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US20120220581A1 - IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS - Google Patents

IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS Download PDF

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US20120220581A1
US20120220581A1 US13/505,187 US201013505187A US2012220581A1 US 20120220581 A1 US20120220581 A1 US 20120220581A1 US 201013505187 A US201013505187 A US 201013505187A US 2012220581 A1 US2012220581 A1 US 2012220581A1
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pyridinyl
imidazo
pyridazine
methyl
morpholinyl
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Inventor
Joaquin Pastor-Fernández
José Manuel Bartolomé-Nebreda
Gregor James MacDonald
Susana Conde-Ceide
Óscar Delgado-González
Greta Constantia Peter Vanhoof
Michiel Luc Maria Van Gool
María Luz Martín-Martín
Sergio-Alvar Alonso-de Diego
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Janssen Pharmaceutica NV
Janssen Cilag SA
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Janssen Cilag SA
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Publication of US20120220581A1 publication Critical patent/US20120220581A1/en
Assigned to JANSSEN-CILAG, S.A. EDIFICIO JOHNSON & JOHNSON reassignment JANSSEN-CILAG, S.A. EDIFICIO JOHNSON & JOHNSON ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ALONSO-DE DIEGO, SERGIO-ALVAR, MARTIN-MARTIN, MARIA LUZ, VAN GOOL, MICHIEL LUC MARIA, DELGADO-GONZALEZ, OSCAR, PASTOR-FERNANDEZ, JOAQUIN, CONDE-CEIDE, SUSANA, BARTOLOME-NEBREDA, JOSE MANUEL
Assigned to JANSSEN PHARMACEUTICA NV reassignment JANSSEN PHARMACEUTICA NV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEYS, CARINA, SWINNEY, KELLY ANN, WEERTS, JOHAN ERWIN EDMOND, VANHOOF, GRETA CONSTANTIA PETER, MACDONALD, GREGOR JAMES
Assigned to JANSSEN PHARMACEUTICA N.V., reassignment JANSSEN PHARMACEUTICA N.V., ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JANSSEN-CILAG S.A., EDIFICIO JOHNSON & JOHNSON
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention relates to novel imidazo[1,2-b]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved.
  • PDE10 phosphodiesterase 10 enzyme
  • the invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.
  • Phosphodiesterases are a family of enzymes encoded by 21 genes and subdivided into 11 distinct families according to structural and functional properties. These enzymes metabolically inactivate widely occurring intracellular second messengers, 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP). These two messengers regulate a wide variety of biological processes, including pro-inflammatory mediator production and action, ion channel function, muscle contraction, learning, differentiation, apoptosis, lipogenesis, glycogenolysis, and gluconeogenesis.
  • cAMP 3′,5′-cyclic adenosine monophosphate
  • cGMP 3′,5′-cyclic guanosine monophosphate
  • PKA protein kinase A
  • PKG protein kinase G
  • Intracellular concentrations of cAMP and cGMP are strictly regulated by the rate of biosynthesis by cyclases and by the rate of degradation by PDEs.
  • PDEs are hydrolases that inactivate cAMP and cGMP by catalytic hydrolysis of the 3′-ester bond, forming the inactive 5′-monophosphate (Scheme A).
  • the PDE families can be divided into three groups: i) the cAMP-specific PDEs, which include PDE4, 7 and 8; ii) the cGMP-selective enzymes PDES and 9; and iii) the dual-substrate PDEs, PDE1, 2 and 3, as well as PDE10 and 11.
  • PDEs are expressed differentially throughout the organism, including the central nervous system. Different PDE isozymes therefore may play different physiological functions. Compounds that inhibit selectively PDE families or isozymes may display particular therapeutic activity, fewer side effects, or both.
  • PDE10A phosphodiesterase 10A
  • PDE10A mRNA and protein are highly expressed in a majority of striatal Medium Spiny Neurons (MSNs). This unique distribution of PDE10A in the brain, together with its increased pharmacological characterization, indicates a potential use of PDE10A inhibitors for treating neurological and psychiatric disorders like schizophrenia.
  • MSNs constitute the major site for reception and integration of cortical glutamatergic and midbrain dopaminergic input, and form key output pathways that help discriminate and act on relevant and irrelevant cognitive and motor patterns.
  • MSNs are GABAergic projection neurons evenly distributed between two distinct pathways. Striatonigral MSNs (in the direct pathway) express the D 1 dopamine receptor and neuropeptides dynorphin and substance P; striatopallidal MSNs (in the indirect pathway) express the D 2 dopamine receptors and neuropeptide enkephalin. D 1 dopamine receptors are positively coupled to cAMP production, while D 2 dopamine receptors are negatively coupled to cAMP production. These pathways affect the concentration of extracellular dopamine and modulate motor and behavioural responses.
  • Schizophrenia is a severe and chronic mental illness that affects approximately 1% of the population. Clinical symptoms are apparent relatively early in life, generally emerging during adolescence or early adulthood. The symptoms of schizophrenia are usually divided into those described as positive, including hallucinations, delusions and disorganised thoughts and those referred to as negative, which include social withdrawal, diminished affection, poverty of speech and the inability to experience pleasure. In addition, schizophrenic patients suffer from cognitive deficits, such as impaired attention and memory. The aetiology of the disease is still unknown, but aberrant neurotransmitter actions have been hypothesized to underlie the symptoms of schizophrenia. The dopaminergic hypothesis is one most often considered, which proposes that hyperactivity of dopamine transmission is responsible for the positive symptoms observed in schizophrenic patients.
  • antipsychotics correlates their ability to inhibit the D 2 dopamine receptors.
  • Acute and chronic administration of antipsychotics such as haloperidol has characteristic effects on striatal gene expression.
  • Inhibition of PDE10A has also been observed to produce alterations in striatal gene expression similar to those exerted by haloperidol.
  • Atypical antipsychotics such as clozapine, olanzapine, risperidone and paliperidone display lower profile of extrapyramidal adverse effects and tardive dyskinesia associated with acute and long-term D 2 receptor blockade.
  • clozapine olanzapine
  • risperidone paliperidone display lower profile of extrapyramidal adverse effects and tardive dyskinesia associated with acute and long-term D 2 receptor blockade.
  • PDE10 inhibitors may possess a pharmacological profile similar to that of the atypical antipsychotics, but lacking the non-target related side effects that are often observed with the currently available antipsychotics. Although EPS-like side effects are observed at relatively low doses, they are relatively mild.
  • PDE10 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10 enzyme, for example neurons that comprise the basal ganglia
  • PDE10 inhibitors may be useful in treating schizophrenia and additionally, a variety of conditions involving the basal ganglia, such as the conditions described herein, for example, obesity, non-insulin dependent diabetes, bipolar disorder, obsessive compulsive disorder and pain.
  • WO 2004/087710 discloses N-(1-ethylpropyl)-7-(6-methoxy-2-methyl-3-pyridinyl)-2,6-dimethyl-pyrrolo[1,2-b]pyridazin-4-amine and 7-(6-methoxy-2-methyl-3-pyridinyl)-2,6-dimethyl-N-(1-methylpropyl)-pyrrolo[1,2-b]pyridazin-4-amine as CRF receptor antagonists
  • WO 2006/102194 (Eli Lilly and Company) discloses imidazo[1,2-b]pyridazines bearing a 5-membered aromatic ring at the 3 position and a linear alkyl substituent at the 8-position as CRF1 receptor antagonists. The CRF receptor has been validated as a possible target for depression, anxiety, cerebrovascular disorders, irritable bowel syndrome and congestive heart failure, but not for schizophrenia.
  • the present compounds are centrally active, potent compounds which display efficacy in preclinical behavior challenge models in which known clinical useful antipsychotics display similar positive responses, such as in the reversal of apomorphine-induced stereotypy and phencyclidine (PCP)-induced hyperlocomotion in rodents. Additionally, representative compounds reverse the hypolocomotion effects exerted by SCH23390, a D1 receptor antagonist. Thus, the present compounds may act as dopamine modulating agents, inhibiting states of dopaminergic (D 2 ) hyperactivity and reversing states of dopaminergic (D 2 ) hypoactivity.
  • the present invention relates to compounds having PDE10 inhibitory activity, said compounds having the Formula (I)
  • R 1 is pyridinyl; pyridinyl optionally substituted with halogen, C 1-4 alkyl, trifluoromethyl or C 1-4 alkyloxy; tetrahydropyranyl; or NR 6 R 7 ;
  • R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl, C 3-8 cycloalkyl, or C 1-4 alkyloxy;
  • R 3 is hydrogen, chloro, C 1-4 alkyl, trifluoromethyl, or C 3-8 cycloalkyl;
  • Het is a 5- or 6-membered heterocyclic ring selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl and triazolyl;
  • R 4 is hydrogen, C
  • each R 8 if present, independently of one another is C 1-4 alkyl; R 9 is hydrogen or C 1-4 alkyloxy; R 10 is hydrogen or C 1-4 alkyl; m is 0, 1, 2, 3, 4 or 5; n is 2, 3, 4, 5 or 6; o is 1 or 2; and the pharmaceutically acceptable salts and the solvates thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient.
  • the invention relates to a compound of Formula (I) for use as a medicament.
  • the invention also relates to the use of a compound according to Formula (I) or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating or preventing neurological, psychiatric or metabolic disorders and diseases.
  • the invention relates to the use of a compound of Formula (I) in combination with an additional pharmaceutical agent for the manufacture of a medicament for treating or preventing neurological, psychiatric or metabolic disorders and diseases.
  • the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of Formula (I).
  • the invention also relates to a product comprising a compound of Formula (I) and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of neurological, psychiatric or metabolic disorders and diseases.
  • halogen or “halo” as used herein alone or as part of another group refers to fluoro, chloro, bromo or iodo, with fluoro or chloro being preferred.
  • C 0-4 alkyl refers to a saturated straight or branched hydrocarbon radical, having unless otherwise stated, from 0 to 4, 1 to 4 or 1 to 5 carbon atoms, which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, propyl, butyl, 1-pentyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, and 3-methylbutyl.
  • C 3-8 cycloalkyl as employed herein alone or as part of another group unless otherwise stated, is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • subject refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
  • a mammal e.g. cat, dog, primate or human
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • treatment is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • heterocyclic substituents in R 1 such as tetrahydropyranyl and pyridinyl may be attached to the remainder of the molecule of formula (I) through any available ring carbon atom.
  • Het when Het is pyridinyl, it may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, unless otherwise specified.
  • Het may be attached to the remainder of the molecule of formula (I) through any available ring carbon or heteroatom as appropriate, if not otherwise specified.
  • Het as used herein is preferably a 5- or 6-aromatic membered heterocyclic ring preferably bound to the imidazo[1,2-b]pyridazine ring system through an available carbon atom of the ring.
  • R 5 When Het is pyridine and R 5 is methyl, the R 5 substituent is placed in Het preferably in meta- or para-position relative to the position of attachment to the imidazo[1,2-b]pyridazine core.
