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WO2011105572A1 - Nouveau dérivé hétéroaryle - Google Patents

Nouveau dérivé hétéroaryle Download PDF

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Publication number
WO2011105572A1
WO2011105572A1 PCT/JP2011/054366 JP2011054366W WO2011105572A1 WO 2011105572 A1 WO2011105572 A1 WO 2011105572A1 JP 2011054366 W JP2011054366 W JP 2011054366W WO 2011105572 A1 WO2011105572 A1 WO 2011105572A1
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alkyl
formula
group
compound
pyrimidin
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PCT/JP2011/054366
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Japanese (ja)
Inventor
智之 神野
央 永末
貴志 水野
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持田製薬株式会社
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Publication of WO2011105572A1 publication Critical patent/WO2011105572A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound useful for inhibiting the function of a pharmaceutical, particularly a fatty acid amide hydrolase (hereinafter referred to as “FAAH”), particularly a heteroaryl derivative represented by the formula (I),
  • FAAH fatty acid amide hydrolase
  • the present invention relates to a pharmaceutical composition containing the derivative as an active ingredient, or a prophylactic or therapeutic agent for a disease involving FAAH including pain.
  • FAAH is an integral membrane-bound enzyme that hydrolyzes endocannabinoids, and its activity is known to disappear due to its catabolism (Nature, 384, 83-87, 1996).
  • Endogenous cannabinoids are a general term for in vivo substances that act on cannabinoid receptors, such as anandamide, palmitoylethanolamine, oleamide, or glycerol 2-arachidonate. These endogenous cannabinoids are analgesic (Nature, 394, 277-281, 1998), regulating feeding (Nature, 414, 209-212, 2001), promoting sleep (Science, 268 Vol. 1506-1509 (1995), etc. are known to have various physiological activities.
  • Endogenous cannabinoid receptors include CB1 receptor (Nature, 346, 561-567, 1990), CB2 receptor (Eur. J. Biochem., 232, 54-61, 1995) and GPR55 ( Br. J. Pharmacol., 152, 1092-1101, 2007) is currently known.
  • ⁇ 9-Tetrahydrocannabinol an active ingredient in cannabis, is a CB1 receptor agonist, but has useful pharmacological effects such as analgesic action, but has undesirable central side effects such as hypothermia and catalepsy. In addition, clinical applications are limited.
  • mice genetically deficient in the FAAH gene In mice genetically deficient in the FAAH gene (Proc. Natl. Acad. Sci., 98, 9371-9376, 2001), the content of anandamide in the brain increased more than 10 times. No changes in the amount of exercise or body temperature and catalepsy via the CB1 receptor have been observed. On the other hand, analgesic effects such as an increase in the reaction threshold in the Taylor Marion test and the hot plate test and a decrease in pain behavior duration in the formalin test have been confirmed.
  • Non-steroidal anti-inflammatory drugs such as morphine, antidepressants such as amitriptyline, antidepressants such as gabapentin, pregabalin, carbamazepine, and phenytoin, not selected for the purpose of pain relief for chronic pain
  • Antiarrhythmic drugs such as mexiletine, which is a typical sodium channel blocker, are diverted and prescribed.
  • the non-steroidal anti-inflammatory drug is not completely satisfied with the analgesic effect, and further has problems of side effects such as gastrointestinal disorders and kidney disorders.
  • narcotic analgesics such as morphine have a high effect mainly on nociceptive pain, but there are serious side effects on the digestive system, respiratory system and central nervous system.
  • the effect on sexual pain is weak.
  • Amitriptyline has dry mouth, drowsiness, sedation, constipation, difficulty in urinating, carbamazepine, phenytoin have wandering, rash, digestive symptoms, cardiotoxicity, etc. Side effects such as symptoms are known.
  • Patent Document 1 International Publication No. 2006/054652 pamphlet
  • Patent Document 2 International Publication No. 2006/074025 pamphlet
  • Patent Document 3 International Publication No. 2007/005510 pamphlet
  • Patent Document 3 International Publication No. 2009/105220 pamphlet
  • Patent Document 4 International Publication No. 2009/127743
  • Patent Document 5 International Publication No. 2009/127944
  • Patent Document 6 International Publication No. 2009/127946
  • Patent Document 7 International Publication No. 2009/127948
  • Patent Document 9 International Publication No.
  • Patent Document 10 International Publication No. 2010/053120 Pamphlet.
  • Patent Document 11 pamphlet of International Publication No. 2010/058318
  • Patent Document 12 pamphlet of International Publication No. 2010/068452
  • Patent Document 13 pamphlet of International Publication No. 2010/068453
  • Patent Document 14 international publication No. 2010/117014 pamphlet (patent document 15), WO 2010/141809 pamphlet (patent document 16), WO 2010/141817 pamphlet (patent document 17), WO 2011/022348 pamphlet (patent) Document 18) is known.
  • these patent documents do not disclose a compound in which a heteroalicyclic group and an arylalkylamino group are bonded to the heteroaryl ring disclosed in the present invention.
  • Patent Document 19 discloses a compound having a structure in which a morpholine ring and an arylalkylamino group are bonded to a pyrimidine ring as a hypotension, a diuretic, an antispasmodic agent, and a care agent, and a compound having a substituent on the morpholine ring.
  • a compound having a strong FAAH inhibitory activity as in the present invention.
  • FAAH inhibitors that can be administered orally, are highly safe, and / or are highly effective, especially preventive or therapeutic agents for diseases involving FAAH (especially pain relief). Preventive or therapeutic agents).
  • gastrointestinal disorders and kidney disorders that are side effects of nonsteroidal anti-inflammatory drugs
  • digestive system that is a side effect of narcotic analgesics such as morphine, Respiratory system, central nervous system disorders, etc .
  • side effects of amitriptyline such as dry mouth, drowsiness, sedation, constipation, difficulty in urinating, etc .
  • amitriptyline such as dry mouth, drowsiness, sedation, constipation, difficulty in urinating, etc .
  • There are issues to be addressed such as somnolence and dizziness, which are side effects of gabapentin; dizziness and digestive symptoms, which are side effects of mexiletine; or heart failure, which is a side effect of COX2 inhibitors.
  • the present inventor has conducted extensive research to obtain a compound that can block the highly selective FAAH function with high safety and / or excellent effectiveness.
  • a compound having a structure in which a heteroalicyclic group and an arylalkylamino group are bonded to a heteroaryl ring represented by (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is excellent in FAAH inhibition.
  • the present invention was completed by finding out that it has an action.
  • the present invention is a pharmaceutical composition containing the novel heteroaryl compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, and the derivative as an active ingredient.
  • the pharmaceutical composition is particularly used for a FAAH inhibitor, or a prophylactic or therapeutic agent for pain, especially a prophylactic or therapeutic agent for inflammatory pain, and / or a prophylactic or therapeutic agent for neuropathic pain.
  • the present invention relates to a novel compound represented by formula (I) having a structure in which a heteroalicyclic group and an arylalkylamino group are bonded to a heteroaryl ring, or a pharmaceutically acceptable salt thereof, or a solvent thereof.
  • the present invention provides a pharmaceutical composition containing a Japanese product and the derivative as an active ingredient.
  • a preferred embodiment of the compound of the invention is a FAAH inhibitor.
  • the pharmaceutical composition containing the compound of the present invention as an active ingredient is a preventive or therapeutic agent for orally administrable pain, particularly a prophylactic or therapeutic agent for neuropathic pain, fibromyalgia, a prophylactic or therapeutic agent for inflammatory pain As expected.
  • a particularly preferred compound group of the present invention is highly useful as a prophylactic / therapeutic agent for the above-mentioned diseases because it also has a feature of highly selective FAAH inhibitory activity.
  • the present invention relates to novel heteroaryl derivatives represented by the following formula (I) or salts thereof, solvates thereof, pharmaceutical compositions containing them as active ingredients, and pharmaceuticals of the derivatives or salts thereof: It is a use.
  • Aspect 1 of the present invention is: The following formula (I) (Where Z 1 , Z 2 and Z 3 each independently represent a nitrogen atom or CH, When Z 1 is CH, the hydrogen atom may be substituted with R 4 , Z 2 and Z 3 are not CH at the same time, m represents an integer of 0-4, q represents an integer of 0-3, Ar represents (6-10 membered ring) aryl or (5-12 membered ring) heteroaryl optionally substituted by 1 to 4 groups selected from substituent group T; Substituent group T includes the following groups: 1)-(C 1 -C 6 ) -alkyl, 2) -OH 3) —O— (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 5) -CHO, 6) —CO— (C 1 -C 6 ) -alkyl, 7)
  • Substituent Group T are each Substituent Group B, ie, “— (C 1 -C 6 ) -alkyl, -N (R 5 ) (R 6 ), -CO-N (R 5 ) (R 6 ), -SO 2 -N (R 5 ) (R 6 ), -N (R 5 ) -CO-R 6 , 1 to 4 groups may be substituted with a group arbitrarily selected from —N (R 5 ) —SO 2 —R 6 , halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl ”. Often,
  • Substituent Group B are further substituted with Substituent Group C, ie, “halogen, —OH, —CN, and — 1 to 4 groups optionally substituted with O— (C 1 -C 6 ) -alkyl ”may be substituted,
  • R 1 is selected from a hydrogen atom and — (C 1 -C 6 ) -alkyl;
  • Each R 2 is independently selected from a hydrogen atom and — (C 1 -C 6 ) -alkyl;
  • R 2 may be bonded to each other to form a 3-6 membered carbocycle, and the 3-6 membered carbocycle may be substituted with one or two groups arbitrarily selected from the substituent group U;
  • R 4 represents the following groups: 1)-(C 1 -C 6 ) -alkyl, 2) -OH 3) —O— (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 5) -CHO, 6) —CO— (C 1 -C 6 ) -alkyl, 7) -CO- (6-10 membered) aryl, 8) -CO- (5-12 membered ring) heteroaryl, 9) -S (O) 0-2- (6-10 membered) aryl, 10) -S (O) 0-2 (5-12 membered) heteroaryl, 11) —CO 2 — (C 1 -C 6 ) -alkyl, 12) —CO 2 H, 13) -N (R 5 ) (R 6 ), 14) -N (R 5 ) -CO-R 6 , 15) —N (R 5 ) —
  • substituent group D -(6-10-membered ring) aryl and-(5-12-membered ring) heteroaryl are each further substituted with substituent group E, that is, "-(C 1 -C 6 ) -alkyl, halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) (R 6 ), —CO 2 — (C 1- C 6 ) -alkyl, —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), ⁇ O (oxo), and —S (O) 0-2 1 to 4 groups may be substituted with a group arbitrarily selected from — (C 1 -C 6 ) -alkyl ”,
  • Group G ie “— (C 1 -C 6 ) -alkyl, —N (R 5 ) (R 6 ), —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) —CO—R 6 , —N (R 5 ) —SO 2 —R 6 , halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl , And ⁇ O (oxo) ”may be optionally substituted with 1 to 4 groups,
  • Substituent Group G The — (C 1 -C 6 ) -alkyl and —O— (C 1 -C 6 ) -alkyl in Substituent Group G are further substituted with Substituent Group H, that is, “—S (O) 0-2 —.
  • R 6 is independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) heteroaryl; -(C 1 -C 6 ) -alkyl in R 5 and R 6 represents substituent group I, ie “halogen, —OH, —CN, — (6-10 membered ring) aryl, — (5-12 membered ring)”.
  • Heteroaryl, —O— (C 1 -C 6 ) -alkyl, —N (R 5 ′) (R 6 ′), —CO 2 — (C 1 -C 6 ) -alkyl, —CO—N (R 5 ′) (R 6 ′), —SO 2 —N (R 5 ′) (R 6 ′), or —S (O) 0-2- (C 1 -C 6 ) -alkyl ” 1 to 4 may be substituted with R 5 ′ and R 6 ′ are each independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) heteroaryl.
  • substituent group I —O— (C 1 -C 6 ) -alkyl, —CO 2 — (C 1 -C 6 ) -alkyl, —S (O) 0-2- (C 1 -C 6 ) — -(C 1 -C 6 ) -alkyl in alkyl may be further substituted with 1 to 4 groups optionally selected from substituent group J, ie, “halogen, —OH, or —CN”.
  • R 5 and R 6 are each further substituted with substituent group K, ie, “— (C 1 -C 6 ) -alkyl, halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —N (R 5 ′) (R 6 ′), —CO 2 — (C 1 -C 6 ) -alkyl, —CO—N (R 5 ′) (R 6 ′), —SO 2 —N (R 5 ′) (R 6 ′), and —S (O) 0-2- (C 1 -C 6 ) -alkyl ” 1 to 4 substituents may be substituted with a selected group, R 5 ′ and R 6 ′ are each independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered
  • R 5 and R 6 are bonded to each other as —N (R 5 ) (R 6 ), —N (R 5 ) —SO 2 —R 6 or —N (R 5 ) —CO—R 6 (3-12 (Member ring)
  • a heteroalicyclic ring may be formed. Or a pharmaceutically acceptable salt or solvate thereof.
  • C 1 -C 6 indicates that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, represents a linear, branched or cyclic group.
  • — (6-10 membered) aryl means a monocyclic or condensed (6-10 membered) aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc., or indanyl, indenyl, Partially hydrogenated fused aryl such as tetrahydronaphthyl and the like.
  • the partially hydrogenated aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring, and the hydrogen atom or hydrogen of the aromatic part of the condensed ring. Either of the hydrogen atoms in the converted moiety may be removed.
  • 1,2,3,4-tetrahydronaphthalene 1,2,3,4-tetrahydronaphthalene (-1-yl, 2-yl, -3-yl, -4-yl, -5-yl, -6-yl,- 7-yl, -8-yl) and the like.
  • “— (5-12 membered ring) heteroaryl” includes monocyclic or condensed ring, and the monocyclic heteroaryl group preferably has 5 to 7 ring members, More preferred are those having 5 to 6, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, Pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,
  • the condensed heteroaryl group preferably has 8 to 10 ring members, and the above 5-7 membered heterocycle is a monocyclic aryl group (for example, a benzene ring) or a monocyclic ring.
  • a monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation with a heteroaryl group is included.
  • the arbitrary hydrogen atom may be removed from any condensed ring.
  • Indolinyl isoindolinyl, dihydrobenzoxazonyl, dihydrobenzothiazolyl, chromanyl, isochromanyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4 -Benzothiazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl (-4-yl), tetrahydrobenzoxazepinyl, tetrahydro Benzazepinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridyl, 5,6,7,8-tetrahydro [1,2,4] triazolo (4,3-a) pyrazinyl , 5,6,7,8-t
  • the partially hydrogenated condensed heteroaryl group and the like are preferably those having 8 to 10 ring members, and this is a monocyclic aryl group having a 5-7 membered heterocycle (for example, a benzene ring).
  • it means a monovalent group formed by removing an arbitrary hydrogen atom from a ring in which a condensed ring formed by condensation with a monocyclic heteroaryl group is partially hydrogenated.
  • Either hydrogen atoms or hydrogenated hydrogen atoms may be removed.
  • tetrahydroquinolyl includes 5,6,7,8-tetrahydroquinolyl or 1,2,3,4-tetrahydroquinolyl.
  • these groups may be, for example, 5,6,7,8-tetrahydroquinolyl-2-yl, -3-yl, -4-yl, -5- Yl, -6-yl, -7-yl, -8-yl and the like, and 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3 Examples include -yl, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like.
