JP2012509912A - New compounds - Google Patents

Abstract

  The present invention relates to imidazopyridazine substituted piperidine derivatives and their use as pharmaceuticals.

Description

  The present invention relates to imidazopyridazinylmethyl substituted piperidine derivatives and their use as pharmaceuticals.

  Many medically significant biological processes are mediated by proteins involved in signal transduction pathways including G proteins and / or second messengers.

  Polypeptides and polynucleotides encoding the human 7-transmembrane G protein-coupled neuropeptide receptor orexin-1 (HFGAN72) have been identified, EP-A-875565, EP-A-875566, and WO 96/34877 Is disclosed. Polypeptides and polynucleotides encoding a second human orexin receptor orexin-2 (HFGANP) have been identified and disclosed in EP-A-893498.

  Polypeptides that are ligands for the orexin-1 receptor, eg orexin-A (Lig72A) and polynucleotides encoding the polypeptides are disclosed in EP-A-849361.

  Orexin receptors have been found in mammalian hosts: depression; anxiety; addiction; obsessive compulsive disorder; emotional disorder / neuropathy; depression neurosis / depressive disorder; anxiety disorder; mood modulation disorder; behavior Disorder; mood disorder; sexual dysfunction; sexual psychological dysfunction; sexual disorder; sexual disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation such as Huntington's disease and Zildra Tolet syndrome and Dyskinesia; biological and circadian rhythm disorders; anorexia, anorexia, cachexia, obesity and other eating disorders; diabetes; appetite / taste disorder; vomiting / nausea; asthma; cancer; Parkinson's disease; Cushing's disease; basophilic adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; pituitary tumor / pituitary adenoma; hypothalamic disease; Florich syndrome; Anterior lobe disease; pituitary disease; pituitary tumor / pituitary adenoma; pituitary growth hormone; anterior pituitary hypofunction; hyperpituitary function hyperfunction; hypothalamic gonadal hypofunction; Amenorrhea or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamus-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorder related to growth hormone deficiency; idiopathic growth hormone Deficiency; stature; giantism; acromegaly; biological and circadian rhythm disorders; and sleep associated with diseases such as neurological disorders, neuropathic pain and restless legs syndrome, heart disease and lung disease Disorders; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic stroke; subarachnoid hemorrhage; Related head injury such as subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; kidney disease; glucose tolerance disorder; migraine; hyperalgesia; pain; Or exaggerated sensitivity; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; type I and type II combined local pain syndrome; joint pain; sports injury pain; infection such as HIV, polio Pain syndrome and pain associated with postherpetic neuralgia; Phantom limb pain; labor pains; Cancer pain; Post-chemotherapy pain; Post-stroke pain; Neuralgia; Nausea and vomiting; Conditions associated with visceral pain, migraine, and angina; bladder incontinence, such as urge urinary incontinence; drug resistance or withdrawal from drugs; sleep disorders; sleep apnea; Cholepsy; insomnia; sleep-related complications; jet lag syndrome; and combined derepression-dementia-Parkinsonism-neurodegenerative disorders including taxonomic entities such as muscle atrophy; It may be responsible for a number of biological functions, including but not limited to pallido-ponto-niger degeneration, epilepsy, and convulsive disorders.

  Experiments have shown that central administration of ligand orexin-A (described in more detail below) stimulated food intake in freely fed rats for 4 hours. This increase was approximately 4 times that of control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite. Therefore, orexin-A receptor antagonists may be useful in the treatment of obesity and diabetes. See Cell, 1998, 92, 573-585.

  There is a significant incidence of obesity in the westernized society. According to the definition of WHO, an average of 35% of subjects in 39 studies were overweight and another 22% were clinically obese. It is estimated that 5.7% of total health care in the United States is the result of obesity. About 85% of type 2 diabetes is obese, and diet and exercise are valuable in all obese people. The incidence of diabetes diagnosed in Western countries is typically 5%, and it is estimated that an equal number has not been diagnosed. The incidence of both diseases is rising, indicating inadequate current treatment that may either be ineffective, including cardiovascular effects, or may be at risk of toxicity. Treatment of diabetes with sulfonylureas or insulin can result in hypoglycemia, whereas metformin produces GI side effects. There is no drug treatment for the disease that has been shown to reduce the long-term complications of type 2 diabetes. Insulin sensitizers may be useful for many diabetics but do not have an anti-obesity effect.

  Rat sleep / electroencephalography studies also show a dose-related increase in arousal when central administration of orexin-A, an orexin receptor agonist, is administered at the beginning of normal sleep phase, paradoxical sleep and slow wave sleep It shows that the sacrifice of a decrease in 2 is greatly paid. Therefore, orexin-A receptor antagonists may be useful in the treatment of sleep disorders, including insomnia.

  WO 03/002561 discloses N-aroyl cyclic amine derivatives as orexin antagonists. Compounds disclosed in WO 03/002561 include piperidine derivatives substituted at the 2-position with a bicyclic heteroarylmethyl group. We have surprisingly found that some piperidine derivatives substituted at the 2-position with an imidazopyridazinylmethyl group include, for example, high oral bioavailability compared to conventional compounds. It has now been unexpectedly found to significantly increase solubility in physiologically relevant media with other beneficial properties. Due to these properties, these imidazopyridazinylmethyl-substituted piperidine derivatives become obese, including obesity, sleep disorders, anxiety, depression, schizophrenia observed in patients with type 2 (non-insulin dependent) diabetes It has become very attractive as a pharmaceutical agent that may be useful in the prevention or treatment of drug dependence, or compulsive behavior. In addition, these compounds may be useful in the treatment of stroke, in particular ischemic or hemorrhagic stroke, and / or in blocking emetic responses, ie in the treatment of nausea and vomiting.

（ここで、Ａｒは、式：

からなる群から選択され；
Ｒ_１が、（Ｃ_１−４）アルキル、ハロ、ハロ（Ｃ_１−４）アルキル、（Ｃ_１−４）アルコキシ、ハロ（Ｃ_１−４）アルコキシ、（Ｃ_１−４）アルキル−Ｏ−（Ｃ_１−４）アルキル、ＣＮ、ＮＲ^５Ｒ^６であり、式中、Ｒ^５は、Ｈまたは（Ｃ_１−４）アルキルであり、かつＲ^６は、Ｈまたは（Ｃ_１−４）アルキルであり；
Ｒ_２が、（Ｃ_１−４）アルキル、ハロ、ハロ（Ｃ_１−４）アルキル、（Ｃ_１−４）アルコキシ、ハロ（Ｃ_１−４）アルコキシ、（Ｃ_１−４）アルキル−Ｏ−（Ｃ_１−４）アルキル、ＣＮ、ＮＲ^７Ｒ^８であり、式中、Ｒ^７は、Ｈまたは（Ｃ_１−４）−アルキルであり、かつＲ^８はＨまたは（Ｃ_１−４）−アルキルであり；
Ｒ_３が、（Ｃ_１−４）アルキル、ハロ、ハロ（Ｃ_１−４）アルキル、（Ｃ_１−４）アルコキシ、ハロ（Ｃ_１−４）アルコキシ、（Ｃ_１−４）アルキル− Ｏ −（Ｃ_１−４）アルキル、ＣＮ、ＮＲ^９Ｒ^１０であり、式中、Ｒ^９は、Ｈまたは（Ｃ_１−４）−アルキルであり、かつＲ^１０は、Ｈまたは（Ｃ_１−４）−アルキルであり；
ｎが、０または１であり；
ｐが、０または１であり；かつ
ｑが、０または１であり；
但し、ｐおよびｑが両方とも０ではないという条件付きである。）
の化合物またはその医薬として許容し得る塩を提供する。 Accordingly, the present invention provides a compound of formula (I)

(Where Ar is the formula:

Selected from the group consisting of:
R ₁ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁵ R ⁶ , wherein R ⁵ is H or (C _1-4 ) alkyl, and R ⁶ is H or (C _1-4 ) alkyl. Is;
R ₂ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁷ R ⁸ , wherein R ⁷ is H or (C _1-4 ) -alkyl, and R ⁸ is H or (C _1-4 ) — Is alkyl;
R ₃ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O −. (C _1-4 ) alkyl, CN, NR ⁹ R ¹⁰ , wherein R ⁹ is H or (C _1-4 ) -alkyl, and R ¹⁰ is H or (C _1-4 ). -Alkyl;
n is 0 or 1;
p is 0 or 1; and q is 0 or 1;
However, there is a condition that both p and q are not 0. )
Or a pharmaceutically acceptable salt thereof.

