JP2007508288A - Condensed lactam compounds - Google Patents

Abstract

The present invention relates to a compound of the formula (I) (wherein R ¹ represents an aryl group having 6 to 10 cyclic carbon atoms, R ² represents a hydrogen atom, etc., and n represents 0, 1 or 2 and the heteroaryl group is unsubstituted or substituted, and the aryl is substituted with at least one substituent selected from the group consisting of the substituent a, and the substituent a is , A halogen atom, an alkyl group having 1 to 6 carbon atoms, etc.), or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof. These compounds are used in the treatment of disease states caused by overactivation of the NMDA NR2B receptor, such as pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression, anxiety, migraine in mammals, particularly humans. Useful for treatment. The present invention also provides a pharmaceutical composition comprising the above compound.
[Chemical 1]

Description

  The present invention relates to a novel condensed lactam compound. These compounds are useful as antagonists of the NMDA (N-methyl-D-aspartate) NR2B receptor, and thus pain, stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, depression in mammals, particularly humans. Useful for treating anxiety, migraine, etc. The present invention also relates to pharmaceutical compositions comprising the above compounds.

  Glutamate plays two roles in the central nervous system (CNS) as an essential amino acid and a major excitatory neurotransmitter. At least four receptors, in particular N-methyl-aspartic acid (NMDA), 2-amino-3- (methyl-3-hydroxyisoxazol-4-yl) propionic acid (AMPA), kainic acid and metabotropic forms There is. Hyperalgesia and allodynia after peripheral tissue or nerve injury is not only due to increased sensitivity of major afferent nociceptors at the site of injury, but also depends on NMDA receptor-mediated central changes in synaptic excitability There is considerable preclinical evidence to do. In humans, NMDA receptor antagonists have also been found to reduce both pain perception and sensitization. Also, NMDA receptor overactivation is an important event that induces neuronal cell death under pathological conditions of acute and chronic forms of neurodegeneration. However, while inhibition of NMDA receptors has therapeutic utility in the treatment of pain and neurodegenerative diseases, there are considerable difficulties with many effective NMDA receptor antagonists that can cause potentially serious side effects. NMDA subunits are differentially distributed within the CNS. In particular, NR2B is believed to be restricted to forebrain and dorsal horn lamina I and II. The more segregated distribution of NR2B subunits within the CNS confirms that the side effect profile of drugs that act selectively at this site is reduced.

  For example, NMDA NR2B selective antagonists have a reduced side effect profile over existing NMDA antagonists and may have clinical utility in the treatment of neuropathy and other pain conditions in humans (S. Boyce et al., Neuropharmacology). 38, 611-623 (1999)).

  International Publication Nos. WO91 / 17156 and WO94 / 10166 disclose various 3,4-dihydroquinolin-2 (1H) -one compounds. In particular, the compounds represented by the following formula are disclosed in WO 94/10166.

  However, known compounds may prolong the QT interval due to their potent inhibitory activity in the HERG (human ether-a-go-go related gene) potassium channel. It is known that QT prolongation has a potential tendency to lead to a torsade de point (TdP) type of fatal cardiac arrhythmia. It was confirmed that the ability to prolong the period of myocardial action potential is due to an action on the HERG potassium channel. For example, drugs recovered from the market due to QT prolongation, such as cisapride and terfenadine, are known to be potent HERG potassium channel blockers (Expert Opinion of Pharmacotherapy .; 2, 947-973, 2000) . Therefore, it is desirable to provide a novel NMDA NR2B selective antagonist that has analgesic activity by systemic administration and has reduced inhibitory activity in the HERG potassium channel.

Surprisingly, it has now been found that the condensed lactam compounds of the present invention are selective NMDA NR2B antagonists with systemic analgesic activity and reduced inhibitory activity in the HERG channel. The inhibitory activity in the HERG channel was evaluated from the affinity for the HERG-type potassium channel examined by examining [ ³ H] dofetilide binding that can predict the inhibitory activity in the HERG channel (Eur. J. Pharmacol., 430, 147-148). Page 2001). Selected compounds with low [ ³ H] dofetilide binding activity were evaluated in the I _HERG assay to determine activity in the HERG channel. The compounds of the present invention show reduced QT prolongation by removing the methyl group from the carbon atom adjacent to the nitrogen atom on the piperidine ring of formula (I).

  The present invention relates to a compound of the following formula (I)

（式中、
Ｒ^１は、６〜１０個の環状炭素原子を有するアリール基または硫黄原子、酸素原子および窒素原子からなる群からそれぞれ独立に選択される１〜４個のヘテロ原子を含む５〜１０個の環原子を有するヘテロアリール基を表し、
Ｒ^２は、水素原子、ハロゲン原子、または１〜６個の炭素原子を有するアルキル基を表し、
ｎは、０、１または２を表し、
前記ヘテロアリール基は、非置換、または置換されており、前記アリールは、置換基αからなる群から選択される少なくとも１個の置換基によって置換されており、
前記置換基αは、ハロゲン原子、１〜６個の炭素原子を有するアルキル基、１〜６個の炭素原子を有するアルコキシ基、１〜６個の炭素原子を有するアルコキシアルキル基、１〜６個の炭素原子を有するアルキルチオ基、前記アルキル基中に１〜６個の炭素原子を有するモノまたはジアルキルアミノ基からなる群から選択され、あるいは２個の隣接するα基が、結合して、その１〜２個の（非隣接）炭素原子が酸素原子によって置き換えられてもよい３〜４個の炭素原子を有するアルキレン鎖を形成してもよく、
ただし、前記アリール基は、１〜６個の炭素原子を有する少なくとも１個のアルコキシアルキル基によって置換されている）、
またはこうした化合物の薬学的に許容できるエステル、
またはその薬学的に許容できる塩
を提供する。

(Where
R ¹ is an aryl group having 6 to 10 cyclic carbon atoms, or 5 to 10 rings containing 1 to 4 heteroatoms independently selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom Represents a heteroaryl group having an atom;
R ² represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms,
n represents 0, 1 or 2;
The heteroaryl group is unsubstituted or substituted, and the aryl is substituted with at least one substituent selected from the group consisting of the substituent α;
The substituent α is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, 1 to 6 Selected from the group consisting of a mono- or dialkylamino group having 1 to 6 carbon atoms in the alkyl group, or two adjacent α groups bonded thereto, ~ 2 (non-adjacent) carbon atoms may form an alkylene chain with 3 to 4 carbon atoms, which may be replaced by oxygen atoms,
Wherein the aryl group is substituted by at least one alkoxyalkyl group having 1 to 6 carbon atoms),
Or a pharmaceutically acceptable ester of such a compound,
Or a pharmaceutically acceptable salt thereof.

  The condensed lactam compounds of the present invention are selectively antagonizing against the NMDA NR2B receptor subtype and are therefore therapeutic, particularly in mammals, particularly human seizures or brain trauma, Parkinson's disease, Alzheimer's disease, Huntington's disease or muscle Chronic neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), epilepsy, convulsive diseases, pain, anxiety, human immunodeficiency virus (HIV) related nerve damage, migraine, depression, schizophrenia, tumor, anesthesia It is useful for the treatment of post-cognitive decline (PACD), glaucoma, tinnitus, late dyskinetics, allergic encephalomyelitis, opioid tolerance, drug abuse, alcoholism, irritable bowel syndrome (IBS) and the like.

  The compounds of the present invention are useful for the general treatment of pain, particularly neuropathic pain. Physiological pain is an important defense mechanism designed to warn of danger from potentially harmful stimuli from the outside environment. This system acts through a specific set of primary sensory neurons and is exclusively activated by noxious stimuli through peripheral transmission mechanisms (for a general review, Millan 1999 Prog. Neurobio. 57: 1-164 ). These sensory fibers are known as nociceptors and are characterized by small diameter axons with slow conduction velocities. Nociceptors encode the site of stimulation by the intensity, duration and quality of the nociceptive stimulus and their tissue-distributed organized projection onto the spinal cord. Nociceptors have been found on nociceptive nerve fibers with two main types, Aδ fibers (myelinated) and C fibers (unmyelinated). The activity produced by nociceptor input is transmitted to the basal ventral thalamus, either directly or through the brainstem relay nucleus, after complex processing in the dorsal horn, and then onto the cortex where pain sensations occur.

  Severe acute pain and chronic pain involve the same pathways that work through pathophysiological processes, thus failing to form a defense mechanism and may instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a hallmark of many trauma and disease states. When significant damage to body tissue occurs due to disease or trauma, the characteristics of nociceptor activation change. Peripherally, sensitization occurs locally around the lesion and centrally at the end of the nociceptor. This results in hypersensitivity at the site of injury and nearby normal tissue. In acute pain, these mechanisms can be useful, causing a repair process, and after the injury heals, hypersensitivity returns to normal. However, in many chronic pain states, the healing process continues much longer due to hypersensitivity, usually due to nervous system damage. This damage often results in afferent fiber maladaptation (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be very uneven and may exhibit various pain symptoms. There are several typical pain subtypes: 1) Spontaneous pain that is dull, burning or stinging; 2) Pain response to noxious stimuli is intensified (hyperalgesia); 3) Pain is Usually caused by non-noxious stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Patients with back pain, arthritic pain, CNS trauma, or neuropathic pain may have similar symptoms, but the underlying mechanisms are different and may therefore require different treatment strategies. Thus, pain can be classified into several different areas for different pathophysiology, including nociceptive, inflammatory, neuropathic pain and the like. It should be noted that some types of pain have multiple etiologies and can therefore be classified into more than one area, eg back pain, cancer pain includes both nociceptive and neuropathic elements.

  Nociceptive pain is induced by intense stimuli that can cause tissue damage or damage. Pain afferents are activated by the transmission of stimuli by nociceptors at the site of injury and sensitize the spinal cord at their terminal level. This is then relayed up the spinal tract to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). Activation of nociceptors activates two types of afferent nerve fibers. Myelinated Aδ fibers are transmitted quickly, causing a sharp and stinging pain sensation, while unmyelinated C fibers transmit at a slower rate and transmit dull or tingling pain. Moderate to severe acute nociceptive pain includes, but is not limited to, muscle / sprain pain, postoperative pain (pain after any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis , And prominent features of renal colic. In addition, cancer-related acute pain syndromes generally result from therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormone therapy, and radiation therapy. Moderate to severe acute nociceptive pain includes but is not limited to cancer pain that can be tumor-related pain (eg, bone pain, headache and facial pain, visceral pain), or cancer pain associated with cancer treatment (Eg post-chemotherapy syndrome, chronic post-operative pain syndrome, post-irradiation syndrome), may be due to herniated or ruptured disc or lumbar facet joint, sacroiliac joint, paraspinal muscle or posterior longitudinal ligament It is a prominent feature of back pain.

  Neuropathic pain is defined as pain caused or caused by a primary lesion or dysfunction of the nervous system (IASP definition). Neuropathy can be caused by trauma and disease, so the term “neuropathic pain” encompasses many disorders with various etiologies. These include, but are not limited to, diabetic neuropathy, postherpetic neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal If you have neuralgia, uremia, or vitamin deficiency. Neuropathic pain is pathological because it has no protective role. This often appears after the disappearance of the first cause and generally lasts for years, significantly reducing the patient's quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). Symptoms of neuropathic pain are difficult to treat because they are often heterogeneous, even among patients with the same disease (Woolf & Decosted 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353 : 1959-1964). They include spontaneous pain, which may be continuous, or paroxysmal and abnormal induced pain such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally non-noxious stimuli) .

  The inflammatory process is a complex series of biochemical cellular events activated in response to tissue damage or the presence of foreign bodies, resulting in swelling and pain (Levine and Taiwo 1994: Textbook of Pain 45- 56). Arthritic pain constitutes the majority of the inflammatory pain population. Rheumatoid disease is one of the most common chronic inflammatory symptoms in developed countries, and rheumatoid arthritis is a common cause of disability. Although the exact pathogenesis of RA is not known, current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson 1994 Textbook of Pain 397-407). . It is estimated that approximately 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of which are over 60 years of age, which is 40 million as the age of the population increases. This is expected to increase to humans, which has become a major public health problem (Houge & Mersfelder 2002 Ann Pharmacother. 36: 679-686; McCarthy et al., 1994 Textbook of Pain 387-395). Most patients with OA seek medical attention because of pain. Arthritis has an important impact on psychosocial and physical functions and is known to be a major cause of disability in later life. Other types of inflammatory pain include, but are not limited to, inflammatory bowel disease (IBD).

Other types of pain include, but are not limited to:
-Musculoskeletal, including but not limited to muscle pain, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-articular rheumatism, dystrophin abnormalities, glycogenolysis, polymyositis, purulent myositis Failure.
-Central pain or "thalamic pain" defined by pain caused by focal post-seizure pain, multiple sclerosis, spinal cord injury, focal or neurological dysfunction, including epilepsy .
-Heart and vascular pain including but not limited to angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, edema sclerosis, edema sclerosis, skeletal muscle ischemia.
-Visceral pain and gastrointestinal disorders. The viscera includes abdominal organs. These organs include the genitals, spleen and parts of the digestive system. Pain associated with the viscera can be classified as digestive visceral pain and non-digestive visceral pain. Commonly experienced gastrointestinal (GI) disorders include functional bowel disease (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that have been moderately managed to date, and in FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS) And IBD include Crohn's disease, ileitis, and ulcerative colitis, all of which always result in visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
-Headaches including but not limited to migraine, migraine with aura, migraine without aura, cluster headache, tension headache.
-Orofacial pain, including but not limited to toothache, temporal mandibular fascial pain.

  The present invention provides a pharmaceutical composition for treating a disease state caused by NMDA NR2B receptor overactivation in a mammalian subject, wherein said subject has a therapeutically effective amount of formula (I) Administering a compound of:

  The present invention further provides a composition comprising a therapeutically effective amount of a cycloalkylene amide compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Among them, the composition is preferably for treating the disease defined above.

  The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof as a medicament.

  The present invention also provides a method for treating a disease state as defined above comprising administering to said subject a therapeutically effective amount of a compound of formula (I).

  Furthermore, the present invention provides a method for treating a disease state as defined above in a mammal, preferably a human, comprising administering to said subject a therapeutically effective amount of a compound of formula (I).

  Furthermore, the present invention provides the use of a therapeutically effective amount of a compound of formula (I) in the manufacture of a medicament for treating a disease state as defined above.

  As used herein, the term “halogen” represents fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

  As used herein, the term “alkyl” includes, but is not limited to, straight or branched chain saturation including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl. Represents a group.

  As used herein, the term “alkoxy” includes, but is not limited to, alkyl-O—, including methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secondary butoxy, tertiary butoxy. Represents.

  As used herein, the term “alkoxyalkyl” includes, but is not limited to, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, n-propoxymethyl, n- Propoxyethyl, n-propoxypropyl, n-propoxybutyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, isopropoxybutyl, n-butoxymethyl, n-butoxyethyl, n-butoxypropyl, iso-butoxymethyl, iso -Butoxyethyl, iso-butoxypropyl, iso-butoxybutyl, secondary butoxymethyl, secondary butoxyethyl, secondary butoxypropyl, secondary butoxybutyl, tertiary butoxymethyl, tertiary butoxyethyl, tertiary butoxy Alkyl -O- alkyl containing Kishipuropiru or tertiary butoxybutyl.

  As used herein, the term “alkylene” as used herein refers to a saturated hydrocarbon (straight chain) in which a hydrogen atom has been removed from each terminal carbon, such as methylene, ethylene, methylethylene, propylene, butylene, pentylene, hexylene. Or branched).

  As used herein, the term “aryl” refers to monocyclic or bicyclic aromatic cyclic carbons of 6 to 10 carbon atoms, including but not limited to phenyl or naphthyl, preferably phenyl. To express.

  The term `` heteroaryl '' includes, but is not limited to, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, triazolyl, furanyl, 5 to 10 containing 1 to 4 heteroatoms independently selected from the group consisting of sulfur, oxygen and nitrogen, including quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromanyl or isochromanyl groups Represents a monocyclic or bicyclic aromatic heterocyclic ring up to a member.

  The term “ordinary protecting group” refers to protecting groups that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

  The term “ester” refers to a protecting group that can be cleaved in vivo by biological methods such as hydrolysis to produce the free acid or salt thereof. Whether a compound is such a derivative is administered by intravenous injection to a laboratory animal such as a rat or mouse, and then the animal's body fluid is studied to detect the compound or pharmaceutically acceptable salt thereof. It can be determined by examining whether it can.