  • — (C 1 -C 6 ) -alkyl means a C 1 -C 6 straight, branched or cyclic alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec- Butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl 2-ethylbutyl, 1,
  • “—O— (C 1 -C 6 ) -alkyl” represents a C 1 -C 6 straight, branched or cyclic alkoxyl group.
  • —S (O) 0-2- (C 1 -C 6 ) -alkyl represents a group in which the above-described — (C 1 -C 6 ) -alkyl is bonded to an S, SO or SO 2 group.
  • “—CO— (C 1 -C 6 ) -alkyl” represents a group in which the above-mentioned “(C 1 -C 6 ) -alkyl” is bonded to a carbonyl group.
  • “—CO 2 — (C 1 -C 6 ) -alkyl” represents a group in which the above-mentioned “(C 1 -C 6 ) -alkyl” is bonded to a carbonyloxy group.
  • R 5 and R 6 are each independently a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) selected from heteroaryl, -(C 1 -C 6 ) -alkyl in R 5 and R 6 represents substituent group I, ie “halogen, —OH, —CN, — (6-10 membered ring) aryl, — (5-12 membered ring)”.
  • Heteroaryl, —O— (C 1 -C 6 ) -alkyl, —N (R 5 ′) (R 6 ′), —CO 2 — (C 1 -C 6 ) -alkyl, —CO—N (R 5 ′) (R 6 ′), —SO 2 —N (R 5 ′) (R 6 ′), or —S (O) 0-2- (C 1 -C 6 ) -alkyl ” 1 to 4 may be substituted with R 5 ′ and R 6 ′ are each independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) heteroaryl.
  • R 5 and R 6 are each further substituted with a substituent group K, ie, “— (C 1 -C 6 ) -alkyl, halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —N (R 5 ′) (R 6 ′), —CO 2 — (C 1 -C 6 ) -alkyl, —CO—N (R 5 ′) (R 6 ′), —SO 2 —N (R 5 ′) (R 6 ′), and —S (O) 0-2- (C 1 -C 6 ) -alkyl ” 1 to 4 substituents may be substituted with a selected group,
  • R 5 ′ and R 6 ′ are each independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) heteroaryl.
  • R 5 and R 6 are bonded to each other as —N (R 5 ) (R 6 ), —N (R 5 ) —SO 2 —R 6 or —N (R 5 ) —CO—R 6 (3-12 (Membered ring) may form a heteroalicyclic ring, Specifically, amino, “mono / di- (C 1 -C 6 ) -alkylamino”, “halogenated mono / di- (C 1 -C 6 ) -alkylamino”, “pyrrolidin-2-one”, Examples thereof include “propane-4-sultam”.
  • —CO—N (R 5 ) (R 6 ) represents a group in which a carbonyl group is bonded to the above-described —N (R 5 ) (R 6 ).
  • a dimethylaminocarbonyl group etc. are mentioned.
  • —SO 2 —N (R 5 ) (R 6 ) represents a group in which the aforementioned N (R 5 ) (R 6 ) group is bonded to a sulfonyl group.
  • An example is a dimethylaminosulfonyl group.
  • —N (R 5 ) —CO—R 6 means that the hydrogen atom of the amino group is “R 5 ” and “—CO—R 6 ”, for example, “R 5 ” as “hydrogen atom” and “—CO— R 6 ”means an amino group substituted with“ —CO— (C 1 -C 6 ) -alkyl ”.
  • acetamide, propionamide, butyramide, isobutylamide, barrel amide, isovaleramide, pivalamide, hexaneamide, heptaneamide, cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, cyclohexanecarboxamide, 4-methylcyclohexanecarboxamide, etc. Can be mentioned.
  • —N (R 5 ) —SO 2 —R 6 means that the hydrogen atom of the amino group is “R 5 ” and “—SO 2 —R 6 ”, for example, “R 5 ” is “hydrogen atom” and “— “SO 2 —R 6 ” means an amino group substituted with “—SO 2 — (C 1 -C 6 ) -alkyl”.
  • examples include amide, cyclopentanesulfonamide, cyclohexanesulfonamide, 4-methylcyclohexanesulfonamide and the like.
  • halogen examples include fluorine atom, chlorine atom, bromine atom and iodine atom.
  • (3-12 membered) non-aromatic heteroalicyclic group refers to a (3-12 membered) non-aromatic heteroalicyclic group, that is, a saturated or partially unsaturated 3- to 12-membered ring.
  • the heteroalicyclic ring contains at least one heteroatom (preferably 1 to 4) arbitrarily selected from N, O, and S in addition to the carbon atom.
  • (3-12 membered ring) non-aromatic heteroalicyclic group” as “ring A of formula (II)” in the present specification means a saturated or partially unsaturated monocyclic or condensed 4-10 member.
  • a cyclic group having a total number of rings of 12 or less in which a benzene ring or a 5- to 7-membered heteroaryl ring is condensed to the group is, for example, indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroiso Quinolyl, tetrahydroquinoxalyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyrazinyl, isochromanyl, chromanyl and the like, more specifically, 3,4-dihydroisoquinolin-2 (1H) -yl, indoline -2-one-1-yl, isoindoline-2-yl, 3,4-dihydroquinolin-1 (2H) -yl, 5,6-dihydro- [1,2,4] triazolo [4,3-a ] Pyrazine-7 (8H) -
  • —CO- (6-10 membered) aryl represents a group in which a carbonyl group is bonded to the aryl group.
  • (6-10 membered) arylcarbonyl such as benzoyl, naphthylcarbonyl and the like can be mentioned.
  • “-CO- (5-12 membered ring) heteroaryl” represents a group in which a carbonyl group is bonded to the heteroaryl group.
  • —S (O) 0-2- (6-10 membered ring) aryl represents a group in which the above-mentioned (6-10 membered ring) aryl is bonded to an S, SO or SO 2 group. Examples thereof include a benzenesulfonyl group.
  • —S (O) 0-2- (5-12 membered ring) heteroaryl represents a group in which the above-described (5-12 membered ring) heteroaryl is bonded to an S, SO or SO 2 group. Examples thereof include a pyridinesulfonyl group.
  • —N (R 5 ) —CO—N (R 5 ) (R 6 ) means that each R 5 bonded to N is independent, and the above-mentioned N (R 5 ) (R 6 ) group is carbonyl And a group bonded to —N (R 5 ) (R 6 ) via a group.
  • N (R 5 ) (R 6 ) is carbonyl
  • a group bonded to —N (R 5 ) (R 6 ) via a group for example, a dimethylaminocarbonylamino group etc. are mentioned.
  • —N (R 5 ) —SO 2 —N (R 5 ) (R 6 ) means that each R 5 bonded to N is independent, and the above-mentioned N (R 5 ) (R 6 ) group is This represents a group bonded to —N (R 5 ) via a sulfonyl group. For example, a dimethylaminosulfonylamino group etc. are mentioned.
  • aryl is a group in which the “aryl group” is substituted with an oxygen atom.
  • aryl group is substituted with an oxygen atom.
  • phenoxy 1-naphthyloxy, 2-naphthyloxy, 2-anthryloxy Phenanthryloxy, 1,2,3,4-tetrahydronaphthalene (8-yloxy) and the like.
  • “—O- (5- to 12-membered ring) heteroaryl” is a group in which the “heteroaryl group” is substituted with an oxygen atom.
  • Z 1 represents CH or N.
  • Z 2 represents CH or N, preferably N.
  • Z 3 represents CH or N, preferably N.
  • m represents an integer of 0-4, preferably an integer of 1-3.
  • q represents an integer of 0-3, preferably 0.
  • R 1 is selected from a hydrogen atom and — (C 1 -C 6 ) -alkyl, preferably a hydrogen atom or Represents methyl.
  • R 2 is preferably each independently selected from a hydrogen atom or — (C 1 -C 6 ) -alkyl.
  • R 2 may be bonded to each other to form a 3-6 membered carbocycle, and R 2 preferably represents a hydrogen atom.
  • R 3 is the following group: 1)-(C 1 -C 6 ) -alkyl, 2) —O— (C 1 -C 6 ) -alkyl, 3) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 4) -CN, 5) -N (R 5 ) (R 6 ), 6) Halogen, 7) —CO—N (R 5 ) (R 6 ), and 8) —SO 2 —N (R 5 ) (R 6 ), Represents a group arbitrarily selected from 1)-(C 1 -C 6 ) -alkyl, 2) -O— (C 1 -C 6 ) -alkyl, and 3) —S (O) 0-2- (C 1 -C 6 ) in R 3
  • The-(C 1 -C 6 ) -alkyl in -alkyl may be substituted
  • Ar is a group arbitrarily selected from the substituent group T and preferably 1 to 4 (preferably 1 to 2) ) Represents an optionally substituted (6-10 membered ring) aryl or (5-12 membered ring) heteroaryl, preferably 1 to 4 (preferably 1 to 4) groups arbitrarily selected from substituent group T 2) represents an optionally substituted (6-10 membered) aryl, and more preferably represents a phenyl group optionally substituted with 1 to 2 groups optionally selected from the substituent group T.
  • Ar is a group arbitrarily selected from the substituent group T (preferably 1 to 4). 2) represents an optionally substituted (6-10 membered ring) aryl or (5-12 membered ring) heteroaryl, and more specifically as part of the Ar cyclic group, b1) to (b16),
  • b-1 group More preferably, the following b-1 group, namely group b-1 And most preferably Is mentioned.
  • the substituent group T is the following group: 1)-(C 1 -C 6 ) -alkyl, 2) -OH 3) —O— (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 5) -CHO, 6) —CO— (C 1 -C 6 ) -alkyl, 7) —CO 2 — (C 1 -C 6 ) -alkyl, 8) —CO 2 H, 9) -N (R 5 ) (R 6 ), 10) —CO—N (R 5 ) (R 6 ), 11) —SO 2 —N (R 5 ) (R 6 ), 12) -N (R 5 ) -CO -R 6 , 13) -N (R 5 ) -SO 2 -R 6 , 14) -
  • Substituent Group T are each Substituent Group B, ie, “— (C 1 -C 6 ) -alkyl. , -N (R 5 ) (R 6 ), -CO-N (R 5 ) (R 6 ), -SO 2 -N (R 5 ) (R 6 ), -N (R 5 ) -CO-R 6 , Halogen, —OH, —CN, — (5-12 membered) heteroaryl and —O— (C 1 -C 6 ) -alkyl ”may be substituted with 1 to 4 groups ,
  • — (C 1 -C 6 ) -alkyl and —O— (C 1 -C 6 ) -alkyl in Substituent Group B are further substituted with Substituent Group C, ie, “halogen, —OH, —CN, and One to four groups may be substituted with a group arbitrarily selected from “—O— (C 1 -C 6 ) -alkyl”.
  • the substituent group T is preferably the following groups: 1)-(C 1 -C 6 ) -alkyl , 2) -OH 3) —O— (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 14) -CN, 15)-(6-10 membered) aryl, 16)-(5-12 membered) heteroaryl, and 17) halogen, Consists of 1)-(C 1 -C 6 ) -alkyl, 3) -O- (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 in substituent group T -(C 1 -C 6 ) -alkyl in) -alkyl may each be substituted with 1 to 3 halogens;
  • Substituent Group T are each 1 to 3 halogen or-(5-12 membered ring) heteroaryl. May be substituted.
  • the substituent group T is more preferably “— (C 1 -C 6 ) -alkyl, —OCH 2 phenyl”. , —OCHF 2 , —F, —Cl, —SMe, —CN, —CF 3 , —OMe, —OCF 3 , —SCF 3 , —OH, or 2-pyridyl ”.
  • the portion of the A ring represented by is a 3-12 membered monocyclic or condensed non-aromatic heteroalicyclic group, and preferably the A ring is a monocyclic or condensed 4-10 membered non-aromatic heterocyclic ring More preferably a saturated 4- to 7-membered non-aromatic heterocyclic group.
  • formula (III) is preferably the following formula (III) Wherein Z 1 , R 4 and m are the same as defined and described in the above embodiment [1], s and r each independently represents an integer of 0-2, and Z 4 represents oxygen Represents an atom, NH or CH 2, and in the case where Z 4 is NH or CH 2 , the hydrogen atom may be substituted with R 4 , and the A ring is bridged with a linker consisting of 1 to 4 carbon atoms May be cross-linked with a linker preferably consisting of two carbon atoms, More preferably, s and r each independently represents an integer of 0-1, m represents an integer of 1-3, Z 1 represents CH or N, Z 4 represents CH 2 or NH, and Z 4 The hydrogen atom in may be substituted with R 4 , and the A ring may be bridged with a linker consisting of two
  • group a-1 namely group a-1 Is mentioned.
  • R 4 is the following group: 1)-(C 1 -C 6 ) -alkyl, 2) -OH 3) —O— (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 5) -CHO, 6) —CO— (C 1 -C 6 ) -alkyl, 7) -CO- (6-10 membered) aryl, 8) -CO- (5-12 membered ring) heteroaryl, 9) -S (O) 0-2- (6-10 membered) aryl, 10) —S (O) 0-2 — (5-12 membered ring) heteroaryl, 11) —CO 2 — (C 1 -C 6 ) -alkyl, 12) —CO 2 H, 13) -N (R 5 ) (R 6 ), 14)
  • Substituent Group D is further substituted with Substituent Group E, that is, "-(C 1 -C 6 ) -alkyl, halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) (R 6 ), —CO 2 — (C 1- C 6 ) -alkyl, —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), ⁇ O (oxo), and —S (O) 0-2 1 to 4 groups may be substituted with a group arbitrarily selected from — (C 1 -C 6 ) -alkyl ”, — (C 1 -C 6 ) -alkyl, —O—
  • Group G ie “— (C 1 -C 6 ) -alkyl, —N (R 5 ) (R 6 ), —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) —CO—R 6 , —N (R 5 ) —SO 2 —R 6 , halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl And 1 to 4 substituents optionally selected from ⁇ O (oxo) ”,
  • Substituent Group G are further substituted with Substituent Group H, that is, “—S (O) 0-2 — ( C 1 -C 6 ) -alkyl, —N (R 5 ) (R 6 ), halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —CO—N (R 5 ) ( R 6 ), —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) —CO—R 6 , ⁇ O (oxo), and —N (R 5 ) —SO 2 —R 6 ” 1 to 4 groups may be substituted with a group arbitrarily selected from R 5 and R 6 of 15) -N (R 5 ) —SO 2 —R 6 in R 4 are bonded to each other
  • R 4 is preferably 1)-(C 1 -C 6 ) -alkyl, 2) -OH, 3) —O— (C 1 -C 6 ) -alkyl, 4) -S (O) 0-2- (C 1 -C 6 ) -alkyl, 6) —CO— (C 1 -C 6 ) -alkyl, 9) —S (O) 2 (6-10 membered) aryl, 11) —CO 2 — (C 1 -C 6 ) -alkyl, 14) -N (R 5 ) -CO-R 6 , 15) —N (R 5 ) —SO 2 —R 6 , 19) -N (R 5 ) -SO 2 -N (R 5 ) (R 6 ), 20) -CN, 21)-(6-10 membered) aryl, 22)-(5-12 membere
  • Substituent Group D is further substituted with Substituent Group E, that is, "-(C 1 -C 6 ) -alkyl, halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) (R 6 ), —CO 2 — (C 1- C 6 ) -alkyl, —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), ⁇ O (oxo), and —S (O) 0-2 1 to 4 groups may be substituted with a group arbitrarily selected from — (C 1 -C 6 ) -alkyl ”, — (C 1 -C 6 ) -alkyl, —O—
  • Substituent Group G are further substituted with Substituent Group H, that is, “—S (O) 0-2 — ( C 1 -C 6 ) -alkyl, —N (R 5 ) (R 6 ), halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —CO—N (R 5 ) ( R 6 ), —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) —CO—R 6 , ⁇ O (oxo), and —N (R 5 ) —SO 2 —R 6 ” 1 to 4 groups may be substituted with a group arbitrarily selected from
  • R 4 represents — (C 1 -C 6 ) -alkyl group, —OH group, —O— (C 1 -C 6 ) -alkyl.
