WO2010064597A1

WO2010064597A1 - Piperidine derivative

Info

Publication number: WO2010064597A1
Application number: PCT/JP2009/070098
Authority: WO
Inventors: 正城郡; 光功高野
Original assignee: 武田薬品工業株式会社
Priority date: 2008-12-01
Filing date: 2009-11-30
Publication date: 2010-06-10

Abstract

A compound represented by formula (I) or a salt thereof. In formula (I), the symbols are as defined in the description.

Description

Piperidine derivatives

The present invention relates to a novel piperidine derivative having an FAAH inhibitory action.

痛み Pain is a disease that can be serious for patients, reduce QOL, and make social life difficult. Pain is classified according to its cause into inflammatory pain, neuropathic pain, nociceptive pain, psychogenic pain and the like. Inflammatory pain is pain caused by inflammation caused by noxious mechanical stimulation, thermal stimulation, chemical stimulation, etc. applied from outside the living body. It is known that inflammatory cytokines and cyclooxygenase play an important role not only in the local area of inflammation but also in the spinal cord for the expression of inflammatory pain. Neuropathic pain is pathological pain due to abnormal function of the peripheral or central nervous system itself. Nociceptive pain is pain caused by the addition of a noxious stimulus that injures normal tissue or has the risk of it, and is divided into somatic pain and visceral pain.

As therapeutic agents for inflammatory pain, cyclooxygenase (COX) inhibitors such as indomethacin, cyclooxygenase II (COX-II) inhibitors such as celecoxib, central analgesics such as tramadol, and antipyretic analgesics such as acetaminophen are used. It has been. However, when a cyclooxygenase inhibitor is used for a long time, gastrointestinal disorders may occur as a side effect, which is problematic. In addition, cyclooxygenase II inhibitors have also been reported to cause gastric ulcers, and recently, cardiovascular side effects such as myocardial infarction and cerebral infarction have become a problem.

As neuropathic pain treatment drugs, opioid analgesics such as morphine and anticonvulsants such as gabapentin and pregabalin are used. However, there are no drugs that can be used safely and without side effects.

Incidentally, a cannabinoid receptor has been identified since around 1990 as a receptor for Δ9-tetrahydrocannabinol (Δ9-THC), which is an active ingredient of cannabis. The CB1 receptor (see Non-Patent Document 1), its splice variant CB1a (see Non-Patent Document 2), and the CB2 receptor (see Non-Patent Document 3) are known to date. About the same time, N-arachidonoylethanolamine (anandamide) was discovered from pig brain as an endogenous ligand of the CB1 receptor (see Non-Patent Document 4). Anandamide belongs to N-acylated ethanolamine as well as N-palmitoylethanolamine and N-oleoylethanolamine. Fatty acid amides containing these N-acylated ethanolamines have physiological functions such as pain (see Non-Patent Documents 5 and 6), adjustment of feeding (see Non-Patent Document 7), and promotion of sleep (see Non-Patent Document 8). It has been shown that it exerts its action. The biosynthesis or degradation pathway of fatty acid amides has been investigated since about 1980. First, transacylase produces N-acylphosphatidylethanolamine anandamide in a calcium-dependent manner (see Non-Patent Document 9), and then fatty acid amide is released by phospholipase D (see Non-Patent Document 10). The presence of enzyme activity that hydrolyzes fatty acid amides to the corresponding fatty acids and eliminates their physiological activity has been suggested, but the substance was not clear until the late 1990s. An active component that hydrolyzes oleamide was purified from rats, and cDNA was cloned (see Non-Patent Document 11). The enzyme produced by gene recombination hydrolyzes various fatty acid amides including oleamide and anandamide, and is named as fatty acid amide hydrolase (hereinafter abbreviated as “FAAH” in this specification). It was. Enzymes that biosynthesize fatty acid amides have not been fully elucidated. However, that fatty acid amides are produced from nerve cells in a calcium-dependent manner, that is, in a nerve activity-dependent manner (see Non-Patent Document 12), is extremely significant in therapeutic drug development. FAAH knockout mice have been created, FAAH inhibitors have been discovered, and the physiological significance of FAAH inhibition is being elucidated. In FAAH knockout mice, the content of fatty acid amide in the brain including anandamide is increased 10 to 15 times, but the exercise capacity, body weight, and body temperature are normal. However, a decrease in pain responsiveness was observed, and this correlated with the brain fatty acid amide content (see Non-Patent Document 13). Examples of FAAH inhibitors include trifluoromethyl ketone derivatives (see Non-Patent Document 14), α-ketoheterocyclic derivatives (see Non-Patent Document 15), sulfonyl fluoride derivatives (see Non-Patent Document 16), fluorophosphonate derivatives ( Non-patent document 17) Allyl carbamate derivatives (see non-patent document 18) and the like are known.

In addition, it has been reported that FAAH and anandamide are involved in various diseases. We have found that FAAH inhibitors have brain / nerve cell protective effects and are useful as therapeutic agents for cerebrovascular disorders. Moreover, it has been reported that there is much FAAH in the brain of an Alzheimer patient (refer nonpatent literature 19). It has been clarified by a test using rats that anti-Parkinson action is exhibited by increasing anandamide (see Non-Patent Document 20). It has been reported that FAAH decreases in miscarried women (see Non-Patent Document 21). Anandamide has been reported to suppress the growth of rectal cancer (see Non-Patent Document 22). FAAH knockout mice have been reported to be less susceptible to colitis and colitis (see Non-Patent Document 23). It has been reported that FAAH inhibitors exhibit an anxiolytic action (see Non-Patent Document 24). FAAH has been reported to be a hydrolase of oleylethanolamide, a satiety factor present in the small intestine (see Non-Patent Document 25). FAAH is a stearoylethanolamide hydrolase, and it has been reported that when stearoylethanolamide is administered to mice, feeding is suppressed (see Non-Patent Document 26). Since anandamide is an agonist of the nociceptor vanilloid receptor, the FAAH inhibitor acts like a vanilloid receptor agonist (eg, frequent urinary urinary incontinence preventive treatment interstitial cystitis) Is also expected (see Patent Document 1).

FAAH is also an enzyme that hydrolyzes oleamide, which is an endogenous sleep substance. For this reason, FAAH inhibitors induce sleep by suppressing the degradation of oleamide (Patent Document 2).
Japanese Patent Laid-Open No. 2002-202204 US2003 / 0092734A International Publication 2007/020888 Nature 1990, 346, 561 J. et al. Biol. Chem. 1995, 270, 3726. Eur. J. et al. Biochem. 1995, 232, 54 Science, 1992, 258, 1946. Nature, 1998, 394, 277 Pain, 1998, 76, 189 Nature, 2001, 414, 209. Science, 1995, 268, 1506. J. et al. Neurochem. 1983, 41, 1303 J. et al. Neurochem. 1984, 42, 1613 Nature, 1996, 384, 83. Nature, 1994, 372, 686. Proc. Natl. Acad. Sci. USA, 2001, 98, 9371. J. et al. Am. Chem. Soc. 1996, 118, 5938. Proc. Natl. Acad. Sci. USA, 2000, 97, 5044 Biochem. Biophys. Res. Commun. 1997, Vol. 231, p. 217 Biochem. Pharmacol. 1997, 53, 255 Nat. Med. 2003, Volume 9, p. 76 The Journal of Neuroscience. 2003, 23, 1136 Neuropsychopharmacology. 2004, 29, 1134 J Clin Endocrinol Metab. 2004, 89, 5168. Gastroenterology. 2003, 125, 677 J Clin Invest. 2004, 113, 1202. Nature Medicine. 2003, Volume 9, p. 76 Nature. 2001, 414, 209 FASEB Journal. 2004, 18: 1580

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics are being used as inflammatory pain and neuropathic pain. Longed for. An object of the present invention is to provide a safe and excellent pain prevention / treatment agent.

In order to achieve the above object, the present inventors have found that a compound represented by the following formula (I) or a salt thereof (hereinafter sometimes referred to as compound (I)) has FAAH inhibitory activity. As a result, they have found that they have excellent analgesic action in various pain models, and have completed the present invention.
That is, the present invention
[1]
Formula (I)

[Where:
Ring Ar ₁ represents an optionally substituted aromatic heterocycle;
A ₁ represents CR ₁ or N, A ₂ represents CR ₂ or N, A ₃ represents CR ₃ or N, A ₄ represents CR ₄ or N, and A ₁ , A ₂ , A ₃ , And at least one of A ₄ represents N;
Ring Ar ₂ represents an aromatic hydrocarbon ring that may be substituted with one or more halogen atoms, or an aromatic heterocycle that may be substituted with one or more halogen atoms;
R ₁ , R ₂ , R ₃ , and R ₄ each independently represent a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group. ]
Or a salt thereof;
[2]
Partial structure of formula (I)

But,

The compound of the above-mentioned [1], which is
[3]
Partial structure of formula (I)

But,

The compound of the above-mentioned [1], which is
[4]
The compound according to any one of the above [1] to [3], wherein the ring Ar ₁ is a pyridine ring, a pyridazine ring, or an isoxazole ring substituted with a C _1-6 alkyl group;
[5]
The compound according to any one of the above [1] to [3], wherein the ring Ar ₂ is a benzene ring, a furan ring, or a thiophene ring optionally substituted with one or two halogen atoms;
[6]
Ring Ar ₁ is a pyridine ring, a pyridazine ring, or an isoxazole ring substituted with a C _1-6 alkyl group,
A ring Ar ₂ may be substituted with one or two halogen atoms, a benzene ring, a furan ring, or a thiophene ring;
The compound according to any one of the above [1] to [3],
[7]
Formula (I) is converted to Formula (Ia)

[Where
Ring Ar ₃ represents a pyridazine ring optionally substituted with a halogen atom;
Ring Ar ₄ represents a benzene ring which may be substituted with a halogen atom. ]
The compound of the above-mentioned [1], which is
[8]
4- (4-phenylpyrimidin-2-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof;
[9]
4- [4- (2,3-difluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof;
[10]
4- [4- (3-fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof;
[11]
4- [4- (4-fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof;
[12]
A prodrug of the compound of the above-mentioned [1];
[13]
A medicament containing the compound of the above-mentioned [1] or a prodrug thereof;
[14]
A FAAH inhibitor comprising the compound according to [1] above or a prodrug thereof;
[15]
A prophylactic or therapeutic agent for pain, depression or anxiety, comprising the compound according to [1] above or a prodrug thereof;
[16]
A method for inhibiting FAAH, comprising administering an effective amount of the compound according to [1] above or a prodrug thereof to a mammal;
[17]
A method for preventing or treating pain, depression or anxiety, which comprises administering an effective amount of the compound or prodrug thereof according to [1] to a mammal;
[18]
Use of the compound of the above-mentioned [1] or a prodrug thereof for producing a FAAH inhibitor;
[19]
Use of the compound of the above-mentioned [1] or a prodrug thereof for producing a prophylactic or therapeutic agent for pain, depression or anxiety;
Is to provide.

The compound represented by the formula (I) of the present invention or a salt thereof has an excellent FAAH inhibitory activity and is useful as a safe and excellent preventive / therapeutic agent for pain, depression or anxiety.

Detailed Description of the Invention

As used herein, “having FAAH inhibitory activity” means “having an activity that directly or indirectly decreases the activity of fatty acid amide hydrolase”.
In the present specification, examples of the “halogen (atom)” include fluorine (atom), chlorine (atom), bromine (atom), and iodine (atom).
In the present specification, examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

In the above formula (I), the ring Ar ₁ represents an optionally substituted aromatic heterocycle.
Examples of the “aromatic heterocycle” represented by the ring Ar ₁ include, for example, 5 to 14 members containing 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. Preferably, it is a 5- to 10-membered, more preferably 5- or 6-membered aromatic heterocycle. Specifically, for example, thienyl (eg, 2-thienyl, 3-thienyl), furyl (eg, 2-furyl, 3-furyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), Thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl), pyrazinyl, pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (eg, 1 -Pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5 Isothiazolyl), and isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) can be mentioned.
The aromatic heterocycle is preferably a 5- or 6-membered aromatic heterocycle, more preferably pyridyl, pyridazinyl, or isoxazolyl, and still more preferably pyridazyl.
The aromatic heterocycle may have 1 to 5, preferably 1 or 2, substituents at substitutable positions. An unsubstituted aromatic heterocyclic ring is also preferable.
Examples of the substituent include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, etc.) which may be halogenated, hydroxylated, or oxoated. C _1-6 alkyl groups such as butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc .; halogenated such as fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, etc. also a C _1-6 alkyl group; hydroxymethyl, hydroxylated which may be C _1-6 alkyl groups such as hydroxyethyl, 2-oxopropyl, 2-oxobutyl may be oxo of such groups C _{1 -6} alkyl group), cycloalkyl group (for example, cyclopropyl Le, cyclobutyl, cyclopentyl, and the like _{C 3-6} cycloalkyl groups such as cyclohexyl), a lower alkynyl group (e.g., ethynyl, 1-propynyl, etc. _{C 2-6} alkynyl group propargyl, etc.), lower alkenyl groups (e.g., vinyl C _2-6 alkenyl groups such as allyl, isopropenyl, butenyl, isobutenyl, etc.), aralkyl groups (eg, C _7-11 aralkyl groups such as benzyl, α-methylbenzyl, phenethyl, etc.), aryl groups (eg, phenyl, C _6-10 aryl group such as naphthyl, etc., preferably phenyl group), aryloxy group (eg C _6-10 aryloxy group etc.), lower alkanoyl group (eg formyl; acetyl, propionyl, butyryl, isobutyryl etc.) the _{C 1-6} alkyl - carbonyl group), Ariruka Boniru (e.g., benzoyl group, C _6-10 aryl such as naphthoyl - such carbonyl group), a lower alkanoyloxy group (e.g., formyloxy; acetyloxy, propionyloxy, butyryloxy, etc. isobutyryloxy C _1-6 Alkyl-carbonyloxy group etc.), arylcarbonyloxy group (eg C _6-10 aryl-carbonyloxy group such as benzoyloxy, naphthoyloxy etc.), lower alkoxycarbonyl group (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc.) , isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, C _1-6 alkoxy, such as tert- butoxycarbonyl - such carbonyl group), an aralkyloxycarbonyl (e.g., benzyloxy carbonitrile _{C 7-11} aralkyloxycarbonyl group, etc.), a carbamoyl group such as Le, mono -, di- - or tri - halogeno - lower alkyl group (e.g., chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2- Mono-, di- or tri-halogeno-C _1-4 alkyl groups such as fluoroethyl), oxo groups, amidino groups, imino groups, amino groups, mono-lower alkylamino groups (eg, methylamino, ethylamino, Mono-C _1-4 alkylamino groups such as propylamino, isopropylamino, butylamino, etc.), di-lower alkylamino groups (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, methylethylamino, etc.) di _{-C 1-4} alkylamino group, etc.), lower alkyl - lower alkyl Other than carbonylamino group (for example, N-methylacetyl group), optionally halogenated lower alkylcarbonylamino group (for example, acetylamino group, trifluoroacetylamino group, etc.), carbon atom and one nitrogen atom 3 to 6-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom (for example, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, Imidazolidinyl, piperidyl, morpholinyl, dihydropyridyl, pyridyl, 3- to 6-membered cyclic amino groups such as N-methylpiperazinyl and N-ethylpiperazinyl), alkylenedioxy groups (eg methylenedioxy, ethylenedi) _{C 1-3} alkylenedioxy groups oxy such like , Hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (for example, N-methylsulfamoyl, N-ethylsulfamoyl, N- Mono-C _1-6 alkylsulfamoyl groups such as propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), dialkylsulfamoyl groups (eg, N, N-dimethylsulfamoyl) N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, di-C _1-6 alkylsulfamoyl groups such as N, N-dibutylsulfamoyl), alkylthio groups (for example, methylthio, Ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butyl C _1-6 alkylthio groups such as thio), arylthio groups (eg, C _6-10 arylthio groups such as phenylthio, naphthylthio, etc.), lower alkylsulfinyl groups (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.) C _1-6 alkylsulfinyl group, etc.), arylsulfinyl groups (eg, C _6-10 arylsulfinyl groups such as phenylsulfinyl, naphthylsulfinyl, etc.), lower alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) C _1-6 alkylsulfonyl groups such as butylsulfonyl), arylsulfonyl groups (for example, C _6-10 arylsulfonyl groups such as phenylsulfonyl, naphthylsulfonyl, etc.) and the like.
The substituent is preferably a C _1-6 alkyl group, and more preferably methyl.

