHz) 5: 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). e 65 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid isopropyl-methyl-amide LCMS: 1.73 min; M+H: 333 1H NMR(CDC13/TMS, 400MHz) 5: 7.78 (s, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 3.99 (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-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid diethylamide LCMS: 1.72 min; M+H: 333 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 67 l-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid methyl- propyl—amide LCMS: 1.73 min; M+H: 333 1H NMR (CDC13/TMS, 400MHz) 5: 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).
Example 68 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid ethyl- isopropyl-amide LCMS: 1.81 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 7.85 (s, 1H), 7.06 (s, 1H), 6.85 (s, 1H), 4.07 (br, 3H), 4.01 (s, 3H), 3.93 (s, 3H), .60 (br, 2H), 1.39 (t, J: 5.6 Hz, 3H), 1.19 (br, 9H).
Example 69 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid tertbutyl —methyl-amide LCMS: 1.87 min; M+H: 347 1H NMR(CDC13/TMS, ) 5: 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).
Example 70 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid isobutyl—methyl—amide LCMS: 1.83 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid butylmethyl-amide LCMS: 1.84 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 8: 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, .1: 5.8 Hz, 3H), 1.19 (br, 2H), 0.82 (br, 3H).
Example 72 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid ethyl- propyl—amide LCMS: 1.82 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 7.77 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 4.01 (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-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (2- dimethylamino-ethyl)-methyl—amide LCMS: 1.56 min; M+H: 362 1H NMR(CDC13/TMS, 400MHz) 5: 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), .71 (br, 2H), 3.01 (s, 3H), 2.58 (br, 2H), 2.28 (br, 6H), 1.40 (t, J: 7.2 Hz, 3H).
Example 74 l-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid ethyl- (2-meth0xy-ethyl)-amide LCMS: 1.70 min; M+H: 363 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid cyclopentyl-methyl—amide LCMS: 1.86 min; M+H: 359 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 76 l-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid ethyl- butyl—amide LCMS: 1.93 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 7.78 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 3.97- 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: .4 Hz, 3H), 0.78-1.11 (br, 6H). e 77 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid methyl- pentyl-amide LCMS: 1.94 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 78 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid ropylamide LCMS: 1.92 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid isopropyl-propyl-amide LCMS: 1.91 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 8: 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, .1: 5.8 Hz, 3H), 0.98-1.17 (br, 9H).
Example 80 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid dipropylamide LCMS: 1.92 min; M+H: 361 1H C13/TMS, 400MHz) 5: 7.65 (s, 1H), 7.51 (s, 1H), 6.75 (s, 1H), 3.97- 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-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (3 - dimethylamino-propyl)-methyl-amide LCMS: 1.48 min; M+H: 376 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 82 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid cyclohexyl-methyl-amide LCMS: 1.93 min; M+H: 373 1H NMR(CDC13/TMS, ) 5: 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 l-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid cyclopropylmethyl—propyl-amide LCMS: 1.94 min; M+H: 373 1H NMR(CDC13/TMS, 400MHz) 8: 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, .1: 7.2 Hz, 3H), 0.81 (br, 4H), 0.48 (s, 2H).
Example 84 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid diisobutylamide LCMS: 2.08 min; M+H: 389 1H NMR(CDC13/TMS, 400MHz) 5: 7.85 (s, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 4.04- 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-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid — methyl-amide LCMS: 1.88 min; M+H: 381 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 86 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (2- fluoro-benzyl)-methyl-amide LCMS: 1.89 min; M+H: 399 1H C13/TMS, 400MHz) 5: 7.82 (s, 1H), 7.40 (br, 1H), .34 (m, 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-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (4- fluoro-benzyl)-methyl-amide LCMS: 1.90 min; M+H: 399 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 88 2-Ethyl-6,7-dimeth0xy0x0-1 ydro-isoquinolinecarb0xylic acid (3 - fluoro-benzyl)-methyl-amide LCMS: 1.90 min; M+H: 399 1H NMR(CDC13/TMS, 400MHz) 5: 7.83 (s, 1H), 7.32-7.36 (m, 1H), .16 (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-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid methyl- phenethyl-amide LCMS: 1.89 min; M+H: 395 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 90 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (2- methoxy-benzyl)-methyl-amide LCMS: 1.89 min; M+H: 411 1H C13/TMS, 400MHz) 5: 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-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (4- methoxy-benzyl)-methyl-amide LCMS: 1.86 min; M+H: 411 1H NMR(CDC13/TMS, 400MHz) 8: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (3 - methoxy-benzyl)-methyl-amide LCMS: 1.88 min; M+H: 411 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 93 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid methyl- (3-trifluoromethyl-benzyl)-amide LCMS: 202 min; M+H: 449 1H C13/TMS, 400MHz) 5: 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 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid benzyl— (2-dimethylamin0-ethyl)-amide LCMS: 1.88 min; M+H: 438 1H NMR(CDC13/TMS, 400MHz) 5: 7.75 (s, 1H), .27 (m, 4H), 7.08 (br, 3H), 4.47 (br, 2H), 3.17-3.93 (m, 10H), 1.98-2.53 (m, 8H), 1.22 (s, 3H).
Example 95 2-Ethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid (1 - benzyl-piperidin—4-yl)-methyl—amide LCMS: 1.94 min; M+H: 464 1H NMR(CDC13/TMS, 400MHz) 5: 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).
The compounds of the following examples 96 to 118 were ed in analogy to example 1, where however, in step 1.6, ethylamine was ed by the respective amine and in step 1.8 butylamine was used instead of methylamine.
Example 96 6,7-Dimethoxyoxo(2,2,2-trifluoro-ethyl)- 1 ,2-dihydro-isoquino line carboxylic acid butylamide LCMS: 1.94 min; M+H: 387 1H NMR(CDC13/TMS, 400MHz) 5: 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 2-(2-Fluoro-ethyl)-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid butylamide LCMS: 1.77 min; M+H: 351 1H NMR(CDC13/TMS, 400MHz) 5: 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: 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-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid butylamide LCMS: 1.81 min; M+H: 345 1H NMR(CDC13/TMS, 400MHz) 5: 7.79 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 6.10 (br, 1H), 4.01 (s, 3H), 4.00 (s, 3H), .53 (m, 2H), .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).
Example 99 2-Isopropyl-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid butylamide WO 68489 LCMS: 1.85 min; M+H: 347 1H NMR(CDC13/TMS, 400MHz) 5: 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), .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).
Example 100 6,7-Dimeth0xy0x0pr0pyl-1 ,2-dihydr0-isoquinolinecarb0xylic acid butylamide LCMS: 1.86 min; M+H: 347 1H NMR(CDC13/TMS, ) 5: 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 6,7-Dimeth0xy0xo(3 ,3 ,3 -triflu0r0-propyl)- 1 ,2-dihydr0-isoquino line carboxylic acid butylamide LCMS: 1.94 min; M+H: 401 1H NMR(CDC13/TMS, 400MHz) 5: 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), 1.60-1.68 (m, 2H), 1.41-1.49 (m, 2H), 0.99 (t, J: 7.4 Hz, 3H).
Example 102 6,7-Dimeth0xy(2-methoxy-ethyl)0x0- 1 ydr0-isoquinolinecarb0xylic acid butylamide LCMS: 1.76 min; M+H: 363 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 1 03 2-Cyclobutyl-6,7-dimeth0xy— 1 -0x0- 1 ,2-dihydr0-isoquin0 linecarb0xylic acid butylamide WO 68489 LCMS: 1.90 min; M+H: 359 1H NMR(CDC13/TMS, 400MHz) 5: 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), .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, .1: 7.2 Hz, 3H).
Example 104 2-tert-Butyl-6,7-dimeth0xy— 1 -0x0- 1 ydro-isoquino linecarb0xylic acid butylamide LCMS: 1.97 min; M+H: 361 1H NMR(CDC13/TMS, ) 5: 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).
Example 105 2-sec-Butyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinolinecarb0xylic acid butylamide LCMS: 1.93 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 7.84 (s, 1H), 7.57 (s, 1H), 7.33 (s, 1H), 5.85 (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 2-Isobutyl-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquin0linecarb0xylic acid butylamide LCMS: 1.94 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 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- 2.23 (m, 1H), 1.61-1.67 (m, 2H), 1.42-1.49 (m, 2H), 0.96-1.01 (m, 9H).
Example 107 2-Butyl—6,7-dimethoxy0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid butylamide LCMS: 1.98 min; M+H: 361 1H NMR(CDC13/TMS, 400MHz) 5: 7.82 (s, 1H), 7.60 (s, 1H), 7.34 (s, 1H), 5.83 (br, 1H), 3.99-4.03 (m, 8H), .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-Cyclopr0pylmethyl-6,7-dimeth0xy0x0-1 ,2-dihydro-isoquinoline carboxylic acid butylamide LCMS: 1.88 min; M+H: 359 1H NMR(CDC13/TMS, 400MHz) 5: 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 (m, 2H), 0.41-0.46 (m, 2H).
Example 109 2-Cyclopentyl-6,7-dimeth0xy0x0- 1 ,2-dihydr0-isoquin0 linecarb0xylic acid mide LCMS: 1.97 min; M+H: 373 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 110 2-(1-Ethyl-pr0pyl)-6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid butylamide LCMS: 1.99 min; M+H: 375 1H NMR(CDC13/TMS, ) 5: 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), .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).
Example 1 1 1 6,7-Dimeth0xy(2-meth0xy-benzyl)0x0- 1 ,2-dihydr0-isoquino line ylic acid butylamide LCMS: 2.00 min; M+H: 425 1H NMR(CDC13/TMS, 400MHz) 5: 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).
Example 112 2-Indan—1-yl—6,7-dimeth0xy0x0-1 ,2-dihydr0-isoquin0linecarb0xylic acid butylamide LCMS: 2.05 min; M+H: 421 1H NMR(CDC13/TMS, 400MHz) 5: 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), .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).
Example 1 1 3 imethylamin0-ethyl)-6,7-dimeth0xy0x0- 1 ,2-dihydro-isoquinoline carboxylic acid butylamide Example 1 14 6,7-Dimeth0xy0x0(2-pyrrolidinyl-ethyl)- 1 ,2-dihydro-isoquinoline carboxylic acid butylamide Example 1 l5 2-Benzyl-6,7-dimeth0xy0x0- 1 ,2-dihydr0-isoquino linecarb0xylic acid butylamide Example 1 16 2-(2,4-Difiuoro-benzyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinoline ylic acid butylamide Example 1 17 6,7-Dimethoxyoxo(2-piperidinyl-ethyl)-1 ,2-dihydro-isoquino line ylic acid butylamide Example 1 18 6,7-Dimethoxyoxophenethyl-1 ,2-dihydro-isoquinolinecarboxylic acid butylamide Example 1 19 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid butylamide 1 1 9. 1 1 -(4,5-Dimethoxymethyl-phenyl)-ethanone A solution of 1,2-dimethoxymethylbenzene in C82 (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 C82 (80 mL). The reaction mixture was stirred for 12 h at 25 CC, then poured into ice-water and ted with DCM. The organic layer was 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. 1 19.2 4,5-Dimethoxyoxalyl-benzoic acid A solution of potassium ganate (11.39 g, 72.1 mmol) in water (45 mL) was added dropwise to a mixture of 1-(4,5-dimethoxymethyl-phenyl)-ethanone obtained in step 119.1 (2 g, 10.30 mmol) and potassium carbonate (2.135 g, 15.45 mmol) in H20 (5 mL), and the reaction mixture was d for 3 hat 50 oC. Then ethanol was added and the resulting mixture was stirred for 30min. The solid was filtered off, the filtrate 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. 1 19.3 6,7-Dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid A solution of 4,5-dimethoxyoxalyl—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 OC. The solid was d to give the title compound (910 mg, 80 % ) as a white solid.
LCMS : m/z 251 (M+H)+, RT: 0.587 min. 1 19.4 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid ethyl ester A mixture of 6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid obtained in step 119.3 (500 mg, 1.998 mmol), cesium carbonate (1954 mg, 6.00 mmol) and hane (768 mg, 4.92 mmol) in DMF (8 mL) was stirred at 65 CC 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 , RT: 0.839 min. 1 19.5 3 -Ethyl-6,7-dimethoxyoxo-3 ydro-phthalazinecarboxylic acid A solution of 3-ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic 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 CC for 3 h. The 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 : m/z 279 (M+H)+, RT: 0.862 min. 1 19.6 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid butylamide A solution of 3-ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid obtained in step 119.5 (200 mg, 0.719 mmol) in SOClz (2 mL) was stirred at 76 0C for 2h. Then SOClz was removed and the residue was dissolved in DCM (5 mL).
Butan—l-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 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 68489 1H—NMR (400 MHz,CDC13) : 5 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).
The compounds of the following examples 120 to 132 were prepared in analogy to example 119.
Example 120 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7,8,9- ydro-5H-benzocyclohepten—7-yl)-amide ESI-MS: [M+Na+] = 444.20, [M+H+] = 422.20; Example 121 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid (R)- 1 5 indanylamide ESI-MS: [M+Na+] = 416.10, [M+H+] = 394.10; Example 122 3-Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid (1,2,3 ,4- tetrahydro-naphthalen- 1 mide : [M+Na+] = , [M+H+] = 408.10; Example 123 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid (R)- (1 ,2,3 ,4-tetrahydro-naphthalenyl)-amide ESI-MS: [M+Na+] = 430.10, [M+H+] = 408.10; Example 124 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7,8,9- tetrahydro-5H-benzocyclohepten—S-yl)-amide ESI-MS: [M+Na+] = 444.10, [M+H+] = 422.10; Example 125 3-Ethyl-6,7-dimeth0xy0x0-3,4-dihydro-phthalazinecarb0xylic acid (1 ,2,3,4- tetrahydro-naphthalen—2-yl)-amide ESI-MS: ] = 430.10, [M+H+] = 408.10; Example 126 3-Ethyl-6,7-dimeth0xyox0-3 ,4-dihydro-phthalazinecarb0xylic acid (4- bromo-indan— 1 mide ESI-MS: 495.10, [M+Na+] = 494.10, 474.10, [M +] = 472.10; Example 127 3-Ethyl-6,7-dimeth0xyox0-3 ydro-phthalazinecarb0xylic acid (5- bromo-indan— 1 -yl)-amide ESI-MS: 496.00, [M+Na+] = 494.00, 474.00, [M +] = 472.00; Example 128 3-Ethyl-6,7-dimeth0xyox0-3 ,4-dihydro-phthalazinecarb0xylic acid 2- dimethylaminomethyl-benzylamide ESI-MS: [M+H+] = 425.20; Example 129 3-Ethyl-6,7-dimeth0xy0x0-3,4-dihydro-phthalazinecarb0xylic acid (6,7- dihydro-5H-[1 ]pyrindin—5-yl)-amide ESI-MS: [M+Na+] = 417.10, [M+H+] = 395.10; Example 130 3-Ethyl-6,7-dimeth0xy0x0-3,4-dihydro-phthalazinecarb0xylic acid (6,7- dihydro-5H-[1 ]pyrindin—7-yl)-amide ESI-MS: [M+H+] = ; Example 13 1 WO 68489 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid 3 - dimethylaminomethyl-benzylamide ESI-MS: [M+Na+] = 447.20, [M+H+] = 425.20; Example 132 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazinecarboxylic acid 4- dimethylaminomethyl-benzylamide ESI-MS: [M+Na+] = 447.20, [M+H+] = 425.20; Example 133 2-Ethylmethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid butylamide 133.1 2-(2-Carboxymethoxy-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 copper(I) bromide (0.248 g, 1.731 mmol) and omethoxy-benzoic acid (4 g, 17.31 mmol) were added and the resulting reaction was stirred at 70 0C for 12 h. Water and EtOAc were added and the organic layer was ted 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.
LCMS : m/z 283 , RT: 0.724 min. 13 3 .2 2-(2-Carboxymethoxy-phenyl)-malonic acid A solution of 2-(2-carboxymethoxy-phenyl)-malonic acid yl ester obtained in step 133.1 (2.5g, 8.86 mmol) and lithium hydroxide (1.061 g, 44.3 mmol) in CH30H (30mL) and water (8 mL) was d for 12 h at 40 CC. The solvent was 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: 0453 min. 133.3 2-Carboxymethylmethoxy-benzoic acid A suspension of 2-(2-carboxymethoxy-phenyl)-malonic acid obtained in step 133.2 (200 mg, 0.787 mmol) in toluene (8 mL) was stirred for 12 h at 105 OC. The solid was filtered to give the title compound (100 mg, 60.5 % ) as a white solid.
