CA2691474C - Cyanoisoquinoline - Google Patents

Cyanoisoquinoline Download PDF

Info

Publication number
CA2691474C
CA2691474C CA2691474A CA2691474A CA2691474C CA 2691474 C CA2691474 C CA 2691474C CA 2691474 A CA2691474 A CA 2691474A CA 2691474 A CA2691474 A CA 2691474A CA 2691474 C CA2691474 C CA 2691474C
Authority
CA
Canada
Prior art keywords
pharmaceutically acceptable
compound
dimethoxy
disorder
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA2691474A
Other languages
French (fr)
Other versions
CA2691474A1 (en
Inventor
Jan Kehler
Jacob Nielsen
Morten Langgaard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by H Lundbeck AS filed Critical H Lundbeck AS
Publication of CA2691474A1 publication Critical patent/CA2691474A1/en
Application granted granted Critical
Publication of CA2691474C publication Critical patent/CA2691474C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

This invention is directed to compounds, which are PDE10A enzyme inhibitors.
The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides a process for the preparation of the compounds of formula l. The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula l. The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula l.
(see formula I)

Description

CYANOISOQUINOLINE
Field of the Invention The present invention provides for compounds that are PDE10A enzyme inhibitors, and as such are useful to treat associated neurodegenerative and psychiatric disorders.
Especially, the invention provides compounds that have preference for PDE10 over PDE3. The present invention also provides for pharmaceutical compositions and methods of treating said disorders using the compounds of the invention.
Background of the Invention The cyclic nucleotides, cyclic-adenosine monophosphate (cAMP) and cyclic-guanosine monophosphate (cGMP) function as intracellular second messengers regulating a vast array of processes in neurons. Intracellular cAMP and cGMP are generated by adenyl and guanyl cyclases, and are degraded by cyclic nucleotide phosphodiesterases (PDEs).
Intracelluar levels of cAMP and cGMP are controlled by intracellular signaling, and stimulation/repression of adenyl and guanyl cyclases in response to GPCR
activation is a well characterized way of controlling cyclic nucleotide concentrations (Antoni, F.A. Front.
Neuroendocrinol. 2000, 21(2), 103-132). In neurons, this includes the activation of cAMP
and cGMP dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival.
There are 21 phosphodiesterase genes that can be divided into 11 gene families. There are ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. PDEs are a class of intracellular enzymes that regulate levels of cAMP and cGMP via hydrolysis of the cyclic nucleotide into their respective nucleotide monophosphates. Some PDEs degrade cAMP, some cGMP and some both. Most PDEs have a relatively widespread expression and have roles in many tissues, while some are more spatially restricted.
Phosphodieasterase 10A (PDE10A) is a dual specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (Loughney, K. et al. Gene 1999, 234, 117; Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127 and Soderling, S. et al.
Proc. Natl. Acad. Sc!. 1999, 96, 7071-7076). PDE10A is primarily expressed in the neurons in the striatum, n. accumbens and in the olfactory tubercle (Kotera, J. et al.
Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger, T.F. et al. Brain Research, 2003, 985, 113-126).
Mouse PDE10A is the first member of the PDE10 family of phosphodiesterases (Fujishige, K. et al. J. Biol. Chem. 1999, 274, 18438-18445 and Loughney, K.
et al. Gene 1999, 234, 109-117) and N-terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127). There is a high degree of homology across species. PDE10A is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed in testis and brain (Fujishige, K. et al.
Eur J Biochem. 1999, 266, 1118-1127; Soderling, S. et al. Proc. Natl. Acad.
Sc!. 1999, 96, 7071-7076 and Loughney, K. et al. Gene 1999, 234,109-117). These studies indicate that within the brain, PDE10 expression is highest in the striatum (caudate and putamen), n.
accumbens and olfactory tubercle. More recently, an analysis has been made of the expression pattern in rodent brain of PDE10A mRNA (Seeger, T.F. et al. Abst.
Soc.
Neurosci. 2000, 26, 345.10) and PDE10A protein (Menniti, F.S. et al. William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec.
5-7, 2001).
PDE10A is expressed at high levels by the medium spiny neurons (MSN) of the caudate n., n. accumbens and the corresponding neurons of the olfactory tubercle. This constitutes the core of the basal ganglia system. The MSN make up a role in a cortical-basal ganglia-thalamocortical loop, integrating convergent cortical/thalamic input, and sending this integrated information back to the cortex. Furthermore, MSN express two functional classes of neurons: the D1 class expressing D1 dopamine receptors and the D2 class expressing D2 dopamine receptors. The D1 class of neurons is part of the 'direct' striatal output pathway, which broadly functions to facilitate behavioral responses.
The D2 class of neurons is part of the 'indirect' striatal output pathway, which functions to suppress behavioral responses that compete with those being facilitated by the 'direct' pathway.
These competing pathways act like the brake and accelerator in a car. In the simplest view, the poverty of movement in Parkinson's disease results from over-activity of the 'indirect' pathway, whereas excess movement in disorders such as Huntington's disease represent over-activity of the direct pathway. PDE10A regulation of cAMP
and/or cGMP
signaling in the dendritic compartment of these neurons may be involved in filtering the cortico/thalamic input into the MSN. Furthermore, PDE10A may be involved in the regulation of GABA release in the substantia nigra and globus pallidus (Seeger, T.F. et al.
Brain Research, 2003, 985, 113-126).
Dopamine D2 receptor antagonism is well established in the treatment of schizophrenia.
Since the 1950's, dopamine D2 receptor antagonism has been the mainstay in psychosis treatment and all effective antipsychotic drugs antagonise D2 receptors. The effects of D2 Most of the 21 phosphodiesterase genes are widely expressed; therefore inhibition is likely to have side effects. Because PDE10A, in this context, has the desired expression profile with high and relatively specific expression in neurons in striatum, n. accumbens and olfactory tubercle, PDE10A inhibition is likely to have effects similar to 02 receptor While PDE10A inhibition is expected to mimic 02 receptor antagonism in part, it might be expected to have a different profile. The 02 receptor has signalling components besides cAMP (Neve, K.A. et al. Journal of Receptors and Signal Transduction 2004, 24(3), 165-PDE10A inhibition is likely to also have effects that mimic D1 receptor agonism. Finally, PDE10A inhibition will not only increase cAMP in cells, but might also be expected to increase cGMP levels, since PDE10A is a dual specificity phosphodiesterase.
cGMP
activates a number of target protein in cells like cAMP and also interacts with the cAMP
signalling pathways. In conclusion, PDE10A inhibition is likely to mimic D2 receptor antagonism in part and therefore has antipsychotic effect, but the profile might differ from that observed with classical D2 receptor antagonists.
The PDE10A inhibitor papaverin is shown to be active in several antipsychotic models.
Papaverin potentiated the cataleptic effect of the D2 receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499). Papaverin reduced hyperactivity in rats induced by PCP, while reduction of amphetamine induced hyperactivity was insignificant (WO 03/093499). These models suggest that inhibition has the classic antipsychotic potential that would be expected from theoretical considerations. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of associated neurologic and psychiatric disorders. Furthermore, inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats (Rodefer, et al. Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A
inhibition might alleviate cognitive deficits associated with schizophrenia.
Accordingly, signal enhancement via elevation of cAMP and cGMP can be induced through the administration of PDE10A inhibitors to treat associated neurological and psychiatric disorders. The PDE10A inhibitors of the present invention are expected to serve as therapies for the treatment of associated neurological and psychiatric disorders and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
Furthermore, recent publications (WO 2005/120514, WO 2005012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873) suggest that inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes.
With respect to inhibitors of PDE10A, EP 1250923 discloses the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.

WO 05/113517 discloses benzodiazepine stereospecific compounds as inhibitors of phosphodiesterase, especially types 2 and 4, and the prevention and treatment of pathologies involving a central and/or peripheral disorder. WO 02/88096 discloses benzodiazepine derivatives and their uses as inhibitors of phosphodiesterase, especially 5 type 4 in the therapeutic field. WO 04/41258 discloses benzodiazepinone derivatives and their uses as inhibitors of phosphodiesterase, especially type 2 in the therapeutic field.
Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10 in WO 05/03129 and WO 05/02579. Piperidinyl-substituted quinazolines and isoquinolines that serve as PDE10 inhibitors are disclosed in WO 05/82883. WO 06/11040 discloses substituted quinazoline and isoquinoline compounds that serve as inhibitors of PDE10.
US20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors.
In particular, US20050182079 relates to said compounds, which are selective inhibitors of PDE-10.
Analogously, US20060019975 discloses piperidine derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors.

also relates to compounds that are selective inhibitors of PDE10.
WO 06/028957 discloses cinnoline derivatives as inhibitors of phosphodiesterase type 10 for the treatment of psychiatric and neurological syndromes.
However, these disclosures do not pertain to compounds comprising cyanoisoquinoline attached to 2-arylpiperazine, 2-arylthiomorpholine or 2-arylmorpholine via a N-C linkage;
said compounds having now been found by the inventors to be highly active enzyme inhibitors. Such compounds may offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients. Hence, there remains the need for alternative methods of treatment.
The Phosphodiesterase 3 (PDE3) family consists of two genes PDE3A and PDE3B.
They encode enzymes that can hydrolyse cAMP and cGMP to AMP and GMP, respectively.
PDE3A is relatively highly expressed in platelets, vascular smooth muscle, cardiac myocytes, and oocytes. PDE3B is a major PDE in adipose tissue, liver, pancreas, as well as in cardiovascular tissues. PDE3 inhibitors have been approved for treatment of congestive heart failure. However, while they are beneficial in acute treatment, chronic treatment with PDE3 inhibitors resulted in a significant increase in mortality (Matthew A.
Movsesian, Journal of Cardiac Failure Vol. 9 No. 6, 2003, 475-480).
Several PDE10 inhibitors containing the 6,7-dimethoxy-quinazoline motif have been described previously (Chappie et al.: Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors, J. Med. Chem., 2007, 50(2), pp. 182-185, Published on Web 12/22/2006). The 6,7-dimethoxy-quinazoline containing compounds described herein all exhibited significant PDE3 activity ¨ all had PDE3A
IC50's of less than 800 nM. Thus, achieving selectivity towards PDE3 appears to be a common problem for PDE10 inhibitors with this motif that poses a serious problem for their potential use in chronic treatment given the propensity of pde3 inhibition to cause cardiac side effects.
Summary of the Invention The present invention provides, in embodiments, compounds that are PDE10A
enzyme inhibitors without affecting the inhibition of PDE3.
The present invention provides, in embodiments, compounds with such activities which have improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.
The invention provides, in embodiments, an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current therapies for neurologic and psychiatric disorders.
Further characteristics of the invention will become apparent upon reading the present specification.
Accordingly, in one aspect the present invention relates to compounds of formula I:
CN