  • the — (C 1 -C 6 ) -alkyl group in R 4 is the substituent group L, ie “—S (O) 0-2- (C 1 -C 6 ) -alkyl, —N (R 5 ) (R 6 ), Halogen, —OH, —CN, —O— (C 1 -C 6 ) -alkyl, —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), 1 to 4 groups may be substituted with a group arbitrarily selected from —N (R 5 ) —CO—R 6 , ⁇ O (oxo), and —N (R 5 ) —SO 2 —R 6 ”,
  • the (6-10 membered) aryl or (5-12 membered) heteroaryl in R 4 is substituted group G, ie “— (C 1 -C 6 ) -alkyl, —N (R 5 ) (R 6 )
  • R 5 and R 6 are each independently selected from a hydrogen atom,-(C 1 -C 6 ) -alkyl,-(6-10 membered ring) aryl, and-(5-12 membered ring) heteroaryl.
  • R 4 is — (C 1 -C 6 ) -alkyl, —OH, —O— (C 1 -C 6 ) -alkyl, — S (O) 0-2- (C 1 -C 6 ) -alkyl, -CO- (C 1 -C 6 ) -alkyl, -SO 2- (6-10 membered) aryl, -CO 2- (C 1 -C 6 ) -alkyl, -N (R 5 ) -CO-R 6 , -N (R 5 ) -SO 2 -R 6 , -CN, -CO-N (R 5 ) (R 6 ),- SO 2 -N (R 5) ( R 6), - N (R 5) (R 6), - N (R 5) -CO-N (R 5) (R 6), -N (R 5) -SO 2 -N (R 5) ( R 6), - N (R 5) -CO-N (R
  • substituents may be substituted with a selected group, 1-3 of (6-10 membered) aryl, (5-12 membered) heteroaryl, and —O- (6-10 membered) aryl in R 4 are substituted with halogen, —CF 3 , —CN.
  • R 5 and R 6 in R 4 each independently represent a hydrogen atom, - (6-10 membered) aryl, or - (C 1 -C 6) - alkyl, or -N in R 4 ( R 5 ) —SO 2 —R 6 , R 5 and R 6 may be bonded to each other to form a 4-6 membered sultam ring as —N (R 5 ) —SO 2 —R 6 , More specifically, R 4 includes the following group c, that is, formulas (c1) to (c54). Group c
  • R 5 and R 6 represents substituent group I, ie “halogen, —OH, —CN, — (6-10 membered ring) aryl, — (5-12 membered ring)”.
  • Heteroaryl, —O— (C 1 -C 6 ) -alkyl, —N (R 5 ′) (R 6 ′), —CO 2 — (C 1 -C 6 ) -alkyl, —CO—N (R 5 ′) (R 6 ′), —SO 2 —N (R 5 ′) (R 6 ′), or —S (O) 0-2- (C 1 -C 6 ) -alkyl ” 1 to 4 may be substituted with R 5 ′ and R 6 ′ are each independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) heteroaryl.
  • the —O— (C 1 -C 6 ) -alkyl, —CO 2 — (C 1 -C 6 ) -alkyl, —S (O) 0-2- (C 1 -C 6 ) — in Substituent Group I -(C 1 -C 6 ) -alkyl in alkyl may be further substituted with 1 to 4 groups optionally selected from substituent group J, ie, “halogen, —OH, and —CN”.
  • R 5 and R 6 are further substituted with substituent group K, ie, “— (C 1 -C 6 ) -alkyl, halogen, —OH.
  • R 5 ′ and R 6 ′ are each independently selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (6-10 membered ring) aryl, and — (5-12 membered ring) heteroaryl.
  • R 5 and R 6 are bonded to each other as —N (R 5 ) (R 6 ), —N (R 5 ) —SO 2 —R 6 or —N (R 5 ) —CO—R 6 (3-12 (Member ring)
  • a heteroalicyclic ring may be formed.
  • R 5 and R 6 are preferably selected from — (C 1 -C 6 ) -alkyl and —SO 2 — (C 1 -C 6 ) -alkyl, and the — (C 1 -C 6 ) -alkyl or -SO 2 - (C 1 -C 6 ) - in alkyl - (C 1 -C 6) - alkyl, which may be three substituents to 1 halogen, Alternatively, R 5 and R 6 may combine with each other to form a (3-12 membered) heteroalicyclic ring as —N (R 5 ) —SO 2 —R 6 .
  • R 4 is-(C 1 -C 6 ) -alkyl, -OH, -O- (C 1 -C 6 ) -alkyl, -S (O) 0-2- (C 1 -C 6 ) -alkyl, -CO- (C 1 -C 6 ) -alkyl, -SO 2- (6-10 membered) aryl, -CO 2- (C 1 -C 6 ) -alkyl, -N (R 5 ) -CO-R 6 , —N (R 5 ) -CO-R 6 , —N (R 5 ) —SO 2 —R 6 , —CN, —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ), —N (R 5 ) (R 6 ), —N (R 5 ) —CO—N (R 5 ) (R 6 ), —N (R 5 ) —CO—N (
  • a19) represents a group arbitrarily selected from R19, and R 4 represents a group arbitrarily selected from Formulas (c1) to (c54) described as specific examples in [1-10-2]. And constitutes part of the compound of formula (I) of the present invention.
  • the formula of the given group a (A1), Formula (a2), Formula (a4) to Formula (a9), Formula (a12), Formula (a17) to Formula (a19) represents a group arbitrarily selected
  • R 4 represents [1-10- 4] represents a group arbitrarily selected from the formulas (c1) to (c54) listed in the group c described as specific examples, and is represented by the formula (I) of the present invention. It constitutes part of the compound.
  • R 4 represents a group arbitrarily selected from the formula of the group c shown as a specific example in [1-10-4]) And constitutes part of the compound of formula (I) of the present invention.
  • (C 1 -C 6) - alkyl can be represented as even may) be substituted with 1-4 halogens, tables in the formula (I) of the present invention Constituting part of the compound.
  • the secondary hydroxyl group is preferably a compound having the configuration of the following formula (VI).
  • Example 1 (R) -1-phenyl-2- (6- (4- (trifluoromethyl) piperidin-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 2 (R)-( ⁇ )-1-phenyl-2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 3 (R) -2- (6- (4-Isopropylpiperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 4 (R) -2- (6- (4- (2,2-difluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 5 (R) -2- (6- (4-Isobuty
  • Example 10 (R) -2- (6- (4- (methylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 11 (R) -2- (6- (4- (Ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 12 (R) -2- (6- (6-Fluoro-3,4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 13 (R) -2- (6- (4-Ethoxypiperidin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 14 (R) -2- (6- (4-Isopropoxypiperidin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 20 (R) -1-phenyl-2- (6- (4- (3,3,3-trifluoropropyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 21 (R) -2- (6- (4-Cyclopropylpiperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 22 (R) -2- (6- (4- (4-Fluorophenyl) -1,4-diazepan-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 23 (R) -4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -1-phenylpiperazin-2-one;
  • Example 24 1-Benzyl-4- (6-((R) -2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -3-methylpiperazin-2
  • Example 30 (R) -4- (4-Fluorophenyl) -1- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperidin-4-ol;
  • Example 31 (1R) -2- (6- (3- (4-fluorophenyl) pyrrolidin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 32 (1R) -1-phenyl-2- (6- (4-phenylazepan-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 33 (R) -2- (6- (4- (4-fluorobenzyl) -1,4-diazepan-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 34 (R) -4- (4-Fluoro-1- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperidin
  • Example 40 (R) -2- (6- (3,3-difluoropiperidin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 41 (R) -2- (6- (4,4-difluoropiperidin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 42 (R) -N- (1- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperidin-4-yl) acetamide;
  • Example 43 (R) -2- (6- (3- (4-fluorophenoxy) azetidin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 44 (R) -N- (1- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperidin-4-yl) methanesulfonamide;
  • Example 45
  • Example 50 (R) -Cyclopropyl (4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperazin-1-yl) methanone;
  • Example 51 (R) -1- (4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperazin-1-yl) butan-1-one;
  • Example 52 1- (4- (6-((R) -2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -2-methylpiperazin-1-yl) ethanone;
  • Example 53 (R) -tert-butyl 4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -1,4-diazepan-1-carboxylate;
  • Example 54 (R) -1- (4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -1
  • Example 60 (R) -1- (3-Chlorophenyl) -2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 61 2- (Methyl (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-yl) amino) -1-phenylethanol;
  • Example 62 1- (Naphthalen-2-yl) -2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 64 1- (3,4-difluorophenyl) -2- (6- (4- (2
  • Example 67 2- (6- (4- (ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) ethanol;
  • Example 68 (1R) -2- (6- (4- (ethylsulfonyl) -3-methylpiperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol;
  • Example 70 1- (4-Chlorophenyl) -2- (6- (4- (ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol;
  • Example 71 2- (6- (4- (ethylsulfonyl) -3-methylpiperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) ethanol;
  • Example 72 2- (6- (4- (ethylsulfonyl) -3,3-dimethylpiperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) ethanol;
  • Example 73 2- (6- (4- (ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) -1- (4- (trifluoromethyl) phenyl) ethanol;
  • Example 74 1- (4-Chlorophenyl) -2
  • Example 80 (1R) -2- (6-((3R) -3-Methyl-4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) -1 -Phenylethanol;
  • Example 81 2- (6- (3,3-Dimethyl-4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) )ethanol;
  • Example 82 2- (6-((3R) -3-Methyl-4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) -1- (4- (trifluoromethyl) Phenyl) ethanol;
  • Example 83 2- (6- (4- (2,2,2-trifluoroethyl) -3-methylpiperazin-1-yl) pyrimidin-4-ylamino) -1-
  • Example 90 Cyclopropyl (4- (6- (2- (4-fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) -2,2-dimethylpiperazin-1-yl) methanone;
  • Example 91 (4- (6- (2- (4-Chlorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) piperazin-1-yl) (cyclopropyl) methanone;
  • Example 92 (4- (6- (2- (4-Chlorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl)-(2R) -2-methylpiperazin-1-yl) (cyclopropyl) Methanone;
  • Example 93 (4- (6- (2- (4-chlorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) -2,2-dimethylpiperazin-1-yl) (cyclopropyl) methanone;
  • Example 100 1- (4- (6- (2- (4-Fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) piperazin-1-yl) propan-1-one;
  • Example 101 1- (4- (6- (2- (4-Fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) -2-methylpiperazin-1-yl) propan-1-one ;
  • Example 102 1- (4- (6- (2- (4-Fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) -2,2-dimethylpiperazin-1-yl) propane-1 -on;
  • Example 103 1- (4- (6- (2- (4-chlorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) piperazin-1-yl) propan-1-one;
  • Example 104 1- (4- (6- (2- (4-Chlorophenyl
  • Example 108 1- [4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -2- (trifluoromethyl) piperazin-1-yl] Propan-1-one;
  • Example 109 1- [5- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -5,8-diazaspiro [2.5] octane-8 -Yl] propan-1-one;
  • Example 110 1- [8- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -3,8-diazabicyclo [3.2.1] octane -3-yl] propan-1-one;
  • Example 111 (1R) -2-[[6- (4-oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-
  • [1-14-2] A pharmaceutically acceptable salt of the compound shown in [1-14-1] or a solvate thereof.
  • the IC 50 value is 1 ⁇ M.
  • a compound that is preferably 100 nM or less, more preferably 30 nM or less, and most preferably 5 nM or less.
  • the second aspect of the present invention contains at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a pharmaceutical composition characterized by these.
  • the third aspect of the present invention contains at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • the “FAAH inhibitor” refers to an agent that binds to FAAH and inhibits the catabolic action of endogenous cannabinoid, thereby sustaining the physiological activity of endogenous cannabinoid. It means an agent (pharmaceutical composition) containing a compound that can be exerted.
  • the FAAH inhibitor of the present invention is expected to show promising preventive or therapeutic effects for the following various diseases, specifically, acute or chronic pain due to inflammatory diseases and nociceptive causes, Pain, postoperative pain, periarthritis, osteoarthritis, arthritis, rheumatoid arthritis pain, migraine, headache, toothache, neuralgia, muscle pain, gout, hyperalgesia , Hypersensitivity, pain due to angina or menstruation; acute or chronic pain due to neurogenic origin, ie inflammatory pain, neuropathic pain, fibromyalgia, postherpetic neuralgia, trigeminal neuralgia, low back pain, after spinal cord injury Pain, leg pain, causalgia, diabetic neuralgia; cancer, cancer pain, dizziness mainly caused by chemotherapy, vomiting, nausea; frequent urination, urinary incontinence, urge incontinence, overactive bladder; sleep apnea Included Sleep disorders, ie internal or extrinsic sleep disorders, circadian rhythm
  • the fourth aspect of the present invention contains at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • a preventive and / or therapeutic agent for pain is included in the fourth aspect of the present invention.
  • the fifth aspect of the present invention contains at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a preventive and / or therapeutic agent for neuropathic pain, characterized by
  • the sixth aspect of the present invention contains at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. Is a prophylactic and / or therapeutic agent for inflammatory pain.
  • the “therapeutic agent” includes not only treatment of a disease or symptom but also improvement of the disease or symptom.
  • the pharmaceutically acceptable salt is also referred to.
  • the compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, and isolated compounds. It is. Isolation and purification of such stereoisomers can be carried out by those skilled in the art through conventional techniques through preferential crystallization, optical resolution using column chromatography or asymmetric synthesis.
  • the compound represented by the formula (I) of the present invention may form an acid addition salt or a salt with a base depending on the type of substituent.
  • a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid , Acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid and other aliphatic monocarboxylic acids, benzoic acid, salicylic acid and other aromatic monocarboxylic acids Carboxylic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, aliphatic dicarboxylic acid such as tartaric acid, aliphatic tricarboxylic acid such as
  • salts can be obtained by a conventional method, for example, by mixing an appropriate amount of the compound of the present invention with a solution containing the desired acid or base, and collecting the desired salt by filtration or distilling off the solvent. Moreover, this invention compound or its salt can form solvates with solvents, such as water, ethanol, and glycerol.
  • the salt of the compound of the present invention includes a mono salt, a di salt and a tri salt.
  • the compound of the present invention can form both an acid addition salt and a base salt at the same time depending on the side chain substituent.
  • the present invention includes hydrates of the compounds represented by the formula (I) of the present invention, various pharmaceutically acceptable solvates, crystal polymorphs, and the like.
  • the present invention is not limited to the compounds described in the examples below, but includes all of the compounds represented by the formula (I) or pharmaceutically acceptable salts of the present invention. It is.
  • the production method of the compound represented by the formula (I) of the present invention is shown below.
  • Method for producing compound of the present invention The compound represented by the formula (I) and related compounds used in the present invention can be obtained by the production method shown below. Hereinafter, each reaction process will be described.
  • the reaction conditions in the production method are as follows unless otherwise specified.
  • the reaction temperature is in the range of ⁇ 78 ° C. to 250 ° C.
  • the reaction time is the time for which the reaction proceeds sufficiently.
  • solvent inert to the reaction examples include aromatic hydrocarbon solvents such as toluene, xylene and benzene, alcohols such as methanol and ethanol, polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and water.