LCMS (ESI+): m/z 211 (M+H)+, RT: 0.630 min. 133.4 5-Methoxymethoxycarbonylmethyl-benzoic acid methyl ester A mixture of 2-carboxymethylmethoxy-benzoic acid obtained in step 133.3 (100 mg, 0.476 mmol) and sulfiJrous dichloride (170 mg, 1.427 mmol) in CHgOH (10 mL) was stirred at 65 0C 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. 1 3 3 .5 2-(2-Dimethylaminomethoxycarbonyl-vinyl)methoxy-benzoic acid methyl ester A solution of oxymethoxycarbonylmethyl-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 trated to give a residue which was purified by Prep-TLC (PE: 1 :1) to give the title compound (600 mg, 69.6 % ) as a yellow oil.
LCMS (1351+); m/z 267 (M—27)+, RT: 0735 min. 13 3 .6 2-Ethylmethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid methyl ester A solution of 2-(2-dimethylaminomethoxycarbonyl-vinyl)methoxy-benzoic acid methyl ester obtained in step 133.5 (500mg, 1.705 mmol), ethanamine (231 mg, .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.
LCMS (ESI+): m/z 262 (M+H)+, RT: 0.867 min. 13 3 .7 2-Ethylmethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid lmethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid methyl ester obtained in step 133.6 and lithium hydroxide (77 mg, 3.22 mmol) in CHgOH (15 mL) and water (2mL) were stirred at 35 0C for 5 h. The reaction solution was concentrated and the ed 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.
LCMS (ESI+): m/z 248 (M+H)+, RT: 0.737 min. 13 3 .8 2-Ethylmethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid butylamide A solution of 2-ethylmethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid obtained in step 133.7 (300mg, 1.209 mmol) in SOClz (4 mL) was stirred at 76 0C for 2h; then SOClz was removed. The obtained residue was dissolved in DCM (6mL) and butanamine (133 mg, 1.813 mmol) and ylamine (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 (200 mg, 0.659 mmol, 54.6 % yield). 1H-NMR (400 MHz :7.93 (d, J: 8.8 Hz, 1H), 7.68 (d, J: 2.8 Hz, , MeOD) 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).
The compounds of the following examples 134 to 136 were prepared in y to example 133. e 1 34 2-(1-Ethyl-propyl)methoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid indanylamide ESI-MS: [M+Na+] = 427.10, [M +] = ; Example 135 thyl-propyl)-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinolinecarboxylic acid indanylamide 13 5. 1 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinoline carboxylic acid methyl ester A solution of 2-(2-dimethylaminomethoxycarbonylvinyl)-4,5-dimethoxy- c 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.
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. 13 5 .2 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinoline ylic acid A mixture of 2-( 1 -ethyl-propyl)-6,7-dimethoxyoxo- 1 ,2-dihydro-isoquino line carboxylic acid methyl ester obtained in step 135.1 (750 mg, 2.250 mmol) and lithium hydroxide (108 mg, 4.50 mmol) in CHgOH (8 mL) and water (2 mL) was stirred at 35 0C for 5 h. The reaction solution was concentrated and the obtained e was 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 : m/z 320 , RT: 0.804 min. 13 5 .3 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1 ,2-dihydro-isoquinoline carboxylic acid indanylamide A solution of 2-(1-ethyl-propyl)-6,7-dimethoxyoxo-1 ,2-dihydro-isoquino line- 4-carboxylic acid obtained in step 135.2 (300 mg, 0.939 mmol) in SOClz (5 mL) was stirred at 76 0C for 2 h. SOClz was removed. The obtained residue was dissolved in DCM (5mL), 2,3-dihydro-1H-indenamine (188 mg, 1.409 mmol) was added dropwise and the resulting reaction was stirred at RT for 3 h. The solvent was d and the obtained e 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. 1H-NMR (400 MHz ,MeOD) : 5 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), 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 :16 Hz, 6H).
Example 1 3 6 2-Ethylmethoxyoxo(2-quinolinyl-ethoxy)-1 ,2-dihydro-isoquino line carboxylic acid butylamide 13 6. 1 1-Bromomethoxymethyl-benzene To a solution of 1-methoxymethylbenzene (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 CC overnight. The on mixture was diluted with 30- 60 oC petroleum ether (200 mL). The e was stirred for 30 min. The reaction mixture was d. 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. 13 6.2 omethoxymethylnitro-benzene 1-Bromomethoxymethylbenzene obtained in step 136.1 (60 g, 298 mmol) was dissolved in acetic acid (150 ml) and TFA (150 ml). The mixture was cooled to -5 0C 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 CC for about 2 h. The reaction mixture was diluted with water (100 ml). The aqueous layer was extracted with ethyl acetate (3 x 100mL) and washed with sat. NaCl (100 mL), sat. NaHC03 (100 mL) and sat. NaCl (100 mL). The organic layer was dried with Na2S04, filtered and trated. The resulting solid was d with silica gel column chromatography (hexane/EtOAc = 50:1). The proper fractions were collected and concentrated to give the title compound (20 g, 27%). 13 6.3 1-Bromomethoxynitro-benzoic acid In a 1 L round-bottomed flask, 1-bromomethoxymethylnitro-benzene obtained in step 136.2 (70 g, 0.28 mol) and KMnO4 (270 g, 1.707mol) were dissolved in water (500 ml) and pyridine (250 ml) and the mixture was stirred and heated to about 110 CC over night. The on was cooled to ambient temperature and filtered through a sintered glass funnel. The aqueous layer was adjusted to pH = 2 and extracted with ethyl acetate (2 x 750 mL). The organic layer was washed with sat. NaCl (300 mL), dried with Na2S04, filtered and trated 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. 1H NMR (MeOD/TMS, 400MHz) 5: 8.09 (s, 1H), 7.64 (s, 1H), 4.00 (s, 3H). 136.4 2-(2-Carboxymethoxynitro-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 at 50 0C until the sodium had disappeared. Copper(I) bromide (0.260 g, 1.811 mmol) and then 2-bromomethoxynitro-benzoic acid obtained in step 136.3 (5.0 g, 18.11 mmol) were added. The mixture was heated at 70 OC overnight. 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 and dried over , 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. 1H NMR(CDC13/TMS, 400 MHz) 5: 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-Carboxymethylmethoxynitro-benzoic acid NaOH (3.05 g, 76 mmol) in water (15 mL) was added over 30 min to a solution of 2-(2-carboxymethoxynitro-phenyl)-malonic acid diethyl ester obtained in step 136.4 (5.42 g, 15.25 mmol) in EtOH (40 mL) at room temperature. The mixture was then stirred at 50 OC overnight, the solvent was d 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 Na2S04, filtered and concentrated in vacuo. The residue was dissolved in toluene (50 mL), and the mixture was heated at 105 0C. The mixture was trated under reduced re and the concentrate was used in the next step without fiarther ation. 136.6 oxymethoxycarbonylmethylnitro-benzoic acid methyl ester SOClz (17.16 mL, 235 mmol) was added dropwise to a solution of 2- carboxymethylmethoxynitrobenzoic acid obtained in step 136.5 (20.0 g, 78 mmol) in MeOH (150 mL) at t temperature. After the addition was completed, the mixture was heated at 65 OC overnight. The mixture was concentrated in vacuo. The e was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHC03 (60 mL), water (60 mL) and brine (60 mL). The organic layer was dried over Na2S04, filtered and concentrated. The residue was purified on a silica gel column OAc=5:1, v/v) to afford the title compound (20.7 g, 93 %) as a yellow solid.
LCMS (ESI+): m/z 284 (M+H)+, RT: 195 min. 1H C13/TMS, 400 MHz) 5: 7.72 (s, 2H), 4.01 (s, 3H), 3.97 (s, 2H), 3.92 (s, 3H), 3.71 (s, 3H). 1 3 6.7 2-((Z)Dimethylaminomethoxycarbonyl-vinyl)methoxy nitro-benzoic acid methyl ester A mixture of methyl 5-methoxymethoxycarbonylmethylnitro-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 0C overnight. The reaction mixture was concentrated under reduced re. The residue was diluted with EtOAc (20 mL) and washed with brine (6 mL*3). The organic layer was dried over Na2S04, 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. 13 6. 8 2-Ethylmethoxynitrooxo-1 ,2-dihydro-isoquino line ylic acid methyl ester A mixture of dimethylaminomethoxycarbonyl-vinyl)methoxy nitro-benzoic acid methyl ester obtained in step 136.7 (237 mg, 0.701 mmol), mine (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 (10 mL). The organic layer was dried over Na2S04, 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. 1H NMR(CDC13/TMS, 400 MHz) 5: 9.24 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 4.14 (q, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 1.45 (t, J: 7.2 Hz, 3H). 13 6.9 6-Aminoethylmethoxyoxo-1 ,2-dihydro-isoquino line carboxylic acid methyl ester To a suspension of lmethoxynitrooxo-1,2-dihydro-isoquinoline carboxylic acid methyl ester obtained in step 136.8 (200 mg, 0.653 mmol) in l (10 mL) and saturated NH4C1 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 brine (6*2 mL). The c layer was dried over Na2S04, filtered and concentrated to afford the title compound (163 mg, 90 %) as a white solid.
LCMS : m/z 277 (M+H)+, RT: 1.83 min. 1H NMR(DMSO-d6/TMS, 400 MHz) 5: 8.22 (s, 1H), 7.87 (s, 1H), 7.50 (s, 1H), .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). 13 6. 10 6-Bromoethylmethoxyoxo-1,2-dihydro-isoquinoline carboxylic acid methyl ester To a suspension of 6-aminoethylmethoxyoxo-1,2-dihydro-isoquinoline- 4-carboxylic acid methyl ester obtained in step 136.9 (1.20 g, 4.34 mmol) in 2 N H2S04 on (25 mL) was added a solution of sodium nitrite (0.899 g, 13.03 mmol) in water (5 mL) dropwise at 0 CC. The mixture was stirred at 0 CC 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 e was stirred for another 1 h at 0 CC, diluted with EtOAc (100 mL) and washed with brine (30 mL*3). The organic layer was dried over Na2S04, filtered and 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. 1H C13/TMS, 400 MHz) 5: 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). 13 6. 1 1 2-Ethylmethoxy(methoxycarbonyl)oxo-1,2- dihydroisoquinolinyl-boronic acid A mixture of 6-bromoethylmethoxyoxo-1,2-dihydro-isoquinoline 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), potassium acetate (1.134 g, 11.55 mmol) and PdC12(dppf)-CH2C12 adduct (0.314 g, 0.385 mmol) in DMF (100 mL) was stirred at 90 CC overnight. The mixture was diluted with EtOAc (200 mL) and washed with brine (60 . The c layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was used in the next step directly without further purification.
LCMS (ESI+): m/z 306 (M+H)+, RT: 1.82 min. 13 6. 12 2-Ethylhydroxymethoxyoxo-1,2-dihydro-isoquinoline carboxylic acid methyl ester A mixture of 2-ethylmethoxy(methoxycarbonyl)-l-oxo-l,2- dihydroisoquinolinyl-boronic acid obtained in step 136.11 (838 mg, 2.75 mmol), water (32 mL), acetone (4 mL), NaOH (1 10 mg, 2.75 mmol) and sodium bicarbonate (231 mg, 2.75 mmol) was warmed to 50 0C for l h. After cooling to rt, 30% H202 (0.337 mL, 10.99 mmol) was added dropwise. The reaction was d at r.t. overnight, then it was ed to pH=4 by se addition of 2 N HCl, and extracted with DCM (50 mL*3). The DCM layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified on a silica column (PE/EtOAc=2: l, V/V) to afford the title compound (220 mg, 28.9 %) as a white solid.
LCMS : m/z 278 (M+H)+, RT: 1.87 min. 1H NMR(DMSO-d6/TMS, 400 MHz) 5: 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). 13 6. l3 2-Ethylmethoxy- l -oxo(2-quino linyl-ethoxy)- l ,2-dihydro- nolinecarboxylic acid methyl ester To a solution of 2-ethylhydroxymethoxy-l-oxo-l,2-dihydro-isoquinoline carboxylic acid methyl ester of step 136.12 (50 mg, 0.180 mmol), 2-(quinolin yl)ethanol (3 l .2 mg, 0.180 mmol) and Pth (142 mg, 0.541 mmol) in anhydrous THF (3 mL) was added DEAD (0.086 mL, 0.541 mmol) dropwise at 0 0C. The mixture was stirred at 0 0C for 30 min. Then it was allowed to warm to ambient temperature and stirred overnight. The mixture was diluted with EtOAc (20 mL) and washed with 2 N HCl (10 mL*3). The aqueous layer was d with 2 NNaOH to pH=10, then extracted with EtOAc (15 mL*3). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE/EtOAc=l :l, V/V) to afford the title compound (55 mg, 47.3 %).
LCMS (ESI+): m/z 433 (M+H)+, RT: 1.91 min. 1H C13/TMS, 400 MHz) 5: 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). 13 6. l4 2-Ethylmethoxy- l -oxo(2-quino linyl-ethoxy)- l ,2-dihydro- isoquinolinecarboxylic acid A mixture of methyl 2-ethylmethoxy-l-oxo(2-quinolinyl-ethoxy)-l,2- dihydro-isoquinolinecarboxylic acid ethyl ester obtained in step 136.13 (55 mg, 2012/072175 0.085 mmol) and NaOH (10.22 mg, 0.256 mmol) in MeOH (3 mL) and water (1 mL) was heated at 50 0C for 3h. The reaction e 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 over Na2S04, filtered and concentrated in vacuo. The residue was used in the next step without filrther purification.
LCMS (ESI+): m/z 419 (M+H)+, RT: 2.08 min. 13 6. 15 2-Ethylmethoxyoxo(2-quinolinyl-ethoxy)-1,2-dihydro- isoquinolinecarboxylic acid mide A sion of 2-ethylmethoxyoxo(2-quinolinyl-ethoxy)-l ,2- dihydro-isoquinolinecarboxylic acid ed in step 136.14 (80 mg, 0.080 mmol), DMF (6.22 uL, 0.080 mmol) and SOC12 (0.018 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-l-amine (11.75 mg, 0.161 mmol) and Et3N (0.034 mL, 0.241 mmol) in DCM (2 mL) at ambient temperature. The on 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 Na2S04, filtered and concentrated in vacuo. The residue was purified on a silica column (PE/EtOAc=l :1, 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. 1H NMR(CDC13/TMS, ) 5: 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 (m, 5H), 0.93 (t, J: 7.2 Hz, 3H).
LCMS (ESI+): m/z 474 (M+H)+, RT: 2.05 min.
Example 1 3 7 2-Ethylmethoxyoxo(3-quinolinyl-propoxy)- 1 ,2-dihydro-isoquino line- 4-carboxylic acid butyl amide 137.1 (E)—3-Quinolinyl-acrylic acid ethyl ester (2-Ethoxyoxoethyl) triphenylphosphonium bromide (16.8 g, 39.1 mmol) and quinolinecarbaldehyde (5.8 g, 36.9 mmol) were dissolved in EtOH (100 ml). The e was heated at about 80 0C over night. The solvent was removed under reduced pressure, and the residue was purified with silica column (eluted with 5:1 /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: l.87lmin 13 7.2 3-Quinolinyl-propanol To a suspension of LiAlH4 (0.534 g, 14.05 mmol) in THF (10 ml), at -78 CC was added (E)—3-quinolinyl-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 d pressure to provide the desired crude product as an off-white solid. The crude product was purified with plate TLC (eluted with 1:1 hexane/EtOAc) to give the title compound (55 mg, 4.2 %).
LCMS : m/z 188 (M+H)+, RT: 1.074 min. 13 7.3 2-Ethylmethoxy- l -oxo(3-quino yl-propoxy)- l ,2-dihydroisoquinolinecarboxylic acid methyl ester To a solution of 2-ethylhydroxymethoxy-l-oxo-l,2-dihydro-isoquinoline carboxylic acid methyl ester obtained in step 136.12 (148 mg, 0.534 mmol) and Pth (420 mg, 1.602 mmol) in anhydrous THF (3 mL) was added DEAD (0.254 mL, 1.602 mmol) dropwise at -30 oC. The mixture was d at -30 0C for 30 min. Then a solution of 3-quinolinyl-propan-l-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 t 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 Na2S04, filtered and concentrated in vacuo. The e was d by pre-TLC (PE/EtOAc=l :1, v/v) to afford the title compound (43 mg, ll.36 %).