Rio 40., \ N
N
le R4 Q

wherein = Q is selected from NH, 0 or S
= R1 and R2 are independently C1-C4 alkyl = R3, Ra, R5, R6 and R7 are independently selected from:
O H, (C1-C6) alkyl, (C1-C6) alkoxy, halogen, halo(C1-C6)alkyl, (Cr C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)hydroxycycloalkyl, (C3-C8)cycloalkoxy, (C1-C6)alkoxy(C3-C8)cycloalkyl, heterocycloalkyl, hydroxyheterocycloalkyl, and (C1-C6)alkoxy-heterocycloalkyl, wherein each (C3-C8)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C1-C6)alkyl;
o a -NR8R9 group, wherein R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl;
O a 6-7-membered aliphatic heterocycle:
/ [ \- n N Z
\ _______________________________________ /
wherein n is 1 or 2 and Z is oxygen or NRio, wherein R10 is hydrogen or (C1-C6) alkyl, or 0 a ketone, sulfone, ester, amide, sulfonic ester or sulfonamide, selected from II I I I
¨C¨X ¨S¨X N¨S¨X or N¨C¨X
I I I I I I I I

wherein Y is hydrogen or (C1-C6) alkyl and X is a selected from:
= a (C1-C6) alkyl group unsubstituted or substituted with one or more halogens, = -0-(C1-C6) alkyl unsubstituted or substituted with one or more halogens, = a ¨NR11R12 group, where R11 and R12 are independently selected from hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, or = a 6-7-membered aliphatic heterocycle:
r _ L
wherein n is 1 or 2; and W is oxygen or NR13, wherein R13 is hydrogen or (C1-C6) alkyl, or = two adjacent substituents selected from R3, R4, R5, R6 and R7 may together with the aromatic ring they are attached to form a 5-7 membered, saturated or unsaturated ring containing carbon and one or two heteroatoms selected from N, 0 or S, and optionally substituted with an (C1-C6) alkoxy group. The remaining three substituents selected from R3, R4, R5, R6 and R7, which do not take part of the ring, are independently selected as stated above.
or a pharmaceutically acceptable salt thereof.
In a particular embodiment, the invention relates to compounds of formula I in the form of a single enantiomer, a single diastereomer, a mixture of enantiomers, a mixture of diastereomers, or a polymorph.
In separate embodiments of the invention, the compound is selected from one of the specific compounds disclosed in the Experimental Section.
The invention provides a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament.
In another aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent.
The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of neurodegenerative or psychiatric disorders.
Furthermore, in yet another aspect the present invention provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a still further aspect the present invention provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In another embodiment the present invention provides a method of treating a subject suffering from a drug addiction such as an alcohol, amphetamine, cocaine, or opiate addiction.
Detailed Description of the Invention Definition of Substitutents As used in the present invention, the terms "halo" and "halogen" are used interchangeably and refer to fluorine, chlorine, bromine or iodine.

Furthermore, the term "C1-C6 alkyl" refers to a straight chained or branched saturated hydrocarbon having from one to six carbon atoms inclusive. Examples of such groups include, but are not limited to, methyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl and n-hexyl. Similarly, the term "C1-04 alkyl" refers to a straight chained or 5 branched saturated hydrocarbon having from one to four carbon atoms inclusive. The expression "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl group as defined above, which is substituted with one hydroxy group. The term "halo(C1-C6)alkyl" refers to a C1-C6 alkyl group as defined above, which is substituted with up to three halogen atoms.
10 The expression "C1-C6 alkoxy" refers to a straight chain or branched saturated alkoxy group having from one to six carbon atoms inclusive with the open valency on the oxygen.
Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy. The term "halo(C1-C6)alkoxy" refers to a C1-C6 alkoxy group as defined above, which is substituted with up to three halogen atoms.
The term "Cl-C6 alkoxy(C1-C6)alkyl" refers to a C1-C6 alkyl group as defined above, which is substituted with a C1-C6 alkoxy group as defined above.
The term "C3-C8 cycloalkyl" typically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "C3-C8 hydroxycycloalkyl"
refers to C3-C8 cycloalkyl as defined above, which is substituted with one hydroxy group. The expression "C1-C6 alkoxy(C3-C8)cycloalkyl" refers to a C3-C8 cycloalkyl as defined above, which is substituted with a straight chained or branched C1-C6 alkoxy. The term "C3-C8 cycloalkoxy"
typically refers to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptoxy and cyclooctoxy in which the open valency is on the oxygen atom.
The term "heterocycloalkyl" refers to a four to eight membered ring containing carbon atoms and up to three N, 0 or S atoms provided that the four to eight membered ring does not contain adjacent 0 or adjacent S atoms. The open valency is on either the heteroatom or carbon atom. Examples of such groups include, but are not limited to, azetidinyl, oxetanyl, piperazinyl, morpholinyl, thiomorpholinyl and [1,4]diazepanyl. The term "hydroxyheterocycloalkyl" refers to a heterocycloalkyl as defined above, which is substituted with one hydroxy group. The term "C1-C6 alkoxy-heterocycloalkyl"
refers to a heterocycloalkyl as defined above, which is substituted with a C1-C6 alkoxy group.
Additionally, the present invention further provides for certain embodiments of the invention, which are described below.
Formula I defines the compounds of the present invention by the ring variable Q, and by the substituents R1, R2, R3,111, R5, R6 and R7.
In a preferred embodiment of the invention, Q=NH
In one embodiment R1 and R2 are independently C1-C2 alkyl, such as methyl.
Typically, R1 and R2 are both methyl In one embodiment, R3 is selected from hydrogen, (CI-CO alkoxy or halogen, such as hydrogen, methoxy, chlorine and bromine; or a carboxamide or sulfonamide selected from:

/ \
¨C¨N NH ¨S¨N NH
0 ____________________________________________ 0 ____ / \ 0 ____ ¨C¨N 0 ¨S--N 0 I I \ __ / II \ __ /

Typically R3 is hydrogen.
In another embodiment of the invention, R4 is selected from hydrogen, (C1-C6) alkoxy, halogen or nitro such as hydrogen, methoxy, chlorine, bromine and nitro, or a carboxamide or sulfonamide selected from:

/ \
¨C¨N NH ¨S¨N NH
0 ____________________________________________ 0 ____ / \ 0 ____ ¨C¨N 0 ¨S¨N 0 0 0 ____ Typically R4 is hydrogen or methoxy.
In yet another embodiment R5 is selected from:
o H, (C1-C6) alkyl, (C1-C6) alkoxy, halogen, halo(C1-C6)alkyl, nitro or o an amino group -N R8R9, where R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, or o a 6-7-membered aliphatic heterocycle:
[
wherein n is 1 or 2 and Z is oxygen or NRio, wherein R10 is hydrogen or (C1-C6) alkyl, or a carboxamide or sulfonamide selected from:

II
¨C¨N NH ¨S¨N NH
0 _____________________________________ 0 I I /
¨C¨N 0 ¨S¨ N 0 0 _____________________________________ 0 such as hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, nitro, dimethylamino, morpholino. Typically R5 is hydrogen, methyl, dimethylamino, methoxy fluorine, chlorine or trifluoromethyl.
In another embodiment, R6 is selected from hydrogen, (C1-C6) alkoxy, halogen or nitro such as hydrogen, methoxy, chlorine, bromine and nitro, or a carboxamide or sulfonamide selected from:
I I /
¨C¨ N NH ¨S¨N NH
I I \ _______________ I I \ __ 0 _____________________________________________________ / I I /
¨C¨N 0 ¨S¨N 0 I I \ _______________ I I \ __ Typically R6 is hydrogen or methoxy.
In one embodiment, R7 is selected from hydrogen, (C1-C6) alkoxy or halogen, such as hydrogen, methoxy, chlorine and bromine; or a carboxamide or sulfonamide selected from:

II /
¨C¨N NH ¨S¨N NH
I I \ _______________ I I \ __ 0 _____________________________________________________ / I I /
¨C¨N 0 ¨S¨N 0 I I \ _______________ I I \ __ Typically R7 is hydrogen.
In another embodiment two adjacent substituents selected from R3, R4, R5, R6 and R7 may, together with the aromatic ring they are attached to, form a 5-7 membered, saturated or unsaturated ring, optionally containing one or two heteroatoms selected from N, 0 or S, such as a five-membered ring containing two oxygen atoms, or a six-membered ring containing only carbon atoms.
In a further embodiment, two to five of R3, R4, IR6, R6 and R7 are H.
Typically three to four of R3, R4, F(6, R6 and R7 are H.
In a preferred embodiment one to three of R4, R5or R6 are electron-donating substituents such as (C1-C6) alkoxy, (C1-C6) alkyl or -NR8R9, where R5 and R9 are independently selected from hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, such as methoxy, methyl, ethyl , dimethylamino and morpholino.
In another embodiment two adjacent substituents selected from R3, R4, R5, R6 and R7 may, together with the aromatic ring they are attached to, form a 5 membered, saturated ring containing two oxygen atoms:
=
In yet another embodiment two adjacent substituents selected from R3, R4, R5, and R7 may, together with the aromatic ring they are attached to, form a 6 membered aromatic ring:
or pharmaceutically acceptable salts thereof.
Another aspect of the present invention is a process for the preparation of the compounds of Formula I comprising reacting a compound of Formula II:
CN
Ri0 N

in which L is a leaving group selected from Cl, Br, I, OSO2CF3, and R1 and R2are as defined above; with a compound of Formula III:

III

either as the free base or an addition salt hereof; wherein Q, R3, R4, R5, R6 and R7 are as defined above; either neat, or in an inert solvent or mixture of solvents, at a temperature 5 between 0 to about 200 C, optionally in the presence of a base, followed by work-up and isolation of the product of Formula I, either as its free base or as an acid addition salt hereof.
In an embodiment of the present invention the solvent used for the preparation of the 10 compounds of Formula I is toluene or mixtures of toluene with a protic solvent such as 2-propanol, preferably a 1:1 mixture of toluene and 2-propanol.
In another embodiment of the present invention the base used for the preparation of the compounds of Formula I is potassium carbonate.
In yet another embodiment of the present invention the preferred reaction temperature used for the preparation of the compounds of Formula I is 180 C.
In a further embodiment the process for the preparation of the compounds of Formula I
comprising reacting a compound of Formula II with a compound of Formula III in the presence of an alkoxide base, such as sodium tert-butoxide, and a palladium catalyst prepared in situ by mixing a palladium (II) source such as Pd(OAc)2 or Pd2(dba)3 with a bisphosphine ligand such as BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), in a convenient reaction solvent such as toluene, followed by heating the reaction mixture at 50-150 C for 3-12 hours, typically for 7 hours at 100 C.