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof, wherein
  • R 1 is selected from pyridinyl; pyridinyl optionally substituted with halogen, C 1-4 alkyl, trifluoromethyl or C 1-4 alkyloxy; tetrahydropyranyl; and NR 6 R 7 ; wherein R 6 and R 7 taken together with the nitrogen can be a radical of Formula (a), (b) or (c) as previously defined;
  • R 2 is selected from hydrogen, methyl, ethyl, cyclopropyl, isopropyl, methoxy and trifluoromethyl;
  • R 3 is selected from hydrogen, chloro, methyl, trifluoromethyl and cyclopropyl
  • Het is selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyl and triazolyl and R 4 -R 10 , m, n and o are as previously defined;
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof, wherein
  • R 1 is selected from pyridinyl which may be optionally substituted with halogen, C 1-4 alkyl, trifluoromethyl or C 1-4 alkyloxy; morpholinyl; and NR 6 R 7 ; wherein R 6 and R 7 taken together with the nitrogen can be a radical of Formula (a) or (c) wherein n is 3 and o is 1;
  • Het is selected from pyridinyl and pyrazolyl
  • R 4 is hydrogen, C 1-4 alkyl, trifluoromethylC 0-4 alkyl, hydroxyC 1-4 alkyl, difluorocyclopropylmethyl, cyclopropyldifluoroethyl, C 3-8 cycloalkyl, C 1-4 alkyloxyC 1-5 alkyl, C 1-4 alkyloxy, trifluoromethylC 0-4 alkyloxy, C 3-8 cycloalkylC 1-4 alkyloxy, C 1-6 alkyloxyC 1-4 alkyloxy, tetrahydropyranyl, pyridinylmethyl, NR 6a R 7a C 1-4 alkyl or NR 6a R 7a ;
  • R 6 , R 6a , R 7 and R 7a are each independently hydrogen or C 1-4 alkyl, or taken together with the nitrogen can be a radical of formula (a), (b) or (c), wherein n is 3, R 9 is hydrogen or C 1-4 alkyloxy, m is 0, o is 1 and R 16 is hydrogen;
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof, wherein
  • R 1 is selected from pyridinyl, morpholinyl and pyrrolidinyl;
  • R 4 is selected from hydrogen; methyl; ethyl; isopropyl; isobutyl; trifluoromethyl; 2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl; (2,2-difluorocyclopropyl)methyl; 2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl; 2-methoxypropyl; (2S)-2-methoxypropyl; 2-isopropoxyethyl; 2-ethoxyethyl; ethoxymethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl; 3-methoxypropyl; 2-methoxy-2-methyl-propyl; isopropoxy; 2,2,2-trifluoroethoxy; cyclopropylmethoxy; 2-methoxyethoxy
  • R 5 is hydrogen or methyl
  • R 2 , R 3 and Het are as previously defined;
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof wherein
  • R 1 is selected from morpholinyl and pyridinyl
  • R 2 is selected from hydrogen, methyl, ethyl, methoxy, and cyclopropyl
  • R 3 is selected from hydrogen, methyl, and cyclopropyl
  • Het is pyridinyl or pyrazolyl
  • R 4 is selected from ethyl; isopropyl; isobutyl; 2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl; 2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl; (2S)-2-methoxypropyl; 2-ethoxyethyl; ethoxymethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl; 3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy; 2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl; morpholin-4-yl; piperazin-1-yl; and (3R)-3-methoxypyrrolidin-1-yl;
  • R 5 is hydrogen or methyl
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof wherein
  • R 1 is selected from morpholinyl and pyridinyl
  • R 2 is selected from hydrogen, methyl, methoxy, and cyclopropyl
  • R 3 is selected from hydrogen, methyl, and cyclopropyl
  • Het is pyridinyl or pyrazolyl
  • R 4 is selected from ethyl; isopropyl; isobutyl; 2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl; 2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl; (2S)-2-methoxypropyl; 2-ethoxyethyl; ethoxymethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl; 3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy; 2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl; morpholin-4-yl; piperazin-1-yl; and (3R)-3-methoxypyrrolidin-1-yl;
  • R 5 is hydrogen or methyl
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof wherein
  • R 1 is selected from morpholinyl and pyridinyl
  • R 2 is selected from hydrogen, methyl, methoxy, and cyclopropyl
  • R 3 is selected from hydrogen, methyl, and cyclopropyl
  • Het is pyridinyl or pyrazolyl
  • R 4 is selected from 2-methoxyethyl; 3-methoxypropyl; 2-methoxy-2-methylpropyl; 2-methoxy-1,1-dimethylethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxyethoxy; ethoxymethyl; 2-methoxy-2-methylpropoxy; morpholin-4-yl; 2-ethoxyethyl; tetrahydro-2H-pyran-4-yl; ethyl; 3-methoxy-3-methylbutyl; piperazin-1-yl; isopropyl; cyclopropyl; (3R)-3-methoxypyrrolidin-1-yl; and isobutyl;
  • R 5 is hydrogen or methyl
  • the invention relates to a compound according to Formula (I) or a stereochemically isomeric form thereof wherein
  • R 1 is selected from morpholin-4-yl, pyridin-3-yl and pyridin-4-yl;
  • Het is selected from pyridin-3-yl, pyridin-4-yl and 1H-pyrazol-4-yl;
  • R 2 -R 5 are as previously defined;
  • the invention relates to a compound according to Formula (I), or a stereochemically isomeric form thereof, wherein
  • R 1 is morpholin-4-yl
  • Het is pyridin-3-yl or pyridin-4-yl
  • R 2 -R 5 are as previously defined;
  • the invention relates to a compound according to Formula (I) wherein
  • R 1 is morpholin-4-yl
  • R 2 is methyl
  • R 3 is hydrogen
  • Het is pyridin-3-yl
  • R 4 is 2-methoxyethyl
  • R 5 is hydrogen
  • An additional embodiment refers to compounds according to Formula (I), wherein R 3 is hydrogen and the rest of variables are as previously defined, and the stereochemically isomeric forms thereof and the pharmaceutically acceptable salts and solvates thereof.
  • the invention relates to compounds according to formula (I), having the formula (I′-a) or (I′-b)
  • R 1 , R 2 , R 3 , R 4 and R 5 are as previously defined.
  • R 1 is morpholin-4-yl.
  • R 1 is pyridin-4-yl.
  • R 1 is pyridin-3-yl.
  • R 3 is hydrogen
  • R 2 is methyl and R 3 is hydrogen.
  • Het is 3-pyridinyl or 4-pyridinyl.
  • Het is 1H-pyrazol-4-yl.
  • R 4 is selected from ethyl; isopropyl; isobutyl; 2,2,2-trifluoroethyl; 2-hydroxy-2-methylpropyl; 2,2-difluoro-2-cyclopropylethyl; cyclopropyl; 2-methoxyethyl; (2S)-2-methoxypropyl; 2-ethoxyethyl; ethoxymethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl; 3-methoxypropyl; 2-methoxy-2-methyl-propyl; 2-methoxyethoxy; 2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl; morpholin-4-yl; piperazin-1-yl; and (3R)-3-methoxypyrrolidin-1-yl.
  • R 4 is selected from ethyl; isopropyl; isobutyl; 2-hydroxy-2-methylpropyl; cyclopropyl; 2-methoxyethyl; 2-ethoxyethyl; ethoxymethyl; 1-ethoxy-1-methylethyl; 1-methoxy-1-methylethyl; 2-methoxy-1,1-dimethylethyl; 3-methoxy-3-methylbutyl; 3-methoxypropyl; 2-methoxy-2-methylpropyl; 2-methoxyethoxy; 2-methoxy-2-methyl-propoxy; tetrahydro-2H-pyran-4-yl; morpholin-4-yl; piperazin-1-yl; and (3R)-3-methoxypyrrolidin-1-yl.
  • R 4 is selected from ethyl; 2-hydroxy-2-methylpropyl; 2-methoxyethyl; 2-methoxy-2-methylpropyl; 2-methoxyethoxy; 2-methoxy-2-methyl-propoxy; and morpholin-4-yl.
  • the invention relates to a compound according to formula (I′-a) of (I′-b) wherein
  • R 1 is morpholin-4-yl
  • R 2 is methyl
  • R 3 is hydrogen
  • Het is pyridin-3-yl
  • R 4 is 2-methoxyethyl
  • R 5 is hydrogen
  • the invention relates to a compound according to formula (I′-c)
  • R 4a is selected from the group consisting of R 4a is selected from the group consisting of hydrogen, C 1-4 alkyl, trifluoromethylC 0-4 alkyl, hydroxyC 1-4 alkyl, difluorocyclopropylmethyl, cyclopropyldifluoroethyl, C 3-8 cycloalkyl, C 1-4 alcyloxyC 1-5 alkyl, tetrahydropyranyl and pyridinylmethyl.
  • R 4a is selected from hydrogen; isobutyl; 2,2,2-trifluoroethyl; (2,2-difluorocyclopropyl)methyl; 2,2-difluoro-2-cyclopropylethyl; 2-methoxyethyl; (2S)-2-methoxypropyl; 2-methoxy-2-methyl-propyl; tetrahydro-2H-pyran-4-yl; and (pyridin-3-yl)methyl.
  • R 4a is selected from isobutyl; 2,2,2-trifluoroethyl; 2,2-difluoro-2-cyclopropylethyl; 2-methoxyethyl; (2S)-2-methoxypropyl; and 2-methoxy-2-methyl-propyl.
  • Particularly preferred compounds may be selected from the group of:
  • More preferred particular compounds are compounds 1 to 38, and pharmaceutically acceptable salts thereof.
  • salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts are defined to comprise the therapeutically active non-toxic acid addition salt forms that the compounds according to Formula (I) are able to form.
  • Said salts can be obtained by treating the base form of the compounds according to Formula (I) with appropriate acids, for example inorganic acids, for example hydrohalic acids, in particular hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.
  • acids for example inorgan
  • salt forms can be converted into the free base form by treatment with an appropriate base.
  • the compounds according to Formula (I) containing acidic protons may also be converted into their therapeutically active non-toxic base salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkaline and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, e.g.
  • primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline, the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids, for example arginine and lysine.
  • methylamine ethylamine, propylamine, isopropylamine
  • the four butylamine isomers dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-buty
  • salt forms can be converted into the free acid forms by treatment with an appropriate acid.
  • solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of formula (I) are able to form.
  • solvent addition forms are e.g. hydrates, alcoholates and the like.
  • stereochemically isomeric forms or “stereoisomeric forms” as used hereinbefore defines all the possible isomeric forms that the compounds of Formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
  • the invention also embraces each of the individual isomeric forms of the compounds of Formula (I) and their salts and solvates, substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers.
  • an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center.
  • the configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*,S*], where R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R*,S*] indicates centers of unlike chirality.
  • R*,R*] indicates centers with the same chirality
  • [R*,S*] indicates centers of unlike chirality.
  • the stereo descriptor would be specified as S—[R*,S*].