  In one embodiment, Ar is a group of formula (II).

  In another embodiment, Ar is a group of formula (III).

  In one embodiment, Ar is a group of formula (II) and n is 0.

In another embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 0, and R ₂ is methyl.

In one embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, and one of R ₂ and R ₃ is halo; And the others are (C _1-4 ) -alkyl.

In one embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) -alkyl, and R ₃ is halo.

In another embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is methyl, and R ₃ is chloro.

In one embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is halo, and R ₃ is (C _{1- 4} ) -alkyl.

In another embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is chloro, and R ₃ is methyl.

  In one embodiment, Ar is a group of formula (III) and n is 0.

In another embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 0, and R ₂ is methyl.

In one embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1 and one of R ₂ and R ₃ is halo; And the others are (C _1-4 ) -alkyl.

In one embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) -alkyl, and R ₃ is halo.

In another embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is methyl and R ₃ is chloro.

In one embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is halo, and R ₃ is (C _1-4 ) -Alkyl.

In another embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is chloro and R ₃ is methyl.

Examples of compounds of the present invention include:
6-chloro-8-methyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2-piperidinyl} methyl) imidazo [1 , 2-b] pyridazine; and 6-chloro-7-methyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2 -Piperidinyl} methyl) imidazo [1,2-b] pyridazine.

When the compound contains a (C _1-4 ) alkyl group, whether alone, to form a larger group, for example a (C _1-4 ) alkoxy moiety, the alkyl group may be linear, branched, or cyclic Or a combination thereof. Examples of (C _1-4 ) alkyl are methyl or ethyl. An example of (C _1-4 ) alkoxy is methyloxy.

Examples of halo (C _1-4 ) alkyl include trifluoromethyl (ie, —CF ₃ ).

Examples of (C _1-4 ) alkoxy include methyloxy and ethyloxy.

Examples of halo (C _1-4 ) alkoxy include trifluoromethyloxy (ie, —OCF ₃ ).

Halogen or “halo” (eg when used in halo (C _1-4 ) alkyl) means fluoro, chloro, bromo, or iodo.

  It is to be understood that the invention extends to all combinations of groups and substituents set forth hereinabove in detail.

  The compound of formula (I) is the S enantiomer. When additional chiral centers are present in the compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. Different isomeric forms may be separated or resolved from one another by conventional methods, or any given isomer may be obtained by conventional synthetic methods, or by stereospecific or asymmetric synthesis. . The invention also extends to any tautomeric form or mixtures thereof.

  It will be understood that the present invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and these are within the scope of the present invention.

  Particular compounds according to the invention include those described in the examples and pharmaceutically acceptable derivatives thereof.

  As used herein, “pharmaceutically acceptable derivative” includes a compound of formula (I) or an active metabolite or residue thereof (directly or indirectly) upon administration to a recipient. And) any pharmaceutically acceptable salt, ester, or salt of such an ester of the compound of formula (I) that can be provided.

  It will be appreciated that for use in medicine, salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include Berge, Bigley and Monkhouse J. et al. Pharm. Sci (1977) 66, p. 1-19 are included. Such pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid. Examples include acid addition salts formed using acids, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalate or formate, may be used, for example, in the isolation of compounds of formula (I) and are included within the scope of the present invention. Also included within the scope of the invention are solvates and hydrates of the compounds of formula (I).

  Certain compounds of formula (I) may form acid addition salts with one or more equivalent acids. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

  The compounds of formula (I) may be prepared in crystalline or amorphous form, and in the case of crystals, optionally solvated, for example as hydrates. The present invention includes within its scope compounds that contain a stoichiometric solvate (eg, hydrate) and a variable amount of solvent (eg, water).

The present invention also includes isotopically-labelled compounds that are identical to those of formula (I) and those listed below, with the exception of what is the most universally recognized atomic mass or mass number in nature. The fact is that one or more atoms are replaced by atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ I, or ¹²⁵ I Isotopes.

Compounds of the present invention and pharmaceutically acceptable salts of such compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the invention, for example those into which radioactive isotopes such as ³ H or ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritium labeled isotopes, ie ³ H, and carbon-14 isotopes, ie ¹⁴ C, are particularly preferred for ease of preparation and detectability. ^{The 11} C and ¹⁸ F isotopes are particularly useful in PET (Positron Emission Tomography).

  Since the compounds of formula (I) are intended for use in pharmaceutical compositions, they are in substantially pure form, such as at least 60% pure, more suitably at least 75% pure, preferably at least 85%, in particular at least It will be readily appreciated that each is suitably provided in 98% pure form (% refers to weight on a weight basis). Impure preparations of the compounds may be used to prepare more pure forms for use in pharmaceutical compositions.

  According to a further aspect of the invention, there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following scheme details examples of synthetic routes to the compounds of the present invention. In the scheme below, the reactive group is protected using a protecting group and can be deprotected according to well-established techniques.

Scheme According to a further feature of the present invention, there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following is an example of a synthetic scheme that may be used to synthesize the compounds of the present invention.

    It will be appreciated by those skilled in the art that certain compounds of the present invention can be converted to other compounds of the present invention according to standard chemical methods.

  Starting materials for use in the scheme are commercially available, known in the literature, or can be prepared by known methods.

  The compounds of formula (I) may be prepared singly or as a compound library comprising at least 2, for example 5 to 1000, preferably 10 to 100, compounds of formula (I). Compound libraries may be prepared by procedures known to those skilled in the art by a combined “branch and mix” approach or by multiple parallel synthesis using either solution phase or solid phase chemistry.

  Thus, according to a further aspect of the present invention, there is provided a compound library comprising at least two compounds of formula (I) or pharmaceutically acceptable derivatives thereof.

  Pharmaceutically acceptable salts may be prepared conventionally by reaction with a suitable acid or acid derivative.

  The present invention provides compounds of formula (I) and pharmaceutically acceptable derivatives thereof for use in human or veterinary medicine.

  Compounds of formula (I) and pharmaceutically acceptable derivatives thereof are obese, schizophrenia, including obesity observed in type 2 (non-insulin dependent) diabetic patients where an antagonist of the human orexin receptor is required , Anxiety, depression, obsessive compulsive disorder, drug dependence, and / or primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780. 59), sleep abnormalities such as circadian rhythm sleep disorders (307.45), and sleep abnormalities not specified otherwise (307.47); sleep-related complications such as nightmare disorders (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.46), and other unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and Sleep disorders associated with another mental disorder, such as hypersomnia associated with another mental disorder (307.44); sleep disorders with general medical conditions; and insomnia, hypersomnia, sleep Useful in the treatment of diseases or disorders such as substance-induced sleep disorders, including concomitant and mixed subtypes, sleep disorders selected from the group consisting of sleep apnea and jet lag syndrome (for the diseases listed) The numbers in parentheses after that refer to the classification codes in DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition, published by the American Psychiatric Association, where the various subtypes mentioned in this specification. Considered as part of the present invention).

  In addition, the compounds of formula (I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or hemorrhagic, and / or for blocking emetic responses, ie nausea and vomiting.

  The invention also provides a method of treating or preventing a disease or disorder for which an antagonist of a human orexin receptor is required, eg, the above-mentioned diseases and disorders, which requires treating or preventing the disease or disorder. Also provided is a method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

  The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of diseases or disorders in which an antagonist of human orexin receptor is required, eg, the aforementioned diseases and disorders Derivatives are also provided.

  The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of diseases or disorders in which an antagonist of human orexin receptor is required, eg, the above diseases and disorders. The use of possible derivatives is also provided.

  The present invention also provides obesity, including obesity observed in type 2 (insulin-independent) diabetic patients, where human orexin receptor antagonists are needed, schizophrenia, anxiety, depression, obsessive compulsive disorder, Drug dependence and / or primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory related sleep disorder (780.59), circadian rhythm sleep disorder (307. 45), and sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307) .46), and other unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder (307.4) ) Sleep disorders associated with other mental disorders; sleep disorders due to general medical conditions; and substance induction including subtypes of insomnia, hypersomnia, parasomnia, and mixed A compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment or prevention of a disease or disorder such as sleep disorder selected from the group consisting of sexual sleep disorder, sleep apnea and jet lag syndrome (The numbers in parentheses after the listed diseases refer to the classification code in DSM-IV: Diagnostic and Statistical Manual of Menordors, 4th edition, published by American Psychiatric Association. Various subties described The disorder is considered as part of the present invention.).