In the above formula (I), the ring Ar ₂ represents an aromatic hydrocarbon ring that may be substituted with one or more halogen atoms, or an aromatic heterocyclic ring that may be substituted with one or more halogen atoms. Show.
Examples of the “aromatic hydrocarbon ring” represented by the ring Ar ₂ include C _6-14 aryl groups such as phenyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, and cyclooctatetraenyl.
The aromatic hydrocarbon ring is preferably phenyl.
The aromatic hydrocarbon ring may have 1 to 5, preferably 1 or 2, halogen atoms, preferably fluorine atoms, at substitutable positions. An unsubstituted aromatic hydrocarbon ring is also preferred.
Examples of the “aromatic heterocycle” represented by the ring Ar ₂ include the same “aromatic heterocycle” as described in the ring Ar ₁ .
The aromatic heterocycle is preferably furyl or thienyl.
The aromatic heterocyclic ring may have 1 to 5, preferably 1 or 2, halogen atoms, preferably fluorine atoms, at substitutable positions. An unsubstituted aromatic heterocyclic ring is also preferable.

In the above formula (I), A ₁ represents CR ₁ or N, A ₂ represents CR ₂ or N, A ₃ represents CR ₃ or N, A ₄ represents CR ₄ or N, and A ₁ , A ₂ , A ₃ , and A ₄ represent N.
Preferably, ₁ to _{2 of} A ₁ , A ₂ , A ₃ , and A ₄ are N, more preferably 2 are N.
R ₁ , R ₂ , R ₃ , and R ₄ each independently represent a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group.
Such optionally substituted C _1-6 alkyl groups include optionally halogenated or oxoated C _1-6 alkyl (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl). 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4 -Trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, 2-oxopropyl, 2-oxobutyl and the like.
R ₁ , R ₂ , R ₃ and R ₄ are preferably a hydrogen atom or a halogen atom (particularly a fluorine atom), more preferably a hydrogen atom.

That is, preferably the partial structure of formula (I)

May be substituted by a halogen atom (preferably a fluorine atom)

And more preferably

And more preferably

It is.

Preferably, the compound represented by formula (I) is:
Ring Ar ₁ is a pyridine ring, a pyridazine ring, or an isoxazole ring substituted with a C _1-6 alkyl group,
A ring Ar ₂ may be substituted with one or two halogen atoms, a benzene ring, a furan ring, or a thiophene ring;
Is a compound.

More preferably, the compound of formula (I) is of formula (Ia)

[Where
Ring Ar ₃ represents a pyridazine ring optionally substituted with a halogen atom;
Ring Ar ₄ represents a benzene ring which may be substituted with a halogen atom. ]
It is a compound represented by these.

In the above formula (Ia), the ring Ar ₃ may have 1 to 3 halogen atoms at substitutable positions. Preferably, ring Ar ₃ is unsubstituted. Here, “unsubstituted” means having no substituent at a substitutable position on the ring Ar ₃ in formula (Ia).
In the above formula (Ia), the ring Ar ₄ may have 1 to 5, preferably 1 or 2, halogen atoms at substitutable positions. An unsubstituted aromatic heterocyclic ring is also preferable. Here, “unsubstituted” means having no substituent at a substitutable position on the ring Ar ₄ in formula (Ia).
Examples of the halogen atom include fluorine, chlorine, bromine, and iodine. Preferably, the halogen atom is fluorine.
Preferably, the compound represented by the formula (Ia) is a compound in which the ring Ar ₃ is unsubstituted and the ring Ar ₄ is a benzene ring optionally having a halogen atom.

More preferably, the compound of formula (I) is:
4- (4-phenylpyrimidin-2-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide;
4- [4- (2,3-difluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide;
4- [4- (3-Fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide; or 4- [4- (4-fluorophenyl) pyrimidin-2-yl]- N-pyridazin-3-ylpiperidine-1-carboxamide.

The salt of the compound represented by the formula (I) is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid. And salts with basic or acidic amino acids.

Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt.

Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like. Particularly preferred is a salt with trifluoroacetic acid.

Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation Compound); a compound wherein the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl , Fumarylation, alanylation, dimethylaminomethylcarbonylation or tetrahydation Compound obtained by esterifying or amidating the carboxy group of compound (I) (eg, carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl) Esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl Esterified or methylamidated compounds) and the like. These compounds can be produced from compound (I) by a method known per se.

In addition, prodrugs of Compound (I) can be obtained under the physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7, Molecular Design, pages 163 to 198. It may change to.
Hereafter, the manufacturing method of this invention compound is demonstrated. In addition, you may use the compound used as a raw material compound as a salt, respectively. As such a salt, those exemplified as the salt of the aforementioned compound (I) can be used.

[Production Method 1]
Compound (I) of the present invention can be synthesized, for example, by the following scheme:

[Wherein L ₁ represents a leaving group, and other symbols are as defined above. ]
It can manufacture by the manufacturing method 1 represented by this, or the method according to this.

According to production method 1, compound (II) and compound (III) are first subjected to a coupling reaction to produce compound (IV).
Examples of the leaving group L ₁ include halides such as chloride, bromide and iodide, and alkylsulfonyloxy groups such as methanesulfonyloxy group and trifluoromethanesulfonyloxy group.
The coupling reaction is performed in the presence of a base and a catalyst with a solvent that does not affect the reaction. The amount of compound (III) to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (II).
Examples of bases include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, tripotassium phosphate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, Tertiary amines such as 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium Metal alkoxides such as tributoxide are used.
The amount of the base to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol equivalent, relative to compound (II), respectively.
Examples of the catalyst used in this reaction include palladium catalysts such as palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, It can also be performed by adding a ligand. As the ligand, phosphine is preferable, and trialkylphosphine (for example, tributylphosphine, tricyclohexylphosphine and the like), triarylphosphine (for example, triphenylphosphine and the like), trialkoxyphosphine and the like can be mentioned.
The amount of the palladium catalyst to be used is generally about 0.001 to about 5 mol, preferably about 0.01 to about 0.5 mol, relative to compound (II). The amount of “phosphine” to be used is generally about 0.001 to about 10 mol, preferably about 0.01 to about 1 mol, relative to compound (II).
Examples of the solvent that does not affect the reaction include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, halogenated hydrocarbons such as chloroform, and aromatics such as benzene and toluene. Group hydrocarbons, nitriles such as acetonitrile and propionitrile, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, and water. These solvents may be used by mixing two or more kinds at an appropriate ratio. The amount of these solvents used is, for example, 1 to 100 times the volume of the compound (II).
The reaction temperature is usually about −50 ° C. to about 250 ° C., preferably 0 ° C. to 120 ° C.
The reaction time is usually about 0.5 to about 36 hours.
In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.
The compound (IV) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like. In addition, compound (IV) may be used for the next reaction without isolation.

Subsequently, compound (IV) is reduced to produce compound (V).
The reduction of compound (IV) can be performed using a metal catalyst in a hydrogen atmosphere. If desired, an appropriate acid catalyst may be added.
Raney nickel, platinum oxide, metallic palladium, palladium carbon, etc. are used as the metal catalyst. The amount of the metal catalyst to be used is generally about 1 to about 1000 wt%, preferably about 5 to about 20 wt%, relative to compound (IV), respectively.
As the acid catalyst, organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, and mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid are used. The amount of the acid catalyst to be used is about 0.1 to excess amount per 1 mol of compound (IV).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Hydrocarbons such as cyclohexane and hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as acetic acid, water and the like are used. These solvents may be used by mixing two or more kinds at an appropriate ratio. The hydrogen pressure is usually about 1 to about 100 atmospheres, preferably about 1 to about 5 atmospheres. The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 to 24 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 20 to about 80 ° C.
The product (V) can be isolated from the reaction mixture according to a conventional method after removing the catalyst, and can be easily purified by a usual separation means (eg, recrystallization, distillation, chromatography, etc.). In addition, compound (V) may be used for the next reaction without isolation.

Next, the tert-butoxycarbonyl group of compound (V) is removed to produce compound (VI).
This reaction is carried out by reacting an acid according to a conventional method in a solvent that does not adversely influence the reaction.
Examples of the acid include hydrogen chloride, hydrogen bromide, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like. The amount of the acid used is preferably about 1 to about 100 molar equivalents relative to compound (V), respectively.
Examples of solvents that do not affect the reaction include hydrocarbons such as hexane and cyclohexane, alcohols such as methanol, ethanol, and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and acetic acid. Esters such as ethyl and methyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide Can be mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio. The amount of these solvents used is, for example, 1 to 100 times the volume of the compound (V).
The reaction temperature is usually about −50 ° C. to about 250 ° C., preferably 0 ° C. to 120 ° C.
The reaction time is usually about 0.5 to about 24 hours.
The compound (VI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. Compound (VI) may be used for the next reaction without isolation.

Next, compound (VI) is uread to produce compound (I).
Ureaization is performed on the compound (VI) with respect to the isocyanate (VII), 2,2,2-trichloroethoxycarbamate (VIII), bis (2,2,2-trichloroethoxycarbamate) (IX), or , Aryl ester (X) can be reacted.
The production of compound (I) by the reaction of compound (VI) and isocyanate (VII) is carried out in the presence of a base and isocyanate (VII) with a solvent that does not affect the reaction. Examples of the base include triethylamine, tributylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride and the like.
The amount of base and isocyanate (VII) to be used is preferably about 1 to about 5 molar equivalents relative to compound (VI), respectively.
Examples of the solvent that does not affect the reaction include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as chloroform and dichloromethane, and aromatic hydrocarbons such as benzene and toluene. Amides such as N, N-dimethylformamide, and sulfoxides such as dimethyl sulfoxide. Two or more of these solvents may be mixed and used at an appropriate ratio. The amount of these solvents to be used is, for example, 1 to 100 times the volume of the compound (VI).
The reaction temperature is usually about −50 ° C. to about 250 ° C., preferably 0 ° C. to 120 ° C.
The reaction time is usually about 0.5 to about 24 hours. The compound (I) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.

Compound (I) by reaction of Compound (VI) with 2,2,2-trichloroethoxycarbamate (VIII), bis (2,2,2-trichloroethoxycarbamate) (VII), or aryl ester (X) In the presence of a base in a solvent that does not affect the reaction. Examples of the base include pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride and the like.
The amount of base, 2,2,2-trichloroethoxycarbamate (VIII), bis (2,2,2-trichloroethoxycarbamate) (IX), and aryl ester (X) used is preferably relative to compound (VI). Is from about 1 to about 5 molar equivalents.
Examples of the solvent that does not affect the reaction include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane and chloroform, and esters such as ethyl acetate and methyl acetate. , Aromatic hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide, and sulfoxides such as dimethyl sulfoxide. Two or more of these solvents may be mixed and used at an appropriate ratio. The amount of these solvents to be used is, for example, 1 to 100 times the volume of the compound (V).
The reaction temperature is usually about −50 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C.
The reaction time is usually about 0.5 to about 36 hours.
The compound (I) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.

[Production Method 2]
Compound (IV) shown in Production Method 1 is

[Wherein L ₂ represents a leaving group, and other symbols are as defined above. ]
It can manufacture also by the manufacturing method 2 represented by this, or the method according to this.

Examples of the leaving group L ₂ include halides such as chloride, bromide, iodide, and alkylsulfonyloxy groups such as methanesulfonyloxy group and trifluoromethanesulfonyloxy group.
According to production method 2, compound (II) and compound (XI) are first subjected to a coupling reaction to produce compound (XII). Compound (XII) can be synthesized by a method similar to the production of compound (IV) shown in Production Method 1.
The compound (XII) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. In addition, compound (XII) may be used for the next reaction without isolation.

Next, compound (IV) is produced by a coupling reaction between compound (XII) and boronic acids or boronic esters.
The coupling reaction is performed in the presence of a base and a catalyst with a solvent that does not affect the reaction.
The amount of the boronic acid or boronic acid ester to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XII).
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, tripotassium phosphate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, Tertiary amines such as 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium Metal alkoxides such as tributoxide are used.
The amount of the base to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 molar equivalent, relative to compound (XII), respectively.
Examples of the catalyst used in this reaction include palladium catalysts such as palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, It can also be performed by adding a ligand. As the ligand, phosphine is preferable, and trialkylphosphine (for example, tributylphosphine, tricyclohexylphosphine and the like), triarylphosphine (for example, triphenylphosphine and the like), trialkoxyphosphine and the like can be mentioned.
The amount of the palladium catalyst to be used is generally about 0.001 to about 5 mol, preferably about 0.01 to about 0.5 mol, relative to compound (XII). The amount of the “phosphine” to be used is generally about 0.001 to about 10 mol, preferably about 0.01 to about 1 mol, relative to compound (XII).
Examples of the solvent that does not affect the reaction include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, halogenated hydrocarbons such as chloroform, and aromatics such as benzene and toluene. Group hydrocarbons, nitriles such as acetonitrile and propionitrile, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, and water. These solvents may be used by mixing two or more kinds at an appropriate ratio. The amount of these solvents to be used is, for example, 1 to 100 times the volume of the compound (XII).
The reaction temperature is usually about −50 ° C. to about 250 ° C., preferably 0 ° C. to 120 ° C.
The reaction time is usually about 0.5 to about 36 hours.
In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.
The compound (IV) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like. In addition, compound (IV) may be used for the next reaction without isolation.

When compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are encompassed in compound (I). For example, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (I). Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a mixture of crystal forms. The crystal can be produced by crystallization by applying a crystallization method known per se.
Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
Compounds labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also encompassed in compound (I). Further, a deuterium converter obtained by converting ¹ H into ² H (D) is also encompassed in compound (I).

Compound (I) or a prodrug thereof (hereinafter sometimes collectively referred to as the compound of the present invention) is a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human) ), It has an excellent FAAH inhibitory activity, and is therefore useful as a prophylactic / therapeutic agent for a disease state or disease involving FAAH.