  • Radiolabelled compounds of Formula (I) may comprise a radioactive isotope selected from the group of 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
  • the compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
  • the compounds can be prepared according to the following synthesis methods.
  • the compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of Formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • a compound of Formula (I) wherein R 1 , R 2 , R 4 and R 5 are as defined before, R 3 is hydrogen and Het is pyridinyl, can be prepared by reacting a compound of Formula (Ia)
  • R 1 , R 2 , R 4 and R 5 are as defined before, with hydrogen in the presence of a suitable catalyst, such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol or ethanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium formate in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof, under suitable reaction conditions, such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol or ethanol
  • a compound of Formula (I) wherein R 1 , R 2 , R 4 and R 5 are as defined before, R 3 is C 1-4 alkyl or C 3-8 cycloalkyl and Het is pyridinyl can be prepared by reacting a compound of Formula (Ia) wherein R 1 , R 2 , R 4 and R 5 are as defined before, with a boronic acid derivative of Formula R 3 B(OH) 2 wherein R 3 is C 1-4 alkyl or C 3-8 cycloalkyl, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0) or palladium (II) acetate, in the presence of a suitable phosphine ligand, such as 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, in the presence of a suitable base, such as sodium carbonate or potassium phosphate, in a suitable inert solvent, such as a mixture
  • compounds of Formula (I) wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined before and Het is pyridinyl can also be prepared by reacting an intermediate of Formula (II)
  • R 1 , R 2 and R 3 are as defined before and halo represents a bromo or iodo, with a boronic acid derivative of Formula (III)
  • R 4 and R 5 are as defined before, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as a mixture of 1,4-dioxane and water
  • R 4 and R 5 are as defined before, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as a mixture of 1,4-dioxane and water
  • R 4 and R 5 are as defined before and halo is bromo or iodo, in the presence of a suitable catalyst, such as palladium (II) acetate, in the presence of a suitable phosphine ligand, such as butyldi-1-adamantylphosphine, in the presence of a suitable base, such as potassium phosphate, in a suitable inert solvent, such as N,N-dimethylformamide or N-methylpyrrolidine, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as palladium (II) acetate
  • a suitable phosphine ligand such as butyldi-1-adamantylphosphine
  • a suitable base such as potassium phosphate
  • a suitable inert solvent such as N,N-dimethylformamide or N-methylpyrrolidine
  • a compound of Formula (II) wherein R 1 , R 2 and R 3 are as defined before, except when simultaneously R 1 is NR 6 R 7 , R 2 is trifluoromethyl and R 3 is chloro, and halo represents a bromo or iodo, can be prepared by reacting a compound of Formula (V) wherein R 1 , R 2 and R 3 are as defined before, with N-bromo- or N-iodosuccinimide, in a suitable inert solvent, such as dichloromethane, in the presence of a suitable acid catalyst, such as acetic acid, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 40° C.
  • a compound of Formula (V) wherein R 1 and R 2 are as defined before and R 3 is hydrogen, can also be prepared by reacting a compound of Formula (Va)
  • R 1 and R 2 are as defined before, with hydrogen in the presence of a suitable catalyst, such as 10% palladium on charcoal, in the presence of a suitable base, such as triethylamine, in a suitable inert solvent, such as methanol or ethanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium formate in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof, under suitable reaction conditions, such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable base such as triethylamine
  • a suitable inert solvent such as methanol or ethanol
  • suitable reaction conditions such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium
  • a compound of Formula (V) wherein R 1 and R 2 are as defined before, and R 3 is C 1-4 alkyl or C 3-8 cycloalkyl can be prepared by reacting a compound of Formula (Va) wherein R 1 and R 2 are as defined before with a boronic acid derivative of Formula R 3 B(OH) 2 where R 3 is C 1-4 alkyl or C 3-8 cycloalkyl, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0) or palladium (II) acetate, in the presence of a suitable phosphine ligand, such as 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, in the presence of a suitable base, such as sodium carbonate or potassium phosphate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water or toluene, under suitable reaction conditions, such as heating
  • a compound of Formula (V) wherein R 1 is pyridinyl, pyridinyl optionally substituted with halogen, C 1-4 alkyl, trifluoromethyl or C 1-4 alkyloxy, R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl or C 3-8 cycloalkyl and R 3 is chloro or trifluoromethyl, can be prepared by reacting a compound of Formula (VII)
  • R 2 is as described before, R 3 is chloro or trifluoromethyl and halo represents chloro, bromo or iodo, with a boronic acid derivative of Formula R 1 B(OH) 2 wherein R 1 is pyridinyl or pyridinyl optionally substituted with halogen, C 1-4 alkyl, trifluoromethyl or C 1-4 alkyloxy, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium
  • a compound of Formula (V) wherein R 1 is NR 6 R 7 , R 2 is as described before, R 3 is chloro or trifluoromethyl and R 6 and R 7 are as defined before can be prepared by reacting a compound of Formula (VII) where R 2 is as described before, R 3 is chloro or trifluoromethyl and halo represents chloro, bromo or iodo with a compound of Formula R 6 R 7 NH wherein R 6 and R 7 are as defined before, in a suitable inert solvent, such as acetonitrile, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable inert solvent such as acetonitrile
  • R 2 is as defined before and R 3 is chloro or trifluoromethyl, with hydrogen in the presence of a suitable catalyst, such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol or ethanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium formate in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof, under suitable reaction conditions, such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol or ethanol
  • suitable reaction conditions such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium formate in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable
  • a compound of Formula (VIII) where R 2 is as defined before and R 3 is chloro or trifluoromethyl can be prepared by reacting a compound of Formula (VII) where R 2 is as defined before, R 3 is chloro or trifluoromethyl and halo represents chloro, bromo or iodo with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as
  • 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester can be obtained by procedures similar to those described in, Qiu, Y. et al. WO 2004075846 A2.
  • R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl or C 3-8 cycloalkyl and R 3 is chloro or trifluoromethyl
  • R 3 is chloro or trifluoromethyl and halo represents chloro or bromo with sodium iodide, in the presence of a suitable acidic catalyst, such as hydriodic acid, in a suitable inert solvent, such as acetonitrile, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable acidic catalyst such as hydriodic acid
  • a suitable inert solvent such as acetonitrile
  • a compound of Formula (VII) where R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl or C 3-8 cycloalkyl, R 3 is chloro or trifluoromethyl and halo represents chloro or bromo, can be prepared by reacting a compound of Formula (IX)
  • R 3 is chloro or trifluoromethyl and halo represents chloro or bromo, with a compound of Formula (X)
  • R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl or C 3-8 cycloalkyl and halo 1 represents chloro or bromo, either neat or in a suitable inert solvent, such as ethanol, isopropanol or 1,2-dimethoxyethane, under suitable reaction conditions, such as heating at a convenient temperature either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable inert solvent such as ethanol, isopropanol or 1,2-dimethoxyethane
  • a compound of Formula (IX) where R 3 is chloro or trifluoromethyl and halo represents bromo can be prepared by reacting an aminopyridazine of Formula (XI)
  • a suitable base such as sodium hydrogen carbonate
  • a suitable inert solvent such as methanol
  • reaction conditions such as a convenient temperature, typically ranging between ⁇ 10° C. and 25° C.
  • a compound of Formula (IX) where R 3 is chloro or trifluoromethyl and halo represents chloro can be obtained from an aminopyridazine of Formula (XI) by procedures similar to those described in Dewdney, N. et al. WO 2009077334 A1.
  • a compound of Formula (X) wherein R 2 is hydrogen, C 1-4 alkyl, trifluoromethyl or C 3-8 cycloalkyl and halo represents chloro or bromo can be obtained commercially or can be prepared by procedures similar to those described in Gaudry, M.; Marquet, A. Organic Syntheses. 1976, 55.
  • a compound of Formula (XI) where R 3 is chloro can be obtained commercially.
  • a compound of Formula (XI) where R 3 is trifluoromethyl can be obtained by procedures similar to those described in De Bruyn, M. F. L. et al. WO 2007048779 A1
  • a compound of Formula (V) wherein R 1 is NR 6 R 7 , R 2 is C 1-4 alkyloxy and R 3 is chloro or trifluoromethyl and R 6 and R 7 are as defined before, can be prepared by reacting an intermediate of Formula (XII)
  • R 1 is NR 6 R 7 , R 3 is chloro or trifluoromethyl and R 6 and R 7 are as defined before, with a reagent of Formula (X) wherein R 2 is C 1-4 alkyloxy and halo 1 represents chloro or bromo, in a suitable inert solvent, such as methanol, under suitable reaction conditions, such as heating at a convenient temperature either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable inert solvent such as methanol
  • a compound of Formula (II) wherein R 1 is NR 6 R 7 , R 2 is trifluoromethyl, R 3 is chloro or trifluoromethyl, and halo represents a iodo, can be prepared by reacting a compound of Formula (XIII)
  • R 3 is chloro or trifluoromethyl with a compound of formula R 6 R 7 NH, where R 6 and R 7 are as defined before in the presence of a suitable base, such as N,N-diisopropylethylamine, in a suitable solvent, such as acetonitrile, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable base such as N,N-diisopropylethylamine
  • a suitable solvent such as acetonitrile
  • a compound of Formula (XIII), where R 3 is chloro or trifluoromethyl can be prepared by reacting a compound of Formula (VII) where R 2 is trifluoromethyl, R 3 is chloro or trifluoromethyl and halo represents a bromo, with N-iodosuccinimide, in a suitable inert solvent, such as dichlorometane, in the presence of a suitable acid catalyst, such as trifluoroacetic acid, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 60° C.
  • a compound of Formula (VII) where R 2 is trifluoromethyl, R 3 is chloro or trifluoromethyl and halo represents a bromo, can be obtained as described before.
  • R 1 , R 2 , R 3 and R 5 are as defined before, R 4 is Alk 1 -oxyethyl and Alk 1 is C 1-4 alkyl, can be prepared by reacting a compound of Formula (XIV)
  • R 1 , R 2 , R 3 and R 5 are as defined before with an alcohol of Formula Alk 1 -OH wherein Alk 1 is C 1-4 alkyl in the presence of a suitable base, such as the sodium or potassium salt of the corresponding alcohol, in a suitable solvent, such as the corresponding alcohol, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable base such as the sodium or potassium salt of the corresponding alcohol
  • suitable solvent such as the corresponding alcohol
  • a compound of Formula (Ib) wherein R 1 , R 2 , R 3 and R 5 are as defined before, R 4 is Alk 1 -oxyethyl and Alk 1 is C 1-4 alkyl can be prepared by reacting a compound of Formula (XIV), where R 1 , R 2 , R 3 and R 5 are as defined before with an alcohol of Formula Alk 1 -OH wherein Alk 1 is C 1-4 alkyl, in the presence of a suitable acid, such as potassium hydrogensulfate, in a suitable solvent, such as the corresponding alcohol, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable acid such as potassium hydrogensulfate
  • An alcohol of Formula Alk 1 -OH wherein Alk 1 is C 1-4 alkyl can be obtained commercially or alternatively can also be obtained by procedures similar to those described in Morel, P. US 2008102028 A1.