  • Basic solvents such as triethylamine and pyridine, organic acid solvents such as acetic acid, halogen solvents such as chloroform, dichloromethane and 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, or these It is a mixed solvent and is appropriately selected depending on the reaction conditions.
  • the base is an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium hydrogen carbonate, or triethylamine, diethylamine, pyridine, N, N-dialkylaniline, lithium diisopropylamide.
  • An organic base such as lithium bis (trimethylsilyl) amide, which is an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid.
  • an organic base such as lithium bis (trimethylsilyl) amide, which is an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid.
  • it is not necessarily limited to what was described above
  • the compound represented by the formula (I) which is the compound of the present invention and a salt thereof can be easily produced from a commercially available compound or a commercially available compound by a method known in the literature, etc. and produced according to the production method shown below. Can do. Further, the present invention is not limited to the manufacturing method described below.
  • R 7 is selected from-(C 1 -C 6 ) -alkyl,-(5-12 membered ring) heteroaryl, and (6-10 membered ring) aryl
  • -N (R 5 ) (R 6 ), 8 is selected from a hydrogen atom, — (C 1 -C 6 ) -alkyl, — (5-12 membered ring) heteroaryl, and (6-10 membered ring) aryl.
  • L is a leaving substituent such as halogen (F, Cl, Br, I), sulfonate ester, phenoxy group, 2,2,2-trichloroethoxy group
  • M is lithium (Li)
  • boronic acid boronic acid ester and the like.
  • the definitions of P, P 1 , and P 2 in the production method represent a protective group for a hydroxyl group (—OH) and an imino group (—NH—).
  • the hydroxyl protecting group include alkoxyalkyl groups such as methoxymethyl group, methoxyethoxymethyl group and tetrahydropyranyl group; arylmethyl groups such as benzyl group and triphenylmethyl group; triethylsilyl group, t-butyldimethyl group
  • a silyl group such as a silyl group; an alkanoyl group such as an acetyl group; an aroyl group such as a benzoyl group; an alkylcarbonyl group such as a methoxycarbonyl group; and an arylmethylcarbonyl group such as a benzyloxycarbonyl group.
  • Examples of the protecting group for the imino group include alkanoyl groups such as acetyl group; alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and t-butoxycarbonyl group; benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, para An arylmethoxycarbonyl group such as a nitrobenzyloxycarbonyl group; an arylmethyl group such as a benzyl group or a triphenylmethyl group; or an aroyl group such as a benzoyl group.
  • alkanoyl groups such as acetyl group
  • alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and t-butoxycarbonyl group
  • benzyloxycarbonyl group paramethoxybenzyloxycarbonyl group
  • para An arylmethoxycarbonyl group such as a nitrobenzyl
  • the protecting group can be removed at an appropriate stage.
  • Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the kind of the protecting group.
  • Green et al. Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons
  • Green et al. [Protective Groups in Organic Synthesis, 4th Edition, 2007, John Willy & Sons]
  • the method can be carried out by a method that can be appropriately selected by those skilled in the art.
  • the compound represented by the formula (I) can be produced by the following production method.
  • a substitution reaction of the compound represented by the formula (AI) and the compound represented by the formula (A-II) is performed.
  • a compound represented by the formula (AI) and a compound represented by the formula (A-II) methods known in the literature, for example, [Tetrahedron, 63 (25), 5394-5405, 2007 In the presence or absence of a base such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium carbonate, etc., dichloromethane, chloroform, etc.
  • Halogen solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, methanol, ethanol, 2- Reaction of alcohol solvents such as propanol and butanol Solvent which does not participate, by reacting at 250 ° C. from 0 ° C., can be prepared a compound of formula (I).
  • ether solvents such as diethyl ether, tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as toluene and benzene
  • polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide
  • methanol ethanol
  • 2- Reaction of alcohol solvents such as propanol and butanol Solvent which does not participate, by reacting
  • a compound of formula (B-IV) can be produced by a method similar to production method A using a compound represented by formula (B-III) and a compound represented by formula (A-II).
  • ⁇ Step 3> A substitution reaction of the compound represented by the formula (BI) and the compound represented by the formula (A-II) is performed.
  • a compound of formula (BV) can be produced by a method similar to production method A using a compound represented by formula (BI) and a compound represented by formula (A-II).
  • ⁇ Step 4> A substitution reaction of the compound represented by the formula (BV) and the compound represented by the formula (B-II) is performed.
  • a compound of formula (B-IV) can be produced by a method similar to production method A, using a compound represented by formula (BV) and a compound represented by formula (B-II).
  • the compound of the formula (B-IV-1) is produced by the same method as the production method A can do.
  • the compound of the formula (B-IV-1) can be produced by a method similar to the production method C ⁇ Step 1> described below.
  • palladium catalyst such as palladium (II) acetate, tetrakistriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) , Triphenylphosphine, tris (tert-butyl) phos
  • phosphine reagents such as tin, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, and triethylamine, N, N-diisopropylethylamine, phosphoric acid
  • an organic or inorganic base such as potassium, or in the presence or absence of tetramethylammonium chloride, tetrabutylammonium chloride or the like instead
  • a reduction reaction of the compound represented by the formula (C-II) is performed.
  • Pd-C palladium-carbon
  • Raney-Ni Raney nickel
  • the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C.
  • a compound represented by (C-III) can be produced.
  • a substitution reaction of the compound represented by the formula (BI) and the compound represented by the formula (CI) is performed.
  • a compound of the formula (C-IV) is produced in the same manner as in the production method C ⁇ Step 1>. Can do.
  • ⁇ Step 4> A substitution reaction of the compound represented by the formula (C-IV) and the compound represented by the formula (A-II) is performed.
  • a compound of formula (C-II) can be produced by a method similar to production method A using a compound represented by formula (C-IV) and a compound represented by formula (A-II).
  • ⁇ Step 5> A reduction reaction of the compound represented by the formula (C-IV) is performed.
  • the compound of the formula (CV) can be produced by a method similar to the production method C ⁇ Step 2>.
  • ⁇ Step 6> A substitution reaction of the compound represented by the formula (CV) and the compound represented by the formula (A-II) is performed.
  • a compound of formula (C-III) can be produced by a method similar to production method A using a compound represented by formula (CV) and a compound represented by formula (A-II).
  • a reductive amination reaction of the compound represented by the formula (D-II) is performed.
  • a compound represented by the formula (D-II) and an aldehyde represented by the formula (D-III) a method known in the literature, for example, [Experimental Chemistry Course 4th Edition 20 Organic Synthesis II -Alcohol Amine-, 300 -302, 1992, Maruzen], in the presence or absence of an acid such as acetic acid, in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, dichloromethane, In a halogen solvent such as chloroform, an alcohol solvent such as methanol or ethanol, an ether solution such as diethyl ether or tetrahydrofuran, a polar solvent such as N, N-dimethylformamide or acetonitrile, or a mixed solvent thereof, 0 Reaction is carried out at a temperature at which the solvent refluxes from 0
  • Step 3> A condensation reaction of the compound represented by the formula (D-II) is performed.
  • a compound represented by the formula (D-II) and a compound represented by the formula (DV) a method known in the literature, for example, [Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191] -309, 1992, Maruzen] and the like, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HCl ), Benzotriazole-1-iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3- Dimethylimidazolinium hexafluor
  • Step 4 The amidation reaction of the compound represented by the formula (D-II) is performed.
  • a compound represented by the formula (D-II) and a compound represented by the formula (D-VII) a method known in the literature, for example, [Journal of Medicinal Chemistry, 50 (3 ), 566-584, 2007], in the presence of a base such as triethylamine or pyridine, a halogen solvent such as dichloromethane or chloroform, an ether solution such as diethyl ether or tetrahydrofuran, N, N—
  • the reaction is carried out in a solvent that does not participate in the reaction such as polar solvents such as dimethylformamide and acetonitrile, or a mixed solvent thereof at a temperature at which the solvent refluxes from ⁇ 78 ° C., and is represented by the formula (D-VIII) Compounds can be made.
  • Step 4> A substitution reaction of the compound represented by the formula (E-II) is performed.
  • a compound represented by the formula (E-II) and a compound represented by the formula (EV) a method known in the literature, for example, [Experimental Chemistry Course 4th Edition 20 Organic Synthesis II Alcohol / Amine, 187- 200 and 284-292, 1992, Maruzen] and [Experimental Chemistry Course 4th Edition 20 Organic Synthesis VI Heteroelements / Typical Metal Element Compounds, 319-350, 1992, Maruzen]
  • bases such as triethylamine, pyridine, sodium hydride, sodium hydroxide, potassium carbonate, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, toluene, benzene, etc.
  • ⁇ Process 2> The deprotection reaction of the protecting groups P 1 and P 2 of the compound represented by the formula (FI) is performed. Using the compound represented by the formula (FI), the compound represented by the formula (D-VI) is produced by deprotecting the protecting groups P 1 and P 2 by a method corresponding to the type of the protecting group. can do.
  • Step 3> A condensation reaction of the compound represented by the formula (E-II) is performed.
  • ⁇ Step 4> A deprotection reaction of the protecting groups P 1 and P 2 of the compound represented by the formula (F-III) is performed.
  • a compound represented by the formula (F-IV) is produced by deprotecting the protecting groups P 1 and P 2 using a compound represented by the formula (F-III) by a method corresponding to the kind of the protecting group. can do.
  • ⁇ Step 5> An amidation reaction of the compound represented by the formula (E-II) is performed. Using the compound represented by the formula (E-II) and (D-VII), the compound of the formula (FV) can be produced by a method similar to the production method D ⁇ Step 4>.
  • Step 6> A deprotection reaction of the protecting groups P 1 and P 2 of the compound represented by the formula (FV) is performed.
  • a compound represented by the formula (D-VIII) is produced by using the compound represented by the formula (FV) and deprotecting the protecting groups P 1 and P 2 by a method corresponding to the type of the protecting group. can do.
  • the compound represented by the formula (EI) can be produced by the following production method.
  • Step 1> A substitution reaction of the compound represented by the formula (GI) is performed.
  • a compound of the formula (EI) can be produced by a method similar to the production method A using a compound represented by the formula (GI) and a compound represented by the (G-II).
  • ⁇ Process 2> The protection reaction of the compound represented by the formula (G-III) with the protecting groups P 1 and P 2 is performed.
  • a compound represented by the formula (EI) is produced by reacting the compound represented by the formula (G-III) with the protecting groups P 1 and P 2 by a method corresponding to the kind of the protecting group. be able to.
  • the formula (I) can be produced by the following production method.
  • a substitution reaction of the compound represented by the formula (HI) and the compound represented by the formula (H-II) is performed.
  • a compound represented by formula (HI) and a compound represented by formula (H-II) a method known in the literature, [Bioorganic & Medicinal Chemistry, 14 (19) , 6525-6538, 2006], in the presence of organic or inorganic bases such as triethylamine, sodium hydride, potassium carbonate, halogen solvents such as dichloromethane and chloroform, ethers such as diethyl ether and tetrahydrofuran.
  • the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction, such as a polar solvent such as a system solution, N, N-dimethylformamide, or acetonitrile, or a mixed solvent thereof. It is possible to produce a compound represented by That.
  • the compound represented by the formula (J-III) can be produced by carrying out the reaction at the temperature to be used.
  • the solvent that does not participate in the reaction in such a polar solvent such as acetonitrile, provides protection at a temperature that the solvent refluxes from 0 ° C., it is possible to produce a compound represented by the formula (L-II).
  • a polar solvent such as acetonitrile
  • the protection of the hydroxyl group (—OH) and the imino group (—NH—) in the compound represented by the formula (LI) is described in Greene et al. [Protective Groups in Organic Synthesis (Protective).
  • ⁇ Process 2> The deprotection reaction of the protecting group P of the compound represented by the formula (L-III) is performed.
  • a compound represented by the formula (L-IV) can be produced by using the compound represented by the formula (L-III) and deprotecting the protecting group P by a method corresponding to the kind of the protecting group. .
  • Step 3> A substitution reaction of the compound represented by the formula (L-IV) is performed. This step is appropriately selected depending on the type of R 4 .
  • the compound of formula (LV) can be produced by the same method as in ⁇ Step 3>, Production Method D ⁇ Step 4>, Production Method E ⁇ Step 4>, Production Method F ⁇ Step 3>.
  • ⁇ Step 4> A substitution reaction of the compound represented by the formula (LV) and the compound represented by the formula (L-II) is performed.
  • Step 5 Deprotection of the compound represented by the formula (L-VI) is performed.
  • the compound represented by the formula (L-VI) is in the presence of an acid such as hydrochloric acid or acetic acid, a halogen solvent such as dichloromethane or chloroform, an ether solvent such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon such as toluene or benzene.
  • a compound represented by the formula (L-VII) can be produced by carrying out a substitution reaction at 0 ° C. to room temperature in an alcoholic solvent such as a system solvent or methanol or ethanol.
  • the protection of the hydroxyl group (—OH) and the imino group (—NH—) represented by acetonide protection is described in Greene et al. [Protective Group Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons], not limited to the acetonide protection shown above. It can be selected as appropriate.
  • a compound represented by the formula (L-VII) can be produced by deprotection by a method that can be appropriately selected by those skilled in the art by a method corresponding to the type of protecting group.
  • a compound represented by the formula (L-VIII) can be produced by performing a substitution reaction at 0 ° C. to room temperature in a solvent such as a polar solvent that does not participate in the reaction.
  • a base such as NaH
  • halogen solvents such as dichloromethane and chloroform
  • ether solvents such as diethyl ether and tetrahydrofuran
  • aromatic hydrocarbon solvents such as toluene and benzene
  • the compound of the formula (L-IX) can be produced by a method similar to the production method L ⁇ Step 5>.
  • ⁇ Step 8> A substitution reaction of the compound represented by the formula (L-III) and the compound represented by the formula (L-II) is performed.
  • the compound of the formula (LX) can be produced by a method similar to the production method L ⁇ Step 4>.
  • ⁇ Step 9> A deprotection reaction of the compound represented by the formula (LX) is performed.
  • the compound of the formula (L-XI) can be produced by a method similar to the production method L ⁇ Step 2>.
  • ⁇ Step 10> A substitution reaction of the compound represented by the formula (L-XI) is performed. This step is appropriately selected depending on the type of R 4 .
  • a compound represented by the formula (L-XI) a compound of the formula (L-VI) can be produced by a method similar to the production method L ⁇ Step 3>.
  • a deprotection reaction of the compound represented by the formula (M-II) is performed.
  • a compound of the formula (M-III) can be produced by a method similar to the production method L ⁇ Step 5>.
  • the deprotection reaction of the protecting group P of the compound represented by the formula (M-III) is performed.
  • a compound represented by the formula (M-IV) can be produced by using the compound represented by the formula (M-III) and deprotecting the protecting group P by a method corresponding to the kind of the protecting group. .
  • a substitution reaction of the compound represented by the formula (M-IV) is performed.
  • This step is appropriately selected depending on the type of R 4 .
  • the compound of formula (MV) can be produced by the same method as in ⁇ Step 3>, Production Method D ⁇ Step 4>, Production Method E ⁇ Step 4>, Production Method F ⁇ Step 3>.
  • Z 1 ⁇ C—R 4 (R 4 is —SO 2 (C 1 -C 6 ) -alkyl, —SO 2 (6-10 membered ring) aryl, —SO 2 (5-12) Membered) heteroaryl, —CO 2 — (C 1 -C 6 ) -alkyl, —CO 2 H, —CO—N (R 5 ) (R 6 ), —SO 2 —N (R 5 ) (R 6 ) -NO 2 ) can be produced by the following production method.