  Preferred examples of the group of esters of hydroxy groups include: lower aliphatic alkanoyl groups such as: formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8- Methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13, 13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanoyl and henicosanoyl groups Alkanoyl groups; halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl groups; alkoxyalkylcarbonyl groups such as methoxyacetyl groups; and acryloyl, propioroyl, methacryloyl, crotonoyl, isocrotonoyl and (E) Unsaturated alkylcarbonyl groups such as 2-methyl-2-butenoyl group; more preferably lower aliphatic alkanoyl groups having 1 to 6 carbon atoms; aromatic alkanoyl groups such as: benzoyl, α-naphthoyl and β Arylcarbonyl groups such as naphthoyl groups; halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl groups; 2,4,6-trimethylbenzoyl and 4-toluoyl Lower alkylated arylcarbonyl groups such as 4-anisoyl groups; lower alkoxylated arylcarbonyl groups such as 4-anisoyl groups; nitrated arylcarbonyl groups such as 4-nitrobenzoyl groups and 2-nitrobenzoyl groups; 2- (methoxycarbonyl) benzoyl groups and the like Lower alkoxycarbonylated arylcarbonyl groups; and arylated arylcarbonyl groups such as 4-phenylbenzoyl groups; alkoxycarbonyl groups such as: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl and Lower alkoxycarbonyl groups such as isobutoxycarbonyl group; and 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl Halogen- or tri (lower alkyl) silyl-substituted lower alkoxycarbonyl groups such as nyl groups; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 2-yl and 4-methoxytetrahydrothiopyran-4-yl groups; tetrahydrofuranyl or tetrahydrothio such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl groups Furanyl group; silyl group, for example: trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups And tri (lower alkyl) silyl groups substituted with one or two aryl groups, such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; alkoxy Methyl groups such as: lower alkoxymethyl groups such as: methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups; 2-methoxyethoxymethyl groups Lower alkoxylated lower alkoxymethyl groups such as; and halo (lower alkoxy) methyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl groups; substituted ethyl groups such as: Lower alkoxylated ethyl groups such as xylethyl and 1- (isopropoxy) ethyl groups; and ethyl halide groups such as 2,2,2-trichloroethyl groups; aralkyl groups such as: benzyl, α-naphthylmethyl, β-naphthyl Lower alkyl groups substituted with 1 to 3 aryl groups such as methyl, diphenylmethyl, diphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl groups; and 4-methylbenzyl, 2,4,6- Trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups, etc. One or more aryl groups A lower alkyl group substituted with 1 to 3 substituted aryl groups, substituted with a plurality of lower alkyl, lower alkoxy, nitro, halogen or cyano substituents; alkenyl such as vinyloxycarbonyl and aryloxycarbonyl groups An oxycarbonyl group; and one or two lower aryl rings such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups There are aralkyloxycarbonyl groups which may be substituted with alkoxy or nitro groups.

  The term “treating” as used herein reverses, alleviates, inhibits or prevents the progression of a disorder or symptom to which such term applies, or one or more of such disorder or symptom. Means that. The term “treatment” refers herein to the act of treating, and “treating” is defined immediately above.

Preferred compounds of the formula (I) according to the invention consist of a phenyl group or sulfur atom, oxygen atom and nitrogen atom in which R ¹ is substituted with at least one alkoxyalkyl group having 1 to 6 carbon atoms A heteroaryl group having 5 to 10 ring atoms each consisting of 1 to 2 heteroatoms independently selected from the group, wherein the heteroaryl group having 5 to 10 atoms is unsubstituted, or Substituted with at least one substituent selected from the group consisting of substituent α, wherein the substituent α is a halogen atom, an alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms. An alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms in the alkyl group Are those selected from the group consisting of mono- or dialkylamino group.

More preferably, R ¹ is at least one alkoxyalkyl phenyl group substituted with a group having 1 to 6 carbon atoms, a thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, a pyrrolyl group, a pyridyl group, Represents a pyrimidine group, a quinolyl group, an isoquinolyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a chromanyl group or an isochromanyl group, the thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridyl, pyrimidine, quinolyl, isoquinolyl, tetrahydroquinolyl The tetrahydroisoquinolyl, chromanyl or isochromanyl group is unsubstituted or substituted with at least one substituent selected from the group consisting of the substituent α, and the substituent α is a halogen atom, 1 to An alkyl group having 1 carbon atom, an alkoxy group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or the above alkyl group Are selected from the group consisting of mono- or dialkylamino groups having 1 to 6 carbon atoms. Most preferably, R ¹ represents a phenyl group, a thiazolyl group, a pyridyl group, or an isochromanyl group that is substituted with at least one alkoxyalkyl group having 1 to 6 carbon atoms. When R ¹ is phenyl, the para position is preferably substituted with one alkoxyalkyl group having 1 to 6 carbon atoms. When R ¹ is heteroaryl, unsubstituted or 1 or 2 substituents are preferred. When R ¹ is monocyclic heteroaryl, 1 or 2 substituents are preferred.

Preferred compounds of formula (I) according to the invention are those in which R ² represents a hydrogen atom or a halogen atom. More preferably, R ² represents a hydrogen atom or a fluorine atom.

  Preferred compounds of the formula (I) according to the invention are those in which n represents 1 or 2.

Preferred individual compounds of the invention are:
6- {2- [4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -On,
5-Fluoro-6- {2- [4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline- 2 (1H) -on,
6- {2- [4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -On,
6- (2- {4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} -1-hydroxyethyl) -3,4-dihydroquinoline-2 (1H) -On,
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -5-fluoro-3,4-dihydroquinoline -2 (1H) -on,
5-Fluoro-6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 (1H) -On,
6- {1-hydroxy-2- [4-hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2 [4-methyl-4- (3-methylisothiazol-5-yl) -1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -On,
6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one,
7- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -1,3,4,5-tetrahydro-2H-1-benzo Azepin-2-one,
6- {2- [4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one,
5-Fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 (1H)- ON, and 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -one or a pharmaceutically acceptable salt thereof.

Other preferred individual compounds of the invention are:
6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin1-yl} ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-
Hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one,
7- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -1,3,4,5-tetrahydro-2H-1-benzo Azepin-2-one,
6- {2- [4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one,
5-Fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 (1H)- ON, and 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -one or a pharmaceutically acceptable salt thereof.

General Synthesis The compounds of the present invention can be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following reaction scheme. Unless otherwise indicated, R ¹ , R ² and R ³ in the reaction scheme and subsequent discussion are defined as above. As used below, the term “protecting group” refers to T.I. W. Represents a hydroxy or amino protecting group selected from the usual hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis (John Wiley & Sons, 1991) edited by Greene et al.

  The following reaction scheme illustrates the preparation of a compound of formula (I).

Scheme 1:
This illustrates the preparation of compounds of formula (I).

In the above formula, X represents a leaving group. Examples of suitable leaving groups include halogen atoms such as chlorine, bromine and iodine, and sulfonic acid esters such as TfO (triflate), MsO (mesylate) and TsO (tosylate). Y represents a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine or iodine, and L represents a metal such as lithium or MgY. PG ¹ represents a protecting group. The term “protecting group” is used herein to refer to T.W. W. Represents a hydroxy or amino protecting group selected from the usual hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis (John Wiley & Sons, 1991) edited by Greene et al. A typical hydroxy or amino protecting groups include _{benzyl, C 2 H 5 O (C} = O) -, CH 3 (C = O) -, t- butyldimethylsilyl (TBS), t-butyldiphenylsilyl, and Z There are benzyloxycarbonyl represented and t-butoxycarbonyl represented as t-Boc or Boc.

Step 1A
In this step, an organometallic compound of formula (1-2) can be prepared by reaction of a halide compound of formula (1-1). This reaction can be carried out in the presence of an organometallic reagent or metal. Examples of suitable organometallic reagents include alkyllithiums such as n-butyllithium, sec-butyllithium and tert-butyllithium, and aryllithiums such as phenyllithium and lithium naphthylide. An example of a suitable metal is magnesium. Preferred reaction inert solvents include, for example, hydrocarbons such as hexane, ethers such as diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof. The reaction temperature is usually in the range of −100 to 50 ° C., preferably in the range of −100 ° C. to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.

Step 1B
In this step, an alcohol compound of formula (1-4) can be prepared by nucleophilic addition of a ketone compound of formula (1-3) and an organometallic compound of formula (1-2). This reaction can be carried out in the presence of a solvent. Examples of suitable solvents include, for example, hydrocarbons such as hexane, ethers such as diethyl ether, diisopropyl ether, dimethoxyethane (DME), tetrahydrofuran (THF) and dioxane, or mixtures thereof. The reaction temperature is usually in the range of −100 to 50 ° C., preferably in the range of −100 ° C. to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.

Step 1C
In this step, the desired compound of formula (1-5) is obtained from T.W. W. By deprotection of compounds of formula 1-4 prepared as described in Step 1B by known procedures such as those described in Protective Groups in Organic Synthesis (John Wiley & Sons, 1991) edited by Greene et al. Can be prepared.

  In the case of Bn or Z protection, the removal of the protecting group can be achieved, for example, in the presence of a metal catalyst in a hydrogen atmosphere or in the presence of a hydrogen source such as formic acid or ammonium formate in a reaction inert solvent. It can be carried out under pyrolysis conditions. If desired, the reaction is carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. Preferred metal catalysts are selected, for example, from palladium-carbon, palladium hydroxide-carbon, platinum oxide, platinum-carbon, ruthenium-carbon, rhodium-aluminum oxide, tris [triphenylphosphine] rhodium chloride. Examples of suitable reaction inert aqueous or non-aqueous organic solvents include alcohols such as methanol, ethanol, ethers such as tetrahydrofuran or dioxane, halogenated hydrocarbons such as acetone, dimethylformamide, dichloromethane, dichloroethane or chloroform, and acetic acid or There is that mixture. This reaction can be carried out at a temperature in the range of 20 ° C to 100 ° C, preferably in the range of 20 ° C to 60 ° C. The reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 24 hours. This reaction can be carried out under a hydrogen atmosphere at a pressure in the range of 1 to 100 atoms, preferably 1 to 10 atoms.

Step 1D
In this step, the desired β-carbonylpiperidine compound of formula 1-7 is an inert solvent, for example aliphatic hydrocarbons such as hexane, heptane and petroleum ether, aromatic hydrocarbons such as benzene, toluene, xylene and nitrobenzene, Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, propanol, isopropanol and butanol, and dimethylformamide (DMF), Halogen compounds of formula 1-6 and dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI) or acetonitrile in formula 1-5 It can be prepared by coupling of Perijin compound. This reaction can be carried out using a base such as an alkali or alkaline earth metal, alkoxide, carbonate, or sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, carbonate It can be carried out in the presence of a hydride such as cesium, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. This reaction can be carried out using suitable additives such as tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, copper (0), copper (I) acetate, copper (I) bromide, chloride. Copper (I), copper (I) iodide, copper oxide (I), copper (I) trifluoromethanesulfonate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper iodide ( II), copper (II) oxide, 1,10-phenanthroline, dibenzoanthracene (DBA) or copper (II) trifluoromethanesulfonate. This reaction can be carried out at a temperature in the range of 0 ° C to 100 ° C, preferably in the range of 20 ° C to 100 ° C. The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

Step 1E
In this step, the desired compound of formula (I) uses a reducing agent such as NaBH ₄ , LiAlH ₄ , LiBH ₄ or ZnBH ₄ in an inert solvent such as methanol, ethanol, diglyme, or mixtures thereof. It can be prepared by reduction of the ketone compound of formula (1-7). This reaction can be carried out at a temperature in the range of 0 ° C to 100 ° C, preferably in the range of 20 ° C to 80 ° C. The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

  Scheme 2

In the above formula, R ³ and R ⁴ represent an alkyl group, or R ³ and R ⁴ together can form an ethylene or propylene group, said ethylene or propylene group being substituted by a hydroxy group Also good.

Step 2A
In this step, the desired β-carbonyl piperidine compound of formula 2-2 can be prepared by coupling of a halide compound of formula 1-6 and a ketal piperidine compound of formula 2-1. This reaction is approximately the same as step 1D in Scheme 1 and can be carried out in the same manner, using the same reagents and reaction conditions.

Step 2B
In this step, the alcohol compound of formula (2-3) can be prepared by reduction of the ketone compound of formula (2-2) using a reducing agent. This reaction is approximately the same as step 1E in Scheme 1 and can be carried out in the same manner, using the same reagents and reaction conditions.

Step 2C
In this step, the piperidone compound of formula (2-4) can be prepared by deprotection of the ketal compound of formula (2-3) in the presence or absence of a catalyst in a reaction inert solvent.

  The hydrolysis reaction can be carried out in an aqueous or non-aqueous organic solvent. Examples of suitable solvents include alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or dioxane, halogenated hydrocarbons such as acetone, dimethylformamide, dichloromethane, dichloroethane or chloroform, acetic acid, hydrogen chloride, hydrogen bromide and sulfuric acid. There is no acid. Examples of suitable catalysts include hydrogen halides such as hydrogen chloride and hydrogen bromide, sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid; ammonium salts such as pyridium p-toluenesulfonate and ammonium chloride; and acetic acid And carboxylic acids such as trifluoroacetic acid. This reaction can be carried out at a temperature of 0 ° C. to 200 ° C., preferably about 20 ° C. to 120 ° C. for 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

Step 2D
In this step, the organometallic compound of formula (1-2) is prepared by reaction of the halide compound of formula (1-1) in the same manner as in step 1A of Scheme 1 and using the same reagents and reaction conditions. can do.

Step 2E
In this step, the desired compound of formula (I) can be prepared by nucleophilic addition of a ketone compound of formula (2-4) and an organometallic compound of formula (1-2). This reaction is substantially the same as Scheme 1 Step 1B and can be carried out in the same manner, using the same reagents and reaction conditions.

  Scheme 3

  In the above formula, Y ′ represents a halogen atom such as chlorine, bromine or iodine.

Step 3A
The halogenated intermediate compound 3-2 can be usually prepared by halogenation using a halogenating reagent in a reaction inert solvent. Examples of suitable solvents include aqueous or non-aqueous organic solvents such as tetrahydrofuran, dioxane, acetone, dimethylformamide, acetonitrile, halogenated hydrocarbons such as dichloromethane, dichloroethane or chloroform; and acetic acid. Suitable halogenating reagents include, for example, bromine, chlorine, iodine, N-chlorosuccinimide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, bis (dimethylacetamide) hydrogen tribromide, tribromide. There are tetrabutylammonium, bromodimethylsulfonium bromide, hydrogen bromide-hydrogen peroxide, nitrodibromoacetonitrile or copper (II) bromide. This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent and the starting materials or reagents used. In general, however, it has been found convenient to carry out the reaction at temperatures between 0 ° C. and 200 ° C., more preferably between 20 ° C. and 120 ° C. The time required for the reaction also varies and depends on many factors, in particular the reaction temperature and the nature of the reagent and the solvent used. However, if the reaction is carried out under the above-mentioned preferred conditions, a time of usually 5 minutes to 48 hours, more preferably 30 minutes to 24 hours is sufficient.

  Scheme 4

In the above formula, R ⁵ represents an alkyl group.

Step 4A
In this step, the desired β-carboxylic acid compound of formula 4-2 can be prepared by decarboxylation of the diester compound of formula 4-1. Hydrolytic decarboxylation can be carried out in a reaction inert solvent. Examples of suitable solvents are alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, dimethylformamide. Solvents include aqueous alkaline solutions such as sodium hydroxide, potassium hydroxide and potassium carbonate. This reaction can be carried out at a temperature in the range of 0 ° C to 100 ° C, preferably about 20 ° C to 80 ° C for 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction mixture can then be acidified with an acid. Examples of suitable acids include hydrogen halides such as hydrogen chloride and hydrogen bromide, sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid, ammonium salts such as p-toluenesulfonic acid pyridium and ammonium chloride, acetic acid and There are carboxylic acids such as trifluoroacetic acid. This reaction can be carried out at a temperature in the range of 0 ° C. to 200 ° C., preferably about 20 ° C. to 120 ° C. for 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

Step 4B
In this step, the cyclized compound of formula (4-3) is converted to a carboxylic acid compound of formula (4-2) using a reducing agent in an inert solvent such as methanol, ethanol, ethyl acetate, THF or mixtures thereof. Can be prepared by cyclization of Reducing the metal catalyst in the presence of a hydrogen source such as hydrogen atmosphere or hydrazine or formic acid, for example, nickel catalysts such as Raney nickel, Pd (OH) a palladium catalyst, such as 2 _-C, platinum catalysts such as PtO ₂ or RuCl, It can be carried out under known hydrogenation conditions in the presence of a ruthenium catalyst such as ₂ (Ph ₃ P) ₃ . If desired, this reaction can be carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. The reduction is carried out in a reaction inert solvent such as methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, or mixtures thereof; or without solvent, a suitable reducing agent, For example, it can also be carried out in the presence of LiAlH ₄ , LiBH ₄ , Fe, Sn or Zn. If desired, when the reducing reagent is Fe, Sn or Zn, the reaction is carried out under acidic conditions in the presence of water.

Step 4C
In this step, β-halocarbonyl compounds of formula (1-6) can be prepared by acylation of compounds of formula (4-3) under Friedel-Crafts reaction conditions. This reaction can be carried out in an inert solvent. Examples of suitable solvents are halogenated hydrocarbons such as dichloromethane, dichloroethane or chloroform, and aromatic hydrocarbons such as nitrobenzene and chlorobenzene. Examples of suitable catalysts include aluminum halides such as aluminum chloride and aluminum bromide. This reaction is carried out in the same manner as in Step 1B of Scheme 1 and using the same reagents and reaction conditions, preferably at a temperature of −50 ° C. to 200 ° C., preferably about −10 ° C. to 150 ° C. for 5 minutes to 48 hours. Can be carried out for 30 minutes to 24 hours.

  The starting materials in the above general synthesis are either commercially available or can be obtained by conventional methods well known to those skilled in the art.

  In Schemes 1 to 4 above, examples of suitable solvents also include mixtures of any two or more solvents described in each step.

  Compounds of formula (I), and intermediates in the above-mentioned preparation methods can be isolated and purified by conventional procedures such as recrystallization or chromatographic purification.

  The optically active compound of the present invention can be prepared by several methods. For example, the optically active compound of the present invention can be obtained by chromatographic separation, enzymatic resolution, or fractional crystallization from the final compound.

Methods for assessing biological activity:
NR2B Binding Assay The activity of the bicyclic amide compounds of the invention as NR2B antagonists is determined by their ability to inhibit the binding of NR2B subunits at their receptor sites using radioligands.