  • a compound of Formula (XIV) where R 1 , R 2 , R 3 and R 5 are as defined before can be prepared by reacting a compound of Formula (XV)
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as a mixture of 1,4-dioxane and water
  • Vinylboronic acid pinacol ester, of Formula (XVI), can be obtained commercially.
  • a compound of Formula (XV) where R 1 , R 2 , R 3 and R 5 are as defined before can be prepared by reacting a compound of Formula (II) wherein R 1 , R 2 and R 3 are as defined before and halo is bromo or iodo, with a boronic acid derivative of Formula (XVII)
  • R 5 is as defined before, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as a mixture of 1,4-dioxane and water
  • a boronic acid derivative of Formula (XVII) where R 5 is as defined before, can be obtained commercially or alternatively can be prepared by reacting a compound of Formula (XVIII)
  • R 5 is as defined before and halo represents a bromo or iodo, with triisopropyl borate, in the presence of a suitable base, such as n-butyllithium in the presence of a suitable diamine such as N,N,N′,N′-tetramethylenediamine, in a suitable inert solvent such as diethylether, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 78° C. and 25° C.
  • a suitable base such as n-butyllithium
  • a suitable diamine such as N,N,N′,N′-tetramethylenediamine
  • a suitable inert solvent such as diethylether
  • a halopyridine of Formula (XVIII) where R 5 is as defined before and halo is bromo or iodo, can be obtained commercially.
  • a compound of Formula (XV) where R 1 , R 2 , R 3 and R 5 are as defined before can be prepared by reacting a compound of Formula (V) wherein R 1 , R 2 and R 3 are as defined before with a halopyridine of Formula (XVIII), where R 5 is as defined before and halo represents a bromo or iodo, in the presence of a suitable catalyst, such as palladium (II) acetate, in the presence of a suitable phosphine ligand, such as butyldi-1-adamantylphosphine, in the presence of a suitable base, such as potassium phosphate, in a suitable inert solvent, such as N,N-dimethylformamide, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as palladium (II) acetate
  • R 1 , R 2 , R 3 and R 5 are as defined before
  • R 4 is NR 6a R 7a ethyl and R 6a and R 7a are as defined before
  • R 6a and R 7a are as defined before
  • a suitable base such as sodium tert-butoxide
  • suitable solvent such as tetrahydrofuran
  • a reagent of Formula R 6 R 7 NH or R 6a R 7a NH, wherein R 6 , R 6a , R 7 and R 7a are as defined before, can be obtained commercially.
  • Compounds of Formula (I) where R 1 , R 2 , R 3 and R 5 are as defined before, R 4 is ethyl and Het is pyridinyl can also be prepared by reacting a compound of Formula (XIV) wherein R 1 , R 2 , R 3 and R 5 are as defined before, with hydrogen in the presence of a suitable catalyst, such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol or ethanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between 25° C. and 40° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol or ethanol
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof
  • suitable reaction conditions such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • R 1 , R 2 , R 3 and R 5 are as defined before with hydrogen in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable inert solvent such as methanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium formate in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof, under suitable reaction conditions, such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof
  • suitable reaction conditions such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • a compound of Formula (XIX) wherein R 1 , R 2 , R 3 and R 5 are as defined before can be prepared by reacting a compound of Formula (XV) wherein R 1 , R 2 , R 3 and R 5 are as defined before, with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as
  • R 1 , R 2 , R 3 , R 5 are as defined before, R 4 is a radical of Formula (a), n is as defined before and Alk 2 is C 1-4 alkyl, can be prepared by reacting a compound of Formula (XX)
  • R 1 , R 2 , R 3 , R 5 and n are as defined before with a reagent of Formula Alk 2 -W wherein Alk 2 is C 1-4 alkyl and W represents a leaving group, such as halo, e.g. chloro, bromo or iodo, in the presence of a base, such as sodium tert-butoxide, in the presence of a suitable crown ether, such as 18-crown-6, in a suitable solvent, such as tetrahydrofuran and under suitable reaction conditions, such as heating at a convenient temperature, typically ranging from 25° C. to 80° C.
  • a base such as sodium tert-butoxide
  • a suitable crown ether such as 18-crown-6
  • suitable solvent such as tetrahydrofuran
  • a reagent of Formula Alk 2 -W where Alk 2 is C 1-4 alkyl and W represents a leaving group, such as halo, e.g. chloro, bromo or iodo can be obtained commercially.
  • compounds of Formula (I) wherein R 1 , R 2 , R 3 , R 5 are as defined before and R 4 is NR 6a R 7a can also be prepared by reacting a compound of Formula (XV) where R 1 , R 2 , R 3 and R 5 are as defined before with a reagent of Formula R 6a R 7a NH, where R 6a and R 7a are as defined before, in the presence of a suitable catalyst, such as palladium (II) acetate, in the presence of a suitable phosphine ligand, such as racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and in the presence of a suitable base, such as cesium carbonate, in a suitable inert solvent, such as toluene, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as pal
  • a reagent of Formula R 6a R 7a NH, where R 6a and R 7a are as defined before, can be obtained commercially.
  • R 1 , R 2 , R 3 and R 5 are as defined before, R 4 is Alk 3 oxy and Alk 3 is C 1-4 alkyl, trifluoromethylC 0-4 alkyl, C 3-8 cycloalkylC 1-4 alkyl, or C 1-4 alkyloxyC 1-5 alkyl, can be prepared by reacting a compound of Formula (XV) where R 1 , R 2 , R 3 and R 5 are as defined before and the chlorine atom is ortho to the pyridinyl nitrogen, with a reagent of Formula Alk 3 —OH, where Alk 3 is C 1-4 alkyl, trifluoromethylC 0-4 alkyl, C 3-8 cycloalkylC 1-4 alkyl, or C 1-4 alkyloxyC 1-5 alkyl in the presence of a suitable base, such as sodium hydride, in a suitable inert solvent such as N,N-dimethylformamide or dimethyl sulfoxide, under suitable reaction conditions, such as
  • a reagent of Formula Alk 3 —OH wherein C 1-4 alkyl, trifluoromethylC 0-4 alkyl, C 3-8 cycloalkylC 1-4 alkyl or C 1-4 alkyloxyC 1-5 alkyl can be obtained commercially or can be prepared by procedures similar to those described in Morel, P. US 2008102028 A1.
  • a Grignard reagent of Formula R 4 Mghalo where R 4 is C 1-6 alkyl and halo is chloro, bromo or iodo, can be obtained commercially.
  • compounds of Formula (I) wherein R 1 , R 2 , R 3 and R 5 are as defined before and R 4 is C 1-4 alkyl or C 3-8 cycloalkyl and Het is pyridinyl can also be prepared by reacting a compound of Formula (XV) where R 1 , R 2 , R 3 and R 5 are as defined before with a boronic acid derivative of Formula R 4 B(OH) 2 , where R 4 is C 1-4 alkyl or C 3-8 cycloalkyl, in the presence of a suitable catalyst, such as palladium (II) acetate, in the presence of a suitable phosphine ligand, such as 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, in the presence of a suitable base, such as potassium phosphate, in a suitable inert solvent, such as toluene, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave
  • a boronic acid derivative of Formula R 4 B(OH) 2 where R 4 is C 1-4 alkyl or C 3-8 cycloalkyl can be obtained commercially.
  • Compounds of Formula (I) wherein R 1 , R 2 , R 3 and R 5 are as defined before and R 4 is C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl and Het is pyridinyl can also be prepared by reacting a compound of Formula (XV) where R 1 , R 2 , R 3 and R 5 are as defined before and the chlorine atom is ortho to the pyridinyl nitrogen with an organozinc reagent of Formula Zn(R 4 ) 2 where R 4 represents a C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating
  • a reagent of Formula Zn(R 4 ) 2 wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl can be obtained commercially.
  • a reagent of Formula Zn(R 4 ) 2 wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl can be prepared by reacting a compound of Formula R 4 -halo wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl and halo represents iodo, with zinc in the presence of 1,2-dibromoethane and chlorotrimethylsilane, in a suitable inert solvent, such as N,N-dimethylformamide, under suitable reaction conditions such as heating at a convenient temperature, typically ranging between 25° C. and 100° C.
  • a reagent of R 4 -halo wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl and halo represents iodo can be obtained commercially or can be prepared by reacting a compound of Formula halo-R 4 wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl and halo represents a chloro or bromo with sodium iodide in a suitable inert solvent, such as acetone, under suitable reaction conditions such as a convenient temperature, typically ranging between 25° C. and 40° C.
  • a suitable inert solvent such as acetone
  • a compound of Formula halo-R 4 wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl and halo represents a chloro or bromo, can be obtained commercially.
  • a boronic acid of Formula (III) wherein R 4 and R 5 are as defined before can be obtained commercially.
  • a boronic acid of Formula (III) wherein R 4 and R 5 are as defined before can be prepared by reacting a halopyridine of Formula (VI), wherein R 4 and R 5 are as defined before and halo is bromo or iodo, with triisopropyl borate, in the presence of a suitable base, such as n-butyllithium, in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 78° C. and ⁇ 10° C.
  • a boronic derivative of Formula (IV) wherein R 4 and R 5 are as defined before can be obtained commercially.
  • a compound of Formula (IV) wherein R 4 and R 5 are as defined before can also be prepared by reacting a halopyridine of Formula (VI), wherein R 4 and R 5 are as defined before and halo represents a bromo or iodo, with bis(pinacolato)diboron in the presence of a suitable catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in the presence of a suitable base, such as potassium acetate, in a suitable inert solvent, such as N,N-dimethylformamide or dimethyl sulfoxide, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as [1,1′-bis(diphenyl
  • a halopyridine of Formula (VI) wherein R 4 and R 5 are as defined before and halo represents a bromo or iodo can be obtained commercially.
  • a halopyridine of Formula (VI) wherein R 5 is as defined before, halo represents a bromo and R 4 is C 1-6 alkyl or C 3-8 cycloalkyl can be prepared by reacting a di-halopyridine of Formula (XXI)
  • halo 1 represent a bromo and halo 2 represent a bromo or iodo ortho to the pyridinyl nitrogen, with a reagent of Formula R 4 B(OH) 2 where R 4 represents a C 1-4 alkyl or C 3-8 cycloalkyl, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium(0), in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • a suitable inert solvent such as tetrahydrofuran
  • a boronic acid derivative of Formula R 4 B(OH) 2 where R 4 is C 1-4 alkyl or C 3-8 cycloalkyl can be obtained commercially.
  • a halopyridine of Formula (VI) wherein R 5 is as defined before, halo represents a bromo an R 4 is C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl can be prepared by reacting a di-halopyridine of Formula (XXI) where R 5 is as defined before and halo 1 and halo 2 represent independently a bromo or iodo and halo 2 is ortho to the pyridinyl nitrogen, with an organozinc reagent of Formula Zn(R 4 ) 2 where R 4 represents a C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions,
  • a reagent of Formula Zn(R 4 ) 2 wherein R 4 represents C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or trifluoromethylC 0-4 alkyl can be obtained as described before.