As shown in the Examples below, administration of a compound of the present invention having FAAH inhibitory activity lowers the threshold in a pain model. Accordingly, the compound of the present invention prevents pain, for example, inflammatory pain associated with osteoarthritis and rheumatoid arthritis, and pain associated with diabetic painful neuropathy, postherpetic pain, trigeminal neuralgia and other neuropathic pain. And useful for treatment.
Further, as the diseases that the compounds of the present invention are considered to be useful for their prevention and treatment, cerebrovascular disorders caused by brain / nerve cell disorders, brain / nerve cell protective effects upon head injury or spinal cord injury, cardiac arrest Brain damage during post-resuscitation, brain function decline before and after brain surgery, hypoxia, hypoglycemia, brain or spinal cord trauma, drug poisoning, gas poisoning, diabetes, administration of antitumor agents, alcohol damage, etc. , Huntington's disease, prion disease, amyotrophic lateral sclerosis, spinocerebellar degeneration, eating disorder, obesity, frequent urination, urinary incontinence, rheumatism, osteoarthritis, interstitial cystitis, Crohn's disease, colitis , Colitis, colon cancer, colon cancer, contraception or AIDS, but is not limited thereto.
Based on the above-mentioned known findings, the compound of the present invention further comprises nausea, nausea or vomiting due to anticancer agents; anorexia or anorexia of cachexia in cancer or infectious diseases (eg, AIDS); convulsions and pain due to multiple sclerosis , Tremor, nystagmus or nocturnal urine; chronic pain; Huntington's chorea; Tourette syndrome; levotoba-induced movement disorder; Depression; anxiety; psychiatric disease; Crohn's disease; Alzheimer's disease; interstitial cystitis; AIDS; colitis; colitis; colon cancer; rectal cancer; hypertriglyceridemia; It is also useful as a preventive / therapeutic agent or contraceptive for Parkinson's disease.

In addition, FAAH is an enzyme that hydrolyzes oleamide, which is an endogenous sleep substance. Therefore, FAAH inhibitors induce sleep by suppressing the degradation of oleamide. Accordingly, the compounds of the present invention are useful for sleep disorders such as endogenous sleep disorders (eg, psychophysiological insomnia), extrinsic sleep disorders, and circadian rhythm disorders (eg, time zone change syndrome (time difference blur)), Sleep abnormalities such as shift work sleep disorder, irregular sleep awakening pattern, sleep phase regression syndrome, sleep phase advance syndrome, non-24-hour sleep awakening); sleep-related complications; internal or psychiatric disorders (eg, chronic obstructive lungs) It is useful as a preventive or therapeutic agent for sleep disorders associated with diseases, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, anxiety).

The subject compounds are further useful in methods for the present invention, methods for prevention, treatment, modulation, amelioration or reduction of the risks of diseases, disorders and conditions described herein. The dosage of active ingredient in the compositions of the invention can vary, however, it is necessary that the amount of active ingredient is such that a suitable dosage form is obtained. The active ingredient can be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dose depends on the desired therapeutic effect, the route of administration and the duration of treatment. Dosages will vary from patient to patient depending on the nature and severity of the disease, the patient's weight, the special diet performed later by the patient, the medications performed simultaneously, and other factors recognized by those skilled in the art. Generally, daily dose levels between 0.0001 mg / kg body weight and 10 mg / kg body weight are administered to patients, such as humans and the elderly, in order to obtain an effective inhibitory effect of FAAH. The range of doses that can be administered in a single dose or multiple doses is generally about 0.5 mg to 1.0 g per patient per day. Preferably, the dosage range is about 0.5 mg to 500 mg per patient per day, more preferably about 0.5 mg to 200 mg per patient per day, even more preferably about 5 mg to 50 mg per patient per day. . The pharmaceutical composition of the present invention may be provided in a solid dosage form preferably containing from about 0.5 mg to 500 mg of the active ingredient, more preferably from about 1 mg to 250 mg of the active ingredient. The pharmaceutical composition is preferably provided in a solid dosage form comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg of the active ingredient. For oral administration, the composition is preferably 1.0 to 1000 mg of active ingredient, especially active ingredient 1, 5, 10, 15, 20, 25, for symptomatic adjustment of the dose to the patient to be treated. Provided in the form of tablets containing 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

Compound (I) or a prodrug thereof has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity), and can be used as it is or pharmacologically. By mixing with a carrier or the like to obtain a pharmaceutical composition, it is possible to prevent or prevent various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys). It can be used as a therapeutic agent.

Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges. Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. Oral preparations are mentioned. These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration).
These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).

The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.

Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.

Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.

Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.

Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.

Preferable examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Suitable examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos. 1 and 2), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, β-carotene, chlorophyll, bengara) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

The compounds of the present invention may be combined with one or more other drugs in the treatment, prevention, amelioration, or reduction of the risk of a disease or condition for which the compounds of the present invention or other drugs may have utility In which case the drug combinations are safer or more effective than each other drug alone. Such other drugs may be administered simultaneously or sequentially with the compounds and compounds of the present invention, in the routes and amounts commonly used for such drugs. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred. However, combination therapy may also include therapies in which the compound of the invention and one or more other drugs are administered on different overlapping schedules. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can each be used in a smaller dose than when used alone. Is also envisaged. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Similarly, the compounds of the present invention are used in combination with other drugs used in the prevention, treatment, modulation, amelioration, or reduction of the risk of diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered concurrently or sequentially with the compounds and compounds of the present invention by the routes and amounts generally used for such drugs. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. In general, each effective dose is used. Thus, for example, when a compound of the present invention is combined with another drug, the weight ratio of the compound of the present invention to the other drug is generally about 1000: 1 to about 1: 1000, preferably about 200: 1 to The range is about 1: 200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations, the compounds of the present invention and other active drugs can be administered separately or together. Furthermore, the administration of one element can be before, simultaneously with, or after administration of the other drug.

Examples of a drug that can be used in combination with the compound of the present invention (hereinafter sometimes abbreviated as a concomitant drug) include, for example, nonsteroidal anti-inflammatory drugs (eg, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc. ), Disease-modifying anti-rheumatic drugs (DMARDs), antipyretic analgesics (acetanilide, acetaminophen, phenacetin, etc.), steroidal anti-inflammatory drugs (hydrocortisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, etc.), narcotic analgesics ( Morphine, fentanyl, codeine phosphate, pethidine, oxycodone, etc., non-narcotic analgesics (eg, tramadol), local anesthetics (eg, lidocaine), anticonvulsants (gabapentin, bupivacaine, carbamazepine, phenytoin) ), Antiarrhythmic drugs (procaine, etc.), anti-cytokine drugs (TNF inhibitor, MAP kinase inhibitor, etc.), aldose reductase inhibitors (Kinedakku etc.), cannabinoid agonists (tetrahydrocannabinol, etc.) and the like. Further, the concomitant drugs include anti-dementia therapeutic agents such as acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, zanapezil, etc.), β amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors [β secretase Inhibitors (eg, compounds described in WO98 / 38156, compounds described in WO02 / 2505, WO02 / 2506, WO02 / 2512, OM99-2 (WO01 / 00663)), γ-secretase inhibitors (such as LY-450139), γ-secretase Modulators (E2012 etc.), β amyloid protein aggregation inhibitors (eg, PTI-00703, ALZHEMED (NC-531), PPI-368 (Special Tables Hei 11-514333), PPI-558 (Special Tables Hei 2001-500852), SKF-74652 ( Biochem. J. (1999), 340 (1), 283-289)), β-amyloid antibody, β-amyloid vaccine, β-amyloid degrading enzyme, etc.], brain function stimulating agents (eg, aniracetam, nicergoline, etc.), neurogenesis / Regenerative promoter (eg, Akt / PKB activator, GSK-3β inhibitor, etc.), Parkinson's disease therapeutic agent [(eg, dopamine receptor agonist (L-dopa, bromocriptene, pergolide, taripexole, pripepexol, cabergoline) , Adamantadine, etc.), monoamine oxidase (MAO) inhibitors (deprenyl, sergiline (selegiline), remacemide, riluzole, etc.), anticholinergic agents (eg, trihexyphenidyl, biperiden, etc.)) , COMT inhibitors (eg, entacapone, etc.)], amyotrophic lateral sclerosis drugs (eg, riluzole, etc.), progression of dementia Abnormal behavior associated with cancer, therapeutic agents such as epilepsy (eg, sedatives, anxiolytics, etc.), apoptosis inhibitors (eg, CPI-1189, IDN-6556, CEP-1347, etc.), neuronal differentiation / regeneration promoters (leteprinim) (Leteprinim), xaliproden (SR-57746-A), SB-216763, etc.), antidepressants (eg, MAO inhibitors, tricyclic antidepressants, selective serotonin uptake inhibitors SSRI, selective serotonin Noradrenaline uptake inhibitor SNRI, triple uptake inhibitor, CRF antagonist, etc.), anxiolytics (eg, benzodiazepines, etc.), hypnotics (eg, benzodiazepines, non-benzodiazepines, melatonin agonists, etc.), thrombolytic agents (Eg, tissue plasminogen activator, urokinase, etc.), anticoagulants (eg, argatroban, warfarin, etc.), factor 10 inhibitor, thromboxane Antilipidemic agents (eg, ozagrel, etc.), antioxidants (eg, edaravone, etc.), anti-edema agents (eg, glycerol, mannitol, etc.), antihyperlipidemic drugs such as cholesterol-lowering drugs [statins (eg, Pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (eg, clofibrate, etc.), squalene synthesis fermentation inhibitors], antihypertensives (ACE inhibitors, angiotensin II antagonists, renin inhibitors, etc.), antidiabetics ( Examples, insulin preparations, insulin secretagogues such as sulfonylureas, PPAR agonists, insulin resistance improvers such as PPAR partial agonists, DPPIV inhibitors, etc.), anticancer agents (eg, platinum preparations, 5-FU, Anthracyclines, molecular targeted drugs, hormone therapy drugs, etc., frequent urination, urinary incontinence drugs (eg, Harncare, Sorif) Nashin etc.), overactive bladder therapeutic agent (e.g., tolterodine, etc.), therapeutic agents for osteoporosis (e.g., vitamin D preparation, PTH, calcium receptor antagonist, calcitonin, risedronate, alendronate, etc.) and the like.

By combining the compound of the present invention and a concomitant drug,
(1) The dose can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone.
(2) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer.
(3) By selecting a concomitant drug having a mechanism of action different from that of the compound of the present invention, the therapeutic effect can be sustained.
(4) By using the compound of the present invention and the concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.

Hereinafter, when the compound of the present invention and a concomitant drug are used in combination, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

As the administration form of the compound of the present invention and the concomitant drug, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separate administration of the compound of the present invention and the concomitant drug Simultaneous administration of the two preparations obtained by formulation into the same administration route, (3) Time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Formulating the compound of the present invention and the concomitant drug separately Administration of the two types of preparations obtained at different times by different administration routes (for example, the compound of the present invention; administration in the order of concomitant drugs, or administration in the reverse order).

The present invention is further explained in detail by the following examples, formulation examples and experimental examples, which are merely examples and do not limit the present invention and do not depart from the scope of the present invention. It may be changed with. In the following description of the production method, the starting compound and reaction product may form a salt that does not interfere with the reaction.

“Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C.
Other abbreviations used in the text have the following meanings.
s: singlet
d: Doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform DMSO-d ₆ : deuterated dimethyl sulfoxide
¹ H NMR: proton nuclear magnetic resonance (R, R) -Me-BPE: (+)-1,2-bis ((2R, 5R) -2,5-dimethylphosphorano) ethane (S, S) -Et -FerroTANE: (-)-1,1'-bis ((2S, 4S) -2,4-diethylphosphotano) ferrocene

Reference example 1
tert-Butyl 4- (4-phenylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

2-Chloro-4-phenylpyrimidine (6.00 g, 31.5 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3 , 6-Dihydropyridine-1 (2H) -carboxylate (10.7 g, 34.7 mmol), sodium carbonate (6.68 g, 63.0 mmol) in 1,4-dioxane (100 ml) / water (25 ml) Was added tetrakistriphenylphosphine palladium (1.82 g, 1.60 mmol) at room temperature and stirred at 80 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25: 1, 0.5% triethylamine was added) to obtain the title compound (8.05 g, 76%) as a solid.
¹ H NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.76 (2H, s), 3.60 (2H, t, J = 5.4 Hz), 4.14 (2H, d, J = 2.4 Hz), 7.20-7.30 (1H, brs), 7.40-7.50 (4H, m), 8.02-8.11 (2H, m), 8.65 ( 1H, d, J = 5.2 Hz).

Reference example 2
4-Phenyl-2-piperidin-4-ylpyrimidine dihydrochloride

Tert-butyl 4- (4-phenylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (8.00 g, 24.0 mmol) obtained in Reference Example 1 in methanol (300 ml) To the solution, 10% palladium carbon (800 mg) was added under a nitrogen atmosphere, and the reaction solution was stirred overnight at room temperature under a hydrogen atmosphere of 3 atm. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (50 ml), saturated hydrogen chloride / ethyl acetate solution (25 ml) was added, and the mixture was stirred at room temperature for 2 hr. The resulting solid was collected by filtration, washed with ethyl acetate, and dried to give the title compound (7.91 g, quant.) As a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.99-2.12 (2H, m), 2.14-2.22 (2H, m), 3.00 (2H, q, J = 11.7 Hz) ), 3.17-3.35 (3H, m), 7.48-7.57 (3H, m), 8.00 (1H, d, J = 5.6 Hz), 8.21 (2H, dd) , J = 7.6, 4.4 Hz), 8.84 (1H, d, J = 9.2 Hz), 9.17 (1H, brs), 9.41 (1H, brs).

Reference example 3
tert-Butyl 4- [4- (2,3-difluorophenyl) pyrimidin-2-yl] -3,6-dihydropyridine-1 (2H) -carboxylate

In the same manner as in Reference Example 1, the title compound (6.11 g, 62%) was obtained as a solid from 2-chloro-4- (2,3-difluorophenyl) pyrimidine.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.78 (2H, d, J = 0.8 Hz), 3.65 (2H, s), 4.19 (2H, s) 7.17-7.36 (3H, m), 7.62 (1H, dd, J = 5.2, 2.0 Hz), 7.96 (1H, t, J = 9.0 Hz), 8. 75 (1H, d, J = 5.2 Hz).

Reference example 4
4- (2,3-Difluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 2, tert-butyl 4- [4- (2,3-difluorophenyl) pyrimidin-2-yl] -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 3 Gave the title compound (4.65 g, 82%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.95-2.09 (2H, m), 2.10-2.20 (2H, m), 3.01 (2H, q, J = 11.6 Hz) ), 3.15-3.25 (1H, m), 3.25-3.45 (2H, m), 7.34-7.45 (1H, m), 7.56-7.68 (1H) M), 7.77 (1H, dd, J = 5.2, 2.0 Hz), 7.84 (1H, t, J = 7.2 Hz), 8.89 (1H, d, J = 5. 2 Hz), 9.04 (1H, brs), 9.33 (1H, brs).

Reference Example 5
tert-Butyl 4- (6-phenylpyrimidin-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

The title compound (1.64 g, 47%) was obtained as a solid from 4-chloro-6-phenylpyrimidine in the same manner as in Reference Example 1.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.62-2.75 (2H, m), 3.69 (2H, t, J = 5.4 Hz), 4.20 ( 2H, d, J = 2.8 Hz), 6.99 (1H, s), 7.47-7.54 (3H, m), 7.71 (1H, s), 8.03-8.12 ( 2H, m), 9.19 (1H, s).

Reference Example 6
4-Phenyl-6-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 2, the title compound (3.30 g) was obtained from tert-butyl 4- (6-phenylpyrimidin-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 5. 74%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.90-2.09 (4H, m), 2.92-3.11 (3H, m), 3.30-3.40 (2H, m), 7.46-7.60 (3H, m), 7.97 (1H, d, J = 1.2 Hz), 8.13-8.23 (2H, m), 9.01 (1H, brs), 9.15 (1H, d, J = 1.2 Hz), 9.30 (1H, brs).

Reference Example 7
tert-Butyl 4- [6- (2,3-difluorophenyl) pyrimidin-4-yl] -3,6-dihydropyridine-1 (2H) -carboxylate

The title compound (7.10 g, 68%) was obtained as a solid from 4-chloro-6- (2,3-difluorophenyl) pyrimidine in the same manner as in Reference Example 1.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.65 (2H, d, J = 2.8 Hz), 3.66 (2H, t, J = 5.4 Hz), 4. 18 (2H, d, J = 2.8 Hz), 6.98 (1H, s), 7.18-7.35 (2H, m), 7.80 (1H, s), 7.87 (1H, t, J = 7.2 Hz), 9.21 (1H, s).