  For use in therapy, the compounds of the present invention are usually administered as a pharmaceutical composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier.

  The compounds of formula (I) and their pharmaceutically acceptable derivatives can be obtained by any convenient method, for example oral, parenteral, buccal, sublingual, nasal, rectal or transdermal. It may be administered by administration and by a suitable pharmaceutical composition accordingly.

  The active compound of formula (I) and pharmaceutically acceptable derivatives thereof as liquid or solid when given orally, for example as syrups, suspensions, emulsions, tablets, capsules or lozenges Can be formulated.

  Liquid formulations will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier, for example, an aqueous solvent such as water, ethanol, or glycerin, or a non-aqueous solvent such as polyethylene glycol or oil. The formulation may also include suspending agents, preservatives, seasonings, and / or coloring agents.

  A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier conventionally used to prepare solid formulations such as magnesium stearate, starch, lactose, sucrose, and cellulose.

  Compositions in the form of capsules can be prepared using conventional encapsulation means, for example, pellets containing the active ingredient are prepared using standard carriers and then filled into hard gelatin capsules. Alternatively, the dispersion or suspension may be prepared using any suitable pharmaceutical carrier such as aqueous gum, cellulose, silicate, or oil and the dispersion or suspension then soft gelatin Can be filled into capsules.

  Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil such as polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil. Alternatively, the solution can be administered immediately after lyophilization and immediately after reconstitution with a suitable solvent.

  Compositions for nasal administration may be conveniently formulated as aerosols, nasal drops, gels, and powders. Aerosol formulations typically include a solution of the active ingredient or a fine suspension of particles in a pharmaceutically acceptable aqueous or non-aqueous solvent and take the form of a cartridge or refill for use with a spray device. It is usually presented in a sterilized single dose or multiple doses in a sealed container capable. Alternatively, the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a dose setting valve. Where the dosage form comprises an aerosol distributor, it will contain a propellant which may be a compressed gas, for example air or an organic propellant such as fluorochlorohydrocarbon or hydrofluorocarbon. The aerosol dosage form can also take the form of a pump sprayer.

  Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastels where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth or gelatin, and glycerin.

  Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

  Compositions suitable for transdermal administration include ointments, gels, and patches.

  Preferably, the composition is in unit dose form such as a tablet, capsule or ampoule.

  The dose of the compound of formula (I) or a pharmaceutically acceptable derivative thereof used in the treatment or prevention of the above disorders or diseases will depend on the particular disorder or disease being treated, the weight of the subject, and other similar factors And will vary in the usual way. However, as a general rule, an appropriate unit dose is administered at least twice a day, for example twice or three times a day, so that the total daily dosage is in the range of about 0.01-100 mg / kg. Such treatment may extend over weeks or months. In the case of pharmaceutically acceptable derivatives, the above numbers are calculated as the parent compound of formula (I).

  No toxicological effect is shown / expected when the compound of formula (I) is administered in the above dosage range.

Human orexin-A has the following amino acid sequence:

  Orexin-A can be employed in screening procedures for compounds that inhibit the activation of orexin-1 receptor ligands.

  In general, such screening procedures involve providing appropriate cells that express orexin-1 receptor on the cell surface. Such cells include cells derived from mammals, yeast, Drosophila, or E. coli. In particular, a polynucleotide encoding an orexin-1 receptor is used to transfect cells to express the receptor. The expressed receptor is then contacted with the test compound and the orexin-1 receptor ligand and observed for inhibition of functional response as appropriate. One such screening procedure involves the use of a melanophore transfected to express the orexin-1 receptor as described in WO 92/01810.

  Another screening procedure involves introducing RNA encoding the orexin-1 receptor into Xenopus oocytes to transiently express the receptor. Receptor oocytes are then contacted with a receptor ligand and a test compound, followed by detection of signal inhibition when screening for compounds that are believed to inhibit receptor activation by the ligand.

  Another method involves screening for compounds that inhibit receptor activation by determining inhibition of binding of labeled orexin-1 receptor ligand to cells having orexin-1 receptor on the cell surface. Include. The method comprises transfecting a eukaryotic cell with orexin-1 receptor such that the cell expresses the receptor on its surface, and in the presence of a labeled form of orexin-1 receptor ligand, Contacting the cell membrane preparation with the compound. The ligand may include a radioactive label. The amount of labeled ligand bound to the receptor is determined, for example, by measuring radioactivity.

  Yet another screening technique involves high throughput of test compounds that inhibit the movement of intracellular calcium ions or other ions by suitably affecting the interaction between the orexin-1 receptor ligand and the orexin-1 receptor. Includes the use of FLIPR instruments for screening.

  Unless the context requires otherwise, throughout the following specification and claims, variations such as the word “comprising” and “including” and “comprising” are stated integers or classes or integers It will be understood that other integers or classes or groups of integers or classes are not excluded.

  All publications, including but not limited to patents and patent applications cited herein, are specifically and individually indicated to be incorporated by reference as if each individual publication was fully presented. As if incorporated herein by reference.

  The following examples illustrate the preparation of pharmacologically active compounds of the invention. Descriptions 1-6 describe the preparation of intermediates leading to the compounds of the present invention.

Examples The invention is illustrated by the examples described below.

  In the procedure below, a citation to the description is typically provided after each starting material. This is provided merely as an aid to those skilled in the art. The starting material may not necessarily have been prepared from the cited batch.

  All compounds described in the examples described hereinafter were prepared as a first step from stereochemically pure methyl 5-oxo-L-prophosphate or ethyl 5-oxo-D-prophosphate. Yes. The stereochemistry of the compounds of the description and examples is given under the assumption that the pure configuration of 5-oxo-prolinate is maintained.

  The compounds are named using ACD / Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). Proton magnetic resonance (NMR) spectra were recorded either on a Varian instrument at 300, 400, or 500 MHz, or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are reported in ppm (δ) using a residual solvent line as an internal standard. The splitting pattern is designed as s, single line; d, double line; t, triple line; q, quadruple line; m, multiple line; b, wide.

  NMR spectra were recorded at a temperature in the range of 25-90 ° C. If more than one conformer is detected, the chemical shift for the highest amount of conformer is reported.

R _t (HPLC): HPLC analysis indicated by x min was performed on an Agilent 1100 series instrument using a Luna 3u C18 (2) 100A (50 × 2.0 mm) column (mobile phase: 100% [water + 0 .05% TFA] to 95% [acetonitrile + 0.05% TFA], 8 minutes, flow rate = 1 mL / min, detection wavelength 220 nm).

Mass spectra (MS) are coupled in 4II triple quadrupole Mass Spectrometer (Micromass UK) operating in ES (+) ionization mode and ES (−) ionization mode or in Agilent MSD 1100 Mass Spectrometer, or with HPLC instrument Agilent 1100 Series. Obtained on an Agilent LC / MSD 1100 Mass Spectrometer operating in the ES (+) ionization mode and ES (−) ionization mode. [LC / MS-ES (+): analysis performed in Supelcosil ABZ + Plus (33 × 4.6 mm, 3 μm) (mobile phase: 100% [water + 0.1% HCO ₂ H] for 1 minute, then 100 % [Water + 0.1% HCO ₂ H] to 5% [water + 0.1% HCO ₂ H] and 95% [CH ₃ CN] for 5 minutes and finally under these conditions for 2 minutes); T = 40 ° C; flow rate = 1 mL / min; LC / MS-ES (-): Supelcosil ABZ + Plus (33 × 4.6 mm, 3 μm) analysis (mobile phase: 100% [water + 0.05% NH ₃ ]) 1 minute, then 100% [water + 0.05% NH ₃ ] to 5% [water + 0.05% NH ₃ ] and 95% [CH ₃ CN] for 5 minutes, and finally 2 minutes under these conditions); T = 40 ° C .; flow rate = 1 m / Min].

  In the mass spectrum, only one peak in the molecular ion cluster is reported.

  For reactions involving microwave irradiation, Personal Chemistry Emrys ™ Optimizer was used.

  Flash silica gel chromatography was performed on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or through a Varian Mega Be-Si pre-filled cartridge or pre-filled Biotage silica cartridge.

  The SPE-SCX cartridge is an ion exchange solid phase extraction column supplied by Varian. The eluent used with the SPE-SCX cartridge is methanol followed by 2N ammonia solution in methanol.

  In some preparations, purification was performed using either a Biotage manual flash chromatography (Flash +) or automated flash chromatography (Horizon) system. All these instruments work with Biotage Silica cartridges.