  • Alk 4 represents a C 1-4 alkyl and Alk 5 represents a C 1-4 alkyl, can be prepared by reacting a compound of Formula (VIb)
  • R 5 is as defined before and Alk 4 represents a C 1-4 alkyl, with a reagent of Formula Alk 5 2 SO 4 where Alk 5 represents a C 1-4 alkyl, in the presence of a suitable base, such as sodium hydride, in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 40° C. or with a reagent of Formula Alk 5 -W wherein Alk 5 represents a C 1-4 alkyl and W represents a leaving group, such as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.
  • a suitable base such as sodium hydride
  • a suitable inert solvent such as tetrahydrofuran
  • methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy in the presence of a base, such as sodium hydride or sodium tert-butoxide, in the presence of a suitable crown ether, such as 18-crown-6, in a suitable solvent, such as tetrahydrofuran and under suitable reaction conditions, such as a convenient temperature, typically ranging from 0° C. to 40° C.
  • a base such as sodium hydride or sodium tert-butoxide
  • a suitable crown ether such as 18-crown-6
  • suitable solvent such as tetrahydrofuran
  • reaction conditions such as a convenient temperature, typically ranging from 0° C. to 40° C.
  • halo e.g. chloro, bromo or iodo
  • a sulfonyloxy group e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy
  • R 5 is as defined before, can be prepared by reacting a methylpyridine of Formula (VId)
  • R 5 is as defined before and the methyl group is ortho to the pyridinyl nitrogen with N,N-dimethylformamide in the presence of a suitable base, such as lithium diisopropylamide, in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 78° C. and ⁇ 10° C., followed by treatment with sodium borohydride in a suitable solvent, such as methanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 40° C.
  • a suitable base such as lithium diisopropylamide
  • a suitable inert solvent such as tetrahydrofuran
  • R 5 is as defined before
  • a methylpyridine of Formula (VId) wherein R 5 is as defined before and the methyl group is ortho to the pyridinyl nitrogen with acetone in the presence of a suitable base, such as lithium diisopropylamide, in a suitable inert solvent, such as tetrahydrofuran, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 78° C. and ⁇ 10° C.
  • a methylpyridine of Formula (VId) wherein R 5 is as defined before, can be obtained commercially.
  • R 5 is as defined before
  • a di-halopyridine of Formula (XXI) where R 5 is as defined before, halo 1 is a bromo and halo 2 represents bromo can be obtained commercially.
  • R 5 is as defined before, can be prepared by reacting a compound of Formula (XXII)
  • R 5 is as defined before, with sodium borohydride, in a suitable inert solvent, such as dichloromethane, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 40° C.
  • a compound of Formula (XXII) wherein R 5 is as defined before and halo represents bromo can be prepared by reacting a compound of Formula (XXIII)
  • R 5 is as defined before, with diisobutylaluminium hydride, in a suitable inert solvent, such as dichloromethane, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 40° C.
  • a compound of Formula (XXIII) wherein R 5 is as defined before, can be prepared by reacting a compound of Formula (XXIV)
  • R 5 is as defined before, with a suitable alkylating reagent such as iodomethane, in the presence of a base, such as sodium tert-butoxide, in the presence of a suitable crown ether, such as 18-crown-6, in a suitable solvent, such as tetrahydrofuran and under suitable reaction conditions, such as a convenient temperature, typically ranging between 0° C. and 40° C.
  • a suitable alkylating reagent such as iodomethane
  • a base such as sodium tert-butoxide
  • a suitable crown ether such as 18-crown-6
  • suitable solvent such as tetrahydrofuran
  • reaction conditions such as a convenient temperature, typically ranging between 0° C. and 40° C.
  • a compound of Formula (XXIV) wherein R 5 is as defined before, can be obtained commercially or alternatively, can also be obtained by reacting a compound of Formula (XXV)
  • R 5 is as defined before, with potassium cyanide, in the presence of a suitable inorganic salt, such as potassium iodide, in a suitable solvent, such as a mixture of ethanol and water and under suitable reaction conditions, such as heating at a convenient temperature, typically ranging from 25° C. to 100° C.
  • a suitable inorganic salt such as potassium iodide
  • a compound of Formula (XXV) wherein R 5 is as defined before, can be obtained commercially or alternatively, can also be obtained by reacting a compound Formula (XXVI)
  • R 5 is as defined before, with thionyl chloride, in a suitable solvent, such as dichoromethane and under suitable reaction conditions, such as a convenient temperature, typically ranging from ⁇ 10° C. to 25° C.
  • a compound of Formula (XXVI) wherein R 5 is as defined before can be obtained commercially.
  • R 5 is as defined before, can be prepared by reacting an amino pyridine of Formula (XXVII)
  • R 5 is as defined before, with sodium nitrite in the presence of a suitable inorganic salt, such as copper (I) bromide and a suitable inorganic acid, such as hydrobromic acid, in a suitable inert solvent, such as water, under suitable reaction conditions, such as a convenient temperature, typically ranging between ⁇ 10° C. and 25° C.
  • a suitable inorganic salt such as copper (I) bromide and a suitable inorganic acid, such as hydrobromic acid
  • a suitable inert solvent such as water
  • R 5 is as defined before, with hydrogen in the presence of a suitable catalyst, such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol or ethanol, under suitable reaction conditions, such as heating at a convenient temperature, typically ranging between 25° C. and 40° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol or ethanol
  • a nitropyridine of Formula (XXVIII) where R 5 is as defined before, can be prepared by reacting an halonitropyridine of Formula (XXIX)
  • R 5 is as defined before and halo represents a chloro, bromo or iodo, with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium(0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent, such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium(0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as a mixture of 1,4-dioxane and water
  • a halonitropyridine of Formula (XXIX) where R 5 is as defined before and halo represents a chloro, bromo or iodo can be obtained commercially.
  • R 5 is as defined before and Alk 6 is C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or C 3-8 cycloalkylC 1-4 alkyl and halo is a bromo or iodo
  • a di-halopyridine of Formula (XVIII) where R 5 is as defined before, halo represents a bromo or iodo and the chlorine atom is ortho to the pyridinyl nitrogen with a reagent of Formula Alk 6 —OH, where Alk 6 is C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or C 3-8 cycloalkylC 1-4 alkyl in the presence of a suitable base, such as sodium hydride, in a suitable inert solvent, such as N,N-dimethylformamide or dimethyl sulfoxide, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for
  • a di-halo pyridine of Formula (XVIII) where R 5 is as defined before, halo represents a bromo or iodo, can be obtained commercially.
  • a reagent of Formula Alk 6 —OH wherein Alk 6 is C 1-4 alkyl, C 1-4 alkyloxyC 1-5 alkyl or C 3-8 cycloalkylC 1-4 alkyl, can be obtained commercially or alternatively can also be obtained by procedures similar to those described in Morel, P. US 2008102028 A1.
  • R 5 , R 6a and R 7a are as defined before and halo represents bromo or iodo
  • a suitable inert solvent such as acetonitrile
  • a reagent of Formula R 6a R 7a NH, wherein R 6a and R 7a are as defined before, can be obtained commercially.
  • a di-halo pyridine of Formula (XVIII) where R 5 is as defined before, halo represents a bromo or iodo, can be obtained commercially.
  • a compound of Formula (I) wherein R 1 , R 2 , R 4 and R 5 are as defined before, R 3 is hydrogen, Het is pyrazolyl and R 4 is attached to the nitrogen atom of the pyrazole can be prepared by reacting a compound of Formula (If)
  • R 1 , R 2 , R 4 and R 5 are as defined before, with hydrogen in the presence of a suitable catalyst, such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol or ethanol, under suitable reaction conditions, such as a convenient temperature, typically ranging between 25° C. and 40° C. or with ammonium formate in the presence of a suitable catalyst such as 10% palladium on charcoal, in a suitable inert solvent, such as methanol, ethanol, ethyl acetate or dichloromethane or mixtures thereof, under suitable reaction conditions, such as heating at a convenient temperature, typically ranging between 40° C. and 100° C.
  • a suitable catalyst such as 10% palladium on charcoal
  • a suitable inert solvent such as methanol or ethanol
  • R 4 and R 5 are as defined before, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), in the presence of a suitable base, such as sodium carbonate, in a suitable inert solvent such as a mixture of 1,4-dioxane and water, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium (0)
  • a suitable base such as sodium carbonate
  • a suitable inert solvent such as a mixture of 1,4-dioxane and water
  • a compound of Formula (XXX) wherein R 4 and R 5 are as defined before and R 4 is attached to the nitrogen atom of the pyrazole can be obtained commercially or alternatively, can be prepared by reacting a compound of Formula (XXXI)
  • R 5 is as defined before, with a reagent of Formula R 4 —W wherein R 4 is as defined before and W represents a leaving group, such as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.
  • methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy in the presence of a base such as cesium carbonate or diisopropylethylamine, in a suitable solvent, such as N,N-dimethylformamide or acetonitrile and under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a base such as cesium carbonate or diisopropylethylamine
  • suitable solvent such as N,N-dimethylformamide or acetonitrile
  • reaction conditions such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • Compounds of Formula R 4 —W wherein R 4 is as defined before and W represents a leaving group, such as halo, e.g. chloro, bromo or iodo, can be obtained commercially.
  • Compounds of formula R 4 —W wherein R 4 is as defined before and W represents a leaving group, such as a sulfonyloxy group, e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy can be prepared by reacting a compound of Formula R 4 —OH with a sulfonyl chloride, e.g.
  • methylsulfonyl chloride trifluoromethylsulfonyl chloride, or methylphenylsulfonyl chloride in the presence of a suitable base, such as pyridine or diisopropylethylamine, in a suitable solvent, such as dichloromethane and under suitable reaction conditions, such as a convenient temperature, typically ranging from ⁇ 10° C. to 25° C.
  • a suitable base such as pyridine or diisopropylethylamine
  • a suitable solvent such as dichloromethane
  • reaction conditions such as a convenient temperature, typically ranging from ⁇ 10° C. to 25° C.
  • R 4 and R 5 are as defined before, with bis(pinacolato)diboron in the presence of a suitable catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), in the presence of a suitable base, such as potassium acetate, in a suitable inert solvent, such as N,N-dimethylformamide or dimethyl sulfoxide, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)
  • a suitable base such as potassium acetate
  • a suitable inert solvent such as N,N-dimethylformamide or dimethyl sulfoxide
  • R 5 is as defined before, with a reagent of Formula R 4 —W wherein R 4 is as defined before and W represents a leaving group such as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.
  • methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy in the presence of a suitable base, such as cesium carbonate or diisopropylethylamine, in a suitable solvent, such as N,N-dimethylformamide or acetonitrile and under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable base such as cesium carbonate or diisopropylethylamine
  • a suitable solvent such as N,N-dimethylformamide or acetonitrile
  • reaction conditions such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a 4-iodo-1H-pyrazole of Formula (XXXIII) where R 5 is as defined before, can be obtained commercially.