Reference Example 8
4- (2,3-Difluorophenyl) -6-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 2, from the tert-butyl 4- [6- (2,3-difluorophenyl) pyrimidin-4-yl] -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 7. The title compound (5.70 g, 86%) was obtained as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.90-2.12 (4H, m), 2.99 (2H, q, J = 11.2 Hz), 3.06-3.21 (1H, m ), 3.30-3.40 (2H, m), 7.33-7.47 (1H, m), 7.63 (1H, d, J = 8.4 Hz), 7.75-7.88. (2H, m), 9.15 (1H, brs), 9.26 (1H, s), 9.35 (1H, brs).

Reference Example 9
4-chloro-2-phenylpyrimidine

A solution of 2-phenyl-4-methoxypyrimidine (9.00 g, 48.6 mmol) in phenylphosphonic dichloride (36 ml) was stirred at 140 ° C. overnight. The reaction solution was diluted with ice water (200 ml), adjusted to pH = 8 using sodium carbonate, and extracted with methylene chloride. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.75 g, 94%) as a solid.
¹ H NMR (CDCl ₃ ) δ: 7.21 (1H, d, J = 5.2 Hz), 7.38-7.52 (3H, m), 8.42 (2H, d, J = 7.4) , 2.2 Hz), 8.65 (1H, d, J = 5.2 Hz).

Reference Example 10
tert-Butyl 4- (2-phenylpyrimidin-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

In the same manner as in Reference Example 1, the title compound (7.08 g, 67%) was obtained as a solid from 4-chloro-2-phenylpyrimidine obtained in Reference Example 9.
¹ H NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.73 (2H, d, J = 5.6 Hz), 3.69 (2H, t, J = 5.6 Hz), 4. 21 (2H, d, J = 1.6 Hz), 7.03 (1H, s), 7.21 (1H, d, J = 5.6 Hz), 7.45-7.56 (3H, m), 8.45-8.55 (2H, m), 8.75 (1H, d, J = 5.2 Hz).

Reference Example 11
2-Phenyl-4-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 2, the title compound (6.38 g) was obtained from tert-butyl 4- (2-phenylpyrimidin-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 10. 97%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.95-2.18 (4H, m), 2.91-3.15 (3H, m), 3.30-3.40 (2H, m), 7.36 (1H, d, J = 5.2 Hz), 7.46-7.55 (3H, m), 8.34-8.47 (2H, m), 8.83 (1H, d, J = 5.2 Hz), 9.12 (1H, brs), 9.43 (1H, brs).

Reference Example 12
2- (2,3-Difluorophenyl) -4-methoxypyrimidine

2-chloro-4-methoxypyrimidine (30.0 g, 210 mmol), 2,3-difluorophenylboronic acid (50.5 g, 320 mmol), sodium carbonate (44.5 g, 420 mmol) of 1,4-dioxane Tetrakistriphenylphosphine palladium (11.6 g, 10.0 mmol) was added to a (240 ml) / water (60 ml) solution at room temperature and stirred at 80 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1, 0.5% triethylamine added) and recrystallized from hexane and methylene chloride to give the title compound (25.6 g, 55%) as a solid Obtained.
¹ H NMR (DMSO-d ₆ ) δ: 3.95 (3H, s), 6.85-6.96 (1H, m), 7.22-7.34 (1H, m), 7.46- 7.60 (1H, m), 8.86 (1H, t, J = 6.4 Hz), 8.62 (1H, d, J = 8.8 Hz).

Reference Example 13
4-Chloro-2- (2,3-difluorophenyl) pyrimidine

In the same manner as in Reference Example 9, the title compound (9.00 g, 88%) was obtained as a solid from 2- (2,3-difluorophenyl) -4-methoxypyrimidine obtained in Reference Example 12.
¹ H NMR (DMSO-d ₆ ) δ: 7.30-7.40 (1H, m), 7.63 (1H, q, J = 4.0 Hz), 7.75 (1H, d, J = 5) .2 Hz), 7.85 (1 H, t, J = 7.4 Hz), 8.94 (1 H, d, J = 5.2 Hz).

Reference Example 14
tert-Butyl 4- [2- (2,3-difluorophenyl) pyrimidin-4-yl] -3,6-dihydropyridine-1 (2H) -carboxylate

In the same manner as in Reference Example 1, the title compound (5.50 g, 56%) was obtained as a solid from 4-chloro-2- (2,3-difluorophenyl) pyrimidine obtained in Reference Example 13.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.68 (2H, d, J = 1.6 Hz), 3.58-3.74 (2H, m), 4.21 ( 2H, s), 7.05 (1H, s), 7.13-7.22 (1H, m), 7.23-7.37 (2H, m), 7.88 (1H, t, J = 7.2 Hz), 8.81 (1H, d, J = 5.2 Hz).

Reference Example 15
2- (2,3-Difluorophenyl) -4-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 2, tert-butyl 4- [2- (2,3-difluorophenyl) pyrimidin-4-yl] -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 14 Gave the title compound (1.13 g, 90%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.88-2.02 (2H, m), 2.03-2.15 (2H, m), 3.30-3.40 (2H, m), 3.05-3.16 (1H, m), 3.34 (2H, d, J = 12.0 Hz), 7.34 (1H, dd, J = 13.4, 7.8 Hz), 7.44 (1H, d, J = 5.2 Hz), 7.58 (1H, dd, J = 7.8, 6.4 Hz), 7.83 (1H, t, J = 7.2 Hz), 8.70− 9.09 (2H, m), 9.13-9.51 (1H, brs).

Reference Example 16
tert-Butyl 4-phenyl-3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate

2-Chloro-4-phenylpyridine (3.51 g, 18.5 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3 , 6-Dihydropyridine-1 (2H) -carboxylate (6.20 g, 19.4 mmol), potassium carbonate (7.67 g, 55.5 mmol) in 1,2-dimethoxyethane (40 ml) / water (20 ml) Tetrakistriphenylphosphine palladium (1.07 g, 0.925 mmol) was added to the solution at room temperature and stirred at 90 ° C. for 17 hours. Water was poured into the reaction solution and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to give the title compound (4.10 g, 66%) as a solid.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.70-2.73 (2H, m), 3.68 (2H, brs), 4.16 (2H, d, J = 2.8 Hz), 6.66-6.68 (1 H, m), 7.38 (1 H, dd, J = 4.8, 1.6 Hz), 7.43-7.52 (3 H, m), 7.52 (1H, brs), 7.62-7.65 (2H, m), 8.61 (1H, dd, J = 4.8, 0.8 Hz).

Reference Example 17
tert-Butyl 4- (4-phenylpyridin-2-yl) piperidine-1-carboxylate

Tert-Butyl 4-phenyl-3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate (4.10 g, 12.2 mmol) ethanol obtained in Reference Example 16 To the (40 ml) suspension, 10% palladium carbon (50.0 mg) was added under a nitrogen atmosphere, and the reaction solution was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (4.15 g, quant.) As an oil.
¹ H NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.73-1.84 (2H, m), 1.97 (2H, d, J = 13.2 Hz), 2.86- 2.96 (3H, m), 4.29 (2H, brs), 7.35-7.37 (2H, m), 7.44-7.51 (3H, m), 7.62-7. 64 (2H, m), 8.58 (1H, dd, J = 4.8, 1.2 Hz).

Reference Example 18
4-Phenyl-2-piperidin-4-ylpyridine dihydrochloride

To a solution of tert-butyl 4- (4-phenylpyridin-2-yl) piperidine-1-carboxylate (4.15 g, 12.3 mmol) obtained in Reference Example 17 in methanol (20 ml), 4.0 M hydrogen chloride. / Methanol solution (12.3 ml) was added and stirred at room temperature for 24 hours. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.77 g, 88%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 2.10-2.20 (4H, m), 2.97-3.06 (2H, m), 3.35-3.42 (3H, m), 7.57-7.63 (3H, m), 7.96-7.98 (2H, m), 8.01 (1H, brs), 8.08 (1H, brs), 8.77 (1H, d, J = 6.0 Hz), 9.08 (1H, brs), 9.24 (1H, brs).

Reference Example 19
tert-Butyl 4- (2-fluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate

The title compound (6.47 g, 89%) was obtained as a solid from 2-chloro-4- (2-fluorophenyl) pyridine in the same manner as in Reference Example 16.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.68-2.71 (2H, m), 3.66 (2H, brs), 4.15-4.16 (2H, m), 6.66-6.67 (1H, m), 7.17-7.29 (2H, m), 7.34-7.36 (1H, m), 7.39-7.44 ( 1H, m), 7.48 (1H, td, J = 7.6, 1.6 Hz), 7.55 (1H, brs), 8.63 (1H, dd, J = 5.4, 0.6 Hz) ).

Reference Example 20
tert-Butyl 4- [4- (2-fluorophenyl) pyridin-2-yl] piperidine-1-carboxylate

Tert-Butyl 4- (2-fluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate obtained in Reference Example 19 in the same manner as Reference Example 17 Gave the title compound (6.51 g, quant.) As an oil.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.72-1.83 (2H, m), 1.97 (2H, d, J = 13.6 Hz), 2.86- 2.95 (3H, m), 4.28 (2H, brs), 7.17-7.28 (2H, m), 7.32-7.34 (2H, m), 7.38-7. 43 (1H, m), 7.46 (1H, td, J = 7.7, 2.0 Hz), 8.60 (1H, dd, J = 5.2, 0.8 Hz).

Reference Example 21
4- (2-Fluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride

Title compound (4.50 g, 67%) from tert-butyl 4- [4- (2-fluorophenyl) pyridin-2-yl] piperidine-1-carboxylate obtained in Reference Example 20 in the same manner as Reference Example 18 Was obtained as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 2.09-2.21 (4H, m), 3.01-3.04 (2H, m), 3.41 (3H, d, J = 11.6 Hz) ), 7.45 (2H, q, J = 7.2 Hz), 7.64 (1H, q, J = 7.2 Hz), 7.81 (1H, t, J = 7.2 Hz), 7.91 (1H, brs), 7.95 (1H, d, J = 4.0 Hz), 8.82 (1H, d, J = 5.2 Hz), 9.29 (1H, brs), 9.44 (1H , Brs).

Reference Example 22
tert-Butyl 4- (3-fluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate

In the same manner as in Reference Example 16, the title compound (4.77 g, 93%) was obtained as a solid from 2-chloro-4- (3-fluorophenyl) pyridine.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.69-2.72 (2H, m), 3.68 (2H, brs), 4.16 (2H, d, J = 2.0 Hz), 6.67-6.70 (1 H, m), 7.12-7.17 (1 H, m), 7.31-7.36 (2 H, m), 7.41-7. 49 (2H, m), 7.54 (1H, brs), 8.63 (1H, dd, J = 5.2, 0.8 Hz).

Reference Example 23
tert-Butyl 4- [4- (3-fluorophenyl) pyridin-2-yl] piperidine-1-carboxylate

In the same manner as in Reference Example 17, tert-butyl 4- (3-fluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxy obtained in Reference Example 22 The title compound (4.80 g, quant.) Was obtained from oil as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.73-1.84 (2H, m), 1.97 (2H, d, J = 13.2 Hz), 2.86- 2.96 (3H, m), 4.29 (2H, brs), 7.11-7.16 (1H, m), 7.30-7.34 (3H, m), 7.39-7. 49 (2H, m), 8.60 (1H, dd, J = 4.8, 1.2 Hz).

Reference Example 24
4- (3-Fluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride

In the same manner as in Reference Example 18, from the tert-butyl 4- [4- (3-fluorophenyl) pyridin-2-yl] piperidine-1-carboxylate obtained in Reference Example 23, the title compound (3.50 g, 71% ) Was obtained as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 2.10-2.23 (4H, m), 2.99-3.08 (2H, m), 3.40-3.43 (3H, m), 7.46 (1H, td, J = 8.4, 2.4 Hz), 7.63-7.69 (1H, m), 7.86 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 10.0 Hz), 8.07 (1 H, s), 8.12 (1 H, d, J = 5.2 Hz), 8.81 (1 H, d, J = 5.6 Hz) , 9.23 (1H, brs), 9.39 (1H, brs).

Reference Example 25
tert-Butyl 4- (4-fluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate

In the same manner as in Reference Example 16, the title compound (4.77 g, 93%) was obtained as a solid from 2-chloro-4- (4-fluorophenyl) pyridine.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.69-2.72 (2H, m), 3.68 (2H, brs), 4.16 (2H, d, J = 2.4 Hz), 6.67-6.68 (1 H, m), 7.16-7.21 (2 H, m), 7.33 (1 H, dd, J = 5.2, 1.6 Hz), 7.52 (1H, brs), 7.60-7.63 (2H, m), 8.61 (1H, dd, J = 5.2, 0.8 Hz).

Reference Example 26
4- (4-Fluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride

In the same manner as in Reference Example 17, tert-butyl 4- (4-fluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxy obtained in Reference Example 25 The tert-butyl 4- [4- (4-fluorophenyl) pyridin-2-yl] piperidine-1-carboxylate (4.80 g, quant.) Was obtained as an oil from the late. This compound (4.80 g, 13.5 mmol) was dissolved in methanol (27 ml), 4.0 M hydrogen chloride / methanol solution (13.5 ml, 53.9 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.80 g, 86%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 2.07-2.19 (4H, m), 2.99-3.02 (2H, m), 3.37-3.40 (3H, m), 7.44 (2H, t, J = 8.6 Hz), 7.99-8.05 (4H, m), 8.75 (1H, d, J = 5.6 Hz), 9.12 (1H, brs) ), 9.29 (1H, brs).

Reference Example 27
2-Chloro-4- (2,3-difluorophenyl) pyridine

4-Bromo-2-chloropyridine (5.00 g, 26.0 mmol), 2,3-difluorophenylboronic acid (4.10 g, 26.0 mmol), potassium carbonate (7.18 g, 52.0 mmol) Tetrakistriphenylphosphine palladium (1.50 g, 1.30 mmol) was added to a methanol (90 ml) solution at room temperature, and the mixture was stirred at 50 ° C. for 17 hours. Water was poured into the reaction solution and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to give the title compound (4.30 g, 73%) as a solid.
¹ H NMR (CDCl ₃ ) δ: 7.18-7.31 (3H, m), 7.41-7.43 (1H, m), 7.52-7.53 (1H, m), 8. 48 (1H, dd, J = 5.0, 1.6 Hz).

Reference Example 28
tert-Butyl 4- (2,3-difluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate

In the same manner as in Reference Example 16, the title compound (6.50 g, 98%) was obtained as a solid from 2-chloro-4- (2,3-difluorophenyl) pyridine obtained in Reference Example 27.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.68-2.71 (2H, m), 3.67 (2H, t, J = 5.4 Hz), 4.15- 4.16 (2H, m), 6.66-6.69 (1H, m), 7.18-7.28 (3H, m), 7.32-7.34 (1H, m), 7. 53 (1H, brs), 8.65 (1H, dd, J = 5.2, 0.8 Hz).