  The SPE-Si cartridge is a silica solid phase extraction column supplied by Varian.

The table below lists the abbreviations used in the text:

２５０ｍＬの丸底フラスコに、（（２Ｓ）−１−｛［（１，１−ジメチルエチル）オキシ］カルボニル｝−２−ピペリジニル）酢酸（１．００ｇ、４．１１ｍｍｏｌ）、ＤＭＦ（２５ｍＬ）、ＤＩＰＥＡ（２．１５ｍＬ、１２．３３ｍｍｏｌ）、およびＴＢＴＵ（１．９８ｇ、６．１７ｍｍｏｌ）を加えた。混合物を室温で２０分間撹拌し、褐色を形成した。この時点の後、ＭｅＯＨ（０．２５ｍＬ、６．１７ｍｍｏｌ）を添加し、得られた溶液を室温で３０分間撹拌した。次に、これを、鹹水を含む分離漏斗に移し、ＥｔＯＡｃ（２０ｍＬ×２）で抽出し、組み合わせた有機層を水／氷（５×２０ｍＬ）で洗浄した。有機層を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。得られた粗物をカラムクロマトグラフィー（Ｂｉｏｔａｇｅ ＳＰ１， Ｃｙ／ＥｔＯＡｃ１００／０〜８５／１５）によって精製した。 回収した画分によって、表題化合物（１．０１ｇ、３．９２ｍｍｏｌ、９５％収率）が無色の油として与えられた。^１Ｈ−ＮＭＲ （５００ ＭＨｚ， ＣＤＣｌ_３） δ（ｐｐｍ）： ４．６７ − ４．７５ （ｍ， １ Ｈ）， ３．９６ − ４．０５ （ｍ， １ Ｈ）， ３．６７ （ｓ， ３ Ｈ）， ２．７９ （ｔ， １ Ｈ）， ２．６１ （ｄｄ， １ Ｈ）， ２．５３ （ｄｄ， １ Ｈ）， １．６０ − １．７０ （ｍ， ６ Ｈ）， １．４６ （ｓ， ９ Ｈ）。 Description Description 1: (2S) -2- [2- (Methyloxy) -2-oxoethyl] -1-piperidinecarboxylic acid 1,1-dimethylethyl (D1)

A 250 mL round bottom flask was charged with ((2S) -1-{[(1,1-dimethylethyl) oxy] carbonyl} -2-piperidinyl) acetic acid (1.00 g, 4.11 mmol), DMF (25 mL), DIPEA. (2.15 mL, 12.33 mmol), and TBTU (1.98 g, 6.17 mmol) were added. The mixture was stirred at room temperature for 20 minutes to form a brown color. After this point, MeOH (0.25 mL, 6.17 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes. This was then transferred to a separatory funnel containing brine, extracted with EtOAc (20 mL × 2), and the combined organic layers were washed with water / ice (5 × 20 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting crude was purified by column chromatography (Biotage SP1, Cy / EtOAc 100/0 to 85/15). The collected fractions afforded the title compound (1.01 g, 3.92 mmol, 95% yield) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.67 to 4.75 (m, 1 H), 3.96 to 4.05 (m, 1 H), 3.67 (s, 3 H), 2.79 (t, 1 H), 2.61 (dd, 1 H), 2.53 (dd, 1 H), 1.60-1.70 (m, 6 H), 46 (s, 9 H).

室温における窒素下の５００ｍＬの丸底フラスコに、Ｄ１（１１．１ｇ、４３．１ｍｍｏｌ）をＴＨＦ（１００ｍＬ）に溶解し、淡黄色の溶液を与えた。この溶液を−７８℃に冷却し、テッベ試薬（トルエンにおける０．５Ｍ溶液１０４ｍＬ、５１．８ｍｍｏｌ）を滴下して添加した。粘稠な混合物をさらなる無水トルエン７０ｍＬで希釈した。得られた褐色−橙色混合物をこの温度で３０分間撹拌した後、室温までゆっくりと加温し、撹拌下で２時間放置しておいた。反応混合物を滴下漏斗へと負荷した後、０℃に冷却したＮａＯＨの１Ｍ水溶液を最大で４００ｍＬ含む２Ｌの丸底フラスコに滴下して添加した。クエンチの終了時に、得られた灰色の懸濁液をＥｔＯＡｃ（２５０ｍＬ）で希釈し、一晩撹拌しておいた（機械的撹拌）。次に、得られた黄色の懸濁液を、Ｇｏｏｃｈ漏斗（Ｓｔｅｒｉｍａｔを用いる）で濾過し：塩をＥｔＯＡｃ（最大５００ｍＬ）で洗浄した。次に、相を分離し、有機層を鹹水（２×５００ｍＬ）で洗浄した。組み合わせた有機相を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮して、濃橙色の油を与えた。この材料を最大５００ｍＬのＥｔ_２Ｏで希釈し：いくらかの塩が沈殿したので、得られた懸濁液をＧｏｏｃｈ漏斗（Ｓｔｅｒｉｍａｔを用いる）で濾過した。濾液を真空下で濃縮して１２．４ｇの粗（２Ｓ）−２−［２−（メチルオキシ）−２−プロペン−１−イル］−１−ピペリジンカルボン酸１，１−ジメチルエチル１２．４ｇを橙色−褐色の油として与えた。（回収された全体量が、理論値より高かったので）材料はいくらかの残余塩を含んでいた。次の反応において材料をさらに精製せずに用い、８９重量％で純粋であると想定した。室温における窒素下の１Ｌ丸底フラスコに、（２Ｓ）−２−［２−（メチルオキシ）−２−プロペン−１−イル］−１−ピペリジンカルボン酸１，１−ジメチルエチル（１２．４ｇ、４３．１ｍｍｏｌ）をＴＨＦ（１２５ｍＬ）および水（３５ｍＬ）に溶解して、淡黄色の溶液を与えた。次に、ＮＢＳ（７．６７ｇ、４３．１ｍｍｏｌ）を添加して、最大１００ｍＬのＴＨＦに溶解した。得られた灰色の混合物を室温で１時間撹拌した。次に、５０ｍＬのＴＨＦに溶解した追加的なＮＢＳ（０．２等量、１．５ｇ）を添加し、反応混合物を室温で１時間撹拌した。混合物を真空下で濃縮して、ＴＨＦを除去した後、ＥｔＯＡｃ（最大５００ｍＬ）および水（２００ｍＬ）で希釈した。相を分離し、水性層をＥｔＯＡｃ（２５０ｍＬ）で溶媒相抽出した。組み合わせた有機層を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮して、１７．８ｇの褐色の油を与えた。この材料をフラッシュクロマトグラフィー（Ｂｉｏｔａｇｅ ７５Ｌ、Ｃｙ−ＥｔＯＡｃ、１００−０〜９０−１０）によって精製して、表題化合物（６．０ｇ、１８．７ｍｍｏｌ、Ｄ１からの４３％収率、２工程）をわずかに黄色の油として与え、静置して凝固させた。ＵＰＬＣ： ｒｔ＝０．７９， 観察したピーク： ３４４ ［Ｍ＋Ｎａ， １００％］， ３４２ ［Ｍ＋Ｎａ， １００％］， ２６６ ［Ｍ−ｔＢｕ，１００％］および２６４ ［Ｍ−ｔＢｕ，１００％］． ^１Ｈ ＮＭＲ （５００ ＭＨｚ， ＣＤＣｌ_３） δ（ｐｐｍ）： ４．７２ − ４．７９ （ｍ， １ Ｈ）， ３．９１ − ４．１０ （ｍ， ３ Ｈ）， ２．７７ − ２．９７ （ｍ， ３ Ｈ）， １．４９ − １．７５ （ｍ， ６ Ｈ）， １．４６ （ｓ， ９ Ｈ）。 Description 2: 1,2-dimethylethyl (D2) (2S) -2- (3-bromo-2-oxopropyl) -1-piperidinecarboxylic acid