  • compounds of formula R 4 —W wherein R 4 is as defined before and W represents a leaving group such as a sulfonyloxy group, e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy can be prepared by reacting a compound of formula R 4 —OH with a sulfonyl chloride, e.g.
  • methylsulfonyl chloride trifluoromethylsulfonyl chloride, or methylphenylsulfonyl chloride in the presence of a suitable base such, as pyridine or diisopropylethylamine, in a suitable solvent, such as dichloromethane and under suitable reaction conditions, such as a convenient temperature, typically ranging from ⁇ 10° C. to 25° C.
  • a suitable base such as pyridine or diisopropylethylamine
  • a suitable solvent such as dichloromethane
  • reaction conditions such as a convenient temperature, typically ranging from ⁇ 10° C. to 25° C.
  • R 5 is as defined before and Alk 7 represents C 1-4 alkyl or C 3-8 cycloalkyl groups can be prepared by reacting a compound of Formula (XXXIIb).
  • R 5 is as defined before and Alk 7 represents C 1-4 alkyl or C 3-8 cycloalkyl groups with (diethylamino)sulphur trifluoride in a suitable inert solvent, such as dichloromethane, and under suitable reaction conditions, such as convenient temperatures, typically ranging from 0° C. to 25° C.
  • a suitable inert solvent such as dichloromethane
  • a compound of Formula (XXXIIb), wherein Alk 7 represents a C 1-4 alkyl or C 3-8 cycloalkyl group can be prepared by reacting a 4-iodo-1H-pyrazole of Formula (XXXIII) with an alpha bromoketone of Formula (XXXV)
  • Alk 7 represents a C 1-4 alkyl or a C 3-8 cycloalkyl group, in the presence of a suitable base, such as cesium carbonate, in a suitable inert solvent, such as acetonitrile, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable base such as cesium carbonate
  • a suitable inert solvent such as acetonitrile
  • alpha bromoketone of Formula (XXXV) wherein Alk 7 is C 1-4 alkyl or C 3-8 cycloalkyl can be obtained commercially or alternatively can be obtained by procedures similar to those described in Carverley, M. J. Tetrahedron, 1987, 43(20), 4609-19.
  • Alk 8 represents C 1-4 alkyl and Alk 9 represents C 1-4 alkyl, can be prepared by reacting a compound of Formula (XXXVI)
  • R 5 is as defined before and Alk 8 represents C 1-4 alkyl with a reagent of Formula Alk 9 -W wherein Alk 9 is C 1-4 alkyl, and W represents a leaving group such as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy, in the presence of a suitable base, such as sodium hydride, in a suitable solvent such as tetrahydrofuran and under suitable reaction conditions, such as a convenient temperature, typically ranging from 0° C. to 40° C.
  • a suitable base such as sodium hydride
  • suitable solvent such as tetrahydrofuran
  • a reagent of Formula Alk 9 -W wherein Alk 9 is C 1-4 alkyl and W represents a leaving group such as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy, can be obtained commercially.
  • a compound of Formula (XXXVI) wherein R 5 is as defined before, can be prepared by reacting a 4-iodo-1H-pyrazole of Formula (XXXIII)
  • R 5 is as defined before, with a reagent of Formula W-Alk 8 —OH, wherein W represents a leaving group such as halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.
  • Alk 8 represents a C 1-4 alkyl, in the presence of a suitable base, such as cesium carbonate, in a suitable inert solvent, such as N,N-dimethylformamide, under suitable reaction conditions, such as heating at a convenient temperature, either by conventional heating or under microwave irradiation for a period of time to ensure the completion of the reaction.
  • a suitable base such as cesium carbonate
  • a suitable inert solvent such as N,N-dimethylformamide
  • W represents a leaving group such as halo, e.g. chloro, bromo or iodo
  • a sulfonyloxy group e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy, or methylphenylsulfonyloxy
  • Alk 8 represents C 1-4 alkyl or C 3-8 cycloalkyl
  • the free base can be dissolved in isopropanol, diisopropylether, diethyl ether and/or dichloromethane and subsequently, 1 to 2 equivalents of the appropriate acid, for example a 6N HCl solution in 2-propanol or a 2N HCl solution in diethyl ether, can be added dropwise.
  • the mixture typically is stirred for 10 min or longer after which the product can be filtered off.
  • the HCl salt is usually dried in vacuo.
  • the compounds according to the invention inhibit PDE10 enzyme activity, in particular PDE10A enzyme activity and hence raise the levels of cAMP or cGMP within cells that express PDE10. Accordingly, inhibition of PDE10 enzyme activity may be useful in the treatment of diseases caused by deficient amounts of cAMP or cGMP in cells. PDE10 inhibitors may also be of benefit in cases in which raising the amount of cAMP or cGMP above normal levels results in a therapeutic effect. Inhibitors of PDE10 may be used to treat disorders of the peripheral and central nervous system, cardiovascular diseases, cancer, gastro-enterological diseases, endocrinological or metabolic diseases and urological diseases.
  • the present invention relates to a compound according to the present invention for use as a medicine, as well as to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament.
  • the present invention also relates to a compound according to the present invention or a pharmaceutical composition according to the invention for use in the treatment or prevention of, in particular treatment of, a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the inhibition of phosphodiesterase 10 enzyme.
  • the present invention also relates to the use of a compound according to the present invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention of, in particular treatment of, a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the inhibition of phosphodiesterase 10 enzyme.
  • the present invention also relates to a compound according to the invention, or a pharmaceutical composition according to the invention for use in the treatment, prevention, amelioration, control or reduction of the risk of various neurological, psychiatric and metabolic disorders associated with phosphodiesterase 10 dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the inhibition of phosphodiesterase 10.
  • the present invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with phosphodiesterase 10 dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the inhibition of phosphodiesterase 10.
  • the invention is said to relate to the use of a compound or composition according to the invention for the manufacture of a medicament for e.g. the treatment of a mammal, it is understood that such use is to be interpreted in certain jurisdictions as a method of e.g. treatment of a mammal, comprising administering to a mammal in need of such e.g. treatment, an effective amount of a compound or composition according to the invention.
  • the indications that may be treated with PDE10 inhibitors include, but are not limited to, those diseases thought to be mediated in part by the basal ganglia, prefrontal cortex and hippocampus.
  • neurological and psychiatric disorders selected from psychotic disorders and conditions; anxiety disorders; movement disorders; drug abuse; mood disorders; neurodegenerative disorders; disorders or conditions comprising as a symptom a deficiency in attention and/or cognition; pain and metabolic disorders.
  • the psychotic disorders and conditions associated with PDE10 dysfunction include one or more of the following conditions or diseases: schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder, such as delusional or depressive type; delusional disorder; substance-induced psychotic disorder such as psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorders of the paranoid type; and personality disorder of the schizoid type.
  • the anxiety disorders include panic disorder; agoraphobia; specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
  • movement disorders include Huntington's disease and dyskinesia; Parkinson's disease; restless leg syndrome and essential tremor. Additionally, Tourette's syndrome and other tic disorders can be included.
  • the central nervous system disorder is a substance-related disorder selected from the group of alcohol abuse; alcohol dependence; alcohol withdrawal; alcohol withdrawal delirium; alcohol-induced psychotic disorder; amphetamine dependence; amphetamine withdrawal; cocaine dependence; cocaine withdrawal; nicotine dependence; nicotine withdrawal; opioid dependence and opioid withdrawal.
  • mood disorders and mood episodes include depression, mania and bipolar disorders.
  • the mood disorder is selected from the group of bipolar disorders (I and II); cyclothymic disorder; depression; dysthymic disorder; major depressive disorder and substance-induced mood disorder.
  • neurodegenerative disorders include Parkinson's disease; Huntington's disease; dementia such as for example Alzheimer's disease; multi-infarct dementia; AIDS-related dementia or fronto temperal dementia.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons.
  • disorders or conditions comprising as a symptom a deficiency in attention and/or cognition include dementia, such as Alzheimer's disease; multi-infarct dementia; alcoholic dementia or drug-related dementia; dementia associated with intracranial tumours or cerebral trauma; dementia associated with Huntington's disease; dementia associated with Parkinson's disease; AIDS-related dementia; other diseases include delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder; attention-deficit/hyperactivity disorder (ADHD); and age-related cognitive impairment.
  • dementia such as Alzheimer's disease; multi-infarct dementia; alcoholic dementia or drug-related dementia; dementia associated with intracranial tumours or cerebral trauma; dementia associated with Huntington's disease; dementia associated with Parkinson's disease; AIDS-related dementia; other diseases include delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder; attention-deficit/hyperactivity disorder (ADHD); and age-related cognitive impairment.
  • ADHD attention-deficit/hyp
  • pain includes acute and chronic states, severe pain, intractable pain, neuropathic pain and post-traumatic pain.
  • metabolic disorders include diabetes, in particular type 1 or type 2 diabetes, and related disorders such as obesity.
  • Additional related disorders include syndrome X, impaired glucose tolerance, impaired fasting glucose, gestational diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), associated diabetic dyslipidemia, hyperglycemia, hyperinsulinemia, dyslipidemia, hypertriglyceridemia, and insulin resistance.
  • the compounds of the invention may be useful in the treatment of cancer, such as renal carcinoma and breast cancer.
  • the psychotic disorder is selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.
  • the central nervous system disorder is a personality disorder selected from the group of obsessive-compulsive personality disorder and schizoid, schizotypal disorder.
  • the central nervous system disorder is a mood disorder selected from the group of bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder and substance-induced mood disorder.
  • bipolar disorders I & II
  • cyclothymic disorder depression
  • dysthymic disorder major depressive disorder
  • substance-induced mood disorder substance-induced mood disorder
  • the central nervous system disorder is attention-deficit/hyperactivity disorder.
  • the central nervous system disorder is a cognitive disorder selected from the group of delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, substance-induced persisting dementia and mild cognitive impairment.
  • disorders treated by the compounds of the present invention are selected from schizophrenia; obsessive-compulsive disorder; generalized anxiety disorder; Huntington's disease; dyskinesia; Parkinson's disease; depression; bipolar disorders; dementia such as Alzheimer's disease; attention-deficit/hyperactivity disorder; drug abuse; pain; diabetes and obesity.
  • the disorders treated by the compounds of the present invention are schizophrenia, including positive and negative symptoms thereof, and cognitive deficits, such as impaired attention or memory.
  • DSM-IV Diagnostic & Statistical Manual of Mental Disorders
  • the invention also relates to a compound according to the invention, for use in the treatment of any one of the diseases mentioned hereinbefore.
  • the invention also relates to a compound according to the invention for use in treating any one of the diseases mentioned hereinbefore.
  • the invention also relates to a compound according to the invention, for the treatment or prevention, in particular treatment, of any one of the diseases mentioned hereinbefore.