Reference Example 29
4- (2,3-Difluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride

In the same manner as in Reference Example 17, tert-butyl 4- (2,3-difluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) obtained in Reference Example 28 The carboxylate gave tert-butyl 4- [4- (2,3-difluorophenyl) pyridin-2-yl] piperidine-1-carboxylate (6.50 g, 99%) as an oil. This compound (6.50 g, 17.4 mmol) was dissolved in methanol (35 ml), 4.0 M hydrogen chloride / methanol solution (17.4 ml, 69.4 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The resulting solid was collected by filtration, washed with ethyl acetate, and dried to give the title compound (4.88 g, 81%) as a solid.
¹ H NMR (DMSO-d6) δ: 2.04-2.17 (4H, m), 3.01-3.06 (2H, m), 3.32-3.41 (3H, m), 7 .42 (1H, q, J = 4.8 Hz), 7.56 (1H, t, J = 6.8 Hz), 7.64 (1H, q, J = 9.2 Hz), 7.80 (2H, brs), 8.79 (1H, d, J = 5.2 Hz), 9.11 (1H, brs), 9.31 (1H, brs).

Reference Example 30
2-Chloro-4- (2,4-difluorophenyl) pyridine

In the same manner as in Reference Example 27, the title compound (3.70 g, 79%) was obtained as a solid from 4-bromo-2-chloropyridine.
¹ H NMR (CDCl ₃ ) δ: 6.95-7.05 (2H, s), 7.37-7.39 (1H, m), 7.43-7.47 (1H, m), 7. 49 (1H, brs), 8.47 (1H, d, J = 13.2 Hz).

Reference Example 31
tert-Butyl 4- (2,4-difluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) -carboxylate

In the same manner as in Reference Example 16, the title compound (4.15 g, 68%) was obtained as a solid from 2-chloro-4- (2,4-difluorophenyl) pyridine obtained in Reference Example 30.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.67-2.71 (2H, m), 3.67 (2H, t, J = 5.6 Hz), 4.15- 4.16 (2H, m), 6.65-6.67 (1H, m), 6.93-7.04 (2H, m), 7.29-7.31 (1H, m), 7. 43-7.49 (1H, m), 7.50 (1H, brs), 8.62 (1H, dd, J = 5.2, 0.8 Hz).

Reference Example 32
4- (2,4-Difluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride

In the same manner as in Reference Example 17, tert-butyl 4- (2,4-difluorophenyl) -3 ′, 6′-dihydro-2,4′-bipyridine-1 ′ (2′H) obtained in Reference Example 31 The carboxylate gave tert-butyl 4- [4- (2,4-difluorophenyl) pyridin-2-yl] piperidine-1-carboxylate (4.07 g, 98%) as an oil. This compound (4.07 g, 10.9 mmol) was dissolved in methanol (36 ml), 4.0 M hydrogen chloride / methanol solution (10.1 ml, 43.5 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.40 g, 82%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 2.01-2.15 (4H, m), 2.98-3.07 (2H, m), 3.28 (1H, t, J = 11.4 Hz ), 3.39 (2H, d, J = 12.4 Hz), 7.33 (1H, td, J = 8.4, 2.0 Hz), 7.49-7.55 (1H, m), 7 .74-7.87 (3H, m), 8.75 (1H, d, J = 5.2 Hz), 9.01 (1H, brs), 9.21 (1H, brs).

Reference Example 33
2-Chloro-4-furan-3-ylpyrimidine

1,2-Dimethoxyethane in 2,4-dichloropyrimidine (1.00 g, 6.71 mmol), furan-3-ylboronic acid (826.1 mg, 7.38 mmol), 2N aqueous sodium carbonate solution (6.7 ml) Tetrakistriphenylphosphine palladium (931 mg, 0.805 mmol) was added to the (10 ml) solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at 105 ° C. for 40 minutes by a microwave reactor (Initiator ™, Biotage). Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (916 mg, 76%) as a solid.
¹ H NMR (CDCl ₃ ) δ: 6.88-6.93 (1H, m), 7.29-7.35 (1H, m), 7.52-7.56 (1H, m), 8. 21-8.25 (1H, m), 8.55 (1H, d, J = 4.9 Hz).

Reference Example 34
tert-Butyl 4- (4-furan-3-ylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

2-Chloro-4-furan-3-ylpyrimidine obtained in Reference Example 33 (500 mg, 2.77 mmol), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (942 mg, 3.05 mmol), 1,2-dimethoxyethane (7.5 ml) in 2N aqueous sodium carbonate (4.2 ml) Tetrakistriphenylphosphine palladium (384 mg, 0.332 mmol) was added to the solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at 105 ° C. for 40 minutes by a microwave reactor (Initiator ™, Biotage). Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (782 mg, 86%) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.77 (2H, brs), 3.59-3.71 (2H, m), 4.12-4.27 (2H, m), 6.89-6.96 (1H, m), 7.20 (1H, d, J = 5.3 Hz), 7.24 (1H, brs), 7.53 (1H, t, J = 1.7 Hz), 8.17 (1 H, s), 8.64 (1 H, d, J = 5.3 Hz).

Reference Example 35
tert-Butyl 4- (4-furan-3-ylpyrimidin-2-yl) piperidine-1-carboxylate

Tert-butyl 4- (4-furan-3-ylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (780 mg, 2.38 mmol) obtained in Reference Example 34 in tetrahydrofuran ( 12 ml), palladium on carbon (156 mg) was added to the solution under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (542 mg, 69%) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.77-1.95 (2H, m), 1.96-2.08 (2H, m), 2.79-3. 10 (3H, m), 4.09-4.35 (2H, m), 6.91 (1H, d, J = 1.9 Hz), 7.21 (1H, d, J = 4.9 Hz), 7.48-7.55 (1 H, m), 8.16 (1 H, s), 8.61 (1 H, d, J = 4.9 Hz).

Reference Example 36
4-furan-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride

To a solution of tert-butyl 4- (4-furan-3-ylpyrimidin-2-yl) piperidine-1-carboxylate (540 mg, 1.64 mmol) obtained in Reference Example 35 in ethyl acetate (5.4 ml) was added 4N A hydrogen chloride-ethyl acetate solution (5.4 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and the resulting crystals were collected by filtration to give the title compound (407 mg, 77%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.94-2.26 (4H, m), 2.93-3.13 (2H, m), 3.13-3.27 (1H, m), 3.27-3.41 (2H, m), 7.12-7.19 (1H, m), 7.75 (1H, d, J = 5.3 Hz), 7.85-7.92 (1H M), 8.58-8.65 (1H, m), 8.80 (1H, d, J = 5.3 Hz), 9.09 (1H, brs), 9.32 (1H, brs).

Reference Example 37
2-Chloro-4-thiophen-3-ylpyrimidine

The title compound (1.02 g, 77%) was obtained as a solid from 2,4-dichloropyrimidine and thiophen-3-ylboronic acid in the same manner as in Reference Example 33.
¹ H NMR (CDCl ₃ ) δ: 7.42-7.50 (2H, m), 7.65-7.72 (1H, m), 8.18-8.25 (1H, m), 8. 58 (1H, d, J = 5.3 Hz).

Reference Example 38
tert-Butyl 4- (4-thiophen-3-ylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

In the same manner as in Reference Example 34, the title compound (793 mg, 90%) was obtained as an oil from 2-chloro-4-thiophen-3-ylpyrimidine obtained in Reference Example 37.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.80 (2H, brs), 3.60-3.71 (2H, m), 4.15-4.26 (2H, m), 7.19-7.32 (1H, m), 7.36 (1H, d, J = 5.3 Hz), 7.43 (1H, dd, J = 5.3, 3.0 Hz), 7.68-7.76 (1H, m), 8.12-8.18 (1H, m), 8.67 (1H, d, J = 5.3 Hz).

Reference Example 39
tert-Butyl 4- (4-thiophen-3-ylpyrimidin-2-yl) piperidine-1-carboxylate

Tert-butyl 4- (4-thiophen-3-ylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (790 mg, 2.30 mmol) of ethyl acetate obtained in Reference Example 38 (12 ml) To the solution was added palladium carbon (158 mg) under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 6 hours under a hydrogen atmosphere of 3 atm. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (477 mg, 60%) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.80-1.97 (2H, m), 1.98-2.11 (2H, m), 2.82-2. 98 (2H, m), 2.99-3.12 (1H, m), 4.12-4.34 (2H, m), 7.37 (1H, d, J = 5.3 Hz), 7. 42 (1H, dd, J = 5.3, 3.0 Hz), 7.67-7.74 (1H, m), 8.11-8.17 (1H, m), 8.65 (1H, d , J = 5.3 Hz).

Reference Example 40
4-thiophen-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 36, the title compound (415 mg, 95%) was obtained as a solid from tert-butyl 4- (4-thiophen-3-ylpyrimidin-2-yl) piperidine-1-carboxylate obtained in Reference Example 39. Got as.
¹ H NMR (DMSO-d ₆ ) δ: 1.96-2.14 (2H, m), 2.14-2.27 (2H, m), 2.97-3.13 (2H, m), 3.14-3.27 (1H, m), 3.28-3.42 (2H, m), 7.71-7.77 (1H, m), 7.81-7.90 (2H, m ), 8.48-8.55 (1H, m), 8.80 (1H, d, J = 5.3 Hz), 8.92 (1H, brs), 9.17 (1H, brs).

Reference Example 41
2-Chloro-4- (3-fluorophenyl) pyrimidine

The title compound (780 mg, 56%) was obtained as a solid from 2,4-dichloropyrimidine and 3-fluorophenylboronic acid in the same manner as in Reference Example 33.
¹ H NMR (CDCl ₃ ) δ: 7.20-7.30 (1H, m), 7.44-7.55 (1H, m), 7.64 (1H, d, J = 4.9 Hz), 7.79-7.91 (2H, m), 8.68 (1 H, d, J = 4.9 Hz).

Reference Example 42
tert-Butyl 4- [4- (3-fluorophenyl) pyrimidin-2-yl] -3,6-dihydropyridine-1 (2H) -carboxylate

In the same manner as in Reference Example 34, the title compound (1.19 g, 90%) was obtained as an oil from 2-chloro-4- (3-fluorophenyl) pyrimidine obtained in Reference Example 41.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.82 (2H, brs), 3.63-3.72 (2H, m), 4.18-4.26 (2H, m), 7.16-7.25 (1H, m), 7.27-7.39 (1H, m), 7.42-7.54 (2H, m), 7.84-7.93 ( 2H, m), 8.75 (1H, d, J = 5.3 Hz).

Reference Example 43
tert-Butyl 4- [4- (3-fluorophenyl) pyrimidin-2-yl] piperidine-1-carboxylate

In the same manner as in Reference Example 35, the title was obtained from tert-butyl 4- [4- (3-fluorophenyl) pyrimidin-2-yl] -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 42. The compound (943 mg, 79%) was obtained as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.82-2.00 (2H, m), 2.01-2.13 (2H, m), 2.83-3. 01 (2H, m), 3.03-3.17 (1H, m), 4.09-4.40 (2H, m), 7.15-7.24 (1H, m), 7.41- 7.57 (2H, m), 7.81-7.90 (2H, m), 8.73 (1H, d, J = 5.3 Hz).

Reference Example 44
4- (3-Fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride

In the same manner as in Reference Example 36, the title compound (836 mg, 96%) was obtained from tert-butyl 4- [4- (3-fluorophenyl) pyrimidin-2-yl] piperidine-1-carboxylate obtained in Reference Example 43. Obtained as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.98-2.16 (2H, m), 2.17-2.30 (2H, m), 2.97-3.15 (2H, m), 3.17-3.43 (3H, m), 7.36-7.48 (1H, m), 7.56-7.69 (1H, m), 7.98-8.15 (3H, m ), 8.89 (1H, d, J = 5.3 Hz), 8.97 (1H, brs), 9.25 (1H, brs).

Reference Example 45
2-Chloro-4- (4-fluorophenyl) pyrimidine

1,2-Dimethoxyethane in 2,4-dichloropyrimidine (1.00 g, 6.71 mmol), 4-fluorophenylboronic acid (1.03 g, 7.38 mmol), 2N aqueous sodium carbonate solution (6.7 ml) Tetrakistriphenylphosphine palladium (931 mg, 0.805 mmol) was added to the (10 ml) solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at 105 ° C. for 40 minutes by a microwave reactor (Initiator ™, Biotage). Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (930 mg, 66%) as a solid.
¹ H NMR (CDCl ₃ ) δ: 7.15-7.25 (2H, m), 7.61 (1H, d, J = 5.3 Hz), 8.08-8.16 (2H, m), 8.64 (1H, d, J = 5.3 Hz).

Reference Example 46
tert-Butyl 4- [4- (4-fluorophenyl) pyrimidin-2-yl] -3,6-dihydropyridine-1 (2H) -carboxylate

2-chloro-4- (4-fluorophenyl) pyrimidine (700 mg, 3.36 mmol) obtained in Reference Example 45, tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (1.04 g, 3.36 mmol), 2N aqueous sodium carbonate (5.0 ml) in 1,2-dimethoxyethane (10 ml) ) Tetrakistriphenylphosphine palladium (465 mg, 0.403 mmol) was added to the solution at room temperature under a nitrogen atmosphere, and the mixture was stirred at 105 ° C. for 40 minutes by a microwave reactor (Initiator ™, Biotage). Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (1.12 g, 94%) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.82 (2H, brs), 3.67 (2H, t, J = 5.7 Hz), 4.17-4.25 ( 2H, m), 7.14-7.23 (2H, m), 7.31 (1H, brs), 7.48 (1H, d, J = 5.3 Hz), 8.10-8.19 ( 2H, m), 8.72 (1H, d, J = 5.3 Hz).

Reference Example 47
tert-Butyl 4- [4- (4-fluorophenyl) pyrimidin-2-yl] piperidine-1-carboxylate

Tert-Butyl 4- [4- (4-fluorophenyl) pyrimidin-2-yl] -3,6-dihydropyridine-1 (2H) -carboxylate obtained in Reference Example 46 (1.12 g, 3.15 mmol) To an ethanol (14 ml) -tetrahydrofuran (7 ml) solution was added palladium carbon (224 mg) under a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (782 mg, 70%) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.81-1.99 (2H, m), 1.99-2.12 (2H, m), 2.81-3. 00 (2H, m), 3.01-3.15 (1H, m), 4.11-4.38 (2H, m), 7.11-7.24 (2H, m), 7.49 ( 1H, d, J = 5.3 Hz), 8.06-8.19 (2H, m), 8.69 (1H, d, J = 5.3 Hz).

Reference Example 48
4- (4-Fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride

To a solution of tert-butyl 4- [4- (4-fluorophenyl) pyrimidin-2-yl] piperidine-1-carboxylate (780 mg, 2.18 mmol) obtained in Reference Example 47 in ethyl acetate (7.8 ml). 4N hydrogen chloride-ethyl acetate solution (7.8 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and the resulting crystals were collected by filtration to give the title compound (686 mg, 95%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.98-2.16 (2H, m), 2.17-2.30 (2H, m), 2.97-3.15 (2H, m), 3.17-3.42 (3H, m), 7.35-7.48 (2H, m), 8.00 (1H, d, J = 5.3 Hz), 8.25-8.38 (2H M), 8.86 (1H, d, J = 5.3 Hz), 9.06 (1H, brs), 9.32 (1H, brs).