In a 500 mL round bottom flask under nitrogen at room temperature, D1 (11.1 g, 43.1 mmol) was dissolved in THF (100 mL) to give a pale yellow solution. The solution was cooled to −78 ° C. and Tebbe reagent (104 mL of 0.5 M solution in toluene, 51.8 mmol) was added dropwise. The viscous mixture was diluted with an additional 70 mL of anhydrous toluene. The resulting brown-orange mixture was stirred at this temperature for 30 minutes, then slowly warmed to room temperature and left under stirring for 2 hours. After loading the reaction mixture into a dropping funnel, it was added dropwise to a 2 L round bottom flask containing up to 400 mL of 1 M NaOH aqueous solution cooled to 0 ° C. At the end of the quench, the resulting gray suspension was diluted with EtOAc (250 mL) and allowed to stir overnight (mechanical stirring). The resulting yellow suspension was then filtered through a Gooch funnel (using Sterimat): the salt was washed with EtOAc (500 mL maximum). The phases were then separated and the organic layer was washed with brine (2 × 500 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated to give a dark orange oil. This material was diluted with a maximum of 500 mL Et ₂ O: some salt precipitated, and the resulting suspension was filtered through a Gooch funnel (using Sterimat). The filtrate was concentrated in vacuo to 12.4 g of 12.4 g of crude (2S) -2- [2- (methyloxy) -2-propen-1-yl] -1-piperidinecarboxylic acid 1,1-dimethylethyl. Was given as an orange-brown oil. The material contained some residual salt (since the total amount recovered was higher than the theoretical value). The material was used in the next reaction without further purification and assumed 89% pure by weight. To a 1 L round bottom flask under nitrogen at room temperature was added 1,2-dimethylethyl (12.4 g, (2S) -2- [2- (methyloxy) -2-propen-1-yl] -1-piperidinecarboxylate. 43.1 mmol) was dissolved in THF (125 mL) and water (35 mL) to give a pale yellow solution. NBS (7.67 g, 43.1 mmol) was then added and dissolved in a maximum of 100 mL of THF. The resulting gray mixture was stirred at room temperature for 1 hour. Then additional NBS (0.2 eq, 1.5 g) dissolved in 50 mL THF was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to remove THF, then diluted with EtOAc (500 mL max) and water (200 mL). The phases were separated and the aqueous layer was solvent phase extracted with EtOAc (250 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give 17.8 g of a brown oil. This material was purified by flash chromatography (Biotage 75L, Cy-EtOAc, 100-0 to 90-10) to give the title compound (6.0 g, 18.7 mmol, 43% yield from D1, 2 steps). It was given as a slightly yellow oil and allowed to solidify on standing. UPLC: rt = 0.79, observed peaks: 344 [M + Na, 100%], 342 [M + Na, 100%], 266 [M-tBu, 100%] and 264 [M-tBu, 100%]. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.72 to 4.79 (m, 1 H), 3.91 to 4.10 (m, 3 H), 2.77 to 2.97 (M, 3H), 1.49-1.75 (m, 6H), 1.46 (s, 9H).

２０ｍＬのマイクロ波フラスコに、３，６−ジクロロ−４−メチルピリダジン（２．３０ｇ、１４．１１ｍｍｏｌ）およびメタノールにおけるＮＨ_３の７Ｍ溶液（１０．０８ｍＬ、７０．６ｍｍｏｌ）を加え、マイクロ波照射の下で１４０℃で４時間加熱した。この時点の後、暗褐色の溶液を蒸発させ、シリカゲル上でカラム処理した（フラッシュマスター、ＤＣＭ／ＭｅＯＨ形１００／０〜８０／２０）。回収した画分によって、６−クロロ−５−メチル−３−ピリダジンアミンおよび６−クロロ−４−メチル−３−ピリダジンアミンの２／１の混合物（０．９１ｇ、６．３３ｍｍｏｌ、４５％）が与えられた。この材料をＥｔＯＡｃから再結晶させ、第一の試行から６−クロロ−４−メチル−３−ピリダジンアミン（Ｄ４）（０．１３６ｇ、０．９５ｍｍｏｌ）を得た。ＨＰＬＣ（階段状）： ｒｔ＝１．２１分。ＭＳ： （ＥＳ／＋） ｍ／ｚ： ２８７ ［二量体＋１， １００％］および２８９ ［二量体＋１， ６６％］。Ｃ_５Ｈ_６ＣｌＮ_３は１４４を要する。ＵＰＬＣ： ｒｔ＝０．３３， 観察されるピーク： １４４ （Ｍ＋１， １００％）および１４６ （Ｍ＋１， ３３％）。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δｐｐｍ： ６．７４ （ｓ， １ Ｈ） ６．４７ （ｓ， ２ Ｈ） ２．１８ （ｓ， ３ Ｈ）。母液を取り、ＥｔＯＡｃでさらに３回再結晶して、６−クロロ−５−メチル−３−ピリダジンアミン（０．１３６ ｇ， ０．９５ ｍｍｏｌ）を与えた。ＨＰＬＣ（階段状）： ｒｔ＝０．７４分。ＭＳ： （ＥＳ／＋） ｍ／ｚ： １６６ ［Ｍ＋Ｎａ， １００％］および１６８ ［Ｍ＋Ｎａ， ３３％］。Ｃ_５Ｈ_６ＣｌＮ_３は１４４を要する。ＵＰＬＣ： ｒｔ＝０．３２， 観察されるピーク： １４４ （Ｍ＋１， １００％）および１４６ （Ｍ＋１， ３３％）。^１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δｐｐｍ： ７．３０ （ｓ， １ Ｈ） ６．４４ （ｓ， ２ Ｈ） ２．０８ （ｓ， ３ Ｈ）。 Description 3 and 4: 6-chloro-4-methyl-3-pyridazineamine (D3) and 6-chloro-5-methyl-3-pyridazineamine (D4):

To a 20 mL microwave flask was added 3,6-dichloro-4-methylpyridazine (2.30 g, 14.11 mmol) and a 7 M solution of NH ₃ in methanol (10.08 mL, 70.6 mmol). Under heating at 140 ° C. for 4 hours. After this point, the dark brown solution was evaporated and columned on silica gel (flash master, DCM / MeOH form 100 / 0-80 / 20). Depending on the fractions collected, a 2/1 mixture of 6-chloro-5-methyl-3-pyridazineamine and 6-chloro-4-methyl-3-pyridazineamine (0.91 g, 6.33 mmol, 45%) Given the. This material was recrystallized from EtOAc to give 6-chloro-4-methyl-3-pyridazineamine (D4) (0.136 g, 0.95 mmol) from the first attempt. HPLC (stepwise): rt = 1.21 min. MS: (ES / +) m / z: 287 [Dimer + 1, 100%] and 289 [Dimer + 1, 66%]. C ₅ H ₆ ClN ₃ requires 144. UPLC: rt = 0.33, observed peaks: 144 (M + 1, 100%) and 146 (M + 1, 33%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 6.74 (s, 1 H) 6.47 (s, 2 H) 2.18 (s, 3 H). The mother liquor was taken and recrystallized three more times with EtOAc to give 6-chloro-5-methyl-3-pyridazineamine (0.136 g, 0.95 mmol). HPLC (stepwise): rt = 0.74 min. MS: (ES / +) m / z: 166 [M + Na, 100%] and 168 [M + Na, 33%]. C ₅ H ₆ ClN ₃ requires 144. UPLC: rt = 0.32, observed peaks: 144 (M + 1, 100%) and 146 (M + 1, 33%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.30 (s, 1 H) 6.44 (s, 2 H) 2.08 (s, 3 H).

ＤＭＦ（２ｍＬ）における（２Ｓ）−２−（３−ブロモ−２−オキソプロピル）−１−ピペリジンカルボン酸１，１−ジメチルエチルＤ２（０．２２３ｇ、０．７０ｍｍｏｌ）の溶液に、６−クロロ−４−メチル−３−ピリダジンアミン（Ｄ３）（０．１００ｇ、０．７０ｍｍｏｌ）を添加し、混合物を８０℃で２時間撹拌した。反応混合物をＳＣＸカラムに負荷し、ＤＣＭおよびＭｅＯＨにおける２Ｍアンモニアで溶出した。回収した画分によって、Ｎ−Ｂｏｃ保護した化合物および脱保護した化合物の混合物を含む粗物（０．２８０ｇ）が与えられた。この混合物（０．２８０ｇ）をＤＣＭ（１ｍＬ）に溶解し、ＴＦＡ（０．５ｍＬ）を添加し、混合物を室温で２時間撹拌した。揮発性物質を真空下で除去し、残留物をＳＣＸカラムに負荷し、ＤＣＭおよびＭｅＯＨにおける２Ｍアンモニアで溶出した。回収した画分によって表題化合物（０．１５２ｇ、０．４７ｍｍｏｌ）が与えられた。ＵＰＬＣ： ｒｔ＝０．６６， 観察されたピーク： ２６５ （Ｍ＋１， １００％）および２６７ （Ｍ＋１， ３３％）． Ｃ_１３Ｈ_１７ＣｌＮ_４は２６５を要する。^１Ｈ ＮＭＲ （５００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δｐｐｍ： ８．０８ （ｓ， １ Ｈ） ７．２２ （ｓ， １ Ｈ） ２．８９ − ２．９５ （ｍ， １ Ｈ） ２．７６ − ２．８４ （ｍ， １ Ｈ） ２．６９ − ２．７２ （ｍ， ２ Ｈ） ２．５３ （ｓ， ３ Ｈ） ２．４７ − ２．５２ （ｍ， １ Ｈ） １．６５ − １．７２ （ｍ， １ Ｈ） １．５６ − １．６３ （ｍ， １ Ｈ） １．４５ − １．５２ （ｍ， １ Ｈ） １．１９ − １．３５ （ｍ， ２ Ｈ） １．０３ − １．１５ （ｍ， １ Ｈ）。 Description 5: 6-Chloro-8-methyl-2-[(2S) -2-piperidinylmethyl] imidazo [1,2-b] pyridazine (D5):