  • ⁇ Step 1> A substitution reaction of the compound represented by the formula (L-II) is performed.
  • the compound of the formula (N-III) is produced by the same method as the production method M ⁇ Step 1>. Can do.
  • ⁇ Process 2> Using the compound represented by the formula (N-II), the compound of the formula (N-III) can be produced by a method similar to the production method L ⁇ Step 5>.
  • ⁇ Step 3> Using the compound represented by the formula (N-III), the compound of the formula (N-IV) can be produced by a method similar to the production method M ⁇ Step 3>.
  • ⁇ Step 4> Using the compound represented by the formula (N-IV), the compound of the formula (NV) can be produced by a method similar to the production method M ⁇ Step 4>.
  • Step 1 A condensation reaction of the compound represented by the formula (O-I) is carried out.
  • a compound represented by the formula (O-I) a compound of the formula (O-II) can be produced by a method similar to the production method D ⁇ Step 3>.
  • An arylation reaction of the compound represented by the formula (O-II) is performed.
  • An ether solution of a compound represented by the formula (O-II) and a Grignard reagent (ArMgX) (diethyl ether, tetrahydrofuran, etc.), or ArLi prepared from ArX and BuLi, can be appropriately selected by a person skilled in the art using dichloromethane, The reaction is carried out at 0 ° C.
  • a solvent not involved in the reaction such as a halogen-based solvent such as chloroform, an ether-based solvent such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon-based solvent such as toluene or benzene.
  • a solvent not involved in the reaction such as a halogen-based solvent such as chloroform, an ether-based solvent such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon-based solvent such as toluene or benzene.
  • a substitution reaction of the compound represented by the formula (O-VI) is performed.
  • a compound of formula (O-VII) can be produced by a method similar to production method A using a compound represented by formula (O-VI) and a compound represented by (OV).
  • a substitution reaction of the compound represented by the formula (O-VII) is performed.
  • a compound of formula (O-VIII) can be produced by a method similar to production method A using a compound represented by formula (O-VII) and a compound represented by (B-II).
  • (Production method P) The compound represented by formula (A-II-1) of production method A, production method B, and production method C can be produced by the same method as in steps 1 to 4 of production method O.
  • Step 1> Using the compound represented by the formula (PI), the compound of the formula (P-II) can be produced by a method similar to the production method O ⁇ Step 1>.
  • Step 2> Using the compound represented by the formula (P-II), the compound of the formula (P-III) can be produced by a method similar to the production method O ⁇ Step 2>.
  • ⁇ Step 3> Using the compound represented by the formula (P-III), the compound of the formula (P-IV) can be produced by a method similar to the production method O ⁇ Step 3>.
  • ⁇ Step 4> Using the compound represented by the formula (P-IV), a compound of the formula (A-II) in which R 1 is a hydrogen atom can be produced by a method similar to Production Method O ⁇ Step 4>.
  • ⁇ Step 5> Using the compound represented by the formula (PV), the compound of the formula (P-IV) can be produced by a method similar to the production method O ⁇ Step 2>.
  • the compound of the present invention and the pharmaceutical composition can be used in combination with other drugs or drugs by a general method performed in the medical field.
  • Other drugs or drugs that can be used in combination include, for example, acetaminophen, aspirin, opioid agonists (specifically, morphine, fentanyl, oxycodone, methadone, codeine, cocaine, pethidine, opium, tocone
  • opioid agonists specifically, morphine, fentanyl, oxycodone, methadone, codeine, cocaine, pethidine, opium, tocone
  • Non-narcotic analgesics prentazine, buprenorphine, nalolphine, cyclazocine, butofanol, etc.
  • antidepressants dueloxetine, amitriptyline, imipramine, clomipramine, trimipramine, lofepramine, dosrepine, amoxipine, nortriptyline, fluoxetine, fluoxetine
  • Other local anesthetics including quinidine, disopyramide, procainamide, ajmarin, prazimarium, cibenzoline, lidocaine, mexiletine, aprindine, tonicoid, phenytoin, flecainide, pilsicainide, propaphenone, propranolol, amiodarone, verapamil, bepridil
  • anesthetics Specific examples include benzodiazepine, diazepam, midazolam, thiopental, thiamylal, propofol, baclofen, droperirol, sufentanil, and the like, and NMDA antagonists (specifically, ketamine, dextromethorphan, memantine, amantadine, and the like). It is done.
  • ⁇ 2 adrenergic receptor agonists clonidine, dexmedetomidine, tizanidine, guanfacine, guanabenz, etc.
  • calcium channel antagonists potassium channel openers, etc.
  • topical drugs capsaicin cream
  • Antiviral agents such as vidarabine, acyclovir, ganciclovir, zidovudine, didanosine, amantadine, idoxuridine, ⁇ or ⁇ interferon.
  • Other drugs or drugs that can be used in combination are preferably morphine, gabapentin, pregabalin, diclofenac, celecoxib, and the like.
  • stimulation and analgesia include acupuncture, percutaneous electrical acupuncture, transcutaneous electrical nerve stimulation, silver spike point (SSP) therapy, peripheral nerve stimulation, spinal cord electrical stimulation, and electroconvulsive therapy.
  • SSP silver spike point
  • electroconvulsive therapy Laser therapy, low frequency therapy, nerve block (specifically, stellate ganglion block, epidural block, brachial plexus block, nerve root block, chest / lumbar sympathetic ganglion block, trigger point block, subarachnoid Block, trigeminal nerve block, sympathetic nerve block, local infiltration block, peripheral nerve block, etc.).
  • the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced.
  • the combination method using the drug is not limited to the above diseases, and the drug used in combination is not limited to the compounds exemplified above.
  • a drug used in combination with the compound of the present invention may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable additive.
  • excipients eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
  • binders eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbo Cymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg; celluloses,
  • Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir.
  • Oral subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
  • the dose of the compound of the present invention is usually 0.005 mg to 3.0 g, preferably 0.05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g per day for an adult. Can be increased or decreased as appropriate.
  • the entire amount can be divided into 1 or 2-6 doses, orally or parenterally, or can be administered continuously by intravenous infusion.
  • the collected supernatant was centrifuged again (12000 g, 20 minutes, 4 ° C.), and the supernatant was ultracentrifuged (100,000 g, 60 minutes, 4 ° C.) to recover the precipitate.
  • the suspension was suspended in a buffer solution (50 mmol / L HEPES-NaOH (pH 7.4), 1 mmol / L EDTA) of 5 times the wet wet weight, and the protein concentration was quantified by BCA protein assay (PIERCE).
  • rat brain microsomal fraction Ten-week-old male Sprague-Dawley (SD rat) were decapitated and the cerebrum was excised. Add 5 volumes of wet buffer weight (50 mmol / L HEPES (pH 8.0), 1 mmol / L EDTA, 0.32 mol / L sucrose, Complete EDTA-free (Roche Diagnostics)), Triturated with a potter homogenizer. The milled liquid was centrifuged (9000 g, 10 minutes, 4 ° C.), and the supernatant was collected. The supernatant was further ultracentrifuged (105000 g, 60 minutes, 4 ° C.) to recover the precipitate.
  • wet buffer weight 50 mmol / L HEPES (pH 8.0), 1 mmol / L EDTA, 0.32 mol / L sucrose, Complete EDTA-free (Roche Diagnostics)
  • the protein concentration was quantified by BCA protein assay (PIERCE) after suspending in a buffer solution (50 mmol / L HEPES (pH 8.0), 1 mmol / L EDTA) of 1/4 volume of the wet wet weight.
  • PIERCE BCA protein assay
  • FAAH inhibitory activity of the test compounds are expressed as an IC 50 value, a compound of the present invention the IC 50 values less than the 0.1 [mu] mol / L as +++, an IC 50 value is 0.1 [mu] mol / L or more and compounds of less than 1 [mu] mol / L Is shown in Table 1 as ++, and compounds having an IC 50 value of 1 ⁇ mol / L or more as +.
  • Pharmacological experiment example 2 in vivo compound evaluation
  • the evaluation of the action of the compound of the present invention in various pains can be carried out by the following method.
  • Rat formalin test 6-7 week old male SD rats are used in the experiment.
  • Each dose of vehicle or test compound is orally administered to rats in a volume of 10 mL / kg.
  • 50 mg / kg of gabapentin is used as a control drug.
  • 50 ⁇ L of 0.5% formaldehyde solution is injected subcutaneously into the sole of the left lower limb of the rat, and the behavior is observed for 45 minutes.
  • the duration of pain behavior (licking, biting) on a leg injected with formalin is measured every 5 minutes.
  • the formalin-stimulated pain response appears biphasic (J. Pharmacol. Exp. Ther. 263, 136-146, 1992), but the first phase reaction is 10 minutes to 45 minutes until 10 minutes after formalin administration.
  • the integrated value of the pain behavior duration of each rat measured in the second phase reaction is used as an index of painful behavior.
  • CCI model Neuropathic pain model
  • the strangulation nerve injury model is prepared according to the report of Bennett et al. (Pain, 33, 87-107, 1988). Under pentobarbital anesthesia, the skin under the left femur of the male 7-week-old SD rat is incised, and then the biceps of the left femur is bluntly dissected. The sciatic nerve is peeled off from the surrounding tissue, and is gently squeezed and sutured at about 1 mm intervals with a medical blade silk thread 4-0 (Matsuda Medical). The analgesic action is evaluated according to a report by Seltzer et al. (Pain, 43, 205-218, 1990).
  • the CFA-induced rat inflammatory pain model is prepared according to a general method, for example, the method of Pomonis JD et al. Specifically, an emulsion is prepared by mixing equal amounts of Complete Freund's Adjuvant (SIGMA) and physiological saline, and injected into the plantar of the right foot of the rat in a volume of 100 ⁇ L. The test compound is orally administered to rats 1 day, 2 days or 5 days after CFA administration to suppress the decrease in pain threshold, that is, the effectiveness as a therapeutic agent for inflammatory pain is proved.
  • SIGMA Complete Freund's Adjuvant
  • Mouse PQ Rising Mouse PQ (Phenyl-p-quinone) rising is prepared by the method of Mustafa AA et al. (General Pharmacology, 23, 1177-1182, 1992). Specifically, after the administration of Phenyl-p-quinone diluted with physiological saline into the abdominal cavity of the mouse, the number of times that the mouse showed an action such as stretching, twisting or rolling is recorded for a certain period of time. By administering a test compound to a mouse before administration of Phenyl-p-quinone, the number of times of behavior such as stretching, twisting, and rounding after administration of Phenyl-p-quinone is reduced, and the effectiveness is shown.
  • DMSO Precipitation Solubility (Kinetic Solubility) A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 ⁇ M. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, filtered through a filter plate (4 ⁇ m, MultiScreen Solidity filter plate (Millipore)), and then using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength.
  • each standard solution absorbance is measured using a solution containing a test compound having a known concentration (1, 3, 10, 30, 100 ⁇ M) as a calibration curve standard solution, and a calibration curve is created.
  • the solubility ( ⁇ M) of the compound is calculated from the absorbance values of the filtrate and standard solution.
  • hERG-HEK human ether-a-go-related gene
  • a depolarizing pulse is periodically applied while maintaining the membrane potential at ⁇ 80 mV. After the generated current has stabilized, the test compound is added. The effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a -40 mV, 0.5 second depolarizing pulse followed by a -40 mV, 0.5 second repolarizing pulse.
  • the Stimulation is performed once every 10 seconds. The measurement is performed at room temperature.
  • the hERG channel inhibition rate is calculated as a reduction rate (inhibition rate) of the tail current 2 minutes after application with respect to the maximum tail current before application of the test compound. By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
  • the compound of the present invention has an excellent FAAH inhibitor blocking activity. Moreover, the analgesic effect in an in vivo pain model is shown.
  • the preferred compound of the present invention has a 50% inhibitory activity of hERG (human ether-a-go-go related gene) channel not lower than 10 ⁇ M.
  • the compound of the present invention is used as a selective FAAH inhibitor for preventing or treating pain, particularly for preventing or treating neuropathic pain, fibromyalgia, inflammatory pain, cancer pain or diabetic neuralgia. It is expected to be used for
  • LC / MS As a high performance liquid chromatography mass spectrometer (LC / MS), a Waters FractionLynx MS system (manufactured by Waters) was used. As the column, SunFire TM (4.6 ⁇ 50 mm, 5 ⁇ m) was used for the analysis system, and SunFire TM (19 ⁇ 50 mm, 5 ⁇ m) was used for the preparative system.
  • ⁇ Step 2> Synthesis of (R)-( ⁇ )-1-phenyl-2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol
  • Example 2 To a solution of the compound (600 mg) obtained in ⁇ Step 1> in ethanol (5.0 mL) was added 1- (2,2,2-trifluoroethyl) piperazine (1.1 g) and triethylamine (2 5 mL) and heated in a microwave reactor at 120 ° C. for 2 hours.
  • Example 2 The compounds of (Example 3) to (Example 16) were obtained by the method according to ⁇ Step 2>.
  • Example 3 (R) -2- (6- (4-Isopropylpiperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol (Example 4)
  • Example 45 Synthesis of (R) -N- (1- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) piperidin-4-yl) -N-methylmethanesulfonamide
  • Example 53 Synthesis of (R) -tert-butyl 4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -1,4-diazepan-1-carboxylate
  • Example 2 ⁇ Step 2 > (Example 2) From the compound (200 mg) obtained in ⁇ Step 1> and tert-butyl 1,4-diazepan-1-carboxylate (0.14 mL), the title compound (228 mg) was obtained as a brown oil.
  • Example 54 Synthesis of (R) -1- (4- (6- (2-hydroxy-2-phenylethylamino) pyrimidin-4-yl) -1,4-diazepan-1-yl) ethanone ⁇ Step 1> (R) -2- (6- (1,4-Diazepan-1-yl) pyrimidin-4-ylamino) -1-phenylethanol Synthesis of hydrochloride The compound (190 mg) obtained in Example 53 was converted to ethyl acetate (3 0.04), 4N hydrogen chloride-ethyl acetate solution (3.0 mL) was added, and the mixture was stirred at room temperature for 18 hours.
  • ⁇ Step 2> Synthesis of (R) -1- (3-chlorophenyl) -2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol
  • (Example 60) The compound obtained in ⁇ Step 1> (50 mg) and (R) -2-amino-1- (4-chlorophenyl) ethanol hydrochloride (34 mg) Gave the title compound (25 mg) as a white solid.
  • Example 61 The compounds of (Example 61) to (Example 65) were obtained by the method according to (Example 60).