The NR2B antagonist activity of bicyclic amide compounds is described, for example, in J. Org. Pharmacol. 331, 117-126, 1997, using standard assay procedures. This method determines the concentration of individual compounds needed to reduce the amount of NR2B ligand radiolabeled at their receptor site by 50%, thereby producing a characteristic IC ₅₀ value for each compound tested. Substantially including obtaining. More specifically, this assay is performed as follows.

  Membranes were prepared by homogenizing the forebrain of male CD rats weighing 170-190 g at 4 ° C. in 0.32 M sucrose using a glass-fluorine resin (Teflon®) homogenizer. The crude nuclear pellet was removed by centrifuging at 1000 × g for 10 minutes, and the supernatant was centrifuged at 17000 × g for 25 minutes. The resulting pellet was resuspended in 5 mM Trisacetic acid pH 7.4 at 4 ° C. for 10 minutes to lyse the cell particles and again centrifuged at 17000 × g. The resulting pellet (P2 membrane) was washed twice in Tris acetic acid, resuspended with 5.5 mg / ml protein and stored at −20 ° C. until use. All manipulations were performed on ice, and stock solutions and equipment were always on ice.

In the saturation assay, receptor saturation was achieved by incubating 50 μg of [ ³ H] -CP-98,113 and P2 membrane protein for 60 minutes at room temperature in a final 100 μl incubation buffer (50 mM Tris HCl, pH 7.4). Were determined. Total and nonspecific binding (in the presence of 10 μM unlabeled CP-98,113) was determined over a range of [ ³ H] -CP-98113 concentrations (0.625 nM-60 nM). [ ³ H] -CP-98,113 is as follows:

In the competition assay, test compounds were incubated in duplicate in 100 μl of 50 mM Tris HCl buffer (pH 7.4) with 5 nM [ ³ H] -CP-98,113 and 50 μg of P2 membrane protein for 60 minutes at room temperature. Nonspecific binding was determined by 10 μM unlabeled CP-98,113 (25 μl). Saturation induction K _D obtained in saturated assay was used for all Ki calculations.

  All incubations were terminated by high speed suction filtration on 0.2% polyethyleneimine soaked Whatman GF / B glass fiber filter paper using a SKATRON cell harvester, followed by ice cold filtration buffer (5 mM Tris HCl, pH 7.4). ) 3 times. Receptor-bound radioactivity was quantified by liquid scintillation counting using a Packard LS counter. Competition assays were performed by counting Wallac GF / B filters on a Betaplate scintillation counter (Wallac).

  All compounds prepared in the examples below were tested by this method and their Ki values for inhibition of binding at the NR2B receptor were 4 nM-30 nM.

Human NR2B cell functional assay HEK293 cells stably expressing the human NR1b / 2B receptor were used in the cell functional assay. Cells were cultured in 75 cm ² culture flasks using Dulbecco's modified Eagle's medium (DMEM, high glucose) supplemented with 10% fetal bovine, 52 μg / ml zeocin, 530 μg / ml geneticin, 100 units / ml penicillin and 100 μg / ml streptomycin. Grown in. Cells were kept in a humidified atmosphere with 5% CO ₂ at 37 ° C. and 50-60% confluent cells were harvested with 0.05% trypsin containing 0.53 mM EDTA. The day before the experiment, expression of NR1b / 2B receptor was induced by 5 μM ponasterone A dissolved in DMEM (40 ml) in the presence of 400 μM ketamine to prevent excitotoxicity. This induction was performed for 19-24 hours using 50-60% confluent cells.

Containing 400μM ketamine, cells were washed with Krebs Ringer Hepes buffer (KRH) 10 ml containing no ^{Ca 2+,} the filling of the 5 [mu] M fura-2 acetoxymethyl ester in the presence of KRH (10 ml) Medium 400μM ketamine ^{Ca 2+} -free 2 hours at room temperature. Subsequently, the cells were collected in a 50 ml tube by pipetting and centrifuged at 850 rpm for 2 minutes. The supernatant was removed, the cells were washed with 10 ml of KRH buffer without Ca ²⁺ and then centrifuged again. This operation was repeated 4 times to remove ketamine, glutamic acid and glycine. Resuspend cells in KRH buffer without Ca ²⁺ and add 50 μl of cell suspension at a density of 100,000 cells / well to each well of a 96-well plate, followed by 50 μl of KRH without Ca ^2+. Dissolved test compound was added. After 30 minutes preincubation, agonists (final 100 μM glutamic acid and 10 μM glycine) dissolved in 25 μl of KRH containing 9 mM Ca ²⁺ (finally 1.8 mM) were added. Fura-2 fluorescence (excitation wavelengths: 340 nm and 380 nm; emission wavelengths 510-520 nm) was monitored with a fluorescence imaging system, FDSS6000. The Δ fluorescence ratio F340 / F380 (ie, the fluorescence ratio immediately after the agonist—the basal fluorescence ratio; calculated as AUC) was used to assess drug action on agonist-induced changes in intracellular Ca ²⁺ . Basal fluorescence ratio was determined in the presence of 10 μM MK-801.

Rat haloperidol-induced catalepsy assay:
Fasted male CD rats were used (7-8 weeks old). Test compound or vehicle is administered subcutaneously followed by haloperidol 0.5 mg / kg s. c. Was administered. Sixty minutes after haloperidol injection, the duration of catalepsy was quantified by measuring the latency to place the animal's front paws on a high bar and remove both front paws from the bar. The cut-off latency was 60 seconds. The experimenter was blinded to treatment during the study.

Human dofetilide binding HEK293S cells transfected with human HERG were prepared and expanded in-house. The collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4 ° C.) and homogenized on ice for 20 seconds using a hand-held Polytron PT 1200 grinder set to full power. The homogenate was centrifuged at 48,000 xg for 20 minutes at 4 ° C. The pellet was then resuspended, homogenized and centrifuged again in the same manner. The final pellet was resuspended in an appropriate amount of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl ₂ (pH 7.4 at 4 ° C.), homogenized, divided and stored at −80 ° C. until use. An aliquot of the membrane fraction was used for protein concentration determination using the BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). The binding assay was performed in a total volume of 200 μl in a 96-well plate. 20 μl of test compound was incubated for 60 minutes at room temperature with 20 μl of [ ³ H] -dofetilide (Amersham, finally 5 nM) and 160 μl of membrane homogenate (25 μg protein). Nonspecific binding was determined by 10 μM dofetilide at the final concentration. Terminate incubation by high-speed suction filtration on a GF / B Betaplate filter pre-soaked with 0.5% with 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl ₂ , pH 7.4 at 4 ° C. using a Skatron cell harvester did. Filters were dried, placed in sample bags and filled with Betaplate Scint. Radioactivity bound to the filter was counted using a Wallac Betaplate counter.

  All the compounds prepared in the examples below exhibited TI values in the range of 900-3900, where TI is the value of {dofetilide binding Ki [μM] / NR2B binding Ki [nM] × 1000}. Structurally similar Comparative Compound A exhibited a TI value of 490.

I _HERG assay HEK293 cells stably expressing the HERG potassium channel were used for electrophysiological studies. Methods for stable transfection of this channel in HEK cells can be found elsewhere (Z. Zhou et al., 1998, Biophysical journal, 74, pages 230-241). Prior to the experimental day, cells were harvested from the culture flasks and plated on coverslips in standard MEM medium containing 10% FCS. Cells seeded in a 37 ° C. incubator maintained in an atmosphere of 95% O ₂ /5% CO ₂ were stored. Cells were studied 15-28 hours after harvesting.

The HERG current was studied using standard patch clamp technology in whole cell mode. During the experiment, they were perfused with cells using standard external solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl 2, 2; MgCl 2, 1; glucose, 10; HEPES, 5; NaOH PH 7.4. Whole cell recording was performed using a patch clamp amplifier and patch pipette with a resistance of 1-3 MOhm when filled with a standard internal solution of the following composition (mM); KCl, 130; MgATP, 5; MgCl ₂ 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only cells with an access resistance of less than 15 MΩ and a seal resistance> 1 GΩ were accepted for subsequent experiments. Series resistance compensation was added up to 80%. No leak subtraction was performed. However, acceptable access resistances depended on the recorded current size and the level of series resistance compensation that could be safely used. Following the achievement of whole cell recording and thorough cell dialysis with pipette solution (> 5 min), a standard potential protocol was applied to the cells to induce membrane current. The potential protocol is as follows. The membrane was depolarized from a holding potential of -80 mV to +20 mV for 1000 ms. Following this, the potential ramp was lowered to the original holding potential (rate 0.5 mV msec ⁻¹ ). This potential protocol was applied to the cells every 4 seconds continuously (0.25 Hz) throughout the experiment. The peak current amplitude was induced at about -40 mV during the lamp measurement. After a stable induced current response was obtained in the external solution, vehicle (0.5% DMSO in standard external solution) was added by a peristaltic pump for 10-20 minutes. When the change in amplitude of the current response induced in vehicle control conditions was very small, either 0.3, 1, 3, 10 μM of the test compound was added for 10 minutes. This 10 minutes included the time that the feed solution passed through the tube from the solution reservoir to the recording chamber by the pump. The exposure time of the cells to the compound solution was greater than 5 minutes after the drug concentration in the chamber had fully reached the concentration being attempted. They were reversible. Finally, cells were exposed to a high dose of a specific IKr blocker, dofetilide (5 μM), to assess insensitive endogenous currents.

  All experiments were performed at room temperature (23 ± 1 ° C.). The induced membrane current was recorded online on a computer, filtered at 500-1 KHz (Bessel-3 dB) and sampled at 1-2 KHz using a patch clamp amplifier and specific data analysis software. The peak current amplitude produced at about −40 mV was measured off-line with a computer.

The arithmetic mean of 10 amplitude values was calculated under controlled conditions and in the presence of drug. The decrease rate of I _N in each experiment is the following formula: I _N = (1−I _D / I _C ) × 100 (where I _D is the average current value in the presence of the drug, and I _C is Is the average current value under control conditions) and obtained by the normalized current value. Separate experiments are performed for each drug concentration or time-matched control, and the arithmetic mean in each experiment is defined as the result of the study.

Mouse PSL Method Partial sciatic nerve ligation (PSL) was performed based on Seltzer et al. (Pain 43, 1990, 205-218). A Von Fray hair test was applied slowly to the plantar surface of the hind paw until the hair was bent. Each hair was tested 10 times in ascending order of force on different parts of the foot at intervals of 1-2 seconds between each applied force. After the escape response was established, the paw was retested for the same hair. The minimum force required to elicit a response was recorded as the foot escape threshold measured in grams.

Chronic constriction injury model (CCI model):
Male Sprague-Dawley rats (270-300 g; BW, Charles River, Tsukuba, Japan) were used.

Chronic constriction injury (CCI) surgery was performed based on the method described by Bennett and Xie ¹⁾ . Briefly, animals were anesthetized with sodium pentobarbital (64.8 mg / kg, ip) and the left common sciatic nerve was exposed at the mid-thigh height by blunt dissection in the biceps femoris. The proximal part of the three branches of the sciatic bone was released from the attached tissue, and four ligatures (4-0 silk) were loosely tied around it at an interval of about 1 mm. Sham surgery was performed in the same manner as CCI surgery except for sciatic nerve ligation. Two weeks after surgery, mechanical allodynia was assessed by applying von Frey hair (VFH) to the plantar surface of the hind paw. The lowest VFH force required to elicit a response was recorded as the paw escape threshold (PWT). The VFH test was conducted 0.5, 1 and 2 hours after administration. Experimental data were analyzed using the Kruskal-Wallis test followed by the Dunn test for multiple comparisons or the Mann-Whitney U test for pairwise comparisons.
¹⁾ Bennett, G. J. et al. And Xie, Y. et al. K Pain, 33: 87-107, 1988

  Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and basic salts (including disalts) thereof.

  Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, cansylate, citrate, edicylate, esylate, fumarate, Glucceptate, gluconate, glucuronate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, 2-naphthylate, nicotinate, nitrate, orotate, palmate, phosphate, sacchar There are acid salts, stearates, succinate sulfates, D- and L-tartrate salts, and tosylate salts. Suitable basic salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, allamine salt, potassium salt, sodium salt, tromethamine salt And zinc salts.

  For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).

  Pharmaceutically acceptable salts of the compound of formula (I) can be readily prepared by mixing together a solution of the compound of formula (I) and the desired acid or base, if desired. The salt precipitates out of solution and can be collected by filtration or can be recovered by evaporation of the solvent.

Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may isotopically, for example D _{2 O,} d 6 _- there are acetone, hydrates and solvates can be substituted in d _6-DMSO .

  Also within the scope of the invention are clathrates, ie drug-host inclusion complexes in which the drug and host are present in non-stoichiometric amounts, as opposed to the solvates described above. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Hallebrian (August 1975).

  Hereinafter, references to compounds of formula (I) include references to salts thereof and solvates and clathrates of compounds of formula (I) and salts thereof. The present invention includes all polymorphs of the compounds of formula (I) as defined above.

  Also within the scope of the invention are so-called “prodrugs” of the compounds of formula (I). That is, certain derivatives of compounds of formula (I) that have little or no pharmacological activity by themselves, when metabolized after administration in or on the body, produce compounds of formula (I) that have the desired activity. Can occur. Such derivatives are called “prodrugs”.

  Prodrugs according to the present invention can be used, for example, to identify suitable functional groups present in compounds of formula (I), for example to those skilled in the art described in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985). It can be created by replacing certain parts known as “promoies”.

  Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

  Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible, and when the compound contains, for example, a keto or oxime group, tautomerism (" tautomerism ") can occur. A single compound may exhibit more than one type of isomerism.

  Included within the scope of the invention are all optical isomers, geometries, of compounds of Formula (I), including compounds exhibiting two or more isomerisms, and mixtures of one or more thereof. Isomer and tautomeric forms.

  Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallization and chromatography.

  Conventional techniques for preparing / isolating individual stereoisomers include transformation of appropriate optically pure precursors, for example, resolution of racemates (or salt or derivative racemates) using chiral HPLC, Alternatively, there are fractional crystals of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, such as tartaric acid.

  The present invention also includes isotopic variations of all pharmaceutically acceptable compounds of formula (I). Isotopic variations are defined as having at least one atom replaced with an atom having the same atomic number but an atomic weight that is different from the atomic weight normally found in nature.

Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen such as ² H and ³ H, carbon such as ¹³ C and ¹⁴ C, nitrogen such as ¹⁵ N, oxygen such as ¹⁷ O and ¹⁸ O, There are isotopes of phosphorus such as ³² P, sulfur such as ³⁵ S, fluorine such as ¹⁸ F, and chlorine such as ³⁶ Cl.

By replacing the compounds of the present invention with isotopes such as deuterium, ie ² H, certain therapeutic benefits resulting from greater metabolic stability, eg, increased in vivo half-life or reduced dosage requirements Therefore it may be preferred in some circumstances.

Certain isotopic variations of compounds of formula (I), such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue dispersion studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

  Isotopic variations of the compounds of formula (I) are those described in the accompanying examples and preparations using conventional techniques well known to those skilled in the art or appropriate isotopic variations of appropriate reagents. It can generally be prepared by similar processes.

  The compounds of formula (I) can be lyophilized, spray dried, or evaporated to produce solid plugs, powders, or films of crystalline or amorphous material. Microwave or radio frequency drying can also be used for this purpose.

  The compounds of the present invention can be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will be highly dependent on the particular mode of administration.

The compounds of the present invention can be administered individually, simultaneously or sequentially in combination with one or more other pharmacologically active agents. Particularly suitable drugs for the treatment of pain include:
(I) Opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalolphine, naltrexone, naltrexone, naltrexone , Butorphanol, nalbuphine and pentazocine,
(Ii) Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, diflucinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid , Nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmethine, zomepilac, and pharmaceutically acceptable salts thereof,
(Iii) Barbituric acid sedatives such as amobarbital, aprobarbital, butabarbital, butabital, mefobarbital, metalbital, methexital, pentobarbital, phenobarbital, secobarbital, tarbutal, theamiral, thiopental and their pharmaceuticals Acceptable salt,
(Iv) benzodiazepines having a sedative action, such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and pharmaceutically acceptable salts thereof,
(V) H ₁ antagonists having a sedative effect, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclidine and pharmaceutically acceptable salts thereof,
(Vi) other sedatives such as glutethimide, meprobamate, metacaron, dichloralphenazone and pharmaceutically acceptable salts thereof,
(Vii) skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metcarbamol, orfrenadine and pharmaceutically acceptable salts thereof,
(Viii) α-2-δ ligands such as gabapentin and pregabalin,
(Ix) α-adrenergic active compounds such as doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl ) -5- (2-pyridyl) quinazoline,
(X) tricyclic antidepressants such as desipramine, imipramine, amitriptyline and nortriptyline,
(Xi) anticonvulsants; such as carbamazepine and valproic acid,
(Xii) serotonin reuptake inhibitors such as fluoxetine, paroxetine, citalopram and sertraline,
(Xiii) mixed serotonin-noradrenaline reuptake inhibitors such as milnacipran, venlafaxine and duloxetine,
(Xiv) a noradrenaline reuptake inhibitor, such as reboxetine,
(Xv) tachykinin (NK) antagonists, in particular Nk-3, NK-2 and NK-1 antagonists such as (αR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9, 10,11-Tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazosino [2,1-g] [1,7] naphtholidine-6-13-dione (TAK-637) ), 5-[[(2R, 3S) -2-[(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl ] -1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), ranepitant, dapitanto and 3-[[2-methoxy-5- (trifluoromethoxy) phenyl] Chiruamino] -2-phenyl - piperidine (2S, 3S),
(Xvi) muscarinic antagonists such as oxybutine, tolterodine, propiverine, tropsium chloride and darifenacin,
(Xvii) COX-2 inhibitors such as celecoxib, lefecoxib and valdecoxib,
(Xviii) non-selective COX inhibitors (preferably exhibiting GI protection), such as nitroflurbiprofen (HCT-1026),
(Xix) coal tar analgesics, in particular paracetamol,
(Xx) neuroleptic drugs such as droperidol,
(Xxi) a vanilloid receptor agonist, such as resinferatoxin,
(Xxii) β-adrenergic compounds such as propranolol,
(Xxiii) local anesthetics such as mexiletine,
(Xxiv) corticosteroids such as dexamethasone,
(Xxv) serotonin receptor agonists and antagonists,
There are (xxvi) cholinergic (nicotinic) analgesics, and (xxvii) other analgesics such as Tramadol®.