LCMS (ESI+): m/z 447 (M+H)+, RT: 2.08 min. 13 7.4 2-Ethylmethoxy- l -oxo(3-quino linyl-propoxy)- l ,2-dihydro- isoquinolinecarboxylic acid A mixture of 2-ethylmethoxy- l -oxo(3-quinolinyl-propoxy)- l ,2-dihydro- isoquinolinecarboxylic acid methyl ester ed 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 CC for 3h. The reaction mixture was acidified with HCl (2 N) to pH=4~5.
The aqueous solution was concentrated in vacuo. and re-evaporated with MeOH (5 mL*3). The residue was used in the next step without fiarther purification.
LCMS (ESI+): m/z 433 (M+H)+, RT: 1.39 min. 13 7.5 2-Ethylmethoxy- l -oxo(3-quino linyl-propoxy)- l ,2-dihydro- isoquinolinecarboxylic acid butylamide A suspension of 2-ethylmethoxy- l -oxo(3-quinolinyl-propoxy)- l ,2- dihydro-isoquinolinecarboxylic acid obtained in step 137.4 (23 mg, 0.023 mmol), DMF (3.54 uL, 0.046 mmol) and sulfiJrous dichloride (8. 16 mg, 0.069 mmol) in DCM (2 mL) was refluxed for 3h. The mixture was trated in vacuo. The residue was dissolved in DCM (2 mL). The solution was added dropwise to a mixture of butan-l- amine (1.673 mg, 0.023 mmol) and Eth (9.56 uL, 0.069 mmol) in DCM (2 mL) at ambient temperature. The reaction mixture was stirred at r.t. for r 3h. Then the solvent was removed under reduced re, the residue was d with EtOAc (15 mL) and washed with brine (5 mL*3). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by pre-HPLC to afford the title compound (3 mg, 26.9 %) as a white solid. 1H NMR (MeOD/TMS, 400MHz) 5: 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- 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 ing to following general procedure: A 4 ml scintillation vial was charged with a stir bar, a on of 2-ethyl-6,7- dimethoxy-l-oxo-l,2-dihydroisoquinolinecarboxylic acid as prepared in step 1.7 (16.57 mg, 0.059 mmol) in 1.0 mL ofN,N—dimethylacetamide (DMA), a solution of the tive amine (1.2 eq, 0.0717 mmol) in DMA, a solution ofHATU (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 minutes. The Vial was decapped and placed to concentrate to dryness. An additional 1.4 mL ofDMSO/MeOH (1 :1 V/V) was added for dissolution and submission for reverse phase HPLC purification.
Example 138 2-Ethyl-6,7-dimethoxyoxo-N-(pyridin-3 -yl)- 1 ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 353.9 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, , 4.73 Hz, 1 H) 7.69 (s, 1 H) 7.74 (s, 1 H) 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-dimethoxyoxo-N-(pyrimidinylmethyl)- 1 ydroisoquino line- 4-carboxamide ESI-MS [M+H+] = 368.15 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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).
Example 140 2-Ethyl-6,7-dimethoxy(2-methoxybenzylamino)carbonyl)isoquino lin- 1 (2H)- ESI-MS [M+H+] = 397.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 ppm 1.30 (t, J=7.02 Hz, 3 H) 3.83 (d, 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) Example 141 2-Ethy1—6,7-dimeth0xy—N—(4-morpho1in0pheny1)OXO- 1 ,2-dihydroisoquino line- 4-carb0xamide ESI-MS [M+H+] = 438.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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 N—(3-Ch10r0benzyl)ethyl-6,7-dimeth0xy— 1 -OXO- 1 ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 400.9 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, 1H) 7.70 (s, 1 H) 7.82 (s, 1H). e 143 2-Ethy1—6,7-dimethoxy0X0-N-(pyridiny1methyl)- 1 ydroisoquino line carboxamide ESI-MS [M+H+] =368.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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).
Example 144 2-Ethy1—6,7-dimethoxyOXO-Nt01y1— 1 ,2-dihydroisoquino1inecarboxamide ESI-MS [M+H+] = 367.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, 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 Example 145 2-Ethyl-6,7-dimethoxy0x0-N-m-tolyl- l ,2-dihydr0isoquinolinecarb0xamide ESI-MS [M+H+] = 367.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 ppm 1.33 (t, J=7.17 Hz, 3 H) 2.33 (s, 3 H) 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, l H) 7.70 (d, J=l4.34 Hz, 2 H) 7.95 (s, l H) Example 146 2-Ethyl-6,7-dimeth0xy—N—(2-meth0xyphenyl)0x0- 1 ,2-dihydr0isoquinoline amide ESI-MS [M+H+] =383.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, l H) 7.11 (d, J=7.32 Hz, 1 H) 7.18 - 7.24 (m, l H) 7.68 (s, l H) 7.73 - 7.79 (m, 2 H) 7.96 (s, l H) Example 147 2-Ethyl-6,7-dimethoxy—N—(3-meth0xyphenyl)0x0- 1 ,2-dihydr0isoquinoline carboxamide ESI-MS [M+H+] =383.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, l H) 7.28 - 7.30 (m, 2 H) 7.38 (d, J=l.83 Hz, 1 H) 7.69 (d, J=6.41 Hz, 2 H) 7.95 (s, l H) Example 148 l-6,7-dimethoxy0x0-N-(pyridinylmethyl)- l ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 368.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 8 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, l H) 7.73 (s, l 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, l H) Example 149 2012/072175 2-Ethyl-6,7-dimethoxy0x0-N-(pyridinylmethyl)- 1 ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 368.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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 - 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-(Dimethylamin0)pr0pyl)ethyl-6,7-dimethoxy0x0-1 ,2- dihydroisoquinolinecarb0xamide ESI-MS [M+H+] = 362.0 1H NMR (500 MHz, DMSO/DZO) 5 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) Example 151 2-Ethyl-6,7-dimethoxyphenyl- 1 ,2-dihydroisoquin0linecarb0xamide ESI-MS [M+H+] = 353.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 ppm 1.33 (t, J=7.17 Hz, 3 H) 3.86 (s, 3 H) 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)0x0- 1 ,2-dihydr0isoquinoline carboxamide ESI-MS [M+H+] = 397.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, 1 H) Example 153 2-Ethy1—6,7-dimethoxy-N—(4-methy1benzy1)OXO- 1 ,2-dihydr0isoquinoline carboxamide ESI-MS [M+H+] = 381.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 8 ppm 1.29 (t, J=7.17 Hz, 3 H) 2.31 (s, 3 H) 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 1 0 2-Ethy1—6,7-dimethoxy-N—(2-methy1benzy1)OXO- 1 ydr0isoquinoline carboxamide ESI-MS [M+H+] = 381.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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) 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-Ethy1—6,7-dimethoxy—N—(2-methoxyethy1)OXO- 1 ,2-dihydr0isoquinoline carboxamide ESI-MS [M+H+] =335.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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) Example 156 2-Ethy1—N—(4-fluor0pheny1)-6,7-dimeth0xy0X0-1 ,2-dihydroisoquino - carboxamide ESI-MS [M+H+] =371.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 ppm 1.33 (t, J=7.02 Hz, 3 H) 3.86 (s, 3 H) 3.89 (s, 3 H) 4.06 (q, J=7.22 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) Example 157 2-Ethyl-6,7-dimethoxy-N—(4-nitr0phenyl)0x0- 1 ydroisoquino line carboxamide ESI-MS [M+H+] =383.0 m/z. 1H NMR (500 MHz, ZO) 5 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 2-Ethyl-6,7-dimethoxy0x0-N-p-tolyl- 1 ,2-dihydr0isoquin0linecarb0xamide ESI-MS [M+H+] = 367.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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) Example 159 2-Ethyl-N—(3-fluor0phenyl)-6,7-dimethoxy0x0-1 ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 371.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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 2-Ethyl-N—(2-fluor0phenyl)-6,7-dimeth0xy0x0-1 ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 371.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, 1 H) 8.01 (s, 1 H) Example 161 1—6,7-dimethoxy-N—(4-methy1benzy1)OXO- 1 ,2-dihydroisoquinoline carboxamide ESI-MS [M+H+] = 381.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 8 ppm 1.29 (t, J=7.02 Hz, 3 H) 2.29 (s, 3 H) 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-Chlorobenzy1)ethy1-6,7-dimeth0xyOXO- 1 ,2-dihydroisoquino line carboxamide ESI-MS [M+H+] = 401.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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 H) Example 163 (R)Ethy1—N—( 1 oropheny1)ethy1)-6,7-dimethoxyOXO- 1 ,2- dihydroisoquino11necarboxamide ESI-MS [M+H+] = 399.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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) Example 164 2-Ethy1—6,7-dimethoxy0X0-N—(pyrid1ny1)- 1 ,2-dihydroisoquin0 line carboxamide ESI-MS [M+H+] = 353.9 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 ppm 1.35 (t, J=7.17 Hz, 3 H) 3.88 (s, 3 H) 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).
Example 165 (S)Ethyl-N-(1-(4-fluorophenyl)ethyl)-6,7-dimethoxyoxo-1 ,2- dihydroisoquinolinecarboxamide ESI-MS [M+H+] = 399.0 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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 2-Ethyl-6,7-dimethoxyoxo-N-(1,2,3 rahydronaphthalenyl)-1,2,3 , 8a- tetrahydroisoquinolinecarboxamide ESI-MS [M+H+] = 407.2 m/z. 1H NMR (500 MHz, DMSO/DZO) 5 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, 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 ed according to following general procedure: In a 4 ml microwave vial was added 2-ethyl-6,7-dimethoxyoxo-1,2-dihydroiso- quinolinecarboxylic acid as prepared in step 1.7 (25 mg, 0.09 mmol), followed by 2- (1Hazabenzotriazo lyl)- 1 , 1 ,3 ,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU; 42 mg, 0.10 mmol), ylamine (37 ul, 0.27 mmol) and the respective amine (0.11 mmol). This mixture was placed in Anton Par with stir bar and heated at 150 0C 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.
Example 167 2-Ethy1—6,7-dimethoxy—N—(6-methy1—2,3-dihydro-1H-inden—1-y1)0X0-1,2- dihydroisoquinolinecarboxamide 1H NMR (500 MHz) 8 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 (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=11.90 Hz, 2 H).
MS (1351+) M/Z 407 [M+H]+.
Example 168 2-Ethy1—6,7-dimethoxy-N—(2-(morpholinomethy1)benzy1)OXO- 1 ,2-dihydroiso- inecarboxamide 1H NMR (500 MHzES 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, 0 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).
MS (1351+) M/Z 466 [M+H]+.
Example 169 N—(5-Chloro-2,3-dihydr0-1H-inden—1-y1)ethy1—6,7-dimeth0xy0X0-1,2- dihydroisoquinolinecarboxamide 1H NMR (500 MHz) 8 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]+.
Example 170 N—(6-Chloro-2,3-dihydr0-1H-inden—1-y1)ethy1—6,7-dimeth0xy0X0-1,2- dihydroisoquinolinecarboxamide 1H NMR (500 MHz) 8 ppm 1.28 (t, J=7.17 Hz, 3 H) 2.01 (dd, J=12.66, 8.09 Hz, 1 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). 2012/072175 MS (1351+) M/Z 427 [M+H]+.
Example 171 2-Ethyl-N—(6-fluoro-2,3-dihydro-1H-inden—1-yl)-6,7-dimeth0xy0x0-1,2- dihydroisoquinolinecarb0xamide 1H NMR (500 MHz) 8 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) .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, .19 Hz, 1 H) 7.66 (s, 1 H) 7.78 (d, J=13.43 Hz, 2 H).
MS (ESI+) M/Z 411 [M+H]+. e 172 N—(5 ,6-Dihydr0-4H-cyclopenta[b]thiophen—4-yl)ethyl-6,7-dimethoxy0x0- 1 ,2-dihydroisoquinolinecarb0xamide 1H NMR (500 MHZ, Solvent) 8 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) .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]+.
Example 173 2-Ethyl-N—(4-fluoro-2,3-dihydro-1H-inden—1-yl)-6,7-dimeth0xy0x0-1,2- dihydroisoquinolinecarb0xamide 1H NMR (500 MHz) 8 ppm 1.28 (t, J=7.17 Hz, 3 H) 2.03 (dd, J=12.66, 8.39 Hz, 1 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]+.
Example 174 2-Ethyl-6,7-dimethoxy—N—(4-methyl-2,3-dihydr0-1H-inden—1-yl)0x0-1 ,2- dihydroisoquinolinecarb0xamide 1H NMR (500 MHz) 5 ppm 1.28 (t, J=7.17 Hz, 3 H) 1.96 (dd, J=12.51, 8.54 Hz, 1 H) 2.25 (5, 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 (5, 1 H) 7.76 (d, J=14.34 Hz, 2 H).
MS (1351+) M/Z 407 . e 175 2-Ethy1—6,7-dimethoxy—N—(5-methy1—2,3-d1hydro-1H-inden—1-y1)0X0-1,2- dihydroisoquino11necarboxamide 1H NMR (500 MHz) 8 ppm 1.27 (t, J=7.17 Hz, 3 H) 1.89 - 2.02 (m, 1 H) 2.30 (5, 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 (5, 1 H) 7.76 (d, J=15.56 Hz, 2 H).
MS (1351+) M/Z 407 [M+H]+.
Example 176 2-Ethy1—6,7-d1meth0xy—N—(6-meth0xy-2,3-d1hydro-1H-inden—1-y1)0X0-1,2- dihydroisoquino11necarboxamide 1H NMR (500 MHz) 8 ppm 1.28 (t, J=7.17 Hz, 3 H) 1.97 (dd, J=12.51, 7.93 Hz, 1 H) 2.70 - 2.85 (m, 1 H) 2.91 (dd, J=8.85, 3.36 Hz, 1 H) 3.72 (5, 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 (5, 1 H) 7.78 (d, J=5.80 Hz, 2 MS (1351+) M/Z 423 [M+H]+.
Example 177 2-Ethy1—N—(5-fluoro-2,3-dihydro-1H-1nden—1-y1)-6,7-d1meth0xy0X0-1,2- dihydroisoquino11necarboxamide 1H NMR (500 MHz) 8 ppm 1.28 (t, J=7.17 Hz, 3 H) 2.01 (dd, J=12.51, 7.93 Hz, 1 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 (5, 1 H) 7.77 (d, J=6.10 Hz, 2 H) 8.73 (d, J=8.24 Hz, 1 H).
MS (ESI+) M/Z 411 [M+H]+.
Example 178 N—(2-((Diethylamino)methyl)benzyl)ethyl-6,7-dimethoxyoxo- 1 ,2- dihydroisoquinolinecarboxamide 1H NMR (500 MHz) 8 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]+.
Example 179 2-Ethyl-6,7-dimethoxyoxo-N-(2-(pyrrolidinylmethyl)benzyl)- 1 ,2- dihydroisoquinolinecarboxamide 1H NMR (500 MHz) 8 ppm 1.22 - 1.34 (m, 4 H) 1.89 - 1.97 (m, 2 H) 2.08 - 2.16 (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]+.
The compounds of the following examples 180 and 181 were prepared by analogy to example 133 starting from lmethoxyoxo-1,2-dihydro-[2,6]naphthyridine- 2-carboxylic acid, which in turn was prepared by analogy to steps 1331-1337 of e 133 ng from commercially available 5-bromomethoxy-isonicotinic acid.
Example 1 80 2-Ethylmethoxyoxo-1 ,2-dihydro-[2,6]naphthyridinecarboxylic acid indan- 1 de ESI-MS: [M+Na+] = 386.20, [M +H 1 = 364.10.
Example 1 8 1 lmethoxy- l -oxo- l ,2—dihydro- [2,6]naphthyridinecarboxylic acid butylamide ESI-MS: [2M+Na+] = 629.20, [M +H 1 = 304.10.
The compound of the following example 182 was prepared according to example 13 3 starting from (Z)-methyl 2—(1-(dimethylamino)methoxyoxoprop- l yl)-5 - methoxybenzoate, which in turn was ed according to step 133.6 of example 133 starting from starting from 2-(quinolinyl)ethanamine.
Example 1 82 7-Methoxy- l -oxo(2-quino linyl-ethyl)- l ,2-dihydro-isoquinoline carboxylic acid butylamide ESI-MS: [M +H+] = 430.20.
The following compounds were prepared in analogy to the above examples.
Example 1 83 7-Methoxy- l -oxo(2-quino linyl-ethyl)- l ,2-dihydro-isoquinoline carboxylic acid indan- l -ylamide ESI-MS: [M +H +] = 490.20.