. 572-W0-PCT 16 Pharmaceutically Acceptable Salts The present invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like.
Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J.
Pharm. Sci.
1977, 66, 2.
Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Racemic forms may be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base.
Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization.
The optically active acids suitable for this purpose may include, but are not limited to d-or 1-tartaric, mandelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix.
The compounds of the present invention may also be resolved by the formation and separation, e.g. chromatographic separation, of diastereomeric derivatives from chiral derivatizing reagents, such as a chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary.

Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York 1981.
Optically active compounds were also be prepared from optically active starting materials.
Pharmaceutical compositions The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent. The present invention also provides a pharmaceutical com-position comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier or diluent.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes.
It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day.
Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day.
Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration.
The present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and at least one pharmaceutically acceptable carrier or diluent. In an embodiment of the present invention, the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of formula I
contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.

For parenteral administration, solutions of the compounds of formula I in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such 5 as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
Treatment of Disorders 10 As mentioned above, the compounds of formula I are PDE10A enzyme inhibitors and as such are useful to treat associated neurological and psychiatric disorders.
The present invention provides a method of treating a subject suffering from a neurodegenerative disorder selected from a cognition disorder or movement disorder which comprises administering to the subject a therapeutically effective amount of a compound of formula I.
This invention also provides a method of treating a subject suffering from a psychiatric disorder, which comprises administering to the subject a therapeutically effective amount of a compound of formula I.
Examples of psychiatric disorders that can be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type;
schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and the anxiety disorder is selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder;
post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
The present invention provides a method of treating a subject suffering from a cognition disorder, which comprises administering to the subject a therapeutically effective amount of a compound of formula I. Examples of cognition disorders that can be treated according to the present invention include, but are not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia;
delirium;
amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression;
attention-deficit/hyperactivity disorder; and age-related cognitive decline.
This invention also provides a method of treating a movement disorder, which comprises administering to the subject a therapeutically effective amount of a compound of formula I.
Examples of movement disorders that can be treated according to the present invention include, but are not limited to, Huntington's disease and dyskinesia associated with dopamine agonist therapy. This invention further provides a method of treating a movement disorder selected from Parkinson's disease and restless leg syndrome, which comprises administering to the subject a therapeutically effective amount of a compound of formula I.
This invention also provides a method of treating a mood disorder, which comprises administering to the subject a therapeutically effective amount of a compound of formula I.
Examples of mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with a typical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder;
minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder. It is understood that a mood disorder is a psychiatric disorder.
The invention also provides the use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of neurodegenerative or psychiatric disorders wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive decline, and wherein the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder;
schizoaffective disorder, for example of the delusional type or the depressive type;
delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
This invention further provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said drug addiction.
This invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I
effective in inhibiting PDE10.
A "drug addiction", as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
The invention also provides a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, and pharmaceutical compositions containing such compounds, for use in the treatment of neurodegenerative disorders, psychiatric disorders and drug addictions in mammals including humans, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive decline, and wherein the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder;

. 572-WO-PCT 23 schizoaffective disorder, for example of the delusional type or the depressive type;
delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, and wherein the drug addiction is an alcohol, amphetamine, cocaine, or opiate addiction.
In another embodiment, the invention provides a method of treating a subject to reduce body fat or body weight, or to treat non-insuline demanding diabetes mellitus (NIDDM), metabolic syndrome, or glucose intolerance, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I. In preferred embodiments, the subject is human, the subject is overweight or obese and the antagonist is administered orally. In another preferred embodiment, the method further comprising administering a second therapeutic agent to the subject, preferably an anti-obesity agent, e.g., rimonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, or peptide YY3-36, or analogs thereof.
The term "metabolic syndrome" as used herein refers to a constellation of conditions that place people at high risk for coronary artery disease. These conditions include type 2 diabetes, obesity, high blood pressure, and a poor lipid profile with elevated LDL ("bad") cholesterol, low HDL ("good") cholesterol, and elevated triglycerides. All of these conditions are associated with high blood insulin levels. The fundamental defect in the metabolic syndrome is insulin resistance in both adipose tissue and muscle.
The present invention will be better understood from the Experimental Section that follows.

. 572-WO-PCT 24 _ Experimental Section General Methods Analytical LC-MS data were obtained on a PE Scieirm API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC
system.
Column: 30 X 4.6 mm WatersTM Symmetry C18 column with 3.5 pm particle size;
Solvent system: A = water/trifluoroacetic acid (100:0.05) and B =
water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Linear gradient elution with 90% A to 100% B in 4 minutes and with a flow rate of 2 mUminute. Purity was determined by integration of the UV
(254 nm) and ELSD trace. The retention times (tR) are expressed in minutes.
Preparative LC-MS-purification was performed on the same instrument with atmospheric pressure chemical ionisation. Column: 50 X 20 mm YMC ODS-A with 5 pm particle size;
Method: Linear gradient elution with 80% A to 100% B in 7 minutes and with a flow rate of 22.7 mL/minute. Fraction collection was performed by split-flow MS detection.
Preparation of the compounds of the invention CN

I
N

I
N

Q

Compounds of the general formula I of the invention may be prepared as described in the following reaction schemes. Unless otherwise indicated, in the reaction schemes and discussion that follow, R1-R7, Q, and L are as defined above. Scheme 1 below depicts a coupling reaction between a compound of formula ll and a derivative of 2-arylpiperazine, 2-arylthiomorpholine or 2-arylmorpholine of formula III, to generate the dialkoxy substituted compounds of formula I

Scheme 1 CN

I
op R4 This reaction is typically carried out in a solvent such as, for example, toluene, optionally in the presence of a carbonate base, at a temperature range of from about 0 C
to about 5 200 C. Other suitable solvents include benzene, chloroform, dioxane, ethyl acetate, 2-propanol and xylene. Alternatively, solvent mixtures such as toluene/2-propanol can be used. Preferably the reactants are heated under reflux in a solvent mixture of toluene and 2-propanol for a period of from about 2 hours to about 24 hours, optionally using a microwave oven.
The reaction depicted in Scheme 1 can also conveniently be carried out in a palladium-catalyzed fashion. Typically, a mixture of a compound of formula II, a compound of formula III and a palladium (II) source such as Pd(OAc)2 or Pd2(dba)3 is heated in a convenient solvent such as toluene in the presence of a bisphosphine ligand, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl "BINAP", and an alkoxide base such as sodium tert-butoxide. The reaction mixture is stirred at 100 C for 7hr, followed by purification of the product by preparative HPLC to obtain the desired product.
The prepared compounds all display a satisfactory aqueous solubility. However, the piperazine derivatives (Formula I, Q = NH) appear in general to be significantly better soluble than the analogous morpholine- or thimorpholine derivatives (Formula I, Q = 0 or S, respectively).
Starting materials of formula II can be prepared as described in the literature e.g.
Canadian Journal of Chemistry, 46 1160 (1968).

Starting materials of formula III are either commercially available or can be prepared as described in the literature e.g. Wolters,R.J. et al.; J. Pharm. Sci.; 63;
1974; 1379-1382, Busch,N. et al.; Eur. J. Med. Chem. Chim. Ther.; 11; 1976; 201-207, Ruano, J.
L. et al. J.
Org. Chem.; 57; 15; 1992; 4215-4224, J. Med. Chem. 1983, 26, p 254; Ref.
Patent;
Hokuriku Pharm.; DE 2718451; 1977; Chem.Abstr.; EN; 88; 89714; Blythin et al.
Bioorg.
Med. Chem. Lett. 2002, 12, 3161.
General procedure for synthesis of the building blocks Starting materials of formula 10Ill A stirred mixture of 0.03 eq of Pd(OAc)2 and 0.04 eq of 1,1-bis(diphenylphosphino) ferrocene(dppf) in dimethylformamide was heated at 50 C for 0.25 h. After cooling, 1 eq of the 2-chloro-pyrazine, 1.1 eq of the areneboronec acid, and 1.4 eq of Et3N
were added, and the mixture was stirred at 90 C for 12 h. After cooling, the black mixture was concentrated to dryness on the evaporator, and the product was taken up in 50 mL of chloroform, washed with 25 mL of dilute NH4OH solution, and concentrated to dryness.
The residue was purified on flash chromatography to give the pure product of formula III.
The invention disclosed herein is further illustrated by the following non-limiting examples.
Example 1 1. 1-[3-(4-Fluoro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile (\11 N