To a solution of (2S) -2- (3-bromo-2-oxopropyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl D2 (0.223 g, 0.70 mmol) in DMF (2 mL) was added 6-chloro. -4-Methyl-3-pyridazineamine (D3) (0.100 g, 0.70 mmol) was added and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was loaded onto an SCX column and eluted with 2M ammonia in DCM and MeOH. The collected fractions gave a crude (0.280 g) containing a mixture of N-Boc protected and deprotected compounds. This mixture (0.280 g) was dissolved in DCM (1 mL), TFA (0.5 mL) was added and the mixture was stirred at room temperature for 2 hours. Volatiles were removed under vacuum and the residue was loaded onto an SCX column and eluted with 2M ammonia in DCM and MeOH. The collected fractions gave the title compound (0.152 g, 0.47 mmol). UPLC: rt = 0.66, observed peaks: 265 (M + 1, 100%) and 267 (M + 1, 33%). C ₁₃ H ₁₇ ClN ₄ requires 265. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 8.08 (s, 1 H) 7.22 (s, 1 H) 2.89-2.95 (m, 1 H) 2.76 -2 .84 (m, 1 H) 2.69-2.72 (m, 2 H) 2.53 (s, 3 H) 2.47-2.52 (m, 1 H) 1.65-1.72 (M, 1 H) 1.56-1.63 (m, 1 H) 1.45-1.52 (m, 1 H) 1.19-1.35 (m, 2 H) 1.03-1 .15 (m, 1 H).

ＤＭＦ（２ｍＬ）における（２Ｓ）−２−（３−ブロモ−２−オキソプロピル）−１−ピペリジンカルボン酸１，１−ジメチルエチルＤ２（０．２２３ｇ、０．７０ｍｍｏｌ）の溶液に、６−クロロ−５−メチル−３−ピリダジンアミン（Ｄ４）（０．１００ｇ、０．７０ｍｍｏｌ）を添加し、混合物を８０℃で２時間撹拌した。反応混合物をＳＣＸカラムに負荷し、ＤＣＭおよびＭｅＯＨにおける２Ｍアンモニアで溶出した。回収した画分によって、Ｎ−Ｂｏｃ保護した化合物および脱保護した化合物の混合物を含む粗物（０．２５４ｇ）が与えられた。この混合物（０．２５４ｇ）をＤＣＭ（１ｍＬ）に溶解し、ＴＦＡ（０．５ｍＬ）を添加し、混合物を室温で２時間撹拌した。揮発性物質を真空下で除去し、残留物をＳＣＸカラムに負荷し、ＤＣＭおよびＭｅＯＨにおける２Ｍアンモニアで溶出した。回収した画分によって、表題化合物（０．１２３ｇ、０．３５ｍｍｏｌ）が与えられた。ＵＰＬＣ： ｒｔ ＝ ０．６６， 観察されたピーク： ２６５ （Ｍ＋１， １００％） ａｎｄ ２６７ （Ｍ＋１， ３３％）． Ｃ_１３Ｈ_１７ＣｌＮ_４は２６５を要する。^１Ｈ ＮＭＲ （５００ ＭＨｚ， ＤＭＳＯ−ｄ_６） δｐｐｍ： ８．０４ （ｓ， ２ Ｈ） ２．９２ （ｄ， １ Ｈ） ２．７９ − ２．８６ （ｍ， １ Ｈ） ２．６７ − ２．７４ （ｍ， ２ Ｈ） ２．４６ − ２．５３ （ｍ， １ Ｈ） ２．３５ − ２．３８ （ｍ， ３ Ｈ） １．６７ （ｄ， １ Ｈ） １．５７ （ｄ， １ Ｈ） １．４８ （ｄ， １ Ｈ） １．１８ − １．３６ （ｍ， ２ Ｈ） １．０２ − １．１７ （ｍ， １ Ｈ）。 Description 6: 6-Chloro-7-methyl-2-[(2S) -2-piperidinylmethyl] imidazo [1,2-b] pyridazine (D6):

To a solution of (2S) -2- (3-bromo-2-oxopropyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl D2 (0.223 g, 0.70 mmol) in DMF (2 mL) was added 6-chloro. -5-Methyl-3-pyridazineamine (D4) (0.100 g, 0.70 mmol) was added and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was loaded onto an SCX column and eluted with 2M ammonia in DCM and MeOH. The collected fractions gave a crude (0.254 g) containing a mixture of N-Boc protected and deprotected compounds. This mixture (0.254 g) was dissolved in DCM (1 mL), TFA (0.5 mL) was added and the mixture was stirred at room temperature for 2 hours. Volatiles were removed under vacuum and the residue was loaded onto an SCX column and eluted with 2M ammonia in DCM and MeOH. The collected fractions gave the title compound (0.123 g, 0.35 mmol). UPLC: rt = 0.66, observed peaks: 265 (M + 1, 100%) and 267 (M + 1, 33%). C ₁₃ H ₁₇ ClN ₄ requires 265. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm: 8.04 (s, 2 H) 2.92 (d, 1 H) 2.79-2.86 (m, 1 H) 2.67 -2 .74 (m, 2 H) 2.46-2.53 (m, 1 H) 2.35-2.38 (m, 3 H) 1.67 (d, 1 H) 1.57 (d, 1 H) 1.48 (d, 1 H) 1.18-1.36 (m, 2 H) 1.02-1.17 (m, 1 H).

２−メチル−５−フェニル１，３−チアゾール−４−カルボン酸（０．０２５ｇ、０．１１ｍｍｏｌ）をＤＣＭ（１ｍＬ）に溶解し、この溶液に、塩化オキサリル（０．０２２ｍＬ、０．２５ｍｍｏｌ）およびＤＭＦ（１滴）を添加した。溶液を撹拌下で３０分間放置した後、溶媒を真空下で除去し、得られた黄色の固体をＤＣＭ（１ｍＬ）に溶解し、溶液をＤＣＭ（１ｍＬ）における６−クロロ−８−メチル−２−［（２Ｓ）−２−ピペリジニルメチル］イミダゾール［１，２−ｂ］ピリダジン（Ｄ５）（０．０３０ｇ、０．１１ｍｍｏｌ）およびＴＥＡ（０．０４７ｍＬ、０．３４ｍｍｏｌ）の氷冷した溶液に滴下して添加した。混合物を撹拌下で室温で１時間放置した。ＤＣＭ（２ｍＬ）を添加し、混合物を飽和ＮａＨＣＯ_３水溶液（２ｍＬ）で洗浄し、有機相を分離し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。残留物をシリカゲル上でのクロマトグラフィーを介して精製した（Ｖａｃ Ｍａｓｔｅｒ， ＥｔＯＡｃ）。回収した画分によって表題化合物の遊離塩基が与えられた（Ｏ．０３１ｇ、０．０６ｍｍｏｌ、５０％収率）。ＵＰＬＣ： ｒｔ＝０．８２， 観察されたピーク： ４６６ （Ｍ＋１， １００％）および４６８ （Ｍ＋１， ３３％）． Ｃ_２４Ｈ_２４ＣｌＮ_５ＯＳは４６６を要する。^１Ｈ ＮＭＲ （５００ ＭＨｚ， ＤＭＳＯ−ｄ_６） ［本生成物は、配座異性体の混合物として存在する（ｃ比約６０／４０）］。遊離アミン（０．０３１ｇ、０．０７ｍｍｏｌ）をＤＣＭ（１ｍＬ）に溶解した後、ＨＣｌ（Ｅｔ_２Ｏ）における１Ｍ溶液０．１０ｍＬ、０．１００ｍｍｏｌ）を添加し、溶液を室温で３０分間撹拌した。揮発性物質を真空下で除去し、得られた固体をＥｔ２Ｏで倍散した後、濾過して、表題化合物（０．０３４ｇ、０．０６ｍｍｏｌ、８３％収率）を与えた。ＨＰＬＣ（階段状）： ｒｔ＝４．４５分。 Examples Example 1: 6-Chloro-8-methyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2-piperidinyl } Methyl) imidazo [1,2-b] pyridazine (HCl salt) (E1):