  Accordingly, the present invention further includes a combination comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof and a compound or class of compounds selected from the above groups (i) to (xxvii). provide. Also provided are pharmaceutical compositions comprising such combinations together with pharmaceutically acceptable excipients, diluents or carriers, particularly for the treatment of diseases involving α-2-δ ligands.

  Combinations of a compound of the present invention and other therapeutic agents can be administered individually, sequentially or simultaneously. Accordingly, the present invention extends to kits comprising a compound of the present invention, one or more other therapeutic agents such as those described above, and a suitable container.

  The compounds of the present invention can be prepared by any convenient means using well-known carriers and excipients. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers.

Oral Administration The compounds of the present invention can be administered orally. Oral administration involves swallowing, whereby the compound enters the gastrointestinal tract, or buccal or sublingual administration can be performed by the compound entering the blood stream directly from the mouth.

  Formulations suitable for oral administration include capsules including tablets, particles, liquids or powders, lozenges (including liquid encapsulation), chewable tablets, multi and nano particles, gels, films (including mucoadhesive formulations) ), Solid preparations such as cavity suppositories and sprays, and liquid preparations.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules, usually in carriers such as water, ethanol, propylene glycol, methylcellulose, or suitable oils, and one or more emulsifiers and / or suspensions. Contains a turbidity agent. Liquid formulations can also be prepared, for example, by dissolving a solid from a sachet.

  The compounds of the present invention can also be used in fast dissolving, fast disintegrating dosage forms such as those described in Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11 (6), 981-986.

  A typical tablet composition according to the present invention may comprise:

  A typical tablet can be prepared using standard processes well known to pharmacists, for example, by direct compression, granulation (dry, wet, or melt), melt coagulation, or extrusion. A tablet may contain one or more layers and may or may not be coated.

  Examples of excipients suitable for oral administration include carriers such as cellulose, calcium carbonate, calcium hydrogen phosphate, mannitol and sodium citrate, granulated binders such as polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and Gelatin, disintegrants such as starch glycolic acid and sodium silicate, lubricants such as magnesium stearate and stearic acid, wetting agents such as sodium lauryl sulfate, preservatives, antioxidants, perfumes and colorants.

  Solid formulations for oral administration may be prepared for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled two-stage, target and programmed release. Details of suitable modified release techniques such as high energy dispersion, permeability and coated particles can be found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other modified release formulations are described in US Pat. No. 6,106,864.

Parenteral Administration The compounds of the present invention can also be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraureteral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion methods.

  Parenteral preparations are aqueous solutions that may usually contain excipients such as salts, carbohydrates and buffering agents (preferably for a pH of 3-9), depending on the application, but may be sterile non-aqueous or sterile. Can be more suitably prepared as a dry form to be used with a suitable vehicle such as water without pyrogens.

  For example, the preparation of parenteral formulations under sterile conditions by lyophilization can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

  The solubility of the compound of formula (I) used in the preparation of parenteral solutions is determined by appropriate processing, such as the use of high energy spray-dried dispersions (see WO01 / 47495) and / or the use of dissolution enhancers. Can be increased through the use of complex formulation techniques.

  Formulations for parenteral administration may be prepared for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled two-stage, target and programmed release.

Topical Administration The compounds of the present invention may also be administered topically to the skin or mucosa, or dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, bandages, foams, films, skin patches, cachets, implants, sponges, There are fibers, bandages and microemulsions. Liposomes can also be used. Common carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated-see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

  Other means of topical administration include delivery by iontophoresis, electroporation, sonophoresis, ultrasound introduction and needle-free or microneedle injection.

  Formulations for topical administration may be prepared for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled two-stage, target and programmed release. Accordingly, the compounds of the present invention can be prepared in a more solid form for administration as an implanted depot that provides a prolonged release of the active compound.

Inhalation / Intranasal Administration The compounds of the invention are usually mixed from a dry powder inhaler into a dry powder (alone, as a mixture, eg, in a dry blend with lactose, or as a mixed component particle, eg, mixed with a phospholipid. Or in the form of pressurized containers, pumps, sprays, nebulizers (preferably nebulizers that use electrohydrodynamics to produce fine mist), or suitable propellants such as dichlorofluoromethane. Or it can be administered as an aerosol spray from an unused nebulizer intranasally or by inhalation.

  Pressurized containers, pumps, sprays, nebulizers, or nebulizers are, for example, ethanol (optionally aqueous ethanol) or suitable alternatives to extend dispersion, solubilization, or release of active compound, propellant as solvent Solutions or suspensions of the active compound comprising (one or more) and any surfactant such as sorbitan trioleate or oligolactic acid.

  Prior to use in a dry powder or suspension dosage form, the formulation is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminuting method such as spiral jet mill, fluid bed jet mill, supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

  A solution suitable for use in a nebulizer using electrohydrodynamics to produce a fine mist may contain 1 μg to 10 mg of the compound of the invention per operation, and the operating volume was 1 μl to 100 μl. It's okay. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Capsules, blisters and cartridges (eg made of gelatin or HPMC) for use with inhalers or insufflators are suitable powder bases such as compounds of the invention, lactose or starch and l-leucine, mannitol, or It can be prepared to include a powder mix of performance modifiers such as magnesium stearate.

  In the case of dry powder inhalers and aerosols, the unit dose is determined by a valve that delivers a metered amount. Units in accordance with the present invention are usually defined to administer a metered dose or “single inhalation”.

  Formulations for inhalation / intranasal administration may be prepared for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled two-stage, target and programmed release.

Rectal / Vaginal Administration The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a conventional suppository base, but various alternatives may be used as needed.

  Formulations for rectal / vaginal administration may be prepared for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled two-stage, target and programmed release.

Ophthalmic / Early Administration The compounds of the invention are usually administered directly to the eye or ear in the form of a finely divided suspension or solution droplet in isotonic, pH adjusted, sterile saline. You can also. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicone) implants, cachets, lenses and niosomes or liposomes. There is a particle or vesicle system. Crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid and other polymers, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum, together with preservatives such as benzalkonium chloride Can be imported. Such formulations can also be delivered by iontophoresis.

  Formulations for ocular / ear administration may be prepared for immediate release and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled two-stage, target or programmed release.

Realization technology The compounds of the present invention may be used in combination with soluble polymeric elements such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, bitterness masking, bioavailability and / or stability. Can do.

  For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, cyclodextrin can be used as an auxiliary additive, ie, a carrier, diluent, or solubilizer. The most commonly used for these purposes are α-, β- and γ-cyclodextrins, examples of which may be found in International Patent Application Nos. WO 91/11172, WO 94/02518 and WO 98/55148. Absent.

Dosage A compound of the present invention can be administered to a mammal by any of the oral, parenteral or topical routes. In general, these compounds are most desirably administered to humans in doses ranging from 0.1 mg to 3000 mg, preferably 1 mg to 500 mg, which can be administered in a single dose or in divided doses throughout the day. Variations will necessarily occur depending on the weight and condition, the disease state being treated and the particular route of administration chosen.

  These dosages are based on an average human subject having a weight of about 65-70 kg. The physician should be able to easily determine the dosage for subjects whose weight does not fall within this range, such as infants and the elderly.

  For example, dosage levels in the range of 0.01 mg to 10 mg per kg body weight per day are most desirably used for the treatment of pain associated with inflammation.

The invention is illustrated in the following non-limiting examples, unless otherwise stated: all operations are carried out at room or ambient temperature, ie in the range 18-25 ° C .; solvent evaporation Was carried out using a rotary evaporator under reduced pressure at a bath temperature of 60 ° C. or lower; the reaction was monitored by thin layer chromatography (tlc) and the reaction time is shown for illustrative purposes only; melting point (m. p.) is uncorrected (polymorphs may result in different melting points); the structure and purity of all isolated compounds are determined by the following technique: tlc (Merck silica gel 60 F ₂₅₄ precoated TLC plates or Merck NH ₂ F _254s precoated HPTLC plates), mass spectrometry, nuclear magnetic resonance (NMR), less of the infrared absorption spectrum (IR) or microanalysis Guaranteed also by one. Yields are shown for illustrative purposes only. Flash column chromatography was performed using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia Chromatorex® DU3050 (amino type, 30-50 μm). Low resolution mass spectral data (EI) was obtained with an Automass 120 (JEOL) mass spectrometer. Low resolution mass spectral data (ESI) were obtained on a Quattro II (Micromass) mass spectrometer. The melting point was obtained using an Exstar 6000 manufactured by Seiko Instruments Inc. NMR data are compared to tetramethylsilane (TMS) as an internal standard for parts per million (ppm) unless otherwise indicated, deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D ) As a solvent at 270 MHz (JEOL JNM-LA270 spectrometer) or 300 MHz (JEOL JNM-LA300); conventional abbreviations used are: s = 1 doublet, d = doublet, t = triple Line, q = double line, m = multiple line, br. = Broad etc. The IR spectrum was measured with a Shimadzu infrared spectrometer (IR-470). The optical rotation was measured using a JASCO DIP-370 digital polarimeter (JASCO Corporation).

  Chemical symbols have their usual meanings; b. p. (Boiling point), m. p. (Melting point), l (liter), mL (milliliter), g (gram), mg (milligram), mol (mol), mmol (mmol), eq. (Equivalent).

Example 1
6-{[4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one Tert-Butyl 4- (6-ethoxypyridin-3-yl) -4-hydroxypiperidine-1-carboxylate Stirred 5-bromo-2-ethoxypyridine (Pharmaceutical Journal, 1952, 72, 381) (5.02 g, N-Butyllithium (1.56M, 15.9 mL, 24.8 mmol) was added dropwise at −78 ° C. under nitrogen at −78 ° C. to a solution of 24.8 mmol) in diethyl ether (90 mL). Stir for minutes. To this mixture was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.49 g, 22.5 mmol) in diethyl ether (10 mL) at -78 ° C. The mixture was stirred at -78 ° C for 2 hours and at room temperature for 3 hours. The mixture was treated with H ₂ O and extracted with ethyl acetate. The combined organic layer was dried and evaporated. The residue was purified by chromatography on silica gel eluting with triethylamine / ethyl acetate / hexane (0.05: 1: 2 v / v / v) to give the title compound as a yellow oil (3.50 g 48%).
¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.23 (dd, J = 2.6, 0.7 Hz, 1H), 7.68 (dd, J = 8.8, 2.6 Hz, 1H), 6 .71 (dd, J = 8.8, 0.7 Hz, 1H), 4.34 (q, J. = 7.1 Hz, 2H), 4.00 (br.s, 2H), 3.16-3 .30 (m, 2H), 2.02-1.86 (m, 2H), 1.80-1.70 (m, 2H), 1.48 (s, 9H), 1.39 (t, J = 7.1 Hz, 3H) ppm.
MS (EI); M ⁺ = 322

B. 4- (6-Ethoxypyridin-3-yl) piperidin-4-ol dihydrochloride A 4.0 M ethyl acetate solution of hydrogen chloride (10 mL, 40 mmol) was added to 4- (6-ethoxypyridin-3-yl) -4. -Addition of tert-butyl hydroxypiperidine-1-carboxylate (3.50 g, 10.9 mmol) to a solution of ethyl acetate (40 mL). The mixture was stirred at 50 ° C. for 1 hour. The precipitate was collected by filtration to give the title compound as a yellow solid (3.09 g, 96%).
¹ H NMR (300 MHz, DMSO) δ = 9.34 (br.s, 1H), 9.21 (br.s, 1H), 8.23 (d, J = 2.6 Hz, 1H), 7.89 (Dd, J = 8.8, 2.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.36 (br.s, 2H), 4.34 (q, J = 7.0 Hz, 2H), 3.30 to 1.75 (m, 8H), 1.33 (t, J = 7.0 Hz, 3H) ppm.
MS (EI); M ⁺ = 295

C. 6-{[4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one Stirred 6- (chloroacetyl) To a solution of 3,4-dihydroquinolin-2 (1H) -one (1.03 g, 4.62 mmol) in ethanol (20 mL) was added 4- (6-ethoxypyridin-3-yl) piperidin-4-ol, Hydrochloride (1.50 g, 5.08 mmol) and triethylamine (3.22 mL, 23.1 mmol) were added at room temperature under nitrogen and the mixture was stirred at reflux for 4 hours. This mixture was treated with H ₂ O and the precipitate was collected by filtration to give the title compound as a yellow solid (1.09 g, 58%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.43 (br.s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz) , 1H), 7.85 (s, 1H), 7.76 (dd, J = 8.6, 2.4 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.72. (D, J = 8.4 Hz, 1H), 4.89 (s, 1H), 4.27 (q, J = 7.0 Hz, 2H), 3.77 (s, 2H), 3.00-2 .48 (m, 8H), 2.00 to 1.58 (m, 4H), 1.30 (t, J = 7.0 Hz, 3H) ppm.
MS (ESI); (M + H) ⁺ = 410.15, (M−H) ⁻ = 408.21
m. p. 213.1 ° C
IR (KBr); 3489, 1678 cm ⁻¹

(Example 2)
A. 6- {2- [4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one 6- {[4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one (1.49 g, 3.64 mmol) and A solution of sodium borohydride (206 mg, 5.46 mmol) in ethanol (30 mL) was stirred at room temperature for 17 hours. After removing ethanol, the residue was treated with H ₂ O and extracted with dichloromethane. The combined organic layer was dried and evaporated. The residue was purified by chromatography on silica gel eluting with methanol / dichloromethane (1: 7 v / v) to give the title compound as a white solid (1.06 g, 71%).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.7, 2 .4 Hz, 1 H), 7.15 (s, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.72 (d , J = 8.7 Hz, 1H), 4.84 (s, 1H), 4.81 (d, J = 3.0 Hz, 1H), 4.68 to 4.60 (m, 1H), 4.27 (Q, J = 7.1 Hz, 2H), 2.96 to 2.34 (m, 10H), 2.00 to 1.90 (m, 2H), 1.68 to 1.54 (m, 2H) 1.30 (t, J = 7.1 Hz, 3H) ppm.

B. 6- {2- [4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride A solution of hydrogen chloride (0.456 mL, 1.83 mmol) in 4.0 M ethyl acetate was added to 6- {2- [4- (6-ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1 -Hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one (751 mg, 1.83 mmol) was added to a suspension of methyl alcohol (20 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was concentrated and the residue was recrystallized from methanol / 2-propanol to give the title compound as a white solid (727 mg, 89%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.20 (s, 1H), 10.14 (s, 1H), 8.25 (s, 1H), 7.76 (d, J = 8. 1 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.17 (br.s, 1H), 5.61 (br.s, 1H), 5.13 (br.s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.57 (s, 2H), 3.50-3. -2.42 (m, 10H), 1.95 to 1.80 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H) ppm.
MS (ESI); (M + H) ⁺ = 412.14, (M−H) ⁻ = 410.23
m. p. 225.1 ° C
IR (KBr); 3294, 3182, 1674 cm ⁻¹

(Example 3)
6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -On hydrochloride A. 6-Bromo-2-fluoropyridin-3-ol Stirred 2-fluoropyridin-3-ol (J. Labeled Compound. Radiopharm., 1998, 41, 451) (3.81 g, 33.7 mmol) and sodium acetate ( To a solution of 2.76 g, 33.7 mmol) in acetic acid (30 mL) was added bromine (1.74 mL, 33.7 mmol) at 0 ° C. and the mixture was stirred at room temperature for 3.5 hours. The mixture was poured onto iced aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried and concentrated to give the title compound as a yellow solid (4.67 g, 72%).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 7.29 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H) ) Ppm.
MS (EI); M ⁺ = 191, 193

B. 6-Bromo-2-fluoro-3-methoxypyridine N of stirred 6-bromo-2-fluoropyridin-3-ol (4.67 g, 24.3 mmol) and sodium methoxide (1.38 g, 25.5 mmol) , N-dimethylformamide (50 mL) was added methyl iodide (1.59 mL, 25.5 mmol) at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The mixture was treated with H ₂ O and extracted with ethyl acetate. The combined organic layer was dried and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1: 5 v / v) to give the title compound as a yellow oil (2.43 g, 49%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.32 to 7.26 (m, 1H), 7.22 to 7.15 (m, 1H), 3.90 (s, 3H) ppm.
MS (EI); M ⁺ = 205, 207

C. Tert-Butyl 4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidine-1-carboxylate from 6-bromo-2-fluoro-3-methoxypyridine by the procedure described in Example 1. The title compound was prepared: 948 mg (49%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.31 (dd, J = 9.9, 8.3 Hz, 1H), 7.18 (dd, J = 8.3, 0.9 Hz, 1H), 4 .15 to 3.95 (m, 2H), 3.91 (s, 3H), 3.32 to 3.15 (m, 2H), 2.02 to 1.80 (m, 2H), 1.70 ~ 1.53 (m, 2H), 1.48 (s, 9H) ppm.