Example 184 (S)ethyl-6,7-dimethoxyoxo-N-(l ,2,3 ,4-tetrahydronaphthalen— l -yl)-3 ,4- dihydrophthalazine- l -carboxamide ESI-MS: [M+Na+] = , [M +H 1 = 408.20.
Example 1 85 3 -Ethyl-6,7-dimethoxyoxo-3 ,4-dihydro-phthalazine- l -carboxylic acid (S)- indan- l -ylamide ESI-MS: [M+Na+] = 416.20, [M +H 1 = .
Example 186 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid (6,7-dihydr0-5H-[ l ]pyrindin-5 -yl)-amide ESI-MS: [M +H 1 = 436.20.
Example 1 87 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid 2-dimethylaminomethyl-benzylamide hloride ESI-MS: [M +H 1: 466.30.
Example 1 8 8 2-( l -propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid 3 ,5 -difluoro-benzylamide ESI-MS: [M +H 1 = 445.20; Example 1 89 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid 3 ,4-diflu0ro-benzylamide ESI-MS: [M +H 1 = 445.20.
Example 190 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid cyclohexylmethyl-amide ESI-MS: [M +H 1 = 415.30; Example 191 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid (R)-indan— l -ylamide ESI-MS: [M +H 1 = .
Example 1 92 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid (S)-indan— l -ylamide ESI-MS: [M +H 1 = 435.30.
Example 193 2-( 1 -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydro-isoquinolinecarb0xylic acid (5 ,6-dihydro-4H-cyclopenta[b]thi0phen—4-yl)-amide ESI-MS: 442.10, [M +H +] = 441.10.
Example 194 2-( 1 -propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydro-isoquinolinecarb0xylic acid (2,3 ro-benz0 furan—3 -yl)-amide ESI-MS: [M +Na+] = 459.15, 438.20, [M +H 1 = 437.15.
Example 195 2-( 1 -Ethyl-propyl)-6,7-dimeth0xy— 1 -0x0- 1 ,2-dihydro-isoquinolinecarb0xylic acid (6-0x0-5 ,6-dihydro-4H-cyclopenta[b]thi0phen—4-yl)-amide ESI-MS: [M +Na+] = 477.05, 456.10, [M +H 1 = 455.10.
Example 196 2-Cyclopropyl—6,7-dimethoxy0x0- 1 ,2-dihydro-isoquino linecarb0xylic acid indan— 1 -ylamide ESI-MS: 406.10, [M +H+] = 405.10.
Example 197 2-sec-Butyl-6,7-dimeth0xy0x0- 1 ,2-dihydro-isoquino linecarb0xylic acid indan— 1 -ylamide ESI-MS: , [M+H+] = 421.10.
Example 198 ropyl-6,7-dimeth0xy0x0- 1 ,2-dihydro-isoquino linecarb0xylic acid 3 0 indan— 1 -ylamide : 408.20, [M +H 1 = 407.15; e 199 (+)( l -Ethyl-pr0pyl)-6,7-dimethoxy0x0- 1 ,2-dihydr0-isoquin0 line carboxylic acid (6,7-dihydro-5H- [ l ]pyrindin—5 -yl)-amide ESI-MS: 437.20, [M +H 1 = 436.20.
Example 200 (-)( l -pr0pyl)-6,7-dimeth0xy0x0- 1 ,2-dihydro-isoquinoline carboxylic acid (6,7-dihydro-5H- [ l ]pyrindin—5 -yl)-amide ESI-MS: 437.20, [M +H 1 = 436.20.
Example 201 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid ([1 ,3 ,4]thiadiaz0 methyl)-amide ESI-MS: 418.20, [M +H +] = 417.10.
Example 202 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid 2-(m0rpholinesulf0nyl)-benzylamide ESI-MS: , , [M +H 1: 558.20; Example 203 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid (thiazolylmethyl)-amide ESI-MS: 417.10, [M+H+] = 416.10.
Example 204 (+)Ethyl-6,7-dimeth0xy0x0- 1 ,2-dihydr0-isoquino linecarb0xylic acid (5 ,6-dihydro-4H-cyclopenta[b]thi0phen—4-yl)-amide ESI-MS: [M +H 1 = 399.10.
Example 205 (-)Ethyl-6,7-dimethoxy0x0-1 ,2-dihydr0-isoquinolinecarb0xylic acid (5 ,6- dihydro-4H-cyclopenta[b]thiophen—4-yl)-amide ESI-MS: [M +H 1: 399.10.
Example 206 2-( 1 -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarboxylic acid (thiophen—3-ylmethyl)-amide ESI-MS: 416.10, [M +H +] = 415.10.
Example 207 2-(1-Ethyl-pr0pyl)-6,7-dimeth0xy(3-phenyl-piperidinecarb0nyl)-2H- isoquino lin0ne ESI-MS: [M +H 1 = .
Example 208 2-(1-Ethyl-pr0pyl)-6,7-dimeth0xy(3-phenoxy-piperidinecarb0nyl)-2H- isoquino lin0ne ESI-MS: [M +H 1 = 479.20.
Example 209 2-( 1 -Ethyl-pr0pyl)-6,7-dimeth0xy [3 -(3 xy-phenyl)-piperazine yl]-2H-isoquino lin0ne ESI-MS: [M +H 1 = 494.20.
Example 2 1 0 2-(1-Ethyl-pr0pyl)-6,7-dimeth0xy—4-[8-(4-methyl-piperazinesulf0nyl)-3 ,4- dihydro-1H-isoquinolinecarb0nyl]-2H-isoquinolin—1-0ne ESI-MS: [M +H 1 = 597.20.
Example 21 1 2-(1-Ethyl-pr0pyl)-6,7-dimeth0xy[8-(morpholinesulfonyl)-3 ,4-dihydr0-1H- isoquinolinecarbonyl]-2H-isoquinolinone ESI-MS: [M +H 1 = 584.20.
Example 2 l 2 2-( l -Ethyl-pr0pyl)-6,7-dimeth0xy [3 -(3 xy-phenyl)methyl-piperazine- l-carbonyl]-2H-isoquino lin- l -0ne ESI-MS: [M +H 1 = 508.30.
Example 2 l 3 2-( l -Ethyl-pr0pyl)-6,7-dimeth0xy [(R)-3 -(quin0xalinyloxy)-pyrrolidine- l - lO carbonyl]-2H-isoquino lin- l -0ne ESI-MS: [M +H 1+: 517.20.
Example 2 l 4 4-(7-Amin0-3 ,4-dihydr0- l H-isoquino linecarb0nyl)( l -ethyl-pr0pyl)-6,7- l 5 dimethoxy-2H-isoquino lin- l -0ne trifluoroacetate ESI-MS: [M +H 1+ = .
Example 2 l 5 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid 3-(4-chlor0-benzenesulfonylamino)-benzylamide ESI-MS: [M]+ = 598.20.
Example 216 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ydr0-isoquinolinecarb0xylic acid (2,3 -dihydr0-benz0 [b]thi0phen—3 -yl)-amide : [M +Na] = 475 .20, [M +H 1 = 453 .20.
Example 217 2-( l -Ethyl-pr0pyl)methoxy0x0- 1 ,2-dihydr0- [2,6]naphthyridinecarboxylic 3 0 acid (5 ,6-dihydro-4H-cyclopenta[b]thiophen—4-yl)-amide ESI-MS: [M +Na] = 434.10, [M +H 1 = 412.10. 2012/072175 Example 2 l 8 2-( l -Ethyl-propyl)methoxy0x0- 1 ,2-dihydro- [2,6]naphthyridinecarboxylic acid (S)-indan— l -ylamide : [M +Na] = 428.10, [M +H 1 = .
Example 219 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydro-isoquinolinecarb0xylic acid 2-(4-methyl—piperazine- l -sulfonyl)-benzylamide ESI-MS: [M +H]+ = 571.30.
Example 220: 2-( l -Ethyl-propyl)methoxy0x0- 1 ,2-dihydro- [2,6]naphthyridinecarboxylic acid 2-(morph0linesulf0nyl)-benzylamide : [M +Na 1+ = 551.20, [M +H] = 529.20.
Example 221: 2-( l -Ethyl-propyl)methoxy0x0- 1 ,2-dihydro- [2,6]naphthyridinecarboxylic acid (6,7-dihydro-5H-[ l din-5 -yl)-amide ESI-MS: [M +Na 1+ = 429.15, [M +H 1+ = 407.20.
Example 222 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydro-isoquinolinecarb0xylic acid 3-(4-methoxy-benzenesulfonylamino)-benzylamide ESI-MS: [M +Na]+ = 616.20, [M +H] = 594.30.
Example 223 2-( l -Ethyl-propyl)methoxy0x0- 1 ,2-dihydro- [2,6]naphthyridinecarboxylic acid 3 ,5-difluoro-benzylamide ESI-MS: [M+Na]+ = 438.15, [M+H] = 416.10 Example 224 2-( l -Ethyl-pr0pyl)methoxy0x0- 1 ,2-dihydr0- aphthyridinecarboxylic acid 4-methyl-benzylamide ESI-MS: [M +Na 1+ = 416.20, [M +H] = 394.20.
Example 225 2-( l -Ethyl-pr0pyl)methoxy0x0- 1 ydr0- [2,6]naphthyridinecarboxylic acid cyclohexylmethyl-amide ESI-MS: [M +Na 1+ = 408.20, [M +H 1+ = 386.20.
Example 226 2-( l -Ethyl-pr0pyl)methoxy0x0- 1 ,2-dihydr0- [2,6]naphthyridinecarboxylic acid butylamide : [M +H 1+ = 346.20. e 227: 2-( l -Ethyl-pr0pyl)methoxy0x0- 1 ,2-dihydr0- [2,6]naphthyridinecarboxylic acid (2,3-dihydr0-benz0furan—3-yl)-amide ESI-MS: [M +Na 1+ = 430.20, [M +H] = 408.20.
Example 228 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid (thiazolylmethyl)-amide ESI-MS: [M+Na]+ = 438.10, [M+H]+ = 416.10.
Example 229 2-( l -Ethyl-propyl)-6,7-dimethoxy— 1 -0x0- 1 ,2-dihydr0-isoquinolinecarb0xylic acid (thiophen—2-ylmethyl)-amide ESI-MS: [M+Na]+ = , [M+H] = 415.10.
Example 230 2-Ethylmeth0xy0x0- 1 ,2-dihydr0- [2,6]naphthyridinecarboxylic acid (5 ,6- dihydro-4H-cyclopenta[b]thiophen—4-yl)-amide ESI-MS: [M +Na]+ = 392.10, [M +H]+ = 370.10.
Example 231 3 -( l -Ethyl-pr0pyl)-6,7-dimethoxyox0-3 ,4-dihydr0-phthalazine- l -carb0xylic acid (5,6-dihydr0-4H-cyclopenta[b]thiophen—4-yl)-amide trifluoroacetate ESI-MS: [M +Na 1+ = 464.10, [M +H 1+ = 442.15.
Example 232 3 -( l -Ethyl-pr0pyl)-6,7-dimethoxyox0-3 ,4-dihydr0-phthalazine- l -carb0xylic l 0 acid (2,3 -dihydr0-benz0 furan—3 -yl)-amide trifluoroacetate ESI-MS: [M +Na 1+ = 460.20, [M +H 1+ = 438.20.
Example 233 3 -( l -Ethyl-pr0pyl)-6,7-dimethoxyox0-3 ,4-dihydr0-phthalazine- l -carb0xylic acid (6,7-dihydr0-5H-[ l din-5 -yl)-amide ESI-MS: [M +Na +] = 459.20, [M +H 1+ = 437.20. e 234: 2-( l -pr0pyl)-6,7-dimeth0xy(3-phenyl-pr0pi0nyl)-2H-is0quino lin- l -0ne ESI-MS: [M +Na]+ = 430.20, [M +H] = 408.20 Example 235 3 -( l -pr0pyl)-6,7-dimethoxyox0-3 ,4-dihydr0-phthalazine- l -carb0xylic acid indan— l -ylamide ESI-MS: [M +Na]+ = 458.20, [M +H 1+ = .
Example 236 6,7-Dimeth0xy- l -0x0(pentan—3 -yl)-N-(pyridin-3 -ylmethyl)- l ,2- dihydroisoquinolinecarb0xamide A microwave Vial was charged with a stir bar and 284 mg of PS-TFP (lO eq.). To the vessel were added 6,7-dimethoxy— l -oxo(pentan—3-yl)- l ,2-dihydroisoquinoline carboxylic acid (29 mg, 0.09 mmol) dissolved in dry THF(1.0 mL) and CClgCN (36 uL, 0.36 mrnol) dissolved in dry THF(0.5 mL). The reaction vessel was sealed and heated to 120°C for 1800 seconds. Then pyridinylmethanamine (15 mg, 0.135 mmol) dissolved in THF (0.5 mL) was added ed by DIEA (47 uL, 0.27 mmol). The mixture was heated again to 150°C for 1800 seconds. After cooling the reaction mixture was filtered and products were ted and trated to dryness. The residues were dissolved in 1:1 DMSO/MeOH. Purification by e phase HPLC provided the title compound (14.7 mg, 31%).
ESI-MS =410 [M+H]+; 1H NMR (500 MHz, DMSO-DZO ,T: 25 CC) 8 ppm 8.86 (s, l 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, l H) 7.67 (d, J=10.99 Hz, 2 H) 4.86 (s, l 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).
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)- l -oxo(pentan-3 -yl)- l ,2- dihydroisoquinolinecarboxamide ESI-MS = 429 ; 1H NMR (500 MHz, DMSO-DgO, T: 25 oC) 8 ppm 7.72 (s, 1 H) 7.67 (s, 1 H) 7.50 (s, l 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=2l.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).
Example 238 N—((3 ,5-Dimethylisoxazolyl)methyl)-6,7-dimethoxy- l -oxo(pentan-3 -yl)- l ,2- dihydroisoquinolinecarboxamide ESI-MS = 428[M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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).
Example 239 6,7-Dimeth0xy-N—((5-methylthiazo1—2-y1)methy1)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino11necarboxamide ESI-MS =430 ; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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).
Example 240 6,7-Dimeth0xy0X0(pentany1)-N-(pyrimidiny1methyl)-1 ,2- oisoquino11necarboxamide ESI-MS =411 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 ppm 9.13 (s, 1 H) 8.76 - 8.79 (m, 1 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-Dimeth0xy-N—((3-methylisoxazo 1y1)methyl)0X0(pentan-3 -y1)-1 ,2- dihydroisoquino11necarboxamide ESI-MS =414 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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).
Example 242: N—((2,5-dimethy1thiophen—3-y1)methy1)-6,7-dimeth0xy0x0 (pentan—3 -y1)- 1 ,2-dihydroisoquino linecarboxamide ESI-MS =443 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 ppm 7.67 (s, 1 H) 7.63 (s, 1 H) 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).
Example 243 6,7-Dimethoxy-N-((2-methylthiazo lyl)methyl)oxo(pentan-3 -yl)- 1 ,2- dihydroisoquinolinecarboxamide ESI-MS =430 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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 6,7-Dimethoxy-N—((5-methylisoxazo lyl)methyl)oxo(pentan-3 -yl)- 1 ,2- dihydroisoquinolinecarboxamide ESI-MS =414 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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) 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-dimethoxyoxo(pentan—3 -yl)- 1 ,2- dihydroisoquinolinecarboxamide The title nd was prepared in analogy to the process described in example 236 but using (R)(4-fluorophenyl)ethanamine instead of pyridineylmethanamine.
ESI-MS =441[M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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 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-dimethoxyoxo(pentan—3 -yl)- 1 ,2- dihydroisoquinolinecarboxamide The title compound was prepared in y to the process bed in e 236 but using (S)(4-fluorophenyl)ethanamine instead of pyridineylmethanamine.
ESI-MS =441[M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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, 1:50.35 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).
The compounds of examples 247 to 269 were prepared in an analogous manner to the process described in example 236. e 247 6,7-Dimethoxy-N—((4-methylthiazolyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide ESI-MS =430 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 ppm 7.78 (s, 1 H) 7.69 (s, 1 H) 7.62 (s, l H) 7.20 (s, l H) 4.81 - 4.94 (m, J=10.38 Hz, 1 H) 4.72 (s, 2 H) 3.87 (d, J=l9.53 Hz, 6 H) 2.36 (s, 3 H) 1.68 - 1.87 (m, 4 H) 0.74 (t, J=7.32 Hz, 6 H).