2-Methyl-5-phenyl 1,3-thiazole-4-carboxylic acid (0.025 g, 0.11 mmol) was dissolved in DCM (1 mL) and to this solution was added oxalyl chloride (0.022 mL, 0.25 mmol). And DMF (1 drop) was added. After the solution was left under stirring for 30 minutes, the solvent was removed in vacuo, the resulting yellow solid was dissolved in DCM (1 mL) and the solution was 6-chloro-8-methyl-2 in DCM (1 mL). -Ice-cooled solution of [(2S) -2-piperidinylmethyl] imidazole [1,2-b] pyridazine (D5) (0.030 g, 0.11 mmol) and TEA (0.047 mL, 0.34 mmol) Added dropwise. The mixture was left under stirring for 1 hour at room temperature. DCM (2 mL) was added and the mixture was washed with saturated aqueous NaHCO ₃ (2 mL), the organic phase was separated, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified via chromatography on silica gel (Vac Master, EtOAc). The collected fractions gave the free base of the title compound (O.031 g, 0.06 mmol, 50% yield). UPLC: rt = 0.82, observed peaks: 466 (M + 1, 100%) and 468 (M + 1, 33%). C ₂₄ H ₂₄ ClN ₅ OS requires 466. ¹ H NMR (500 MHz, DMSO-d ₆ ) [This product exists as a mixture of conformers (c ratio about 60/40)]. After free amine (0.031 g, 0.07 mmol) was dissolved in DCM (1 mL), 1M solution in HCl (Et ₂ O) 0.10 mL, 0.100 mmol) was added and the solution was stirred at room temperature for 30 min. . Volatiles were removed in vacuo and the resulting solid was triturated with Et 2 O and then filtered to give the title compound (0.034 g, 0.06 mmol, 83% yield). HPLC (stepwise): rt = 4.45 min.

２−メチル−５−フェニル−１，３−チアゾール−４−カルボン酸（０．０２５ｇ、０．１１ｍｍｏｌ）をＤＣＭ（１ｍＬ）に溶解し、この溶液に、塩化オキサリル（０．０２２ｍＬ、０．２５ｍｍｏｌ）およびＤＭＦ（１滴）を添加した。溶液を撹拌下で３０分間放置した後、溶媒を真空下で蒸発させ、得られた黄色の固体をＤＣＭ（１ｍＬ）に溶解し、溶液をＤＣＭ（１ｍＬ）における６−クロロ−７−メチル−２−［（２Ｓ）−２−ピペリジニルメチル］イミダゾ［１，２−ｂ］ピリダジン（Ｄ６）（０．０３０ｇ、０．１１３ｍｍｏｌ）およびＴＥＡ（０．０４７ｍＬ、０．３４ｍｍｏｌ）の氷冷した溶液に滴下して添加した。混合物を撹拌下で室温で１時間放置した。ＤＣＭ（２ｍＬ）を添加し、混合物を飽和ＮａＨＣＯ_３水溶液（２ｍＬ）で洗浄し、有機相を分離し、乾燥させ（Ｎａ２ＳＯ４）、濾過し、濃縮した。残留物をシリカゲル上でのクロマトグラフィーを介して精製した（Ｖａｃ Ｍａｓｔｅｒ， ＥｔＯＡｃ）。回収した画分によって、表題化合物の遊離塩基が与えられた（０．０３７ｇ、０．０７ｍｍｏｌ、６３％収率）。ＵＰＬＣ： ｒｔ＝０．８１， 観察されたピーク： ４６６ （Ｍ＋１， １００％） ａｎｄ ４６８ （Ｍ＋１， ３３％）． Ｃ_２４Ｈ_２４ＣｌＮ_５ＯＳは４６６を要する。^１Ｈ ＮＭＲ （５００ ＭＨｚ， ＤＭＳＯ−ｄ_６） ［本生成物は、配座異性体の混合物として存在する（ｃ比約６０／４０）］。遊離アミン（０．０３７ｇ、０．０８ｍｍｏｌ）をＤＣＭ（１ｍＬ）に溶解した後、ＨＣｌ（Ｅｔ_２Ｏにおける１Ｍ溶液０．１２ｍＬ、０．１２ｍｍｏｌ）を添加し、溶液を室温で３０分間撹拌した。揮発性物質を真空下で除去して、得られた固体をＥｔ２Ｏで倍散した後、濾過して、表題化合物（０．０３９ ｇ、０．０７ ｍｍｏｌ、８８％収率）を与えた。ＨＰＬＣ（階段状）： ｒｔ＝４．２０分。 Example 2: 6-chloro-7-methyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2-piperidinyl} methyl ) Imidazo [1,2-b] pyridazine (HCl salt) (E2):

2-Methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (0.025 g, 0.11 mmol) was dissolved in DCM (1 mL) and to this solution was added oxalyl chloride (0.022 mL, 0.25 mmol). ) And DMF (1 drop) were added. After the solution was left under stirring for 30 minutes, the solvent was evaporated under vacuum, the resulting yellow solid was dissolved in DCM (1 mL) and the solution was 6-chloro-7-methyl-2 in DCM (1 mL). -Ice-cooled solution of [(2S) -2-piperidinylmethyl] imidazo [1,2-b] pyridazine (D6) (0.030 g, 0.113 mmol) and TEA (0.047 mL, 0.34 mmol) Added dropwise. The mixture was left under stirring for 1 hour at room temperature. DCM (2 mL) was added and the mixture was washed with saturated aqueous NaHCO ₃ (2 mL), the organic phase was separated, dried (Na 2 SO 4), filtered and concentrated. The residue was purified via chromatography on silica gel (Vac Master, EtOAc). The collected fractions gave the free base of the title compound (0.037 g, 0.07 mmol, 63% yield). UPLC: rt = 0.81, observed peaks: 466 (M + 1, 100%) and 468 (M + 1, 33%). C ₂₄ H ₂₄ ClN ₅ OS requires 466. ¹ H NMR (500 MHz, DMSO-d ₆ ) [This product exists as a mixture of conformers (c ratio about 60/40)]. After free amine (0.037 g, 0.08 mmol) was dissolved in DCM (1 mL), HCl (0.12 mL of 1M solution in Et ₂ O, 0.12 mmol) was added and the solution was stirred at room temperature for 30 min. Volatiles were removed in vacuo and the resulting solid was triturated with Et 2 O and then filtered to give the title compound (0.039 g, 0.07 mmol, 88% yield). HPLC (stepwise): rt = 4.20 min.

Example 3: Determination of antagonist affinity at human orexin-1 receptor and 2 receptor using FLIPR Cell culture Recombinant recombinant human orexin-1 receptor (hOX1) or human orexin-2 receptor (hOX2) Adherent Chinese hamster ovary (CHO) cells expressed in 10% fetal bovine serum (Life Technologies, catalog number 10106-078) and 400 μg / mL geneticin G418 (Calbiochem, catalog number 345810) without complement. Maintained in culture in alpha minimal essential medium supplemented with (Gibco / Invitrogen, catalog number; 22571-020). Cells were grown as monolayers at 37 ° C. under 95%: 5% air: CO ₂ and passaged every 3-4 days. The highest passage used was 25 times.

  The sequences of human orexin 1 receptor and human orexin 2 receptor used in this example are described in Sakurai, T .; et al (1998) Cell, 92 p. The exception was that the human orexin 1 receptor sequence used had the amino acid residue alanine at position 280, as described in Sakurai et al. It was not glycine reported in

Measurement of [Ca ²⁺ ] _i using FLIPR ™ Seed CHO-hOX1 or CHO-hOX2 cells in a black clear bottom 384 well plate at a density of 20,000 per well in the above medium, Maintained overnight (95% at 37 ° C .: 5% air: CO ₂ ).