  • Example 61 2- (Methyl (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-yl) amino) -1-phenylethanol
  • Example 62 1- (Naphthalen-2-yl) -2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol
  • Example 63 1- (4-Chlorophenyl) -2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol
  • Example 64 1- (3,4-Difluorophenyl) -2- (6- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) pyrimidin
  • Example 67 2- (6- (4- (Ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) ethanol
  • Example 68 (1R) -2- (6- (4- (Ethylsulfonyl) -3-methylpiperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol
  • Example 69 (R) -2- (6- (4- (Ethylsulfonyl) -3,3-dimethylpiperazin-1-yl) pyrimidin-4-ylamino) -1-phenylethanol
  • Example 70 1- (4-Chlorophenyl) -2- (6- (4- (ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) ethanol (Example 71) 2- (6- (4- (Ethylsulfonyl) -3-methylpiperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) ethanol (Example 72) 2- (6- (4- (Ethylsulfonyl) -3,3-dimethylpiperazin-1-yl) pyrimidin-4-ylamino) -1- (4-fluorophenyl) ethanol (Example 73) 2- (6- (4- (Ethylsulfonyl) piperazin-1-yl) pyrimidin-4-ylamino) -1- (4- (trifluoromethyl) phenyl) ethanol (Example 74) 1- (4-Chloropheny
  • Example 100 1- (4- (6- (2- (4-Fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) piperazin-1-yl) propan-1-one
  • Example 101 1- (4- (6- (2- (4-Fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) -2-methylpiperazin-1-yl) propan-1-one
  • Example 102 1- (4- (6- (2- (4-Fluorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) -2,2-dimethylpiperazin-1-yl) propan-1-one
  • Example 103 1- (4- (6- (2- (4-Chlorophenyl) -2-hydroxyethylamino) pyrimidin-4-yl) piperazin-1-yl) propan-1-one
  • Example 104 1- (4- (6- (2- (4-Chlorophenyl) -2-hydroxy
  • Step 2> Synthesis of 1- [5- (6-iodopyrimidin-4-yl) -5,8-diazaspiro [2.5] octane-8-yl] propan-1-one Propionic acid (0.12 g) To a tetrahydrofuran (5.0 mL) solution of triethylamine (0.53 mL) and benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (0.62 g) were added, and the mixture was stirred at room temperature for 30 minutes. (Example 109) ⁇ A tetrahydrofuran solution of the compound (0.20 g) obtained in step 1> was added and stirred overnight.
  • Example 110 The compounds of (Example 110) to (Example 117) were obtained by the method according to (Example 17) or (Example 44).
  • Example 110 1- [8- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -3,8-diazabicyclo [3.2.1] octane-3-yl] Propan-1-one (Example 111) (1R) -2-[[6- (4-Oxa-8-azaspiro [4.5] decan-8-yl) pyrimidin-4-yl] amino] -1-phenylethanol (Example 112) (1R) -2-[[6- (3,3-Dimethylpyrrolidin-1-yl) pyrimidin-4-yl] amino] -1-phenylethanol (Example 113) (1R) -2-[[6- [4- (2-Hydroxyethyl) piperidin-1-yl
  • ⁇ Step 2> Synthesis of 2-[[6- (4-ethylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] -1- [4- (trifluoromethoxy) phenyl] ethanol (Example 17) (Example 118) From the compound obtained in ⁇ Step 1> (34.0 mg) and 2-amino-1- [4- (trifluoromethoxy) phenyl] ethanol (38.9 mg), The title compound (4.6 mg) was obtained.
  • ⁇ Step 2> 1- [4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] -2-methoxypyrimidin-4-yl] piperazin-1-yl] propan-1-one (Example 120) From the compound (50.0 mg) obtained in ⁇ Step 1> and 1- (propionyl) piperazine (50.8 mg), the title compound (43 mg ) was obtained as a pale yellow amorphous.
  • ⁇ Step 2> 1- [4- [2-Amino-6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] piperazin-1-yl] propan-1-one (Example 121) From the compound (45.0 mg) obtained in ⁇ Step 1> and 1- (propionyl) piperazine (48.4 mg), the title compound (25 mg ) was obtained as a white solid.
  • ⁇ Step 2> 1- [4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] -5-methylpyrimidin-4-yl] piperazin-1-yl] propan-1-one (Example 122) From the compound (0.10 g) obtained in ⁇ Step 1> and 1- (propionyl) piperazine (80.8 mg), the title compound (40 mg ) was obtained as a colorless amorphous.
  • Example 123 4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -1- (2,2,2-trifluoroethyl) piperidin-4-ol ⁇ Step 1 > Synthesis of (5R) -3- (6-iodopyrimidin-4-yl) -2,2-dimethyl-5-phenyl-1,3-oxazolidine (Example 108) By a method according to ⁇ Step 2> Example 2 The title compound (2.12 g) was obtained as an orange solid from the compound (5.00 g) obtained in ⁇ Step 1>.
  • ⁇ Step 2> 4- [6-[(5R) -2,2-dimethyl-5-phenyl-1,3-oxazolidin-3-yl] pyrimidin-4-yl] -1- (2,2,2- Synthesis of (trifluoroethyl) piperidin-4-ol (Example 123)
  • tetrahydrofuran 2.0 mL
  • n-butyllithium- Hexane solution (1.57M, 0.92 mL
  • Example 125 4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -1- (2,2,2-trifluoroethyl) piperidine-4 -Carbonitrile ⁇ Step 1> tert-Butyl 4-cyano-4- [6-[(5R) -2,2-dimethyl-5-phenyl-1,3-oxazolidin-3-yl] pyrimidin-4-yl] Synthesis of Piperidine-1-carboxylate (Example 123) To a solution of the compound (50 mg) obtained in ⁇ Step 1> in tetrahydrofuran (3.0 mL) was added tert-butyl 4-cyanopiperidine-1-carboxylate (52.
  • ⁇ Step 2> Synthesis of tert-butyl 4-cyano-4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] piperidine-1-carboxylate (Examples) 123)
  • the title compound (21.2 mg) was obtained as a colorless oil from the compound (23.5 mg) obtained in (Example 125) ⁇ Step 1> by a method analogous to ⁇ Step 3>.
  • Step 3> Synthesis of 4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] piperidine-4-carbonitrile hydrochloride (Example 54) ⁇ Step 1 > (Example 125) The title compound (18.0 mg) was obtained from the compound (21.2 mg) obtained in ⁇ Step 2>.
  • ⁇ Step 4> 4- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -1- (2,2,2-trifluoroethyl) piperidine-4- Synthesis of carbonitrile (Example 125)
  • acetonitrile 3.0 mL
  • diisopropylethylamine 43.5 ⁇ L
  • 2,2,2-trifluoroethyl After adding trifluoromethanesulfonate (21.6 ⁇ L), the mixture was stirred at room temperature for 5 hours.
  • Example 126 1- (4-Chloro-2-methylphenyl) -2-[[6- [1- (trifluoromethylsulfonyl) -3,6-dihydro-2H-pyridin-4-yl] pyrimidine- 4-yl] amino] ethanol ⁇ Step 1> Synthesis of 1- (trifluoromethylsulfonyl) piperidin-4-one To a solution of 4-piperidone hydrochloride (5.0 g) in dichloromethane (50.0 mL) was added triethylamine (12.
  • Step 4 Synthesis of tert-butyl N- [2- (4-chloro-2-methylphenyl) -2-oxoethyl] carbamate N- (tert-butoxycarbonyl) glycine N′-methoxy-N′-methylamide (2 2 g) in tetrahydrofuran (20.0 mL) under ice-cooling, 2-methyl-4-chlorophenylmagnesium bromide-tetrahydrofuran solution (0.5 M, 50.4 mL) was added, stirred for 10 minutes, and then at room temperature for 3 hours. Stir.
  • ⁇ Step 5> Synthesis of tert-butyl N- [2- (4-chloro-2-methylphenyl) -2-hydroxyethyl] carbamate (Example 126)
  • Compound obtained in ⁇ Step 4> (0.40 g)
  • Sodium borohydride (56.0 mg) was added to an ethanol (4.0 mL) solution, and the mixture was stirred at room temperature for 90 minutes.
  • Ethyl acetate and saturated aqueous ammonium chloride water were added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, and then dried over sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain the title compound (0.35 g) as a white solid.
  • ⁇ Step 6> Synthesis of 2-amino-1- (4-chloro-2-methylphenyl) ethanol hydrochloride (Example 54) By a method according to ⁇ Step 1>, (Example 126) In ⁇ Step 5> The title compound (6.70 g) was obtained as a white solid from the obtained compound (9.80 g).
  • ⁇ Step 7> Synthesis of 1- (4-chloro-2-methylphenyl) -2-[(6-iodopyrimidin-4-yl) amino] ethanol (Example 2) By a method according to ⁇ Step 1>
  • Example 126 The title compound (1.04 g) was obtained as a yellow solid from the compound (0.72 g) obtained in ⁇ Step 6>.
  • Example 127 1- (4-Chloro-2-methylphenyl) -2-[[6- [1- (trifluoromethylsulfonyl) piperidin-4-yl] pyrimidin-4-yl] amino] ethanol
  • Platinum (IV) oxide 5.0 mg was added to a methanol solution (2.0 mL) of the compound (17.0 mg) obtained in Example 126), and the mixture was stirred under a hydrogen atmosphere for 20 hours. After filtration through celite, the solvent was distilled off under reduced pressure, and the residue was purified by LC-MS to obtain the title compound (3.2 mg) as amorphous.
  • Example 129 1- (5-Pyridin-2-ylthiophen-2-yl) -2-[[6- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] pyrimidine- 4-yl] amino] ethanol ⁇ Step 1> Synthesis of tert-butyl N- [2-hydroxy-2- (5-pyridin-2-ylthiophen-2-yl) ethyl] carbamate 2- (5-bromothien-2 To a solution of -yl) pyridine (0.10 g) in tetrahydrofuran (1.5 mL) was added n-butyllithium-hexane solution (1.57 M, 0.4 mL) at -78 ° C, and the mixture was stirred for 1 hour.
  • ⁇ Step 4> 1- (5-Pyridin-2-ylthiophen-2-yl) -2-[[6- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] pyrimidine-4 Synthesis of —yl] amino] ethanol (Example 2)
  • ⁇ Step 3> the title compound (4.7 mg) ) was obtained as a white solid.
  • Example 130 4- [1-Hydroxy-2-[[6- [4- (2,2,2-trifluoroethyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethyl] benzonitrile ⁇ Step 1> Synthesis of tert-butyl N- [2- (4-cyanophenyl) -2-oxoethyl] carbamate Isopropyl 4-iodobenzonitrile (1.47 g) in tetrahydrofuran (9 mL) at ⁇ 45 ° C. Magnesium bromide-diethyl ether solution (2.0 M, 3.44 mL) was added and stirred for 2 hours.
  • N- (tert-butoxycarbonyl) glycine N′-methoxy-N′-methylamide 1.0 g
  • tetrahydrofuran 14 mL
  • Saturated aqueous ammonium chloride solution was added.
  • ⁇ Step 3> Synthesis of 4- (2-amino-1-hydroxyethyl) benzonitrile hydrochloride (Example 54) By a method according to ⁇ Step 1>, obtained in (Example 130) ⁇ Step 2> The title compound (278 mg) was obtained as a white solid from the compound (0.39 g).
  • ⁇ Step 4> Synthesis of 4- [1-hydroxy-2-[(6-iodopyrimidin-4-yl) amino] ethyl] benzonitrile (Example 2) In the same manner as in ⁇ Step 1>, (Example 130) The title compound (254 mg) was obtained as a yellow amorphous form from the compound (0.28 g) obtained in ⁇ Step 3>.
  • ⁇ Step 2> Synthesis of tert-butyl N- [2-hydroxy-2- [2- (trifluoromethyl) phenyl] ethyl] carbamate (Example 126) In the same manner as in ⁇ Step 5> (Example 131) ) The title compound (0.77 g) was obtained as a yellow oil from the compound (0.80 g) obtained in ⁇ Step 1>.
  • Example 132 1- (4-Chloro-2-methylphenyl) -2-[[6- (4-methylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] ethanol ⁇ Step 1> 4- Synthesis of iodo-6- (4-methylsulfonylpiperazin-1-yl) pyrimidine (Example 2) 4,6-diiodopyrimidine (2.2 g) and 1-methylsulfonyl by a method according to ⁇ Step 1> The title compound (2.1 g) was obtained as a pale yellow solid from piperazine (1.1 g).
  • ⁇ Step 2> Synthesis of 1- (4-chloro-2-methylphenyl) -2-[[6- (4-methylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] ethanol (Example 17) (Example 132) From the compound obtained in ⁇ Step 1> (0.10 g) and (Example 126) in ⁇ Step 6> (0.12 g), the title compound (0.12 g) was used. 84 mg) was obtained as a white solid.
  • Example 133 1- [4- [6-[[2-Hydroxy-2- (2-methylphenyl) ethyl] amino] pyrimidin-4-yl] piperazin-1-yl] propan-1-one ⁇ Step 1> Synthesis of tert-butyl N- [2- (2-methylphenyl) -2-oxoethyl] carbamate (Example 126) N- (tert-butoxycarbonyl) glycine N ′ by the method according to ⁇ Step 4> The title compound (1.78 g) was obtained as a yellow solid from -methoxy-N′-methylamide (2.00 g) and 2-methylphenylmagnesium bromide-diethyl ether solution (2.0 M, 11.0 mL).
  • ⁇ Step 2> Synthesis of tert-butyl N- [2-hydroxy-2- (2-methylphenyl) ethyl] carbamate (Example 126) In the same manner as in ⁇ Step 5>, (Example 133) ⁇ Step 1 From the compound (1.59 g) obtained in>, the title compound (1.64 g) was obtained as a white solid.
  • ⁇ Step 3> Synthesis of 2-amino-1- (2-methylphenyl) ethanol hydrochloride (Example 54) In the same manner as in ⁇ Step 1>, compound obtained in (Example 133) ⁇ Step 2> (1.62 g) gave the title compound (1.07 g) as a white solid.
  • ⁇ Step 4> Synthesis of 2-[(6-iodopyrimidin-4-yl) amino] -1- (2-methylphenyl) ethanol (Example 2) In the same manner as in ⁇ Step 1> (Example 133) ) The title compound (0.67 g) was obtained as a pale yellow solid from the compound (0.50 g) obtained in ⁇ Step 3>.
  • ⁇ Step 4> Synthesis of tert-butyl N- [2- (2-methoxyphenyl) -2-oxoethyl] carbamate (Example 126) N- (tert-butoxycarbonyl) glycine by the method according to ⁇ Step 4> The title compound (2.5 g) was obtained as a white solid from N′-methoxy-N′-methylamide (2.00 g) and 2-methoxyphenylmagnesium bromide-tetrahydrofuran solution (1.0 M, 22.0 mL).
  • ⁇ Step 5> Synthesis of tert-butyl N- [2-hydroxy-2- (2-methoxyphenyl) ethyl] carbamate (Example 126) In the same manner as in ⁇ Step 5>, (Example 134) ⁇ Step 4 The title compound (2.33 g) was obtained as a white solid from the compound obtained in the above (2.40 g).
  • ⁇ Step 6> Synthesis of 2-amino-1- (2-methoxyphenyl) ethanol hydrochloride (Example 54) In the same manner as in ⁇ Step 1>, the compound obtained in (Example 134) ⁇ Step 5> (2.29 g) gave the title compound (1.47 g) as a white solid.
  • Example 136 2-Fluoro-1- [4- [6-[[2-hydroxy-2- (2-hydroxyphenyl) ethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2- Methylpropan-1-one (Example 135) To a methanol solution (2.0 mL) of the compound (30.0 mg) obtained in ⁇ Step 4> was added 10% palladium-activated carbon (5.0 mg), and a hydrogen atmosphere Stirred for 18 hours.
  • Example 137 1- [6- (trifluoromethyl) pyridin-3-yl] -2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino Ethanol ⁇ Step 1> Synthesis of tert-butyl 4- (trifluoromethylsulfonyl) piperazine-1-carboxylate Tert-butyl 1-piperazinecarboxylate (3.00 g) and triethylamine (3.40 mL) in dichloromethane (32 0.0 mL) was added trifluoromethanesulfonic anhydride (2.98 mL) at ⁇ 78 ° C., stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour.