D. 4- (6-Fluoro-5-methoxypyridin-2-yl) piperidin-4-ol dihydrochloride 4- (6-Fluoro-5-methoxypyridin-2-yl) -4 by the procedure described in Example 1 The title compound was prepared from tert-butyl hydroxypiperidine-1-carboxylate: 623 mg (72%) as a white solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 9.24 to 9.12 (m, 1H), 8.78 (br.s, 1H), 7.69 (dd, J = 10.6, 8 .2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 5.74 (br.s, 1H), 3.88 (s, 3H), 3.20-3.10 (m , 4H), 2.30 to 2.16 (m, 2H), 1.80 to 1.66 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 227.01

E. 6-{[4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one To a solution of (chloroacetyl) -3,4-dihydroquinolin-2 (1H) -one (1.02 g, 4.57 mmol) in N, N-dimethylformamide (20 mL) was added 4- (6-fluoro-5-methoxy). Pyridin-2-yl) piperidin-4-ol dihydrochloride (1.50 g, 5.03 mmol) and triethylamine (1.91 mL, 13.7 mmol) were added at room temperature under nitrogen and the mixture was stirred at room temperature for 4 hours. . This mixture was treated with H ₂ O and the precipitate was collected by filtration to give the title compound as a yellow solid (1.34 g, 71%).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.41 (s, 1H), 7.92 to 7.82 (m, 2H), 7.62 (dd, J = 10.4, 8.2 Hz) , 1H), 7.49 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.02 (s, 1H), 3.85 (s, 3H) ), 3.72 (s, 2H), 3.00 to 2.90 (m, 2H), 2.72 to 2.63 (m, 2H), 2.56 to 2.44 (m, 4H), 2.10 to 1.96 (m, 2H), 1.52 to 1.44 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 414.12, (M−H) ⁻ = 412.19
m. p. 231.1 ° C
IR (KBr); 3541, 1673 cm ⁻¹

F. 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -ON 6-{[4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinoline- by the procedure described in Example 2 The title compound was prepared from 2 (1H) -one: 1.07 g (76%) as a yellow solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 7.63 (dd, J = 10.4, 8.3 Hz, 1H), 7.49 (d, J = 8 .3 Hz, 1 H), 7.15 (s, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 5.00 (s , 1H), 4.81 (br.s, 1H), 4.66 to 4.58 (m, 1H), 3.86 (s, 3H), 2.90 to 2.84 (m, 2H), 2.76 to 2.32 (m, 8H), 2.15 to 1.92 (m, 2H), 1.54 to 1.45 (m, 2H) ppm.

G. 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -On hydrochloride 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl}-by the procedure of Example 2 3,4-Dihydroquinolin-2 (1H) -one was converted to the title compound and obtained as a white solid in 83% (110 mg) after recrystallization from 2-propanol.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.12 (s, 1H), 9.66 (s, 1H), 7.73-7.65 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6. 12 (s, 1H), 5.72 (s, 1H), 5.05 (br.s, 1H), 3.88 (s, 3H), 3.56 to 2.42 (m, 12H), 1 .89 to 1.70 (m, 2H), ppm.
MS (ESI); (M + H) ⁺ = 416.12, (M−H) ⁻ = 414.21
IR (KBr); 3274, 1670 cm ⁻¹

Example 4
6- {1-hydroxy-2- [4-hydroxy-4- (6-propoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride A. 5-Bromo-2-propoxypyridine To a stirred solution of sodium (591 mg, 24.6 mmol) in 2-propanol (20 mL), 5-bromo-2-nitropyridine (5 g, 24.6 mmol) in 2-propanol (10 mL). The solution was added at room temperature and the mixture was stirred at reflux for 2.5 hours. After removing all solvent, the residue was diluted with dichloromethane and H ₂ O and extracted with dichloromethane. The combined organic layer was dried and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1:10, v / v) to give the title compound as a colorless oil (3.84 g, 72%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 8.17 (d, J = 2.6 Hz, 1H), 7.63 (dd, J = 8.7, 2.6 Hz, 1H), 6.64 (d , J = 8.7 Hz, 1H), 4.21 (t, J = 6.6 Hz, 2H), 1.84 to 1.70 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H) ppm.
MS (EI); M ⁺ = 215, 217

B. Tert-butyl 4-hydroxy-4- (6-propoxypyridin-3-yl) piperidine-1-carboxylate The title compound was prepared from 5-bromo-2-propoxypyridine by the procedure described in Example 1: Yellow oil As 2.57 g (75%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 8.23 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 8.7, 2.6 Hz, 1H), 6.72 (d , J = 8.7 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 4.00 (br.s, 2H), 3.29-3.19 (m, 2H), 2 .04 to 1.70 (m, 6H), 1.48 (s, 9H), 1.02 (t, J = 7.4 Hz, 3H) ppm.
MS (EI); M ⁺ = 336

C. 4- (6-propoxypyridin-3-yl) piperidin-4-ol dihydrochloride 4-hydroxy-4- (6-propoxypyridin-3-yl) piperidine-1-carboxylic acid according to the procedure described in Example 1 The title compound was prepared from tert-butyl: 2.5 g (quant.) as a yellow solid.
^{1 H NMR (300MHz, DMSO)} δ = 9.35~9.00 (m, 1H), 8.22 (d, J = 2.4Hz, 1H), 7.94~7.80 (m, 1H) 7.02 to 6.88 (m, 1H), 4.60 to 4.00 (m, 4H), 3.22 to 3.10 (m, 4H), 2.32 to 2.15 (m, 2H), 1.83 to 1.76 (m, 2H), 1.77 to 1.66 (m, 2H), 0.96 (t, J = 6.8 Hz, 3H) ppm.
MS (EI); M ⁺ = 236

D. 6-{[4-Hydroxy-4- (6-propoxypyridin-3-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one By the procedure described in Example 1 The title compound was prepared from 4- (6-propoxypyridin-3-yl) piperidin-4-ol: 584 mg (69%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.42 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.88-7.84 (m, 2H), 7.76 (dd, J = 8.6, 2.5 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 4 .88 (s, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.77 (s, 2H), 3.02 to 2.90 (m, 2H), 2.69 to 2 .47 (m, 8H), 1.95 to 1.85 (m, 2H), 1.75 to 1.58 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H) ppm.
MS (ESI); (M + H) ⁺ = 424.18, (M−H) ⁻ = 422.24
m. p. 185.9 ° C
IR (KBr); 3431, 3192, 1665 cm ⁻¹

E. 6- {1-hydroxy-2- [4-hydroxy-4- (6-propoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one From 6-{[4-hydroxy-4- (6-propoxypyridin-3-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one by the procedure described in 2. The compound was prepared: 408 mg (74%) as a yellow solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.03 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.6, 2 .3 Hz, 1 H), 7.15 (s, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.74 (d , J = 8.6 Hz, 1H), 4.90 to 4.70 (m, 2H), 4.63 (br.s, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3 .75 to 2.40 (m, 10H), 1.96 to 1.89 (m, 2H), 1.68 to 1.54 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H) ppm.
MS (ESI); (M + H) ⁺ = 426.21, (M−H) ⁻ = 424.25

F. 6- {1-hydroxy-2- [4-hydroxy-4- (6-propoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride According to the procedure of Example 2, 6- {1-hydroxy-2- [4-hydroxy-4- (6-propoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 The (1H) -one was converted to the title compound and obtained as a white solid after recrystallization from 2-propanol in 93% (408 mg).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.12 (s, 1H), 9.82 (s, 1H), 8.23 (s, 1H), 7.76 (d, J = 8. 1 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.16 (s, 1H), 5.53 (s, 1H), 5.07 (br.s, 1H), 4.20 (t, J = 6.8 Hz, 2H), 3.57 to 2.42 (m, 12H), 1.92 to 1.66 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H) ppm.
MS (ESI); (M + H) ⁺ = 426.19, (M−H) ⁻ = 424.25
m. p. 218.5 ° C
IR (KBr); 3240, 3136, 1678 cm ⁻¹

(Example 5)
A. 6-Bromo-2-chloropyridin-3-ol The title compound was prepared from 2-chloropyridin-3-ol by the procedure described in Example 3: 7.6 g (quant.) As a yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.35 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H) ppm.
MS (EI); M ⁺ = 207, 209

B. 6-Bromo-2-chloro-3-methoxypyridine The title compound was prepared from 6-bromo-2-chloropyridin-3-ol by the procedure described in Example 3: 4.37 g (54%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.38 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H) ppm .

C. Tert-Butyl 4- (6-chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidine-1-carboxylate from 6-bromo-2-chloro-3-methoxypyridine by the procedure described in Example 1. The title compound was prepared: 1.30 g (46%) as a yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.28 to 7.21 (m, 2H), 4.19 to 4.03 (m, 2H), 3.93 (s, 3H), 3.30 to 3.20 (m, 2H), 2.00 to 1.86 (m, 2H), 1.72-1.60 (m, 2H), 1.48 (s, 9H) ppm.
MS (EI); M ⁺ = 342

D. 4- (6-Chloro-5-methoxypyridin-2-yl) piperidin-4-ol dihydrochloride 4- (6-Chloro-5-methoxypyridin-2-yl) -4 by the procedure described in Example 1 The title compound was prepared from tert-butyl hydroxypiperidine-1-carboxylate: 963 mg (81%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 9.32 (br.s, 1H), 8.78 (br.s, 1H), 7.67-7.60 (m, 2H), 3. 90 (s, 3H), 4.20 to 3.10 (m, 6H), 2.33 to 2.20 (m, 2H), 1.80 to 1.70 (m, 2H) ppm.
MS (EI); M ⁺ −18 = 224

E. 6-{[4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one in Example 3 The title compound was prepared from 4- (6-chloro-5-methoxypyridin-2-yl) piperidin-4-ol by the described procedure: 671 mg (78%) as a yellow solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.43 (s, 1H), 7.89-7.83 (m, 2H), 7.62-7.54 (m, 2H), 6. 93 (d, J = 8.0 Hz, 1H), 5.07 (s, 1H), 3.87 (s, 3H), 3.74 (s, 2H), 2.98 to 2.92 (m, 2H), 2.74 to 2.64 (m, 2H), 2.56 to 2.42 (m, 4H), 2.14 to 2.00 (m, 2H), 1.53 to 1.46 ( m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 430.13, (M−H) ⁻ = 428.20.
m. p. 215.9 ° C
IR (KBr); 3508, 3195, 1678 cm ⁻¹

F. 6- {2- [4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -ON 6-{[4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinoline- by the procedure described in Example 2 The title compound was prepared from 2 (1H) -one: 357 mg (57%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 7.63-7.54 (m, 2H), 7.15 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.02 (s, 1H), 4.82 (s, 1H), 4.67 to 4.58 ( m, 1H), 3.87 (s, 3H), 2.90 to 2.68 (m, 4H), 2.54 to 2.34 (m, 6H), 2.18 to 2.00 (m, 2H), 1.54-1.46 (m, 2H) ppm.

G. 6- {2- [4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -On hydrochloride 6- {2- [4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl}-by the procedure of Example 2 3,4-Dihydroquinolin-2 (1H) -one was converted to the title compound and obtained as a white solid after recrystallization from methanol-2-propanol in 100% (284 mg).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.09 (s, 1H), 7.66-7.58 (m, 2H), 7.21 (s, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.49 (s, 1H), 4.90 (s, 1H), 3.89 (s, 3H) 3.33-2.30 (m, 12H), 1.78-1.50 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 432.14, (M−H) ⁻ = 430.22
IR (KBr); 3206, 1686 cm ⁻¹

(Example 6)
6- {1-hydroxy-2- [4-hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride A. Tert-Butyl 4-hydroxy-4- (5-methoxypyridin-2-yl) piperidine-1-carboxylate By the procedure described in Example 1, 2-bromo-5-methoxypyridine (J. Chem. Soc. Perkin Trans) , 1988, 3085): 647 mg (49%) as a yellow oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.21 (t, J = 1.8 Hz, 1H), 7.25 (d, J = 1.8 Hz, 2H), 4.97 (s, 1H), 4.20 to 1.56 (m, 8H), 3.87 (s, 3H), 1.49 (s, 9H) ppm.
MS (EI); M ⁺ = 308

B. 4- (5-Methoxypyridin-2-yl) piperidin-4-ol tert-Butyl 4-hydroxy-4- (5-methoxypyridin-2-yl) piperidine-1-carboxylate by the procedure described in Example 1 The title compound was prepared from: 1.53 g (87%) as a yellow solid.
MS (EI); M ⁺ = 208

C. 6-{[4-Hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one By the procedure described in Example 3 The title compound was prepared from 4- (5-methoxypyridin-2-yl) piperidin-4-ol: 729 mg (92%) as a yellow solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.43 (s, 1H), 8.20 (d, J = 2.9 Hz, 1H), 7.90-7.83 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.8, 2.9 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4 .96 (s, 1H), 3.81 (s, 3H), 3.73 (s, 2H), 2.98 to 2.90 (m, 2H), 2.75 to 2.55 (m, 2H) ), 2.54 to 2.45 (m, 4H), 2.17 to 2.09 (m, 2H), 1.52 to 1.43 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 396.14, (M−H) ⁻ = 394.21
m. p. 218.8 ° C
IR (KBr); 3327, 3188, 1681 cm ⁻¹

D. 6- {1-hydroxy-2- [4-hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one The title from 6-{[4-Hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one according to the procedure described in 2. The compound was prepared: 162 mg (24%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 8.20 (d, J = 3.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H) ), 7.36 (dd, J = 8.8, 3.0 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.79 (d , J = 7.9 Hz, 1H), 4.92 (s, 1H), 4.79 (br.s, 1H), 4.67 to 4.56 (m, 1H), 3.81 (s, 3H) ) 2.90-2.66 (m, 4H), 2.60-2.35 (m, 6H), 2.24-2.05 (m, 2H), 1.52-1.44 (m) , 2H) ppm.

E. 6- {1-hydroxy-2- [4-hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride According to the procedure of Example 2, 6- {1-hydroxy-2- [4-hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 The (1H) -one was converted to the title compound and obtained as a white solid in 72% (103 mg) after recrystallization from 2-propanol.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.12 (s, 1H), 9.82 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.61 ( d, J = 8.7 Hz, 1H), 7.43 (dd, J = 8.7, 2.6 Hz, 1H), 7.24 (s, 1H), 7.20 (d, J = 7.9 Hz). , 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.13 (s, 1H), 5.61 (s, 1H), 5.07 (br.s, 1H), 3. 83 (s, 3H), 3.65 to 2.40 (m, 12H), 1.90 to 1.70 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 398.15
m. p. 236.5 ° C
IR (KBr); 3188, 1686 cm ⁻¹

(Example 7)
6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl) -3,4-dihydroquinolin-2 (1H) -one hydrochloride A. Tert-Butyl 4-hydroxy-4- (4-methylpyridin-2-yl) piperidine-1-carboxylate The title compound was prepared from 2-bromo-4-methylpyridine by the procedure described in Example 1: Yellow 1.72 g (53%) as an oil.
¹ H NMR (270 MHz, CDCl ₃ ) δ = 8.38 (d, J = 5.1 Hz, 1H), 7.13 (s, 1H), 7.04 (d, J = 5.1 Hz, 1H), 5.32 (s, 1H), 4.19-4.03 (m, 2H), 3.37-3.17 (m, 2H), 2.38 (s, 3H), 2.00-1. 85 (m, 2H), 1.64-1.50 (m, 2H), 1.48 (s, 9H) ppm.
MS (EI); M ⁺ = 292

B. 4- (4-Methylpyridin-2-yl) piperidin-4-ol dihydrochloride 4-Hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-carboxylic acid according to the procedure described in Example 1 The title compound was prepared from tert-butyl: 1.26 g (81%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 9.34 (br.s, 2H), 8.62 (d, J = 5.8 Hz, 1H), 7.83 (br.s, 1H), 7.70 (d, J = 5.8 Hz, 1H), 3.30-2.34 (m, 6H), 2.58 (s, 3H), 2.00-1.88 (m, 2H) ppm .

C. 6-{[4-Hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one By the procedure described in Example 3 The title compound was prepared from 4- (4-methylpyridin-2-yl) piperidin-4-ol: 501 mg (66%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.42 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H) ), 7.85 (s, 1H), 7.49 (s, 1H), 7.05 (d, J = 4.9 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.01 (s, 1H), 3.73 (s, 2H), 3.00 to 2.46 (m, 8H), 2.32 (s, 3H), 2.24 to 2.10 (m, 2H), 1.52-1.40 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 380.17, (M−H) ⁻ = 378.24
IR (KBr); 3234, 1682 cm ⁻¹

D. 6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one The title from 6-{[4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one by the procedure described in 2. The compound was prepared: 134 mg (28%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 8.37-8.32 (m, 1H), 7.49 (s, 1H), 7.18-7. 04 (m, 3H), 6.79 (d, J = 8.1 Hz, 1H), 4.98 (s, 1H), 4.80 (br.s, 1H), 4.63 (br.s, 1H), 2.90 to 2.70 (m, 4H), 2.54 to 2.06 (m, 8H), 2.32 (s, 3H), 1.50 to 1.40 (m, 2H) ppm.

E. 6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride According to the procedure of Example 2, 6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 The (1H) -one was converted to the title compound and obtained as a white solid in 71% (104 mg) after recrystallization from 2-propanol.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.13 (s, 1H), 9.83 (br.s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7. 52 (s, 1H), 7.24 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 4.9 Hz, 1H), 6.86 ( d, J = 8.2 Hz, 1H), 6.13 (s, 1H), 5.67 (s, 1H), 5.08 (br.s, 1H), 3.65 to 2.42 (m, 12H), 2.35 (s, 3H), 1.86-1.70 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 382.19
m. p. 251.7 ° C
IR (KBr); 3242, 1661 cm ⁻¹

(Example 8)
6- (2- {4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} -1-hydroxyethyl) -3,4-dihydroquinoline-2 (1H) -one hydrochloride A.1. 6-Bromo-2-fluoropyridin-3-amine The title compound was prepared from 2-fluoropyridin-3-amine (Heterocycles, 1986, 24, 3213) by the procedure described in Example 3: 1.68 g as a red solid (76%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.15 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 10.2, 7.9 Hz, 1H), 3.82 (br .S, 2H) ppm.
MS (EI); M ⁺ = 190, 192

B. 6-Bromo-2-fluoro-N, N-dimethylpyridin-3-amine 6-Bromo-2-fluoropyridin-3-amine (800 mg, 4.19 mmol) and formaldehyde (35% aqueous solution, 2 mL) formic acid (2 mL) ) The mixture was heated at reflux for 5 hours. The mixture was treated with aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layer was dried and evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1:10 v / v) to give the title compound as a colorless oil (770 mg, 84%).
¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.22 (dd, J = 8.3, 1.1 Hz, 1H), 7.03 (dd, J = 10.3, 8.3 Hz, 1H), 2 .88 (s, 3H), 2.88 (s, 3H) ppm.
MS (EI); M ⁺ = 218, 220

C. Tert-Butyl 4- [5- (dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidine-1-carboxylate By the procedure described in Example 1, 6-bromo-2-fluoro-N, The title compound was prepared from N-dimethylpyridin-3-amine: 718 mg (61%) as a yellow solid.
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.19 (dd, J = 10.0, 7.9 Hz, 1H), 7.09 (dd, J = 7.9, 2.1 Hz, 1H), 4 .15 to 4.00 (m, 2H), 3.40 to 3.07 (m, 2H), 2.89 (s, 3H), 2.88 (s, 3H), 2.00 to 1.86 (M, 2H), 1.70-1.59 (m, 2H), 1.48 (s, 9H) ppm.
MS (EI); M ⁺ = 339

D. 4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] piperidin-4-ol dihydrochloride 4- [5- (Dimethylamino) -6-fluoropyridine- by the procedure described in Example 1 The title compound was prepared from tert-butyl 2-yl] -4-hydroxypiperidine-1-carboxylate: 643 mg (87%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 9.10 (br.s, 1H), 8.72 (br.s, 1H), 7.50-7.40 (m, 1H), 3. 25-1.69 (m, 14H) ppm.
MS (EI); M ⁺ = 239

E. 6-({4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} acetyl) -3,4-dihydroquinolin-2 (1H) -one The title compound was prepared from 4- [5- (dimethylamino) -6-fluoropyridin-2-yl] piperidin-4-ol by the procedure described in Example 3: 239 mg (56%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.42 (s, 1H), 7.90-7.82 (m, 2H), 7.44-7.32 (m, 2H), 6. 93 (d, J = 8.2 Hz, 1H), 4.95 (s, 1H), 3.72 (s, 2H), 3.02 to 2.45 (m, 8H), 2.78 (s, 6H), 2.10 to 2.06 (m, 2H), 1.54 to 1.43 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 427.16, (M−H) ⁻ = 425.10

F. 6- (2- {4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} -1-hydroxyethyl) -3,4-dihydroquinoline-2 (1H) -one According to the procedure described in Example 2, 6-({4- [5- (dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} acetyl) -3 The title compound was prepared from 1,4-dihydroquinolin-2 (1H) -one: 120 mg (50%) as a yellow solid.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 7.44-7.32 (m, 2H), 7.15 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.92 (s, 1H), 4.81 (s, 1H), 4.63 (br.s, 1H), 2.90 to 2.40 (m, 10H), 2.78 (s, 6H), 2.10 to 2.00 (m, 2H), 1.58 to 1.45 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ = 429.22, (M−H) ⁻ = 427.19.

G. 6- (2- {4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} -1-hydroxyethyl) -3,4-dihydroquinoline-2 (1H) -one hydrochloride According to the procedure of Example 2, 6- (2- {4- [5- (dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl}- 1-Hydroxyethyl) -3,4-dihydroquinolin-2 (1H) -one was converted to the title compound and obtained as a white solid in 95% (114 mg) after recrystallization from 2-propanol.
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.09 (s, 1H), 9.58 (s, 1H), 7.51 to 7.36 (m, 2H), 7.25-7. 15 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 4.96 (br.s, 1H), 3.73 to 1.57 (m, 14H), 2.79 ( s, 6H) ppm.
MS (ESI); (M + H) ⁺ = 428.99, (M−H) ⁻ = 426.93
IR (KBr); 3223,1691cm ^-1

Example 9
A. 4- [4- (Methoxymethyl) phenyl] piperidin-4-ol Stirred 1-bromo-4- (methoxymethyl) benzene (J. Med. Chem. 1998, 41, 940-951.) (3.4 g, 20 mmol) in tetrahydrofuran (60 mL) was added N-butyllithium (1.56 M in hexane, 13.5 mL, 21 mmol) at −78 ° C. and the mixture was stirred for 1 hour. To this mixture was then added a solution of ethyl 4-oxopiperidine-1-carboxylate in tetrahydrofuran at −78 ° C., and the mixture was stirred at room temperature for 16 hours. The mixture was treated with saturated aqueous ammonium chloride and extracted with CH ₂ Cl ₂ . The extract was dried over MgSO _4. After evaporation, the crude product was dissolved with ethyl alcohol (10 mL). To this solution was added KOH (5.6 g, 100 mmol) and the mixture was refluxed for 2 hours. The mixture was diluted with water and extracted with CH ₂ Cl ₂ . The extract was dried over MgSO _4. Amino Gel (Fuji Silysia; DU3050) column chromatography resulted in a 4 [4- (methoxymethyl) phenyl] piperidin-4-ol (450 mg) by _{(CH 2 Cl 2 -MeOH 8 1} ).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.50 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.45 (s, 2H), 3.40 (s, 3H), 3.19 to 2.97 (m, 4H), 2.10 to 1.96 (m, 2H), 1.78 to 1.70 (m, 2H) ppm.

B. 6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one hydrochloride 6 -(Chloroacetyl) -3,4-dihydroquinolin-2 (1H) -one (450 mg, 2.0 mmol), 4- [4- (methoxymethyl) phenyl] piperidin-4-ol (450 mg, 2.0 mmol) And a mixture of N, N-dimethylformamide (4 mL) in triethylamine (0.56 mL, 4.0 mmol) was stirred at room temperature for 24 hours. The reaction mixture was then added to a suspension of sodium borohydride (227 mg, 6.0 mmol) in ethyl alcohol (20 mL) at room temperature and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO _4. After evaporation, 6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one (155 mg) was purified by silica gel column chromatography _{(CH 2 Cl 2 -MeOH 8:} 1) gave the. 6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one (155 mg, To a suspension of 0.38 mmol) in ethyl alcohol (3 mL) was added 4N hydrogen chloride in ethyl acetate (0.1 mL, 0.4 mmol). 6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one hydrochloride ( 112 mg) was crystallized from ethyl alcohol.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.22 to 10.10 (br, 2H), 7.60 to 7.18 (m, 6H), 6.87 (d, J = 8.1 Hz) , 1H), 6.18 (br, 1H), 5.52 (br, 1H), 5.17-5.10 (m, 1H), 4.40 (s, 2H), 3.65-3. 15 (m, 9H), 2.88 (t, J = 7.9, 2H), 2.56 to 2.37 (m, 2H), 1.87 to 1.74 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ (411.14), (M−H) ⁻ (409.19)
IR (KBr) 3404, 1674, 1508, 1375, 1238, 1203 cm ⁻¹
m. p. 208.4 ° C

(Example 10)
4-Hydroxy-4 (6-methoxypyridin-3-yl) piperidine-1-carboxylate tert-butyl 5-bromo-2-methoxypyridine (36 g / 193 mmol) in diethyl ether (200 ml) was dissolved in hexane. To a solution of N-butyllithium (1.59 M / 121 ml) and diethyl ether (500 ml) was added dropwise at -78 ° C. After the addition was complete, the mixture was stirred at −78 ° C. for 30 minutes, and a solution of tert-butyl 4-oxopiperidine-1-carboxylate in diethyl ether (300 ml) was added at −78 ° C. to the mixture. The mixture was warmed to room temperature and stirred overnight. Water (400 ml) was added to this mixture, and the organic layer was extracted with diethyl ether (500 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate / hexane = 1/2) to give the title compound (16.5 g / 42%) as an oil.

4- (6-Methoxypyridin-3-yl) piperidin-4-ol hydrochloride Stirred 4-hydroxy-4- (6-methoxypyridin-3-yl) piperidine-1-carboxylate tert-butyl (15 g / 49 mmol) ) In ethyl acetate (300 ml) was added 4N hydrochloride (45 ml / 150 mmol) dissolved in ethyl acetate and the resulting suspension was stirred at 50 ° C. for 2 hours. To this suspension was further added 4N hydrogen chloride (27.5 ml / 75 mmol) dissolved in ethyl acetate, and the mixture was stirred at 50 ° C. for 3 hours. After cooling, the precipitate was collected and dried in vacuo for 1 hour to yield the title compound as a white solid (12.7 g / 93%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 9.25 to 8.90 (br, 2H), 8.24 (dd, J = 0.5, 2.6 Hz, 1H), 7.79 (dd , J = 2.6, 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.00 to 5.40 (br, 1H), 3.86 (s, 3H) 3.30-3.00 (m, 4H), 2.30-2.10 (m, 2H), 1.86-1.76 (m, 2H) ppm.

6-{[4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one stirred 6- (chloroacetyl) To a solution of 3,4-dihydroquinolin-2 (1H) -one (WO9302052) (544 mg, 2.42 mmol) in DMF (15 ml), 4- (6-methoxypyridin-3-yl) piperidin-4-ol hydrochloride Salt (680 mg, 2.42 mmol) and triethylamine (3.6 ml, 26 mmol) were added at room temperature under nitrogen and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the resulting solid was collected to give the title compound (650 mg / 68%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.4 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.90-7.80 (m, 2H), 7.78 (dd, J = 2.4, 8.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H, 4.H). 90 (s, 1H), 3.82 (s, 3H), 3.77 (s, 2H), 2.95 (t, J = 8.1 Hz, 2H), 2.75 to 2.65 (m, 2H), 2.65 to 2.45 (m, 4H), 2.00 to 1.85 (m, 2H), 1.70 to 1.55 (m, 2H) ppm.
MS (ESI); (M + H) ⁺ (427.25), (M−H) ⁻ (425.32)

6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one 6- Hydrogenation with {[4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one (560 mg, 1.4 mmol) A mixture of sodium boron (60 mg, 1.56 mmol) in methanol (15 ml) was stirred at room temperature for 18 hours and at 60 ° C. for 1 hour. The resulting white precipitate was collected (366 mg / 65%).
¹ H NMR (300 MHz, DMSO-d ₆ ) = 10.0 (s, 1H), 8.24 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 2.6, 8. 8 Hz, 1 H), 7.15 (s, 1 H), 7.10 (d, J = 9.3 Hz, 1 H), 6.78 (d, J = 7.9 Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1H), 4.95 to 4.75 (br, 1H), 4.70 to 4.55 (m, 1H), 3.82 (s, 3H), 2.86 (t, J = 7.9 Hz, 2H), 2.80 to 2.65 (m, 2H), 2.65 to 2.35 (m, 6H), 2.00 to 1.85 (m, 2H), 65 to 1.55 (m, 2H) ppm

6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloride 6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one (538 mg , 1.36 mmol) in methanol (14 ml) was added 4.0 M ethyl acetate in hydrogen chloride (0.339 mL, 1.36 mmol) and the mixture was concentrated. The residue was crystallized from IPA to give the title compound as a white solid (430 mg / 73%).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ 9.9 (s, 1 H), 8.27 (d, J = 2.6 Hz, 1 H), 7.78 (dd, J = 2.6, 8.9 Hz) , 1H), 7.23 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.40-5.20 (br, 1H), 5.20-4.90 (br, 1H), 3.86 (s, 3H), 3.60-2.80 (M, 8H), 2.60 to 2.20 (m, 4H), 2.00 to 1.70 (m, 2H) ppm
MS (ESI); (M + H) ⁺ (398.18), (M−H) ⁻ (396.25)
IR (KBr) 3308, 3173, 2949, 2823, 1653, 1599, 1493, 1389, 1292, 1223, 1200, 1134, 1051, 1029, 914, 829 cm ⁻¹

(Example 11)
Diethyl 2- (2-fluoro-6-nitrobenzyl) malonate Sodium hydride (5.2 g, 130 mmol) in N, N-dimethylformamide / tetrahydrofuran (110 ml / 45 ml) suspension in diethyl malonate (19 ml, 125 mmol) ) Was added dropwise and stirred at room temperature for 30 minutes. To this suspension, DMF / THF (40 ml / 30 ml) of 2- (bromomethyl) -1-fluoro-3-nitrobenzene (29 g, 124 mmol) was added and refluxed for 3 hours. After cooling, the mixture was quenched with brine and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to give the title compound as a brown oil (48 g). This crude product was used in the next step without further purification.
¹ H NMR (CDCl ₃ ) δ 7.77 (d, J = 8.1 Hz, 1H), 7.50-7.24 (m, 2H), 4.18 (q, J = 7.1 Hz, 4H), 3.76 (t, J = 7.7 Hz, 1H), 3.55 (dd, J = 7.7, 1.6 Hz, 2H), 1.23 (t, J = 7.1 Hz, 6H)

3- (2-Fluoro-6-nitrophenyl) propanoic acid A mixture of diethyl 2- (2-fluoro-6-nitrobenzyl) malonate (crude 48 g) and 6N hydrogen chloride (100 ml) dissolved in acetic acid (100 ml) Was refluxed for 7 hours. After evaporating the solvent, the resulting solid is collected and triturated with water to give 3- (2-fluoro-6-nitrophenyl) propanoic acid and 3- (2-fluoro-6-nitrophenyl) propane. This resulted in a mixture of ethyl acids. This mixture (18 g) and 2N aqueous NaOH solution (450 ml) in ethanol (450 ml) were refluxed for 1 hour. After cooling, the mixture was acidified with 2N hydrogen chloride and extracted with dichloromethane. The extract was concentrated in vacuo to give the title compound (15 g) as a brown solid. This crude product was used in the next step without further purification.
¹ H NMR (d-DMSO) δ 7.82 (d, J = 7.9 Hz, 1H), 7.66-7.50 (m, 2H), 3.03 (t, J = 7.5 Hz, 2H) 2.54 (t, J = 7.5 Hz, 2H)

Suspension of 5-fluoro-3,4-dihydro-2 (1H) -quinolinone 3- (2-fluoro-6-nitrophenyl) propanoic acid (6.0 g, 28 mmol) and 10% Pd-C (300 mg) Was hydrogenated under H ₂ (4 atm) for 3 hours. After filtration, the filtrate was concentrated in vacuo to give the title compound (4.6 g) as a slightly brown solid. This crude product was used in the next step without further purification.
¹ H NMR (d-DMSO) δ 10.2 (s, 1H), 7.16 (dd, J = 14.5, 8.2 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H) 6.69 (d, J = 8.1 Hz, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H)

6- (Bromoacetyl) -5-fluoro-3,4-dihydro-2 (1H) -quinolinone To a stirred suspension of aluminum chloride (8.0 g, 60 mmol) in 1,2-dichloroethane (16 ml) brominated. Bromoacetyl (4.2 ml, 48 mmol) was added at 0 ° C. After 30 minutes, 5-fluoro-3,4-dihydro-2 (1H) -quinolinone (4.0 g, 24 mmol) was added in portions to the suspension, then the mixture was warmed to 50 ° C. and stirred for 4 hours. After cooling, the solvent was evaporated in vacuo and the residue was quenched with ice water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to give the title compound (2 g) as a yellow solid.
¹ H NMR (d-DMSO) δ 10.7 (s, 1H), 7.75 (t, J = 8.3 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 4.74 (D, J = 2.4 Hz, 1H), 2.95 (t, J = 7.9 Hz, 2H), 2.54 (t, J = 8.1 Hz, 2H)

5-Fluoro-6-{[4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one cooled to 0 ° C. To a solution of 6- (bromoacetyl) -5-fluoro-3,4-dihydro-2 (1H) -quinolinone (1 g, 3.5 mmol) and triethylamine (4.5 ml, 32 mmol) in DMF (70 ml), 4- A solution of (3-methoxyphenyl) -4-piperidinol (1.2 g, 4.2 mmol) in DMF (15 ml) was added dropwise and stirred at the same temperature for 3 hours. Ice water was added to the reaction mixture and the resulting precipitate was collected to give the title compound as a brown solid (943 mg / 65%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.6 (s, 1H), 8.23 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 2.6, 8.6 Hz) , 1H), 7.69 (t, J = 8.3 Hz, 1H), 6.76 (t, J = 8.6 Hz, 2H), 4.89 (s, 1H), 3.82 (s, 3H) ), 3.71 (d, J = 2.2 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H,), 2.75 to 2.50 (m, 4H), 2.00 1.80 (m, 2H), 1.65 to 1.55 (m, 2H) ppm

5-Fluoro-6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 (1H) -One 5-fluoro-6-{[4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one (943 mg 2.3 mmol) and sodium borohydride (95 mg, 2.5 mmol) in ethanol (23 ml) was stirred at room temperature overnight. The resulting white precipitate was collected (586 mg / 61%).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ 10.2 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.3, 8.6 Hz) , 1H), 7.26 (t, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5 20 to 4.75 (br, 2H), 3.82 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H,), 2.80 to 2.35 (m, 6H), 2.00 to 1.80 (m, 2H), 1.65 to 1.55 (m, 2H) ppm

5-Fluoro-6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 (1H) -On hydrochloride 5-fluoro-6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline- To a suspension of 2 (1H) -one (586 mg, 1.41 mmol) in methanol (14 ml) was added 4N hydrogen chloride in 4.0 M ethyl acetate (0.355 mL, 1.42 mmol) and the mixture was concentrated. . The residue was crystallized from IPA to give the title compound as a white solid (500 mg / 79%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.3 (s, 1 H), 10.1 to 9.80 (br, 1 H), 8.26 (s, 1 H), 7.77 (d, J = 7.0 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H) ), 6.40-6.15 (br, 1H), 5.65-5.50 (br, 1H), 5.40-5.20 (br, 1H), 3.84 (s, 3H), 3.70 to 3.00 (m, 6H), 2.90 (t, J = 7.5 Hz, 2H,), 2.54 to 2.44 (m, 2H), 1.96 to 1.76 ( m, 2H) ppm
MS (ESI); (M + H) ⁺ (416.10), (M−H) ⁻ (414.17)
IR (KBr) 3333, 2955, 2748, 2345, 1670, 1630, 1604, 1489, 1377, 1286, 1223, 1069, 1022, 960, 831 cm ⁻¹
m. p. 204.1 ° C

(Example 12)
7- (Bromoacetyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one N, N-dimethylformamide (3 ml) was added dropwise to aluminum chloride (22 g / 168 mmol). . The suspension was stirred at 45 ° C. and bromoacetyl bromide (4.2 ml / 48 ml) and 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Terahedon., 49, 1867). (1993) .3.8 g / 24 mmol) was added. The suspension was warmed to 78 ° C. with stirring for 3 hours, poured onto ice and the resulting precipitate was collected to give the title compound (7 g). This crude product was used in the next step without further purification.

7-{[4-Hydroxy-4- (6-methoxypyridin-3-yl) piperidin-4-yl] acetyl} -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one stirred To a solution of 7- (bromoacetyl) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (500 mg, 1.78 mmol) in DMF (6 ml) was added 4- (6-methoxypyridine- 3-yl) piperidin-4-ol hydrochloride (400 mg, 1.42 mmol) and triethylamine (1.2 ml, 8.9 mmol) were added at room temperature and the mixture was stirred at room temperature for 2 days. Saturated aqueous NaHCO ₃ solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound as a yellow solid (126 mg / 22%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 9.85 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.98-7.86 (m, 2H), 7.78 (dd, J = 2.6, 8.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 4 .91 (s, 1H), 3.82 (s, 3H), 2.84 to 2.48 (m, 4H), 2.30 to 2.04 (m, 6H), 2.00 to 1.86 (M, 2H), 1.70 to 1.56 (m, 2H) ppm

7- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -1,3,4,5-tetrahydro-2H-1-benzo Azepin-2-one 7-{[4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] acetyl} -1,3,4,5-tetrahydro-2H-1-benzazepine A mixture of 2-one (126 mg, 0.31 mmol) and sodium borohydride (13 mg, 0.34 mmol) in ethanol (3 ml) was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and methanol. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 5/1) to give a solid (70 mg). This solid was crystallized from methanol-ethyl acetate-hexane to give the title compound as a white solid (40 mg / 30%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 9.47 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 2.6, 8 .6 Hz, 1H), 7.23 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.76 (d , J = 8.6 Hz, 1H), 4.95 to 4.85 (m, 2H), 4.75 to 4.65 (br, 1H), 3.82 (s, 3H), 2.80 to 2 .35 (m, 8H), 2.20 to 1.85 (m, 6H), 1.70 to 1.50 (m, 2H) ppm
MS (ESI); (M + H) ⁺ (412.13), (M−H) ⁻ (410.23)
IR (KBr) 3246, 2943, 2827, 1662, 1606, 1496, 1373, 1288, 1120, 1028, 831 cm ⁻¹
m. p. 187.7 ° C

(Example 13)
5-Fluoro-6-({4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} acetyl) -3,4-dihydroquinolin-2 (1H) -one cooled to 0 ° C. To a solution of 6- (bromoacetyl) -5-fluoro-3,4-dihydro-2 (1H) -quinolinone (425 mg, 1.5 mmol) and triethylamine (0.63 ml, 4.5 mmol) in DMF (10 ml) was added 4 -A solution of [4- (methoxymethyl) phenyl] piperidin-4-ol (492 mg, 2.23 mmol) in DMF (5 ml) was added dropwise. Ice water was added to the reaction mixture, and the mixture was extracted from ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound as a brown solid (600 mg). The crude product (600 mg) contained impurities but was used in the next step without further purification.

5-Fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 (1H)- With 5-fluoro-6-({4-hydroxy-4- {4- (methoxymethyl) phenyl] piperidin-1-yl} acetyl) -3,4-dihydroquinolin-2 (1H) -one (600 mg) A mixture of sodium borohydride (114 mg, 3.0 mmol) in ethanol was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel (dichloromethane / methanol = 10/1) to give the title compound (123 mg / 20% 2 steps).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.2 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.30-7.20 (m, 3H), 6.68 (d, J = 8.3 Hz, 1H), 5.10 to 4.90 (m, 2H), 4.78 (s, 1H), 4.37 (s, 2H), 3.27 ( s, 3H), 2.87 (t, J = 7.7 Hz, 2H), 2.85 to 2.65 (m, 2H), 2.65 to 2.35 (m, 6H), 2.05 1.85 (m, 2H), 1.65 to 1.50 (m, 2H) ppm

5-Fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 (1H)- On-hydrochloride 5-fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 ( To a suspension of 1H) -one (123 mg, 0.30 mmol) in methanol (3 ml) was added 4N hydrogen chloride in 4.0 M ethyl acetate (0.075 mL, 0.30 mmol) and the mixture was concentrated. The residue was crystallized from IPA to give the title compound as a white solid (100 mg / 75%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.3 (s, 1H), 10.3 to 10.0 (br, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.38-7.26 (m, 3H), 6.75 (d, J = 8.3 Hz, 2H), 6.27 (d, J = 4.2 Hz, 1H), 5.49 (s, 1H) ) 5.49-5.30 (m, 1H), 4.40 (s, 2H), 3.70-3.00 (m, 9H), 2.90 (t, J = 7.7 Hz, 2H) ) 2.60-2.25 (m, 4H), 1.90-1.70 (m, 2H) ppm
MS (ESI); (M + H) ⁺ (429.17), (M−H) ⁻ (427.25)
IR (KBr) 3331, 3198, 2936, 2668, 1684, 1633, 1604, 1380, 1098, 1064, 1037, 815 cm ⁻¹
m. p. 238.3 ° C

(Example 14)
5-Fluoro-6-{[4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one A solution of 6- (bromoacetyl) -5-fluoro-3,4-dihydro-2 (1H) -quinolinone (912 mg, 3.2 mmol) and triethylamine (2.3 ml, 16 mmol) in DMF (20 ml) cooled to 0 ° C. To the solution, 4- (6-fluoro-5-methoxypyridin-2-yl) piperidin-4-ol in DMF (12 ml) was added dropwise and stirred at the same temperature for 1.5 hours. Ice water (100 ml) was added to the reaction mixture and the resulting precipitate was collected to give the title compound as a yellow solid. (794 mg / 57%).
¹ H NMR (300 MHz, DMSO-d ₆ ) 10.6 (s, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.2, 10.6 Hz) , 1H), 7.49 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.04 (s, 1H), 3.85 (s, 3H) ), 3.67 (d, J = 2.1 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H,), 2.70-2.60 (m, 2H), 2.60- 2.46 (m, 4H), 2.10 to 1.94 (m, 2H), 1.53 to 1.40 (m, 2H) ppm
MS (ESI); (M + H) ⁺ (432.13), (M−H) ⁻ (430.20)

5-Fluoro-6- {2- [4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline- 2 (1H) -one 5-fluoro-6-{[4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinoline- A mixture of 2 (1H) -one (750 mg, 1.73 mmol) and sodium borohydride (69 mg, 1.82 mmol) in ethanol (18 ml) was stirred at room temperature for 15 hours. The resulting white precipitate was collected to yield the title compound (506 mg / 68%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.2 (s, 1 H), 7.62 (dd, J = 8.4, 10.6 Hz, 1 H), 7.49 (d, J = 7.9 Hz) , 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 5.08 to 4.98 (m, 2H), 3.85. (S, 3H), 2.87 (t, J = 7.3 Hz, 2H), 2.77-2.60 (br, 2H), 2.58-2.36 (m, 6H), 2.12 ˜1.96 (m, 2H), 1.54 to 1.40 (m, 2H) ppm

5-Fluoro-6- {2- [4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline- 2 (1H) -one hydrochloride 5-fluoro-6- {2- [4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} A solution of 4.0 N ethyl acetate (0.292 mL, 1.17 mmol) in 4N hydrogen chloride in a suspension of 3,4-dihydroquinolin-2 (1H) -one (506 mg, 1.17 mmol) in methanol (10 ml) Was added and the mixture was concentrated. The residue was crystallized from methanol-ethyl acetate-2-propanol to give the title compound as a white solid (360 mg / 66%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.3 (s, 1 H), 10.1 to 9.8 (br, 1 H), 7.69 (dd, J = 8.3, 10.5 Hz, 1 H ), 7.54 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.35. ˜6.15 (br, 1H), 5.85 to 5.60 (br, 1H), 5.45 to 5.20 (br, 1H), 3.88 (s, 3H), 3.70 to 3 .45 (br, 2H), 3.40 to 3.10 (br, 4H), 2.87 (t, J = 8.3 Hz, 2H), 2.55 to 2.25 (m, 4H), 1 .90 to 1.65 (m, 2H) ppm
MS (ESI); (M + H) ⁺ (434.14), (M−H) ⁻ (432.23)
IR (KBr) 3325, 3196, 3082, 2908, 2651, 2570, 1693, 1630, 1601, 1483, 1379, 1313, 1134, 1034, 993, 827 cm ⁻¹
m. p. 251.7 ° C

(Example 15)
Ethyl 4- (3,4-dihydro-1H-isochromen-7-yl) -4-hydroxypiperidine-1-carboxylate 7-bromoisochroman (WO 9305772A1) (5.3 g, 25 mmol) in THF (35 ml) , 1.5 M N-butyllithium in hexane (17 ml, 26 mmol) was added dropwise at -78 ° C. The mixture was stirred at -78 ° C for 1 hour. To this mixture was added a solution of N-carboethoxy-4-piperidone (4.3 g, 25 mmol) in THF (35 ml) at -78 ° C. The mixture was stirred at −78 ° C. for an additional hour and allowed to warm to room temperature. Water (30 ml) was carefully added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 ml × 2). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over potassium carbonate, filtered and concentrated under reduced pressure to give 7.8 g of white powder. This powder was washed with 2-propanol to give the title compound as a white powder (5.7 g, 75%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.36 to 7.08 (m, 3H), 4.77 (s, 2H), 4.31 to 3.93 (m, 4H), 4.16 ( q, J = 7.1 Hz, 2H), 3.44 to 3.20 (m, 2H), 2.93 to 2.80 (m, 2H), 2.09 to 1.91 (m, 2H), 1.81-1.67 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H) ppm.

4- (3,4-Dihydro-1H-isochromen-7-yl) piperidin-4-ol 4- (3,4-dihydro-1H-isochromen-7-yl) -4-hydroxypiperidine-1-carboxylate ( To a suspension of 5.7 g, 19 mmol) in ethanol (6.3 ml), potassium hydroxide (5.3 g, 94 mmol) was added. The mixture was stirred at reflux for 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (20 ml) and the resulting suspension was washed with water (20 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 ml × 2). The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid (3.9 g, 89%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 7.38 to 7.23 (m, 1H), 7.20 to 7.02 (m, 2H), 4.77 (s, 2H), 4.03 to 3.90 (m, 2H), 3.20 to 3.02 (m, 2H), 3.00 to 2.77 (m, 4H), 2.12 to 1.90 (m, 2H), 1. 87-1.58 (m, 2H) ppm.

6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -One mesylate To a stirred solution of 6- (chloroacetyl) -3,4-dihydroquinolin-2 (1H) -one (WO9302052) (0.61 g, 2.7 mmol) in DMF (2.7 ml), 4- ( 3,4-Dihydro-1H-isochromen-7-yl) piperidin-4-ol (0.64 g, 2.7 mmol) and triethylamine (0.55 g, 5.5 mmol) were added at room temperature under nitrogen and the mixture was added at room temperature. And stirred overnight. The reaction mixture was poured into water (40 ml) and the precipitate was collected by filtration and then dissolved in methanol (40 ml). The filtrate was extracted with dichloromethane (40 ml × 1). The organic layer was separated and combined with the methanol solution of the precipitate. The combined organic solution was dried over potassium carbonate, filtered and concentrated under reduced pressure to give 1.4 g of brown oil. To a suspension of crude oil in ethanol (14 ml), a suspension of sodium borohydride (0.10 mg, 2.7 mmol) in ethanol (14 ml) was added at room temperature. The mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure to give a residue that was diluted with dichloromethane (20 ml). The solution was washed with saturated aqueous ammonium chloride, dried over potassium carbonate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, eluent dichloromethane: methanol = 7: 1) gave the title compound as a pale yellow powder (0.25 g, 22% over two steps).
¹ H NMR (270 MHz, DMSO-d ₆ ) δ = 10.02 (br, 1H), 7.29 to 7.23 (m, 1H), 7.18 to 7.04 (m, 4H), 6. 79 (d, J = 8.1 Hz, 1H), 4.83 to 4.58 (m, 5H), 3.68 (t, J = 5.7 Hz, 2H), 2.91 to 2.65 (m) , 6H), 2.63 to 2.39 (m, 6H), 2.05 to 1.83 (m, 2H), 1.64 to 1.47 (m, 2H) ppm.

To a suspension of Example 15 (0.25 g, 0.59 mmol) in isopropanol (5.9 ml) was added methanesulfonic acid (57 mg, 0.59 mmol) at room temperature. The mixture was changed to a clear solution after heating (60 ° C.). The solution was filtered and cooled to room temperature. After overnight, a white solid (0.23 g, 76%) was formed.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.13 (br, 1H), 9.19 (br, 1H), 7.30-7.09 (m, 5H), 6.90-6. 83 (m, 1H), 6.19 (br, 1H), 5.41 (br, 1H), 5.07 to 4.97 (m, 1H), 4.69 (s, 2H), 3.92 To 3.84 (m, 2H), 3.70 to 3.55 (m, 2H), 3.54 to 3.16 (m, 4H), 2.94 to 2.84 (m, 2H), 2 .80 to 2.71 (m, 2H), 2.50 to 2.17 (m, 4H), 2.31 (s, 3H), 1.88 to 1.68 (m, 2H) ppm.
MS (ESI); M + H ⁺ = 423.06, M−H ⁺ = 421.03
IR (KBr); 3244, 2847, 1688, 1151 cm ⁻¹
m. p. 229 ° C

(Example 16)
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -5-fluoro-3,4-dihydroquinoline -2 (1H) -one hydrochloride Stirred 4- (3,4-dihydro-1H-isochromen-7-yl) piperidin-4-ol (0.29 g, 1.2 mmol) and triethylamine (0.25 g, 2 .5 mmol) in DMF (6.0 ml), 6- (bromoacetyl) -5-fluoro-3,4-dihydro-2 (1H) -quinolinone (0.35 g, 1.2 mmol) in DMF (6. 0 ml) solution was added at 0 ° C. under nitrogen and the mixture was stirred at 0 ° C. for 2 h. The reaction mixture was poured into water (100 ml) and the precipitate was collected by filtration. This solid was washed with water (10 ml × 2), isopropanol (15 ml × 2) and dried to give 0.34 g of the crude product as a pale orange powder. To a suspension of the crude product in ethanol (8 ml), sodium borohydride (0.030 mg, 0.79 mmol) was added at 0 ° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (50 ml) and the precipitate was collected by filtration. The precipitate was washed with isopropanol (15 ml × 2) and dried to give the title compound as a white powder (0.26 g, 49% over two steps).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.21 (br, 1H), 7.29 to 7.22 (m, 2H), 7.12 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.02 to 4.98 (m, 1H), 4.97 to 4.90 (m, 1H), 4.69 (s, 1H), 4.66 (s, 2H), 3.86 (t, J = 5.7 Hz, 2H), 2.91 to 2.83 (m, 2H), 2.77 to 2.66 (m, 4H), 2.60 to 2.40 (m, 6H), 1.97 to 1.80 (m, 2H), 1.57 to 1.48 (m, 2H) ppm.

To a suspension of Example 16 (0.26 mg, 0.59 mmol) in 2-propanol (6.0 ml) was added a 4.0 M ethyl acetate (0.15 mL, 0.59 mmol) solution of hydrogen chloride at room temperature. 70 ml of methanol was added to this mixture to dissolve the precipitate. The solution was filtered and concentrated to give a white powder (0.23 g, 82%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.34 (br, 1H), 10.09 (br, 1H), 7.40-7.21 (m, 2H), 7.18-7. 10 (m, 2H), 6.79 to 6.72 (m, 1H), 6.27 (br, 1H), 5.48 to 5.31 (m, 2H), 4.69 (s, 2H) 3.92 to 3.83 (m, 2H), 3.66 to 3.49 (m, 2H), 3.46 to 3.20 (m, 4H), 2.94 to 2.85 (m, 2H), 2.80 to 2.72 (m, 2H), 2.52 to 2.30 (m, 4H), 1.83 to 1.70 (m, 2H) ppm.
MS (ESI); M + H ⁺ = 441.03, M−H ⁺ = 439.00
IR (KBr); 3300, 3178, 2939, 2671, 1661, 1383 cm ⁻¹
m. p. 264 ° C

(Example 17)
6- {2- [4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -One hydrochloride Ethyl 4- (2-ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidine-1-carboxylate Stirred 2-ethoxy-1,3-thiazole (J. Chem. Soc. Perkin Trans2. 1589 (1986)) (1.02 g, 7.90 mmol) in tetrahydrofuran (15 ml), n-butyllithium (1.55 M, 5.10 ml) was added dropwise at 0 ° C. under nitrogen, and the mixture was added to 0 ° C. Stir at 10 ° C. for 10 minutes. To this mixture was added 1-carboethoxy-4-piperidone (1.13 g, 6.58 mmol) in tetrahydrofuran (3 ml) and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 2 hours. The mixture was treated with H ₂ O and extracted with ethyl acetate. The combined organic layer was dried and evaporated. The residue was purified by chromatography on silica gel eluting with methyl alcohol / dichloromethane (1:20 v / v) to give the title compound as a yellow oil (1.36 g, 69%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 6.95 (s, 1H), 4.42 (q, J = 7.08 Hz, 2H), 4.14 (q, J = 7.08 Hz, 2H), 4.05 to 3.84 (m, 2H), 3.45 to 3.25 (m, 2H), 2.10 to 1.75 (m, 5H), 1.42 (t, J = 7.08 Hz) , 3H), 1.27 (t, J = 7.08 Hz, 3H) ppm.

B. 4- (2-Ethoxy-1,3-thiazol-5-yl) piperidin-4-ol 4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidine-1-carboxylate A mixture of ethyl alcohol (3 ml) of (1.36 g, 4.53 mmol) and potassium hydroxide (1.27 g, 22.7 mmol) was heated at reflux for 7 hours. The mixture was evaporated in vacuo and the residue was treated with dichloromethane (200 ml) and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (0.81 g, 78%).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 6.96 (s, 1H), 4.42 (q, J = 7.08 Hz, 2H), 3.12 to 2.97 (m, 2H), 2. 95-2.83 (m, 2H), 2.06-1.80 (m, 4H), 1.42 (t, J = 7.08 Hz, 3H) ppm.

C. 6-{[4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one 6- ( Chloroacetyl) -3,4-dihydroquinolin-2 (1H) -one (J. Med. Chem., 35, 620 (1992)), 4- (2-ethoxy-1,3-thiazol-5-yl) A mixture of piperidin-4-ol (0.81 g, 3.55 mmol) and triethylamine (1.0 ml, 7.11 mmol) in dimethylformamide (3.3 ml) was stirred at room temperature for 1 day. This mixture was treated with H ₂ O and the precipitate was collected by filtration to give the title compound as a yellow solid (0.49 g, 50%).
¹ H NMR (300 MHz, CDCl ₃ ) δ = 10.42 (s, 1H), 7.89-7.78 (m, 2H), 6.97 (s, 1H), 6.92 (d, J = 8.80 Hz, 1H), 4.34 (q, J = 7.15 Hz, 2H), 3.74 (s, 2H), 3.39 to 2.42 (m, 7H), 3.00 to 2. 86 (m, 2H), 1.96 to 1.68 (m, 4H), 1.33 (t, J = 7.15 Hz, 3H) ppm.
MS (ESI); M + H ⁺ = 416.10, M−H ⁻ = 414.18

D. 6- {2- [4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -One To a stirred solution of sodium borohydride (0.074 g, 1.95 mmol) in ethanol (8.5 ml), 6-{[4- (2-ethoxy-1,3-thiazol-5-yl)- 4-Hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one (0.41 g, 0.98 mmol) in ethanol (8.5 ml) was added at 0 ° C. The mixture was stirred at room temperature overnight. The precipitate was collected by filtration to give the title compound as a white solid (0.26 g, 64%).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 7.13 (s, 1H), 7.17 to 7.04 (m, 1H), 6.95 (s, 1H), 6.78 (d, J = 8.07 Hz, 1H), 5.34 (brs, 1H), 4.81 (brs, 1H), 4.66 to 4.54 (m, 1H), 4 .35 (q, J = 6.97 Hz, 2H), 2.91 to 2.79 (m, 2H), 2.71 to 2.29 (m, 8H), 1.97 to 1.81 (m, 4H), 1.33 (t, J = 6.97 Hz, 3H) ppm.
MS (ESI); M + H ⁺ = 418.12, M−H ⁻ = 416.21

E. 6- {2- [4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -One hydrochloride Hydrogen chloride (0.17 ml, 0.69 mmol), 4.0 M ethyl acetate solution was added to 6- {2- [4- (2-ethoxy-1,3-thiazol-5-yl)- 4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one (0.26 g, 0.63 mmol) was added to a suspension of methyl alcohol (3 ml). . The mixture was stirred at room temperature for 5 hours and filtered. The filtrate was evaporated and the residue was recrystallized from 2-propanol to give the title compound as a white solid (0.22 g, 77%).
¹ H NMR (300 MHz, DMSO-δ ₆ ) δ = 10.12 (s, 1H), 10.20-9.67 (m, 1H), 7.23 (s, 1H), 7.28-7. 13 (m, 1H), 7.03 (s, 1H), 6.85 (d, J = 8.07 Hz, 1H), 6.16 (brs, 1H), 6.01 (brs, 1H), 5 .14 to 4.96 (m, 1H), 4.38 (q, J = 6.97 Hz, 2H), 3.70 to 2.19 (m, 10H), 2.95 to 2.81 (m, 2H), 2.10 to 1.88 (m, 2H), 1.34 (t, J = 6.97 Hz, 3H) ppm.
MS (ESI); M + H ⁺ = 418.11, M−H ⁻ = 416.20
IR (KBr) 3275, 2739, 1655, 1601, 1545, 1514, 1472, 1379, 1286, 1248, 1169, 1061, 1026, 988, 955, 866, 826, 789 cm ⁻¹ .

(Example 18)
6- {1-hydroxy-2 [4-methyl-4- (3-methylisothiazol-5-yl) -1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one Ethyl 4-hydroxy-4- (3-methylisothiazol-5-yl) piperidine-1-carboxylate Based on the method described in Example 17, 3-methylisothiazole (J. Chem. Soc., 2032 (1963)) (1.9 g), the title compound is prepared as an oil (0.57 g).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 6.84 (s, 1H), 4.15 (q, J = 7 Hz, 2H), 4.03 (br, 2H), 3.36 to 3.20 ( m, 2H), 2.90 (s, 1H), 2.45 (s, 3H), 1.94 (br, 4H), 1.27 (t, J = 7 Hz, 3H) ppm.

B. 4- (3-Methylisothiazol-5-yl) piperidin-4-ol Based on the method described in Example 17, 4-hydroxy-4- (3-methylisothiazol-5-yl) piperidin-1- Prepare the title compound as a solid (0.36 g) from ethyl carboxylate (0.63 g).
¹ H NMR (270 MHz, CDCl ₃ ) δ = 6.86 (s, 1H), 3.12 to 2.91 (m, 4H), 2.47 (s, 3H), 2.07 to 1.80 ( m, 5H) ppm.

C. 6-{[4-Hydroxy-4- (3-methylisothiazol-5-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinolin-2 (1H) -one The method described in Example 17 On the basis of 4- (2-ethoxy-1,3-thiazol-5-yl) piperidin-4-ol, 4- (3-methylisothiazol-5-yl) piperidin-4-ol (0. The title compound is prepared as a solid (0.57 g) from 36 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.43 (s, 1H), 7.87-7.83 (m, 2H), 7.04 (s, 1H), 6.93 (d, J = 9 Hz, 1H), 5.73 (br, 1H), 3.80 (br, 2H), 2.95 (dd, J = 8.7 Hz, 2H), 2.8 to 2.6 (br, 2H), 2.6-2.45 (m, 4H), 2.36 (s, 3H), 2.00-1.85 (m, 2H), 1.82-1.72 (br, 2H) ppm.

D. 6- {1-hydroxy-2- [4-hydroxy-4- (3-methylisothiazol-5-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one Based on the method described in Example 17, 6-{[4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] acetyl} -3,4-dihydroquinoline 6-{[4-Hydroxy-4- (3-methylisothiazol-5-yl) piperidin-1-yl] acetyl} -3,4-dihydroquinoline-2 (1H instead of -2 (1H) -one The title compound is prepared as amorphous (0.35 g) from) -one (0.57 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 10.01 (s, 1H), 7.13 to 7.16 (m, 2H), 7.00 to 6.99 (m, 1H), 6. 77 (d, J = 8 Hz, 1H), 5.65 (s, 1H), 4.82 (d, J = 3 Hz, 1H), 4.65 to 4.56 (m, 1H), 2.87 to 2.79 (m, 2H), 2.74 to 2.65 (m, 2H), 2.53 to 2.33 (m, 6H), 2.34 (s, 3H), 1.97 to 1. 83 (m, 2H), 1.79 to 1.70 (m, 2H) ppm.

E. 6- {1-hydroxy-2- [4-hydroxy-4- (3-methylisothiazol-5-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one hydrochloric acid Salt A solution of 4.0 M ethyl acetate in hydrogen chloride (0.23 mL) was added to 6- {1-hydroxy-2- [4-hydroxy-4- (3-methylisothiazol-5-yl) piperidin-1-yl]. Ethyl} -3,4-dihydroquinolin-2 (1H) -one (0.35 g) was added to a solution of methyl alcohol (3 ml) -tetrahydrofuran (6 ml). The mixture was stirred at room temperature for 0.5 hour and concentrated in vacuo. The precipitate was washed with isopropyl alcohol to give the title compound as a white amorphous (0.21 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) 10.08 (s, 1H), 7.20-7.12 (m, 2H), 7.01 (br, 1H), 6.82 (d, J = 8Hz, 1H), 4.93 (br, 1H), 3.35 to 3.27 (2H), 2.88 to 2.83 (m, 2H), 2.50 to 2.35 (m, 10H) 2.37 (s, 3H), 2.00-1.85 (br, 2H) ppm.
Elemental _{analysis: C 20 H 26 N 3 O} 3 SCl _{Calculated: 0.3H 2 O: C, 56.87} ; H, 6.25; N, 9.77. Found: C, 55.91; H, 6.27; N, 9.83.
MS (ESI); M + H ⁺ = 387.96, M−H ⁻ = 385.91

Claims (16)

Compound of formula (I)

(Where
R ¹ is an aryl group having 6 to 10 cyclic carbon atoms, or 5 to 10 rings containing 1 to 4 heteroatoms independently selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom Represents a heteroaryl group having an atom;
R ² represents a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms,
n represents 0, 1 or 2;
The heteroaryl group is unsubstituted or substituted, and the aryl is substituted with at least one substituent selected from the group consisting of the substituent α;
The substituent α is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, 1 to 6 Selected from the group consisting of a mono- or dialkylamino group having 1 to 6 carbon atoms in the alkyl group, or two adjacent α groups bonded thereto, Two (non-adjacent) carbon atoms may be replaced by oxygen atoms to form an alkylene chain having 3 to 4 carbon atoms,
Wherein the aryl group is substituted by at least one alkoxyalkyl group having 1 to 6 carbon atoms),
Or a pharmaceutically acceptable ester of such a compound,
Or a pharmaceutically acceptable salt thereof. R ¹ is a phenyl group substituted with at least one alkoxyalkyl group having 1 to 6 carbon atoms, or 1 to 2 independently selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom A heteroaryl group having 5 to 10 ring atoms consisting of
The heteroaryl group having 5 to 10 atoms is unsubstituted or substituted with at least one substituent selected from the group consisting of the substituent α;
The substituent α is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, 1 to 6 The compound according to claim 1, which is selected from the group consisting of an alkylthio group having the following carbon atoms, or a mono- or dialkylamino group having 1 to 6 carbon atoms in the alkyl group. R ¹ is phenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridyl, pyrimidine, quinolyl substituted with at least one alkoxyalkyl group having 1 to 6 carbon atoms Group, isoquinolyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, chromanyl group or isochromanyl group,
The thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridyl, pyrimidine, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromanyl or isochromanyl group is unsubstituted or at least one selected from the group consisting of the substituent α Substituted with
The substituent α is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 6 carbon atoms, 1 to 6 The compound according to claim 1, which is selected from the group consisting of an alkylthio group having 5 carbon atoms or a mono- or dialkylamino group having 1 to 6 carbon atoms in the alkyl group. R ¹ is representative of at least one alkoxyalkyl phenyl group substituted with a group, a thiazolyl group, a pyridyl group, or isochromanyl group, having 1-6 carbon atoms, A compound according to claim 1. The compound according to any one of claims 1 to 4, wherein R ² represents a hydrogen atom or a halogen atom. The compound according to any one of claims 1 to 4, wherein R ² represents a hydrogen atom or a fluorine atom.   7. A compound according to any one of claims 1 to 6, wherein n represents 1 or 2. 6- {2- [4- (6-Chloro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H) -On,
5-Fluoro-6- {2- [4- (6-fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline- 2 (1H) -on,
6- {2- [4- (2-Ethoxy-1,3-thiazol-5-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -On,
6- (2- {4- [5- (Dimethylamino) -6-fluoropyridin-2-yl] -4-hydroxypiperidin-1-yl} -1-hydroxyethyl) -3,4-dihydroquinoline-2 (1H) -On,
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -5-fluoro-3,4-dihydroquinoline -2 (1H) -on,
5-Fluoro-6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinoline-2 (1H) -On,
6- {1-hydroxy-2- [4-hydroxy-4- (5-methoxypyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2 [4-methyl-4- (3-methylisothiazol-5-yl) -1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -On,
6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one,
7- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -1,3,4,5-tetrahydro-2H-1-benzo Azepin-2-one,
6- {2- [4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one,
5-Fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 (1H)- ON, and 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 The compound according to claim 1, which is selected from (1H) -one or a pharmaceutically acceptable salt thereof. 6- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin1-yl} ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {1-hydroxy-2- [4-hydroxy-4- (4-methylpyridin-2-yl) piperidin-1-yl] ethyl} -3,4-dihydroquinolin-2 (1H) -one,
6- {2- [4- (3,4-Dihydro-1H-isochromen-7-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 (1H ) -On,
6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinolin-2 (1H) -one,
7- {1-hydroxy-2- [4-hydroxy-4- (6-methoxypyridin-3-yl) piperidin-1-yl] ethyl} -1,3,4,5-tetrahydro-2H-1-benzo Azepin-2-one,
6- {2- [4- (6-Ethoxypyridin-3-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinolin-2 (1H) -one,
5-Fluoro-6- (1-hydroxy-2- {4-hydroxy-4- [4- (methoxymethyl) phenyl] piperidin-1-yl} ethyl) -3,4-dihydroquinoline-2 (1H)- ON, and 6- {2- [4- (6-Fluoro-5-methoxypyridin-2-yl) -4-hydroxypiperidin-1-yl] -1-hydroxyethyl} -3,4-dihydroquinoline-2 The compound according to claim 1, which is selected from (1H) -one or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable carrier.   9. A pharmaceutical composition for treating a disease state caused by NMDA NR2B receptor overactivation in a mammalian subject, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, Or a pharmaceutical composition comprising a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof, and a suitable pharmaceutically acceptable carrier.   The disease state is seizure or brain trauma, Parkinson's disease, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, epilepsy, convulsive disease, pain, anxiety, human immunodeficiency virus (HIV) related nerve damage, migraine, depression, schizophrenia, tumor, cognitive decline after anesthesia (PACD), glaucoma, tinnitus, late dyskinesia, allergic encephalomyelitis, opioid tolerance, drug abuse, 12. A pharmaceutical composition according to claim 11 selected from alcoholism and irritable bowel syndrome (IBS).   10. A method for treating a disease state caused by NMDA NR2B receptor overactivation in a mammalian subject, wherein the subject is in a therapeutically effective amount according to any one of claims 1-9. Administering a compound, or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof.   The disease state is seizure or brain trauma, Parkinson's disease, Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, epilepsy, convulsive disease, pain, anxiety, human immunodeficiency virus (HIV) related nerve damage, migraine, depression, schizophrenia, tumor, post-anesthetic cognitive decline (PACD), glaucoma, tinnitus, late dyskinesia, allergic encephalomyelitis, opioid tolerance, drug abuse and 14. The method of claim 13, wherein the method is selected from alcoholism.   Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof as a medicament.   10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt of such a compound in the manufacture of a medicament for treating a disease state caused by overactivation of the NMDA NR2B receptor in a mammalian subject. Use of an acceptable ester, or a pharmaceutically acceptable salt thereof.