2-(4-fluorophenyI)-piperazine (1.12 g; 6.2 mmol) ), 1-Chloro-6,7-dimethoxy-isoquinoline-4-carbonitrile (1.4 g; 6.2 mmol) and triethyl amine (2.59 ml) were added to a 1:1 mixture of toluene (8 ml) and 2-propanol (8 ml), corresponding to a final concentration of about 0.39 molar. The reaction mixture was heated in a microwave oven at 180 C for 15 minutes.
The solvent was removed under vacuum and the resultant solid was subjected to preparative chromatography on silicagel using a mixture of ethylacetat:methanol:triethyl amine (95:5:1) as eluent. Fractions containing the product were collected, pooled and evaporated in vacuo to give the product.
The following compounds were prepared analogously:
2. 6,7-Dimethoxy-143-(3-methoxy-pheny1)-piperazin-1-y1Fisoquinoline-4-carbonitrile 3. 6,7-Dimethoxy-143-(3-methoxy-pheny1)-piperazin-1-y1]-3-methyl-isoquinoline-carbonitrile 4. 6,7-Dimethoxy-1-(3-naphthalen-1-yl-piperazin-1-yI)-isoquinoline-4-carbonitrile 5. 6,7-Dimethoxy-143-(4-methoxy-pheny1)-piperazin-1-y1Fisoquinoline-4-carbonitrile 6. 6,7-Dimethoxy-143-(2-methoxy-pheny1)-piperazin-1-y1Fisoquinoline-4-carbonitrile 7. 143-(4-Dimethylamino-pheny1)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 8. 1-(3-Benzo[1,3]dioxo1-5-yl-piperazin-1-y1)-6,7-dimethoxy-isoquinoline-4-carbonitrile 9. 6,7-Dimethoxy-143-(3-nitro-phenyl)-piperazin-1-y11-isoquinoline-4-carbonitrile 10. 6,7-Dimethoxy-1-(3-naphthalen-2-yl-piperazin-1-yI)-isoquinoline-4-carbonitrile 11. 143-(3,5-Dimethoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 12. 143-(2,5-Dimethoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 13. 6,7-Dimethoxy-143-(4-trifluoromethyl-phenyl)-piperazin-1-y1]-isoquinoline-carbonitrile 14. 143-(2,5-Dichloro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 15. 143-(2,4-Dichloro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 16. 6,7-Dimethoxy-143-(4-morpholin-4-yl-phenyl)-piperazin-1-y1]-isoquinoline-4-carbonitrile 17. 143-(2,4-Dichloro-5-fluoro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 18. 6,7-Dimethoxy-142-(4-methoxy-pheny1)-morpholin-4-y1]-isoquinoline-4-carbonitrile 19. 6,7-Dimethoxy-1-(2-p-tolyl-morpholin-4-yI)-isoquinoline-4-carbonitrile 20. 142-(4-Chloro-phenyl)-morpholin-4-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 21. 142-(2-Chloro-phenyl)-morpholin-4-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 22. 6,7-Dimethoxy-142-(4-trifluoromethyl-phenyl)-morpholin-4-y1Fisoquinoline-4-carbonitrile 23. (+)-6,7-Dimethoxy-143-(3-methoxy-phenyl)-piperazin-1-y1Fisoquinoline-4-carbonitrile 24. (-)-6,7-Dimethoxy-143-(3-methoxy-phenyl)-piperazin-1-y1Fisoquinoline-4-carbonitrile 25. 6,7-Dimethoxy-1-(3-p-tolyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 26. 143-(3-Chloro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 27. 143-(4-Bromo-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 28. 6,7-Dimethoxy-143-(6-methoxy-naphthalen-2-y1)-piperazin-1-y1Fisoquinoline-carbonitrile 29. 6,7-Dimethoxy-1-(2-phenyl-thiomorpholin-4-yI)-isoquinoline-4-carbonitrile 30. 143-(4-Chloro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 31. 6,7-Dimethoxy-3-methyl-1-(3-p-tolyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 32. 6,7-Dimethoxy-143-(4-methoxy-pheny1)-piperazin-1-y1]-3-methyl-isoquinoline-carbonitrile 33. 6,7-Dimethoxy-3-methy1-1-(3-naphthalen-2-yl-piperazin-1-y1)-isoquinoline-4-carbonitrile 34. 6,7-Dimethoxy-3-methy1-1-(3-naphthalen-1-yl-piperazin-1-y1)-isoquinoline-4-carbonitrile 35. 143-(3,5-Dimethoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile 36. 143-(2,5-Dimethoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile 37. 143-(4-Bromo-phenyl)-piperazin-1-y1]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile 38. 6,7-Dimethoxy-143-(6-methoxy-naphthalen-2-y1)-piperazin-1-y1]-3-methyl-isoquinoline-4-carbonitrile 39. 6,7-Dimethoxy-142-(4-methoxy-pheny1)-morpholin-4-y1]-3-methyl-isoquinoline-carbonitrile 40. 6,7-Dimethoxy-3-methy1-1-((R)-3-phenyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 41. 143-(4-Fluoro-phenyl)-piperazin-1-y1]-6,7-dimethoxy-3-methyl-isoquinoline-carbonitrile 42. 6,7-Dimethoxy-143-(2-methoxy-pheny1)-piperazin-1-y1]-3-methyl-isoquinoline-carbonitrile 43. 1-(3-Benzo[1,3]clioxo1-5-yl-piperazin-1-y1)-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile 44. 6,7-Dimethoxy-1-((S)-3-phenyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 45. 6,7-Dimethoxy-1-(4-methy1-3-p-tolyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 46. 143-(4-Ethyl-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 47. 143-(4-Dimethylamino-pheny1)-piperazin-1-y1]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile 48. 6,7-Dimethoxy-3-methy1-143-(3,4,5-trimethoxy-phenyl)-piperazin-1-y1Fisoquinoline-4-carbonitrile 49. 6,7-Dimethoxy-3-methyl-1-((S)-3-phenyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 50. 6,7-Dimethoxy-3-methy1-143-(3-nitro-phenyl)-piperazin-1-y1Fisoquinoline-4-carbonitrile 51. 6,7-Dimethoxy-3-methy1-143-(4-morpholin-4-yl-phenyl)-piperazin-1-y1]-isoquinoline-4-carbonitrile 52. 6,7-Dimethoxy-1-( -3-phenyl-piperazin-1-y1)-isoquinoline-4-carbonitrile 53. 6,7-Dimethoxy-143-(4-methoxy-2-methyl-phenyl)-piperazin-1-y1Fisoquinoline-carbonitrile 54. 143-(3-Fluoro-4-methoxy-phenyl)-piperazin-1-y11-6,7-dimethoxy-isoquinoline-carbonitrile 55. 1-[3-(4-Ethoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 56. 1-[3-(3-Chloro-4-methoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 57. 143-(4-lsopropoxy-pheny1)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 58. 143-(2,4-Dimethoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 59. 143-(4-Ethoxy-3-methyl-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-carbonitrile 60. 6,7-Dimethoxy-143-(4-trifluoromethoxy-phenyl)-piperazin-1-y1Fisoquinoline-carbonitrile 61. 6,7-Dimethoxy-1-[(R)-3-(4-methoxy-pheny1)-piperazin-1-y1Fisoquinoline-4-carbonitrile 62. 6,7-Dimethoxy-1-[(S)-3-(4-methoxy-phenyl)-piperazin-1-y1]-isoquinoline-4-carbonitrile 63. 143-(4-lsopropoxy-3-methyl-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 5 64. 6,7-Dimethoxy-143-(4-methoxy-2,6-dimethyl-phenyl)-piperazin-1-A-isoquinoline-4-carbonitrile 65. 6,7-Dimethoxy-143-(4-methoxy-3,5-dimethyl-phenyl)-piperazin-1-A-isoquinoline-4-carbonitrile 66. 143-(2,3-Dihydro-benzo[1,4]dioxin-6-y1)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-10 4-carbonitrile 67. 143-(4-lsobutoxy-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-4-carbonitrile 68. 6,7-Dimethoxy-143-(4-methoxy-3-trifluoromethyl-phenyl)-piperazin-1-y1]-isoquinoline-4-carbonitrile 69. 143-(4-Ethoxy-2-methyl-phenyl)-piperazin-1-y1]-6,7-dimethoxy-isoquinoline-15 carbonitrile 70. N-{544-(4-Cyano-6,7-dimethoxy-isoquinolin-1-y1)-piperazin-2-y1]-2-methoxy-phenylyacetamide 71. (-)-N-1544-(4-Cyano-6,7-dimethoxy-isoquinolin-1-y1)-piperazin-2-y1]-2-methoxy-phenyll-acetamide 20 72. (+)-N-{544-(4-Cyano-6,7-dimethoxy-isoquinolin-1-y1)-piperazin-2-y11-2-methoxy-phenylyacetamide The following table summarizes the analytical data for the exemplified compounds Compound RETENTION Measured No. TIME PURITY UV (%) PURITY ELSD CYO M+H+
1 2,72 97,76 100 393,4 2 0,94 99,40 98,33 405,5 3 1,03 93,58 98,62 419,5 4 1,04 98,88 99,33 425,5 5 2,70 96,05 100 405,5 6 2,77 99,05 100 405,5 7 2,59 91,23 100 418,5 a 2,61 96,51 100 419,5 9 2,71 96,08 100 420,4 10 2,74 98,33 99,88 425,5 11 2,82 97,21 100 435,5 12 2,72 100 99,74 435,5 13 2,67 98,44 100 443,4 14 2,62 100 100 444,3 15 2,68 95,28 100 444,3 16 2,61 100 92,25 460,5 17 2,71 100 100 462,3 18 3,49 100 100 406,5 19 3,43 100 100 390,5 20 3,54 100 100 410,9 21 3,55 93,43 100 410,9 22 2,96 100 100 444,4 23 0,82 96,0 100 405,5 24 0,83 98,0 100 405,5 25 2,56 92,82 100 389,5 26 2,70 90,14 100 409,9 27 2,44 92,68 100 454,3 28 2,64 93,39 100 455,5 29 3,21 96,81 94,22 392,5 30 2,76 95,18 94,43 409,9 31 2,60 96,14 100 403,5 32 2,69 100 100 419,5 33 2,70 95,2 100 439,5 34 2,73 97,59 100 439,5 35 2,75 90,13 99,62 449,5 36 2,75 90,23 99,08 449,5 37 2,65 95,03 100 468,4 38 2,72 99,1 100 469,6 39 3,58 98,76 100 420,5 40 2,66 95,7 90,28 389,5 41 2,77 99,47 99,48 407,5 42 2,77 93,34 100 419,5 43 2,74 93,58 100 433,5 44 2,57 93,53 100 375,4 45 2,24 98,8 99,54 403,5 46 2,69 91,48 100 403,5 47 2,63 91,06 99,62 432,5 48 2,83 97,03 91,45 479,5 49 2,81 93,74 99,9 389,5 50 2,72 98,93 96,38 434,5 51 2,84 96,3 100 474,6 52 2,70 90,26 95,38 375,4 53 2,81 90,06 96,03 419,5 54 2,73 100 96,75 423,5 55 2,87 99,11 98,33 419,5 56 2,81 100 94,19 439,9 57 2,71 98,14 97 433,5 58 2,81 99 97,25 435,5 59 2,79 98,77 92,92 433,5 60 2,76 100 92,37 459,4 61 0,86 97 100 405,5 62 0,87 96 100 405,5 63 2,88 100 90,09 447,5 64 2,89 98,36 97,4 433,5 65 2,68 90,31 94,27 433,5 66 2,66 99,64 94,49 433,5 67 2,91 100 95,26 447,5 68 2,72 98,86 98,58 473,5 69 2,72 90,69 91,56 433,5 70 3,04 97,88 90,71 462,5 71 0,88 96,61 100 423,5 72 0,89 97,94 100 423,5 ..
Pharmacological Testing PDE10A enzyme Active PDE10A enzyme is prepared in a number of ways for use in PDE assays (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. et al. Eur J
Biochem. 1999, 266, 1118-1127 and Soderling, S. et al. Proc. Natl. Acad. ScL 1999, 96, 7071-7076).
PDE10A can be expressed as full-length proteins or as truncated proteins, as long as they express the catalytic domain. PDE10A can be prepared in different cell types, for example insect cells or E. coli. An example of a method to obtain catalytically active PDE10A is as follows: The catalytic domain of human PDE10A (amino acids 440-779 from the sequence with accession number NP 006652) is amplified from total human brain total RNA by standard RT-PCR and is cloned into the BamH1 and Xho1 sites of the pET28a vector (Novagen). Expression in coil is performed according to standard protocols. Briefly, the expression plasmids are transformed into the BL21(DE3) E. coil strain, and 50 mL
cultures inoculated with the cells allowed to grow to an 0D600 of 0.4-0.6 before protein expression is induced with 0.5mM IPTG. Following induction, the cells are incubated overnight at room temperature, after which the cells are collected by centrifugation. Cells expressing PDE10A are resuspended in 12 mL (50 mM TRIS-HCI-pH8.0, 1 mM MgCl2 and protease inhibitors). The cells are lysed by sonication, and after all cells are lysed, Triton TmX100 is added according to Novagen protocols. PDE10A is partially purified on Q sepharose TM and the most active fractions were pooled.
PDE10A and Pde3A inhibition assay PDE10A and Pde3A assays can for example be performed as follows: PDE10A and Pde3A assays are performed in 60 uL samples containing a fixed amount of the relevant PDE enzyme (sufficient to convert 20-25% of the cyclic nucleotide substrate), a buffer (50 mM HEPES7.6; 10mM MgC12; 0.02% TweenTm20), 0.1mg/m1 BSA, 225 pCi of 3H-labelled cyclic nucleotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors. Reactions are initiated by addition of the cyclic nucleotide substrate, and reactions are allowed to proceed for one hr at room temperature before being terminated through mixing with 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to an uninhibited control (100 %) and IC50 values can be calculated using the Xlfit extension to EXCELTM.