Reference Example 49
tert-Butyl 4- (5-fluoro-4-phenylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

2,4-Dichloro-5-fluoropyrimidine (5.29 g, 31.7 mmol), phenylboronic acid (3.86 g, 31.7 mmol), 1,2-dimethoxyethane (98 ml) in 2N aqueous sodium carbonate (98 ml) 200 ml) under nitrogen atmosphere, tetrakistriphenylphosphine palladium (7.33 g, 6.34 mmol) was added at room temperature and stirred at 100 ° C. for 5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 10: 1) to give a white solid (4.75 g). The resulting solid (2.0 g), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -Carboxylate (0.98 g, 3.2 mmol), a solution of 2N aqueous sodium carbonate (10 ml) in 1,2-dimethoxyethane (30 ml) under a nitrogen atmosphere, tetrakistriphenylphosphine palladium (0.733 g,. 634 mmol) at room temperature and stirred at 100 ° C. for 5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 10: 1) to give the title compound (1.0 g, 21%) as a white solid.
¹ H NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.75-2.85 (2H, m), 3.64-3.68 (2H, m), 4.17-4. 23 (2H, m), 7.17-7.24 (1H, m), 7.51-7.55 (3H, m), 8.16-8.19 (2H, m), 8.57 ( 1H, d, J = 3.3 Hz).

Reference Example 50
tert-Butyl 4- (5-fluoro-4-phenylpyrimidin-2-yl) piperidine-1-carboxylate

Of tert-butyl 4- (5-fluoro-4-phenylpyrimidin-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (0.75 g, 2.11 mmol) obtained in Reference Example 49 After adding 10% palladium carbon (containing 50% water, 220 mg) to an ethanol (100 ml) solution under a nitrogen atmosphere, the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 1) to give the title compound (620 mg, 82%) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.81-2.10. (4H, m), 2.87-3.13 (3H, m), 4.17-4. 30 (2H, m), 7.51-7.53 (3H, m), 8.14-8.16 (2H, m), 8.55 (1H, d, J = 3.9 Hz).

Reference Example 51
5-Fluoro-4-phenyl-2-piperidin-4-ylpyrimidine dihydrochloride

To a suspension of tert-butyl 4- (5-fluoro-4-phenylpyrimidin-2-yl) piperidine-1-carboxylate (580 mg, 1.62 mmol) in methanol obtained in Reference Example 50 in 4N hydrogen chloride-acetic acid. Ethyl solution (10 ml, 40 mmol) was added and stirred at room temperature for 4 hours. Diisopropyl ether (20 ml) was added, and the mixture was stirred for 1 hour under ice cooling. The precipitate was collected by filtration and washed with diisopropyl ether to give the title compound (400 mg, 75%) as a white solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.96-2.24 (4H, m), 3.00-3.12 (2H, m), 3.20-3.43 (4H, m), 7.59-7.63 (3H, m), 8.06-8.09 (2H, m), 8.82 (1H, brs), 8.92 (1H, d, J = 3.3 Hz), 9.10 (1H, brs).

Example 1
4- (4-Phenylpyrimidin-2-yl) -N-pyridin-3-ylpiperidin-1-carboxamide

Triethylamine was added to a solution of 4-phenyl-2-piperidin-4-ylpyrimidine dihydrochloride (250 mg, 1.00 mmol) and 3-pyridine isocyanate (127 mg, 1.0 mmol) obtained in Reference Example 2 in tetrahydrofuran (4 ml). (210 mg, 2.1 mmol) was added and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane and methylene chloride to give the title compound (345 mg, 92%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.68-1.85 (2H, m), 2.00-2.18 (2H, m), 3.01 (2H, t, J = 12.8 Hz) ), 3.07-3.18 (1H, m), 4.20-4.30 (2H, m), 7.23 (1H, dd, J = 8.4, 4.8 Hz), 7.45. -7.58 (3H, m), 7.82-7.94 (2H, m), 8.11 (1H, dd, J = 4.8, 1.6 Hz), 8.15-8.23 ( 2H, m), 8.62 (1H, s), 8.70 (1H, s), 8.78 (1H, d, J = 5.2 Hz).

Example 2
N- (3,4-dimethylisoxazol-5-yl) -4- (4-phenylpyrimidin-2-yl) piperidine-1-carboxamide

4-Phenyl-2-piperidin-4-ylpyrimidine dihydrochloride (250 mg, 1.00 mmol), (3,4-dimethylisoxazol-5-yl) carbamic acid 2,2,2 obtained in Reference Example 2 A mixture of trichloroethyl (295 mg, 1.00 mmol), diisopropylethylamine (268 mg, 2.10 mmol) in dimethyl sulfoxide (2.0 ml) was stirred at 80 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1, 0.5% triethylamine added) and recrystallized from hexane and methylene chloride to obtain the title compound (158 mg, 40%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.68-1.84 (5H, m), 2.01-2.10 (2H, m), 2.09 (3H, s), 3.00 ( 2H, t, J = 12.8 Hz), 3.06-3.17 (1H, m), 4.12-4.20 (2H, m), 7.44-7.58 (3H, m), 7.88 (1H, d, J = 5.2 Hz), 8.15-8.25 (2H, m), 8.78 (1H, d, J = 5.2 Hz), 9.12 (1H, s ).

Example 3
4- (4-Phenylpyrimidin-2-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide

4-Phenyl-2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 2 (250 mg, 1.0 mmol), pyridazin-3-ylcarbamate 2,2,2-trichloroethyl (281 mg, 1.0 Mmol), diisopropylethylamine (268 mg, 2.10 mmol) in dimethyl sulfoxide (2.0 ml) was stirred at 80 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1, 0.5% triethylamine added) and recrystallized from hexane and methylene chloride to obtain the title compound (277 mg, 74%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.71-1.87 (2H, m), 2.02-2.10 (2H, m), 3.03 (2H, t, J = 12.8 Hz) ), 3.09-3.17 (1H, m), 4.20-4.35 (2H, m), 7.45-7.60 (4H, m), 7.88 (1H, d, J = 5.6 Hz), 7.97 (1H, dd, J = 9.2, 1.2 Hz), 8.12-8.26 (2H, m), 8.72-8.85 (2H, m) , 9.83 (1H, s).

Example 4
4- [4- (2,3-Difluorophenyl) pyrimidin-2-yl] -N-pyridin-3-ylpiperidin-1-carboxamide trifluoroacetate

4- (2,3-difluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride (250 mg, 0.900 mmol), 3-pyridine isocyanate (111 mg, 0.900 mmol) obtained in Reference Example 4 Triethylamine (184 mg, 1.80 mmol) was added to a tetrahydrofuran (4 ml) solution, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane and methylene chloride and purified by high performance liquid chromatography (Fuji C18 HPLC column A solution 0.1% trifluoroacetic acid acetonitrile solution, solution B 0.1% trifluoroacetic acid aqueous solution) to give the title compound (300 mg, 83%).
¹ H NMR (DMSO-d ₆ ) δ: 1.70-1.84 (2H, m), 2.00-2.10 (2H, m), 3.06 (2H, t, J = 12.4 Hz) ), 3.12-3.24 (1H, m), 4.20-4.30 (2H, m), 7.38 (1H, dd, J = 13.0, 7.2 Hz), 7.55 -7.68 (1H, m), 7.69-7.94 (3H, m), 8.22-8.43 (2H, m), 8.88 (1H, d, J = 5.2Hz) , 8.92-9.07 (1H, m), 9.22-9.42 (1H, m).

Example 5
4- [4- (2,3-Difluorophenyl) pyrimidin-2-yl] -N-pyridin-3-ylpiperidine-1-carboxamide

4- (2,3-Difluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride (1.00 g, 2.87 mmol) obtained in Reference Example 4, 2,3-pyridin-3-ylcarbamic acid 2,2, Triethylamine (1.60 ml, 11.5 mmol) was added dropwise at room temperature to a suspension of 2-trichloroethyl (851 mg, 3.16 mmol) in acetone (5 ml), and the reaction solution was stirred at 65 ° C. overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane and tetrahydrofuran to give the title compound (773 mg, 68%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.70-1.89 (2H, m), 1.98-2.14 (2H, m), 2.93-3.10 (2H, m), 3.10-3.25 (1H, m), 4.16-4.32 (2H, m), 7.26 (1H, dd, J = 8.1, 4.7 Hz), 7.34-7 .47 (1H, m), 7.56-7.70 (1H, m), 7.77 (1H, dd, J = 5.1, 2.3 Hz), 7.83-7.95 (2H, m), 8.14 (1H, dd, J = 4.7, 1.5 Hz), 8.65 (1H, d, J = 2.3 Hz), 8.73 (1H, s), 8.91 ( 1H, d, J = 5.1 Hz).

Example 6
4- [4- (2,3-Difluorophenyl) pyrimidin-2-yl] -N- (3,4-dimethylisoxazol-5-yl) piperidine-1-carboxamide

In the same manner as in Example 2, 4- (2,3-difluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 4 and (3,4-dimethylisoxazol-5-yl) The title compound (222 mg, 59%) was obtained as a solid from 2,2,2-trichloroethyl carbamate.
¹ H NMR (DMSO-d ₆ ) δ: 1.67-1.83 (5H, m), 1.95-2.05 (2H, m), 2.09 (3H, s), 3.00 ( 2H, t, J = 12.2 Hz), 3.06-3.22 (1H, m), 4.00-4.15 (2H, m), 7.34-7.42 (1H, m), 7.55-7.68 (1H, m), 7.74 (1H, dd, J = 5.2, 1.6 Hz), 7.86 (1H, t, J = 7.4 Hz), 8.88 (1H, d, J = 5.2 Hz), 9.14 (1H, s).

Example 7
4- [4- (2,3-Difluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide

In the same manner as in Example 3, 4- (2,3-difluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 4 and pyridazin-3-ylcarbamic acid 2,2,2- The title compound (229 mg, 63%) was obtained as a solid from trichloroethyl.
¹ H NMR (DMSO-d ₆ ) δ: 1.64-1.85 (2H, m), 1.92-2.05 (2H, m), 3.02 (2H, t, J = 12.0 Hz) ), 3.09-3.21 (1H, m), 4.20-4.30 (2H, m), 7.30-7.40 (1H, m), 7.54 (1H, dd, J) = 9.2, 4.8 Hz), 7.61 (1H, q, J = 8.8 Hz), 7.73 (1H, dd, J = 5.2, 2.4 Hz), 7.84-7. 88 (1H, m), 7.97 (1H, dd, J = 9.2, 1.2 Hz), 8.80 (1H, dd, J = 4.4, 1.2 Hz), 8.87 (1H , D, J = 5.2 Hz), 9.86 (1H, s).

Example 8
4- (6-Phenylpyrimidin-4-yl) -N-pyridin-3-ylpiperidin-1-carboxamide trifluoroacetate

In the same manner as in Example 4, the title compound (123 mg, 54%) was obtained as a solid from 4-phenyl-6-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 6 and 3-pyridine isocyanate.
¹ H NMR (DMSO-d ₆ ) δ: 1.62-1.87 (2H, m), 1.90-2.05 (2H, m), 2.91-3.16 (3H, m), 4.30-4.40 (2H, m), 7.50-7.60 (3H, m), 7.89-7.95 (1H, m), 8.02-8.05 (1H, m ), 8.20-8.30 (2H, m), 8.40-8.50 (2H, m), 9.13 (2H, d, J = 16.8 Hz), 9.54 (1 H, s) ).

Example 9
N- (3,4-Dimethylisoxazol-5-yl) -4- (6-phenylpyrimidin-4-yl) piperidine-1-carboxamide

In the same manner as in Example 2, 4-phenyl-6-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 6 and (3,4-dimethylisoxazol-5-yl) carbamic acid 2,2,2 The title compound (149 mg, 47%) was obtained as a solid from trichloroethyl.
¹ H NMR (DMSO-d ₆ ) δ: 1.70-1.80 (5H, m), 1.90-2.00 (2H, m), 2.12 (3H, s), 2.91- 3.06 (3H, m), 4.15-4.25 (2H, m), 7.50-7.60 (3H, m), 8.03 (1H, s), 8.15-8. 32 (2H, m), 9.15 (2H, brs).

Example 10
4- (6-Phenylpyrimidin-4-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide

In the same manner as in Example 3, the title compound (104 mg) was obtained from 4-phenyl-6-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 6 and 2,2,2-trichloroethyl pyridazin-3-ylcarbamate. 34%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.64-1.85 (2H, m), 1.90-2.00 (2H, m), 2.86-3.08 (3H, m), 4.30-4.40 (2H, m), 7.45-7.60 (4H, m), 7.94-8.06 (2H, m), 8.22-8.35 (2H, m) ), 8.83 (1H, d, J = 3.6 Hz), 9.14 (1H, s), 9.87 (1H, s).

Example 11
4- [6- (2,3-Difluorophenyl) pyrimidin-4-yl] -N-pyridin-3-ylpiperidine-1-carboxamide

4- (2,3-difluorophenyl) -6-piperidin-4-ylpyrimidine dihydrochloride (300 mg, 1.10 mmol), 3-pyridine isocyanate (135 mg, 1.1 mmol) obtained in Reference Example 8 Triethylamine (223 mg, 2.2 mmol) was added to a tetrahydrofuran (3 ml) solution, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane and ethyl acetate to give the title compound (99.0 mg, 23%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.67-1.83 (2H, m), 1.95-2.05 (2H, m), 2.93-3.12 (3H, m), 4.25-4.35 (2H, m), 7.28 (1H, dd, J = 8.4, 4.4 Hz), 7.37-7.46 (1H, m), 7.65 (1H , Q, J = 8.4 Hz), 7.80-7.95 (3H, m), 8.16 (1H, dd, J = 4.6, 1.4 Hz), 8.67 (1H, d, J = 2.4 Hz), 8.75 (1H, s), 9.26 (1H, s).

Example 12
4- [6- (2,3-Difluorophenyl) pyrimidin-4-yl] -N- (3,4-dimethylisoxazol-5-yl) piperidine-1-carboxamide

In the same manner as in Reference Example 2, 4- (2,3-difluorophenyl) -6-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 8 and (3,4-dimethylisoxazol-5-yl) The title compound (114 mg, 25%) was obtained as a solid from 2,2,2-trichloroethyl carbamate.
¹ H NMR (DMSO-d ₆ ) δ: 1.61-1.76 (5H, m), 1.85-1.95 (2H, m), 2.09 (3H, s), 2.87- 3.06 (3H, m), 4.10-4.20 (2H, m), 7.31-7.40 (1H, m), 7.60 (1H, q, J = 6.8 Hz), 7.74-7.85 (2H, m), 9.11 (1H, s), 9.21 (1H, s).

Example 13
4- [6- (2,3-Difluorophenyl) pyrimidin-4-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide trifluoroacetate

4- (2,3-difluorophenyl) -6-piperidin-4-ylpyrimidine dihydrochloride (300 mg, 1.10 mmol), pyridazin-3-ylcarbamic acid 2,2,2-trichloro obtained in Reference Example 8 A mixture of ethyl (295 mg, 1.10 mmol), diisopropylethylamine (281 mg, 2.20 mmol) in dimethyl sulfoxide (2.0 ml) was stirred at 80 ° C. overnight. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride, 0.5% triethylamine added), and high performance liquid chromatography (Fuji C18 HPLC column A solution 0.1% trifluoroacetic acid acetonitrile solution, solution B 0.1% trifluoroacetic acid aqueous solution. To give the title compound (85.0 mg, 20%).
¹ H NMR (DMSO-d ₆ ) δ: 1.64-1.85 (2H, m), 1.90-2.00 (2H, m), 2.94-3.17 (3H, m), 4.30-4.40 (2H, m), 7.35-7.46 (1H, m), 7.58-7.70 (2H, m), 7.79-7.90 (2H, m) ), 8.07 (1H, d, J = 9.2 Hz), 8.88 (1H, d, J = 3.6 Hz), 9.25 (1H, s).