Example 248 6,7-Dimethoxy-N—((2-methylthiazolyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- dihydroisoquinolinecarboxamide ESI-MS =430 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 ppm 7.75 (s, 1 H) 7.68 (s, 1 H) 7.60 (s, l H) 7.32 (s, l H) 4.85 (s, l 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 6,7-Dimethoxy-N—((4-methylthiazo lyl)methyl)- l -oxo(pentan—3 -yl)- l ,2- oisoquinolinecarboxamide ESI-MS =430[M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 5 ppm 8.96 (s, l H) 7.68 (d, J=8.54 Hz, 2 H) 7.50 (s, l H) 4.85 (s, l H) 4.61 (s, 2 H) 3.86 (d, J=22.28 Hz, 6 H) 2.45 (s, 3 H) 1.67 - 1.89 (m, 4 H) 0.73 (t, J=7.32 Hz, 6 H).
Example 250 6,7-Dirnethoxy0X0(pentan-3 -y1)-N-((5 -(trifluorornethy1)filrany1)rnethy1)- 1 ,2-d1hydroisoquino 11necarboxarnide ESI-MS =467 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 ppm 7.72 (s, 1 H) 7.68 (s, 1 H) 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 (111,4 H) 0.73 (t, J=7.32 Hz, 6 H).
Example 251 6,7-Dimethoxy-N-((5-methy1fiJrany1)rnethy1)0X0(pentan-3 -y1)- 1 ,2- dihydroisoquino11necarboxarnide ESI-MS =413 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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, 4 Hz, 6 H) 2.24 (s, 3 H) 1.66 - 1.87 (111,4 H) 0.73 (t, J=7.32 Hz, 6 H). e 252 N—(5-F1uoro-2,3-d1hydro-1H-1nden—1-y1)-6,7-dirnethoxy0X0(pentan-3 -y1)- 1 ,2-d1hydroisoquino -carboxarnide ESI-MS [M+H]+ = 453 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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) .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 (111,4 H) 0.73 (q, J=7.02 Hz, 6 H).
Example 253 6,7-Dimethoxy-N—(5-rnethy1—2,3-d1hydro-1H-inden—1-y1)0X0(pentan-3 -y1)- 1 ,2-d1hydroisoquino 11necarboxarnide ESI-MS =449 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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 2012/072175 (m, 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). e 254 6,7-Dirnethoxy-N—(4-rnethy1—2,3-dihydro-1H-inden—1-y1)0X0(pentan-3 -y1)- 1 ,2-dihydroisoquino11necarboxarnide ESI-MS =449 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 ppm 7.74 (s, 1 H) 7.68 (s, 1 H) 7.51 (s, 1 H) 7.12 - 7.21 (111,2 H) 7.07 (d, J=7.32 Hz, 1 H) 5.57 (t, J=7.93 Hz, 1 H) 4.84 (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 (111,4 H) 0.68 - 0.77 (m, 6 H).
Example 255 N—((2-Ethy1thiaz01y1)rnethy1)-6,7-dirnethoxy0X0(pentan-3 -y1)- 1 ,2- dihydroisoquino11necarboxarnide ESI-MS =444 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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 (111,4 H) 1.30 (t, J=7.48 Hz, 3 H) 0.73 (t, J=7.32 Hz, 6 H).
Example 256 6,7-Dirnethoxy-N—(6-methoxy-2,3-dihydro-1H-inden—1-y1)0X0(pentan-3 -y1)- 1 ,2-dihydroisoquino11necarboxarnide ESI-MS =465 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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 (111,4 H) 0.73 (q, J=7.02 Hz, 6 H).
Example 257 2012/072175 6,7-D1meth0xy-N—((4-methy1thiopheny1)methy1)0X0(pentan-3 -y1)- 1 ,2- oisoquino11necarboxamide ESI-MS = 429 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 ppm 7.72 (s, 1 H) 7.67 (s, 1 H) 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-methy1thiopheny1)methy1)oxo(pentan-3 -y1)- 1 ,2- dihydroisoquino11necarboxamide ESI-MS =429 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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).
Example 259 6,7-Dimethoxy-N-((5-methy10xaz01y1)methy1)0X0(pentan-3 -y1)- 1 ,2- dihydroisoquino11necarboxamide ESI-MS =414 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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 6,7-Dimeth0xy-N—(6-methy1—2,3-d1hydro-1H-inden—1-y1)0X0(pentan-3 -y1)- 1 ,2-d1hydroisoquino11necarboxamide ESI-MS =449 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 0C) 5 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 (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 e 261 6,7-Dimeth0xy0X0(pentany1)-N-(pyridiny1methy1)-1,2- dihydroisoquino1inecarboxamide ESI-MS = 410 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 CC) 8 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).
Example 262 6,7-Dimethoxy-N—(4-methy1benzy1)0X0(pentan-3 -y1)- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS =423 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 CC) 8 ppm 7.69 (d, J=10.99 Hz, 2 H) 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-Dimeth0xy0X0(pentany1)-N-(pyridiny1methy1)-1,2- dihydroisoquino1inecarboxamide ESI-MS =410 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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 Hz, 6 H).
Example 264 Cyan0furan—2-y1)methy1)-6,7-dimethoxy—1-0xo(pentan—3 -y1)- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS =424 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 0C) 5 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, 1:14.04 Hz, 6 H) 1.67 — 1.89 (m, J=12.82 Hz, 4 H) 0.73 (t, J=7.32 Hz, 6 H).
Example 265 N—(4-Chloro-2,3-d1hydro-1H-1'nden—1-y1)-6,7-d1methoxy0X0(pentan-3 -y1)- 1 ydroisoquino11necarboxamide ESI-MS =469 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 CC) 5 ppm 7.67 - 7.74 (m, J=17.70 Hz, 2 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 N—((5-Ethy1thiophen—2-y1)methy1)-6,7-d1methoxy0X0(pentan-3 -y1)- 1 ,2- oisoquino11necarboxamide ESI-MS =443 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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 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-methy1fiJrany1)methy1)0X0(pentan-3 -y1)- 1 ,2- dihydroisoquino11necarboxamide ESI-MS =413 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 CC) 8 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).
Example 268 WO 68489 methoxy-N—((2-methylfuran—3-yl)methyl)oxo(pentan-3 -yl)- 1 ,2- oisoquinolinecarboxamide ESI-MS =413 [M+H]+: 1H NMR (500 MHz, DMSO-Dz o, T: 27 °C) 5 ppm 7.67 (s, 2 H) 7.42 — 7.48 (m, 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-1H-pyrazolyl)methyl)oxo(pentan-3 -yl)-1,2- dihydroisoquinolinecarboxamide ESI-MS =413 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 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).
Example 270 N—[(3 ,4-Dimethylphenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquino line carboxamide To a solution of 2-ethyl-6,7-dimethoxyoxo-1,2-dihydroisoquinoline carboxylic acid (25 mg, 0.09 mmol) in DMA (1.0 mL) was added a solution ofHATU (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 (40uL, 0.27mmol). The reaction was shaken at 65°C overnight. The reaction was checked by LC/MS and concentrated to s. The residues were dissolved in 1:1 DMSO/MeOH. Purification by e phase HPLCprovided the titled compound (17.9 mg, 50 %) ESI-MS: m/z 395 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 ppm 7.75 (s, 1 H) 7.70 (s, 1 H) 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 68489 The compounds of examples 271 to 292 were prepared in analogy to the process described in example 270.
Example 271 N-[(2-Chloromethyl-phenyl)methyl]ethyl-6,7-dimethoxyoxo- isoquinolinecarboxamide ESI-MS: m/z 415 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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) 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 Example 272 N— [ [2-(Dimethylamino)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxo- isoquinolinecarboxamide ESI-MS: m/z 424 [M+H]+. 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 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, 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-fluoromethyl-phenyl)methyl]-6,7-dimethoxyoxo- nolinecarboxamide ESI-MS: m/z 399 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 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).
Example 274 2-Ethy1—6,7-dimethoxy-N— [(3-meth0xymethy1—pheny1)methy1]OXO- isoquino1inecarboxamide ESI-MS: m/z 411 ; 1H NMR (500 MHz, ZO, T: 27 oC) 8 ppm 7.77 (s, 1 H) 7.71 (s, 1 H) 7.66 (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 1 0 2-Ethy1—6,7-dimethoxy-N—[(4-methy1—2-morph01ino-pheny1)methy1] OXO- isoquino1inecarboxamide ESI-MS: m/z 466 [M+H]+. 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 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 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-Butoxymethy1—pheny1)methy1]ethy1—6,7-dimethoxyOXO- isoquino1inecarboxamide ESI-MS: m/z 453 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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, J=7.17 Hz, 3 H).
Example 277 N— [ [2-(1 1 -Dimethy1pr0p0xy)methy1—pheny1]methy1]ethy1—6,7-dimethoxy oxo-isoquino1inecarboxamide ESI-MS: m/z 467 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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) 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 N—[(2,3-Difluorornethy1—pheny1)rnethy1]ethy1—6,7-dirnethoxyOXO- no11necarboxarnide ESI-MS: m/z 417 r 1H NMR (500 MHz, DMso—Dgo, T: 27 0C) 5 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 (111,2 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-Ethy1—N— [(3 -fluorornethy1—pheny1)rnethy1]-6,7-dirnethoxyOXO- isoquino11necarboxarnide ESI-MS: m/z 399 [M+H]Jr 1H NMR (500 MHz, DMso—Dgo, T: 27 0C) 5 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 (111,2 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).
Example 280 N—[(3 -chlorornethy1—pheny1)rnethy1]ethy1—6,7-dirnethoxyOXO- isoquino11necarboxarnide ESI-MS: m/z 413 [M+H]' 1H NMR (500 MHz, DMso—Dgo, T: 27 0C) 5 ppm 7.79 (s, 1 H) 7.69 (s, 1 H) 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 28 1 2-Ethy1—6,7-dirnethoxyOXO-N- [(2,4,6-trirnethy1pheny1)rnethy1] isoquino line carboxarnide ESI-MS: m/z 409 [M+H]+: 1H NMR (500 MHz, DMSO-DZO, T: 27 0C) 5 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).
Example 282 N—[(2,4-Dimethylphenyl)methyl]ethyl-6,7-dimeth0xy— 1 -0x0-isoquino line carboxamide ESI-MS: m/z 395 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 0C) 5 ppm 7.74 (s, 1 H) 7.69 (s, 1 H) 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 Example 283 2-Ethyl-6,7-dimethoxy-N— [ [2-(3-meth0xyprop0xy)methyl-phenyl]methyl] oxo-isoquinolinecarb0xamide : m/z 469 [M+H]+; 1H NMR (500 MHz, ZO, T: 27 oC) 8 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) 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-Eth0xyeth0xy)methyl-phenyl]methyl]ethyl-6,7-dimeth0xy0x0- isoquinolinecarb0xamide ESI-MS: m/z 469 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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).
Example 285 WO 68489 N—[[2-(Cyc10pentoxy)methy1—pheny1]methy1]ethy1—6,7-dimeth0xy— 1 -OXO- isoquino1inecarboxamide ESI-MS: m/z 465 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 ppm 7.74 (d, J=4.58 Hz, 2 H) 7.66 (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 2-Ethy1—6,7-dimethoxy-N—[(4-methy1—2-phen0xy-pheny1)methy1] OXO- isoquino1inecarboxamide ESI-MS: m/z 473 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 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) 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-Ethy1—6,7-dimethoxy-N— [[2-(2-methoxy- 1 1—ethoxy)methy1— pheny1]methy1]0X0-isoquino1inecarboxamide ESI-MS: m/z 469 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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 (m, 2 H) 3.23 (s, 3 H) 2.29 (s, 3 H) 1.22 - 1.34 (m, 6 H).
Example 288 2-Ethy1—6,7-dimethoxy-N— [[4-methy1—2-(2,2,2-triflu0r0ethoxy)pheny1]methy1] oxo-isoquinolinecarboxamide ESI-MS: m/z 479 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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 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 N—[[2-(Cyc10hexyloxy)methy1—pheny1]methy1]ethy1—6,7-dimethoxyOXO- nolinecarboxamide ESI-MS: m/z 479 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 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 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 1 5 N— [ [2-(Cyc10pr0py1meth0xy)methy1—pheny1]methyl]ethy1—6,7-dimethoxy oxo-isoquinolinecarboxamide : m/z 451 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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) 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-Ethy1—N—[(2-hex0xymethy1—pheny1)methy1]-6,7-dimeth0xy— 1 -OXO- isoquinolinecarboxamide ESI-MS: m/z 481 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 27 oC) 8 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 - 1.49 (m,2H) 1.15-1.34 (m,7H) 0.81 (t,3H).
Example 292 WO 68489 2-Ethyl-6,7-dimethoxy-N-[[4-methyl(tetrahydrofuran ylmethoxy)phenyl]methyl] oxo-isoquinolinecarboxamide ESI-MS: m/z 481 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 27 °C) 5 ppm 7.77 (s, 1 H) 7.73 (s, 1 H) 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).
Example 293 2-Ethyl-6,7-dimethoxy-N- [[2-(2-methoxyethoxy)methyl-phenyl]methyl] oxo-isoquinolinecarboxamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydroisoquinolinecarboxylic acid (22 mg, 0.08 mrnol) dissolved in N,N—dimethylacetamide (1.0 mL) was added to a 4mL vial charged with a stir bar ed by a solution ofHATU (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 on of (2-(2-methoxyethoxy)methylphenyl)methanamine (19.5 mg, 0.1 mrnol) dissolved in methylacetamide (0.4 mL) was added followed by ylamine neat (33 uL, 0.24 mmol) and the mixture was stirred and heated at 65°C 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 ofthe title compound (46%).
ESI-MS: m/z 455 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 ppm 7.77 (s, 1 H) 7.70 (s, 1 H) 7.66 (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 to the processes described in the examples above.
Example 294 2012/072175 2-Ethy1—N—(2-isobutoxymethy1benzy1)-6,7-dimeth0xyOXO- 1 ,2- oisoquino1inecarboxamide ESI-MS: m/z 453 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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) 6.81 (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 2-Ethy1—N—(2-(filrany1methoxy)methy1benzy1)-6,7-dimeth0xyOXO- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 477 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 25 °C) 5 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 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-Ethy1—6,7-dimethoxy-N—(4-methy1—2-(penty10xy)benzy1)OXO- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 467 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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 - 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-methy1benzy1)ethy1—6,7-dimeth0xyOXO- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 425 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 °C) 5 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 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 N-(2-sec-But0xymethy1benzy1)ethy1-6,7-dimethoxy0X0-1,2- dihydroisoquino11necarboxamide ESI-MS: m/z 453 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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 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-Ethy1—N—(2-(isopenty10xy)methy1benzy1)-6,7-dimethoxyOXO- 1 ,2- dihydroisoquino11necarboxamide : m/z 467 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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) 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-Ethy1—6,7-dimeth0xy-N—(4-methy1—2-propoxybenzy1)0X0-1 ,2- dihydroisoquino11necarboxamide : m/z 439 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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).
Example 301 2-Ethy1—6,7-dimethoxy-N—(4-methy1—2-(methylthio)benzy1)OXO- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 427 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 ppm 7.80 (s, 1 H) 7.73 (s, 1 H) 7.66 (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 2-Ethy1—N—(2-isopr0p0xymethy1benzy1)-6,7-dimeth0xyOXO- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 439 [M+H]Jr 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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 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-Ethy1—6,7-dimethoxy-N—(4-methy1—2-(tetrahydrofuran—3 )benzy1)OXO- 1 ,2-dihydr0isoquino1inecarboxamide ESI-MS: m/z 467 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 °C) 5 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 (s, 3 H) 2.16 - 2.27 (m, 1 H) 2.03 (dd, 1, 6.10 Hz, 1 H) 1.29 (t, J=7.17 Hz, 3 H).
Example 304 2-Ethy1—6,7-dimethoxy0X0-N—(2,4,5-trimethy1benzy1)- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 409 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 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). e 305 2-Ethy1—6,7-dimethoxy-N—(4-methy1—2-((tetrahydrofuran—2-y1)methoxy)benzy1)- 1-0X0- 1 ,2-dihydr0isoquino1inecarboxamide ESI-MS: m/z 481 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 ppm 7.77 (s, 1 H) 7.70 (s, 1 H) 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).
Example 306 2-Ethy1—6,7-dimethoxy-N—(4-methy1—2-(4-methy1pentan—2-y10xy)benzy1)OXO- 1 ,2-dihydr0isoquino1inecarboxamide ESI-MS: m/z 481 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 oC) 8 ppm 7.76 (s, 1 H) 7.75 (s, 1 H) 7.66 (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, , 6.71 Hz, 6 H).
Example 307 2-Ethy1—6,7-dimethoxy-N—(4-methy1—2-(4-methy1penty10xy)benzy1)OXO- 1 ,2- dihydroisoquino1inecarboxamide ESI-MS: m/z 481 [M+H]+; 1H NMR (500 MHz, DMSO-DZO, T: 25 °C) 5 ppm 7.78 (s, 1 H) 7.75 (s, 1 H) 7.65 (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).
Example 308 2-Ethyl-6,7-dimethoxy-N—(2-methoxymethylbenzyl)0x0- 1 ,2- dihydroisoquinolinecarb0xamide ESI-MS: m/z 411 [M+H]+; 1H NMR (500 MHz, ZO, T: 25 °C) 5 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 Example 309 2-Ethyl-6,7-dimethoxy0x0-N-(thiaz0lylmethyl)isoquinolinecarb0xamide ESI-MS: m/z 374.1 [M+H]Jr Example 310 2-Ethyl-6,7-dimethoxy0x0-N-[[4-(trifluoromethyl)phenyl] - methyl]isoquin0linecarb0xamide 1H NMR (DMSO-d6 ,600MHz): 5: 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 H), 1.27 - 1.32 (m, 3 H).
Example 31 1 2-Ethyl-6,7-dimeth0xy0x0-N-[(1 S)(p-tolyl)ethyl]isoquinoline carboxamide : m/z 395.2 [M+H]+ e 3 12 2-Ethyl-N—[(4-isopr0pylphenyl)methyl]-6,7-dimeth0xy0x0-isoquino line carboxamide ESI-MS: m/z 409.2 [M+H]+ Example 3 l3 1 79 l—N—[(4-ethylphenyl)methyl]-6,7-dimeth0xy- l -0x0-isoquino line carboxamide ESI-MS: m/z 395.2 [M+H]+ Example 3 14 2-Ethyl—6,7-dimethoxy0x0-N-[(l R)- l -(p-tolyl)ethyl]isoquino line amide ESI-MS: m/z 395.2 [M+H]+ Example 3 15 N— [ [4-(Difluoromethyl)phenyl]methyl]ethyl-6,7-dimeth0xy— 1 -0x0- isoquinolinecarb0xamide ESI-MS: m/z 417.1 [M+H]+ Example 3 l6 2-Ethyl—6,7-dimeth0xy-N—[(2-methylthiaz0lyl)methyl] - l -0x0-isoquino line carboxamide ESI-MS: m/z 388.1 [M+H]+ Example 3 l7 l-6,7-dimethoxy-N—[(4-methylthienyl)methyl] - l -0x0-isoquino line carboxamide ESI-MS: m/z 387.1 [M+H]+ Example 3 18 N—[(4-Cyclopropylphenyl)methyl]ethyl—6,7-dimethoxy- l soquino line carboxamide ESI-MS: m/z 407.2 [M+H]+ Example 3 l9 N—Indan— l -yl—6,7-dimethoxy [2-(5 -methylpyridyl)ethyl] - l -0x0-isoquino line- 4-carb0xamide ESI-MS: m/z 484.20 [M+H]+ Example 320 N—Butyl-6,7-dimethoxy [2-(5-methylpyridyl)ethyl] - l -oxo-isoquino line carboxamide : m/z 424.20 [M+H]+ Example 321 2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxypyridyl)ethyl] - l -oxo-isoquino line lO carboxamide; 2,2,2-trifluoroacetic acid ESI-MS: m/z 412.10 [M+H]+ Example 322 N—Butyl-6,7-dimethoxy- l -oxo[2-(2-quino lyl)ethyl]isoquinoline carboxamide; 2,2,2-trifluoroacetic acid ESI-MS: m/z 460.20 [M+H]+ Example 323 N—Indan— l -yl-6,7-dimethoxy- l -oxo [2-(2-quino lyl)ethyl]isoquino line carboxamide; 2,2,2-trifluoroacetic acid ESI-MS: m/z 520.20 [M+H]+ Biological Tests a) Measurement of PDE ty The recombinant PDE proteins are used in in vitro enzymatic reaction for measurement of PDE activity. These recombinant proteins, including PDElOA (human, rat and mouse PDElO) and isoforms of PDEs l, 3, 4, and 5, were purchased from commercial vendor BPS Bioscience. The enzymatic activity ofPDEs was ined by cAMP ement kit from CisBio (IBA) using HTRF technology.
The PDE tic reaction was d out in assay buffer (20mM Tris-HCl pH7.5, lOmM MgClz, 0.1% bovine serum albumin) containing enzyme and substrate.
The PDE enzymes concentration ranged from 10pM — 250pM, depending on each enzyme’s specific activity. The ate cyclic tide (CAMP or cGMP) concentration used in the assay was 20nM for PDElO, and 100nM for other PDEs. The inhibitory effect of compound was determined by ting various concentration of 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 on was stopped by addition of lysis buffer from assay kit. The cAMP-d2 and anti-CAMP cryptate in the lysis buffer detected 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, IC50 value of inhibitor can be obtained by plotting inhibitor concentration against PDE ty at that concentration.
The results are shown in Table 1.
Table 1 Example IC501) Example IC501) Example low” 36 149 —— 1 --+ 37 151 -- 39 152 -- 40 153 21 -- 154 23 -- 129 156 -- 135 158 26 --+ 136 161 I 28 -- 141 165 --+ 31 -- 142 167 -- 34 __ 147 ——+ 171 -—+ WO 68489 Example IC501) Example IC501) Example IC501) 173 -- 233 266 -- 236 267 --+ 175 -- 237 268 -- 238 269 -- 239 273 -- 182 241 276 -- 186 242 -- 188 246 288 -- 189 247 290 -- 190 248 293 -- 192 251 302 -- 193 252 303 -- 194 253 305 -- 195 254 308 -- 197 255 -- 256 i 311 -- 257 313 -- 258 316 --+ 202 --++ 260 --+ 318 --++ 216 262 323 -- 219 263 228 264 -- 230 265 -- 1) i: IC50 < 100 nM 100 nM 5 IC50 5 200 nM --: 200 nM < IC50 < 500 nM b) Determination of the omal half-life: The metabolic stability of the compounds of the invention was determined in the following assay.
The test substances were incubated in a concentration of 0.5 uM as follows: 0.5 uM test substance are preincubated together with liver microsomes from different species (from rat, human or other s) (0.25 mg of microsomal protein/ml) in 0.05 M potassium phosphate buffer ofpH 7.4 in microtiter plates at 37°C for 5 min.
The reaction is started by adding NADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 ul aliquots are removed, and the reaction is ately stopped and cooled with the same volume of acetonitrile. The samples are frozen until ed. The remaining concentration ofundegraded test substance is determined by MSMS. The half-life (Tl/2) is determined from the gradient of the signal of test substance/unit time plot, it being le to calculate the half-life of the test substance, assuming first order kinetics, from the decrease in the concentration of the compound with time. The microsomal nce (mCl) is calculated from mCl = ln2/T1/2 / (content of microsomal protein in mg/ml) X 1000 n/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.
Table 2 EX. Rat mClZ) Human mClZ) EX. Rat mClZ) Human mClZ) [ulmin'1 mg'l] [ulmin'1 mg'l] [ulmin'1 mg'l] [ulmin'1 mg'l] 40 ++ ——+ 186 ——+ ++ 136 o -- o 141 192 -- o 147 195 -- -- 158 196 --+ ——+ 161 197 -- o 165 198 -- 171 199 172 200 2012/072175 EX. Rat mClZ) Human mClZ) EX. Rat mClZ) Human mClZ) [n1 min"1 mg'l] [n1 min"1 mg'l] [n1 min"1 mg'l] [n1 min"1 mg'l] 201 ——+ ++ 25 1 o + 202 -- o 256 -- o 203 --+ 263 --+ ——+ 204 -- 267 0 ‘— 205 --+ 309 nd 219 -- -- 3 10 ++ 228 --+ 31 1 nd 236 -- 3 12 -- 23 8 -- --+ 3 13 239 -- -- 3 14 241 -- 3 15 244 --+ 3 16 246 -- 0 3 17 -- 3 18 --+ 248 -- EX. Example mCl mikrosomal clearance 2) --+: < 100 nl min"1 mg"1 ——: 100 — 220 “1 min'1 mg'l o: > 220 “1 min"1 mg"1 nd: not determined WE

Claims (48)

CLAIM :
1. Compound of formula I R4 O R1 X2 X1 O N where in formula I X1 is CH or N, X2 is C-R5 or N, Y is O or S, R1 is selected from the group ting of C2-C8-alkyl, C2-C8-alkenyl, C1-C4- fluoroalkyl, C3-C8-cycloalkyl, C5-C8-cycloalkyl carrying a fused benzene ring, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8- cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4- alkyl-N(Rb)(Rc) and a moiety Z1-Ar1; R2 is a radical of the formula CR21R22R23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are ed from O, S and N, where phenyl and clic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra, where R21 is selected from the group consisting of hydrogen, C1-C8-alkyl, hylsilyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated cycloalkyl, C3-C8- cycloalkyl-C1-C4-alkyl, nated C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1- C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), (CH2)mC(O)O-Rd, (CH2)mC(O)N(Re)(Rf) and Z2-Ar2, R22 is selected from the group consisting of en, fluorine, C1-C8-alkyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8- cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1- C4-alkyl, hydroxy-C1-C4-alkyl and C1-C4-alkyl-N(Rb)(Rc), or R21 and R22 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a ted 5- to 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the AH26(11396167_1):JIN group of O, N, S, SO and SO2 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 Rg, 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, R23 is selected from the group ting of hydrogen, fluorine, C1-C8-alkyl and C1-C4- fluoroalkyl; R3 is selected from the group consisting of hydrogen, C1-C8-alkyl, alkenyl, C1-C4- alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4- alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), and trimethylsilyl, or 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 atoms or heteroatom containing groups selected from the group of O, N, S, SO and SO2 as ring s, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R31, 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 1, 2 or 3 substituents R32, where R31 is selected from the group ting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), where one radical R31 may also be a moiety Z3-Ar3, R32 is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, Rc), Rd and C(O)N(Re)(Rf); R4 is selected from the group consisting of C1-C4-alkyl, fluoroalkyl, C3-C6- cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl and Z4-Ar4; R5 is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4- fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, -Z5-Ar5, -O-Z5-Ar5, C3-C6- cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, cycloalkoxy and C3-C6-cycloalkyl- C1-C4-alkoxy, where the cyclic radical in the last four mentioned groups may be unsubstituted, partially or completely fluorinated or carries 1, 2, 3 or 4 methyl groups; AH26(11396167_1):JIN Ar1 is ed from the group consisting of phenyl, clic 5- or 6-membered hetaryl or ic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring s which are selected from O, 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 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar3 is phenyl or monocyclic 5- or ered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and clic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different tuents Rh; Ar4 and Ar5 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 O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 cal or different substituents Rk; Z1, Z4, Z5 are independently of each other C1-C4-alkylene; Z2 is a single bond or C1-C4-alkylene; Z3 is a single bond, C1-C4-alkylene, O, N, S, SO or SO2; Ra is selected from the group consisting of halogen, CN, OH, NO2, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, (CH2)mN(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(Re)(Rf); Rb, Rc, independently of each other are selected from the group consisting of hydrogen, C1- C4-alkyl, fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl or Rb and Rc form together with the N atom to which they are attached a 3- to 7- membered, nitrogen cycle which may have 1, 2 or 3 further different or identical heteroatoms or atom containing groups selected from the group of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; Rd is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6- cycloalkyl, C3-C6-cycloalkylmethyl and benzyl; Re, Rf, ndently of each other are selected from the group consisting of hydrogen, C1- C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-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 AH26(11396167_1):JIN identical heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; Rg is selected from the group consisting of halogen, CN, OH, C1-C6-alkyl, C2-C6- alkenyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6- cycloalkyl-C1-C4-alkyl, fluorinated cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1- C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), C1-C4-alkoxy, fluorinated C1- C4-alkoxy, one Rg er with a carbon atom to which Rg is ed may also form a carbonyl group, one Rg may also be phenyl or benzyl, where 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, C1-C4-alkyl, nated C1-C4-alkyl, C1-C6-alkoxy, fluorinated C1-C4-alkoxy, C1-C4-alkylsulfanyl, C1-C4- alkoxy-C1-C4-alkoxy, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6- cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkoxy, y, N(Rb)(Rc), C1-C4-alkyl- N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff), S(O)2N(Re)(Rf), 3- to 7- membered heterocyclyloxy, 3- to 7-membered heterocyclyl-C1-C4-alkoxy, where heterocyclyl in the two last mentioned radicals has 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, and 5- to 6-membered hetaryl-C1-C4- , where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N; Rk is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, nated C1-C4-alkoxy, N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(Re)(Rf) or two radicals Rk that are bound to adjacent carbon atoms together with said carbon atoms may form fused e ring or a fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring s ed from O, N and S, where the fused benzene ring and the fused aromatic ring are unsubstituted or may carry 1, 2 or 3 radicals Rh; Ree is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl; Rff is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl and phenyl, which is unsubstituted or s 1, 2 or 3 radicals Rh; m is 0, 1, 2, 3 or 4, the N-oxides, hydrates, tautomers thereof and the pharmaceutically acceptable salts thereof, except for: AH26(11396167_1):JIN l-6,7-dimethoxy[4-(4-methoxyphenyl)piperazinecarbonyl]isoquinolinone; 2-ethyl-6,7-dimethoxy-N-(3-methoxypropyl)oxo-isoquinolinecarboxamide; 2-ethyl-6,7-dimethoxyoxo-N-(pyridineylmethyl)isoquinolinecarboxamide; 2-(2-methylpropyl)-6,7-dimethoxyoxo-N-(pyridineylmethyl)isoquinoline carboxamide; N,N,2-triethyl-6,7-dimethoxyoxo-isoquinolinecarboxamide; methyl 2-[(2-isobutyl-6,7-dimethoxyoxo-isoquinolinecarbonyl)amino]acetate; 2-ethyl-6,7-dimethoxyoxo-N-(3-propanyloxypropyl)isoquinolinecarboxamide; ethyl 1-[(2-ethyl-6,7-dimethoxyoxo-1,2-dihydroisoquinolinyl)carbonyl]piperidine carboxylate; and ethyl 2-{[(2-ethyl-6,7-dimethoxyoxo-1,2-dihydroisoquinolin bonyl]amino}benzoate.
2. The compound as d in claim 1, where Rh is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, N(Rb)(Rc), C1-C4-alkyl-N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), S(O)2(Rff) and S(O)2N(Re)(Rf).
3. The compound as claimed in any of claims 1 or 2, where X1 is C-H.
4. The nd as claimed in any of claims 1 or 2, where X1 is N.
5. The compound as claimed in any of claims 1 to 4, where X2 is C-R5.
6. The compound as claimed in any of claims 1 to 4, where X2 is N.
7. The compound as claimed in any of the preceding , where Y is O.
8. The compound as claimed in any of the preceding claims, where R1 is C2-C8-alkyl, C3-C8- cycloalkyl or C3-C8-cycloalkylmethyl.
9. The compound as claimed in claim 8, where R1 is a radical of the formula CHR1aR1b, where R1a is selected from the group consisting of hydrogen and C1-C3-alkyl and where R1b is selected from the group consisting of C1-C4-alkyl.
10. The compound as claimed in any of claims 1 to 7, where R1 is a moiety Z1-Ar1. AH26(11396167_1):JIN
11. The compound as claimed in any of the preceding claims, where R2 is a radical of the formula CR21R22R23.
12. The compound as claimed in claim 11, where R21 and R22 together with the carbon atom, to which they are bound form a saturated 5- to 7- membered yclic ring or a saturated 5- to 7-membered cyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO2 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 Rg, and where the carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a fused 5- or ered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, where Rh and Rg are as defined in claim 1, and where R23 is hydrogen.
13. The compound as claimed in claim 11, where R21 and R22 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-tetrahydrothienyl, where the 5- to 7- membered carbocyclic ring and the ahydrofuryl 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 R23 is en.
14. The compound as claimed in claim 11, where R21 is ed from the group consisting of C1-C8-alkyl, trimethylsilyl, C2-C8-alkenyl, C1-C4- fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl and Z2-Ar2, where Z2 and Ar2 are as defined in claim 1; R22 is ed from the group consisting of hydrogen, fluorine, C1-C8-alkyl; and R23 is hydrogen.
15. The nd as claimed in claim 14, where R21 is a moiety Z2-Ar2, where Z2 and Ar2 are as defined in claim 1.
16. The compound as claimed in any of the preceding claims, where R3 is hydrogen or C1-C4- alkyl. AH26(11396167_1):JIN
17. The compound as claimed in any of claims 1 to 10, where R2 and R3 together with the nitrogen atom, to which they are bound form a saturated 5- to 7-membered cyclic ring which, in on to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO2 as ring members, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or ent substituents R31, 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 1, 2 or 3 substituents R32, where R31 and R32 are as defined in claim 1.
18. The compound as claimed in any of the ing claims, where R4 is C1-C4-alkyl.
19. The compound as claimed in any of the preceding claims, where X2 is C-R5 and R5 is hydrogen, fluorine, C1-C4-alkoxy or a radical O-Z5-Ar5.
20. The compound as claimed in claim 19, where R4 is methyl and R5 is hydrogen, fluorine or methoxy.
21. The compound as d in claim 19, where R4 is methyl and R5 is O-Z5-Ar5.
22. The compound as claimed in any of the preceding claims which is a compound of the formula Ia R4 O R1 (Ia) O N where R1, R2, R3, R4 and R5 are as defined in any of the preceding claims.
23. The compound as claimed in any of claims 1 to 21 which is a compound of the formula Ib AH26(11396167_1):JIN R4 O R1 (Ib) O N where R1, R2, R3, R4 and R5 are as defined in any of claims 1 to 23.
24. The compound as claimed in claim 22 or 23, where R1 is a radical of the formula CHR1aR1b, where R1a is selected from the group consisting of hydrogen and C1-C3-alkyl and where R1b is selected from the group ting of C1-C4-alkyl; R2 is a radical of the formula CR21R22R23; R3 is hydrogen or C1-C4-alkyl; R4 is C1-C4-alkyl, and R5 is hydrogen, fluorine, C1-C4-alkoxy or a l O-Z5-Ar5.
25. The compound as claimed in claim 22 or 23, where R1 is a moiety Z1-Ar1; R2 is a radical of the formula 2R23; R3 is en or C1-C4-alkyl; R4 is C1-C4-alkyl, and R5 is hydrogen, fluorine or C1-C4-alkoxy.
26. The compound as claimed in claim 24 or 25, where R21 and R22 together with the carbon atom, to which they are bound form a 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 lves are unsubstituted or carry 1, 2 or 3 substituents Rh, where Rh are as defined in claim 1, and where R23 is en.
27. The compound as claimed in claim 24 or 25, where R21 is selected from the group consisting of C1-C8-alkyl, trimethylsilyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl- AH26(11396167_1):JIN C1-C4-alkyl, fluorinated cycloalkyl-C1-C4-alkyl and Z2-Ar2, where Z2 and Ar2 are as defined in claim 1; R22 is selected from the group consisting of hydrogen, fluorine, C1-C8-alkyl; and R23 is hydrogen.
28. The compound as claimed in any of claims 22 to 27, where R4 is methyl and R5 is hydrogen, fluorine or methoxy.
29. The compound as claimed in any of claims 22 to 27, where R4 is methyl and R5 is O-Z5- Ar5.
30. The compound as claimed in claim 1, which is selected from the group consisting of l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclopropylmethyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid methylphenethyl-amide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid hoxybenzyl )-methyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (4-methoxybenzyl )-methyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3-methoxybenzyl )-methyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid methyl-(3- trifluoromethyl-benzyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid benzyl-(2- dimethylamino-ethyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1-benzylpiperidinyl )-methyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid tert-butylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid sec-butylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid isobutyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclopentylamide, AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1-methylbutyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1,1-dimethylpropyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1,2-dimethylpropyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid imethylpropyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1-ethyl-propyl)- amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ethylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid hylbutyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid pentylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclohexylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1,3-dimethylbutyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3,3-dimethylbutyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2-ethyl-butyl)- amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid dicyclopropylmethyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2-fluoro-ethyl)- amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclohexylmethyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1-phenyl-ethyl)- amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-fluorobenzylamide AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3-fluorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid robenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2,3-difluorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2,4-difluorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2,6-difluorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid fluorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2,2,2-trifluoroethyl )-amide, l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3,5-difluorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid phenethylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid [1-(4-fluorophenyl )-ethyl]-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid indanylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid indanylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid [1-(4-fluorophenyl )methyl-ethyl]-amide, 4-(Azetidinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclopropylamide, 2-Ethyl-6,7-dimethoxy(2-methyl-pyrrolidinecarbonyl)-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxy(morpholinecarbonyl)-2H-isoquinolinone, 2-Ethyl(3-fluoro-pyrrolidinecarbonyl)-6,7-dimethoxy-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxy(4-methyl-piperazinecarbonyl)-2H-isoquinolinone, 4-(3,3-Difluoro-pyrrolidinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 4-(3-Dimethylamino-pyrrolidinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolin one, AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxy((R)methoxymethyl-pyrrolidinecarbonyl)-2H-isoquinolin- 1-one, -Dihydro-isoindolecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 4-(4,4-Difluoro-piperidinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid isopropylamide, l(4-isopropyl-piperazinecarbonyl)-6,7-dimethoxy-2H-isoquinolinone, 4-(4-Dimethylamino-piperidinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxy(2-trifluoromethyl-pyrrolidinecarbonyl)-2H-isoquinolin one, 4-(4-Cyclopropylmethyl-piperazinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolin one, 2-Ethyl-6,7-dimethoxy((S)pyrrolidinylmethyl-pyrrolidinecarbonyl)-2H- isoquinolinone, 2-Ethyl-6,7-dimethoxy(4-pyrrolidinyl-piperidinecarbonyl)-2H-isoquinolinone, 4-[4-(2-Dimethylamino-ethyl)-piperazinecarbonyl]ethyl-6,7-dimethoxy-2H- isoquinolinone, 4’]Bipiperidinyl-1’-carbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 4-[4-(3-Dimethylamino-propyl)-piperazinecarbonyl]ethyl-6,7-dimethoxy-2H- isoquinolinone, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid propylamide, 2-Ethyl-6,7-dimethoxy[4-(2-pyrrolidinyl-ethyl)-piperazinecarbonyl]-2H- isoquinolinone, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid dimethylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ethyl-methylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid isopropylmethyl-amide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid diethylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid methyl-propylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ethyl-isopropylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid tert-butylmethyl-amide AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid isobutyl-methylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butyl-methylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ethyl-propylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2- dimethylamino-ethyl)-methyl-amide, l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ethyl-(2- methoxy-ethyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclopentylmethyl-amide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butyl-ethylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid methyl-pentylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid diisopropylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid isopropylpropyl-amide l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclobutylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid dipropylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3- dimethylamino-propyl)-methyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclohexylmethyl-amide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclopropylmethyl-propyl-amide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid diisobutylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid -methylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2-fluorobenzyl )-methyl-amide, AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (4-fluorobenzyl )-methyl-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3-fluorobenzyl )-methyl-amide, 2-tert-Butyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-sec-Butyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid mide, 2-Isobutyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Butyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Cyclopropylmethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-(2-Dimethylamino-ethyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Cyclopentyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, thyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 6,7-Dimethoxyoxo(2,2,2-trifluoro-ethyl)-1,2-dihydro-isoquinolinecarboxylic acid butylamide 6,7-Dimethoxyoxo(2-pyrrolidinyl-ethyl)-1,2-dihydro-isoquinolinecarboxylic acid butylamide, luoro-ethyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Benzyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-(2,4-Difluoro-benzyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Cyclopropyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 6,7-Dimethoxyoxo(2-piperidinyl-ethyl)-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 6,7-Dimethoxyoxophenethyl-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 6,7-Dimethoxy(2-methoxy-benzyl)oxo-1,2-dihydro-isoquinolinecarboxylic acid mide, 2-Indanyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Isopropyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, AH26(11396167_1):JIN 6,7-Dimethoxyoxopropyl-1,2-dihydro-isoquinolinecarboxylic acid mide, 6,7-Dimethoxyoxo(3,3,3-trifluoro-propyl)-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 6,7-Dimethoxy(2-methoxy-ethyl)oxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-Cyclobutyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid butylamide, 2-Ethylmethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid butylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid indanylamide, 2-Ethylmethoxyoxo(2-quinolinyl-ethoxy)-1,2-dihydro-isoquinoline carboxylic acid butylamide, 2-Ethylmethoxyoxo(3-quinolinyl-propoxy)-1,2-dihydro-isoquinoline carboxylic acid butylamide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7,8,9- tetrahydro-5H-benzocycloheptenyl)-amide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (R)-indan ylamide, 2-Ethylmethoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid indan ylamide, 2-Ethylmethoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid butylamide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid indan ylamide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7,8,9- tetrahydro-5H-benzocycloheptenyl)-amide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (1,2,3,4- tetrahydro-naphthalenyl)-amide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (1,2,3,4- tetrahydro-naphthalenyl)-amide, l-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (4-bromo-indan- 1-yl)-amide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid mo-indan- amide, AH26(11396167_1):JIN 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid 2- dimethylaminomethyl-benzylamide, l-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7-dihydro-5H- pyrindinyl)-amide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7-dihydro-5H- pyrindinyl)-amide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid 3- dimethylaminomethyl-benzylamide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid 4- ylaminomethyl-benzylamide, 7-Methoxyoxo(2-quinolinyl-ethyl)-1,2-dihydro-isoquinolinecarboxylic acid butylamide, oxyoxo(2-quinolinyl-ethyl)-1,2-dihydro-isoquinolinecarboxylic acid indanylamide, 3-Ethyl-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (S)-indan ylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (6,7- dihydro-5H-[1]pyrindinyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2- dimethylaminomethyl-benzylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3,5- difluoro-benzylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3,4- difluoro-benzylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid cyclohexylmethyl-amide, thyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (R)- indanylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (S)- indanylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (1,2,3,4- tetrahydro-naphthalenyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid pyridine ylamide, AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (pyrimidin ylmethyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-methoxybenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (4-morpholin yl-phenyl)-amide, l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3-chlorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (pyridine ylmethyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid o-tolylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid m-tolylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2-methoxyphenyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3-methoxyphenyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ine ylmethyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3- dimethylamino-propyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid phenylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 4-methoxybenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3-methylbenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-methylbenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2-methoxyethyl 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (4-fluorophenyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid hoxyphenyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid p-tolylamide, AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3-fluorophenyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2-fluorophenyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 4-methylbenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-chlorobenzylamide 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid [(R)(4-fluorophenyl )-ethyl]-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid pyridine ylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid [(S)(4-fluorophenyl )-ethyl]-amide, l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (6-methyl-indan- 1-yl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-morpholin ylmethyl-benzylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid oro-indan- 1-yl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (6-chloro-indan- 1-yl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid oro-indan- amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (5,6-dihydro- 4H-cyclopenta[b]thiophenyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (4-fluoro-indan- 1-yl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (4-methyl-indan- 1-yl)-amide, l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (5-methyl-indan- 1-yl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (6-methoxyindanyl )-amide, AH26(11396167_1):JIN 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (5-fluoro-indan- 1-yl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2- diethylaminomethyl-benzylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-pyrrolidin ylmethyl-benzylamide, 2-Ethyl-6,7-dimethoxy(4-methyl-piperidinecarbonyl)-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (tetrahydrofuranylmethyl )-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3-methoxypropyl )-amide, 4-(3,5-Dimethyl-piperidinecarbonyl)ethyl-6,7-dimethoxy-2H-isoquinolinone, 2-Ethyl(4-ethyl-piperazinecarbonyl)-6,7-dimethoxy-2H-isoquinolinone, 2-Isobutyl-6,7-dimethoxy(4-methyl-piperazinecarbonyl)-2H-isoquinolinone, 2-Isobutyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2- dimethylamino-ethyl)-amide, 2-Isobutyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid methylamide [(2-Isobutyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarbonyl)-amino]-acetic acid methyl ester, l-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (3-isopropoxypropyl )-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (5,6- o-4H-cyclopenta[b]thiophenyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2,3- dihydro-benzofuranyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (6- oxo-5,6-dihydro-4H-cyclopenta[b]thiophenyl)-amide, 2-Cyclopropyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid indan ylamide, 2-sec-Butyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid indan ylamide, 2-Isopropyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 1- ylamide, AH26(11396167_1):JIN 2-(1-Ethyl-propyl)-6,7-dimethoxy(3-phenyl-piperidinecarbonyl)-2H-isoquinolin one, thyl-propyl)-6,7-dimethoxy(3-phenoxy-piperidinecarbonyl)-2H-isoquinolin one, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (S)indan ylamide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ®indan ylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxy[3-(3-methoxy-phenyl)-piperazinecarbonyl]-2H- nolinone, 2-(1-Ethyl-propyl)-6,7-dimethoxy[8-(4-methyl-piperazinesulfonyl)-3,4-dihydro-1H- isoquinolinecarbonyl]-2H-isoquinolinone, 2-(1-Ethyl-propyl)-6,7-dimethoxy[8-(morpholinesulfonyl)-3,4-dihydro-1H- isoquinolinecarbonyl]-2H-isoquinolinone, 2-(1-Ethyl-propyl)-6,7-dimethoxy[3-(3-methoxy-phenyl)methyl-piperazine carbonyl]-2H-isoquinolinone, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid ([1,3,4]thiadiazolylmethyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2- (morpholinesulfonyl)-benzylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (thiazolylmethyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxy[(R)(quinoxalinyloxy)-pyrrolidinecarbonyl]- 2H-isoquinolinone, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 6-dihydro- 4H-cyclopenta[b]thiophenyl)-amide, 2-Ethyl-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (R)(5,6-dihydro- 4H-cyclopenta[b]thiophenyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (thiophenylmethyl)-amide, 4-(7-Amino-3,4-dihydro-1H-isoquinolinecarbonyl)(1-ethyl-propyl)-6,7-dimethoxy- 2H-isoquinolinone, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3-(4- chloro-benzenesulfonylamino)-benzylamide, AH26(11396167_1):JIN 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (2,3- dihydro-benzo[b]thiophenyl)-amide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophenyl)-amide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid (S)-indanylamide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 2-(4- -piperazinesulfonyl)-benzylamide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid 2- (morpholinesulfonyl)-benzylamide, thyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid (6,7-dihydro-5H-[1]pyrindinyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid 3-(4- methoxy-benzenesulfonylamino)-benzylamide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid 3,5-difluoro-benzylamide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid 4- methyl-benzylamide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid cyclohexylmethyl-amide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid butylamide, 2-(1-Ethyl-propyl)methoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid (2,3-dihydro-benzofuranyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (thiazolylmethyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxyoxo-1,2-dihydro-isoquinolinecarboxylic acid (thiophenylmethyl)-amide, lmethoxyoxo-1,2-dihydro-[2,6]naphthyridinecarboxylic acid (5,6-dihydro- 4H-cyclopenta[b]thiophenyl)-amide, 3-(1-Ethyl-propyl)-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (5,6- dihydro-4H-cyclopenta[b]thiophenyl)-amide, 3-(1-Ethyl-propyl)-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (2,3- dihydro-benzofuranyl)-amide, AH26(11396167_1):JIN 3-(1-Ethyl-propyl)-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid indan- 1-ylamide, 3-(1-Ethyl-propyl)-6,7-dimethoxyoxo-3,4-dihydro-phthalazinecarboxylic acid (6,7- dihydro-5H-[1]pyrindinyl)-amide, 2-(1-Ethyl-propyl)-6,7-dimethoxy(3-phenyl-propionyl)-2H-isoquinolinone, 2-Ethyl-6,7-dimethoxy-N-(4-nitrophenyl)oxo-1,2-dihydroisoquinolinecarboxamide, and the es, the tautomers, the hydrates, and the pharmaceutically able salts thereof.
31. The compound as d in claim 1, which is selected from the group consisting of 6,7-Dimethoxyoxo(pentanyl)-N-(pyridinylmethyl)-1,2-dihydroisoquinoline carboxamide, 6,7-Dimethoxy-N-((5-methylthiophenyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, N-((3,5-Dimethylisoxazolyl)methyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-dimethoxy-N-((5-methylthiazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxyoxo(pentanyl)-N-(pyrimidinylmethyl)-1,2-dihydroisoquinoline- 4-carboxamide, 6,7-Dimethoxy-N-((3-methylisoxazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, N-((2,5-Dimethylthiophenyl)methyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((2-methylthiazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((5-methylisoxazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, (R)-N-(1-(4-Fluorophenyl)ethyl)-6,7-dimethoxyoxo(pentanyl)-1,2- oisoquinolinecarboxamide, (S)-N-(1-(4-Fluorophenyl)ethyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((4-methylthiazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, AH26(11396167_1):JIN methoxy-N-((2-methylthiazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((4-methylthiazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxyoxo(pentanyl)-N-((5-(trifluoromethyl)furanyl)methyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((5-methylfuranyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, luoro-2,3-dihydro-1H-indenyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroiso-quinolinecarboxamide, 6,7-Dimethoxy-N-(5-methyl-2,3-dihydro-1H-indenyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-(4-methyl-2,3-dihydro-1H-indenyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, N-((2-Ethylthiazolyl)methyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-(6-methoxy-2,3-dihydro-1H-indenyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((4-methylthiophenyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((3-methylthiophenyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((5-methyloxazolyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, methoxy-N-(6-methyl-2,3-dihydro-1H-indenyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxyoxo(pentanyl)-N-(pyridinylmethyl)-1,2-dihydroisoquinoline carboxamide, 6,7-Dimethoxy-N-(4-methylbenzyl)oxo(pentanyl)-1,2-dihydroisoquinoline carboxamide, 6,7-Dimethoxyoxo(pentanyl)-N-(pyridinylmethyl)-1,2-dihydroisoquinoline carboxamide, N-((5-Cyanofuranyl)methyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, AH26(11396167_1):JIN N-(4-Chloro-2,3-dihydro-1H-indenyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, N-((5-Ethylthiophenyl)methyl)-6,7-dimethoxyoxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((3-methylfuranyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((2-methylfuranyl)methyl)oxo(pentanyl)-1,2- dihydroisoquinolinecarboxamide, 6,7-Dimethoxy-N-((1-methyl-1H-pyrazolyl)methyl)oxo(pentanyl)-1,2- oisoquinolinecarboxamide, N-[(3,4-Dimethylphenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, N-[(2-Chloromethyl-phenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, N-[[2-(Dimethylamino)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxoisoquinolinecarboxamide 2-Ethyl-N-[(2-fluoromethyl-phenyl)methyl]-6,7-dimethoxyoxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(3-methoxymethyl-phenyl)methyl]oxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(4-methylmorpholino-phenyl)methyl]oxo-isoquinoline amide, tert-Butoxymethyl-phenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, N-[[2-(1,1-Dimethylpropoxy)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxoisoquinolinecarboxamide N-[(2,3-Difluoromethyl-phenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, 2-Ethyl-N-[(3-fluoromethyl-phenyl)methyl]-6,7-dimethoxyoxo-isoquinoline carboxamide, N-[(3-Chloromethyl-phenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxyoxo-N-[(2,4,6-trimethylphenyl)methyl]isoquinoline carboxamide, AH26(11396167_1):JIN N-[(2,4-Dimethylphenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[2-(3-methoxypropoxy)methyl-phenyl]methyl]oxoisoquinolinecarboxamide N-[[2-(2-Ethoxyethoxy)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxoisoquinolinecarboxamide N-[[2-(Cyclopentoxy)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxoisoquinolinecarboxamide 2-Ethyl-6,7-dimethoxy-N-[(4-methylphenoxy-phenyl)methyl]oxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxymethyl-ethoxy)methyl-phenyl]methyl] oquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-[[4-methyl(2,2,2-trifluoroethoxy)phenyl]methyl]oxoisoquinolinecarboxamide N-[[2-(Cyclohexoxy)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxoisoquinolinecarboxamide N-[[2-(Cyclopropylmethoxy)methyl-phenyl]methyl]ethyl-6,7-dimethoxyoxoisoquinolinecarboxamide 2-Ethyl-N-[(2-hexoxymethyl-phenyl)methyl]-6,7-dimethoxyoxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[[4-methyl(tetrahydrofuranylmethoxy)phenyl]methyl] oxo-isoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-[[2-(2-methoxyethoxy)methyl-phenyl]methyl]oxoisoquinolinecarboxamide 2-Ethyl-N-(2-isobutoxymethylbenzyl)-6,7-dimethoxyoxo-1,2-dihydroisoquinoline carboxamide, 2-Ethyl-N-(2-(furanylmethoxy)methylbenzyl)-6,7-dimethoxyoxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl(pentyloxy)benzyl)oxo-1,2-dihydroisoquinoline- 4-carboxamide, N-(2-Ethoxymethylbenzyl)ethyl-6,7-dimethoxyoxo-1,2-dihydroisoquinoline carboxamide, N-(2-sec-Butoxymethylbenzyl)ethyl-6,7-dimethoxyoxo-1,2-dihydroisoquinoline- oxamide, AH26(11396167_1):JIN 2-Ethyl-N-(2-(isopentyloxy)methylbenzyl)-6,7-dimethoxyoxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methylpropoxybenzyl)oxo-1,2-dihydroisoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl(methylthio)benzyl)oxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-N-(2-isopropoxymethylbenzyl)-6,7-dimethoxyoxo-1,2-dihydroisoquinoline- 4-carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl(tetrahydrofuranyloxy)benzyl)oxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxyoxo-N-(2,4,5-trimethylbenzyl)-1,2-dihydroisoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl((tetrahydrofuranyl)methoxy)benzyl)oxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl(4-methylpentanyloxy)benzyl)oxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-(4-methyl(4-methylpentyloxy)benzyl)oxo-1,2- dihydroisoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxy-N-(2-methoxymethylbenzyl)oxo-1,2-dihydroisoquinoline carboxamide, 2-Ethyl-6,7-dimethoxyoxo-N-(thiazolylmethyl)isoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxyoxo-N-[[4-(trifluoromethyl)phenyl]methyl]isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxyoxo-N-[(1S)(p-tolyl)ethyl]isoquinolinecarboxamide, 2-Ethyl-N-[(4-isopropylphenyl)methyl]-6,7-dimethoxyoxo-isoquinolinecarboxamide, l-N-[(4-ethylphenyl)methyl]-6,7-dimethoxyoxo-isoquinolinecarboxamide, 2-Ethyl-6,7-dimethoxyoxo-N-[(1R)(p-tolyl)ethyl]isoquinolinecarboxamide, (Difluoromethyl)phenyl]methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, l-6,7-dimethoxy-N-[(2-methylthiazolyl)methyl]oxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[(4-methylthienyl)methyl]oxo-isoquinoline carboxamide, AH26(11396167_1):JIN N-[(4-Cyclopropylphenyl)methyl]ethyl-6,7-dimethoxyoxo-isoquinoline carboxamide, N-Indanyl-6,7-dimethoxy[2-(5-methylpyridyl)ethyl]oxo-isoquinoline carboxamide, N-Butyl-6,7-dimethoxy[2-(5-methylpyridyl)ethyl]oxo-isoquinoline carboxamide, 2-Ethyl-6,7-dimethoxy-N-[2-(6-methoxypyridyl)ethyl]oxo-isoquinoline carboxamide, N-Butyl-6,7-dimethoxyoxo[2-(2-quinolyl)ethyl]isoquinolinecarboxamide, N-Indanyl-6,7-dimethoxyoxo[2-(2-quinolyl)ethyl]isoquinolinecarboxamide; and the N-oxides, the ers, the hydrates, and the pharmaceutically able salts thereof.
32. The compound as claimed in claim 1 being 2-(1-ethyl-propyl)-6,7-dimethoxyoxo-1,2- dihydro-isoquinolinecarboxylic acid indanylamide, or a e thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically acceptable salt thereof.
33. The compound as claimed in claim 1 being 2-(1-ethyl-propyl)-6,7-dimethoxyoxo-1,2- dihydro-isoquinolinecarboxylic acid (S)-indanylamide, or a N-oxide thereof, or a tautomer thereof, or a e thereof or a pharmaceutically acceptable salt thereof.
34. The compound as d in claim 1 being 2-ethyl-6,7-dimethoxy-N-(4-methylbenzyl) oxo-1,2-dihydroisoquinolinecarboxamide or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically acceptable salt thereof.
35. The compound as claimed in claim 1 being lmethoxyoxo(2-quinolinylethoxy )-1,2-dihydro-isoquinolinecarboxylic acid butylamide or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a ceutically acceptable salt thereof.
36. The compound as claimed in claim 1 being N-butyl-6,7-dimethoxyoxo[2-(2-quinolyl )ethyl]isoquinolinecarboxamide or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically acceptable salt thereof.
37. The nd of formula I AH26(11396167_1):JIN R4 O R1 X2 X1 O N where in formula I X1 is CH or N, X2 is C-R5 or N, Y is O or S, R1 is selected from the group consisting of C2-C8-alkyl, C2-C8-alkenyl, C1-C4- fluoroalkyl, C3-C8-cycloalkyl, C5-C8-cycloalkyl carrying a fused benzene ring, nated C3-C8-cycloalkyl, cycloalkyl-C1-C4-alkyl, fluorinated C3-C8- cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4- N(Rb)(Rc) and a moiety Z1-Ar1; R2 is a radical of the formula CR21R22R23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 atoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra, where R21 is selected from the group consisting of hydrogen, alkyl, hylsilyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8- cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1- C4-alkyl, y-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), (CH2)mC(O)O-Rd, (CH2)mC(O)N(Re)(Rf) and , R22 is selected from the group consisting of hydrogen, fluorine, C1-C8-alkyl, C2-C8- alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8- cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1- C4-alkyl, hydroxy-C1-C4-alkyl and C1-C4-alkyl-N(Rb)(Rc), or R21 and R22 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 selected from the group of O, N, S, SO and SO2 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 Rg, and where the carbocyclic ring and the heterocyclic ring AH26(11396167_1):JIN may carry a fused benzene ring or a fused 5- or 6-membered aromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh, R23 is selected from the group consisting of hydrogen, fluorine, C1-C8-alkyl and C1-C4- fluoroalkyl; R3 is selected from the group consisting of hydrogen, C1-C8-alkyl, C2-C8-alkenyl, C1-C4- alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4- alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), and trimethylsilyl, or 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 O, N, S, SO and SO2 as ring s, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R31, and where the heterocyclic ring may carry a fused e ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents R32, where R31 is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), where one l R31 may also be a moiety Z3-Ar3, R32 is selected from the group consisting of n, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, Rc), C(O)O-Rd and C(O)N(Re)(Rf); R4 is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6- cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl and Z4-Ar4; R5 is ed from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4- fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, -Z5-Ar5, -O-Z5-Ar5, C3-C6- cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy and C3-C6-cycloalkyl- C1-C4-alkoxy, where the cyclic radical in the last four mentioned groups may be unsubstituted, partially or completely fluorinated or carries 1, 2, 3 or 4 methyl Ar1 is selected from the group consisting of phenyl, monocyclic 5- or 6-membered hetaryl or ic 9- or 10-membered hetaryl, where l has 1, 2 or 3 heteroatoms as ring s which are selected from O, S and N, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; AH26(11396167_1):JIN Ar2 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic l are tituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar3 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic l are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh; Ar4 and Ar5 are independently of each other selected from the group consisting of phenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 atoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different tuents Rk; Z1, Z4, Z5 are independently of each other alkylene; Z2 is a single bond or C1-C4-alkylene; Z3 is a single bond, C1-C4-alkylene, O, N, S, SO or SO2; Ra is selected from the group consisting of n, CN, OH, NO2, alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(Re)(Rf); Rb, Rc, independently of each other are selected from the group consisting of hydrogen, C1- C4-alkyl, C1-C4-fluoroalkyl, cycloalkyl, C3-C6-cycloalkylmethyl and benzyl or Rb and Rc 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 of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; Rd is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6- lkyl, C3-C6-cycloalkylmethyl and benzyl; Re, Rf, independently of each other are selected from the group consisting of hydrogen, C1- C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-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 of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 substituents selected from C1-C4-alkyl; Rg is selected from the group consisting of halogen, CN, OH, C1-C6-alkyl, C2-C6- alkenyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, nated C3-C6-cycloalkyl, C3-C6- AH26(11396167_1):JIN cycloalkyl-C1-C4-alkyl, fluorinated C3-C6-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1- C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), C1-C4-alkoxy, fluorinated C1- C4-alkoxy, one Rg together with a carbon atom to which Rg is attached may also form a yl group, one Rg may also be phenyl or benzyl, where the phenyl ring in the last 2 mentioned radicals is tituted or carries 1, 2 or 3 radicals Rh; Rh is selected from the group consisting of n, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C6-alkoxy, fluorinated C1-C4-alkoxy, C1-C4-alkylsulfanyl, C1-C4- alkoxy-C1-C4-alkoxy, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6- cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkoxy, phenoxy, N(Rb)(Rc), C1-C4-alkyl- N(Rb)(Rc), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff), S(O)2N(Re)(Rf), 3- to 7- ed heterocyclyloxy, 3- to 7-membered cyclyl-C1-C4-alkoxy, where heterocyclyl in the two last mentioned radicals has 1, 2 or 3 atoms as ring members which are selected from O, S and N, and 5- to 6-membered hetaryl-C1-C4- alkoxy, where hetaryl has 1, 2 or 3 heteroatoms as ring s which are selected from O, S and N; Rk is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, nated C1-C4-alkoxy, Rc), C(O)O-Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(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 members selected from O, 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, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl; Rff is selected from the group ting of C1-C4-alkyl, C1-C4-fluoroalkyl and phenyl, which is unsubstituted or s 1, 2 or 3 radicals Rh; m is 0, 1, 2, 3 or 4, or a e thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically able salt thereof 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.
38. The compounds of formula I as defined in claim 37 or a N-oxide thereof, or a tautomer thereof, or a e thereof or a pharmaceutically acceptable salt thereof for treating, controlling, ameliorating or reducing the risk of CNS disorders in a mammalian. AH26(11396167_1):JIN
39. The compounds of formula I as defined in claim 37 or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically acceptable salt thereof for treating, controlling, ameliorating or reducing the risk of schizophrenia in a mammalian.
40. The compounds of formula I as defined in claim 37 or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically able salt thereof for treating, controlling, ameliorating or reducing cognitive dysfunction associated with schizophrenia in a mammalian.
41. The compounds of formula I as defined in claim 37 or a e f, or a er thereof, or a hydrate thereof or a pharmaceutically acceptable salt thereof for treating, lling, rating or ng the risk of r disorders in a mammalian.
42. The compounds of formula I as d in claim 37 or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a ceutically acceptable salt thereof for treating, controlling, ameliorating or reducing the risk of depression in a mammalian.
43. The compounds of formula I as defined in claim 37 or a N-oxide thereof, or a tautomer thereof, or a hydrate thereof or a pharmaceutically acceptable salt thereof for treating, controlling, ameliorating or reducing cognitive dysfunction associated with Alzheimer's e in a mammalian.
44. The compound of formula I as defined in claim 37 or a N-oxide thereof, or a tautomer thereof, or a hydrate f or a pharmaceutically acceptable salt thereof for treating, controlling, ameliorating or reducing the risk of diet-induced obesity in a ian.
45. Use of at least one compound of formula I as defined in claim 37, the N-oxides, hydrates, and tautomers thereof and the pharmaceutically able salts thereof, in the preparation of a medicament for treating a medical disorder, selected from neurological and psychiatric disorders which can be treated by modulation of phosphodiesterase type 10.
46. Use of at least one compound of formula I as defined in claim 37, the N-oxides, hydrates and tautomers thereof and the ceutically acceptable salts thereof, in the preparation of a medicament for treating, controlling, ameliorating or reducing the risk of a medical disorder, AH26(11396167_1):JIN selected from CNS disorders, schizophrenia, bipolar disorders, depression and diet-induced obesity.
47. Use of at least one compound of formula I as defined in claim 37, the N-oxides, hydrates and tautomers thereof and the pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating, controlling, ameliorating or reducing cognitive dysfunction associated with schizophrenia or Alzheimer’s disease.
48. Pharmaceutical composition which ses a r and a compound as claimed in any one of claims 1 to 36. AbbVie Deutschland GmbH & Co. KG; AbbVie Inc. By the eys for the Applicant SPRUSON & ON Per: AH26(11396167_1):JIN
NZ624124A 2011-11-09 2012-11-08 Heterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10a NZ624124B2 (en)

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US201161557878P 2011-11-09 2011-11-09
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PCT/EP2012/072175 WO2013068489A1 (en) 2011-11-09 2012-11-08 Heterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10a

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