  • the invention also relates to the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.
  • the invention also relates to the use of a compound according to the invention for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned hereinbefore.
  • the compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a compound according to the invention to warm-blooded animals, including humans.
  • the invention also relates to a method for the prevention and/or treatment of any one of the diseases mentioned hereinbefore comprising administering a therapeutically effective amount of compound according to the invention to a patient in need thereof.
  • the PDE10 inhibitors described herein can be used alone, in combination or in combination with other pharmaceutical agents such as other agents used in the treatment of psychoses, such as schizophrenia and bipolar disorder, obsessive-compulsive disorder, Parkinson's disease, cognitive impairment and/or memory loss, e.g. nicotinic ⁇ -7 agonists, PDE4 inhibitors, other PDE10 inhibitors, calcium channel blockers, muscarinic m1 and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, cannabinoid modulators, and cholinesterase inhibitors (e.g.
  • the compounds of the present invention may be utilized in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • a therapeutically effective amount of the PDE10 inhibitors of the present invention is the amount sufficient to inhibit the PDE10 enzyme and that this amount varies inter alia, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient.
  • an amount of PDE10 inhibitor to be administered as a therapeutic agent for treating diseases in which inhibition of the PDE10 enzyme is beneficial, such as the disorders described herein, will be determined on a case by case by an attending physician.
  • a suitable dose is one that results in a concentration of the PDE10 inhibitor at the treatment site in the range of 0.5 nM to 200 ⁇ M, and more usually 5 nM to 50 ⁇ M.
  • a patient in need of treatment likely will be administered between 0.001 mg/kg to 15 mg/kg body weight, in particular from 0.01 mg/kg to 2.50 mg/kg body weight, in particular, from 0.01 to 1.5 mg/kg body weight, in particular from 0.1 mg/kg to 0.50 mg/kg body weight.
  • the amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutical effect will, of course vary on case-by-case basis, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to admission.
  • suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
  • the present invention also provides compositions for preventing or treating diseases in which inhibition of the PDE10 enzyme is beneficial, such as the disorders described herein. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a stereochemically isomeric form thereof.
  • the carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the compounds according to the invention in particular the compounds according to Formula (I), the pharmaceutically acceptable salts thereof, the solvates and the stereochemically isomeric forms thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture).
  • a therapeutically effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier or diluent, which carrier or diluent may take a wide variety of forms depending on the form of preparation desired for administration.
  • compositions are desirable in unitary dosage form suitable, in particular, for oral, topical (for example via a nose spray, eye drops or via a cream, gel, shampoo or the like), rectal or percutaneous administration, by parenteral injection or by inhalation, such as a nose spray.
  • topical for example via a nose spray, eye drops or via a cream, gel, shampoo or the like
  • percutaneous administration by parenteral injection or by inhalation, such as a nose spray.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as, for example, suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of the ease in administration, oral administration is preferred, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, surfactants to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, said additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on treatment, as an ointment.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, teaspoonfuls, tablespoonfuls, and segregated multiples thereof.
  • compositions comprising aid compounds for oral administration are especially advantageous.
  • ⁇ -, ⁇ - or ⁇ -cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the pharmaceutical composition will comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight of the active ingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • suitable unit doses for the compounds of the present invention can, for example, preferably contain between 0.1 mg to about 1000 mg of the active compound.
  • a preferred unit dose is between 1 mg to about 500 mg.
  • a more preferred unit dose is between 1 mg to about 300 mg.
  • Even more preferred unit dose is between 1 mg to about 100 mg.
  • Such unit doses can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration.
  • a preferred dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds according to the invention and one or more other drugs for use as a medicament or for use in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility as well.
  • the use of such a composition for the manufacture of a medicament, as well as the use of such a composition for the manufacture of a medicament in the treatment, prevention, control, amelioration or reduction of risk of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility are also contemplated.
  • the present invention also relates to a combination of a compound according to the present invention and an additional pharmaceutical agent.
  • the present invention also relates to such a combination for use as a medicine.
  • the present invention also relates to a product comprising (a) a compound according to the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof, and (b) an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the effect of PDE10 inhibitors, in particular PDE10A inhibitors.
  • the different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.
  • LCMS liquid chromatography/mass spectrometry
  • HPLC high-performance liquid chromatography
  • min. means minutes
  • h.” means hours
  • R t means retention time (in minutes)
  • [M+H] + means the protonated mass of the free base of the compound
  • m.p.” means melting point.
  • Microwave assisted reactions were performed in a single-mode reactor: EmrysTM Optimizer microwave reactor (Personal Chemistry A.B., currently Biotage).
  • TLC Thin layer chromatography
  • Reverse phase HPLC was performed on a C18 XBridge 30 ⁇ 100 5 ⁇ m column.
  • Melting Point values are peak values, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
  • melting points were determined in open capillary tubes either on a Mettler FP62 or on a Mettler FP81HT-FP90 apparatus. Melting points were measured with a temperature gradient of 10° C./minute. Maximum temperature was 300° C. The melting point was read from a digital display.
  • the HPLC measurement was performed using an HP 1100 (Agilent Technologies) system comprising a pump (quaternary or binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods.
  • the MS detector was configured with either an electrospray ionization source or an ESCI dual ionization source (electrospray combined with atmospheric pressure chemical ionization). Nitrogen was used as the nebulizer gas.
  • the source temperature was maintained either at 140° C. or 100° C.
  • Data acquisition was performed either with MassLynx-Openlynx software or Chemsation-Agilent Data Browser software.
  • the HPLC (Ultra Performance Liquid Chromatography) measurement was performed using an Acquity HPLC (Waters) system comprising a sampler organizer, a binary pump with degasser, a four column's oven, a diode-array detector (DAD) and a column as specified in the respective methods.
  • the MS detector was configured with an ESCI dual ionization source (electrospray combined with atmospheric pressure chemical ionization). Nitrogen was used as the nebulizer gas. The source temperature was maintained at 140° C. Data acquisition was performed with MassLynx-Openlynx software.
  • High-resolution mass spectra (Time of Flight, TOF detector) were acquired only in positive ionization mode or in positive/negative modes by scanning from 100 to 750 umas.
  • the capillary needle voltage was 2.5 kV for positive mode and 2.9 kV for negative ionization mode.
  • the cone voltage was 20 V for both positive and negative ionization modes.
  • Leucine-Enkephaline was the standard substance used for the lock mass calibration.
  • Low-resolution mass spectra (single quadrupole, SQD detector) were acquired only in positive ionization mode or in positive/negative modes by scanning from 100 to 1000 umas.
  • the capillary needle voltage was 3 kV.
  • For positive ionization mode the cone voltage was 20 V, 25 V or 20 V/50 V.
  • For negative ionization mode the cone voltage was 30 V.
  • Low-resolution mass spectra (single quadrupole, MSD detector) were acquired in positive/negative modes by scanning from 100 to 1000 umas.
  • the capillary needle voltage was 1.0 kV and the fragmentor voltage was 70V for both positive and negative ionization modes.
  • Reversed phase HPLC was carried out on a Sunfire-C18 column (2.5 ⁇ m, 2.1 ⁇ 30 mm) from Waters, with a flow rate of 1.0 ml/min, at 60° C.
  • the gradient conditions used are: 95% A (0.5 g/L ammonium acetate solution+5% of acetonitrile), 5% B (acetonitrile or or acetonitrile/methanol 1/1), to 100% B and equilibrated to initial conditions up to 7 or 9 minutes run. Injection volume 2 ⁇ L.
  • Reversed phase HPLC was carried out on an Eclipse Plus-C18 column (3.5 ⁇ m, 2.1 ⁇ 30 mm) from Agilent, with a flow rate of 1.0 mL/min, at 60° C.
  • the gradient conditions used are: 95% A (0.5 g/L ammonium acetate solution+5% acetonitrile), 5% B (acetonitrile or mixture of acetonitrile/methanol, 1/1), to 100% B and equilibrated to initial conditions up to 7 or 9 minutes run. Injection volume 2 ⁇ L.
  • Reversed phase HPLC was carried out on an Eclipse Plus-C18 column (3.5 ⁇ m, 2.1 ⁇ 30 mm) from Agilent, with a flow rate of 1.0 mL/min, at 60° C.
  • the gradient conditions used are: 95% A (0.5 g/L ammonium acetate solution+5% acetonitrile), 5% B (acetonitrile), to 100% B in 5 0 minutes, kept till 5.15 minutes and equilibrated to initial conditions at 5.3 minutes until 7.0 minutes. Injection volume 2 ⁇ L.
  • Reversed phase HPLC was carried out on a BEH-C18 column (1.7 ⁇ m, 2.1 ⁇ 50 mm) from Waters, with a flow rate of 0 8 mL/min, at 60° C.
  • the gradient conditions used are: 95% A (0.5 g/L ammonium acetate solution+5% acetonitrile), 5% B (mixture of acetonitrile/methanol, 1/1), to 20% A, 80% B, then to 100% B and equilibrated to initial conditions up to 5 or 7 minutes run. Injection volume 0.5 ⁇ L.
  • Reversed phase HPLC was carried out on a BEH-C18 column (1.7 ⁇ m, 2.1 ⁇ 50 mm) from Waters, with a flow rate of 1.0 mL/min, at 50° C.
  • the gradient conditions used are: 95% A (0.5 g/L ammonium acetate solution+5% acetonitrile), 5% B (acetonitrile), to 40% A, 60% B, then to 5% A, 95% B and equilibrated to initial conditions up to 5, 7, or 9 minutes run.
  • Injection volume 0.5 ⁇ L.
  • Reversed phase HPLC was carried out on a BEH-C18 column (1.7 ⁇ m, 2.1 ⁇ 50 mm) from Waters, with a flow rate of 0 8 mL/min, at 50° C.
  • the gradient conditions used are: 95% A (formic acid solution, 0.1%), 5% B (methanol), to 40% A, 60% B, then to 5% A, 95% B and equilibrated to initial conditions up to 7.0 minutes run. Injection volume 0.5 ⁇ L.
  • intermediate 3 (19.5 g, 66%) as a white solid, in a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.
  • C 2 H 5 Cl 2 N 3 requires 201; Found 202 [M+H] + ; R t : 1.25 min and C 2 H 5 BrClN 3 requires 247; Found 248 [M+H] + ; R t : 1.33 min (method 5).
  • Morpholine (6.48 ml, 74 2 mmol) was added to a stirred solution of intermediate 3 (a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine) (12.5 g, 58 0 mmol) and N,N-diisopropylethylamine (16.2 ml, 92.8 mmol) in acetonitrile (40 ml). The mixture was stirred at 80° C. for 16 h. and then diluted with dichloromethane and washed with a saturated solution of ammonium chloride.
  • intermediate 3 a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine
  • Tetrakis(triphenylphosphine)palladium (0) (0.114 g, 0.10 mmol) was added to a stirred solution of intermediate 3 (a mixture 70/30 of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine) (0.4 g, 2.0 mmol) and 4-pyridineboronic acid (0.243 g, 2 0 mmol) in a mixture of 1,4-dioxane (2 ml) and a saturated solution of sodium carbonate (2 ml). The mixture was stirred at 100° C. for 16 h.