Example 14
4- (2-Phenylpyrimidin-4-yl) -N-pyridin-3-ylpiperidine-1-carboxamide

In the same manner as in Example 1, the title compound (334 mg, 89%) was obtained as a solid from 2-phenyl-4-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 11 and 3-pyridine isocyanate.
¹ H NMR (DMSO-d ₆ ) δ: 1.62-1.82 (2H, m), 1.90-2.10 (2H, m), 2.86-3.07 (3H, m), 4.25-4.35 (2H, m), 7.23 (1H, dd, J = 8.4, 4.8 Hz), 7.36 (1H, d, J = 4.8 Hz), 7.40 -7.50 (3H, m), 7.88 (1H, d, J = 8.4 Hz), 8.12 (1H, d, J = 4.4 Hz), 8.39 (2H, t, J = 3.0 Hz), 8.64 (1 H, s), 8.72 (1 H, s), 8.78 (1 H, d, J = 4.8 Hz).

Example 15
N- (3,4-dimethylisoxazol-5-yl) -4- (2-phenylpyrimidin-4-yl) piperidine-1-carboxamide

In the same manner as in Example 2, 2-phenyl-4-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 11 and (3,4-dimethylisoxazol-5-yl) carbamic acid 2,2,2 The title compound (200 mg, 51%) was obtained as a solid from trichloroethyl.
¹ H NMR (DMSO-d ₆ ) δ: 1.64-1.82 (5H, m), 1.90-2.00 (2H, m), 2.12 (3H, s), 2.89- 3.08 (3H, m), 4.10-4.20 (2H, m), 7.37 (1H, d, J = 4.8 Hz), 7.51 (3H, t, J = 3.2 Hz) ), 8.39 (2H, dd, J = 6.4, 2.8 Hz), 8.79 (1H, d, J = 5.2 Hz), 9.15 (1H, s).

Example 16
4- (2-Phenylpyrimidin-4-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide

In the same manner as in Example 3, the title compound (253 mg) was obtained from 2-phenyl-4-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 11 and 2,2,2-trichloroethyl pyridazin-3-ylcarbamate. 67%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.63-1.85 (2H, m), 1.90-2.00 (2H, m), 2.91-3.06 (3H, m), 4.30-4.40 (2H, m), 7.36 (1H, d, J = 5.2 Hz), 7.50 (3H, t, J = 3.2 Hz), 7.55 (1H, dd , J = 8.8, 4.4 Hz), 8.00 (1H, dd, J = 8.8, 0.8 Hz), 8.34-8.43 (2H, m), 8.78 (1H, d, J = 5.2 Hz), 8.81 (1H, d, J = 4.4 Hz), 9.86 (1H, s).

Example 17
4- [2- (2,3-Difluorophenyl) pyrimidin-4-yl] -N-pyridin-3-ylpiperidine-1-carboxamide

In the same manner as in Example 1, the title compound (309 mg, 86%) was obtained from 2- (2,3-difluorophenyl) -4-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 15 and 3-pyridine isocyanate. Was obtained as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.62-1.76 (2H, m), 1.90-2.00 (2H, m), 2.91-3.08 (3H, m), 4.25-4.35 (2H, m), 7.25 (1 H, dd, J = 8.4, 4.8 Hz), 7.27-7.36 (1 H, m), 7.49 (1 H , D, J = 5.2 Hz), 7.52-7.62 (1H, m), 7.80-7.94 (2H, m), 8.13 (1H, dd, J = 4.4). 1.2 Hz), 8.64 (1 H, d, J = 2.4 Hz), 8.74 (1 H, s), 8.87 (1 H, d, J = 5.2 Hz).

Example 18
4- [2- (2,3-Difluorophenyl) pyrimidin-4-yl] -N- (3,4-dimethylisoxazol-5-yl) piperidine-1-carboxamide trifluoroacetate

In the same manner as in Example 2, 2- (2,3-difluorophenyl) -4-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 15 (250 mg, 0.90 mmol), (3,4- A mixture of 2,2,2-trichloroethyl dimethylisoxazol-5-yl) carbamate (258 mg, 0.9 mmol), diisopropylethylamine (235 mg, 1.80 mmol) and dimethyl sulfoxide (2.0 ml) Stir overnight at ° C. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride, 0.5% triethylamine added), and high performance liquid chromatography (Fuji C18 HPLC column A solution 0.1% trifluoroacetic acid acetonitrile solution, solution B 0.1% trifluoroacetic acid aqueous solution. To give the title compound (43 mg, 11%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.52-1.81 (5H, m), 1.90-2.00 (2H, m), 2.11 (3H, s), 2.88- 3.11 (3H, m), 4.15-4.25 (2H, m), 7.28-7.42 (1H, m), 7.47 (1H, d, J = 5.2 Hz), 7.58 (1H, q, J = 8.4 Hz), 7.85 (1H, t, J = 6.6 Hz), 8.86 (1H, d, J = 4.8 Hz), 9.15 (1H , S).

Example 19
4- [2- (2,3-Difluorophenyl) pyrimidin-4-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide

In the same manner as in Example 3, 2- (2,3-difluorophenyl) -4-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 15 and pyridazin-3-ylcarbamic acid 2,2,2- The title compound (63 mg, 17%) was obtained as an oil from trichloroethyl.
¹ H NMR (DMSO-d ₆ ) δ: 1.62-1.82 (2H, m), 1.90-2.00 (2H, m), 2.91-3.11 (3H, m), 4.30-4.40 (2H, m), 7.33 (1H, q, J = 6.4 Hz), 7.48 (1H, d, J = 5.2 Hz), 7.52-7.64 (2H, m), 7.85 (1H, t, J = 7.4 Hz), 7.99 (1H, dd, J = 9.0, 1.0 Hz), 8.82 (1H, dd, J = 4.6, 1.0 Hz), 8.86 (1H, d, J = 5.2 Hz), 9.87 (1H, s).

Example 20
N- (3,4-dimethylisoxazol-5-yl) -4- (4-phenylpyridin-2-yl) piperidine-1-carboxamide

Diisopropylethylamine (0.588 ml, 3.37 mmol) was added to a solution of 4-phenyl-2-piperidin-4-ylpyridine dihydrochloride (300 mg, 0.964 mmol) obtained in Reference Example 18 in dimethyl sulfoxide (3.2 ml). After stirring the reaction solution for 30 minutes, 2,3,4-trichloroethyl (3,4-dimethylisoxazol-5-yl) carbamate (333 mg, 1.16 mmol) was added at room temperature, Stir at 45 ° C. for 17 hours. Water was poured into the reaction solution and extracted with methylene chloride. The extract was washed with saturated brine and water, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (210 mg, 58%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.87-1.98 (2H, m), 1.90 (3H, s), 2.05-2.21 (2H, m), 2.21 ( 3H, s), 2.98-3.13 (3H, m), 4.21 (2H, d, J = 13.6 Hz), 6.52 (1H, brs), 7.37-7.39 ( 2H, m), 7.43-7.52 (3H, m), 7.62-7.65 (2H, m), 8.60 (1H, dd, J = 3.6, 2.4 Hz).

Example 21
N- (3,4-dimethylisoxazol-5-yl) -4- [4- (2-fluorophenyl) pyridin-2-yl] piperidine-1-carboxamide

In the same manner as in Example 20, 4- (2-fluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride obtained in Reference Example 21 and (3,4-dimethylisoxazol-5-yl) carbamic acid 2 , 2,2-Trichloroethyl gave the title compound (210 mg, 58%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.67-1.77 (2H, m), 1.76 (3H, s), 1.89-1.92 (2H, m), 2.13 ( 3H, s), 2.93-3.04 (3H, m), 4.19 (2H, d, J = 12.8 Hz), 7.34-7.40 (2H, m), 7.42- 7.44 (1H, m), 7.49-7.55 (2H, m), 7.66 (1H, td, J = 7.9, 1.6 Hz), 8.60 (1H, d, J = 4.8 Hz), 9.15 (1H, brs).

Example 22
N- (3,4-dimethylisoxazol-5-yl) -4- [4- (3-fluorophenyl) pyridin-2-yl] piperidine-1-carboxamide

In the same manner as in Example 20, 4- (3-fluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride obtained in Reference Example 24 and (3,4-dimethylisoxazol-5-yl) carbamic acid 2 , 2,2-Trichloroethyl gave the title compound (160 mg, 45%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.74-1.81 (2H, m), 1.77 (3H, s), 1.90-1.93 (2H, m), 2.13 ( 3H, s), 2.93-3.02 (3H, m), 4.21 (2H, d, J = 13.6 Hz), 7.29-7.34 (1H, m), 7.54- 7.60 (2H, m), 7.68-7.74 (3H, m), 8.58 (1H, d, J = 5.2 Hz), 9.15 (1H, brs).

Example 23
N- (3,4-dimethylisoxazol-5-yl) -4- [4- (4-fluorophenyl) pyridin-2-yl] piperidine-1-carboxamide

In the same manner as in Example 20, 4- (4-fluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride obtained in Reference Example 26 and (3,4-dimethylisoxazol-5-yl) carbamic acid 2 , 2,2-Trichloroethyl gave the title compound (160 mg, 45%) as a solid.
¹ H NMR (DMSO-d ₆ ) δ: 1.71-1.77 (2H, m), 1.79 (3H, s), 1.89 (2H, d, J = 10.8 Hz), 2. 11 (3H, s), 2.91-3.01 (3H, m), 4.19 (2H, d, J = 13.2 Hz), 7.34 (2H, t, J = 8.8 Hz), 7.51-7.53 (1H, m), 7.60 (1H, s), 7.86-7.89 (2H, m), 8.54 (1H, d, J = 5.2 Hz), 9.12 (1H, brs).

Example 24
4- [4- (2,3-Difluorophenyl) pyridin-2-yl] -N- (3,4-dimethylisoxazol-5-yl) piperidine-1-carboxamide

In the same manner as in Example 20, 4- (2,3-difluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride and (3,4-dimethylisoxazol-5-yl) carbamine obtained in Reference Example 29 The title compound (110 mg, 31%) was obtained as a solid from the acid 2,2,2-trichloroethyl.
¹ H NMR (DMSO-d ₆ ) δ: 1.71-1.76 (2H, m), 1.76 (3H, s), 1.91 (2H, d, J = 12.0 Hz), 2. 13 (3H, s), 2.93-3.02 (3H, m), 4.20 (2H, d, J = 12.8 Hz), 7.36-7.59 (5H, m), 8. 63 (1H, d, J = 4.4 Hz), 9.15 (1H, brs).

Example 25
4- [4- (2,4-Difluorophenyl) pyridin-2-yl] -N- (3,4-dimethylisoxazol-5-yl) piperidine-1-carboxamide

In the same manner as in Example 20, 4- (2,4-difluorophenyl) -2-piperidin-4-ylpyridine dihydrochloride and (3,4-dimethylisoxazol-5-yl) carbamine obtained in Reference Example 32 The title compound (203 mg, 57%) was obtained as a solid from the acid 2,2,2-trichloroethyl.
¹ H NMR (DMSO-d ₆ ) δ: 1.66-1.75 (2H, m), 1.74 (3H, s), 1.90 (2H, d, J = 11.6 Hz), 2. 13 (3H, s), 2.92-3.03 (3H, m), 4.19 (2H, d, J = 13.2 Hz), 7.24-7.29 (1 H, m), 7. 40-7.48 (3H, m), 7.71-7.77 (1H, m), 8.60 (1H, d, J = 5.2 Hz), 9.15 (1H, brs).

Example 26
4- (4-Furan-3-ylpyrimidin-2-yl) -N-pyridin-3-ylpiperidin-1-carboxamide

4-furan-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride (120 mg, 0.397 mmol) obtained in Reference Example 36, 2,2,2-trichloroethyl pyridin-3-ylcarbamate ( Triethylamine (0.221 ml, 1.59 mmol) was added dropwise to a suspension of 126 mg, 0.437 mmol) in acetone (1 ml) at room temperature, and the reaction solution was stirred at 65 ° C. overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane and ethyl acetate to give the title compound (41.8 mg, 30%) as a solid. Melting point: 145-146 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.67-1.68 (2H, m), 1.95-2.09 (2H, m), 2.92-3.15 (3H, m), 4.16-4.30 (2H, m), 7.10-7.17 (1H, m), 7.26 (1H, dd, J = 8.1, 4.3 Hz), 7.63 (1H , D, J = 5.3 Hz), 7.81-7.94 (2H, m), 8.10-8.18 (1H, m), 8.55 (1H, s), 8.63-8 .68 (1H, m), 8.70-8.76 (2H, m).

Example 27
N- (3,4-Dimethylisoxazol-5-yl) -4- (4-furan-3-ylpyrimidin-2-yl) piperidine-1-carboxamide

4-furan-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride (120 mg, 0.397 mmol), (3,4-dimethylisoxazol-5-yl) carbamic acid 2 obtained in Reference Example 36 , 2,2-Trichloroethyl (126 mg, 0.437 mmol) in acetone (1 ml) was added dropwise triethylamine (0.221 ml, 1.59 mmol) at room temperature, and the reaction solution was stirred at 45 ° C. for 3 hours. Stir. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, passed through a small amount of silica gel, eluted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane and tetrahydrofuran to give the title compound (107 mg, 73%) as a solid. Melting point 190-191 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.65 to 1.84 (5H, m), 1.92 to 2.05 (2H, m), 2.13 (3H, s), 2.92— 3.15 (3H, m), 4.07-4.22 (2H, m), 7.10-7.15 (1H, m), 7.63 (1H, d, J = 5.3 Hz), 7.85 (1H, t, J = 1.7 Hz), 8.52-8.58 (1H, m), 8.73 (1H, d, J = 5.3 Hz), 9.14 (1H, s ).

Example 28
4- (4-Furan-3-ylpyrimidin-2-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide

4-furan-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride (120 mg, 0.397 mmol), phenyl pyridazin-3-ylcarbamate (94.0 g, 0.437) obtained in Reference Example 36. To a suspension of (mmol) of acetone (1 ml), triethylamine (0.221 ml, 1.59 mmol) was added dropwise at room temperature, and the reaction solution was stirred at 45 ° C. for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane and ethyl acetate to give the title compound (51.5 mg, 37%) as a solid. Melting point: 146-147 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.66-1.88 (2H, m), 1.92-2.11 (2H, m), 2.94-3.17 (3H, m), 4.17-4.42 (2H, m), 7.13 (1H, s), 7.50-7.69 (2H, m), 7.84 (1H, s), 8.01 (1H, d, J = 8.7 Hz), 8.55 (1H, s), 8.73 (1H, d, J = 5.3 Hz), 8.83 (1H, d, J = 3.8 Hz), 9. 86 (1H, s).

Example 29
N-pyridin-3-yl-4- (4-thiophen-3-ylpyrimidin-2-yl) piperidine-1-carboxamide

In the same manner as in Example 26, from 4-thiophen-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 40 and 2,2,2-trichloroethyl pyridin-3-ylcarbamate The title compound (39.5 mg, 27%) was obtained as a solid. Melting point 160-161 ° C (ethyl acetate-hexane)
¹ H NMR (DMSO-d ₆ ) δ: 1.69-1.88 (2H, m), 1.97-2.10 (2H, m), 2.94-3.18 (3H, m), 4.16-4.30 (2H, m), 7.26 (1H, dd, J = 8.3, 5.3 Hz), 7.71 (1H, dd, J = 4.9, 3.0 Hz) , 7.78 (1H, d, J = 5.3 Hz), 7.82-7.87 (1H, m), 7.87-7.93 (1H, m), 8.14 (1H, dd, J = 4.9, 1.5 Hz), 8.48 (1H, dd, J = 3.0, 1.5 Hz), 8.66 (1H, d, J = 2.3 Hz), 8.73 (1H , S), 8.76 (1H, d, J = 5.3 Hz).

Example 30
N- (3,4-Dimethylisoxazol-5-yl) -4- (4-thiophen-3-ylpyrimidin-2-yl) piperidine-1-carboxamide

In the same manner as in Example 27, 4-thiophen-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 40 and (3,4-dimethylisoxazol-5-yl) carbamic acid 2 , 2,2-Trichloroethyl gave the title compound (108 mg, 69%) as a solid. Melting point 180-181 ° C (ethyl acetate-hexane)
¹ H NMR (DMSO-d ₆ ) δ: 1.68-1.86 (5H, m), 1.94-2.07 (2H, m), 2.13 (3H, s), 2.94- 3.17 (3H, m), 4.06-4.22 (2H, m), 7.72 (1H, dd, J = 5.3, 3.0 Hz), 7.78 (1H, d, J = 5.3 Hz), 7.82-7.87 (1 H, m), 8.48 (1 H, dd, J = 3.0, 1.5 Hz), 8.76 (1 H, d, J = 5. 3 Hz), 9.14 (1 H, s).

Example 31
N-pyridazin-3-yl-4- (4-thiophen-3-ylpyrimidin-2-yl) piperidine-1-carboxamide

In the same manner as in Example 28, the title compound (68.0 mg, 4-thiophen-3-yl-2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 40 and phenyl pyridazin-3-ylcarbamate was obtained. 45%) was obtained as a solid. Melting point 132-133 ° C (ethyl acetate-hexane)
¹ H NMR (DMSO-d ₆ ) δ: 1.69-1.90 (2H, m), 1.93-2.11 (2H, m), 2.94-3.19 (3H, m), 4.18-4.39 (2H, m), 7.57 (1H, dd, J = 9.0, 4.5 Hz), 7.71 (1H, dd, J = 4.5, 3.0 Hz) 7.78 (1H, d, J = 5.3 Hz), 7.81-7.88 (1H, m), 7.96-8.07 (1H, m), 8.44-8.51 ( 1H, m), 8.76 (1H, d, J = 5.3 Hz), 8.83 (1H, d, J = 3.0 Hz), 9.87 (1H, s).

Example 32
4- [4- (3-Fluorophenyl) pyrimidin-2-yl] -N-pyridin-3-ylpiperidin-1-carboxamide

In the same manner as in Example 26, 4- (3-fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 44 and 2,2,2-trichloroethyl pyridin-3-ylcarbamate Gave the title compound (84.9 mg, 37%) as a solid. Melting point 149-150 ° C (ethyl acetate-hexane)
¹ H NMR (DMSO-d ₆ ) δ: 1.70-1.93 (2H, m), 1.96-2.17 (2H, m), 2.94-3.25 (3H, m), 4.10-4.38 (2H, m), 7.19-7.34 (1H, m), 7.34-7.49 (1H, m), 7.53-7.71 (1H, m) ), 7.82-7.24 (5H, m), 8.66 (1H, d, J = 1.9 Hz), 8.74 (1H, s), 8.86 (1H, d, J = 5) .3 Hz).

Example 33
N- (3,4-dimethylisoxazol-5-yl) -4- [4- (3-fluorophenyl) pyrimidin-2-yl] piperidine-1-carboxamide

In the same manner as in Example 27, the title compound (198 mg, 83%) was obtained as a solid from 4- (3-fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride obtained in Reference Example 44. Melting point 181-182 ° C. (ethyl acetate-hexane)
¹ H NMR (DMSO-d ₆ ) δ: 1.69-1.88 (5H, m), 1.96-2.10 (2H, m), 2.13 (3H, s), 2.97- 3.22 (3H, m), 4.09-4.22 (2H, m), 7.36-7.47 (1H, m), 7.56-7.66 (1H, m), 7. 98 (1H, d, J = 5.3 Hz), 8.01-8.13 (2H, m), 8.86 (1H, d, J = 5.3 Hz), 9.15 (1H, s).

Example 34
4- [4- (3-Fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide

In the same manner as in Example 28, the title compound (149 mg, 65 %) As a solid. Melting point 163-164 ° C. (ethyl acetate-hexane)
¹ H NMR (DMSO-d ₆ ) δ: 1.72-1.91 (2H, m), 1.99-2.14 (2H, m), 2.96-3.24 (3H, m), 4.23-4.37 (2H, m), 7.36-7.46 (1H, m), 7.52-7.66 (2H, m), 7.94-8.14 (4H, m) ), 8.79-8.90 (2H, m), 9.87 (1H, s).

Example 35
4- [4- (4-Fluorophenyl) pyrimidin-2-yl] -N-pyridin-3-ylpiperidin-1-carboxamide

4- (4-Fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride (200 mg, 0.606 mmol) obtained in Reference Example 48, 2,2,2-trichloroethyl pyridin-3-ylcarbamate Triethylamine (0.338 ml, 2.42 mmol) was added dropwise to a suspension of (180 mg, 0.666 mmol) in acetone (1 ml) at room temperature, and the reaction solution was stirred at 65 ° C. overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane and ethyl acetate to give the title compound (87.8 mg, 38%) as a solid. Melting point 156-157 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.71-1.90 (2H, m), 1.99-2.14 (2H, m), 2.94-3.22 (3H, m), 4.16-4.33 (2H, m), 7.26 (1H, dd, J = 8.5, 4.7 Hz), 7.33-7.45 (2H, m), 7.85-7 .96 (2H, m), 8.09-8.19 (1H, m), 8.24-8.36 (2H, m), 8.67 (1H, d, J = 2.3 Hz), 8 .74 (1H, s), 8.82 (1H, d, J = 4.7 Hz).

Example 36
N- (3,4-dimethylisoxazol-5-yl) -4- [4- (4-fluorophenyl) pyrimidin-2-yl] piperidine-1-carboxamide

4- (4-Fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride (200 mg, 0.606 mmol), (3,4-dimethylisoxazol-5-yl) carbamic acid obtained in Reference Example 48 Triethylamine (0.338 ml, 2.42 mmol) was added dropwise at room temperature to a suspension of 2,2,2-trichloroethyl (192 mg, 0.666 mmol) in acetone (1 ml), and the reaction solution was added at 45 ° C. for 3 hours. Stir for hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane and ethyl acetate to give the title compound (171 mg, 72%) as a solid. Melting point: 145-146 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.68-1.88 (5H, m), 1.96-2.10 (2H, m), 2.13 (3H, s), 2.95- 3.21 (3H, m), 4.09-4.23 (2H, m), 7.33-7.46 (2H, m), 7.92 (1H, d, J = 5.3 Hz), 8.25-8.36 (2H, m), 8.82 (1 H, d, J = 5.3 Hz), 9.14 (1 H, s).

Example 37
4- [4- (4-Fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide

4- (4-Fluorophenyl) -2-piperidin-4-ylpyrimidine dihydrochloride (200 mg, 0.606 mmol), phenylpyridazin-3-ylcarbamate (143 mg, 0.666 mmol) obtained in Reference Example 48 ) In acetone (1 ml) was added dropwise triethylamine (0.338 ml, 2.42 mmol) at room temperature, and the reaction solution was stirred at 45 ° C. for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from hexane and ethyl acetate to give the title compound (130 mg, 57%) as a solid. Melting point 115-116 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.71-1.91 (2H, m), 1.96-2.14 (2H, m), 2.98-3.24 (3H, m), 4.21-4.39 (2H, m), 7.31-7.45 (2H, m), 7.57 (1H, dd, J = 9.1, 4.5 Hz), 7.92 (1H , D, J = 5.3 Hz), 8.01 (1H, d, J = 9.1 Hz), 8.23-8.37 (2H, m), 8.75-8.91 (2H, m) , 9.86 (1H, s).

Example 38
4- (5-Fluoro-4-phenylpyrimidin-2-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide

5-fluoro-4-phenyl-2-piperidin-4-ylpyrimidine dihydrochloride (0.16 g, 0.48 mmol), phenyl pyridazin-3-ylcarbamate (0.13 g,. Triethylamine (0.20 g, 2.0 mmol) was added dropwise to a suspension of 60 mmol) in acetone (2 ml) at room temperature, and the reaction solution was stirred at 40 ° C. for 2 hours. Water (4 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The resulting crystals were filtered and washed with water to obtain crude crystals as a solid. The obtained crude crystals were recrystallized (ethyl acetate) to give the title compound (140 mg, 77%) as white crystals. Melting point 135-136 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.72-1.86 (2H, m), 2.00-2.10 (2H, m), 3.02-3.24 (3H, m), 4.27-4.31 (2H, m), 7.54-7.62 (4H, m), 7.9-8.10 (3H, m), 8.83-8.84 (1H, m ), 8.89-8.90 (1H, m), 9.87 (1H, s).

Example 39
4- (5-Fluoro-4-phenylpyrimidin-2-yl) -N-pyridin-3-ylpiperidin-1-carboxamide

5-Fluoro-4-phenyl-2-piperidin-4-ylpyrimidine dihydrochloride (0.16 g, 0.48 mmol) obtained in Reference Example 51, 2,2,2-trichloroethyl pyridin-3-ylcarbamate Triethylamine (0.20 g, 2.0 mmol) was added dropwise at room temperature to a suspension of acetone (2 ml) in (0.24 g, 0.90 mmol), and the reaction solution was stirred at 40 ° C. for 2 hours. Water (4 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and extracted by adding water. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized (hexane-ethyl acetate) to give the title compound (10 mg, 6%) as white crystals. Melting point 148-150 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.71-1.85 (2H, m), 2.00-2.10 (2H, m), 2.98-3.25 (3H, m), 4.20-4.30 (2H, m), 7.24-7.28 (1H, m), 7.57-7.62 (3H, m), 7.88-7.91 (1H, m ), 8.07-8.15 (3H, m), 8.64-8.66 (1H, m), 8.73 (1H, s), 8.89-8.90 (1H, m).

Formulation Example 1
(1) 10 mg of the compound of Example 1
(2) Lactose 60mg
(3) Corn starch 35mg
(4) Hydroxypropyl methylcellulose 3mg
(5) Magnesium stearate 2mg
A mixture of 10 mg of the compound obtained in Example 1, 60 mg of lactose and 35 mg of corn starch was granulated with 0.03 mL of 10 wt% aqueous hydroxypropylmethylcellulose solution (3 mg as hydroxypropylmethylcellulose), and then dried at 40 ° C. Sift through. The obtained granules are mixed with 2 mg of magnesium stearate and compressed. The resulting uncoated tablets are coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablet is polished with beeswax to obtain a coated tablet.

Experimental example 1
Measurement of FAAH inhibitory activity (1) Preparation of cell fraction The human FAAH gene amplified by the PCR method was inserted into a pcDNA3.1 vector to construct an expression plasmid. This plasmid was introduced into the K562 cell line, and a cell line K562 / human FAAH in which human FAAH was stably expressed by a method known per se was constructed. After culturing at 37 ° C. in a CO ₂ incubator using K562 / human FAAH in a medium (RPMI1640 medium supplemented with FBS (fetal bovine serum) to a final concentration of 10% and G418 to a final concentration of 300 μg / mL), Cells were collected. The cells were washed with PBS, suspended in a buffer (all of which had a final concentration of 10 mM Tris-HCl, 1 mM EDTA, 10 mM MgCl ₂ ), and the cells were disrupted using a polytron homogenizer. After centrifugation at 2,000 rpm, the supernatant was collected and further centrifuged at 40,000 rpm, and the pellet was suspended in the above buffer to prepare an enzyme fraction.
(2) Enzyme reaction Using a 96-well plate (manufactured by Costar), each concentration of test compound, enzyme fraction (final concentration 37.5 μg / mL), and substrate AMC arachidonil amide (AMCAA: CAYMAN CHEMICAL): Final concentration 3 μM) in reaction buffer (both 125 mM Tris-HCl pH 9.0), 1 mM EDTA, 0.4 mM HEPES, 0.2% glycerol, 0.02% Triton X-100 and The reaction was carried out in 50 μL of 0.3% BSA) at 37 ° C. for 90 minutes. After the reaction, the fluorescence intensity of the plate was measured with an ARVO SX 1420 MULTILABEL COUNTER (manufactured by WALLAC) at excitation of 355 nm and emission of 460 nm. The inhibition rate of the test compound was calculated with the reaction containing no enzyme as the inhibition rate of 100%.

From the results in Table 1, it can be seen that the compounds of the present invention have excellent FAAH inhibitory activity.

Experimental example 2
Analgesic effect in mouse acetic acid rising test A suspension of test compound (10 mg / kg) was orally administered to mice, and 60 minutes after administration, a 0.6% acetic acid aqueous solution was intraperitoneally administered at 10 ml / kg body weight. Mice were housed in dedicated cages and the number of rising reactions was counted using a counter. The control group was tested for difference in mean value between the two groups (Student's t-test) to evaluate the analgesic effect.

From the results in Table 2, it can be seen that the compound of the present invention has an excellent analgesic effect.

Claims

Formula (I)

[Where:
Ring Ar 1 represents an optionally substituted aromatic heterocycle;
A 1 represents CR 1 or N, A 2 represents CR 2 or N, A 3 represents CR 3 or N, A 4 represents CR 4 or N, and A 1 , A 2 , A 3 , And at least one of A 4 represents N;
Ring Ar 2 represents an aromatic hydrocarbon ring that may be substituted with one or more halogen atoms, or an aromatic heterocycle that may be substituted with one or more halogen atoms;
R 1 , R 2 , R 3 , and R 4 each independently represent a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group. ]
Or a salt thereof.
Partial structure of formula (I)

But,

The compound according to claim 1, wherein
Partial structure of formula (I)

But,

The compound according to claim 1, wherein
The compound according to any one of claims 1 to 3, wherein the ring Ar 1 is a pyridine ring, a pyridazine ring, or an isoxazole ring substituted with a C 1-6 alkyl group.
The compound according to any one of claims 1 to 3, wherein the ring Ar 2 is a benzene ring, a furan ring, or a thiophene ring optionally substituted with one or two halogen atoms.
Ring Ar 1 is a pyridine ring, a pyridazine ring, or an isoxazole ring substituted with a C 1-6 alkyl group,
A ring Ar 2 may be substituted with one or two halogen atoms, a benzene ring, a furan ring, or a thiophene ring;
The compound according to any one of claims 1 to 3, wherein
Formula (I) is converted to Formula (Ia)

[Where
Ring Ar 3 represents a pyridazine ring optionally substituted with a halogen atom;
Ring Ar 4 represents a benzene ring which may be substituted with a halogen atom. ]
The compound of claim 1, wherein
4- (4-phenylpyrimidin-2-yl) -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof.
4- [4- (2,3-difluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof.
4- [4- (3-Fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof.
4- [4- (4-fluorophenyl) pyrimidin-2-yl] -N-pyridazin-3-ylpiperidin-1-carboxamide or a salt thereof.
A prodrug of the compound according to claim 1.
A pharmaceutical comprising the compound according to claim 1 or a prodrug thereof.
A FAAH inhibitor containing the compound according to claim 1 or a prodrug thereof.
A prophylactic or therapeutic agent for pain, depression or anxiety, comprising the compound according to claim 1 or a prodrug thereof.
A method for inhibiting FAAH, comprising administering an effective amount of the compound according to claim 1 or a prodrug thereof to a mammal.
A method for preventing or treating pain, depression or anxiety, which comprises administering an effective amount of the compound or prodrug thereof according to claim 1 to a mammal.
Use of the compound according to claim 1 or a prodrug thereof for producing a FAAH inhibitor.
Use of the compound according to claim 1 or a prodrug thereof for producing a prophylactic or therapeutic agent for pain, depression or anxiety.