  • ⁇ Step 4> Synthesis of tert-butyl N- [2-oxo-2- [6- (trifluoromethyl) pyridin-3-yl] ethyl] carbamate (Example 130)
  • N- (tert-butoxycarbonyl) glycine From N′-methoxy-N′-methylamide (0.40 g) and 5-bromo-2-trifluoromethylpyridine (2.07 g), the title compound (0.38 g) was white. Obtained as a solid.
  • ⁇ Step 5> Synthesis of tert-butyl N- [2-hydroxy-2- [6- (trifluoromethyl) pyridin-3-yl] ethyl] carbamate (Example 126)
  • Example 137 The title compound (0.4 g) was obtained as a white solid from the compound (0.40 g) obtained in ⁇ Step 4>.
  • Example 138 [4- [6-[[2- [6- (Difluoromethoxy) -2-methylpyridin-3-yl] -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazine-1- Yl]-(1-fluorocyclopropyl) methanone ⁇ Step 1> Synthesis of benzyl 4- (1-fluorocyclopropanecarbonyl) piperazine-1-carboxylate 4-chlorophenyl 1-fluorocyclopropanecarboxylate (0.50 g) Benzyl 1-piperazinecarboxylate (1.03 g) was added to an acetonitrile solution (2.50 mL) under ice cooling, and the mixture was stirred for 30 minutes.
  • Step 3> Synthesis of 3-bromo-6- (difluoromethoxy) -2-methylpyridine Sodium chloride (50.0 mL) in 3-bromo-6-hydroxy-2-methylpyridine (2.00 g) in acetonitrile 0.15 g) and 2- (fluorosulfonyl) difluoroacetic acid (1.32 mL) were added and stirred for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain the title compound (1.77 g) as a colorless oil.
  • ⁇ Step 5> Synthesis of 6- (difluoromethoxy) -2-methyl-3- (oxiran-2-yl) pyridine (Example 138)
  • a dichloromethane solution of the compound (0.24 g) obtained in ⁇ Step 4> 1.0 mL) was added m-chloroperbenzoic acid (0.35 g) at 0 ° C. and stirred at room temperature for 2 hours. Further, m-chloroperbenzoic acid (0.18 g) was added, and after stirring for 1 hour, m-chloroperbenzoic acid (0.088 g) was added and stirred for 30 minutes. 1N sodium hydroxide solution was added and extracted with dichloromethane.
  • Example 139 3- [1-Hydroxy-2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethyl] benzonitrile ⁇ Step 1> tert Synthesis of N-butyl N- [2- (3-cyanophenyl) -2-oxoethyl] carbamate (Example 130) N- (tert-butoxycarbonyl) glycine N′-methoxy- by a method according to ⁇ Step 1> The title compound (0.19 g) was obtained as a pale yellow solid from N′-methylamide (0.50 g) and 3-bromobenzonitrile (1.0 g).
  • ⁇ Step 2> tert-butyl N- [2- ( Synthesis of 3-cyanophenyl) -2-hydroxyethyl] carbamate (Example 126) According to the method according to ⁇ Step 5>, (Example 139) obtained in ⁇ Step 1> The title compound (0.16 g) was obtained as a yellow solid from the compound (0.18 g).
  • ⁇ Step 3> Synthesis of 3- (2-amino-1-hydroxyethyl) benzonitrile hydrochloride (Example 54) According to ⁇ Step 1>, obtained in (Example 135) ⁇ Step 2>. The title compound (0.11 g) was obtained as a white solid from the compound (0.16 g).
  • ⁇ Step 4> Synthesis of 3- [1-hydroxy-2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethyl] benzonitrile (Example 17) ) From the compound obtained in (Example 139) ⁇ Step 3> (47.1 mg) and (Example 137) from the compound (50.0 mg) obtained in ⁇ Step 3>. (19 mg) was obtained as a pale yellow solid.
  • Example 140 1- [4- [6-[[2- (2-Cyclopropylphenyl) -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2-fluoro-2 -Methylpropan-1-one ⁇ Step 1> Synthesis of tert-butyl N- [2- (2-cyclopropylphenyl) -2-oxoethyl] carbamate Add 1M methylmagnesium bromide-tetrahydrofuran solution to magnesium for 5 minutes at 70 ° C. Stir.
  • ⁇ Step 3> Synthesis of 2-amino-1- (2-cyclopropylphenyl) ethanol hydrochloride (Example 54) According to ⁇ Step 1>, obtained in (Example 140) ⁇ Step 2>. The title compound (139 mg) was obtained as a white solid from the compound (0.20 g).
  • Step 4> 1- [4- [6-[[2- (2-Cyclopropylphenyl) -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2-fluoro-2- Synthesis of methylpropan-1-one
  • the title compound (32 mg) was obtained as a colorless amorphous form from the obtained compound (40.0 mg).
  • Example 141 1- [4- [6-[[2- (1,3-Benzodioxol-5-yl) -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2 2-Fluoro-2-methylpropan-1-one (Example 134) and (Example 134) according to a method similar to that in Example 17 and 2-amino-1-benzo [1,3] dioxol-5-ylethanol (34 mg) The title compound (11.5 mg) was obtained from the compound (30.0 mg) obtained in Step 3>.
  • Example 142 According to 1-thiophen-2-yl-2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethanol (Example 17) (Example 137) From the compound (33 mg) obtained in ⁇ Step 3> and 2-amino-1- (thiophen-2-yl) ethan-1-ol (43 mg), the title compound (20. 6 mg) was obtained as a colorless amorphous.
  • Example 143 1- [4- [6-[[2- [4- (Difluoromethoxy) phenyl] -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2-fluoro -2-Methylpropan-1-one
  • ⁇ Step 1> Synthesis of tert-butyl N- [2- (4-benzyloxyphenyl) -2-oxoethyl] carbamate (Example 126)
  • ⁇ Step 4> From the 4-benzyloxyphenylmagnesium bromide-tetrahydrofuran solution (1M, 21.99 mL), the title compound (2.49 g) was obtained as a yellow solid.
  • ⁇ Step 2> Synthesis of tert-butyl N- [2- (2-hydroxyphenyl) -2-hydroxyethyl] carbamate (Example 143) Methanol solution of the compound (1.32 g) obtained in ⁇ Step 1> 20.0 mL) was added 10% palladium-activated carbon (0.13 g), and the mixture was stirred under a hydrogen atmosphere for 3.5 hours. After Celite filtration, the solvent was distilled off under reduced pressure, and the resulting residue was triturated with dichloromethane to obtain the title compound (567 mg) as a white solid.
  • ⁇ Step 3> Synthesis of tert-butyl 5- (4-hydroxyphenyl) -2,2-dimethyloxazolidone-3-carboxylate (Example 108) In the same manner as in ⁇ Step 2>, (Example 143) ⁇ The title compound (40.6 mg) was obtained as a white solid from the compound (50.0 mg) obtained in Step 2>.
  • ⁇ Step 4> Synthesis of tert-butyl 5-[(4-difluoromethoxy) phenyl] -2,2-dimethyloxazolidone-3-carboxylate (Example 143) Compound obtained in ⁇ Step 3> (33.0 mg ) In N, N-dimethylformamide (1.00 mL) -water (0.10 mL) solution was added potassium carbonate (62.2 mg) and sodium 2-chloro-2,2-difluoroacetate (18.9 mg). Stir for 1 hour at ° C. Further, sodium 2-chloro-2,2-difluoroacetate (17.2 mg) was added and stirred overnight.
  • Step 6> 1- [4- [6-[[2- [4- (Difluoromethoxy) phenyl] -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2-fluoro- Synthesis of 2-methylpropan-1-one Obtained by (Example 143) ⁇ Step 5> compound (44.4 mg) and (Example 134) ⁇ Step 3> by a method analogous to Example 17 The title compound (9.9 mg) was obtained as a colorless oil from the obtained compound (35.0 mg).
  • Example 144 1- [4- [6-[[2- (2,3-Dihydro-1-benzofuran-5-yl) -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazine-1- Yl] -2-fluoro-2-methylpropan-1-one ⁇ Step 1> Synthesis of tert-butyl (2- (2,3-dihydrobenzofuran-5-yl) -2-hydroxyethyl) carbamate 5-bromo- N-Butyllithium-hexane solution (1.67M, 6.58 mL) was added to tetrahydrofuran (11 mL) of 2,3-dihydrobenzofuran (2.2 g) at ⁇ 78 ° C.
  • the obtained crude product was dissolved in ethanol (20 mL), sodium borohydride (0.44 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 145 (4-Chlorophenyl)-[1-[[6- (4-ethylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] cyclopropyl] methanol ⁇ Step 1> tert-butyl N— Synthesis of [1- [methoxy (methyl) carbamoyl] cyclopropyl] carbamate (Example 134) 1-[(tert-butoxycarbonyl) amino] cyclopropanecarboxylic acid (3.00 g) according to the method of ⁇ Step 1> ) And N, O-dimethylhydroxylamine hydrochloride (1.53 g) to give the title compound (2.7 g) as a white solid ⁇ Step 2> tert-butyl N- [1- (4-chlorobenzoyl) Synthesis of cyclopropyl] carbamate (Example 126) According to the method according to ⁇ Step 4>, (Example
  • ⁇ Step 3> Synthesis of tert-butyl N- [1-[(4-chlorophenyl) -hydroxymethyl] cyclopropyl] carbamate (Example 126) In the same manner as in ⁇ Step 5>, (Example 145) ⁇ Step From the compound obtained in 2> (1.10 g), the title compound (1.1 g) was obtained as a white solid.
  • ⁇ Step 4> Synthesis of (1-aminocyclopropyl)-(4-chlorophenyl) methanol hydrochloride (Example 54) By a method according to ⁇ Step 1>, obtained in (Example 145) ⁇ Step 3> The title compound (0.86 g) was obtained as a white solid from the compound (1.10 g).
  • ⁇ Step 5> Synthesis of (4-chlorophenyl)-[1-[(6-iodopyrimidin-4-yl) amino] cyclopropyl] methanol (Example 2) In the same manner as in ⁇ Step 1>, (Example 145) The title compound (0.15 g) was obtained as a yellow solid from the compound (0.35 g) obtained in ⁇ Step 4>.
  • Example 146 1-[(2R) -4- [6-[[1- (4-Chlorophenyl) -1-hydroxypropan-2-yl] amino] pyrimidin-4-yl] -2-methylpiperazine- 1-yl] propan-1-one ⁇ Step 1> Synthesis of tert-butyl (3R) -3-methyl-4-propanoylpiperazine-1-carboxylate tert-butyl (3R) -3-methylpiperazine-1- Propionic acid anhydride (1.18 g) was added to a dichloromethane solution (30 mL) of carboxylate (3.00 g) and triethylamine (6.32 mL) and stirred overnight.
  • ⁇ Step 3> Synthesis of 1- (4-chlorophenyl) -2-[(6-iodopyrimidin-4-yl) amino] propan-1-ol (Example 2) In the same manner as in ⁇ Step 1>, 2 The title compound (170 mg) was obtained as a yellow solid from -amino-1- (4′-chlorophenyl) propan-1-ol (0.18 g).
  • Example 147 1- (4-Chlorophenyl) -2-[[6- (4-ethylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] propan-1-ol ⁇ Step 1> 4- ( Synthesis of 4-ethylsulfonylpiperazin-1-yl) -6-iodopyrimidine (Example 2) From 1- (ethylsulfonyl) piperazine (1.13 g) by the method according to ⁇ Step 1>, the title compound (2 .17 g) was obtained as a white solid.
  • Step 2> Synthesis of 1- (4-chlorophenyl) -2-[[6- (4-ethylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] propan-1-ol (Example 17)
  • the title compound was obtained. (1.9 mg) was obtained as a colorless oil.
  • Example 148 1- (4-Chloro-2-methylphenyl) -2-[[6- [3- (2,2,2-trifluoroethoxy) azetidin-1-yl] pyrimidin-4-yl] Amino] ethanol ⁇ Step 1> Synthesis of 1-benzhydryl-3- (2,2,2-trifluoroethoxy) azetidine (Example 124) 1- (Diphenylmethyl) -3- by a method analogous to ⁇ Step 1> The title compound (0.8 g) was obtained as a colorless oil from hydroxyazetidine (2.00 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.24 mL).
  • ⁇ Step 2> Synthesis of 3- (2,2,2-trifluoroethoxy) azetidine hydrochloride
  • Example 148 To a solution of the compound obtained in ⁇ Step 1> (0.75 g) in dichloromethane solution (4.0 mL), 1- Chloroethyl chloroformate (0.39 mL) was added, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated, methanol (4.0 mL) was added, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated and washed with diethyl ether to give the title compound (0.51 g) as a white solid.
  • Example 149 1- (4-Chloro-2-methylphenyl) -2-[[6- [3- (2,2,2-trifluoroethylamino) azetidin-1-yl] pyrimidin-4-yl Amino] ethanol ⁇ Step 1> Synthesis of 1-benzhydryl-N- (2,2,2-trifluoroethyl) azetidin-3-amine 1- (Diphenylmethyl) -4-azetidinone (1.60 g) in dichloroethane (2,0.0 mL) was added 2,2,2-trifluoroethylamine (0.80 mL), acetic acid (0.46 mL) and sodium triacetoxyborohydride (2.14 g), and the mixture was stirred at room temperature overnight.
  • ⁇ Step 2> Synthesis of N- (2,2,2-trifluoroethyl) azetidin-3-amine trifluoroacetate
  • Example 149 Compound (0.10 g) obtained in ⁇ Step 1>, palladium hydroxide ( II)-Activated charcoal (33.0 mg) and 2,2,2-trifluoroacetic acid (0.30 mL) in methanol (2.0 mL) were stirred overnight under a hydrogen atmosphere. After Celite filtration, the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether to give the title compound (60 mg) as a white solid.
  • Step 3> 1- (4-Chloro-2-methylphenyl) -2-[[6- [3- (2,2,2-trifluoroethylamino) azetidin-1-yl] pyrimidin-4-yl] Synthesis of Amino] ethanol Compound (25.0 mg) obtained in (Example 126) ⁇ Step 7> and compound obtained in (Example 149) ⁇ Step 2> by a method according to (Example 19) (49.1 mg) gave the title compound (22 mg) as a white solid.
  • Example 150 2-Fluoro-1- [4- [6-[[2-hydroxy-2- [4- (trifluoromethoxy) phenyl] ethyl] amino] pyrimidin-4-yl] piperazin-1-yl ] -2-Methylpropan-1-one ⁇ Step 1> Synthesis of 2-[(6-iodopyrimidin-4-yl) amino] -1- [4- (trifluoromethoxy) phenyl] ethanol (Example 2) By the method according to ⁇ Step 1>, the title compound (770 mg) was obtained as a pale yellow amorphous form from 2-amino-1- [4- (trifluoromethoxy) phenyl] ethane-1-ol (0.53 g).
  • Example 151 2-[[6- (4-Cyclopropylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] -1- [4- (trifluoromethyl) phenyl] ethanol ⁇ Step 1> 2 Synthesis of — [(6-iodopyrimidin-4-yl) amino] -1- [4- (trifluoromethyl) phenyl] ethanol (Example 2) 2-amino-1 by the method according to ⁇ Step 1> The title compound (1.23 g) was obtained as a brown solid from-[4- (trifluoromethyl) phenyl] ethane-1-ol (0.77 g).
  • ⁇ Step 2> Synthesis of 2-[[6- (4-cyclopropylsulfonylpiperazin-1-yl) pyrimidin-4-yl] amino] -1- [4- (trifluoromethyl) phenyl] ethanol (Example 19) ) (Example 151) From the compound (50.0 mg) obtained in ⁇ Step 1> and 1- (cyclopropanesulfonyl) piperazine hydrochloride (55.4 mg), the title compound (26 mg) was obtained. Obtained.
  • Example 152 (1R) -2-[[6- [4- (Difluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] -1-phenylethanol ⁇ Step 1> tert-butyl 4 Synthesis of — (difluoromethylsulfonyl) piperazine-1-carboxylate tert-butyl piperazine-1-carboxylate (62.0 mg) in dichloromethane solution under ice-cooling, pyridine (53.6 ⁇ L) and difluoromethanesulfonyl chloride (0. 10 g) was added and stirred overnight. 0.1N hydrochloric acid was added, and the mixture was extracted with dichloromethane.
  • Example 153 1- (4-Chlorophenyl) -2-[[6-[(2S) -2-methyl-4- (2,2,2-trifluoroethyl) piperazin-1-yl] pyrimidine-4 -Il] amino] ethanol ⁇ Step 1> Synthesis of 4-iodo-6-[(2S) -2-methyl-4- (2,2,2-trifluoroethyl) piperazin-1-yl] pyrimidine (2S) N, N-diisopropylethylamine (0.34 mL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.46 g) were added to a tetrahydrofuran solution (2 mL) of -2-methylpiperazine (50.0 mg).
  • Example 154 [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -4- (2,2,2-trifluoroethyl) piperazine-2 -ON ⁇ Step 1> Synthesis of 4- (2,2,2-trifluoroethyl) piperazin-2-one (Example 125) Piperazine-2-one (1.2 g) according to the method of ⁇ Step 4> ) Gave the title compound (950 mg).
  • ⁇ Step 2> 1- [6-[[(2R) -2-hydroxy-2-phenylethyl] amino] pyrimidin-4-yl] -4- (2,2,2-trifluoroethyl) piperazine-2- ON (Example 2)
  • a toluene solution 1.0 mL
  • the compound 32.0 mg
  • Palladium (II) acetate 3.95 mg
  • xantphos (15.3 mg)
  • cesium carbonate 21.0 mg
  • Example 155 1- (4-Chlorophenyl) -2-[[6- [4-methoxy-4- (trifluoromethyl) piperidin-1-yl] pyrimidin-4-yl] amino] ethanol ⁇ Step 1> 2-[(6-Iodopyrimidin-4-yl) amino] -1- (4-chlorophenyl) ethanol (Example 2) In the same manner as in ⁇ Step 1>, 2-amino-1- (4-chlorophenyl) The title compound (556 mg) was obtained as a colorless amorphous form from ethanol (0.32 g).
  • Tetrabutylammonium fluoride-tetrahydrofuran solution 1.0 M, 13.5 mL was added to a tetrahydrofuran solution (10.0 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours.
  • 1N Hydrochloric acid was added, ethyl acetate was added for extraction, and the organic layer was washed with saturated brine.
  • ⁇ Step 4> 1- (4-Chlorophenyl) -2-[[6- [4-methoxy-4- (trifluoromethyl) piperidin-1-yl] pyrimidin-4-yl] amino] ethanol (Example 155) 10% Palladium-carbon was added to an ethanol solution of the compound obtained in ⁇ Step 3> (0.10 g), and the mixture was stirred at 40 ° C. for 2 hours in a hydrogen atmosphere. The mixture was further stirred at room temperature for 15 hours. After Celite filtration, a hydrogen chloride-methanol solution was added, and the solvent was distilled off under reduced pressure to obtain a yellow oil (90 mg). The title compound (9.6 mg) was obtained from this yellow oil (32.9 mg) and the compound (37.6 mg) obtained in (Example 155) ⁇ Step 1> according to the method of (Example 19). .
  • Example 156 2- [Methyl- [6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] -1-phenylethanol According to a method according to (Example 17) (Example 137) The title compound (27.4 mg) was obtained from the compound (33 mg) obtained in ⁇ Step 3> and ⁇ - (methylaminoethyl) benzyl alcohol (24 mg).
  • Example 157 (1-Fluorocyclopropyl)-[4- [6-[[2-hydroxy-2- [2-methyl-4- (trifluoromethoxy) phenyl] ethyl] amino] pyrimidin-4-yl ] Piperazin-1-yl] methanone ⁇ Step 1> Synthesis of tert-butyl N- [2- [2-methyl-4- (trifluoromethoxy) phenyl] -2-oxoethyl] carbamate (Example 140) ⁇ Step 1 The title compound (1.04 g) was obtained as a yellow oil from 2-methyl-4- (trifluoromethoxy) bromobenzene (3.51 g) by a method according to>.
  • ⁇ Step 2> Synthesis of tert-butyl N- [2- [2-methyl-4- (trifluoromethoxy) phenyl] -2-hydroxyethyl] carbamate (Example 126)
  • Example 157 The title compound (1.0 g) was obtained as a yellow solid from the compound (1.00 g) obtained in ⁇ Step 1>.
  • ⁇ Step 4> Synthesis of 2-[(6-iodopyrimidin-4-yl) amino] -1- [2-methyl-4- (trifluoromethoxy) phenyl] ethanol (Example 2) According to ⁇ Step 1>
  • the title compound (850 mg) was obtained as a pale yellow amorphous product from the compound (0.77 g) obtained in (Example 157) ⁇ Step 3>.
  • Example 158 [4- [6-[[2- (4-Chloro-2-methylphenyl) -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl]-(1 -Fluorocyclopropyl) methanone
  • the compound (39.0 mg) obtained in (Example 126) ⁇ Step 7> and (Example 138) obtained in ⁇ Step 2> The title compound (43.4 mg) was obtained from the compound (35.0 mg).
  • Example 159 1- [4- [6-[[2- (4-Chloro-2-methylphenyl) -2-hydroxyethyl] amino] pyrimidin-4-yl] piperazin-1-yl] -2- Fluoro-2-methylpropan-1-one
  • Example 160 2-[[6- [4- (Cyclopropylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] -1- [2-methyl-4- (trifluoromethoxy) phenyl]
  • the compound (39.5 mg) obtained in (Example 157) ⁇ Step 4> and 1- (cyclopropylsulfonyl) piperazine hydrochloride (40.0 mg)
  • the title Compound (45.1 mg) was obtained.
  • Example 161 4- [6-[[2-Hydroxy-2- [4- (trifluoromethoxy) phenyl] ethyl] amino] pyrimidin-4-yl] -N, N-dimethylpiperazine-1-sulfonamide
  • the title compound (20.5 mg) was obtained from the compound (43 mg) obtained in (Example 150) ⁇ Step 1> and piperazine-1-sulfonic acid dimethylamide (19 mg) by a method according to (Example 19). Obtained.
  • Example 162 1- (4-Chloro-2-methylphenyl) -2-[[6- [4- (difluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethanol
  • Step 1 Synthesis of 2-[(6-chloropyrimidin-4-yl) amino] -1- (4-chloro-2-methylphenyl) ethanol (Example 2)
  • Example 126 The title compound (0.49 g) was obtained as a white solid from the compound (0.91 g) obtained in ⁇ Step 6> and 4,6-dichloropyrimidine (0.73 g).
  • ⁇ Step 2> Synthesis of 1- (4-chloro-2-methylphenyl) -2-[[6- [4- (difluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethanol
  • ⁇ Step 3> the compound (60.7 mg) obtained in (Example 152)
  • ⁇ Step 2> the compound obtained in ⁇ Step 1> (38.
  • the title compound (8 mg) was obtained as a pale yellow amorphous product from 0 mg).
  • Example 163 1- (4-Chloro-2-methylphenyl) -2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethanol From the compound (50.0 mg) obtained in (Example 126) ⁇ Step 7> and the compound (49.2 mg) obtained in (Example 137) ⁇ Step 2> by the method according to Example 19), The title compound (31 mg) was obtained.
  • Example 164 2-[[6- [4- (Difluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] -1- (4-fluoro-2-methylphenyl) ethanol ⁇ Step 1 > Synthesis of tert-butyl N- [2- (4-fluoro-2-methylphenyl) -2-oxoethyl] carbamate (Example 140) 2-bromo-5-fluorotoluene by a method according to ⁇ Step 1> (2.60 g) gave the title compound (1.1 g) as a pale yellow oil.
  • ⁇ Step 2> Synthesis of tert-butyl N- [2- (4-fluoro-2-methylphenyl) -2-hydroxyethyl] carbamate (Example 126) In the same manner as in ⁇ Step 5> (Example 164) ) The title compound (1.1 g) was obtained from the compound (1.10 g) obtained in ⁇ Step 1>.
  • ⁇ Step 3> Synthesis of 2-amino-1- (4-fluoro-2-methylphenyl) ethanol hydrochloride (Example 54) By a method according to ⁇ Step 1>, (Example 164) ⁇ Step 2> The title compound was obtained as a white solid from the obtained compound (1.10 g).
  • ⁇ Step 4> Synthesis of 2-[(6-iodopyrimidin-4-yl) amino] -1- (4-fluoro-2-methylphenyl) ethanol (Example 2) By a method according to ⁇ Step 1>
  • Example 164 The title compound (1.0 g) was obtained as an amorphous form from the compound (0.78 g) obtained in ⁇ Step 3>.
  • ⁇ Step 5> Synthesis of 2-[[6- [4- (difluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] -1- (4-fluoro-2-methylphenyl) ethanol
  • Example 152 Compound (50.0 mg) obtained in (Example 164) ⁇ Step 4> and compound obtained in (Example 152) ⁇ Step 2> by the method according to ⁇ Step 3> (Example 164) From the compound obtained in ⁇ Step 4> (50.0 mg) and (Example 152) in the method according to Step 3> (63.4 mg) obtained in ⁇ Step 2>, The title compound (35 mg) was obtained.
  • Example 165 1- [6- (Difluoromethoxy) -2-methylpyridin-3-yl] -2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidine-4- Yl] amino] ethanol
  • Example 166 1- [2-Methyl-4- (trifluoromethoxy) phenyl] -2-[[6- (1-[(trifluoromethylsulfonyl) -1,2,3,6-tetrahydropyridine- 4-yl] pyrimidin-4-yl) amino] ethanol (Example 56)
  • Example 157 The compound (0.10 g) obtained in ⁇ Step 4> and (Working) Example 126)
  • the title compound (43.3 mg) was obtained as an amorphous form from the compound (93.2 mg) obtained in ⁇ Step 3>.
  • Step 2> Synthesis of (R) -1-phenyl-2-[[6- [4- (trifluoromethylsulfonyl) piperazin-1-yl] pyrimidin-4-yl] amino] ethanol (Example 167) ⁇ Trifluoromethanesulfonic anhydride (16.3 ⁇ L) was added to a dichloromethane solution (3.00 mL) of the compound (30.0 mg) obtained in step 1> and triethylamine (18.5 ⁇ L) at ⁇ 78 ° C. for 1 hour. After stirring, the mixture was stirred at room temperature for 15 minutes.
  • the structures of the compounds synthesized in Examples 1 to 66 are shown in [Compound Lists 1 to 3].
  • the structures of the compounds of Examples 67 to 107 are shown in [Compound List 4, 5].
  • the structures of the compounds of Examples 108 to 167 are shown in [Compound Lists 6 to 8].
  • LC / MS data of these examples are shown in Tables 2-1 to 2-3, and NMR data of representative compounds are shown in Table 3.
  • the structures of intermediate compounds are shown in [Compound Lists 9 to 15].
  • LC / MS data of these intermediate compounds are shown in Tables 4-1 to 4-3, and NMR data of representative compounds are shown in Tables 5-1 to 5-2.
  • the measurement apparatus is shown as follows: (*): 400 MHz, (no mark): 300 MHz.
  • the mobile phase is shown as follows: (A) methanol: 0.05% aqueous acetic acid solution, (B) methanol: 0.05% aqueous trifluoroacetic acid solution.

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Abstract

L'invention porte sur un inhibiteur de FAAH extrêmement efficace et notamment sur un agent prophylactique ou sur un médicament pour la douleur sévère, qui peut être administré par voie orale. L'invention décrit une composition pharmaceutique qui possède, comme principe actif, un nouveau dérivé hétéroaryle ou un sel, tel que représenté dans la formule (I) ci-dessous, et un solvate de celui-ci. Ladite composition pharmaceutique peut être utilisée notamment comme inhibiteur de FAAH ou en tant qu'agent prophylactique ou médicament pour la douleur sévère.
PCT/JP2011/054366 2010-02-26 2011-02-25 Nouveau dérivé hétéroaryle WO2011105572A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014054634A1 (fr) * 2012-10-02 2014-04-10 大日本住友製薬株式会社 Dérivé pyrimidine
WO2015123398A1 (fr) * 2014-02-12 2015-08-20 Purdue Pharma L.P. Dérivés d'isoquinoline et leur utilisation
US20170327503A1 (en) * 2014-08-04 2017-11-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
CN114341125A (zh) * 2019-05-02 2022-04-12 星座制药公司 Trex1调节剂
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

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WO2000002865A1 (fr) * 1998-07-08 2000-01-20 Monash University Agents pharmaceutiques
WO2009105220A1 (fr) * 2008-02-19 2009-08-27 Janssen Pharmaceutica N.V. Aryl-hydroxyéthylamino-pyrimidines et triazines en tant que modulateurs d'amide d'acide gras hydrolase

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GB1143167A (en) * 1967-01-25 1969-02-19 Ucb Sa Derivatives of pyrimidine
WO2000002865A1 (fr) * 1998-07-08 2000-01-20 Monash University Agents pharmaceutiques
WO2009105220A1 (fr) * 2008-02-19 2009-08-27 Janssen Pharmaceutica N.V. Aryl-hydroxyéthylamino-pyrimidines et triazines en tant que modulateurs d'amide d'acide gras hydrolase

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014054634A1 (fr) * 2012-10-02 2014-04-10 大日本住友製薬株式会社 Dérivé pyrimidine
US11401258B2 (en) 2014-02-12 2022-08-02 Purdue Pharma L.P. Isoquinoline derivatives and use thereof
US10738026B2 (en) 2014-02-12 2020-08-11 Purdue Pharma L.P. Isoquinoline derivatives and use thereof
JP2017511794A (ja) * 2014-02-12 2017-04-27 パーデュー、ファーマ、リミテッド、パートナーシップ イソキノリン誘導体及びその使用
WO2015123398A1 (fr) * 2014-02-12 2015-08-20 Purdue Pharma L.P. Dérivés d'isoquinoline et leur utilisation
AU2015217185B2 (en) * 2014-02-12 2018-04-05 Purdue Pharma L.P. Isoquinoline derivatives and use thereof
CN106103422B (zh) * 2014-02-12 2020-09-18 普渡制药公司 异喹啉衍生物及其用途
CN106103422A (zh) * 2014-02-12 2016-11-09 普渡制药公司 异喹啉衍生物及其用途
US10689383B2 (en) 2014-08-04 2020-06-23 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US11254681B2 (en) 2014-08-04 2022-02-22 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US10683293B2 (en) 2014-08-04 2020-06-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
US20170327503A1 (en) * 2014-08-04 2017-11-16 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
CN114341125A (zh) * 2019-05-02 2022-04-12 星座制药公司 Trex1调节剂
US11447479B2 (en) 2019-12-20 2022-09-20 Nuevolution A/S Compounds active towards nuclear receptors
US11613532B2 (en) 2020-03-31 2023-03-28 Nuevolution A/S Compounds active towards nuclear receptors
US11780843B2 (en) 2020-03-31 2023-10-10 Nuevolution A/S Compounds active towards nuclear receptors

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