Results of the experiments showed that the tested compounds of the invention inhibit the PDE10A enzyme with IC50 values below 700 nM.
Compound MOL-CHEMICAL NAME
2,1334003 2,1334005 No. WEIGHT 1050 1050 143-(4-Fluoro-phenyl)-piperazin-1-y1]-1 392,4 6,7-dimethoxy-isoquinoline-4- 80 carbonitrile 6,7-Dimethoxy-1-[3-(3-methoxy-2 404,5 phenyl)-piperazin-1-y1]-isoquinoline-4- 320 280 carbonitrile 6,7-Dimethoxy-1-[3-(3-methoxy-3 418,5 phenyl)-piperazin-1-y1]-3-methyl- 240 360 isoquinoline-4-carbonitrile 6,7-Dimethoxy-1-(3-naphthalen-1-yl-4 424,5 piperazin-1-yI)-isoquinoline-4- 78 carbonitrile 6,7-Dimethoxy-1-[3-(4-methoxy-404,5 phenyl)-piperazin-1-y1]-isoquinoline-4- 54 carbonitrile 6,7-Dimethoxy-1-[3-(2-methoxy-6 404,5 phenyl)-piperazin-1-y1]-isoquinoline-4- 420 carbonitrile 1-[3-(4-Dimethylamino-phenyl)-7 417,5 piperazin-1-yI]-6,7-dimethoxy- 76 isoquinoline-4-carbonitrile 1 -(3-Benzo[1,3]d ioxo1-5-yl-piperazin-1 -418,5 yI)-6,7-dimethoxy-isoquinoline-4- 81 carbonitrile 6 ,7-Dimethoxy-1-[3-(3-nitro-pheny1)-9 419,4 piperazin-1-yl]-isoquinoline-4- 120 carbonitrile 6 ,7-Dimethoxy-1-(3-naphthalen-2-yl-10 424,5 piperazin-1-y1)-isoquinoline-4- 73 carbonitrile 1-[3-(3,5-Dimethoxy-pheny1)-piperazin-11 434,5 1-y1]-6,7-dimethoxy-isoquinoline-4- 41 carbonitrile 1-[3-(2,5-Dimethoxy-pheny1)-piperazin-12 434,5 1-y1]-6,7-dimethoxy-isoquinoline-4- 42 carbonitrile 6 ,7-Dimethoxy-1-[3-(4-trifluoromethyl-13 442,4 pheny1)-piperazin-1-yl]-isoquinoline-4- 160 carbon itrile 143-(2,5-Dich loro-phenyl)pi perazin-1-14 443,3 y1]-6,7-dimethoxy-isoquinoline-4- 650 carbonitrile 1-[3-(2,4-Dich loro-phenyl)-pi perazin-1-15 443,3 y1]-6,7-dimethoxy-isoquinoline-4- 520 carbonitrile 6 ,7-Dimethoxy-1-[3-(4-morpholin-4-yl-16 459,5 phenyl)-piperazin-1-y1]-isoquinoline-4- 76 carbonitrile 1-[3-(2,4-Dich loro-5-fluoro-pheny1)-17 461,3 piperazin-1-y1]-6,7-dimethoxy- 1000 isoquinoline-4-carbonitrile 6,7-Di meth oxy-1-[2-(4-meth oxy-18 405,5 phenyl )-morpholin-4-y1]-isoquinoli ne-4- 97 carbonitrile 6' 7-Dimethoxy-1-(2-p-tolyl-morpholin-19 389,5 . . . 580 490 4-y1)-isoquinoline-4-carbonitrile 142-(4-Chloro-pheny1)-morpholin-4-y1]-20 409,9 6,7-d imethoxy-isoquinoli ne-4- 800 carbonitrile 142-(2-Chloro-pheny1)-morpholin-4-y1]-21 409,9 6,7-d imethoxy-isoquinoli ne-4- 530 carbonitrile 6 ,7-Dimethoxy-1-[2-(4-trifluoromethyl-22 443,4 phenyl )-morpholin-4-y1]-isoquinoli ne-4- 1600 carbonitrile (+)-6,7-Di m ethoxy-1-[3-(3-methoxy-23 404,5 phenyl )-piperazin-1-y1]-isoqu inoline-4- 1300 carbonitrile (-)-6,7-Di m ethoxy-1-[3-(3-meth oxy-24 404,5 phenyl )-piperazin-1-y1]-isoqu inoline-4- 27 carbonitrile 6' 300 7-Dimethoxy-1-(3-p-tolyl-piperazin-1-'5 yl)-isoquinoline-4-carbonitrile 143-(3-Chloro-phenyl )-piperazin-1-y1]-26 408,9 6,7-d imethoxy-isoquinoli ne-4- 390 330 carbonitrile 143-(4-Bromo-phenyl )-piperazin-1-y1]-27 453,3 6,7-d imethoxy-isoquinoli ne-4- 510 720 carbonitrile 6,7-Di meth oxy-1-[3-(6-meth oxy-28 454,5 naphthalen-2-y1)-piperazin-1-y1]- 330 680 isoquinoline-4-carbonitrile 6,7-Dimethoxy-1-(2-phenyl-29 391,5 thiomorpholin-4-yI)-isoquinoline-4- 2500 3300 carbonitrile 143-(4-Chloro-phenyl )-piperazin-1-y1]-30 408,9 6,7-d imethoxy-isoquinoli ne-4- 700 620 carbonitrile 6,7-Dimethoxy-3-methy1-1-(3-p-tolyl-31 402,5 piperazin-1-yI)-isoquinoline-4- 1000 600 carbonitrile 6,7-Di meth oxy-1-[3-(4-meth oxy-32 418,5 phenyl )-piperazin-1-y1]-3-methyl- 290 310 isoquinoline-4-carbonitrile 6,7-Di meth oxy-3-methy1-1-(3-33 438,5 naphthalen-2-yl-piperazin-1-y1)- 2100 2300 isoquinoline-4-carbonitrile 6,7-Di meth oxy-3-methy1-1-(3-34 438,5 naphthalen-1-yl-piperazin-1-y1)- 880 1200 isoquinoline-4-carbonitrile 1-[3-(3,5-Dimethoxy-pheny1)-piperazin-35 448,5 1-y1]-6,7-dimethoxy-3-methyl- 710 600 isoquinoline-4-carbonitrile 143-(2,5-Dimethoxy-phenyl)-piperazin-36 448,5 1-y1]-6,7-dimethoxy-3-methyl- 960 1200 isoquinoline-4-carbonitrile 143-(4-Bromo-phenyl)-piperazin-1-y1]-37 467,4 6,7-d imethoxy-3-methyl-isoq uinoli ne-4- 2600 carbonitrile 6,7-Di meth oxy-1-[3-(6-meth oxy-38 468,6 naphthalen-2-y1)-piperazin-1-y1]-3- 980 1300 methyl-isoquinoline-4-carbonitrile 6,7-Di meth oxy-1-[2-(4-meth oxy-39 419,5 phenyl)-morpholin-4-y1]-3-methyl- 930 1900 isoquinoline-4-carbonitrile 6,7-Dimethoxy-3-methy1-1-((R)-3-40 388,5 phenyl-piperazin-1 -y1)-isoquinoline-4- 520 650 carbonitrile 143-(4-Fluoro-phenyl)-piperazin-1-y1]-41 406,5 6,7-d imethoxy-3-methyl-isoq uinoli ne-4- 1200 carbonitrile 6,7-Dimeth oxy-1-[3-(2-meth oxy-42 418,5 phenyl)-piperazin-1-y1]-3-methyl- 1400 1300 isoquinoline-4-carbonitrile 1-(3-Benzo[1,3]d ioxo1-5-yl-piperazin-1-43 432,5 yI)-6,7-dimethoxy-3-methyl- 510 350 isoquinoline-4-carbonitrile 6,7-Dimethoxy-1-((S)-3-phenyl-44 374,4 piperazin-1-yI)-isoquinoline-4- 410 280 carbonitrile 6,7-Dimethoxy-1-(4-methy1-3-p-tolyl-45 402,5 piperazin-1-yI)-isoquinoline-4- 350 900 carbonitrile 143-(4-Ethyl-phenyl)-piperazin-1-y1]-46 402,5 6,7-d imethoxy-isoquinoli ne-4- 1300 480 carbonitrile 1-[3-(4-Dimethylami no-phenyl)-47 431,5 piperazin-1-yI]-6,7-dimethoxy-3-methyl- 1200 2000 isoquinoline-4-carbonitrile 6 ,7-Dimeth oxy-3-methy1-1-[3-(3,4,5-48 478,5 trimethoxy-phenyl)piperazin-1-y1]- 1500 1300 isoquinoline-4-carbonitrile 6,7-Dimethoxy-3-methy1-1-((S)-3-49 388,5 phenyl-piperazin-1-y1)-isoquinoline-4- 460 220 carbonitrile 6,7-Dimethoxy-3-methyl-1-[3-(3-nitro-433,5 phenyl)-piperazin-1-y1]-isoquinoline-4- 1100 1300 carbonitrile 6,7-Dimeth oxy-3-methy1-1-[3-(4-51 473,6 morpholin-4-yl-phenyl)piperazin-1-y1]- 1500 1800 isoquinoline-4-carbonitrile 6,7-Dimethoxy-1-(0-3-phenyl-52 374,4 piperazin-1-yI)-isoquinoline-4- 210 370 carbonitrile 6,7-Dimeth oxy-143-(4-methoxy-2-53 418,5 methyl-phenyl)piperazin-1-y1]- 500 630 isoquinoline-4-carbonitrile 1-[3-(3-Fluoro-4-methoxy-pheny1)-54 422,5 piperazin-1-yI]-6,7-dimethoxy- 36 85 isoquinoline-4-carbonitrile 143-(4-Ethoxy-pheny1)-piperazin-1-y1F
418,5 6,7-d imethoxy-isoquinoli ne-4- 200 280 carbonitrile 1-[3-(3-Chloro-4-methoxy-pheny1)-56 438,9 piperazin-1-yI]-6,7-dimethoxy- 81 160 isoquinoline-4-carbonitrile 1 43-(4-lsopropoxy-phenyl)-piperazin-57 432,5 1 -y1]-6,7-dimethoxy-isoquinoline-4- 530 440 carbonitrile 1 -[3-(2,4-Dimethoxy-pheny1)-piperazin-58 434,5 1 -y1]-6,7-dimethoxy-isoquinoline-4- 850 390 carbonitrile 1 -[3-(4-Ethoxy-3-methyl-pheny1)-59 432,5 piperazin-1-y1]-6,7-dimethoxy- 650 870 isoquinoline-4-carbonitrile 6,7-Di meth oxy-1 -[3-(4-60 458,4 trifluoromethoxy-phenyl)-piperazin-1- 2300 2900 yl]-isoquinoline-4-carbonitrile 6 ,7-Dimethoxy-1-[(R)-3-(4-methoxy-61 404,5 pheny1)-piperazin-1-A-isoquinoline-4- 1200 1 carbonitrile 6 ,7-Di meth oxy-1 -[(S)-3-(4-meth oxy-62 404,5 phenyl)-piperazin-1-y1]-isoquinoline-4- 47 81 carbonitrile 1 43-(4-lsopropoxy-3-methyl-pheny1)-63 446,5 piperazin-1-y1]-6,7-dimethoxy- 870 1 000 isoquinoline-4-carbonitrile 6 ,7-Di meth oxy-1 -[3-(4-meth oxy-2,6-64 432,5 dimethyl-phenyl)piperazin-1-y1]- 2100 1 700 isoquinoline-4-carbonitrile 6 ,7-Di meth oxy-1-[3-(4-meth oxy-3,5-65 432,5 dimethyl-phenyl)piperazin-1-A- 1700 1700 isoquinoline-4-carbonitrile 143-(2,3-Dihyd ro-benzo[1,4]dioxin-6-66 432,5 yl)-piperazin-1-y1]-6,7-dimethoxy- 130 110 isoquinoline-4-carbonitrile 143-(4-lsobutoxy-pheny1)-pi perazin-1-67 446,5 yI]-6,7-dimethoxy-isoquinoline-4- 1100 1700 carbonitrile 6,7-Di meth oxy-1-[3-(4-meth oxy-3-68 472,5 trifluoromethyl-phenyl)-piperazin-1-y1]- 440 1100 isoquinoline-4-carbonitrile 143-(4-Ethoxy-2-methyl-pheny1)-69 432,5 piperazin-1-yI]-6,7-dimethoxy- 790 1100 isoquinoline-4-carbonitrile N-{5-[4-(4-Cyano-6,7-dimethoxy-70 461,5 isoquinolin-1-y1)-piperazin-2-y1]-2- 66 methoxy-phenyl}-acetamide (-)-N-{5-[4-(4-Cya no-6,7-di meth oxy-71 422,5 isoquinolin-1-y1)-piperazin-2-y1]-2-methoxy-phenyll-acetamide (+)-N-1544-(4-Cyano-6,7-dimethoxy-72 422,5 isoquinolin-1-y1)-piperazin-2-y1]-2-methoxy-phenyll-acetamide

Claims (251)

1. A compound having the structure l:
wherein:
.cndot. Q is NH, .cndot. R1 and R2 are independently C1-C4 alkyl, and .cndot. R3, R4, R5, R6 and R7 are independently H, (C1-C6) alkyl, (C1-C6) alkoxy, halogen, halo(C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)hydroxycycloalkyl, (C3-C8)cycloalkoxy, (C1-C6)alkoxy(C3-C8)cycloalkyl, heterocycloalkyl, hydroxyheterocycloalkyl, or (C1-C6)alkoxy-heterocycloalkyl, wherein each (C3-C8)cycloalkyl and heterocycloalkyl moiety may be independently substituted with from one to three (C1-C6)alkyl, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R1 and R2 are independently alkyl.
3. The compound according to claim 1 or 2, wherein R3 is H, (C1-C6) alkoxy or halogen.
4. The compound according to any one of claims 1 to 3, wherein R4 is H, (C1-C6) alkoxy, or halogen.
5. The compound according to any one of claims 1 to 4, wherein R5 is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, halogen, or halo(C1-C6)alkyl.
6. The compound according to any one of claims 1 to 5, wherein R6 is H, (C1-C6) alkoxy, or halogen.
7. The compound according to any one of claims 1 to 6, wherein R7 is H, (C1-C6) alkoxy or halogen.
8. The compound of claim 1 being 1-[3-(4-Fluoro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(3-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(3-methoxy-phenyl)-piperazin-1-yl]-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 being 6,7-Dimethoxy-1-(3-naphthalen-1-yl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(2-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 being 1-(3-Benzo[1,3]dioxol-5-yl-piperazin-1-yl)-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 being 6,7-Dimethoxy-1-(3-naphthalen-2-yl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 being 1-[3-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 being 1-[3-(2,5-Dimethoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 being 1-[3-(2,5-Dichloro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 being 1-[3-(2,4-Dichloro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-morpholin-4-yl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 being 143-(2,4-Dichloro-5-fluoro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 being 6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-morpholin-4-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 being 6,7-Dimethoxy-1-(2-p-tolyl-morpholin-4-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 being 1-[2-(4-Chloro-phenyl)-morpholin-4-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 being 1-[2-(2-Chloro-phenyl)-morpholin-4-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 being 6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 being (+)-6,7-Dimethoxy-1-[3-(3-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 being (-)-6,7-Dimethoxy-1-[3-(3-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 being 6,7-Dimethoxy-1-(3-p-tolyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
31. The compound of claim 1 being 1-[3-(3-Chloro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
32. The compound of claim 1 being 1-[3-(4-Bromo-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(6-methoxy-naphthalen-2-yl)-piperazin-1-yI]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1 being 6,7-Dimethoxy-1-(2-phenyl-thiomorpholin-4-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 being 1-[3-(4-Chloro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-(3-p-tolyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-methoxy-phenyl)-piperazin-1-yl]-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-(3-naphthalen-2-yl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-(3-naphthalen-1-yl-piperazin-1-yI)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1 being 143-(3,5-Dimethoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
41. The compound of claim 1 being 1-[3-(2,5-Dimethoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
42. The compound of claim 1 being 1-[3-(4-Bromo-phenyl)-piperazin-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
43. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(6-methoxy-naphthalen-2-yl)-piperazin-1-yl]-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
44. The compound of claim 1 being 6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-morpholin-4-yl]-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
45. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-((R)-3-phenyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
46. The compound of claim 1 being 1-[3-(4-Fluoro-phenyl)-piperazin-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
47. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(2-methoxy-phenyl)-piperazin-1-yl]-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
48. The compound of claim 1 being 1-(3-Benzo[1,3]dioxol-5-yl-piperazin-1-yl)-6,7-dimethoxy-3-methyl-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
49. The compound of claim 1 being 6,7-Dimethoxy-1-((S)-3-phenyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
50. The compound of claim 1 being 6,7-Dimethoxy-1-(4-methyl-3-p-tolyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
51. The compound of claim 1 being 1-(3-(4-Ethyl-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
52. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-[3-(3,4,5-trimethoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
53. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-((S)-3-phenyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
54. The compound of claim 1 being 6,7-Dimethoxy-3-methyl-1-[3-(4-morpholin-4-yl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
55. The compound of claim 1 being 6,7-Dimethoxy-1-((R)-3-phenyl-piperazin-1-yl)-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
56. The compound of claim 1 being 6,7-Dimethoxy-1-(3-(4-methoxy-2-methyl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
57. The compound of claim 1 being 1-[3-(3-Fluoro-4-methoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
58. The compound of claim 1 being 1-[3-(4-Ethoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
59. The compound of claim 1 being 1-[3-(3-Chloro-4-methoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
60. The compound of claim 1 being 1-[3-(4-isopropoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
61. The compound of claim 1 being 1-[3-(2,4-Dimethoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
62. The compound of claim 1 being 1-[3-(4-Ethoxy-3-methyl-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
63. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-trifluoromethoxy-phenyl)-piperazin-1-yl]isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
64. The compound of claim 1 being 6,7-Dimethoxy-1-[(R)-3-(4-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
65. The compound of claim 1 being 6,7-Dimethoxy-1-[(S)-3-(4-methoxy-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
66. The compound of claim 1 being 1-[3-(4-isopropoxy-3-methyl-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
67. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-methoxy-2,6-dimethyl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
68. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-methoxy-3,5-dimethyl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
69 The compound of claim 1 being 1-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
70. The compound of claim 1 being 1-[3-(4-isobutoxy-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
71. The compound of claim 1 being 6,7-Dimethoxy-1-[3-(4-methoxy-3-trifluoromethyl-phenyl)-piperazin-1-yl]-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof.
72. The compound of claim 1 being 1-[3-(4-Ethoxy-2-methyl-phenyl)-piperazin-1-yl]-6,7-dimethoxy-isoquinoline-4-carbonitrile or a pharmaceutically acceptable salt thereof
73 The compound of claim 1 being N-{5-[4-(4-Cyano-6,7-dimethoxy-isoquinolin-1-yl)-piperazin-2-yl]-2-methoxy-phenyl}-acetamide or a pharmaceutically acceptable salt thereof.
74. The compound of claim 1 being (-)-N-{5-[4-(4-Cyano-6,7-dimethoxy-isoquinolin-1-yl)-piperazin-2-yl]-2-methoxy-phenyl}-acetamide or a pharmaceutically acceptable salt thereof
75. The compound of claim 1 being (+)-N-{5-[4-(4-Cyano-6,7-dimethoxy-isoquinolin-1-yl)-piperazin-2-yl]-2-methoxy-phenyl}-acetamide or a pharmaceutically acceptable salt thereof.
76. A process for the preparation of a compound according to any one of claims 1 to 75, the process comprising reacting a compound of Formula II:

in which L is CI, Br, I, or OSO2CF3, and R1 and R2 are as defined in Claim 1;
with a compound of Formula either as the free base or an addition salt thereof; wherein Q, R3, R4, R5, R6 and R7 are as defined in Claim 1; either neat, or in an inert solvent or mixture of solvents, at a temperature between 0 to about 200 °C, optionally in the presence of a base, optionally in the presence of a palladium catalyst, followed by work-up and isolation of the product of the compound of any one of claims 1 to 75, either as its free base or as an acid addition salt thereof.
77. The process of claim 76 in which the palladium catalyst is formed in situ by mixing a palladium (II) source with a bisphosphine ligand in the reaction solvent.
78. The process of claim 77, wherein the palladium (II) source is Pd(OAc)2 or Pd2(dba)3.
79. The process of claim 77 or 78, wherein the bisphosphine ligand is BINAP
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl).
80. A pharmaceutical composition comprising a compound according to any one of claims 1 to 75 and a pharmaceutically acceptable carrier or diluent.
81. The pharmaceutical composition of claim 80 for the treatment of Alzheimer's disease.
82. The pharmaceutical composition of claim 80 for the treatment of multi-infarct dementia.
83. The pharmaceutical composition of claim 80 for the treatment of alcoholic dementia or other drug-related dementia.
84. The pharmaceutical composition of claim 80 for the treatment of dementia associated with intracranial tumors or cerebral trauma.
85. The pharmaceutical composition of claim 80 for the treatment of dementia associated with Huntington's disease or Parkinson's disease.
86. The pharmaceutical composition of claim 80 for the treatment of AIDS-related dementia.
87. The pharmaceutical composition of claim 80 for the treatment of delirium.
88. The pharmaceutical composition of claim 80 for the treatment of amnestic disorder.
89. The pharmaceutical composition of claim 80 for the treatment of post-traumatic stress disorder.
90. The pharmaceutical composition of claim 80 for the treatment of mental retardation.
91. The pharmaceutical composition of claim 80 for the treatment of a learning disorder.
92. The pharmaceutical composition of claim 91, wherein the learning disorder is a reading disorder.
93. The pharmaceutical composition of claim 91, wherein the learning disorder is a mathematics disorder.
94. The pharmaceutical composition of claim 91, wherein the learning disorder is a disorder of written expression.
95. The pharmaceutical composition of claim 80 for the treatment of attention-deficit/hyperactivity disorder.
96. The pharmaceutical composition of claim 80 for the treatment of age-related cognitive decline.
97. The pharmaceutical composition of claim 80 for the treatment of schizophrenia.
98. The pharmaceutical composition of claim 97, wherein the schizophrenia is of the paranoid type.
99. The pharmaceutical composition of claim 97, wherein the schizophrenia is of the disorganized type.
100. The pharmaceutical composition of claim 97, wherein the schizophrenia is of the catatonic type.
101. The pharmaceutical composition of claim 97, wherein the schizophrenia is of the undifferentiated type.
102. The pharmaceutical composition of claim 97, wherein the schizophrenia is of the residual type.
103. The pharmaceutical composition of claim 80 for the treatment of schizophreniform disorder.
104. The pharmaceutical composition of claim 80 for the treatment of schizoaffective disorder.
105. The pharmaceutical composition of claim 104, wherein the schizoaffective disorder is of the delusional type.
106. The pharmaceutical composition of claim 104, wherein the schizoaffective disorder is of the depressive type.
107. The pharmaceutical composition of claim 80 for the treatment of delusional disorder.
108. The pharmaceutical composition of claim 80 for the treatment of substance-induced psychotic disorder.
109. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by alcohol.
110. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by amphetamine.
111. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by cannabis.
112. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by cocaine.
113. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by hallucinogens
114. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by inhalants.
115. The pharmaceutical composition of claim 108, wherein the substance-induced 'psychotic disorder is psychosis induced by opioids.
116. The pharmaceutical composition of claim 108, wherein the substance-induced psychotic disorder is psychosis induced by phencyclidine
117. The pharmaceutical composition of claim 80 for the treatment of personality disorder of the paranoid type.
118. The pharmaceutical composition of claim 80 for the treatment of personality disorder of the schizoid type.
119. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of Alzheimer's disease.
120. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of multi-infarct dementia.
121. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of alcoholic dementia or other drug-related dementia.
122. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of dementia associated with intracranial tumors or cerebral trauma.
123. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of dementia associated with Huntington's disease or Parkinson's disease.
124. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of AIDS-related dementia.
125. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of delirium.
126. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of amnestic disorder.
127. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of post-traumatic stress disorder.
128. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of mental retardation.
129. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a learning disorder.
130. The use of claim 129, wherein the learning disorder is a reading disorder.
131. The use of claim 129, wherein the learning disorder is a mathematics disorder.
132. The use of claim 129, wherein the learning disorder is a disorder of written expression.
133. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of attention-deficit/hyperactivity disorder.
134. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of age-related cognitive decline.
135. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of schizophrenia.
136. The use of claim 135, wherein the schizophrenia is of the paranoid type.
137. The use of claim 135, wherein the schizophrenia is of the disorganized type.
138. The use of claim 135, wherein the schizophrenia is of the catatonic type.
139. The use of claim 135, wherein the schizophrenia is of the undifferentiated type.
140. The use of claim 135, wherein the schizophrenia is of the residual type.
141. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of schizophreniform disorder.
142. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of schizoaffective disorder.
143. The use of claim 142, wherein the schizoaffective disorder is of the delusional type.
144. The use of claim 142, wherein the schizoaffective disorder is of the depressive type.
145. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of delusional disorder.
146. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of substance-induced psychotic disorder.
147. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by alcohol.
148. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by amphetamine.
149. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by cannabis.
150. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by cocaine.
151. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by hallucinogens.
152. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by inhalants.
153. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by opioids.
154. The use of claim 146, wherein the substance-induced psychotic disorder is psychosis induced by phencyclidine.
155. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of personality disorder of the paranoid type.
156. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of personality disorder of the schizoid type.
157. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of Alzheimer's disease.
158. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of multi-infarct dementia.
159. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of alcoholic dementia or other drug-related dementia.
160. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of dementia associated with intracranial tumors or cerebral trauma.
161. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of dementia associated with Huntington's disease or Parkinson's disease.
162. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of AIDS-related dementia.
163. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of delirium.
164. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of amnestic disorder.
165. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of post-traumatic stress disorder.
166. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of mental retardation.
167. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of a learning disorder.
168. The use of claim 167, wherein the learning disorder is a reading disorder.
169. The use of claim 167, wherein the learning disorder is a mathematics disorder.
170. The use of claim 167, wherein the learning disorder is a disorder of written expression.
171. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of attention-deficit/hyperactivity disorder.
172. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of age-related cognitive decline.
173. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of schizophrenia.
174. The use of claim 173, wherein the schizophrenia is of the paranoid type.
175. The use of claim 173, wherein the schizophrenia is of the disorganized type.
176. The use of claim 173, wherein the schizophrenia is of the catatonic type.
177. The use of claim 173, wherein the schizophrenia is of the undifferentiated type.
178. The use of claim 173, wherein the schizophrenia is of the residual type.
179. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of schizophreniform disorder.
180. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of schizoaffective disorder.
181. The use of claim 180, wherein the schizoaffective disorder is of the delusional type.
182. The use of claim 180, wherein the schizoaffective disorder is of the depressive type.
183. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of delusional disorder.
184. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of substance-induced psychotic disorder.
185. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by alcohol.
186. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by amphetamine.
187. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by cannabis.
188. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by cocaine.
189. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by hallucinogens.
190. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by inhalants.
191. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by opioids.
192. The use of claim 184, wherein the substance-induced psychotic disorder is psychosis induced by phencyclidine.
193. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of personality disorder of the paranoid type.
194. Use of a compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of personality disorder of the schizoid type.
195. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of Alzheimer's disease.
196. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of multi-infarct dementia.
197. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of alcoholic dementia or other drug-related dementia.
198. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of dementia associated with intracranial tumors or cerebral trauma.
199. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of dementia associated with Huntington's disease or Parkinson's disease.
200. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of AIDS-related dementia.
201. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of delirium.
202. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of amnestic disorder.
203. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of post-traumatic stress disorder.
204. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of mental retardation.
205. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of a learning disorder.
206. The compound of claim 205, wherein the learning disorder is a reading disorder.
207. The compound of claim 205, wherein the learning disorder is a mathematics disorder.
208. The compound of claim 205, wherein the learning disorder is a disorder of written expression.
209. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of attention-deficit/hyperactivity disorder.
210. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of age-related cognitive decline.
211. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of schizophrenia.
212. The compound of claim 211, wherein the schizophrenia is of the paranoid type.
213. The compound of claim 211, wherein the schizophrenia is of the disorganized type.
214. The compound of claim 211, wherein the schizophrenia is of the catatonic type.
215. The compound of claim 211, wherein the schizophrenia is of the undifferentiated type.
216. The compound of claim 211, wherein the schizophrenia is of the residual type.
217. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of schizophreniform disorder.
218. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of schizoaffective disorder.
219. The compound of claim 218, wherein the schizoaffective disorder is of the delusional type.
220. The compound of claim 218, wherein the schizoaffective disorder is of the depressive type.
221. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of delusional disorder.
222. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of substance-induced psychotic disorder.
223. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by alcohol.
224. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by amphetamine.
225. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by cannabis.
226. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by cocaine.
227. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by hallucinogens.
228. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by inhalants.
229. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by opioids.
230. The compound of claim 222, wherein the substance-induced psychotic disorder is psychosis induced by phencyclidine.
231. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of personality disorder of the paranoid type.
232. A compound according to any one of claims 1 to 75 or a pharmaceutically acceptable acid addition salt thereof for the treatment of personality disorder of the schizoid type.
233. A compound according to any one of claims 1 to 75 for the treatment of a drug addiction in a mammal.
234. The compound of claim 233, wherein the mammal is a human.
235. The compound of claim 233 or 234, wherein the addiction is an alcohol addiction.
236. The compound of claim 233 or 234, wherein the addiction is an amphetamine addiction.
237. The compound of claim 233 or 234, wherein the addiction is cocaine addiction.
238. The compound of claim 233 or 234, wherein the addiction is an opiate addiction.
239. Use of a compound according to any one of claims 1 to 75 for the treatment of a drug addiction in a mammal.
240. Use of a compound according to any one of claims 1 to 75 for the preparation of a medicament for the treatment of a drug addiction in a mammal.
241. The use of claim 239 or 240, wherein the mammal is a human.
242. The use of any one of claims 239 to 241, wherein the addiction is an alcohol addiction.
243. The use of any one of claims 239 to 241, wherein the addiction is an amphetamine addiction.
244. The use of any one of claims 239 to 241, wherein the addiction is cocaine addiction.
245. The use of any one of claims 239 to 241, wherein the addiction is an opiate addiction.
246. The pharmaceutical composition of claim 80 for the treatment of a drug addiction in a mammal.
247. The pharmaceutical composition claim 246, wherein the mammal is a human.
248. The pharmaceutical composition of claim 246 or 247, wherein the addiction is an alcohol addiction.
249. The pharmaceutical composition of claim 246 or 247, wherein the addiction is an amphetamine addiction.
250. The pharmaceutical composition of claim 246 or 247, wherein the addiction is cocaine addiction.
251. The pharmaceutical composition of claim 246 or 247, wherein the addiction is an opiate addiction.
CA2691474A 2007-09-19 2008-09-18 Cyanoisoquinoline Expired - Fee Related CA2691474C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DKPA200701348 2007-09-19
DKPA200701348 2007-09-19
PCT/DK2008/050225 WO2009036766A1 (en) 2007-09-19 2008-09-18 Cyanoisoquinoline

Publications (2)

Publication Number Publication Date
CA2691474A1 CA2691474A1 (en) 2009-03-26
CA2691474C true CA2691474C (en) 2013-09-10

Family

ID=40011353

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2691474A Expired - Fee Related CA2691474C (en) 2007-09-19 2008-09-18 Cyanoisoquinoline

Country Status (8)

Country Link
EP (1) EP2203438A1 (en)
JP (1) JP2010539195A (en)
CN (1) CN101743239A (en)
AR (1) AR068466A1 (en)
CA (1) CA2691474C (en)
CL (1) CL2008002809A1 (en)
TW (1) TW200918519A (en)
WO (1) WO2009036766A1 (en)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7858620B2 (en) * 2007-09-19 2010-12-28 H. Lundbeck A/S Cyanoisoquinoline
TW201215607A (en) * 2010-07-02 2012-04-16 Lundbeck & Co As H Aryl-and heteroarylamid derivatives as PDE10A enzyme inhibitor
KR20140009372A (en) 2011-02-18 2014-01-22 알러간, 인코포레이티드 Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (pde10a)
US9938269B2 (en) 2011-06-30 2018-04-10 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
US20130116229A1 (en) 2011-11-09 2013-05-09 Abbvie Inc. Novel inhibitor compounds of phosphodiesterase type 10a
US20130116241A1 (en) 2011-11-09 2013-05-09 Abbvie Inc. Novel inhibitor compounds of phosphodiesterase type 10a
US9464085B2 (en) 2012-08-17 2016-10-11 AbbVie Deutschland GmbH & Co. KG Inhibitor compounds of phosphodiesterase type 10A
RU2015114331A (en) 2012-09-17 2016-11-10 Эббви Дойчланд Гмбх Унд Ко. Кг NEW COMPOUNDS AS PHOSPHODESTERASE TYPE 10A INHIBITORS
WO2014071044A1 (en) 2012-11-01 2014-05-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a)
US9790203B2 (en) 2012-11-26 2017-10-17 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
US9200005B2 (en) 2013-03-13 2015-12-01 AbbVie Deutschland GmbH & Co. KG Inhibitor compounds of phosphodiesterase type 10A
JP2016510788A (en) 2013-03-14 2016-04-11 アッヴィ・ドイチュラント・ゲー・エム・ベー・ハー・ウント・コー・カー・ゲー Novel inhibitor compound of phosphodiesterase type 10A
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US20210379061A1 (en) 2018-09-28 2021-12-09 Takeda Pharmaceutical Company Limited Balipodect for treating or preventing autism spectrum disorders

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006509832A (en) * 2002-10-30 2006-03-23 ニューロ３デー Cyclic nucleotide phosphodiesterase inhibitors, their preparation and use
JP2009513494A (en) * 2003-06-30 2009-04-02 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Pyrrodihydroisoquinoline as a PDE10 inhibitor
EP1651251A4 (en) * 2003-07-31 2008-06-18 Bayer Pharmaceuticals Corp Methods for treating diabetes and related disorders using pde10a inhibitors
WO2005120514A1 (en) * 2004-06-07 2005-12-22 Pfizer Products Inc. Phosphodiesterase 10 inhibition as treatment for obesity-related and metabolic syndrome-related conditions
US20060019975A1 (en) * 2004-07-23 2006-01-26 Pfizer Inc Novel piperidyl derivatives of quinazoline and isoquinoline
AU2007223801A1 (en) * 2006-03-08 2007-09-13 Amgen Inc. Quinoline and isoquinoline derivatives as phosphodiesterase 10 inhibitors

Also Published As

Publication number Publication date
CL2008002809A1 (en) 2009-11-27
CA2691474A1 (en) 2009-03-26
CN101743239A (en) 2010-06-16
AR068466A1 (en) 2009-11-18
TW200918519A (en) 2009-05-01
WO2009036766A1 (en) 2009-03-26
JP2010539195A (en) 2010-12-16
EP2203438A1 (en) 2010-07-07

Similar Documents

Publication Publication Date Title
CA2691474C (en) Cyanoisoquinoline
US8492394B2 (en) (3-aryl-piperazin-1-yl), (2-aryl-morpholin-4-yl) and (2-aryl-thiomorpholin-4-yl) derivatives of 6,7-dialkoxy-quinazoline, 6,7-dialkoxyphtalazine and 6,7-dialkoxyisoquinoline as PDE10A enzyme inhibitors
US8841297B2 (en) Phenylimidazole derivative as PDE10A enzyme inhibitor
AU2010333437B2 (en) 2-arylimidazole derivatives as PDE10A enzyme inhibitors
AU2010262190B2 (en) Novel phenylimidazole derivative as PDE10A enzyme inhibitor
EP2513106B1 (en) Heteroaromatic aryl triazole derivatives as pde10a enzyme inhibitors
KR101363091B1 (en) Heteroaryl substituted pyridazinone derivatives
JP2014526453A (en) Pyridine compounds and their use
KR20110048076A (en) Trisubstituted pyrimidine compounds and their use as PD10 inhibitors
WO2014021337A1 (en) Compound and pharmaceutical composition for neuropsychological disorder or malignant tumor
US7858620B2 (en) Cyanoisoquinoline
WO2012000519A1 (en) Aryl- and heteroarylamid derivatives as pde10a enzyme inhibitor
KR20140105574A (en) Quinoline derivatives as pde10a enzyme inhibitors

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20150918