  • Tetrakis(triphenylphosphine)palladium (0) (0.457 g, 0.396 mmol) was added to a stirred solution of intermediate 7 (1 g, 3.96 mmol) and methylboronic acid (1.18 g, 19.79 mmol) in a mixture of 1,4-dioxane (12 ml) and a saturated solution of sodium carbonate (4 ml). The mixture was stirred at 175° C. for 45 min. in a sealed tube under nitrogen and under microwave irradiation. The mixture was filtered through a pad of diatomaceous earth and the filtrate diluted with ethylacetate and washed with water.
  • N-Iodosuccinimide (1.08 g, 4 8 mmol) was added to a stirred solution of intermediate 14 (1 g, 4.58 mmol) in a mixture of dichloromethane (50 ml) and acetic acid (2 ml). The mixture was stirred at 0° C. for 30 min. and then extracted with a saturated solution of sodium carbonate and a 10% solution of sodium thiosulfite. The organic layer was filtered over cotton wool and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, dichloromethane in heptane 70/30 first, then ethyl acetate in heptane 10/90 to 30/70). The desired fractions were collected and concentrated to yield intermediate 26 (4.68 g, 83%) as a white solid.
  • LCMS 345 [M+H] + ; R t : 2.59 min (method 1).
  • N-Iodosuccinimide (0.95 g, 4.36 mmol) was added to a stirred solution of a mixture 70/30 of intermediate 3 (0.95 g, 3.36 mmol) in a mixture of dichloromethane (9 ml) and acetic acid (1 ml). The mixture was stirred at room temperature for 16 h. and then washed with a saturated solution of sodium carbonate. The organic layer was separated, dried (Na 2 SO 4 ), filtered and the solvents evaporated in vacuo to yield 1.33 g of crude product.
  • N-Bromosuccinimide (0.273 g, 1.53 mmol) was added to a stirred solution of intermediate 14 (0.335 g, 1.53 mmol) in acetonitrile (10 ml). The mixture was stirred at room temperature for 1 h., then diluted with ethyl acetate and washed with a saturated solution of sodium carbonate. The organic layer was separated, dried (Na 2 SO 4 ), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica, 7 M solution of ammonia in methanol in dichloromethane 4/96).
  • Tetrakis(triphenylphosphine)palladium (0) (0.403 g, 0.35 mmol) was added to a stirred solution of intermediate 26 (4 g, 11.6 mmol) and 2-chloropyridine-5-boronic acid (2.01 g, 12.79 mmol) in a mixture of 1,4-dioxane (40 ml) and a saturated solution of sodium carbonate (20 ml). The mixture was stirred at 100° C. for 16 h. in a sealed tube under nitrogen and then diluted with dichloromethane and extracted with water. The organic layer was separated, dried (Na 2 SO 4 ), filtered and the solvents evaporated in vacuo. The crude product was precipitated from methanol to yield intermediate 35 (0.364 g, 40%).
  • Tetrakis(triphenylphosphine)palladium (0) (0.099 g, 0.086 mmol) was added to a stirred solution of intermediate 35 (0.945 g, 2.86 mmol) and vinylboronic acid pinacol ester (0.58 ml, 3.44 mmol) in a mixture of 1,4-dioxane (20 ml) and a saturated solution of sodium carbonate (4 ml). The mixture was stirred at 90° C. for 16 h. in a sealed tube under nitrogen. The mixture was diluted with dichloromethane and washed with water. The organic layer was separated, filtered over cotton and the solvents evaporated in vacuo.
  • Tetrakis(triphenylphosphine)palladium (0) (0.037 g, 0.032 mmol) was added to a stirred solution of intermediate 35 (0.35 g, 1.06 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.267 ml, 1.24 mmol) (obtained by procedures similar to those described in, Qiu, Y. et al. WO 2004/075846-A2 published on 20040910) in a mixture of 1,4-dioxane (5 ml) and a saturated solution of sodium carbonate (2 ml). The mixture was stirred at 85° C. for 5 h.
  • Triphenylphosphine (12.3 g, 47 0 mmol) was added to a stirred solution of 3-methoxy-3-methyl-butan-1-ol (4 ml, 31.3 mmol) and carbon tetrabromide (15.6 g, 47 0 mmol) in dichloromethane (300 ml) at 0° C. The mixture was stirred at room temperature for 18 h. and then a solution of sodium thiosulphate was added. The organic layer was separated, dried (Na 2 SO 4 ), filtered and the solvents evaporated in vacuo.
  • Tetrakis(triphenylphosphine)palladium(0) (1.82 g, 1.53 mmol) was added to a stirred suspension of 2,5-dibromopyridine (15 g, 63 3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (11.8 ml, 69 6 mmol) in a mixture of 1,4-dioxane (120 ml) and a saturated solution of sodium carbonate (36 ml). The mixture was stirred at 100° C. for 16 h. in a sealed tube under nitrogen. The mixture was diluted with dichloromethane and washed with water.
  • 1,2-Dibromoethane (0.237 ml, 2.75 mmol) was added to a stirred suspension of zinc (3.6 g, 55.0 mmol) in dry N,N-dimethylformamide (40 ml). The mixture was stirred at 90° C. for 30 min. under nitrogen and then allowed to warm to room temperature. Chlorotrimethylsilane (0.09 ml, 0.69 mmol) was added and the mixture was stirred at room temperature for 15 min. A solution of intermediate 44 (5.5 g, 27 5 mmol) in tetrahydrofuran (20 ml) was added dropwise and the mixture was stirred at 45° C. for 2.5 h.
  • Tetrakis(triphenylphosphine)palladium(0) (0.068 g, 0.059 mmol) was added to a stirred solution of intermediate 34 (0.30 g, 0.84 mmol) and intermediate 67 (0.446 g, 1.59 mmol) in a mixture of 1,4-dioxane (20 ml) and a saturated solution of sodium carbonate (6 ml). The mixture was stirred at 150° C. for 15 min, in a sealed tube under nitrogen and under microwave irradiation. The mixture was diluted with dichlorometane and washed with water. The organic layer was separated, dried (Na 2 SO 4 ), filtered and the solvents evaporated in vacuo.
  • Tetrakis(triphenylphosphine)palladium (0) (0.034 g, 0.009 mmol) was added to a stirred solution of intermediate 26 (0.2 g, 0.58 mmol) and intermediate 63 (0.243 g, 0.87 mmol), in a mixture of 1,4-dioxane (5 ml) and a saturated solution of sodium carbonate (3 ml). The mixture was stirred at 80° C. for 16 h. in a sealed tube under nitrogen and then diluted with dichloromethane and washed with water. The organic layer was separated, filtered over cotton, and the solvents evaporated in vacuo.
  • 1,2-Dibromoethane (0.016 ml, 0.19 mmol) was added to a stirred suspension of zinc (0.337 g, 5.17 mmol) in dry N,N-dimethylformamide (8 ml). The mixture was stirred at 90° C. for 30 min. under nitrogen and then allowed to cool down to room temperature. Chlorotrimethylsilane (0.006 ml, 0.048 mmol) was added and the mixture was stirred at room temperature for 15 min. A solution of intermediate 43 (0.7 g, 2.58 mmol) in tetrahydrofuran (3 ml) was added dropwise and the mixture was stirred at 50° C. for 1.5 h.
  • Tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol) was added to a stirred solution of intermediate 26 (0.2 g, 0.58 mmol) and 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.18 g, 0.73 mmol) in a mixture of 1,4-dioxane (8 ml) and a saturated solution of sodium carbonate (2 ml). The mixture was stirred at 140° C. for 20 min. in a sealed tube under nitrogen, under microwave irradiation.
  • the compounds provided in the present invention are inhibitors of PDE10, particularly, of PDE10A.
  • the behaviour of the PDE10 inhibitors according to Formula (I) in vitro and using an apomorphine induced stereotypy model in vivo is shown in Table 3.
  • the in vitro selectivity towards PDE10A, occupancy, and results using PCP-induced hyperlocomotion, conditioned avoidance response models, SCH-23390-induced hypolocomotion in mice and object recognition test in rats of selected compounds are shown in tables 4 to 7.
  • Rat recombinant PDE10A (rPDE10A2) was expressed in Sf9 cells using a recombinant rPDE10A baculovirus construct.
  • Cells were harvested after 48 h of infection and the rPDE10A protein was purified by metal chelate chromatography on Ni-sepharose 6FF.
  • Tested compounds were dissolved and diluted in 100% DMSO to a concentration 100 fold of the final concentration in the assay.
  • Compound dilutions (0.4 ⁇ l) were added in 384 well plates to 20 ⁇ l of incubation buffer (50 mM Tris pH 7.8, 8.3 mM MgCl 2 , 1.7 mM EGTA).
  • Control values were obtained by addition of a final concentration of 1% DMSO instead of compound.
  • the same assay principle is applied for the measurement of the affinity of the compound for other members of the PDE family with appropriate modifications in incubation buffer, substrate concentration, incubation time and stop solution.
  • An overview of the different protocols is presented in table A.
  • a best fit curve is fitted by a minimum sum of squares method to the plot of % of control value substracted with blanc value versus compound concentration and the half maximal inhibitory concentration (IC 50 ) value is derived from this curve.
  • the compounds of the invention are generally selective for PDE10 compared to other PDEs and there are a few that also have affinity for PDE1B1, 4D3 and 5A3.
  • Table 4 provides data of some compounds according to the invention.
  • Apomorphine (1.0 mg/kg, i.v.)-induced stereotypy was scored every 5 min over the first hour after injection of apomorphine, following a 1 hour interval pre-treatment with the test compound.
  • the score system was: (3) pronounced, (2) moderate, (1) slight, and (0) absent.
  • Criteria for drug-induced inhibition of stereotypy fewer than 6 scores of 3 (0.16% false positives), fewer than 6 scores of ⁇ 2 (0.0% false positives), or fewer than 7 scores of ⁇ 1 (0.81% false positives).
  • Dose-response or single dose experiments were performed to measure PDE10 occupancy 1 hour after subcutaneous (s.c.) or oral (p.o.) administration.
  • Male Wistar rats (200 g) were treated by s.c. or p.o. administration of various PDE10 inhibitors.
  • the PDE10 radioligand [ 3 H]-MP-10 (10 ⁇ Ci/animal) was injected intravenously (i.v.) 30 minutes before sacrifice. Brains were immediately removed from the skull and rapidly frozen. Twenty ⁇ m-thick brain sections were cut using a cryostat-microtome, thaw-mounted on microscope slides and loaded in a ⁇ -imager to quantify PDE10 occupancy in the striatum.
  • Vertical activity was defined as the number of periods of continuous breaks reported by an infrared array of 32 light beams in a horizontal plane 13 cm above the floor.
  • the intensity of the light within the activity meters ranged between 110 and 130 LUX.

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