On the day of the experiment, the medium was discarded and the cells were washed with standard buffer supplemented with 2.5 mM Probenecid (NaCl, 145 mM; KCl, 5 mM; HEPES, 20 mM; glucose, 5.5 mM; MgCl ₂ , 1 mM; CaCl ₂ , 2 mM ) 3 times.

  The plate is then incubated with 1 μM FLUO-4AM dye for 60 minutes in the dark at room temperature to allow FLUO-4AM to be taken up by the cells and then converted to FLUO-4 that cannot remain in the cells by intracellular esterases. did.

  After incubation, the cells were washed 3 times with standard buffer to remove extracellular dye, and 30 μL of buffer was left in each well after washing. The compounds of the invention were tested at final assay concentrations ranging from 1.66E-05M to 1.58E-11M.

  The compounds of the invention were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were serially diluted with DMSO in a 384 compound plate and 1 μL of each dilution was transferred to the test compound plate. Just prior to compound addition to cells, buffer (50 μL / well) was added to 1 μL compound copy plate.

  Immediately after preparing an agonist-stimulated 384-well plate containing 50 μL / well human orexin A (hOrexinA), use by diluting the stock plate with buffer: final concentration is equivalent to EC80 calculated for hOrexinA is there. This value was obtained by testing hOrexinA in a concentration response curve (at least 16 replicates) on the same day of the experiment.

The loaded cells were then incubated with the test compound at 37 ° C. for 10 minutes. The plates were then placed on FLIPR ™ (Molecular Devices, UK) and cell fluorescence (λ _ex = 488 nm, λ _EM = 540 nm) was monitored (Sullivan E, Tucker EM, Dale IL. Measurement of [Ca ²⁺ ] _i using the fluometric imaging reader (FLIPR). Labeled DG (eds.), Calcium Signaling Protocols. New Jersey: Humana Press, 1999, 125-136). After baseline fluorescence readings were taken for 5-10 seconds, 10 μL of EC80 hOrexin A solution was added. The fluorescence was then read for 4-5 minutes.

Data Analysis Functional response using FLIPR was measured as peak fluorescence intensity-baseline fluorescence and expressed as a percentage of the response induced by uninhibited orexin A on the same plate. Iterative curve fitting and parameter estimation was performed using a four parameter logistic model and Microsoft Excel (Bowen WP, Jerman JC. Nonlinear regression using spreadsheets. Trends Pharmacol. Sci. 1995: 16: 1995); Antagonist affinity values (IC ₅₀ ) were converted to functional pK _i values using a modified Cheng-Prusoff correction (Cheng YC, Prusoff WH. Relationship between the inhibint constant (K _i ). 50 percent inhibition (IC ₅₀ ) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22: 3099-3108).

Where [agonist] is the agonist concentration, EC ₅₀ is the concentration of agonist that gives 50% activity from the agonist dose response curve, and n = slope of the dose response curve. When n = 1, the equation is folded into the more familiar Cheng-Prusoff equation.

  Example compounds tested according to this method have fpKi values of 8.8 to 9.1 at the human cloned orexin-1 receptor (having the amino acid residue alanine at position 280, not glycine), and human The cloned orexin-2 receptor was 7.7 to 8.4.

Claims (32)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(In the above formula, Ar represents the formula:

Selected from the group consisting of
R ₁ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁵ R ⁶ , wherein R ⁵ is H or (C _1-4 ) alkyl, and R ⁶ is H or (C _1-4 ) alkyl. And
R ₂ represents (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁷ R ⁸ , wherein R ⁷ is H or (C _1-4 ) -alkyl, and R ⁸ is H or (C _1-4 ) — Alkyl,
R ₃ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁹ R ¹⁰ , wherein R ⁹ is H or (C _1-4 ) -alkyl, and R ¹⁰ is H or (C _1-4 ). -Alkyl,
n is 0 or 1,
p is 0 or 1, and q is 0 or 1,
However, both p and q are not 0).   2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (II).   2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (III).   The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ar is a group of the formula (II) and n is 0. A compound according to claim 1, 2 or 4, wherein Ar is a group of formula (II), n is 0, p is 1, q is 0 and R ₂ is methyl. Its pharmaceutically acceptable salt. Ar is a group of formula (II), n is 0, p is 1, q is 1, and one of R ₂ and R ₃ is halo and the other is (C _{1- 4.} The compound according to claim 1, 2, or 4, or a pharmaceutically acceptable salt thereof, which is ₄ ) -alkyl. Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) -alkyl, and R ₃ is halo. Or a pharmaceutically acceptable salt thereof. 8. The group according to claim 7, wherein Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is methyl and R ₃ is chloro. A compound or a pharmaceutically acceptable salt thereof. Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is halo, and R ₃ is (C _1-4 ) -alkyl. A compound according to claim 1, 2, 4, or 6, or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (II), n is 0, p is 1, R ₂ is chloro, and R ₃ is methyl. Possible salt.   The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein Ar is a group of the formula (III) and n is 0. A compound according to claim 1, 3 or 11, wherein Ar is a group of formula (III), n is 0, p is 1, q is 0 and R ₂ is methyl. Its pharmaceutically acceptable salt. Ar is a group of formula (III), n is 0, p is 1, q is 1, and one of R ₂ and R ₃ is halo and the other is (C _{1- 4} ) A compound according to claim 1, 3 or 11, or a pharmaceutically acceptable salt thereof, which is alkyl). Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) -alkyl, and R ₃ is halo. 14. A compound according to claim 1, 3, 11, or 13, or a pharmaceutically acceptable salt thereof. 15. Ar according to claim 14, wherein Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is methyl and R ₃ is chloro. A compound or a pharmaceutically acceptable salt thereof. Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is halo, and R ₃ is (C _1-4 ) -alkyl. 12. The compound according to claim 1, 3, or 11, or a pharmaceutically acceptable salt thereof. 17. Ar according to claim 16, wherein Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is chloro and R ₃ is methyl. A compound or a pharmaceutically acceptable salt thereof. 6-chloro-8-methyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2-piperidinyl} methyl) imidazo [1 , 2-b] pyridazine, and 6-chloro-7-methyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2 -Piperidinyl} methyl) imidazo [1,2-b] pyridazine or a pharmaceutically acceptable salt thereof.   19. A compound as defined in any one of claims 1-18 or a pharmaceutically acceptable salt thereof for use in therapy.   19. A compound as defined in any one of claims 1-18 or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder in which an antagonist of human orexin receptor is required.   21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is sleep disorder, depression or mood disorder, anxiety disorder, substance related disorder, or eating disorder.   22. A compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a sleep disorder.   The sleep disorders include primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45). ), And sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.47) 46), and primary sleep disorders such as unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder Sleep disorders associated with another mental disorder, such as symptom (307.44); sleep disorders with general medical conditions, especially neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease, etc. Associated with other diseases Claims selected from the group consisting of sleep disorders; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia, and mixed subtypes; sleep apnea and jet lag syndrome Item 22. The compound according to Item 22 or a pharmaceutically acceptable salt thereof.   Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which an antagonist of human orexin receptor is required. .   25. Use according to claim 24, wherein the disease or disorder is a sleep disorder, depression or mood disorder, anxiety disorder, substance-related disorder, or eating disorder.   26. Use according to claim 25, wherein the disease or disorder is a sleep disorder.   The sleep disorders include primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45). ), And sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.47) 46), and primary sleep disorders such as unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder Sleep disorders associated with another mental disorder, such as symptom (307.44); sleep disorders with general medical conditions, especially neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease, etc. Associated with other diseases Claims selected from the group consisting of sleep disorders; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia, and mixed subtypes; sleep apnea and jet lag syndrome Item 27. Use according to Item 26.   19. A method of treating or preventing a disease or disorder in which an antagonist of human orexin receptor is needed, in a subject in need thereof, an effective amount of a compound as defined in any one of claims 1-18. Or administering a pharmaceutically acceptable salt thereof.   30. The method of claim 28, wherein the disease or disorder is a sleep disorder, depression or mood disorder, anxiety disorder, substance-related disorder, or eating disorder.   30. The method of claim 29, wherein the disease or disorder is a sleep disorder.   The sleep disorders include primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45). ), And sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.47) 46), and primary sleep disorders such as unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder Sleep disorders associated with another mental disorder, such as symptom (307.44); sleep disorders with general medical conditions, especially neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease, etc. Associated with other diseases Claims selected from the group consisting of sleep disorders; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia, and mixed subtypes; sleep apnea and jet lag syndrome Item 30. The method according to Item 30.   A pharmaceutical composition comprising: a) a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier.