WO2012077655A1 - Spiro derivative having gpr119 agonist activity - Google Patents

Spiro derivative having gpr119 agonist activity Download PDF

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Publication number
WO2012077655A1
WO2012077655A1 PCT/JP2011/078125 JP2011078125W WO2012077655A1 WO 2012077655 A1 WO2012077655 A1 WO 2012077655A1 JP 2011078125 W JP2011078125 W JP 2011078125W WO 2012077655 A1 WO2012077655 A1 WO 2012077655A1
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Prior art keywords
substituted
unsubstituted
compound
mmol
pharmaceutically acceptable
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PCT/JP2011/078125
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French (fr)
Japanese (ja)
Inventor
小川　知行
田中　悟
梓 岡野
輝和 加藤
仁資 矢里
功嗣 増田
麻童 中嶋
光拡 米原
香菜 渡辺
士郎 木田
俊博 和田
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塩野義製薬株式会社
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Publication of WO2012077655A1 publication Critical patent/WO2012077655A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to a compound having a G protein-coupled receptor (hereinafter referred to as GPR119) agonist activity and useful as a medicine.
  • GPR119 G protein-coupled receptor
  • GPR119 is a 7-transmembrane G protein-coupled receptor (GPCR) expressed in the islets of Langerhans in the pancreas.
  • GPR119 agonists have been reported to cause an increase in intracellular cAMP (cyclic adenosine 3 ′, 5′-monophosphate) levels and promote glucose-dependent insulin secretion from pancreatic ⁇ -cells. .
  • cAMP cyclic adenosine 3 ′, 5′-monophosphate
  • Patent Documents 1 to 9 disclose various compounds having GPR119 agonist activity, but none of the spiro derivatives such as the compounds of the present invention are disclosed.
  • Patent Documents 10 and 11 disclose spirochroman derivatives and spirodihydrobenzofuran derivatives as compounds useful for sleep disorders.
  • Patent Documents 12 and 13 describe the following spirochroman derivatives as compounds useful for hypertension, obesity, diabetes, and the like.
  • Patent Document 14 describes the following spirochroman derivatives as compounds useful for diabetic complications.
  • Patent Document 15 discloses a spirodihydrobenzofuran derivative as a compound useful for Alzheimer or diabetes.
  • Patent Document 16 describes the following spirodihydrobenzofuran derivatives as compounds useful for Alzheimer's disease.
  • Patent Documents 10 to 16 do not describe GPR119 agonistic action.
  • An object of the present invention is to provide an excellent GPR119 agonist.
  • the present inventors have succeeded in synthesizing an excellent compound having a GPR119 agonistic action.
  • the present invention relates to the following.
  • R 8A , R 8B And p are as defined above, and R 8D Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8A , R 8B And p are as defined above, and R 8E And R 8F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8G Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8H Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl, and q is 1 or 2.
  • R 8I And R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • n are each independently 0, 1 or 2
  • r is an integer from 0 to 12
  • R 9 Are each independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl; When r is 2 or more, two R bonded to the same carbon atom 9 Together may form an oxo and / or two R bonded to different carbon atoms. 9 Together with the carbon atom to which they are attached may form a substituted or unsubstituted ring.
  • X CH- and Y 1 Is -O- and R 8 Is the formula:-(CR 8A R 8B P-R 8C And a group represented by R 8C Wherein is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, and the compounds shown below: except for. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (2) Y 1 The compound according to the above (1), pharmaceutically acceptable salt or solvate thereof, wherein is —O—.
  • Y 2 Is -C (R 6 ) (R 6A The compound according to any one of the above (1) to (4), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • (6) Y 2 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A
  • R 6 And R 6A The compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein is hydrogen.
  • R 6 And R 6A The compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein at least one of is halogen or substituted or unsubstituted alkyl. (9) R 3 Or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocyclyl; Or a solvate thereof.
  • R 3 Is substituted aryl or substituted heteroaryl, and at least one of the substituents on the aryl or heteroaryl is —C ( ⁇ O) NR 10A R 10B And a group represented by R 10A And R 10B Is a compound according to any one of (1) to (8), a pharmaceutically acceptable salt thereof, or a solvate thereof, which forms a substituted or unsubstituted ring together with an adjacent nitrogen atom.
  • R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (1) above.
  • Group represented by Formula:-(CR 8A R 8B ) PC ( O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is the same as (1) above.
  • Group represented by Formula:-(CR 8A R 8B ) PC ( O) R 8G (Wherein R 8A , R 8B , P and R 8G Is the same as (1) above. )
  • Or a group Formula: -S ( O) q-R 8H (Wherein R 8H And q are as defined in the above (1).
  • R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (1) above. Or a pharmaceutically acceptable salt or solvate thereof.
  • R 8A , R 8B And p are as defined above, and R 8D Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8A , R 8B And p are as defined above, and R 8E And R 8F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8G Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8H Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl, and q is 1 or 2.
  • R 8I And R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • n are each independently 0, 1 or 2
  • r is an integer from 0 to 12
  • R 9 Are each independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl; When r is 2 or more, two R bonded to the same carbon atom 9 Together may form an oxo, and two R bonded to different carbon atoms. 9 Together with the carbon atom to which they are attached may form a substituted or unsubstituted ring.
  • Ring A is And Y 3 Is -O- and Y 4 Is -C (R 6 ) (R 6A )-, M is 1, n is 1, and R 8 Is the formula:-(CR 8A R 8B P-R 8C And a group represented by R 8C In which is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition having GPR119 receptor agonist activity. (21) Ring A is (Where R 1 , R 2 , R 3A And R 4 Is as defined in (20) above.
  • a pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to (20), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (22) Y 3 A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to the above (20) or (21), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R is —O—.
  • (23) Y 4 Is -C (R 6 ) (R 6A A pharmaceutical composition having GPR119 receptor agonist activity, which comprises the compound according to any one of the above (20) to (22), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 6 and R 6A A pharmaceutical composition having GPR119 receptor agonist activity, which comprises the compound according to any one of the above (20) to (22), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 6 And R 6A A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of (20) to (24), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is hydrogen.
  • R 6 And R 6A GPR119 containing the compound according to any one of the above (20) to (24), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein at least one of is halogen or substituted or unsubstituted alkyl A pharmaceutical composition having receptor agonist activity.
  • R 3A Or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, Or the pharmaceutical composition which has GPR119 receptor agonist activity containing those solvates.
  • R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitute
  • R 3A Is substituted aryl or substituted heteroaryl, and at least one of the substituents on the aryl or heteroaryl is —C ( ⁇ O) NR 10A R 10B And a group represented by R 10A And R 10B Is a compound according to any one of the above (20) to (28), a pharmaceutically acceptable salt thereof, or a solvate thereof, which forms a substituted or unsubstituted ring together with an adjacent nitrogen atom.
  • a pharmaceutical composition having GPR119 receptor agonist activity (30) A GPR119 receptor agonist comprising the compound according to any one of (20) to (29), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1.
  • R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is as defined in (20) above.
  • Group represented by Formula:-(CR 8A R 8B ) PC ( O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is as defined in (20) above.
  • Group represented by Formula:-(CR 8A R 8B ) PC ( O) R 8G (Wherein R 8A , R 8B , P and R 8G Is as defined in (20) above. )
  • Or a group Formula: -S ( O) q-R 8H (Wherein R 8H And q are as defined in (20) above.
  • a pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of (20) to (30) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is as defined in (20) above.
  • a pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of the above (20) to (31), a pharmaceutically acceptable salt thereof, or a solvate thereof, .
  • a pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to (31) or (32), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is 0.
  • R 8C A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to (33), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is a substituted or unsubstituted heteroaryl.
  • a pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of (20) to (34), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r is 0.
  • a method for preventing or treating diabetes comprising administering the compound according to any one of (1) to (35), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Another diabetes therapeutic agent is administered to a diabetic patient treated with the compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof, or a solvate thereof. How to treat diabetes.
  • a method for treating diabetes comprising administering another therapeutic agent for diabetes in combination with the compound represented by the formula (I) or formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • X CH- and Y 1 Is -O- and R 8 Is the formula:-(CR 8A R 8B P-R 8C And p is 0, and R is 8C
  • X is substituted or unsubstituted cycloalkyl
  • X is ⁇ CH—
  • M is 1
  • n 1, and R 8 Is the formula:-(CR 8A R 8B P-R 8C And p is 0, and R is 8C
  • R is 8C
  • R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstit
  • R 8 The compound according to any one of (1A) to (7A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1.
  • R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (1A) above.
  • Group represented by Formula:-(CR 8A R 8B ) PC ( O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is the same as (1A) above.
  • Group represented by Formula: -C ( O) R 8G (Wherein R 8G Is the same as (1A) above.
  • (12A) A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of (1A) to (10A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (14A) Y 4 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-And R 6 And R 6A
  • a pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to (13A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of is halogen or substituted or unsubstituted alkyl object.
  • R 3A Or a pharmaceutically acceptable salt thereof or a solvent thereof, wherein is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl
  • R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubsti
  • a GPR119 receptor agonist comprising the compound according to any one of (13A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1.
  • (20A) The pharmaceutical composition according to any one of the above (13A) to (19A), for the treatment and / or prevention of diabetes.
  • 21A A method for preventing or treating diabetes, which comprises administering the compound according to any one of (1A) to (12A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • 22A The compound according to any one of the above (1A) to (12A), a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment and / or prevention of diabetes.
  • (23A) The compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof, a compound having a DPP-IV inhibitory action, a pharmaceutically acceptable salt thereof or a solvent thereof A medicine that combines Japanese products.
  • Another diabetes therapeutic agent is administered to a diabetic patient treated with the compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof, or a solvate thereof. How to treat diabetes.
  • (25A) A method for treating diabetes, comprising administering another therapeutic agent for diabetes in combination with the compound represented by the formula (I) or formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the present inventors have confirmed that the compound of the present invention has a glucagon-like peptide-1 (hereinafter referred to as GLP-1) secretion action.
  • GLP-1 glucagon-like peptide-1
  • the compound of the present invention has excellent GPR119 agonist activity, activates GPR119 expressed in pancreatic ⁇ -cells to promote insulin secretion dependent on blood glucose elevation, and activates GPR119 expressed in the intestinal tract to induce GLP-1 secretion. By promoting, it has an excellent hypoglycemic effect.
  • GLP-1 is known to stimulate insulin secretion in a glucose-dependent manner, but it is easily cleaved by dipeptidyl peptidase IV (DPP-IV) to inactivate its biological activity. was there.
  • DPP-IV dipeptidyl peptidase IV
  • the compound of the present invention is not decomposed by DPP-IV and can be used in combination with a compound having a DPP-IV inhibitory action.
  • the present inventors have confirmed that there is a remarkable combined effect by using the compound of the present invention having GPR119 agonist activity and the compound having DPP-IV inhibitory action in combination.
  • Examples of the compound having DPP-IV inhibitory action include Sitagliptin, Vildagliptin, Alogliptin, Saxagliptin and the like.
  • compositions containing the compounds of the present invention can be used to treat pharmaceuticals, particularly type I diabetes, type II diabetes, insulin resistance, metabolic diseases, hyperglycemia and / or obesity. Or it is very useful as a medicine for prevention.
  • the compound of the present invention promotes insulin secretion in a glucose-dependent manner, the risk of hypoglycemia is low and the safety is high compared to existing drugs.
  • it is a compound having utility as a medicine.
  • the point includes a point having a small clearance, a point having a sufficiently long half-life for exhibiting a drug effect, a point having a strong enzyme activity, a point having a high maximum activation rate, and a point having a good drug effect.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl having 1 to 6 or 1 to 4 carbon atoms for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.
  • Alkenyl means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.
  • Alkynyl means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, you may have a double bond.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Groups and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.
  • “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.
  • the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.
  • “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropenyl (eg, 1-cyclopropenyl), cyclobutenyl (eg, 1-cyclobutenyl), cyclopentenyl.
  • Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • Aryl means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like.
  • Heteroaryl refers to monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.
  • the “monocyclic aromatic heterocyclic group” is derived from a 5- to 8-membered aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring. And a group which may have a bond at any substitutable position.
  • the “fused aromatic heterocyclic group” has 1 to 4 5- to 8-membered aromatic rings having one or more hetero atoms in the ring which are optionally selected from an oxygen atom, a sulfur atom and a nitrogen atom. And a group optionally having a bond at any substitutable position which is condensed with the other 5- to 8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.
  • heteroaryl examples include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl).
  • Imidazolyl eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • triazolyl eg, 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl
  • tetrazolyl eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl
  • oxazolyl eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl eg 3-isoxazolyl, 4-isoxazolyl, -Isoxazolyl
  • thiazolyl eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • thiadiazolyl isothiazolyl (eg 3-isothiazo
  • Heterocyclyl means a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring, or cycloalkane (preferably 5-6 members), benzene ring and / or such ring
  • a non-aromatic heterocyclic group which may have a bond at any substitutable position on a ring condensed with a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring.
  • the “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic. A 5- to 8-membered ring is preferred.
  • Acyl refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, It means substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl.
  • alkenylcarbonyl alkenylcarbonyl
  • cycloalkylcarbonyl cycloalkenylcarbonyl
  • arylcarbonyl cycloalkenylcarbonyl
  • heteroarylcarbonyl cyclocyclylcarbonyl
  • alkyl part of “alkyloxy”, “alkylthio”, “alkylsulfinyl”, “alkylsulfonyl” and “alkyloxycarbonyl” means the above “alkyl”.
  • alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl” and “alkenyloxycarbonyl” means the above “alkenyl”.
  • the aryl part of “aryloxy”, “arylthio”, “arylsulfinyl” and “arylsulfonyl” means the above “aryl”.
  • heteroaryl part of “heteroaryloxy”, “heteroarylthio”, “heteroarylsulfinyl” and “heteroarylsulfonyl” means the above “heteroaryl”.
  • the cycloalkyl part of “cycloalkyloxy”, “cycloalkylthio”, “cycloalkylsulfinyl” and “cycloalkylsulfonyl” means the above “cycloalkyl”.
  • the cycloalkenyl part of “cycloalkenyloxy”, “cycloalkenylthio”, “cycloalkenylsulfinyl” and “cycloalkenylsulfonyl” means the above “cycloalkenyl”.
  • heterocyclyl part of “heterocyclyloxy”, “heterocyclylthio”, “heterocyclylsulfinyl” and “heterocyclylsulfonyl” means the above “heterocyclyl”.
  • Substituted or unsubstituted alkyloxy substituted or unsubstituted aryl (substituent is alkyloxy), heteroaryl, cycloalkyl, cycloalkenyl, Heterocyclyl, eg methoxy, ethoxy
  • Substituted or unsubstituted aryloxy substituted or unsubstituted aryloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, eg, phenyloxy)
  • Substituted or unsubstituted aryl hydroxy is substituted
  • heteroaryl heterocyclyl, substituted or unsubstituted carbamoyl (alkyl is substituted), alkyloxy, alkylsulfonyl, alkylcarbamoyl, Sulfamoyl, acylamino.
  • Aryl substituted or unsubstituted cycloalkyl (substituents are hydroxy, —CH 2 OH, alkyl, alkyloxy, carbamoyl.), Heteroaryl, substituted or unsubstituted heterocyclyl (substituted)
  • Substituted or unsubstituted heteroarylalkyl (alkyl as a substituent), acylaminoalkyl, heterocyclylalkyl, Alkylaminoalkyl, C 2 H 4 OH, alkyloxyalkyl, eg, alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, isopropylcarbamoyl), heteroarylalkylcarbamoyl).
  • alkylcarbamoyl eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, isopropylcarbamoyl
  • heteroarylalkylcarbamoyl
  • Substituted or unsubstituted carbamoyloxy substituted or unsubstituted carbamoyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl), Substituted or unsubstituted acyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl (substituents are hydroxy, cycloalkyl, alkyloxy, carbamoyl), aryl, heteroaryl , Cycloalkyl, cycloalkenyl, heterocyclyl, alkyloxy, alkyloxycarbonyl, alkyloxyalkyl, alkylamino, carbamoyloxy, substituted or unsubstituted carbamoyl (the substituent is alky
  • methoxycarbonyl, ethoxycarbonyl, tert -Butoxycarbonyl), Substituted or unsubstituted silyloxy, Aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, Alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, Nitroso, Alkenyloxy (eg vinyloxy, allyloxy), Azide, Isocyanato, isocyanato, thiocyanato, isothiocyanato, mercapto, Alkylthio (eg methylthio), P ( O) (OH) 2 , Formyloxy, haloformyl, oxaro, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfon
  • R 10A and R 10B are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • R 10C may be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Substi
  • substituted carbamoyl As the substituent of “substituted carbamoyl”, “substituted sulfamoyl”, “substituted imino” or “substituted amino”, preferably Substituted or unsubstituted alkyl (halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl) Substituted or unsubstituted aryl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, alkylsulfonyl), Substituted or unsubstituted heteroaryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl,
  • Arylalkyl “arylalkyloxy”, “alkylamino”, “arylalkylamino”, “alkylaminoalkyl”, “alkyloxycarbonylamino”, “alkylsulfonylamino”, “acylaminoalkyl”, “alkyloxy”
  • alkyl part of “alkyl”, “alkylcarbamoyl”, “heteroarylalkylcarbamoyl”, “alkyloxyimino” and “alkylcarbonyl” means the above “alkyl”.
  • aryl part of “arylalkyl”, “arylalkyloxy”, “arylamino”, “arylalkylamino”, “arylsulfonylamino”, “arylcarbonyl” and “aryloxycarbonyl” means the above “aryl” .
  • the heteroaryl part of “heteroarylsulfonylamino”, “heteroarylalkyl”, “heteroarylalkylcarbamoyl”, “heteroarylcarbonyl” and “heteroaryloxycarbonyl” means the above “heteroaryl”.
  • heterocyclyl part of “heterocyclylcarbonylamino”, “heterocyclylalkyl”, “heterocyclylcarbonyl” and “heterocyclyloxycarbonyl” means the above “heterocyclyl”.
  • the following compounds are preferable.
  • R 1 , R 2 and R 4 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl Substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulf
  • R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • Preferred is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl. More preferred is substituted aryl, substituted heteroaryl or substituted heterocyclyl.
  • At least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl consists of —C ( ⁇ O) NR 10A R 10B , —SO 2 NR 10A R 10B and —SO 2 —R 10C More preferably, it is a group selected from the group.
  • the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is further substituted with another substituent or a group selected from the above group. It may be.
  • R 3 include the following. Preferably, the following are mentioned. More preferably, the following are mentioned.
  • R 10A and R 10B are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, or R 10A and R 10B together with the adjacent nitrogen atom form a substituted or unsubstituted ring. It may be.
  • R 10A and R 10B together with the adjacent nitrogen atom form a substituted or unsubstituted ring. Examples of the ring formed by R 10A and R 10B together with the adjacent nitrogen atom include the following.
  • R 10C is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • Preferred is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl.
  • R 10D is hydrogen or substituted or unsubstituted alkyl, preferably hydrogen.
  • Y 1 is —C (R 7 ) (R 7A ) — or —O—, preferably —O—.
  • Y 2 is —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) — or —C (R 6 ) (R 6A ) —.
  • Preferred is —C (R 6 ) (R 6A ) —.
  • R 5 , R 5A , R 6 , R 6A , R 7 and R 7A are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or
  • Examples of the ring formed by R 6 and R 6A together with adjacent carbon atoms include 3 to 15 saturated or unsaturated hydrocarbon rings, oxygen atoms, sulfur atoms, and / or nitrogen atoms. It means a saturated or unsaturated heterocycle containing 1 to 4 rings in the ring.
  • Non-aromatic rings are preferred, and examples of such rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and oxygen and sulfur atoms.
  • / or a saturated or unsaturated heterocycle containing 1 to 4 nitrogen atoms in the hydrocarbon ring Preferably, the following are mentioned. More preferably, the following are mentioned.
  • R 6 and R 6A are halogen or substituted or unsubstituted alkyl
  • R 6 and R 6A are preferably fluorine.
  • R 6 and R 6A are halogen or substituted or unsubstituted alkyl, and in particular, R 6 and R 6A It is preferable that one of these is substituted or unsubstituted alkyl and the other is hydrogen.
  • R 6 and R 6A When at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl, the other is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Substituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted
  • R 8 is cyano, Formula:-(CR 8A R 8B ) p-R 8C wherein R 8A is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, and R 8B is independently And hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer of 0 to 3, and R 8C is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.), Formula: — (CR 8A R 8B ) pC ( ⁇ O) OR 8D (wherein R 8A , R 8B and p are as defined above, and R 8D is substituted or unsubstituted alkyl,
  • R 8A , R 8B and p are as defined above, and R 8G is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by Formula: —S ( ⁇ O) q—R 8H where R 8H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted
  • -(CR 8A R 8B ) p- has the same meaning as- (C (R 8A ) (R 8B )) p-.
  • Each R 8A is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, preferably hydrogen.
  • Each R 8B is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, preferably hydrogen.
  • P is an integer of 0 to 3, preferably 0 or 1, more preferably 0.
  • R 8C is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • Preferred is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. More preferably, it is substituted or unsubstituted heteroaryl, for example, the following are mentioned. Preferably, the following are mentioned. The following are particularly preferable.
  • R 8D is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl. Preferably, it is substituted or unsubstituted alkyl.
  • R 8E and R 8F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8G is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • R 8H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl. Preferably, it is substituted or unsubstituted alkyl.
  • Q is 1 or 2, preferably 2.
  • R 8I and R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
  • M and n are each independently 0, 1 or 2.
  • m is 1 and n is 1.
  • R is an integer from 0 to 12, preferably an integer from 0 to 3. More preferably, it is 0.
  • Each R 9 is independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl.
  • r is 2 or more, two R 9 bonded to the same carbon atom may be combined to form oxo and / or two R 9 bonded to different carbon atoms are May be combined with the carbon atom to which is bonded to form a substituted or unsubstituted ring.
  • R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
  • substituent in “a ring formed by r 9 having two or more R 9 bonded to different carbon atoms together with the carbon atom to which they are bonded” include, for example, carboxy, Halogen, alkyl halide (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3 ), nitro, nitroso, cyano, alkyl (eg, methyl, ethyl, isopropyl, tert-butyl), alkenyl (eg, vinyl), Alkynyl (eg: ethynyl), cycloalkyl (eg: cyclopropyl), cycloalkylalkyl (eg: cyclohexylmethyl), cycloalkenyl (eg
  • Ring A is (Here, R 1 , R 2 , R 3A and R 4 are as defined above.) It is. Preferably, (Here, R 1 , R 2 , R 3A and R 4 are as defined above.) It is. More preferably, (Here, R 1 , R 3A and R 4 are as defined above.) It is.
  • R 3A is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted Or unsubstituted heterocyclyloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or un
  • substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl More preferred is substituted aryl, substituted heteroaryl or substituted heterocyclyl.
  • At least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl consists of —C ( ⁇ O) NR 10A R 10B , —SO 2 NR 10A R 10B and —SO 2 —R 10C More preferably, it is a group selected from the group.
  • the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is further substituted with another substituent or a group selected from the above group. It may be.
  • R 3A include the following. Preferably, the following are mentioned. More preferably, the following are mentioned.
  • Y 3 is —C (R 7 ) (R 7A ) —, —C ( ⁇ O) — or —O—, preferably —O—.
  • -C (R 5) R 5A) -C (R 6) (R 6A) - and -O-C (R 6) ( R 6A) - -C in (R 6) (R 6A) -
  • This carbon atom shall be bonded to a spiro carbon atom.
  • R 6 and R 6A are halogen or substituted or unsubstituted alkyl
  • R 6 and R 6A are preferably fluorine.
  • R 6 and R 6A are halogen or substituted or unsubstituted alkyl, and in particular, R 6 and R 6A It is preferable that one of these is substituted or unsubstituted alkyl and the other is hydrogen.
  • R 6 and R 6A When at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl, the other is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Substituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted
  • One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) and formula (II) of the present invention may be replaced with hydrogen, carbon and / or other isotopes, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compounds of formula (I) and formula (II) also include compounds substituted with such isotopes.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compounds represented by formula (I) and formula (II).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • Radiolabeled compounds of the compounds represented by formula (I) and formula (II) can be prepared by methods well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
  • Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and strontium salt; metal salts such as beryllium salt, magnesium salt, zinc salt and transition metal salt; ammonium salt An aliphatic amine salt such as a trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; Aralkylamine salts such as salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltols Examples include quaternary am
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Acidic amino acids such as aspartate and glutamate are included.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate,
  • Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate
  • sulfonates such as methanesulfonate, isethionate, benz
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate.
  • examples of the hydrate include monohydrate, dihydrate and the like.
  • the compounds represented by the formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof may form solvates (for example, hydrates and the like) and / or crystalline polymorphs.
  • the present invention also encompasses such various solvates and polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compounds represented by formula (I) and formula (II).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) and the formula (II) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) and the formula (II) or a pharmaceutically acceptable salt thereof is left in the air, it absorbs moisture and adsorbs water or forms a hydrate. There is a case.
  • the crystalline polymorphs may be formed by recrystallizing the compounds represented by the formulas (I) and (II) or pharmaceutically acceptable salts thereof.
  • the compounds represented by the formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is hydrolyzed by a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I) or formula (II), gastric acid, etc.
  • the compound etc. which are converted into the compound shown by Formula (I) or Formula (II) are included.
  • the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • the compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate acid anhydride examples include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl chloride, a suitable sulfonyl anhydride and mixed anhydride, or by reacting with a condensing agent.
  • agonist means that the compound of the present invention has agonist activity (activation effect) on the GPR119 receptor.
  • pharmaceutically acceptable means not prophylactically or therapeutically harmful.
  • the general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the compound represented by the formula (I-1) can be synthesized as follows. (In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (I′-1) may be a known compound or a compound derived from a known compound by a conventional method. “Hal” means halogen, “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc.
  • Ms is a methanesulfonyl group
  • Ts represents a p-toluenesulfonyl group
  • Tf represents a trifluoromethanesulfonyl group
  • Ns represents an orthonitrobenzenesulfonyl group
  • PG represents a protecting group, and examples of the protecting group include tert-butoxycarbonyl or benzyl.
  • Reaction solvents include N, N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated carbon Hydrogen (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.) , Ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water and
  • the second step is a step for producing a compound represented by the formula (I′-4) by reducing a compound represented by the formula (I′-3).
  • the solvent the solvent described in Step 1 can be used.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • sodium borohydride or the like can be used.
  • the reaction may be performed at 0 to 60 ° C., preferably 0 ° C. to room temperature for 0.5 to 12 hours.
  • the third step is a step for producing a compound represented by the formula (I′-5) by reducing a compound represented by the formula (I′-4). For example, it can be obtained by reacting with triethylsilane in trifluoroacetic acid. The reaction may be performed at 0 to 80 ° C., preferably 0 ° C. to room temperature for 0.5 to 24 hours.
  • the deprotection reaction of the protecting group is known and can be carried out, for example, by the method described in Protective Groups in Organic synthesis, 2nd edition (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1991). .
  • the solvent described in the first step can be used as the solvent.
  • the reaction solvent the solvent described in Step 1 can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ether Eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles eg, acetonitrile, etc.
  • alcohols eg, methanol, ethanol, t-butanol, etc.
  • the base examples include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides eg, sodium hydride
  • metal hydroxides eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide
  • metal carbonates eg, sodium carbonate
  • Calcium carbonate calcium carbonate
  • a metal carbonate eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction may be performed at 0 to 150 ° C. for 0.5 to 48 hours.
  • Examples of the compound represented by the formula: LG-R 8 include benzoyl chloride and the like.
  • N, N-dimethylformamide, dimethylacetamide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) or ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) are used.
  • the base the base described in Step 5 can be used.
  • a metal carbonate eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • an organic amine eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction is used in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.)
  • a palladium catalyst eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.
  • a phosphine ligand eg PPh 3 , BINAP etc.
  • the reaction may be performed for 0.5 to 12 hours at a temperature at which the solvent to be refluxed.
  • the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour.
  • the solvent described above can be used as the solvent.
  • Examples of the compound represented by the formula: R 1 —B (OH) 2 include 4- (methoxycarbonylamino) phenylbor
  • the compound represented by the formula (I-2) can be synthesized as follows. Wherein each symbol is as defined above, and the compound represented by the formula (I′-8) may be a known compound or a compound derived from a known compound by a conventional method.
  • “Ak” means alkyl having 1 to 3 carbon atoms
  • “Hal” means halogen
  • “LG” means leaving group, and examples thereof include halogen, —OMs, —OTs, —OTf, —ONs and the like.
  • Ms represents a methanesulfonyl group
  • Ts represents a paratoluenesulfonyl group
  • Tf represents a trifluoromethanesulfonyl group
  • Ns represents an orthonitrobenzenesulfonyl group
  • PG represents a protecting group
  • the protecting group include tert-butoxycarbonyl and benzyl.
  • the eighth step is a step of producing a compound represented by the formula (I'-11) from a compound represented by the formula (I'-10). It may be performed in a strong acid such as hydrobromic acid. The reaction may be performed at room temperature to 110 ° C. for 0.5 to 24 hours.
  • the ninth step is a step for producing a compound represented by the formula (I'-12) by deprotecting the compound represented by the formula (I'-11). What is necessary is just to carry out like the said 4th process.
  • a compound represented by the tenth step formula (I'-12), formula: and a compound represented by LG-R 8 is reacted, to produce a compound represented by the formula (I'-13). What is necessary is just to carry out like the said 5th process.
  • a compound in which Y 3 is —O— and Y 4 is —C (R 5 ) (R 5A ) —O— or —O— can be synthesized as follows. it can.
  • each symbol is as defined above, and the compound represented by the formula (II′-1) may be a known compound or a compound derived from a known compound by a conventional method.
  • LG means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc.
  • Ms is a methanesulfonyl group
  • Ts is a paratoluenesulfonyl group.
  • Tf represents a trifluoromethanesulfonyl group
  • Ns represents an orthonitrobenzenesulfonyl group
  • PG represents a protecting group
  • examples of the protecting group include tert-butoxycarbonyl and benzyl.
  • Twelfth step is a step of producing a compound represented by the formula (II'-2) by reacting a compound represented by the formula (II'-1) with a compound represented by the formula: (I'-2) .
  • a compound represented by the formula (II′-1) a commercially available compound can be used, or it can be produced by performing a well-known organic synthesis reaction.
  • a compound represented by formula (II′-1) having such a substituent on ring A may be used. Such a substituent may be introduced into the ring A in the middle of the 12th to 14th steps, or after introduction to the compound represented by the formula (II-1).
  • the solvent described in Step 1 can be used.
  • aromatic hydrocarbons eg, toluene, benzene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • the reaction may be performed at a temperature at which the solvent to be used is refluxed for 0.5 to 24 hours.
  • the reaction is preferably carried out in the presence of an acid catalyst such as p-toluenesulfonic acid monohydrate.
  • an acid catalyst such as p-toluenesulfonic acid monohydrate.
  • Examples of the compound represented by the formula: (I′-2) include N-carbethoxy-4-piperidone.
  • Thirteenth step is a step of producing a compound represented by the formula (II'-3) by deprotecting the compound represented by the formula (II'-2). What is necessary is just to carry out like the said 4th process.
  • the compound represented by the formula (II-2) can be synthesized as follows.
  • the compound represented by the formula (II′-4) a commercially available compound can be used, or it can be produced by performing a well-known organic synthesis reaction.
  • a compound in which Y 3 is —C (R 7 ) (R 7A ) — can be synthesized with reference to Example 37-40.
  • the various substituents of the compound of the present invention are (1) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry (2) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry II (3) RODD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYLIC COMPOUNDS etc.
  • the compound of the present invention has excellent GPR119 agonist activity. Therefore, it can be used for the treatment or prevention of diseases such as type I diabetes, type II diabetes, insulin resistance, metabolic diseases, hyperglycemia and / or obesity. In particular, it is useful in the treatment or prevention of type I diabetes and type II diabetes.
  • the compound used in the present invention can be administered orally or parenterally.
  • the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can be used also as any dosage form.
  • the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used.
  • Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent.
  • the preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
  • the dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary.
  • parenteral administration In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.
  • Administration of another therapeutic agent for diabetes to a diabetic patient treated with a compound of formula (I) or formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof How to treat diabetes.
  • a method for treating diabetes comprising administering another therapeutic agent for diabetes in combination with a compound represented by formula (I) or formula (II), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • anti-diabetic drugs are not particularly limited as long as they have anti-diabetic effects, such as insulin secretagogues (for example, sulfonylurea (SU) drugs, fast-acting insulin secretagogues, phenylalanine derivative drugs), biguanides Drugs, insulin sensitizers (eg thiazolidinedione derivatives), ⁇ -glucosidase inhibitors, insulin preparations, DPP-IV inhibitors, GLP-1 receptor agonists, type 2 sodium-dependent glucose transporter (SGLT2) inhibitors, etc. Is mentioned.
  • insulin secretagogues for example, sulfonylurea (SU) drugs, fast-acting insulin secretagogues, phenylalanine derivative drugs
  • biguanides Drugs eg thiazolidinedione derivatives
  • ⁇ -glucosidase inhibitors eg thiazolidinedione derivatives
  • insulin preparations eg thiazolidinedione derivative
  • method C Shim-pack XR-ODS 50Lx3.0 (manufactured by Shimazu) was used for the measurement, and a straight line of acetonitrile / water (formic acid 0.1%) 10:90 to 100: 0/3 min at a flow rate of 1.6 ml / min. Measured with a gradient.
  • method E Use Gemini-NX 5 ⁇ m C18 110A, 50x4.6mm (manufactured by Phenomenex) for measurement, and apply a linear gradient of methanol / water (ammonium carbonate 10 mM) 5:95 to 100: 0 / 3.5 min at a flow rate of 3 ml / min. Measured.
  • method F Use Gemini-NX 5 ⁇ m C18 110A, 50x4.6mm (manufactured by Phenomenex) for measurement, and apply a linear gradient of acetonitrile / water (formic acid 0.1%) 5:95 to 100: 0 / 3.5 min at a flow rate of 3 ml / min. Measured.
  • method G ACQUITY UPLC (R) BEH C18 (1.7 ⁇ m id 2.1x50mm) (Waters) is used for the measurement.
  • Acetonitrile / water (ammonium carbonate 10 mM) at a flow rate of 0.8 ml / min 5:95 to 100: 0 / 3.5 min linear Measured with a gradient method H: ACQUITY UPLC® BE C18 (1.7 ⁇ m i.d. 2.1 ⁇ 50 mm) (Waters) was used for the measurement, and acetonitrile / water (formic acid 0.1%) 10:90 to 100: 0 / 3.5 at a flow rate of 0.8 ml / min. Measured with a linear gradient of minutes.
  • the meaning of each term in an Example is as follows.
  • HATU 2- (1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate
  • BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl)
  • IBX 2-iodoxybenzoic acid
  • 1-Boc-4-piperidone 1-tert-butoxycarbonyl-4-piperidone
  • aqueous sodium hydroxide solution (18.7 ml, 112 mmol) was added to a solution of compound 2 (5.0 g, 14.0 mmol) in ethanol (75 ml), and the mixture was heated to reflux for 4 hours.
  • the solvent was distilled off, ethyl acetate was added, and the mixture was washed with water and saturated brine in this order. It dried with magnesium sulfate and the solvent was distilled off and the compound 3 (3.98 g, 100%) was obtained.
  • Step 3 To a solution of compound 3 (3.98 g, 14.0 mmol) in tetrahydrofuran (40 ml) was added triethylamine (3.88 ml, 28.0 mmol) and benzyl chloroformate (1.99 ml, 14.0 mmol) under ice-cooling for 30 minutes. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 4 (4.71 g, 80%).
  • Step 5 To a solution of compound (I-1-1) (4.1 g, 8.43 mmol) in methanol (80 ml) was added 10% palladium carbon (410 mg), and the mixture was stirred under a hydrogen gas stream for 2 hours. The catalyst was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 5 (2.93 g, 99%).
  • Step 6 Pyrazine-2-carboxylic acid (16.9 mg, 0.136 mmol) was added to a solution of HATU (56.1 mg, 0.148 mmol) in dimethylacetamide (400 ⁇ l), triethylamine (20.5 ⁇ l, 0.148 mmol), compound 5 (40 mg, 0.113 mmol) in dimethylacetamide (400 ⁇ l) was added and stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-2) (26.5 mg, 51.1%).
  • Step 1 To a solution of compound 3 (3.1 g, 10.9 mmol) in tetrahydrofuran (31 ml) was added triethylamine (2.27 ml, 16.4 mmol) and benzoyl chloride (1.39 ml, 12.0 mmol) under ice-cooling, and 30 minutes at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 6 (4.05 g, 96%).
  • Step 1 To a solution of 4-bromocatechol 7 (0.5 g, 2.65 mmol) in toluene (8 ml) was added N-carbethoxy-4-piperidone (0.52 ml, 3.44 mmol), p-toluenesulfonic acid monohydrate ( 100 mg, 0.529 mmol) was added, and the mixture was heated to reflux for 4 hours. 2N Aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 8 (280 mg, 31%).
  • Step 4 Compound 10 (60 mg) in a dimethylformamide (0.7 ml) solution, 4- (methylsulfonyl) phenylboronic acid (42 mg, 0.211 mmol), 2M aqueous sodium carbonate solution (243 ⁇ l, 0.486 mmol), tetrakis ( Triphenylphosphine) palladium (19 mg, 0.016 mmol) was added, and the reaction was performed at 105 ° C. for 15 minutes under microwave irradiation. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate.
  • Step 4 To a solution of compound 14 (500 mg, 1.77 mmol) in methylene chloride (5 ml) is added triethylamine (368 ⁇ l, 2.66 mmol) and benzoyl chloride (226 ⁇ l, 1.95 mmol) under ice cooling, and the mixture is stirred for 1 hour. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 15 (490 mg, 72%).
  • Step 5 To a solution of compound 15 (80 mg, 0.207 mmol) in ethanol (1 ml), 4- (methoxycarbonylamino) phenylboronic acid (48.5 mg, 0.249 mmol), 2M aqueous sodium carbonate solution (207 ⁇ l, 0.414 mmol), Tetrakis (triphenylphosphine) palladium (23.9 mg, 0.021 mmol) was added, and the reaction was performed at 120 ° C. for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • the compounds I-1-145, I-1-146, I-1-147, I-1-148, I-1-149, I-1-150, I-1-155, I-1 -156, I-1-157, I-1-158, I-1-159, I-1-163, I-1-210, I-1-211, I-1-212, I-1-213 I-214, I-215, I-218, I-219, I-1-220, I-221, I-122, I-1-223, I -1-224, I-1-225, I-1-226, I-1-227, I-1-228, I-1-229, I-1-230, I-1-232, I-1 -233, I-I-235, I-I-236, I-I-237, I-I-238, I-I-240 and I-I-241 were synthesized.
  • Step 1 Compound 16 (200 mg, 0.523 mmol) to toluene (3 ml), 1-methylsulfonylpiperazine (86 mg, 0.523 mmol), Pd 2 (dba) 3 (24 mg, 0.026 mmol), sodium tert-butoxide (101 mg, 1.05 mmol) and BINAP (33 mg, 0.052 mmol) were added and stirred at 100 ° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.
  • the compounds I-1-169, I-1-170, I-1-171, I-1-172, I-1-183, I-1-190, I-1-191, I-1 -210, I-1-211, I-1-212, I-1-213, I-1-214, I-1-215, I-1-218, I-1-219, I-1-220 I-1-221, I-1-222, I-1-223, I-1-224 and I-1-225 were synthesized.
  • Step 1 To a solution of compound 14 (500 mg, 1.77 mmol) in dimethylacetamide (5 ml) was added potassium carbonate (490 mg, 3.54 mmol) and 2-chloro-5-ethylpyrimidine (300 mg, 2.12 mmol). Stir at 4 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 18 (420 mg, 61%).
  • Step 3 Compound 21 obtained in the previous step was dissolved in dimethylformamide (56 ml), potassium carbonate (5.38 g, 38.9 mmol) and morpholine-4-carbonyl chloride (3.1 ml, 25.9 mmol) were added, and at room temperature. Stir for 4 days. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 22 (1.6 g, 44%).
  • Step 6 To a solution of compound 24 obtained in the previous step in ethanol (120 ml) was added 10% palladium carbon (120 mg), and the mixture was stirred under a hydrogen gas stream for 3 hours. The catalyst was filtered off and the solvent was distilled off to obtain compound (I-1-14) (1163 mg).
  • Step 7 4N Hydrochloric acid-ethyl acetate solution (4.0 ml, 16.0 mmol) was added to compound (I-1-14) (168 mg, 0.309 mmol), and the mixture was stirred at room temperature for 1 day. The solvent was distilled off to obtain Compound 25. Used in the next reaction without purification.
  • Step 8 Methylene chloride (5 ml) and triethylamine (128 ⁇ l, 0.924 mmol) were added to the compound 25 obtained in the previous step, cooled to 0 ° C., and isopropyl chloroformate (42 ⁇ l, 0.370 mmol) was added dropwise. .
  • Step 3 To a solution of compound 28 (2.75 g, 12.3 mmol) in methylene chloride (30 ml) was added triethylamine (3.41 ml, 24.6 mmol) and neopentyl chloroformate (2.22 g, 14.7 mmol) under ice-cooling. Stir for 1.5 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 29 (3.65 g, 88%).
  • Step 4 Compound 29 (80 mg, 0.237 mmol) was dissolved in dimethylacetamide (2 ml), water (0.2 ml), 4- (methylsulfonyl) phenylboronic acid (57 mg, 0.284 mmol), PdCl 2 (dppf ) (17.3 mg, 0.024 mmol) and potassium carbonate (98 mg, 0.710 mmol) were added, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.
  • Step 1 Compound 29 (2.1 g, 6.22 mmol) was dissolved in dimethylacetamide (20 ml), water (2 ml), 4- (tert-butoxycarbonyl) phenylboronic acid (2.07 g, 9.32 mmol), PdCl 2 (dtbpf) (203 mg, 0.311 mmol) and potassium carbonate (1.71 g, 12.43 mmol) were added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.
  • Second Step Compound 30 (0.95 g, 1.98 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (3.05 ml, 39.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration. Compound 31 (0.77 g, 92%) was obtained after drying.
  • Step 3 Compound 31 (50 mg, 0.118 mmol) in dimethylacetamide (2 ml) was added to HATU (67.3 mg, 0.177 mmol), triethylamine (82 ⁇ l, 0.590 mmol), 4-methoxypiperidine (20.4 mg, 0.177 mmol). And stirred at room temperature for 80 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-17) (45 mg, 73%).
  • Step 2 Compound 32 (50 mg, 0.127 mmol) in dimethylacetamide (2 ml) was added to HATU (72.3 mg, 0.190 mmol), triethylamine (53 ⁇ l, 0.380 mmol), 2-ethoxyacetic acid (19.8 mg, 0.190 mmol). And stirred at room temperature for 50 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.
  • Step 1 To a solution of compound 32 (50 mg, 0.127 mmol) in dichloromethane (2 ml) was added triethylamine (53 ⁇ l, 0.380 mmol) and methanesulfonyl chloride (10.9 ⁇ l, 0.139 mmol) under ice-cooling. Stir for 30 minutes. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-20) (44 mg, 74%).
  • Step 2 Compound 36 (50.3 mg, 0.128 mmol) in dimethylformamide (1.5 ml) was added potassium carbonate (55.2 mg, 0.399 mmol), 2-chloro-5- (trifluoromethyl) pyrimidine (40.2 mg, 0.220 mmol). And stirred at 80 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-23) (40.4 mg, 59%).
  • Step 1 (Z) -N'-hydroxy-2-methylpropanimidamide (50.2 mg, 0.491 mmol), chloride in a suspension of compound (I-1-24) (151.2 mg, 0.361 mmol) in ethyl acetate (4 ml) Zinc (0.5 M / L tetrahydrofuran solution, 867 ⁇ l, 0.434 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, the residue was washed with ether, ethanol (4 ml) and concentrated hydrochloric acid (1 ml) were added, and the mixture was stirred at 60 ° C. for 4 hr.
  • Step 1 Triethylamine (45 ⁇ l, 0.325 mmol) and tert-butylacetyl chloride (18 ⁇ l, 0.130 mmol) were added to a suspension of compound 36 (43.5 mg, 0.111 mmol) in dichloromethane (1 ml), and the mixture was stirred at room temperature for 1.5 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain compound (I-1-27) (39.0 mg, 72%).
  • Step 1 Triethylamine (54 ⁇ l, 0.391 mmol) and tert-butyl isocyanate (18 ⁇ l, 0.154 mmol) are added to a suspension of compound 36 (51.3 mg, 0.130 mmol) in tetrahydrofuran (1 ml) and stirred at room temperature for 2 hours. did. The crystals were collected by filtration and washed with ethyl acetate. After drying, compound (I-1-28) (33.2 mg, 52%) was obtained.
  • Step 1 Triethylamine (59 ⁇ l, 0.426 mmol) and 2,2-dimethylpropane-1-sulfonyl chloride (38.4 mg, 0.225 mmol) were added to a suspension of compound 36 (56.1 mg, 0.143 mmol) in dichloromethane (1 ml). The mixture was further stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-29) (32.7 mg, 44%).
  • Step 3 To a solution of compound 39 (2.0 g, 5.03 mmol) in tetrahydrofuran (40 ml) was added 4- (benzyloxycarbonylamino) phenylboronic acid (2.73 g, 10.1 mmol), 2M aqueous sodium carbonate solution (10.1 ml, 20.2 mmol). , Tetrakis (triphenylphosphine) palladium (582 mg, 0.503 mmol) was added, and the mixture was heated to reflux for 4 hours.
  • Step 6 Using compound 42 obtained in the previous step, the reaction was carried out in the same manner as in Step 6 of Example 13 to obtain compound 43 (1.55 g, 58%).
  • Step 7 To a solution of compound 43 (1.5 g, 2.83 mmol) in methanol (10 ml) was added 40% aqueous potassium hydroxide solution (10 ml), and the mixture was heated to reflux for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 44 (1.1 g, 98%). Used in the next reaction without purification.
  • Step 1 Add 1,1'-carbonyldiimidazole (1.53 g, 9.45 mmol) to a solution of 5-bromo-2-hydroxynicotinic acid 45 (2.0 g, 9.17 mmol) in tetrahydrofuran (20 ml) and heat to reflux for 8 hours. Went. After cooling, the precipitate was collected by filtration and washed with diethyl ether. The mixture was suspended in dioxane (30 ml), O, N-dimethylhydroxyamine (1.79 g, 18.4 mmol) and triethylamine (2.8 ml, 20.2 mmol) were added, and the mixture was heated to reflux for 9 hours.
  • Second Step To a tetrahydrofuran (37 ml) solution of Compound 46 obtained in the previous step, methylmagnesium bromide (3M diethyl ether solution, 7.1 ml, 21.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 day. The reaction mixture was neutralized with 6N aqueous hydrochloric acid and extracted with ethyl acetate.
  • Step 6 Using compound 50 obtained in the previous step, the reaction was carried out in the same manner as in Step 5 of Example 32 to obtain compound 51. Used in the next reaction without purification.
  • Step 7 Using compound 51 obtained in the previous step, the reaction was carried out in the same manner as in Step 6 of Example 13 to obtain compound 52 (865 mg, 65%).
  • Eighth Step Using compound 52 (200 mg, 0.378 mmol), the reaction was carried out in the same manner as in the seventh step of Example 32 to obtain compound 53. Used in the next reaction without purification.
  • Ninth Step Using compound 53 obtained in the previous step, the reaction was carried out in the same manner as in the third step of Example 13 to obtain compound (I-1-35) (77 mg, 40%).
  • Second Step n-Butyllithium (1.67 M n-hexane solution, 26 ml, 43.3 mmol) was added dropwise to a solution of diisopropylamine (6.1 ml, 43.3 mmol) in tetrahydrofuran (35 ml) under ice cooling. The mixture was stirred at the same temperature for 1 hour, cooled to ⁇ 60 ° C., and a solution of compound 55 (7.86 g, 36.0 mmol) in tetrahydrofuran (35 ml) was added dropwise. After stirring at ⁇ 60 ° C.
  • Step 5 Add 1-Boc-4-piperidone (6.13 g, 30.8 mmol) and pyrrolidine (3.3 ml, 40.0 mmol) to a solution of compound 58 (6.65 g, 30.8 mmol) in methanol (100 ml) and heat to reflux for 20 minutes. Went. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 59 (11.18 g, 91%).
  • Step 6 To a solution of compound 59 (1.0 g, 2.52 mmol) in dimethoxyethane (10 ml) was added 4-methylsulfonylphenylboronic acid (604 mg, 3.02 mmol), 2M aqueous sodium carbonate solution (3.78 ml, 7.55 mmol), tetrakis ( Triphenylphosphine) palladium (291 mg, 0.252 mmol) was added, and the mixture was heated to reflux for 4 hours under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • Step 7 Sodium borohydride (32 mg, 0.846 mmol) was added to a solution of compound 60 (400 mg, 0.846 mmol) in ethanol (5 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 61 (334 mg, 83%).
  • Step 8 To a solution of compound 61 (100 mg, 0.211 mmol) in methylene chloride (5 ml) was added triethylamine (61 ⁇ l, 0.443 mmol) and methanesulfonyl chloride (26 ⁇ l, 0.337 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 62 (114 mg, 98%).
  • Step 9 To a solution of compound 62 (108 mg, 0.195 mmol) in ethanol (10 ml) was added 10% palladium carbon (11 mg), and the mixture was stirred under a hydrogen gas stream for 3 hours. The catalyst was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-36) (21 mg, 23%).
  • Step 1 Compound 59 (2.0 g, 5.03 mmol) in dimethoxyethane (20 ml) was added to 4-nitrophenylboronic acid (1.01 g, 6.04 mmol), 2M aqueous sodium carbonate solution (7.55 ml, 15.1 mmol), tetrakis (tri Phenylphosphine) palladium (291 mg, 0.252 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • Step 2 A solution of compound 63 (400 mg, 0.91 mmol) in tetrahydrofuran (4 ml) was cooled to ⁇ 78 ° C., lithium hexamethyldisilazane (1.0 M tetrahydrofuran solution, 3.64 ml, 3.64 mmol) was added, and 0 ° C. Stir for 2 hours.
  • Step 3 to Step 4 Using compound 64 (219 mg, 0.461 mmol), the reaction was carried out in the same manner as in Step 7 to Step 8 of Example 21 to obtain compound 66 (144 mg, 56%). .
  • Step 5 Using compound 66 (128 mg, 0.230 mmol), the reaction was carried out in the same manner as in Step 9 of Example 21 to obtain compound 67 (99 mg, 100%).
  • Step 6 To a solution of compound 67 (99 mg, 0.229 mmol) in tetrahydrofuran (5 ml) was added pyridine (56 ⁇ l, 0.688 mmol) and phenyl chloroformate (32 ⁇ l, 0.252 mmol), and the mixture was stirred at room temperature for 45 minutes.
  • Step 7 To a solution of compound (I-1-37) (40 mg, 0.073 mmol) in ethyl acetate (2 ml) was added 4N hydrochloric acid-ethyl acetate solution (2 ml, 8.0 mmol), and the mixture was stirred at room temperature for 2 hours. Diluted with diisopropyl ether, and the crystals were collected by filtration. Drying gave Compound 68 (36 mg, 95%).
  • Step 8 To a solution of compound 68 (36 mg, 0.070 mmol) in methylene chloride (5 ml) was added triethylamine (41 ⁇ l, 0.294 mmol) and neopentyl chloroformate (14 ⁇ l, 0.095 mmol), and the mixture was stirred for 0.5 hour. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-38) (26 mg, 63%).
  • Step 4 To a solution of compound 72 (2.9 g, 7.36 mmol) in dimethylacetamide (20 ml), add sodium hydride (60% oil suspension; 353 mg, 8.83 mmol) under ice cooling, and stir at 150 ° C. for 18 hours did. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate.
  • Step 5 To a solution of compound 73 (800 mg, 2.14 mmol) in dioxane (20 ml), 4-aminophenylboronic acid pinacol ester (656 mg, 2.99 mmol), 2M aqueous sodium carbonate solution (2.14 ml, 4.18 mmol), tetrakis ( Triphenylphosphine) palladium (123 mg, 0.107 mmol) was added, and the mixture was heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Step 7 Chloroform (10 ml) and 1-chloroethyl chloroformate (229 mg, 1.60 mmol) were added to compound 75 (400 mg, 0.801 mmol), and the mixture was heated to reflux. Thereafter, the solvent was distilled off, methanol (10 ml) was added, and the mixture was further heated to reflux for 2 hours. After completion of the reaction, the solvent was distilled off, ethyl acetate was added, and the precipitate was collected by filtration. Drying gave Compound 76 (255 mg, 71%).
  • Step 8 To compound 76 (100 mg, 0.224 mmol) was added methylene chloride (2 ml), triethylamine (93 ⁇ l, 0.673 mmol), di-tert-butyl dicarbonate (73.4 mg, 0.336 mmol), and the mixture was stirred for 20 minutes. . Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-39) (70 mg, 61%).
  • Step 3 A suspension of lithium aluminum hydride (126 mg, 3.31 mmol) in tetrahydrofuran (10 ml) was cooled to ⁇ 10 ° C., and a solution of compound 84 (894 mg, 2.36 mmol) in tetrahydrofuran (10 ml) was added dropwise. . The mixture was stirred at 0 ° C. for 1 hour, and then stirred at room temperature for 9 days. After cooling to 0 ° C., water (2 ml) was added and stirred for 1 hour.
  • Step 5 Using compound 86 (290 mg, 0.754 mmol), the reaction was carried out in the same manner as in Step 6 of Example 36 to obtain compound 87 (141 mg, 15%).
  • Step 6 Using compound 87 (141 mg, 0.284 mmol), the reaction was carried out in the same manner as in Step 7 of Example 36 to obtain compound 88. Used in the next reaction without purification.
  • Step 7 Using compound 88 obtained in the previous step, the reaction was carried out in the same manner as in Step 8 of Example 36 to obtain compound (I-1-41) (14 mg, 10%).
  • Step 3 Compound 90 obtained in the previous step was dissolved in acetonitrile (50 ml), diisopropylamine (3.9 ml, 22.3 mmol) and benzyl bromide (1.8 ml, 14.9 mmol) were added under ice cooling, and the mixture was stirred for 1 hour. did.
  • Step 6 Using the compound 93 (1.0 g, 2.60 mmol) obtained in the previous step, the reaction was carried out in the same manner as in the second step of Example 5 to obtain the compound 94. Used in the next reaction without purification.
  • Step 7 Using compound 94 obtained in the previous step, reaction was performed in the same manner as in step 3 of Example 5 to obtain compound 95. Used in the next reaction without purification.
  • Eighth Step Using compound 95 obtained in the previous step, the reaction was carried out in the same manner as in the fifth step of Example 36 to obtain compound 96. Used in the next reaction without purification.
  • Ninth Step Using compound 96 obtained in the previous step the reaction was carried out in the same manner as in the sixth step of Example 36 to obtain compound 97. Used in the next reaction without purification.
  • Step 10 Using compound 97 obtained in the previous step, reaction was performed in the same manner as in step 5 of Example 1 to obtain compound 98. Used in the next reaction without purification.
  • Step 11 Using compound 98 obtained in the previous step, the reaction was carried out in the same manner as in Step 8 of Example 36 to obtain compound (I-1-42) (216.5 mg, 17%).
  • Step 2 Triethylamine (676 ⁇ l, 4.87 mmol) and neopentyl chloroformate (293 ⁇ l, 1.95 mmol) were added to a suspension of compound 100 obtained in the previous step in methylene chloride (5 ml) and stirred for 16.5 hours. did. A 2N aqueous hydrochloric acid solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 101 (463 mg, 72%).
  • Ice water was added, neutralized with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and methylene chloride (5 ml), triethylamine (676 ⁇ l, 4.87 mmol) and neopentyl chloroformate (293 ⁇ l, 1.95 mmol) were added to the residue and stirred for 0.5 hours. A 2N aqueous hydrochloric acid solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • Step 5 To a solution of compound 103 (93 mg, 0.266 mmol) in ethanol (2 ml) was added sodium borohydride (50 mg, 0.266 mmol), and the mixture was stirred at room temperature for 50 minutes. After completion of the reaction, 2N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain Compound 104 (97 mg). Used in the next reaction without purification.
  • Step 7 To a solution of compound 105 (82 mg, 0.244 mmol) in dimethylacetamide (2 ml), 4-aminophenylboronic acid pinacol ester (80 mg, 0.366 mmol), PdCl 2 (dtbpf) (16 mg, 0.024 mmol), An aqueous potassium carbonate solution (101 mg, 0.732 mmol) and water (0.2 ml) were added, and the mixture was stirred at 90 ° C. for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • Step 8 Compound 106 (68 mg, 0.173 mmol) was dissolved in dimethylacetamide (2 ml), potassium carbonate (72 mg, 0.520 mmol) and morpholine-4-carbonyl chloride (61 ⁇ l, 0.520 mmol) were added, and room temperature was added. For 2 days. 2N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate.
  • Step 4 Compound 110 (8.5 g, 27.7 mmol) was dissolved in N, N-dimethylformamide (425 ml), phosphorus oxychloride (10.31 ml, 11.1 mmol) was added and the mixture was stirred at 50 ° C. for 4.5 hours. Stir. The mixture was cooled to 0 ° C., 15% aqueous potassium carbonate solution (230 ml) was added, and the mixture was stirred at room temperature for 10 minutes.
  • Step 5 Compound 111 (5.0 g, 15.39 mmol) was suspended in dioxane (70 ml), 4-methoxycarbonylphenylboronic acid (3.74 g, 20.78 mmol), 2 mol / L aqueous sodium carbonate solution (38.5 ml).
  • Step 6 Compound 112 (5.16 g, 12.16 mmol) was suspended in a mixture of dioxane (35 ml) and methanol (26 ml), 4 mol / L dioxane hydrochloride solution (15.2 ml) was added, and the mixture was stirred at 50 ° C. for 1 hour. Stir. The mixture was cooled to room temperature, diethyl ether (77 ml) was added, and the mixture was stirred at room temperature for 15 minutes.
  • Step 7 Compound 113 (4.54 g, 11.43 mmol) was dissolved in tetrahydrofuran (68 ml) and water (45 ml), sodium bicarbonate (3.84 g, 45.7 mmol), 2-chloro-3-trifluoromethyl. Pyrazine (90%, 2.55 g, 12.57 mmol) was added and stirred at 60 ° C. for 5 hours. After cooling to room temperature, water was added and stirred for 30 minutes.
  • Step 8 Compound 114 (5.36 g, 11.39 mmol) was suspended in a mixture of tetrahydrofuran (25 ml) and methanol (25 ml), 4 mol / L aqueous lithium hydroxide solution (15 ml) was added, and the mixture was stirred at 50 ° C. for 4 hr. did. After cooling to 0 ° C., 10% aqueous citric acid solution was added to adjust to pH 4-5, water was added, and the mixture was stirred at room temperature for 30 min.
  • Step 9 Compound 115 (4.19 g, 9.18 mmol) was suspended in N, N-dimethylformamide (80 ml), and 3-pyrrolidinol (880 mg, 10.10 mmol), 1-hydroxybenzotriazole monohydrate (1 0.55 g, 10.10 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.94 g, 10.10 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
  • Second step Compound 116 (737 mg, 1.46 mmol) is dissolved in dimethyl sulfoxide (15 ml), sodium bicarbonate (615 mg, 7.32 mmol) and pre-activated powdered molecular sieve 4A (1.5 g) are added at room temperature. , And stirred at 120 ° C. for 2.5 hours. After cooling to room temperature, ethyl acetate was added, and the mixture was filtered through celite, and the filtrate was washed with water.
  • Step 4 Compound 118 (32 mg, 0.075 mmol) was dissolved in N, N-dimethylformamide (1 ml), 3-pyrrolidinol (7.9 mg, 0.090 mmol), diisopropylethylamine (40 ⁇ l, 0.226 mmol), O -(7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (43 mg, 0.113 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate.
  • Step 5 Compound (I-2-2) (29 mg, 0.059 mmol) was suspended in a mixture of dioxane (1.2 ml) and methanol (0.6 ml), 4 mol / L dioxane hydrochloride solution (294 ⁇ l) was added, Stir at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then the operation of adding diethyl ether to the residue and concentrating under reduced pressure was repeated three times to obtain compound 119 as a crude product.
  • Step 6 Compound 119 obtained in Step 5 was dissolved in N-methylpyrrolidone (1 ml), potassium carbonate (24.4 mg, 0.176 mmol), 2-chloro-3-trifluoromethylpyrazine (11.8 mg, 0.065 mmol) and diisopropylethylamine (26 ⁇ l, 0.147 mmol) were added and stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, water was added and extracted three times with ethyl acetate. The organic layers were combined, washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 1 Compound 118 (124 mg, 0.292 mmol) was suspended in tetrahydrofuran (5.6 ml), and 1 mol / L (trimethylsilyl) methylmagnesium chloride in tetrahydrofuran (1.46 ml, 1.46 mmol) was added dropwise at 0 ° C. And stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added, the pH was adjusted to 4-5 with 10% aqueous citric acid solution, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Second Step The crude product (150 mg) of the compound 120 obtained in the first step was dissolved in tetrahydrofuran (10 ml), and a 0.5 mol / L potassium hexamethyldisilazide solution in toluene (2.34 ml, 1.17 mmol). Was added dropwise at 0 ° C. and stirred for 45 minutes. Saturated aqueous ammonium chloride solution was added, the pH was adjusted to 4-5 with 10% aqueous citric acid solution, and the mixture was extracted 3 times with ethyl acetate.
  • Step 5 Compound 124 (57 mg) was obtained as a crude product according to Step 5 of Example 42 using compound 123 (60 mg).
  • Step 6 Using the crude product of compound 124 (29 mg) obtained in Step 5, according to Step 6 of Example 42, compound (I-2-4) (22 mg, yield 66%) was obtained. .
  • Step 4 The crude product of Compound 126 (20 mg) obtained in Step 3 was dissolved in N-methylpyrrolidone (1 ml) to give 2-chloro-3-trifluoromethylpyrazine (8.3 mg, 0.046 mmol) and Diisopropylethylamine (43 ⁇ l, 0.249 mmol) was added, and the mixture was stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, water was added and extracted three times with ethyl acetate.
  • Step 5 Compound 133 (29 mg, 100%) was obtained according to the third step of Example 42 using Compound 132 (30 mg, 0.062 mmol).
  • Step 5 Compound 133 (29 mg) was dissolved in N, N-dimethylformamide (1 ml), and 2-aminoethanol (4.6 mg, 0.075 mmol), diisopropylethylamine (33 ⁇ l, 0.186 mmol), O- (7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (35.4 mg, 0.093 mmol) was added and stirred at room temperature for 30 minutes.
  • the GPR119 receptor responsiveness of this compound is determined by using the human GPR119 receptor-expressing cell line GPR119 / CHO-K1 cells prepared by introducing the human GPR119 receptor gene into CHO-K1 cells. Production of internal cAMP was measured as an index.
  • the base sequence of the gene encoding the human GPR119 receptor is described in NM_178471 (GenBank).
  • GPR119 / CHO-K1 cells grown in ⁇ -MEM medium supplemented with 10% FBS were washed once with PBS (phosphate buffered saline) ( ⁇ ), and made into a cell suspension using trypsin / EDTA.
  • HBSS Hanks' Balanced Salt Solution
  • BSA Bovine serum albumin
  • HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid
  • the compound of the present invention has a GPR119 agonist activity as shown in Test Example 1, and exhibits excellent drug efficacy.
  • the durability of the drug effect was examined by the following test.
  • Test Example 2 Oral glucose tolerance test Male C57BL / 6J mice (8-10 weeks old, CLEA Japan, Inc.), 20% hydroxypropyl- ⁇ -cyclodextrin aqueous solution in the control group at a rate of 10 mL / kg, and 20% hydroxy in the compound group A compound suspended in a propyl- ⁇ -cyclodextrin aqueous solution was orally administered at a dose of 1 to 30 mg / kg, and after 12 to 14 hours, a 2 g / kg aqueous glucose solution was orally administered.
  • the amount of change in blood glucose level from immediately before glucose administration to 120 minutes after administration was calculated as the area under the blood glucose level-time curve (AUC) by the trapezoidal method.
  • the AUC of the control group was taken as 100%, and the AUC of the compound group was calculated as the rate of change.
  • Test Example 3 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ mol / L or more was designated as (+), and the case where it was 3 ⁇ mol / L or less was designated as ( ⁇ ).
  • Test Example 4 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. Calculated.
  • Test Example 5 FAT test 20 ml of Salmonella typhimurium TA98 strain, TA100 strain frozen and stored in 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) at 37 ° C for 10 hours, Incubated before shaking.
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution each 12 ⁇ L and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L of the mixture), and cultured with shaking at 37 ° C.
  • Test Example 7 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
  • the compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%.
  • the hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
  • Test Example 8 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, HEK293 cells expressing a human ether-a-go-go related gene (hERG) channel are used in the ventricular repolarization process.
  • a fully automatic patch clamp system PatchXpress 7000A, Axon Instruments Inc.
  • the cell was held at a membrane potential of ⁇ 80 mV by the whole cell patch clamp method, a leak potential of ⁇ 50 mV was applied, and then a depolarization stimulus of +40 mV was applied.
  • the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
  • Test Example 9 Powder Solubility Test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution in each container. 200 ⁇ L of 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution was added to 1.08 g of TCA to make 100 mL) Added in increments. When the entire amount was dissolved after adding the test solution, the compound of the present invention was appropriately added. After sealing and shaking at 37 ° C.
  • the compound of the present invention was quantified using HPLC by an absolute calibration curve method.
  • Test Example 11 Fluctuation Ames Test The mutagenicity of the compounds of the present invention was evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.
  • MicroF containing 110 mL Exposure medium Biotin: 8 ⁇ g / mL, Histidine: 0.2 ⁇ g / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) Buffer).
  • the TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (under the metabolic activation conditions, 498 ⁇ L of the test bacterial solution and S9 (mix solution of 90 ⁇ L of mix) was mixed and incubated at 37 ° C.
  • Hard gelatin capsules are manufactured using the following ingredients: Dose (mg / capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate 10 Total 460mg
  • Tablets are manufactured using the following ingredients: Dose (mg / tablet) Active ingredient 250 Cellulose (microcrystal) 400 Silicon dioxide (fume) 10 Stearic acid 5 665mg total The ingredients are mixed and compressed into tablets each weighing 665 mg.
  • Aerosol solution is prepared containing the following ingredients: weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00
  • the active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to ⁇ 30 ° C. and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
  • a tablet containing 60 mg of active ingredient is prepared as follows: Active ingredient 60mg 45mg starch Microcrystalline cellulose 35mg Polyvinylpyrrolidone (10% solution in water) 4mg Sodium carboxymethyl starch 4.5mg Magnesium stearate 0.5mg Talc 1mg 150mg total The active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
  • Capsules containing 80 mg of active ingredient are prepared as follows: Active ingredient 80mg Starch 59mg Microcrystalline cellulose 59mg Magnesium stearate 2mg Total 200mg Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
  • a suppository containing 225 mg of active ingredient is prepared as follows: Active ingredient 225mg Saturated fatty acid glyceride 2000mg Total 2225mg The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
  • a suspension containing 50 mg of active ingredient is prepared as follows: Active ingredient 50mg Sodium carboxymethylcellulose 50mg Syrup 1.25ml Benzoic acid solution 0.10ml Fragrance q. v. Dye q. v. 5ml in total with purified water The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add benzoic acid solution and perfume diluted with a portion of water and stir. Then add a sufficient amount of water to the required volume.
  • the intravenous formulation is manufactured as follows: Active ingredient 100mg Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • the compound according to the present invention exhibits a GPR119 agonistic action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for type I diabetes, a therapeutic agent for type II diabetes, a therapeutic agent for insulin resistance, a therapeutic agent for metabolic diseases, a therapeutic agent for hyperglycemia, and a therapeutic agent for obesity.

Abstract

A compound represented by formula (I) (wherein X represents =C(R2)- or =N-; R1, R2 and R4 independently represent a hydrogen atom, a halogen atom, a hydroxy group or the like; R3 represents an aryl group, a heteroaryl group or the like; Y1 represents -C(R7)(R7A)- or -O-; Y2 represents -C(R5)(R5A)-C(R6)(R6A)- or -C(R6)(R6A)-; R5, R5A, R6, R6A, R7 and R7A independently represent a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group or the like; R8 represents a formula -(CR8AR8B)p-R8C or the like (wherein R8A and R8B independently represent a hydrogen atom or the like; p represents an integer of 0-3; and R8C represents an aryl group, a heteroaryl group, a cycloalkyl group or the like); m and n independently represent 0, 1 or 2; R9's independently represent a halogen atom or the like; and r represents an integer of 0-12, wherein, when r is 2 or greater, two R9's that are bound to the same carbon atom may together form an oxo), a pharmaceutically acceptable salt of the compound, or a solvate of the compound or the pharmaceutically acceptable salt.

Description

ＧＰＲ１１９アゴニスト活性を有するスピロ誘導体Spiro derivatives having GPR119 agonist activity
　本発明は、Ｇタンパク質共役受容体（G protein-coupled receptor 119、以下ＧＰＲ１１９とする。）アゴニスト活性を有し、医薬として有用な化合物に関する。 The present invention relates to a compound having a G protein-coupled receptor (hereinafter referred to as GPR119) agonist activity and useful as a medicine.
　糖尿病は、慢性的な高血糖状態を伴う疾患であり、多くの環境因子と遺伝的因子とが作用した結果生じるといわれている。血糖の主要な調整因子は、膵臓のβ細胞から分泌されるインスリンであることは古くから知られている。
　ＧＰＲ１１９は、膵臓のランゲルハンス島に発現する７回膜貫通型のＧタンパク質共役受容体（ＧＰＣＲ）である。ＧＰＲ１１９アゴニストは、細胞内のｃＡＭＰ（サイクリックアデノシン３’，５’- 一リン酸）レベルの増加を引き起こし、膵臓のβ細胞からのグルコース依存的なインスリンの分泌を促進することが報告されている。（非特許文献１および２）
　これらの知見は、ＧＰＲ１１９アゴニストの糖尿病薬としての可能性を示唆するものである。 Diabetes mellitus is a disease with a chronic hyperglycemic state, and is said to result from the action of many environmental and genetic factors. It has long been known that the main regulator of blood glucose is insulin secreted from pancreatic β cells.
GPR119 is a 7-transmembrane G protein-coupled receptor (GPCR) expressed in the islets of Langerhans in the pancreas. GPR119 agonists have been reported to cause an increase in intracellular cAMP (cyclic adenosine 3 ′, 5′-monophosphate) levels and promote glucose-dependent insulin secretion from pancreatic β-cells. . (Non-Patent Documents 1 and 2)
These findings suggest the possibility of GPR119 agonists as diabetes drugs.
　特許文献１～９には、ＧＰＲ１１９アゴニスト活性を有する種々の化合物が開示されているが、本発明化合物のようなスピロ誘導体については、そのいずれにも開示されていない。
　特許文献１０および１１には、睡眠障害に有用な化合物として、スピロクロマン誘導体およびスピロジヒドロベンゾフラン誘導体が開示されている。
　特許文献１２および１３には、高血圧症、肥満症または糖尿病等に有用な化合物として、以下のスピロクロマン誘導体が記載されている。
Figure JPOXMLDOC01-appb-C000007
　特許文献１４には、糖尿病性合併症に有用な化合物として、以下のスピロクロマン誘導体が記載されている。
Figure JPOXMLDOC01-appb-C000008
　特許文献１５には、アルツハイマーまたは糖尿病等に有用な化合物として、スピロジヒドロベンゾフラン誘導体が開示されている。
　特許文献１６には、アルツハイマー病に有用な化合物として、以下のスピロジヒドロベンゾフラン誘導体が記載されている。
Figure JPOXMLDOC01-appb-C000009
　しかし、特許文献１０～１６には、ＧＰＲ１１９アゴニスト作用については記載されていない。
Patent Documents 1 to 9 disclose various compounds having GPR119 agonist activity, but none of the spiro derivatives such as the compounds of the present invention are disclosed.
Patent Documents 10 and 11 disclose spirochroman derivatives and spirodihydrobenzofuran derivatives as compounds useful for sleep disorders.
Patent Documents 12 and 13 describe the following spirochroman derivatives as compounds useful for hypertension, obesity, diabetes, and the like.
Figure JPOXMLDOC01-appb-C000007
Patent Document 14 describes the following spirochroman derivatives as compounds useful for diabetic complications.
Figure JPOXMLDOC01-appb-C000008
Patent Document 15 discloses a spirodihydrobenzofuran derivative as a compound useful for Alzheimer or diabetes.
Patent Document 16 describes the following spirodihydrobenzofuran derivatives as compounds useful for Alzheimer's disease.
Figure JPOXMLDOC01-appb-C000009
However, Patent Documents 10 to 16 do not describe GPR119 agonistic action.
国際公開第２００９／０５５３３１号パンフレットInternational Publication No. 2009/055331 Pamphlet 国際公開第２０１０／００９２０８号パンフレットInternational Publication No. 2010/009208 Pamphlet 国際公開第２００８／０３３４６４号パンフレットInternational Publication No. 2008/033464 Pamphlet 国際公開第２００８／０３３４６５号パンフレットInternational Publication No. 2008/033465 Pamphlet 国際公開第２００８／００５５７６号パンフレットInternational Publication No. 2008/005576 Pamphlet 国際公開第２００８／００８８８７号パンフレットInternational Publication No. 2008/008887 Pamphlet 国際公開第２００８／１３７４３５号パンフレットInternational Publication No. 2008/137435 Pamphlet 国際公開第２００８／１３７４３６号パンフレットInternational Publication No. 2008/137436 Pamphlet 国際公開第２００９／０１２２７５号パンフレットInternational Publication No. 2009/012275 Pamphlet 国際公開第２００９／０９７３０９号パンフレットInternational Publication No. 2009/097309 Pamphlet 国際公開第２００９／０９７５６７号パンフレットInternational Publication No. 2009/097567 Pamphlet 国際公開第２００８／０８８６９２号パンフレットInternational Publication No. 2008/088692 Pamphlet 国際公開第２００７／０１１８０９号パンフレットInternational Publication No. 2007/011809 Pamphlet 国際公開第２０００／０５９５１０号パンフレットInternational Publication No. 2000/059510 Pamphlet 国際公開第２０１０／１４４５７１号パンフレットInternational Publication No. 2010/144571 Pamphlet 国際公開第２０１０／１０５１７９号パンフレットInternational Publication No. 2010/105179 Pamphlet
　本発明の目的は、優れたＧＰＲ１１９アゴニストを提供することである。 An object of the present invention is to provide an excellent GPR119 agonist.
　本発明者らは、鋭意研究の結果、ＧＰＲ１１９アゴニスト作用を有する優れた化合物の合成に成功した。
　本発明は、以下に関する。
（１）
式（Ｉ）：
Figure JPOXMLDOC01-appb-C000010
（式中、
Ｘは＝Ｃ（Ｒ２）－または＝Ｎ－であり、
Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノであり、
Ｒ３は置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
Ｙ１は－Ｃ（Ｒ７）（Ｒ７Ａ）－または－Ｏ－であり、
Ｙ２は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－または－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、
Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｒ６とＲ６Ａは一緒になってオキソまたは置換もしくは非置換のイミノを形成してもよく、
Ｒ６とＲ６Ａは隣接する炭素原子と一緒になって置換もしくは非置換の環または置換もしくは非置換のアルキリデンを形成してもよく、
Ｒ８はシアノ、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、Ｒ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８ＥおよびＲ８Ｆは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基であり、
ｍおよびｎは各々独立して０、１または２であり、
ｒは０～１２の整数であり、
Ｒ９は各々独立してハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルであり、
ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、および／または、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。
但し、Ｘが＝ＣＨ－であり、Ｙ１が－Ｏ－であり、Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃで示される基であり、かつ、Ｒ８Ｃが置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のヘテロサイクリルである化合物、および以下に示される化合物：
Figure JPOXMLDOC01-appb-C000011
を除く。）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物。
（２）
Ｙ１が－Ｏ－である、前記（１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（３）
Ｘが＝Ｎ－である、前記（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（４）
Ｘが＝Ｃ（Ｒ２）－である、前記（１）または（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（５）
Ｙ２が－Ｃ（Ｒ６）（Ｒ６Ａ）－である、前記（１）～（４）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（６）
Ｙ２が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である、前記（１）～（４）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（７）
Ｒ６およびＲ６Ａが水素である、前記（１）～（６）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（８）
Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである、前記（１）～（６）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（９）
Ｒ３が置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のヘテロサイクリルである、前記（１）～（８）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１０）
Ｒ３が置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルであり、該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であり、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
またはＲ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよく、
Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
Ｒ１０Ｄは水素または置換もしくは非置換のアルキルである、前記（１）～（８）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１１）
Ｒ３が置換アリールまたは置換ヘテロアリールであり、該アリールまたはヘテロアリール上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂで示される基であり、Ｒ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成する、前記（１）～（８）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１２）
ｍが１であり、かつ、ｎが１である、前記（１）～（１１）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１３）
Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは前記（１）と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは前記（１）と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｇは前記（１）と同意義である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは前記（１）と同意義である。）で示される基である、前記（１）～（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１４）
Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは前記（１）と同意義である。）で示される基である、前記（１）～（１３）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１５）
ｐが０である、前記（１３）または（１４）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１６）
Ｒ８Ｃが置換もしくは非置換のヘテロアリールである、前記（１５）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１７）
ｒが０である、前記（１）～（１６）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１８）
前記（１）～（１７）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
（１９）
前記（１）～（１７）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２０）
式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000012
（式中、破線は結合の存在または不存在を示し、
環Ａは
Figure JPOXMLDOC01-appb-C000013
であり、
Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノであり、
Ｒ３Ａは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアリールオキシ、置換もしくは非置換のヘテロアリールオキシ、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換のヘテロサイクリルオキシ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換のヘテロサイクリルチオ、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換のヘテロサイクリルスルフィニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のヘテロアリールスルホニル、置換もしくは非置換のシクロアルキルスルホニル、置換もしくは非置換のシクロアルケニルスルホニル、置換もしくは非置換のヘテロサイクリルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｙ３は－Ｃ（Ｒ７）（Ｒ７Ａ）－、－Ｃ（＝Ｏ）－または－Ｏ－であり、
Ｙ４は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｏ－、－Ｏ－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｏ－または－Ｃ（Ｒ５）＝Ｃ（Ｒ６）－であり、
Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｒ６とＲ６Ａは一緒になってオキソまたは置換もしくは非置換のイミノを形成してもよく、
Ｒ６とＲ６Ａは隣接する炭素原子と一緒になって置換もしくは非置換の環または置換もしくは非置換のアルキリデンを形成してもよく、
Ｒ８はシアノ、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、Ｒ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８ＥおよびＲ８Ｆは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基であり、
ｍおよびｎは各々独立して０、１または２であり、
ｒは０～１２の整数であり、
Ｒ９は各々独立してハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルであり、
ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。
但し、環Ａが
Figure JPOXMLDOC01-appb-C000014
であり、
Ｙ３が－Ｏ－であり、Ｙ４が－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、ｍが１であり、ｎが１であり、Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃで示される基であり、かつ、Ｒ８Ｃが置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のヘテロサイクリルである化合物を除く。）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２１）
環Ａが
Figure JPOXMLDOC01-appb-C000015
（ここで、Ｒ１、Ｒ２、Ｒ３ＡおよびＲ４は前記（２０）と同意義である。）である、前記（２０）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２２）
Ｙ３が－Ｏ－である、前記（２０）または（２１）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２３）
Ｙ４が－Ｃ（Ｒ６）（Ｒ６Ａ）－である、前記（２０）～（２２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２４）
Ｙ４が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である、前記（２０）～（２２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２５）
Ｒ６およびＲ６Ａが水素である、前記（２０）～（２４）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２６）
Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである、前記（２０）～（２４）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２７）
Ｒ３Ａが置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のヘテロサイクリルである、前記（２０）～（２６）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２８）
Ｒ３Ａが置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルであり、該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であり、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、またはＲ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよく、
Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
Ｒ１０Ｄは水素または置換もしくは非置換のアルキルである、前記（２０）～（２６）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２９）
Ｒ３Ａが置換アリールまたは置換ヘテロアリールであり、該アリールまたはヘテロアリール上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂで示される基であり、Ｒ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成する、前記（２０）～（２８）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３０）
ｍが１であり、かつ、ｎが１である、前記（２０）～（２９）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３１）
Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは前記（２０）と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは前記（２０）と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｇは前記（２０）と同意義である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは前記（２０）と同意義である。）で示される基である、前記（２０）～（３０）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３２）
Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは前記（２０）と同意義である。）で示される基である、前記（２０）～（３１）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３３）
ｐが０である、前記（３１）または（３２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３４）
Ｒ８Ｃが置換もしくは非置換のヘテロアリールである、前記（３３）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３５）
ｒが０である、前記（２０）～（３４）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（３６）
糖尿病の治療および／または予防のための、前記（１９）～（３５）のいずれかに記載の記載の医薬組成物。
（３７）
前記（１）～（３５）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、糖尿病の予防または治療方法。
（３８）
糖尿病の治療および／または予防のための、前記（１）～（３５）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（３９）
前記式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物と、ＤＰＰ－ＩＶ阻害作用を有する化合物、その製薬上許容される塩またはそれらの溶媒和物を組み合わせてなる医薬。
（４０）
前記式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物による治療を受けている糖尿病患者に、他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法。
（４１）
前記式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物と併用して他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法。
（１Ａ）
式（Ｉ）：
Figure JPOXMLDOC01-appb-C000016
（式中、
Ｘは＝Ｃ（Ｒ２）－または＝Ｎ－であり、
Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノであり、
Ｒ３は置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
Ｙ１は－Ｃ（Ｒ７）（Ｒ７Ａ）－または－Ｏ－であり、
Ｙ２は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－または－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、
Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｒ８はシアノ、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８ＡおよびＲ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８ＥおよびＲ８Ｆは各々独立して置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２の整数である）で示される基または
式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基であり、
ｍおよびｎは各々独立して０、１または２であり、
ｒは０～１２の整数であり、
Ｒ９はハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルであり、
ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、および／または、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。
但し、Ｘが＝ＣＨ－であり、Ｙ１が－Ｏ－であり、Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃで示される基であり、ｐが０であり、かつ、Ｒ８Ｃが置換もしくは非置換のシクロアルキルである化合物、Ｘが＝ＣＨ－であり、Ｙ１が－Ｏ－であり、Ｙ２が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、ｍが１であり、ｎが１であり、Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃで示される基であり、ｐが０であり、かつ、Ｒ８Ｃが置換もしくは非置換の４－ピリミジンまたは６-ピリミジンである化合物、および以下に示される化合物：
Figure JPOXMLDOC01-appb-C000017
を除く。）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物。
（２Ａ）
Ｙ１が－Ｏ－である、前記（１Ａ）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（３Ａ）
Ｘが＝Ｃ（Ｒ２）－である、前記（１Ａ）または（２Ａ）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（４Ａ）
Ｙ２が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である、前記（１Ａ）～（３Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（５Ａ）
Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである、前記（４Ａ）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（６Ａ）
Ｒ３が置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のヘテロサイクリルである、前記（１Ａ）～（５Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（７Ａ）
Ｒ３が置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルであり、該置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ａ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ａ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ａ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂおよび－ＮＲ１０ＡＳＯ２－Ｒ１０Ｃからなる群から選択される基であり、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである、前記（１Ａ）～（５Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（８Ａ）
ｍが１であり、かつ、ｎが１である、前記（１Ａ）～（７Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（９Ａ）
Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは前記（１Ａ）と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは前記（１Ａ）と同意義である。）で示される基、
式：－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ｇは前記（１Ａ）と同意義である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは前記（１Ａ）と同意義である。）で示される基である、前記（１Ａ）～（８Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１０Ａ）
ｒが０である、前記（１Ａ）～（９Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１１Ａ）
前記（１Ａ）～（１０Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。
（１２Ａ）
前記（１Ａ）～（１０Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１３Ａ）
式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000018
（式中、破線は結合の存在または不存在を示し、
環Ａは
Figure JPOXMLDOC01-appb-C000019
であり、
Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノであり、
Ｒ３Ａは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアリールオキシ、置換もしくは非置換のヘテロアリールオキシ、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換のヘテロサイクリルオキシ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換のヘテロサイクリルチオ、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換のヘテロサイクリルスルフィニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のヘテロアリールスルホニル、置換もしくは非置換のシクロアルキルスルホニル、置換もしくは非置換のシクロアルケニルスルホニル、置換もしくは非置換のヘテロサイクリルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｙ３は－Ｃ（Ｒ７）（Ｒ７Ａ）－、－Ｃ（＝Ｏ）－または－Ｏ－であり、
Ｙ４は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｏ－、－Ｏ－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｏ－または－Ｃ（Ｒ５）＝Ｃ（Ｒ６）－であり、
Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｒ８はシアノ、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８ＡおよびＲ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８ＥおよびＲ８Ｆは各々独立して置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基、
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２の整数である）で示される基または
式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである）で示される基であり、
ｍおよびｎは各々独立して０、１または２であり、
ｒは０～１２の整数であり、
Ｒ９はハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルであり、
ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１４Ａ）
Ｙ４が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、かつＲ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである、前記（１３Ａ）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１５Ａ）
Ｒ３Ａが置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のヘテロサイクリルである、前記（１３Ａ）または（１４Ａ）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１６Ａ）
Ｒ３Ａが置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルであり、該置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ａ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ａ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ａ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂおよび－ＮＲ１０ＡＳＯ２－Ｒ１０Ｃからなる群から選択される基であり、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである、前記（１３Ａ）または（１４Ａ）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１７Ａ）
ｍが１であり、かつ、ｎが１である、前記（１３Ａ）～（１６Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１８Ａ）
Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは前記（１３Ａ）と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは前記（１３Ａ）と同意義である。）で示される基、
式：－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ｇは前記（１３Ａ）と同意義である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは前記（１３Ａ）と同意義である。）で示される基である、前記（１３Ａ）～（１７Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（１９Ａ）
ｒが０である、前記（１３Ａ）～（１８Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。
（２０Ａ）
糖尿病の治療および／または予防のための、前記（１３Ａ）～（１９Ａ）のいずれかに記載の記載の医薬組成物。
（２１Ａ）
前記（１Ａ）～（１２Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、糖尿病の予防または治療方法。
（２２Ａ）
糖尿病の治療および／または予防のための、前記（１Ａ）～（１２Ａ）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（２３Ａ）
前記式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物と、ＤＰＰ－ＩＶ阻害作用を有する化合物、その製薬上許容される塩またはそれらの溶媒和物を組み合わせてなる医薬。
（２４Ａ）
前記式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物による治療を受けている糖尿病患者に、他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法。
（２５Ａ）
前記式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物と併用して他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法。 As a result of intensive studies, the present inventors have succeeded in synthesizing an excellent compound having a GPR119 agonistic action.
The present invention relates to the following.
(1)
Formula (I):
Figure JPOXMLDOC01-appb-C000010
(Where
X is = C (R 2 )-Or = N-
R 1 , R 2 And R 4 Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Other is a substituted or unsubstituted amino,
R 3 Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;
Y 1 Is -C (R 7 ) (R 7A )-Or -O-
Y 2 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-Or -C (R 6 ) (R 6A )-
R 5 , R 5A , R 6 , R 6A , R 7 And R 7A Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
R 6 And R 6A Together may form oxo or substituted or unsubstituted imino,
R 6 And R 6A Together with adjacent carbon atoms may form a substituted or unsubstituted ring or substituted or unsubstituted alkylidene;
R 8 Is cyano,
Formula:-(CR 8A R 8B P-R 8C (Wherein R 8A Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl; 8B Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer from 0 to 3, and R 8C Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B And p are as defined above, and R 8D Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) NR 8E R 8F (Wherein R 8A , R 8B And p are as defined above, and R 8E And R 8F Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) R 8G (Wherein R 8A , R 8B And p are as defined above, and R 8G Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl. Group represented by
Formula: -S (= O) q-R 8H (Wherein R 8H Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl, and q is 1 or 2. ) Or a group
Formula: -S (= O) q-NR 8I R 8J Wherein q is as defined above and R 8I And R 8J Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. )
m and n are each independently 0, 1 or 2,
r is an integer from 0 to 12,
R 9 Are each independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl;
When r is 2 or more, two R bonded to the same carbon atom 9 Together may form an oxo and / or two R bonded to different carbon atoms. 9 Together with the carbon atom to which they are attached may form a substituted or unsubstituted ring.
However, X is = CH- and Y 1 Is -O- and R 8 Is the formula:-(CR 8A R 8B P-R 8C And a group represented by R 8C Wherein is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, and the compounds shown below:
Figure JPOXMLDOC01-appb-C000011
except for. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(2)
Y 1 The compound according to the above (1), pharmaceutically acceptable salt or solvate thereof, wherein is —O—.
(3)
The compound according to (1) or (2), a pharmaceutically acceptable salt or a solvate thereof, wherein X is = N-.
(4)
X is = C (R 2 )-, The pharmaceutically acceptable salt or solvate thereof according to (1) or (2) above.
(5)
Y 2 Is -C (R 6 ) (R 6A The compound according to any one of the above (1) to (4), a pharmaceutically acceptable salt thereof or a solvate thereof.
(6)
Y 2 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A The compound according to any one of the above (1) to (4), a pharmaceutically acceptable salt thereof or a solvate thereof.
(7)
R 6 And R 6A The compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein is hydrogen.
(8)
R 6 And R 6A The compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein at least one of is halogen or substituted or unsubstituted alkyl.
(9)
R 3 Or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocyclyl; Or a solvate thereof.
(10)
R 3 Is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl, and at least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is —C (═ O) NR 10A R 10B , -NR 10D -C (= O) -R 10C , -NR 10D -C (= O) -NR 10A R 10B , -NR 10D -S (= O) 2 -NR 10A R 10B , -SO 2 NR 10A R 10B , -NR 10D SO 2 -R 10C And -SO 2 -R 10C A group selected from the group consisting of R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
Or R 10A And R 10B May be combined with an adjacent nitrogen atom to form a substituted or unsubstituted ring,
R 10C Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl;
R 10D The compound according to any one of the above (1) to (8), its pharmaceutically acceptable salt, or a solvate thereof, wherein is hydrogen or substituted or unsubstituted alkyl.
(11)
R 3 Is substituted aryl or substituted heteroaryl, and at least one of the substituents on the aryl or heteroaryl is —C (═O) NR 10A R 10B And a group represented by R 10A And R 10B Is a compound according to any one of (1) to (8), a pharmaceutically acceptable salt thereof, or a solvate thereof, which forms a substituted or unsubstituted ring together with an adjacent nitrogen atom.
(12)
The compound according to any one of (1) to (11), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1.
(13)
R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (1) above. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is the same as (1) above. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) R 8G (Wherein R 8A , R 8B , P and R 8G Is the same as (1) above. ) Or a group
Formula: -S (= O) q-R 8H (Wherein R 8H And q are as defined in the above (1). Or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of (1) to (12) above, which is a group represented by
(14)
R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (1) above. Or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of the above (1) to (13), which is a group represented by
(15)
The compound according to (13) or (14), a pharmaceutically acceptable salt or a solvate thereof, wherein p is 0.
(16)
R 8C The compound according to (15), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein is substituted or unsubstituted heteroaryl.
(17)
The compound according to any one of (1) to (16), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r is 0.
(18)
A pharmaceutical composition comprising the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(19)
A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(20)
Formula (II):
Figure JPOXMLDOC01-appb-C000012
(Where the dashed line indicates the presence or absence of a bond,
Ring A is
Figure JPOXMLDOC01-appb-C000013
And
R 1 , R 2 And R 4 Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Other is a substituted or unsubstituted amino,
R 3A Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted Substituted heterocyclyloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterozygous Kurylthio, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted heterocyclylsulfinyl, substituted or unsubstituted Substituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl, substituted Or unsubstituted carbamoyl or substituted or unsubstituted amino,
Y 3 Is -C (R 7 ) (R 7A )-, -C (= O)-or -O-
Y 4 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-, -C (R 5 ) (R 5A ) -O-, -O-C (R 6 ) (R 6A )-, -C (R 6 ) (R 6A )-, -O- or -C (R 5 ) = C (R 6 )-
R 5 , R 5A , R 6 , R 6A , R 7 And R 7A Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
R 6 And R 6A Together may form oxo or substituted or unsubstituted imino,
R 6 And R 6A Together with adjacent carbon atoms may form a substituted or unsubstituted ring or substituted or unsubstituted alkylidene;
R 8 Is cyano,
Formula:-(CR 8A R 8B P-R 8C (Wherein R 8A Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl; 8B Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer from 0 to 3, and R 8C Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B And p are as defined above, and R 8D Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) NR 8E R 8F (Wherein R 8A , R 8B And p are as defined above, and R 8E And R 8F Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) R 8G (Wherein R 8A , R 8B And p are as defined above, and R 8G Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl. Group represented by
Formula: -S (= O) q-R 8H (Wherein R 8H Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl, and q is 1 or 2. ) Or a group
Formula: -S (= O) q-NR 8I R 8J Wherein q is as defined above and R 8I And R 8J Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl. )
m and n are each independently 0, 1 or 2,
r is an integer from 0 to 12,
R 9 Are each independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl;
When r is 2 or more, two R bonded to the same carbon atom 9 Together may form an oxo, and two R bonded to different carbon atoms. 9 Together with the carbon atom to which they are attached may form a substituted or unsubstituted ring.
However, ring A is
Figure JPOXMLDOC01-appb-C000014
And
Y 3 Is -O- and Y 4 Is -C (R 6 ) (R 6A )-, M is 1, n is 1, and R 8 Is the formula:-(CR 8A R 8B P-R 8C And a group represented by R 8C In which is a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition having GPR119 receptor agonist activity.
(21)
Ring A is
Figure JPOXMLDOC01-appb-C000015
(Where R 1 , R 2 , R 3A And R 4 Is as defined in (20) above. And a pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to (20), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(22)
Y 3 A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to the above (20) or (21), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R is —O—.
(23)
Y 4 Is -C (R 6 ) (R 6A A pharmaceutical composition having GPR119 receptor agonist activity, which comprises the compound according to any one of the above (20) to (22), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(24)
Y 4 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A A pharmaceutical composition having GPR119 receptor agonist activity, which comprises the compound according to any one of the above (20) to (22), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(25)
R 6 And R 6A A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of (20) to (24), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is hydrogen.
(26)
R 6 And R 6A GPR119 containing the compound according to any one of the above (20) to (24), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein at least one of is halogen or substituted or unsubstituted alkyl A pharmaceutical composition having receptor agonist activity.
(27)
R 3A Or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl, Or the pharmaceutical composition which has GPR119 receptor agonist activity containing those solvates.
(28)
R 3A Is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl, and at least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is —C (═ O) NR 10A R 10B , -NR 10D -C (= O) -R 10C , -NR 10D -C (= O) -NR 10A R 10B , -NR 10D -S (= O) 2 -NR 10A R 10B , -SO 2 NR 10A R 10B , -NR 10D SO 2 -R 10C And -SO 2 -R 10C A group selected from the group consisting of R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, or R 10A And R 10B May be combined with an adjacent nitrogen atom to form a substituted or unsubstituted ring,
R 10C Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl;
R 10D GPR119 receptor agonist activity containing a compound according to any one of the above (20) to (26), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is hydrogen or substituted or unsubstituted alkyl A pharmaceutical composition comprising.
(29)
R 3A Is substituted aryl or substituted heteroaryl, and at least one of the substituents on the aryl or heteroaryl is —C (═O) NR 10A R 10B And a group represented by R 10A And R 10B Is a compound according to any one of the above (20) to (28), a pharmaceutically acceptable salt thereof, or a solvate thereof, which forms a substituted or unsubstituted ring together with an adjacent nitrogen atom. A pharmaceutical composition having GPR119 receptor agonist activity.
(30)
A GPR119 receptor agonist comprising the compound according to any one of (20) to (29), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1. A pharmaceutical composition having activity.
(31)
R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is as defined in (20) above. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is as defined in (20) above. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) R 8G (Wherein R 8A , R 8B , P and R 8G Is as defined in (20) above. ) Or a group
Formula: -S (= O) q-R 8H (Wherein R 8H And q are as defined in (20) above. And a pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of (20) to (30) above, a pharmaceutically acceptable salt thereof, or a solvate thereof. .
(32)
R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is as defined in (20) above. A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of the above (20) to (31), a pharmaceutically acceptable salt thereof, or a solvate thereof, .
(33)
A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to (31) or (32), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is 0.
(34)
R 8C A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to (33), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is a substituted or unsubstituted heteroaryl.
(35)
A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of (20) to (34), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r is 0.
(36)
The pharmaceutical composition according to any one of the above (19) to (35), for the treatment and / or prevention of diabetes.
(37)
A method for preventing or treating diabetes, comprising administering the compound according to any one of (1) to (35), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(38)
The compound according to any one of (1) to (35), a pharmaceutically acceptable salt thereof, or a solvate thereof, for the treatment and / or prevention of diabetes.
(39)
The compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof, a compound having a DPP-IV inhibitory action, a pharmaceutically acceptable salt thereof or a solvent thereof A medicine that combines Japanese products.
(40)
Another diabetes therapeutic agent is administered to a diabetic patient treated with the compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof, or a solvate thereof. How to treat diabetes.
(41)
A method for treating diabetes, comprising administering another therapeutic agent for diabetes in combination with the compound represented by the formula (I) or formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof.
(1A)
Formula (I):
Figure JPOXMLDOC01-appb-C000016
(Where
X is = C (R 2 )-Or = N-
R 1 , R 2 And R 4 Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Other is a substituted or unsubstituted amino,
R 3 Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;
Y 1 Is -C (R 7 ) (R 7A )-Or -O-
Y 2 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-Or -C (R 6 ) (R 6A )-
R 5 , R 5A , R 6 , R 6A , R 7 And R 7A Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
R 8 Is cyano,
Formula:-(CR 8A R 8B P-R 8C (Wherein R 8A And R 8B Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer from 0 to 3, and R 8C Is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl),
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B And p are as defined above, and R 8D Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl),
Formula: -C (= O) NR 8E R 8F (Wherein R 8E And R 8F Each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclyl),
Formula: -C (= O) R 8G (Wherein R 8G Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl),
Formula: -S (= O) q-R 8H (Wherein R 8H Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl, q is an integer of 1 or 2, or
Formula: -S (= O) q-NR 8I R 8J Wherein q is as defined above and R 8I And R 8J Each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclyl),
m and n are each independently 0, 1 or 2,
r is an integer from 0 to 12,
R 9 Is halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl;
When r is 2 or more, two R bonded to the same carbon atom 9 Together may form an oxo and / or two R bonded to different carbon atoms. 9 Together with the carbon atom to which they are attached may form a substituted or unsubstituted ring.
However, X is = CH- and Y 1 Is -O- and R 8 Is the formula:-(CR 8A R 8B P-R 8C And p is 0, and R is 8C Wherein X is substituted or unsubstituted cycloalkyl, X is ═CH—, Y 1 Is -O- and Y 2 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-, M is 1, n is 1, and R 8 Is the formula:-(CR 8A R 8B P-R 8C And p is 0, and R is 8C Wherein is a substituted or unsubstituted 4-pyrimidine or 6-pyrimidine, and compounds shown below:
Figure JPOXMLDOC01-appb-C000017
except for. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
(2A)
Y 1 Wherein-is -O-, the pharmaceutically acceptable salt or solvate thereof according to the above (1A).
(3A)
X is = C (R 2 ) —, The pharmaceutically acceptable salt or solvate thereof according to (1A) or (2A).
(4A)
Y 2 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-, The compound according to any one of the above (1A) to (3A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(5A)
R 6 And R 6A Or a pharmaceutically acceptable salt or solvate thereof according to the above (4A), wherein at least one of is halogen or substituted or unsubstituted alkyl.
(6A)
R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of (1A) to (5A), wherein is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl Or a solvate thereof.
(7A)
R 3 Is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl, and at least one of the substituents is —C (═O) NR 10A R 10B , -NR 10A -C (= O) -R 10C , -NR 10A -C (= O) -NR 10A R 10B , -NR 10A -S (= O) 2 -NR 10A R 10B , -SO 2 NR 10A R 10B And -NR 10A SO 2 -R 10C A group selected from the group consisting of R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, R 10C Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted The compound according to any one of the above (1A) to (5A), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is cycloalkenyl or substituted or unsubstituted heterocyclyl.
(8A)
The compound according to any one of (1A) to (7A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1.
(9A)
R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (1A) above. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is the same as (1A) above. Group represented by
Formula: -C (= O) R 8G (Wherein R 8G Is the same as (1A) above. ) Or a group
Formula: -S (= O) q-R 8H (Wherein R 8H And q are as defined in (1A) above. Or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of (1A) to (8A) above, which is a group represented by
(10A)
The compound according to any one of (1A) to (9A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r is 0.
(11A)
A pharmaceutical composition comprising the compound according to any one of (1A) to (10A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(12A)
A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of (1A) to (10A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(13A)
Formula (II):
Figure JPOXMLDOC01-appb-C000018
(Where the dashed line indicates the presence or absence of a bond,
Ring A is
Figure JPOXMLDOC01-appb-C000019
And
R 1 , R 2 And R 4 Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl Other is a substituted or unsubstituted amino,
R 3A Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted Substituted heterocyclyloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterozygous Kurylthio, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted heterocyclylsulfinyl, substituted or unsubstituted Substituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl, substituted Or unsubstituted carbamoyl or substituted or unsubstituted amino,
Y 3 Is -C (R 7 ) (R 7A )-, -C (= O)-or -O-
Y 4 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-, -C (R 5 ) (R 5A ) -O-, -O-C (R 6 ) (R 6A )-, -C (R 6 ) (R 6A )-, -O- or -C (R 5 ) = C (R 6 )-
R 5 , R 5A , R 6 , R 6A , R 7 And R 7A Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl Substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
R 8 Is cyano,
Formula:-(CR 8A R 8B P-R 8C (Wherein R 8A And R 8B Each independently is hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer from 0 to 3, and R 8C Is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl),
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B And p are as defined above, and R 8D Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl),
Formula: -C (= O) NR 8E R 8F (Wherein R 8E And R 8F Each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclyl),
Formula: -C (= O) R 8G (Wherein R 8G Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl),
Formula: -S (= O) q-R 8H (Wherein R 8H Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl or substituted or unsubstituted heterocyclyl, q is an integer of 1 or 2, or
Formula: -S (= O) q-NR 8I R 8J Wherein q is as defined above and R 8I And R 8J Each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclyl),
m and n are each independently 0, 1 or 2,
r is an integer from 0 to 12,
R 9 Is halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl;
When r is 2 or more, two R bonded to the same carbon atom 9 Together may form an oxo, and two R bonded to different carbon atoms. 9 Together with the carbon atom to which they are attached may form a substituted or unsubstituted ring. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition having GPR119 receptor agonist activity.
(14A)
Y 4 Is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-And R 6 And R 6A A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to (13A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of is halogen or substituted or unsubstituted alkyl object.
(15A)
R 3A Or a pharmaceutically acceptable salt thereof or a solvent thereof, wherein is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl A pharmaceutical composition having GPR119 receptor agonist activity, comprising a Japanese product.
(16A)
R 3A Is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl, and at least one of the substituents is —C (═O) NR 10A R 10B , -NR 10A -C (= O) -R 10C , -NR 10A -C (= O) -NR 10A R 10B , -NR 10A -S (= O) 2 -NR 10A R 10B , -SO 2 NR 10A R 10B And -NR 10A SO 2 -R 10C A group selected from the group consisting of R 10A And R 10B Are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, R 10C Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A pharmaceutical having GPR119 receptor agonist activity comprising a compound according to (13A) or (14A), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is cycloalkenyl or substituted or unsubstituted heterocyclyl Composition.
(17A)
A GPR119 receptor agonist comprising the compound according to any one of (13A) to (16A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1. A pharmaceutical composition having activity.
(18A)
R 8 Is the formula:-(CR 8A R 8B P-R 8C (Wherein R 8A , R 8B , P and R 8C Is the same as (13A) above. Group represented by
Formula:-(CR 8A R 8B ) PC (= O) OR 8D (Wherein R 8A , R 8B , P and R 8D Is the same as (13A) above. Group represented by
Formula: -C (= O) R 8G (Wherein R 8G Is the same as (13A) above. ) Or a group
Formula: -S (= O) q-R 8H (Wherein R 8H And q have the same meaning as in the above (13A). And a pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of (13A) to (17A) above, a pharmaceutically acceptable salt thereof, or a solvate thereof. .
(19A)
A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of (13A) to (18A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r is 0.
(20A)
The pharmaceutical composition according to any one of the above (13A) to (19A), for the treatment and / or prevention of diabetes.
(21A)
A method for preventing or treating diabetes, which comprises administering the compound according to any one of (1A) to (12A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(22A)
The compound according to any one of the above (1A) to (12A), a pharmaceutically acceptable salt thereof, or a solvate thereof for the treatment and / or prevention of diabetes.
(23A)
The compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof, a compound having a DPP-IV inhibitory action, a pharmaceutically acceptable salt thereof or a solvent thereof A medicine that combines Japanese products.
(24A)
Another diabetes therapeutic agent is administered to a diabetic patient treated with the compound represented by the formula (I) or the formula (II), a pharmaceutically acceptable salt thereof, or a solvate thereof. How to treat diabetes.
(25A)
A method for treating diabetes, comprising administering another therapeutic agent for diabetes in combination with the compound represented by the formula (I) or formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof.
　本発明者らは、本発明化合物がグルカゴン様ペプチド－１（以下、ＧＬＰ－１とする。）分泌作用を有することを確認した。本発明化合物は優れたGPR119アゴニスト活性を有し、膵臓β細胞に発現するGPR119を活性化して血糖上昇に依存したインスリン分泌を促進し、また腸管に発現するGPR119を活性化してGLP-1分泌を促進することで、優れた血糖降下作用を有する。ＧＬＰ－１は、グルコース依存的にインスリン分泌を刺激することが知られているが、ジペプチジルペプチダーゼＩＶ（ＤＰＰ－ＩＶ）によって容易に切断されて、その生物活性を不活化してしまうという問題点があった。本発明化合物はＤＰＰ－ＩＶによって分解されず、ＤＰＰ－ＩＶ阻害作用を有する化合物と併用することができる。本発明者らは、ＧＰＲ１１９アゴニスト活性を有する本発明化合物とＤＰＰ－ＩＶ阻害作用を有する化合物を併用することにより、顕著な併用効果があることを確認した。
　ＤＰＰ－ＩＶ阻害作用を有する化合物としては、Sitagliptin、Vildagliptin、Alogliptin、Saxagliptinなどが挙げられる。 The present inventors have confirmed that the compound of the present invention has a glucagon-like peptide-1 (hereinafter referred to as GLP-1) secretion action. The compound of the present invention has excellent GPR119 agonist activity, activates GPR119 expressed in pancreatic β-cells to promote insulin secretion dependent on blood glucose elevation, and activates GPR119 expressed in the intestinal tract to induce GLP-1 secretion. By promoting, it has an excellent hypoglycemic effect. GLP-1 is known to stimulate insulin secretion in a glucose-dependent manner, but it is easily cleaved by dipeptidyl peptidase IV (DPP-IV) to inactivate its biological activity. was there. The compound of the present invention is not decomposed by DPP-IV and can be used in combination with a compound having a DPP-IV inhibitory action. The present inventors have confirmed that there is a remarkable combined effect by using the compound of the present invention having GPR119 agonist activity and the compound having DPP-IV inhibitory action in combination.
Examples of the compound having DPP-IV inhibitory action include Sitagliptin, Vildagliptin, Alogliptin, Saxagliptin and the like.
　本発明化合物はＧＰＲ１１９アゴニスト活性を有するので、本発明化合物を含む医薬組成物は、医薬品、特にＩ型糖尿病、ＩＩ型糖尿病、インスリン抵抗性、代謝性疾患、高血糖および／または肥満の治療および／または予防のための医薬として非常に有用である。　また、本発明化合物は、グルコース依存的にインスリンの分泌を促進することから低血糖リスクが低く既存薬と比較して、安全性が高い。その他、医薬としての有用性を備えた化合物である。ここで、医薬としての有用性としては、代謝安定性がよい点、薬物代謝酵素の誘導も少ない点、他の薬剤を代謝する薬物代謝酵素の阻害も小さい点、経口吸収性の高い化合物である点、クリアランスが小さい点、半減期が薬効を発現するために十分長い点、酵素活性が強い点、最大活性化率が高い点、または薬効の持続性が良い点などが含まれる。 Since the compounds of the present invention have GPR119 agonist activity, pharmaceutical compositions containing the compounds of the present invention can be used to treat pharmaceuticals, particularly type I diabetes, type II diabetes, insulin resistance, metabolic diseases, hyperglycemia and / or obesity. Or it is very useful as a medicine for prevention. In addition, since the compound of the present invention promotes insulin secretion in a glucose-dependent manner, the risk of hypoglycemia is low and the safety is high compared to existing drugs. In addition, it is a compound having utility as a medicine. Here, as usefulness as a medicine, it is a compound with high metabolic stability, low induction of drug metabolizing enzymes, small inhibition of drug metabolizing enzymes that metabolize other drugs, and high oral absorbability The point includes a point having a small clearance, a point having a sufficiently long half-life for exhibiting a drug effect, a point having a strong enzyme activity, a point having a high maximum activation rate, and a point having a good drug effect.
　以下に本明細書中で使用する各用語を説明する。なお、本明細書中、各用語は単独で使用されている場合も、または他の用語と一緒になって使用されている場合も、同一の意義を有する。 The terms used in this specification are explained below. In the present specification, each term has the same meaning whether used alone or in combination with other terms.
　「ハロゲン」とは、フッ素、塩素、臭素およびヨウ素が挙げられる。 “Halogen” includes fluorine, chlorine, bromine and iodine.
　「アルキル」とは、炭素数１～１０個の直鎖状又は分枝状のアルキル基を意味し、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ぺンチル、イソぺンチル、ネオぺンチル、n-ヘキシル、イソヘキシル、n-ヘプチル、n-オクチル、n-ノニル、n-デシル等が挙げられる。好ましくは、炭素数１～６または１～４個のアルキルであり、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ぺンチル、イソぺンチル、ネオぺンチル、n-ヘキシル、イソヘキシルが挙げられる。 “Alkyl” means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred is alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.
　「アルケニル」とは、上記「アルキル」に１個又はそれ以上の二重結合を有する炭素数２～８個の直鎖状又は分枝状のアルケニルを意味し、例えば、ビニル、1-プロペニル、2-プロペニル、1-ブテニル、2-ブテニル、3-ブテニル、1,3-ブタジエニル、3-メチル-2-ブテニル等が挙げられる。 “Alkenyl” means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.
　「アルキニル」とは、上記「アルキル」に１個又はそれ以上の三重結合を有する炭素数２～８個の直鎖状又は分枝状のアルキニルを意味し、例えば、エチニル、プロピニル、ブチニル等が挙げられる。さらに二重結合を有してもよい。 “Alkynyl” means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, you may have a double bond.
　「シクロアルキル」とは、炭素数３～１５の環状飽和炭化水素基を意味し、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、橋かけ環式炭化水素基、スピロ炭化水素基などが挙げられる。好ましくは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、橋かけ環式炭化水素基が挙げられる。 “Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Groups and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.
　「橋かけ環式炭化水素基」とは、２つ以上の環が２個またはそれ以上の原子を共有している炭素数５～８の脂肪族環から水素を１つ除いてできる基を包含する。具体的にはビシクロ［２．１．０］ペンチル、ビシクロ［２．２．１］ヘプチル、ビシクロ［２．２．２］オクチルおよびビシクロ［３．２．１］オクチル、トリシクロ［２．２．１．０］ヘプチルなどが挙げられる。 “Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.
　「スピロ炭化水素基」とは、２つの炭化水素環が１個の炭素原子を共有して構成されている環から水素を１つ除いてできる基を包含する。具体的にはスピロ［３．４］オクチルなどが挙げられる。 The “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.
　「シクロアルケニル」とは、炭素数３～１０の環状の不飽和脂肪族炭化水素基を意味し、例えば、シクロプロペニル（例えば、1-シクロプロペニル）、シクロブテニル（例えば、1-シクロブテニル）、シクロペンテニル（例えば、1-シクロペンテン-1-イル、2-シクロペンテン-1-イル、3-シクロペンテン-1-イル）、シクロヘキセニル（例えば、1-シクロヘキセン-1-イル、2-シクロヘキセン-1-イル、3-シクロヘキセン-1-イル）、シクロヘプテニル（例えば、1-シクロヘプテニル）、シクロオクテニル（例えば、1-シクロオクテニル）等が挙げられる。好ましくはシクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニルである。シクロアルケニルには、環中に不飽和結合を有する橋かけ環式炭化水素基およびスピロ炭化水素基も含む。 “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropenyl (eg, 1-cyclopropenyl), cyclobutenyl (eg, 1-cyclobutenyl), cyclopentenyl. (Eg 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (eg 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3 -Cyclohexen-1-yl), cycloheptenyl (eg 1-cycloheptenyl), cyclooctenyl (eg 1-cyclooctenyl) and the like. Cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl are preferable. Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
　「アリール」とは、単環芳香族炭化水素基（例：フェニル）及び多環芳香族炭化水素基（例：１－ナフチル、２－ナフチル、１－アントリル、２－アントリル、９－アントリル、１－フェナントリル、２－フェナントリル、３－フェナントリル、４－フェナントリル、９－フェナントリル等）を意味する。好ましくは、フェニル又はナフチル（１－ナフチル、２－ナフチル）が挙げられる。 “Aryl” means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferable is phenyl or naphthyl (1-naphthyl, 2-naphthyl).
　「ヘテロアリール」とは、単環芳香族複素環式基及び縮合芳香族複素環式基を意味する。
　「単環芳香族複素環式基」とは、酸素原子、硫黄原子および窒素原子から任意に選択される同一または異なるヘテロ原子を環内に１以上有する５～８員の芳香環から誘導される、置換可能な任意の位置に結合手を有していてもよい基を意味する。
　「縮合芳香族複素環式基」は、酸素原子、硫黄原子および窒素原子から任意に選択される同一または異なるヘテロ原子を環内に１以上有する５～８員の芳香環が、１～４個の５～８員の芳香族炭素環もしくは他の５～８員の芳香族ヘテロ環と縮合している、置換可能な任意の位置に結合手を有していてもよい基を意味する。
“Heteroaryl” refers to monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.
The “monocyclic aromatic heterocyclic group” is derived from a 5- to 8-membered aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom in the ring. And a group which may have a bond at any substitutable position.
The “fused aromatic heterocyclic group” has 1 to 4 5- to 8-membered aromatic rings having one or more hetero atoms in the ring which are optionally selected from an oxygen atom, a sulfur atom and a nitrogen atom. And a group optionally having a bond at any substitutable position which is condensed with the other 5- to 8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle.
　「ヘテロアリール」としては、例えば、フリル（例：　２－フリル、３－フリル）、チエニル（例：　２－チエニル、３－チエニル）、ピロリル（例：　１－ピロリル、２－ピロリル、３－ピロリル）、イミダゾリル（例：　１－イミダゾリル、２－イミダゾリル、４－イミダゾリル）、ピラゾリル（例：　１－ピラゾリル、３－ピラゾリル、４－ピラゾリル）、トリアゾリル（例：　１，２，４－トリアゾール－１－イル、１，２，４－トリアゾール－３－イル、１，２，４－トリアゾール－４－イル）、テトラゾリル（例：１－テトラゾリル、２－テトラゾリル、５－テトラゾリル）、オキサゾリル（例：２－オキサゾリル、４－オキサゾリル、５－オキサゾリル）、イソキサゾリル（例：３－イソキサゾリル、４－イソキサゾリル、５－イソキサゾリル）、チアゾリル（例：２－チアゾリル、４－チアゾリル、５－チアゾリル）、チアジアゾリル、イソチアゾリル（例：３－イソチアゾリル、４－イソチアゾリル、５－イソチアゾリル）、ピリジル（例：２－ピリジル、３－ピリジル、４－ピリジル）、ピリダジニル（例：３－ピリダジニル、４－ピリダジニル）、ピリミジニル（例：２－ピリミジニル、４－ピリミジニル、５－ピリミジニル）、フラザニル（例：３－フラザニル）、ピラジニル（例：２－ピラジニル）、オキサジアゾリル（例：１，３，４－オキサジアゾール－２－イル）、ベンゾフリル（例：２－ベンゾ［ｂ］フリル、３－ベンゾ［ｂ］フリル、４－ベンゾ［ｂ］フリル、５－ベンゾ［ｂ］フリル、６－ベンゾ［ｂ］フリル、７－ベンゾ［ｂ］フリル）、ベンゾチエニル（例：２－ベンゾ［ｂ］チエニル、３－ベンゾ［ｂ］チエニル、４－ベンゾ［ｂ］チエニル、５－ベンゾ［ｂ］チエニル、６－ベンゾ［ｂ］チエニル、７－ベンゾ［ｂ］チエニル）、ベンゾイミダゾリル（例：１－ベンゾイミダゾリル、２－ベンゾイミダゾリル、４－ベンゾイミダゾリル、５－ベンゾイミダゾリル）、ジベンゾフリル、ベンゾオキサゾリル、ベンゾチアゾリル、キノキサリル（例：２－キノキサリニル、５－キノキサリニル、６－キノキサリニル）、シンノリニル（例：３－シンノリニル、４－シンノリニル、５－シンノリニル、６－シンノリニル、７－シンノリニル、８－シンノリニル）、キナゾリル（例：２－キナゾリニル、４－キナゾリニル、５－キナゾリニル、６－キナゾリニル、７－キナゾリニル、８－キナゾリニル）、キノリル（例：２－キノリル、３－キノリル、４－キノリル、５－キノリル、６－キノリル、７－キノリル、８－キノリル）、フタラジニル（例：１－フタラジニル、５－フタラジニル、６－フタラジニル）、イソキノリル（例：１－イソキノリル、３－イソキノリル、４－イソキノリル、５－イソキノリル、６－イソキノリル、７－イソキノリル、８－イソキノリル）、プリル、プテリジニル（例：２－プテリジニル、４－プテリジニル、６－プテリジニル、７－プテリジニル）、カルバゾリル、フェナントリジニル、アクリジニル（例：１－アクリジニル、２－アクリジニル、３－アクリジニル、４－アクリジニル、９－アクリジニル）、インドリル（例：１－インドリル、２－インドリル、３－インドリル、４－インドリル、５－インドリル、６－インドリル、７－インドリル）、イソインドリル、ファナジニル（例：１－フェナジニル、２－フェナジニル）又はフェノチアジニル（例：１－フェノチアジニル、２－フェノチアジニル、３－フェノチアジニル、４－フェノチアジニル）等が挙げられる。 Examples of “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl). ), Imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg, 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, -Isoxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg 2-pyridyl, 3-thiazolyl) Pyridinyl, 4-pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg, 3-furazanyl), pyrazinyl (eg: 2-pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] Furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl Benzothienyl (eg, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [ b] thienyl), benzimidazolyl (eg, 1-benzimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, benzothiazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6- Quinoxalinyl), cinnolinyl (eg: 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6- Quinazolinyl, 7-quinazolini 8-quinazolinyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg, 1-phthalazinyl, 5-quinolyl) Phthalazinyl, 6-phthalazinyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1 -In-drill, 2-in-drill, 3-in-drill, -Indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, fanadinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl) , 4-phenothiazinyl) and the like.
　「ヘテロサイクリル」とは、窒素原子、酸素原子、又は硫黄原子を少なくとも１以上環内に有する環、または、そのような環にシクロアルカン（５～６員が好ましい）、ベンゼン環および／または窒素原子、酸素原子、又は硫黄原子を少なくとも１以上環内に有する環が縮合した環に、置換可能な任意の位置に結合手を有していてもよい非芳香族複素環式基を意味する。なお、「非芳香族複素環式基」は、非芳香族であれば、飽和でも不飽和でもよい。好ましくは５～８員環である。例えば、1-ピロリニル、2-ピロリニル、3-ピロリニル、1-ピロリジニル、2-ピロリジニル、3-ピロリジニル、1-イミダゾリニル、2-イミダゾリニル、4-イミダゾリニル、1-イミダゾリジニル、2-イミダゾリジニル、4-イミダゾリジニル、1-ピラゾリニル、3-ピラゾリニル、4-ピラゾリニル、1-ピラゾリジニル、3-ピラゾリジニル、4-ピラゾリジニル、ピペリジノ、2-ピペリジニル、3-ピペリジニル、4-ピペリジニル、1-ピペラジニル、2-ピペラジニル、2-モルホリニル、3-モルホリニル、モルホリノ、テトラヒドロピラニル、1,2,3,4-テトラヒドロイソキノリニル、1,2,3,4-テトラヒドロキノリニル、1,3-ジヒドロ-2H-イソインドール-5-イル等が挙げられる。
　さらに、「ヘテロサイクリル」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000020
 “Heterocyclyl” means a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring, or cycloalkane (preferably 5-6 members), benzene ring and / or such ring A non-aromatic heterocyclic group which may have a bond at any substitutable position on a ring condensed with a ring having at least one nitrogen atom, oxygen atom or sulfur atom in the ring. . The “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic. A 5- to 8-membered ring is preferred. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,3-dihydro-2H-isoindole-5- Ir etc. are mentioned.
Furthermore, “heterocyclyl” includes a group which forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000020
　「アシル」とは、ホルミル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のシクロアルキルカルボニル、置換もしくは非置換のシクロアルケニルカルボニル、置換もしくは非置換のアリールカルボニル、置換もしくは非置換のヘテロアリールカルボニル、置換もしくは非置換のヘテロサイクリルカルボニルを意味する。
　「アルキルカルボニル」、「アルケニルカルボニル」、「シクロアルキルカルボニル」、「シクロアルケニルカルボニル」、「アリールカルボニル」、「ヘテロアリールカルボニル」、「ヘテロサイクリルカルボニル」の「アルキル」部分、「アルケニル」部分、「シクロアルキル」部分、「シクロアルケニル」部分、「アリール」部分、「ヘテロアリール」部分、「ヘテロサイクリル」部分は、それぞれ、上記「アルキル」、「アルケニル」、「シクロアルキル」、「シクロアルケニル」、「アリール」、「ヘテロアリール」、「ヘテロサイクリル」を意味する。 “Acyl” refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, It means substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl.
“Alkylcarbonyl”, “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl”, “heterocyclylcarbonyl” “alkyl” moiety, “alkenyl” moiety, The “cycloalkyl” moiety, “cycloalkenyl” moiety, “aryl” moiety, “heteroaryl” moiety, and “heterocyclyl” moiety are the above “alkyl”, “alkenyl”, “cycloalkyl”, “cycloalkenyl”, respectively. ”,“ Aryl ”,“ heteroaryl ”,“ heterocyclyl ”.
　「アルキルオキシ」、「アルキルチオ」、「アルキルスルフィニル」、「アルキルスルホニル」および「アルキルオキシカルボニル」のアルキル部分は、上記「アルキル」を意味する。
　「アルケニルオキシ」、「アルケニルチオ」、「アルケニルスルフィニル」、「アルケニルスルホニル」および「アルケニルオキシカルボニル」のアルケニル部分は、上記「アルケニル」を意味する。
　「アリールオキシ」、「アリールチオ」、「アリールスルフィニル」および「アリールスルホニル」のアリール部分は、上記「アリール」を意味する。
　「ヘテロアリールオキシ」、「ヘテロアリールチオ」、「ヘテロアリールスルフィニル」および「ヘテロアリールスルホニル」のヘテロアリール部分は、上記「ヘテロアリール」を意味する。
　「シクロアルキルオキシ」、「シクロアルキルチオ」、「シクロアルキルスルフィニル」および「シクロアルキルスルホニル」のシクロアルキル部分は、上記「シクロアルキル」を意味する。
　「シクロアルケニルオキシ」、「シクロアルケニルチオ」、「シクロアルケニルスルフィニル」および「シクロアルケニルスルホニル」のシクロアルケニル部分は、上記「シクロアルケニル」を意味する。
　「ヘテロサイクリルオキシ」、「ヘテロサイクリルチオ」、「ヘテロサイクリルスルフィニル」および「ヘテロサイクリルスルホニル」のヘテロサイクリル部分は、上記「ヘテロサイクリル」を意味する。 The alkyl part of “alkyloxy”, “alkylthio”, “alkylsulfinyl”, “alkylsulfonyl” and “alkyloxycarbonyl” means the above “alkyl”.
The alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl” and “alkenyloxycarbonyl” means the above “alkenyl”.
The aryl part of “aryloxy”, “arylthio”, “arylsulfinyl” and “arylsulfonyl” means the above “aryl”.
The heteroaryl part of “heteroaryloxy”, “heteroarylthio”, “heteroarylsulfinyl” and “heteroarylsulfonyl” means the above “heteroaryl”.
The cycloalkyl part of “cycloalkyloxy”, “cycloalkylthio”, “cycloalkylsulfinyl” and “cycloalkylsulfonyl” means the above “cycloalkyl”.
The cycloalkenyl part of “cycloalkenyloxy”, “cycloalkenylthio”, “cycloalkenylsulfinyl” and “cycloalkenylsulfonyl” means the above “cycloalkenyl”.
The heterocyclyl part of “heterocyclyloxy”, “heterocyclylthio”, “heterocyclylsulfinyl” and “heterocyclylsulfonyl” means the above “heterocyclyl”.
　「置換アルキル」、「置換アルケニル」、「置換アルキニル」、「置換アルキルオキシ」、「置換アルケニルオキシ」、「置換アルキルチオ」、「置換アルケニルチオ」、「置換アルキルスルフィニル」、「置換アルケニルスルフィニル」、「置換アルキルスルホニル」、「置換アルケニルスルホニル」、「置換アシル」、「置換カルバモイル」、「置換スルファモイル」、「置換アルキルオキシカルボニル」、「置換アルケニルオキシカルボニル」、「置換アミノ」、「置換アリール」、「置換ヘテロアリール」、「置換シクロアルキル」、「置換シクロアルケニル」、「置換ヘテロサイクリル」、「置換アリールオキシ」、「置換ヘテロアリールオキシ」、「置換シクロアルキルオキシ」、「置換シクロアルケニルオキシ」、「置換ヘテロサイクリルオキシ」、「置換アリールチオ」、「置換ヘテロアリールチオ」、「置換シクロアルキルチオ」、「置換シクロアルケニルチオ」、「置換ヘテロサイクリルチオ」、「置換アリールスルフィニル」、「置換ヘテロアリールスルフィニル」、「置換シクロアルキルスルフィニル」、「置換シクロアルケニルスルフィニル」、「置換ヘテロサイクリルスルフィニル」、「置換アリールスルホニル」、「置換ヘテロアリールスルホニル」、「置換シクロアルキルスルホニル」、「置換シクロアルケニルスルホニル」、「置換ヘテロサイクリルスルホニル」、「Ｒ６とＲ６Ａが隣接する炭素原子と一緒になって形成する環」、「Ｒ６とＲ６Ａが隣接する炭素原子と一緒になって形成するアルキリデン」または「Ｒ１０ＡとＲ１０Ｂが隣接する窒素原子と一緒になって形成する環」における置換基としては、例えば、
ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、
置換もしくは非置換のアルキル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、アルキルオキシ、置換もしくは非置換のアシル（置換基としては、ヒドロキシ、－ＣＨ２ＯＨ）、置換もしくは非置換のカルバモイル（置換基としては、アルキル、－ＣＨ２ＣＨ２ＯＨ）、アルキルオキシカルボニル、置換もしくは非置換のアミノ（置換基としては、アルキル、アシル）。例：メチル、エチル、イソプロピル、ｔｅｒｔ－ブチル、－ＣＦ３、１－ピロリジニルメチル）、
置換もしくは非置換のアルケニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：ビニル）、
置換もしくは非置換のアルキニル（置換基としては、置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：エチニル）、
置換もしくは非置換のアリール（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、置換もしくは非置換のアシル（置換基としては、アルキルオキシ。）。例：フェニル、ナフチル）、
置換もしくは非置換のシクロアルキル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：シクロプロピル、シクロブチル、シクロペンチル）、
置換もしくは非置換のシクロアルケニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：シクロプロペニル）、
置換もしくは非置換のヘテロアリール（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のヘテロサイクリル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、オキソ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、アルキルオキシカルボニル、アルキルスルホニル。）、
置換もしくは非置換のアルキルオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、置換もしくは非置換のアリール（置換基としては、アルキルオキシ）、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：メトキシ、エトキシ）、
置換もしくは非置換のアリールオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：フェニルオキシ）、
置換もしくは非置換のヘテロアリールオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のシクロアルキルオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のシクロアルケニルオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のヘテロサイクリルオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のアリールアルキル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のアリールアルキルオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：ベンジルオキシ）、
置換もしくは非置換のアミノ（例：アルキルアミノ（例：メチルアミノ、エチルアミノ、ジメチルアミノ）、置換もしくは非置換のアシルアミノ（置換基としては、ヒドロキシ、アルキル、アシル、アルキルスルホニル、アルキルアミノ、アミノ、アシルアミノ、アルキルオキシ、アルキルオキシカルボニル、置換もしくは非置換のヘテロサイクリル（置換基としては、アルキル。）、カルバモイル。例：アセチルアミノ、ベンゾイルアミノ）、アリールアミノ、アリールアルキルアミノ（例：ベンジルアミノ、トリチルアミノ）、ヒドロキシアミノ、アルキルオキシカルボニルアミノ、アルキルスルホニルアミノ、置換もしくは非置換のカルバモイルアミノ（置換基としては、アルキル、ヘテロアリールアルキル。）、ヘテロサイクリルカルボニルアミノ、アリールスルホニルアミノ、ヘテロアリールスルホニルアミノ、置換もしくは非置換のスルファモイルアミノ（置換基としては、アルキル。））、
置換もしくは非置換のカルバモイル（置換基としては、置換もしくは非置換のアルキル（置換基としては、ヒドロキシ、カルボキシ、シアノ、置換もしくは非置換のシクロアルキル（置換基としては、カルバモイル、－ＣＨ２ＯＨ。）、置換もしくは非置換のアリール（置換基としては、ヒドロキシ。）、ヘテロアリール、ヘテロサイクリル、置換もしくは非置換のカルバモイル（置換基としては、アルキル。）、アルキルオキシ、アルキルスルホニル、アルキルカルバモイル、スルファモイル、アシルアミノ。）、アリール、置換もしくは非置換のシクロアルキル（置換基としては、ヒドロキシ、－ＣＨ２ＯＨ、アルキル、アルキルオキシ、カルバモイル。）、ヘテロアリール、置換もしくは非置換のヘテロサイクリル（置換基としては、ヒドロキシ、アルキル、－ＣＨ２ＯＨ、－ＣＨ２Ｃ（＝Ｏ）ＮＨ２。）、置換もしくは非置換のヘテロアリールアルキル（置換基としては、アルキル。）、アシルアミノアルキル、ヘテロサイクリルアルキル、アルキルアミノアルキル、Ｃ２Ｈ４ＯＨ、アルキルオキシアルキル。例：アルキルカルバモイル（例：メチルカルバモイル、エチルカルバモイル、プロピルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、イソプロピルカルバモイル）、ヘテロアリールアルキルカルバモイル。）、
置換もしくは非置換のカルバモイルオキシ（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のアシル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、置換もしくは非置換のアルキル（置換基としては、ヒドロキシ、シクロアルキル、アルキルオキシ、カルバモイル。）、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、アルキルオキシ、アルキルオキシカルボニル、アルキルオキシアルキル、アルキルアミノ、カルバモイルオキシ、置換もしくは非置換のカルバモイル（置換基としては、アルキル。）、アシルアミノ、アルキルスルホニル、アルキルオキシイミノ、オキソ。例：アルキルカルボニル、アリールカルボニル、ヘテロアリールカルボニル、ヘテロサイクリルカルボニル、ホルミル、アセチル、４－メチルピペラジニルカルボニル。）、
置換もしくは非置換のアルキルスルホニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：メタンスルホニル、エタンスルホニル）、
置換もしくは非置換のアリールスルホニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のヘテロアリールスルホニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のシクロアルキルスルホニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のシクロアルケニルスルホニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のヘテロサイクリルスルホニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のスルファモイル（置換基としては、ヒドロキシ、置換もしくは非置換のアルキル（置換基としては、ヒドロキシ、ヘテロアリール、シクロアルキル、ヘテロサイクリル、アルキルオキシ。）、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、Ｃ２Ｈ４ＯＨ）、
置換もしくは非置換のアルキルオキシカルボニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。例：メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル）、
置換もしくは非置換のシリルオキシ、
アリールオキシカルボニル、ヘテロアリールオキシカルボニル、ヘテロサイクリルオキシカルボニル、
アルキルスルフィニル、シクロアルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、ヘテロサイクリルスルフィニル、
ニトロソ、
アルケニルオキシ（例：ビニルオキシ、アリルオキシ）、
アジド、
イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、
アルキルチオ（例：メチルチオ）、
Ｐ（＝Ｏ）（ＯＨ）２、
ホルミルオキシ、ハロホルミル、オキザロ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、スルホアミノ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、フタルイミド、オキソ、式：－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂで示される基、式：－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃで示される基、式：－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂで示される基、式：－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂで示される基、式：－ＳＯ２ＮＲ１０ＡＲ１０Ｂで示される基、式：－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃで示される基、式：－ＳＯ２－Ｒ１０Ｃで示される基等からなる群から選択される基があげられる。１～４個の当該置換基で置換されていてもよい。ここで、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、またはＲ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよく、Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、Ｒ１０Ｄは水素または置換もしくは非置換のアルキルである。 “Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkylthio”, “substituted alkenylthio”, “substituted alkylsulfinyl”, “substituted alkenylsulfinyl”, “Substituted alkylsulfonyl”, “substituted alkenylsulfonyl”, “substituted acyl”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted amino”, “substituted aryl” , “Substituted heteroaryl”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted heterocyclyl”, “substituted aryloxy”, “substituted heteroaryloxy”, “substituted cycloalkyloxy”, “substituted cycloalkenyl” Oxy ”,“ Substitute Hete "Cyclyloxy", "substituted arylthio", "substituted heteroarylthio", "substituted cycloalkylthio", "substituted cycloalkenylthio", "substituted heterocyclylthio", "substituted arylsulfinyl", "substituted heteroarylsulfinyl", “Substituted cycloalkylsulfinyl”, “substituted cycloalkenylsulfinyl”, “substituted heterocyclylsulfinyl”, “substituted arylsulfonyl”, “substituted heteroarylsulfonyl”, “substituted cycloalkylsulfonyl”, “substituted cycloalkenylsulfonyl”, “ substituted heterocyclyl sulfonyl "," ring R 6 and R 6A are formed together with the adjacent carbon atom "," alkylidene R 6 and R 6A are formed together with the carbon atom adjacent "or" R 10A and R 10B is Examples of the substituent in the ring "formed together with the nitrogen atom which is in contact, for example,
Halogen, hydroxy, carboxy, nitro, cyano,
Substituted or unsubstituted alkyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, alkyloxy, substituted or unsubstituted acyl (substituted) As the group, hydroxy, —CH 2 OH), substituted or unsubstituted carbamoyl (substituent is alkyl, —CH 2 CH 2 OH), alkyloxycarbonyl, substituted or unsubstituted amino (substituent is Alkyl, acyl), eg, methyl, ethyl, isopropyl, tert-butyl, —CF 3 , 1-pyrrolidinylmethyl),
Substituted or unsubstituted alkenyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, eg vinyl),
Substituted or unsubstituted alkynyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, eg ethynyl),
Substituted or unsubstituted aryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, substituted or unsubstituted acyl (substituents , Alkyloxy)), eg phenyl, naphthyl),
Substituted or unsubstituted cycloalkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, such as cyclopropyl, cyclobutyl, cyclopentyl),
Substituted or unsubstituted cycloalkenyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, eg cyclopropenyl),
Substituted or unsubstituted heteroaryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted heterocyclyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, oxo, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, alkyloxycarbonyl, alkylsulfonyl. ),
Substituted or unsubstituted alkyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, substituted or unsubstituted aryl (substituent is alkyloxy), heteroaryl, cycloalkyl, cycloalkenyl, Heterocyclyl, eg methoxy, ethoxy),
Substituted or unsubstituted aryloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, eg, phenyloxy),
Substituted or unsubstituted heteroaryloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted cycloalkyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted cycloalkenyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted heterocyclyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted arylalkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted arylalkyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, eg benzyloxy),
Substituted or unsubstituted amino (eg, alkylamino (eg, methylamino, ethylamino, dimethylamino), substituted or unsubstituted acylamino (substituents are hydroxy, alkyl, acyl, alkylsulfonyl, alkylamino, amino, Acylamino, alkyloxy, alkyloxycarbonyl, substituted or unsubstituted heterocyclyl (the substituent is alkyl), carbamoyl, eg acetylamino, benzoylamino, arylamino, arylalkylamino (eg, benzylamino, Tritylamino), hydroxyamino, alkyloxycarbonylamino, alkylsulfonylamino, substituted or unsubstituted carbamoylamino (substituents are alkyl, heteroarylalkyl), heterocyclylca Boniruamino, arylsulfonylamino, heteroaryl-sulfonylamino, substituted or unsubstituted sulfamoylamino (Examples of the substituent include an alkyl.)),
Substituted or unsubstituted carbamoyl (substituent is substituted or unsubstituted alkyl (substituent is hydroxy, carboxy, cyano, substituted or unsubstituted cycloalkyl (substituent is carbamoyl, —CH 2 OH. ), Substituted or unsubstituted aryl (hydroxy is substituted), heteroaryl, heterocyclyl, substituted or unsubstituted carbamoyl (alkyl is substituted), alkyloxy, alkylsulfonyl, alkylcarbamoyl, Sulfamoyl, acylamino.), Aryl, substituted or unsubstituted cycloalkyl (substituents are hydroxy, —CH 2 OH, alkyl, alkyloxy, carbamoyl.), Heteroaryl, substituted or unsubstituted heterocyclyl (substituted) As a basis , Hydroxy, alkyl, —CH 2 OH, —CH 2 C (═O) NH 2. ), Substituted or unsubstituted heteroarylalkyl (alkyl as a substituent), acylaminoalkyl, heterocyclylalkyl, Alkylaminoalkyl, C 2 H 4 OH, alkyloxyalkyl, eg, alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, isopropylcarbamoyl), heteroarylalkylcarbamoyl).
Substituted or unsubstituted carbamoyloxy (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted acyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl (substituents are hydroxy, cycloalkyl, alkyloxy, carbamoyl), aryl, heteroaryl , Cycloalkyl, cycloalkenyl, heterocyclyl, alkyloxy, alkyloxycarbonyl, alkyloxyalkyl, alkylamino, carbamoyloxy, substituted or unsubstituted carbamoyl (the substituent is alkyl), acylamino, alkylsulfonyl, alkyl Oxyimino, oxo, eg alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, formyl, acetyl, 4-methylpiperazinylcarbonyl)
Substituted or unsubstituted alkylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, for example, methanesulfonyl, ethanesulfonyl),
Substituted or unsubstituted arylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted heteroarylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted cycloalkylsulfonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted cycloalkenylsulfonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted heterocyclylsulfonyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted sulfamoyl (substituent is hydroxy, substituted or unsubstituted alkyl (substituent is hydroxy, heteroaryl, cycloalkyl, heterocyclyl, alkyloxy), aryl, heteroaryl, cycloalkyl , Cycloalkenyl, heterocyclyl, C 2 H 4 OH),
Substituted or unsubstituted alkyloxycarbonyl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl. Examples: methoxycarbonyl, ethoxycarbonyl, tert -Butoxycarbonyl),
Substituted or unsubstituted silyloxy,
Aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl,
Alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl,
Nitroso,
Alkenyloxy (eg vinyloxy, allyloxy),
Azide,
Isocyanato, isocyanato, thiocyanato, isothiocyanato, mercapto,
Alkylthio (eg methylthio),
P (= O) (OH) 2 ,
Formyloxy, haloformyl, oxaro, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino, ureido, amidino, guanidino, phthalimide, oxo, represented by the formula: —C (═O) NR 10A R 10B A group represented by the formula: —NR 10D —C (═O) —R 10C , a group represented by the formula: —NR 10D —C (═O) —NR 10A R 10B , a formula: —NR 10D —S (═O) 2 —NR 10A R 10B , group represented by formula: —SO 2 NR 10A R 10B , group represented by formula: —NR 10D SO 2 —R 10C , formula: —SO 2 — And groups selected from the group consisting of groups represented by R 10C and the like. It may be substituted with 1 to 4 such substituents. Wherein R 10A and R 10B are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, or R 10A and R 10B together with the adjacent nitrogen atom are substituted or unsubstituted rings R 10C may be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted A heterocyclyl alkenyl or substituted or unsubstituted, R 10D is hydrogen or a substituted or unsubstituted alkyl.
　「置換カルバモイル」、「置換スルファモイル」、「置換イミノ」または「置換アミノ」の置換基としては、好ましくは、
置換もしくは非置換のアルキル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のアリール（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、アルキルスルホニル。）、
置換もしくは非置換のヘテロアリール（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のシクロアルキル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のシクロアルケニル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
置換もしくは非置換のヘテロサイクリル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル、アルキルオキシカルボニル、アルキルスルホニル。）、置換もしくは非置換のアシル（置換基としては、ハロゲン、ヒドロキシ、カルボキシ、ニトロ、シアノ、アルキル、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル、ヘテロサイクリル。）、
アルキルオキシカルボニル、アリールアルキル、アルキルオキシ、アリールオキシ、ヘテロアリールオキシ、シクロアルキルオキシ、シクロアルケニルオキシ、ヘテロサイクリルオキシ、アリールオキシカルボニル、ヘテロアリールオキシカルボニル、ヘテロサイクリルオキシカルボニル、スルファモイル、アルキルスルホニル、アリールスルホニル、ヘテロアリールスルホニル、シクロアルキルスルホニル、シクロアルケニルスルホニル、ヘテロサイクリルスルホニル、カルバモイル、ヒドロキシ、アルキルスルフィニル、シクロアルキルスルフィニル、アリールスルフィニル、ヘテロアリールスルフィニル、ヘテロサイクリルスルフィニル、アミノなどが挙げられる。 As the substituent of “substituted carbamoyl”, “substituted sulfamoyl”, “substituted imino” or “substituted amino”, preferably
Substituted or unsubstituted alkyl (halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl)
Substituted or unsubstituted aryl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, alkylsulfonyl),
Substituted or unsubstituted heteroaryl (substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted cycloalkyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted cycloalkenyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Substituted or unsubstituted heterocyclyl (the substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, alkyloxycarbonyl, alkylsulfonyl), Substituted or unsubstituted acyl (substituents are halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl),
Alkyloxycarbonyl, arylalkyl, alkyloxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclyloxy, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, sulfamoyl, alkylsulfonyl, Examples include arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heterocyclylsulfonyl, carbamoyl, hydroxy, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, amino and the like.
　「アリールアルキル」、「アリールアルキルオキシ」、「アルキルアミノ」、「アリールアルキルアミノ」、「アルキルアミノアルキル」、「アルキルオキシカルボニルアミノ」、「アルキルスルホニルアミノ」、「アシルアミノアルキル」、「アルキルオキシアルキル」、「アルキルカルバモイル」、「ヘテロアリールアルキルカルバモイル」、「アルキルオキシイミノ」および「アルキルカルボニル」のアルキル部分は、上記「アルキル」を意味する。
　「アリールアルキル」、「アリールアルキルオキシ」、「アリールアミノ」、「アリールアルキルアミノ」、「アリールスルホニルアミノ」、「アリールカルボニル」および「アリールオキシカルボニル」のアリール部分は、上記「アリール」を意味する。
　「ヘテロアリールスルホニルアミノ」、「ヘテロアリールアルキル」、「ヘテロアリールアルキルカルバモイル」、「ヘテロアリールカルボニル」および「ヘテロアリールオキシカルボニル」のヘテロアリール部分は、上記「ヘテロアリール」を意味する。
　「ヘテロサイクリルカルボニルアミノ」、「ヘテロサイクリルアルキル」、「ヘテロサイクリルカルボニル」および「ヘテロサイクリルオキシカルボニル」のヘテロサイクリル部分は、上記「ヘテロサイクリル」を意味する。 “Arylalkyl”, “arylalkyloxy”, “alkylamino”, “arylalkylamino”, “alkylaminoalkyl”, “alkyloxycarbonylamino”, “alkylsulfonylamino”, “acylaminoalkyl”, “alkyloxy” The alkyl part of “alkyl”, “alkylcarbamoyl”, “heteroarylalkylcarbamoyl”, “alkyloxyimino” and “alkylcarbonyl” means the above “alkyl”.
The aryl part of “arylalkyl”, “arylalkyloxy”, “arylamino”, “arylalkylamino”, “arylsulfonylamino”, “arylcarbonyl” and “aryloxycarbonyl” means the above “aryl” .
The heteroaryl part of “heteroarylsulfonylamino”, “heteroarylalkyl”, “heteroarylalkylcarbamoyl”, “heteroarylcarbonyl” and “heteroaryloxycarbonyl” means the above “heteroaryl”.
The heterocyclyl part of “heterocyclylcarbonylamino”, “heterocyclylalkyl”, “heterocyclylcarbonyl” and “heterocyclyloxycarbonyl” means the above “heterocyclyl”.
　本発明化合物のうち、以下の態様の化合物が好ましい。 Among the compounds of the present invention, the following compounds are preferable.
　Ｘは＝Ｃ（Ｒ２）－または＝Ｎ－であり、好ましくは＝Ｎ－である。 X is = C (R 2 )-or = N-, preferably = N-.
　Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノである。
　好ましくは、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルである。更に好ましくは、水素である。 R 1 , R 2 and R 4 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl Substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkyl Kenyloxycarbonyl or substituted or unsubstituted amino.
Preferably, it is hydrogen, halogen, cyano or substituted or unsubstituted alkyl. More preferred is hydrogen.
　Ｒ３は置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。
　好ましくは、置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルである。
　さらに好ましくは、置換アリール、置換ヘテロアリールまたは置換ヘテロサイクリルである。
　該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であることが好ましい。
　該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であることがさらに好ましい。
　該置換基の少なくとも一つが上記群から選択される基である場合、該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリルは他の置換基や上記群から選択される基でさらに置換されていてもよい。
　Ｒ３として、例えば、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000022
　好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
　さらに好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000025
 R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
Preferred is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl.
More preferred is substituted aryl, substituted heteroaryl or substituted heterocyclyl.
At least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl is —C (═O) NR 10A R 10B , —NR 10D —C (═O) —R 10C , —NR 10D -C (= O) -NR 10A R 10B , -NR 10D -S (= O) 2 -NR 10A R 10B , -SO 2 NR 10A R 10B , -NR 10D SO 2 -R 10C and -SO 2 -R A group selected from the group consisting of 10C is preferred.
At least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl consists of —C (═O) NR 10A R 10B , —SO 2 NR 10A R 10B and —SO 2 —R 10C More preferably, it is a group selected from the group.
When at least one of the substituents is a group selected from the above group, the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is further substituted with another substituent or a group selected from the above group. It may be.
Examples of R 3 include the following.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000022
Preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
More preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000025
　Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、またはＲ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよい。
　好ましくは、Ｒ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成する。
　Ｒ１０ＡとＲ１０Ｂが隣接する窒素原子と一緒になって形成する環としては、例えば、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000026
 R 10A and R 10B are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, or R 10A and R 10B together with the adjacent nitrogen atom form a substituted or unsubstituted ring. It may be.
Preferably, R 10A and R 10B together with the adjacent nitrogen atom form a substituted or unsubstituted ring.
Examples of the ring formed by R 10A and R 10B together with the adjacent nitrogen atom include the following.
Figure JPOXMLDOC01-appb-C000026
　Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。
　好ましくは、置換もしくは非置換のアルキル、置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のヘテロサイクリルである。 R 10C is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
Preferred is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl.
　Ｒ１０Ｄは水素または置換もしくは非置換のアルキルであり、好ましくは水素である。 R 10D is hydrogen or substituted or unsubstituted alkyl, preferably hydrogen.
　Ｙ１は－Ｃ（Ｒ７）（Ｒ７Ａ）－または－Ｏ－であり、好ましくは－Ｏ－である。 Y 1 is —C (R 7 ) (R 7A ) — or —O—, preferably —O—.
　Ｙ２は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－または－Ｃ（Ｒ６）（Ｒ６Ａ）－である。
　好ましくは、－Ｃ（Ｒ６）（Ｒ６Ａ）－である。
　ここで、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－における－Ｃ（Ｒ６）（Ｒ６Ａ）－の炭素原子は、スピロ炭素原子に結合するものとする。 Y 2 is —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) — or —C (R 6 ) (R 6A ) —.
Preferred is —C (R 6 ) (R 6A ) —.
Here, -C (R 5) (R 5A) -C (R 6) (R 6A) - -C (R 6) in (R 6A) - carbon atoms, and those that bind to the spiro carbon atom .
　Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
Ｒ６とＲ６Ａは一緒になってオキソまたは置換もしくは非置換のイミノを形成してもよく、
Ｒ６とＲ６Ａは隣接する炭素原子と一緒になって置換もしくは非置換の環または置換もしくは非置換のアルキリデンを形成してもよい。 R 5 , R 5A , R 6 , R 6A , R 7 and R 7A are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
R 6 and R 6A may together form an oxo or substituted or unsubstituted imino;
R 6 and R 6A may be taken together with adjacent carbon atoms to form a substituted or unsubstituted ring or substituted or unsubstituted alkylidene.
　Ｒ６とＲ６Ａが隣接する炭素原子と一緒になって形成する環としては、３～１５の飽和または不飽和の炭化水素環や、酸素原子、硫黄原子、および／または窒素原子を該炭化水素環内に１～４個含んだ飽和または不飽和のヘテロ環を意味する。非芳香環が好ましく、そのような環としては、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテンや、それらに酸素原子、硫黄原子、および／または窒素原子を該炭化水素環内に１～４個含んだ飽和または不飽和のヘテロ環が例示される。
　好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000027
　さらに好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000028
 Examples of the ring formed by R 6 and R 6A together with adjacent carbon atoms include 3 to 15 saturated or unsaturated hydrocarbon rings, oxygen atoms, sulfur atoms, and / or nitrogen atoms. It means a saturated or unsaturated heterocycle containing 1 to 4 rings in the ring. Non-aromatic rings are preferred, and examples of such rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and oxygen and sulfur atoms. And / or a saturated or unsaturated heterocycle containing 1 to 4 nitrogen atoms in the hydrocarbon ring.
Preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000027
More preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000028
　Ｙ２が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である場合、Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルであることが好ましく、特に、Ｒ６およびＲ６Ａがフッ素であることが好ましい。 When Y 2 is —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) —, at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl In particular, R 6 and R 6A are preferably fluorine.
　Ｙ２が－Ｃ（Ｒ６）（Ｒ６Ａ）－である場合、Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルであることが好ましく、特に、Ｒ６およびＲ６Ａの一方が置換もしくは非置換のアルキルであり、他方が水素であることが好ましい。
　Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである場合、他方は水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノである。
When Y 2 is —C (R 6 ) (R 6A ) —, it is preferable that at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl, and in particular, R 6 and R 6A It is preferable that one of these is substituted or unsubstituted alkyl and the other is hydrogen.
When at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl, the other is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Substituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino.
　Ｒ８はシアノ、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、Ｒ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８ＥおよびＲ８Ｆは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基である。
　好ましくは、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは上記と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは上記と同意義である。）で示される基、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｇは上記と同意義である。）で示される基または
式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは上記と同意義である。）で示される基である。
　更に好ましくは、
式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは上記と同意義である。）で示される基である。
　なお、上記式中、－（ＣＲ８ＡＲ８Ｂ）ｐ－は、－（Ｃ（Ｒ８Ａ）（Ｒ８Ｂ））ｐ－と同意義である。 R 8 is cyano,
Formula:-(CR 8A R 8B ) p-R 8C wherein R 8A is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, and R 8B is independently And hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer of 0 to 3, and R 8C is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.),
Formula: — (CR 8A R 8B ) pC (═O) OR 8D (wherein R 8A , R 8B and p are as defined above, and R 8D is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by
Formula: — (CR 8A R 8B ) pC (═O) NR 8E R 8F (wherein R 8A , R 8B and p are as defined above, and R 8E and R 8F are each independently hydrogen) Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkenyl or a substituted or unsubstituted heterocyclyl).
Formula: — (CR 8A R 8B ) pC (═O) R 8G (wherein R 8A , R 8B and p are as defined above, and R 8G is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by
Formula: —S (═O) q—R 8H where R 8H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, q is 1 or 2.) (═O) q—NR 8I R 8J (wherein q is as defined above, R 8I and R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted) Or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloal Le, a group represented by a heterocyclyl cycloalkenyl or substituted or unsubstituted substituted or unsubstituted.).
Preferably,
A group represented by the formula:-(CR 8A R 8B ) p-R 8C (wherein R 8A , R 8B , p and R 8C are as defined above);
A group represented by the formula: — (CR 8A R 8B ) pC (═O) OR 8D (wherein R 8A , R 8B , p and R 8D are as defined above);
A group represented by the formula: — (CR 8A R 8B ) pC (═O) R 8G (wherein R 8A , R 8B , p and R 8G are as defined above) or a formula: —S (═O) q—R 8H (wherein R 8H and q are as defined above).
More preferably,
A group represented by the formula:-(CR 8A R 8B ) pR 8C (wherein R 8A , R 8B , p and R 8C are as defined above).
In the above formula,-(CR 8A R 8B ) p- has the same meaning as- (C (R 8A ) (R 8B )) p-.
　Ｒ８Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、好ましくは水素である。 Each R 8A is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, preferably hydrogen.
　Ｒ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、好ましくは水素である。 Each R 8B is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, preferably hydrogen.
　ｐは０～３の整数であり、好ましくは０または１であり、さらに好ましくは０である。 P is an integer of 0 to 3, preferably 0 or 1, more preferably 0.
　Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。
　好ましくは、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールである。
　さらに好ましくは、置換もしくは非置換のヘテロアリールであり、例えば、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000029
　好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000030
　特に好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000031
 R 8C is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
Preferred is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
More preferably, it is substituted or unsubstituted heteroaryl, for example, the following are mentioned.
Figure JPOXMLDOC01-appb-C000029
Preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000030
The following are particularly preferable.
Figure JPOXMLDOC01-appb-C000031
　Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。
　好ましくは、置換もしくは非置換のアルキルである。 R 8D is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
Preferably, it is substituted or unsubstituted alkyl.
　Ｒ８ＥおよびＲ８Ｆは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。 R 8E and R 8F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
　Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。 R 8G is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
　Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。
　好ましくは、置換もしくは非置換のアルキルである。 R 8H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
Preferably, it is substituted or unsubstituted alkyl.
　ｑは１または２であり、好ましくは２である。 Q is 1 or 2, preferably 2.
　Ｒ８ＩおよびＲ８Ｊは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。 R 8I and R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
　ｍおよびｎは各々独立して０、１または２である。好ましくは、ｍが１であり、かつ、ｎが１である。 M and n are each independently 0, 1 or 2. Preferably, m is 1 and n is 1.
　ｒは０～１２の整数であり、好ましくは０～３の整数である。さらに好ましくは０である。 R is an integer from 0 to 12, preferably an integer from 0 to 3. More preferably, it is 0.
　Ｒ９は各々独立してハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルである。
　ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、および／または、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。 Each R 9 is independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl.
When r is 2 or more, two R 9 bonded to the same carbon atom may be combined to form oxo and / or two R 9 bonded to different carbon atoms are May be combined with the carbon atom to which is bonded to form a substituted or unsubstituted ring.
　ここで、ｒが２以上であり、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成する場合、および／または、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成する場合の式（Ｉ）または式(ＩＩ)における
Figure JPOXMLDOC01-appb-C000032
で示される基としては、例えば、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000033
　（ここで、Ｒ１１は水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のアルキニルである。）
　ここで、「ｒが２以上であり、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって形成する環」における置換基としては、例えば、カルボキシ、ハロゲン、ハロゲン化アルキル（例：ＣＦ３、ＣＨ２ＣＦ３、ＣＨ２ＣＣｌ３）、ニトロ、ニトロソ、シアノ、アルキル（例：メチル、エチル、イソプロピル、ｔｅｒｔ－ブチル）、アルケニル（例：ビニル）、アルキニル（例：エチニル）、シクロアルキル（例：シクロプロピル）、シクロアルキルアルキル（例：シクロヘキシルメチル）、シクロアルケニル（例：シクロプロペニル）、アリール（例：フェニル、ナフチル）、アリールアルキル（例：ベンジル、フェネチル）、ヘテロアリール（例：ピリジル、フリル）、ヘテロアリールアルキル（例：ピリジルメチル）、ヘテロサイクル（例：ピペリジル）、ヘテロサイクルアルキル（例：モルホリルメチル）、アルキルオキシカルボニル（例：メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル）、アルキルアミノアルキル（例：ジエチルアミノメチル）、スルファモイル等が挙げられる。１～４個の当該置換基で置換されていてもよい。 Here, when r is 2 or more and two R 9 bonded to the same carbon atom together form an oxo, and / or two R 9 bonded to different carbon atoms are In formula (I) or formula (II) when a substituted or unsubstituted ring is formed together with the carbon atom to which
Figure JPOXMLDOC01-appb-C000032
Examples of the group represented by: include the following.
Figure JPOXMLDOC01-appb-C000033
(Wherein R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.)
Here, examples of the substituent in “a ring formed by r 9 having two or more R 9 bonded to different carbon atoms together with the carbon atom to which they are bonded” include, for example, carboxy, Halogen, alkyl halide (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3 ), nitro, nitroso, cyano, alkyl (eg, methyl, ethyl, isopropyl, tert-butyl), alkenyl (eg, vinyl), Alkynyl (eg: ethynyl), cycloalkyl (eg: cyclopropyl), cycloalkylalkyl (eg: cyclohexylmethyl), cycloalkenyl (eg: cyclopropenyl), aryl (eg: phenyl, naphthyl), arylalkyl (eg: benzyl) , Phenethyl), heteroaryl (eg, pyridyl, furyl), heteroarylalkyl ( : Pyridylmethyl), heterocycle (eg piperidyl), heterocycle alkyl (eg morpholylmethyl), alkyloxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), alkylaminoalkyl (eg diethylaminomethyl), And sulfamoyl. It may be substituted with 1 to 4 such substituents.
　環Ａは
Figure JPOXMLDOC01-appb-C000034
（ここで、Ｒ１、Ｒ２、Ｒ３ＡおよびＲ４は上記と同意義である。）
である。
　好ましくは、
Figure JPOXMLDOC01-appb-C000035
（ここで、Ｒ１、Ｒ２、Ｒ３ＡおよびＲ４は上記と同意義である。）
である。
　さらに好ましくは、
Figure JPOXMLDOC01-appb-C000036
（ここで、Ｒ１、Ｒ３ＡおよびＲ４は上記と同意義である。）
である。 Ring A is
Figure JPOXMLDOC01-appb-C000034
(Here, R 1 , R 2 , R 3A and R 4 are as defined above.)
It is.
Preferably,
Figure JPOXMLDOC01-appb-C000035
(Here, R 1 , R 2 , R 3A and R 4 are as defined above.)
It is.
More preferably,
Figure JPOXMLDOC01-appb-C000036
(Here, R 1 , R 3A and R 4 are as defined above.)
It is.
　Ｒ３Ａは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアリールオキシ、置換もしくは非置換のヘテロアリールオキシ、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換のヘテロサイクリルオキシ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換のヘテロサイクリルチオ、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換のヘテロサイクリルスルフィニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のヘテロアリールスルホニル、置換もしくは非置換のシクロアルキルスルホニル、置換もしくは非置換のシクロアルケニルスルホニル、置換もしくは非置換のヘテロサイクリルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノである。
　好ましくは、置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルである。
　さらに好ましくは、置換アリール、置換ヘテロアリールまたは置換ヘテロサイクリルである。
　該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であることが好ましい。
　該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であることがさらに好ましい。
　該置換基の少なくとも一つが上記群から選択される基である場合、該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリルは他の置換基や上記群から選択される基でさらに置換されていてもよい。
　Ｒ３Ａとして、例えば、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000038
　好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000040
　さらに好ましくは、以下のものが挙げられる。
Figure JPOXMLDOC01-appb-C000041
 R 3A is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted Or unsubstituted heterocyclyloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted Telocyclylthio, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted heterocyclylsulfinyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl Substituted or unsubstituted carbamoyl or substituted or unsubstituted amino.
Preferred is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl.
More preferred is substituted aryl, substituted heteroaryl or substituted heterocyclyl.
At least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl is —C (═O) NR 10A R 10B , —NR 10D —C (═O) —R 10C , —NR 10D -C (= O) -NR 10A R 10B , -NR 10D -S (= O) 2 -NR 10A R 10B , -SO 2 NR 10A R 10B , -NR 10D SO 2 -R 10C and -SO 2 -R A group selected from the group consisting of 10C is preferred.
At least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl consists of —C (═O) NR 10A R 10B , —SO 2 NR 10A R 10B and —SO 2 —R 10C More preferably, it is a group selected from the group.
When at least one of the substituents is a group selected from the above group, the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is further substituted with another substituent or a group selected from the above group. It may be.
Examples of R 3A include the following.
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000038
Preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000040
More preferably, the following are mentioned.
Figure JPOXMLDOC01-appb-C000041
　Ｙ３は－Ｃ（Ｒ７）（Ｒ７Ａ）－、－Ｃ（＝Ｏ）－または－Ｏ－であり、好ましくは－Ｏ－である。 Y 3 is —C (R 7 ) (R 7A ) —, —C (═O) — or —O—, preferably —O—.
　Ｙ４は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｏ－、－Ｏ－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｏ－または－Ｃ（Ｒ５）＝Ｃ（Ｒ６）－である。
　好ましくは、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－または－Ｃ（Ｒ６）（Ｒ６Ａ）－である。
　さらに好ましくは、－Ｃ（Ｒ６）（Ｒ６Ａ）－である。
　ここで、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－および－Ｏ－Ｃ（Ｒ６）（Ｒ６Ａ）－における－Ｃ（Ｒ６）（Ｒ６Ａ）－の炭素原子は、スピロ炭素原子に結合するものとする。
　－Ｃ（Ｒ５）＝Ｃ（Ｒ６）－における＝Ｃ（Ｒ６）－の炭素原子は、スピロ炭素原子に結合するものとする。 Y 4 represents —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) —, —C (R 5 ) (R 5A ) —O—, —O—C (R 6 ) (R 6A )-, -C (R 6 ) (R 6A )-, -O- or -C (R 5 ) = C (R 6 )-.
Preferably, -C (R 5) (R 5A) -C (R 6) (R 6A) - or -C (R 6) (R 6A ) - a.
More preferred is —C (R 6 ) (R 6A ) —.
Here, -C (R 5) (R 5A) -C (R 6) (R 6A) - and -O-C (R 6) ( R 6A) - -C in (R 6) (R 6A) - This carbon atom shall be bonded to a spiro carbon atom.
-C (R 5) = C ( R 6) - in = C (R 6) - carbon atoms, and those that bind to the spiro carbon atom.
　Ｙ４が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である場合、Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルであることが好ましく、特に、Ｒ６およびＲ６Ａがフッ素であることが好ましい。
When Y 4 is —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) —, at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl In particular, R 6 and R 6A are preferably fluorine.
　Ｙ４が－Ｃ（Ｒ６）（Ｒ６Ａ）－である場合、Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルであることが好ましく、特に、Ｒ６およびＲ６Ａの一方が置換もしくは非置換のアルキルであり、他方が水素であることが好ましい。
　Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである場合、他方は水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノである。 When Y 4 is —C (R 6 ) (R 6A ) —, it is preferable that at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl, and in particular, R 6 and R 6A It is preferable that one of these is substituted or unsubstituted alkyl and the other is hydrogen.
When at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl, the other is hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Substituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino.
　本発明の式（Ｉ）および式（ＩＩ）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）および式（ＩＩ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）および式（ＩＩ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) and formula (II) of the present invention may be replaced with hydrogen, carbon and / or other isotopes, respectively. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compounds of formula (I) and formula (II) also include compounds substituted with such isotopes. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compounds represented by formula (I) and formula (II). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
　式（Ｉ）および式（ＩＩ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）を参照にできる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。
Radiolabeled compounds of the compounds represented by formula (I) and formula (II) can be prepared by methods well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
　本発明化合物の製薬上許容される塩としては、以下の塩が含まれる。
　塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、ストロンチウム塩等のアルカリ土類金属塩；ベリリウム塩、マグネシウム塩、亜鉛塩、遷移金属塩などの金属塩；アンモニウム塩；トリメチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩、メグルミン塩、ジエタノールアミン塩またはエチレンジアミン塩等の脂肪族アミン塩；N,N-ジベンジルエチレンジアミン、ベネタミン塩等のアラルキルアミン塩；ピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等のヘテロ環芳香族アミン塩；テトラメチルアンモニウム塩、テトラエチルアモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第４級アンモニウム塩；アルギニン塩、リジン塩等の塩基性アミノ酸塩等が含まれる。
　酸性塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩；酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩等の有機酸塩；メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のスルホン酸塩；アスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸等が含まれる。 Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and strontium salt; metal salts such as beryllium salt, magnesium salt, zinc salt and transition metal salt; ammonium salt An aliphatic amine salt such as a trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, brocaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; Aralkylamine salts such as salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts; tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltols Examples include quaternary ammonium salts such as liethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt.
Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Acidic amino acids such as aspartate and glutamate are included.
　溶媒和物とは、本発明化合物またはその製薬上許容される塩の溶媒和物を意味し、例えば、アルコール（例：エタノール）和物や水和物等が挙げられる。水和物としては、１水和物、２水和物等を挙げることができる。 The solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.
　本発明の式（Ｉ）および式（ＩＩ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、式（Ｉ）および式（ＩＩ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）および式（ＩＩ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）および式（ＩＩ）で示される化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compounds represented by the formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof may form solvates (for example, hydrates and the like) and / or crystalline polymorphs. The present invention also encompasses such various solvates and polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compounds represented by formula (I) and formula (II). When the compound represented by the formula (I) and the formula (II) or a pharmaceutically acceptable salt thereof is left in the air, it absorbs moisture and adsorbs water or forms a hydrate. There is a case. In addition, the crystalline polymorphs may be formed by recrystallizing the compounds represented by the formulas (I) and (II) or pharmaceutically acceptable salts thereof.
　本発明の式（Ｉ）および式（ＩＩ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）または式（ＩＩ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）または式（ＩＩ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compounds represented by the formulas (I) and (II) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is hydrolyzed by a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I) or formula (II), gastric acid, etc. The compound etc. which are converted into the compound shown by Formula (I) or Formula (II) are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
　式（Ｉ）および式（ＩＩ）で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate acid anhydride, Examples include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl chloride, a suitable sulfonyl anhydride and mixed anhydride, or by reacting with a condensing agent. For example, CH 3 COO—, C 2 H 5 COO—, tert-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3- , PhSO 3- , p-CH 3 PhSO 3 -can be mentioned.
　「アゴニスト」なる用語は、本発明化合物が、ＧＰＲ１１９受容体に対してアゴニスト活性（活性化作用）を有することを意味する。
　「製薬上許容される」なる用語は、予防上又は治療上有害ではないことを意味する。 The term “agonist” means that the compound of the present invention has agonist activity (activation effect) on the GPR119 receptor.
The term “pharmaceutically acceptable” means not prophylactically or therapeutically harmful.
　本発明化合物の一般的製造法を以下に例示する。また、抽出、精製などは、通常の有機化学の実験で行う処理を行えばよい。 The general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
　式（Ｉ－１）で示される化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000042
（式中、各記号は前記と同意義であり、式（Ｉ’－１）で示される化合物は公知の化合物を用いてもよく、公知の化合物から常法により誘導された化合物を用いてもよい。「Ｈａｌ」はハロゲン、「ＬＧ」は脱離基を意味し、ハロゲン、－ＯＭｓ、－ＯＴｓ、－ＯＴｆ、－ＯＮｓ等があげられる。ここで、「Ｍｓ」はメタンスルホニル基、「Ｔｓ」はパラトルエンスルホニル基、「Ｔｆ」はトリフルオロメタンスルホニル基、「Ｎｓ」はオルトニトロベンゼンスルホニル基を表す。ＰＧは保護基を意味し、保護基としてはtert-ブトキシカルボニルまたはベンジル等が挙げられる。） The compound represented by the formula (I-1) can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000042
(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (I′-1) may be a known compound or a compound derived from a known compound by a conventional method. “Hal” means halogen, “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc. Here, “Ms” is a methanesulfonyl group, “Ts” "Represents a p-toluenesulfonyl group," Tf "represents a trifluoromethanesulfonyl group," Ns "represents an orthonitrobenzenesulfonyl group, PG represents a protecting group, and examples of the protecting group include tert-butoxycarbonyl or benzyl. )
第１工程
　式（Ｉ’－１）で示される化合物と、式：（Ｉ’－２）で示される化合物とをピロリジンなどのアミン存在下で反応させ、式（Ｉ’－３）で示される化合物を製造する工程である。
　反応溶媒としては、N,N－ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、飽和炭化水素類（例、シクロヘキサン、ヘキサンなど）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）、エステル類（例、酢酸メチル、酢酸エチルなど）、ケトン類（例、アセトン、メチルエチルケトンなど）、ニトリル類（例、アセトニトリルなど）、アルコール類（例、メタノール、エタノール、ｔ－ブタノールなど）、水およびそれらの混合溶媒等が挙げられる。
　好ましくは、アルコール類（例、メタノール、エタノール、ｔ－ブタノールなど）を用いればよい。
　使用する溶媒が還流する温度で０．５～４８時間反応させればよい。 First Step The compound represented by the formula (I′-1) is reacted with the compound represented by the formula: (I′-2) in the presence of an amine such as pyrrolidine to represent the compound represented by the formula (I′-3). This is a process for producing a compound.
Reaction solvents include N, N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated carbon Hydrogen (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.) , Ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water and a mixed solvent thereof.
Preferably, alcohols (eg, methanol, ethanol, t-butanol, etc.) may be used.
The reaction may be performed at a temperature at which the solvent to be used is refluxed for 0.5 to 48 hours.
第２工程
　式（Ｉ’－３）で示される化合物を還元し式（Ｉ’－４）で示される化合物を製造する工程である。
　溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、アルコール類（例、メタノール、エタノール、ｔ－ブタノールなど）を用いればよい。
　還元剤としては、水素化ほう素ナトリウムなどを用いることができる。
０～６０℃、好ましくは０℃～室温で０．５～１２時間反応させればよい。 Second Step The second step is a step for producing a compound represented by the formula (I′-4) by reducing a compound represented by the formula (I′-3).
As the solvent, the solvent described in Step 1 can be used. Preferably, alcohols (eg, methanol, ethanol, t-butanol, etc.) may be used.
As the reducing agent, sodium borohydride or the like can be used.
The reaction may be performed at 0 to 60 ° C., preferably 0 ° C. to room temperature for 0.5 to 12 hours.
第３工程
　式（Ｉ’－４）で示される化合物を還元し式（Ｉ’－５）で示される化合物を製造する工程である。
　例えば、トリフルオロ酢酸中、トリエチルシランと反応させることで、得ることができる。
　０～８０℃、好ましくは０℃～室温で０．５～２４時間反応させればよい。 Third Step The third step is a step for producing a compound represented by the formula (I′-5) by reducing a compound represented by the formula (I′-4).
For example, it can be obtained by reacting with triethylsilane in trifluoroacetic acid.
The reaction may be performed at 0 to 80 ° C., preferably 0 ° C. to room temperature for 0.5 to 24 hours.
第４工程
　式（Ｉ’－５）で示される化合物の脱保護を行い式（Ｉ’－６）で示される化合物を製造する工程である。保護基の脱保護反応は公知であり、例えばProtective Groups in Organic synthesis, 2nd edition (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1991) に記載の方法で実施することができる。
　溶媒は上記第１工程記載の溶媒を用いることができる。 Fourth Step This is a step for producing a compound represented by the formula (I′-6) by deprotecting the compound represented by the formula (I′-5). The deprotection reaction of the protecting group is known and can be carried out, for example, by the method described in Protective Groups in Organic synthesis, 2nd edition (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1991). .
The solvent described in the first step can be used as the solvent.
第５工程
　式（Ｉ’－６）で示される化合物と、式：ＬＧ－Ｒ８で示される化合物とを反応させ、式（Ｉ’－７）で示される化合物を製造する工程である。
　反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、N,N－ジメチルホルムアミド、ジメチルスルホキシド、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）、ニトリル類（例、アセトニトリルなど）、アルコール類（例、メタノール、エタノール、ｔ－ブタノールなど）等を用いればよい。
　塩基としては、例えば金属水素化物（例、水素化ナトリウムなど）、金属水酸化物（例、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなど）、金属炭酸塩（例、炭酸ナトリウム、炭酸カルシウム、炭酸セシウムなど）、金属アルコキシド（例、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔ－ブトキシドなど）、炭酸水素ナトリウム、金属ナトリウム、金属アミド、有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、２，６－ルチジンなど）、ピリジン、アルキルリチウム（ｎ－ＢｕＬｉ、ｓｅｃ－ＢｕＬｉ、ｔｅｒｔ－ＢｕＬｉ）等が挙げられる。
　好ましくは、金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなど）または有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、２，６－ルチジンなど）を用いればよい。
　０～１５０℃で、０．５～４８時間反応させればよい。
　式：ＬＧ－Ｒ８で示される化合物としては、例えば、ベンゾイルクロリドなどが挙げられる。 A compound represented by the fifth step formula (I'-6), wherein: a compound represented by LG-R 8 is reacted, to produce a compound represented by the formula (I'-7).
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, N, N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ether (Eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), etc. may be used.
Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium bicarbonate, metal sodium, metal amide, organic amine (eg, triethylamine, diisopropylethylamine, DBU) 2,6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
Preferably, a metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.) or an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
The reaction may be performed at 0 to 150 ° C. for 0.5 to 48 hours.
Examples of the compound represented by the formula: LG-R 8 include benzoyl chloride and the like.
第６工程
　式（Ｉ’－７）で示される化合物と、式：Ｒ３－Ｂ（ＯＨ）２で示される化合物とをパラジウム触媒下で反応させ、式（Ｉ－１）で示される化合物を製造する工程である。
　式：Ｒ３－Ｂ（ＯＨ）２で示される化合物については、ボロン酸エステルを用いてもよい。
　溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、N,N－ジメチルホルムアミド、ジメチルアセトアミド、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）またはエーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）を用いればよい。
　塩基としては、工程５記載の塩基を用いることができる。好ましくは、金属炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなど）または有機アミン（例、トリエチルアミン、ジイソプロピルエチルアミン、DBU、２，６－ルチジンなど）を用いればよい。
　反応は、パラジウム触媒（例：Ｐｄ（ＰＰｈ３）４、ＰｄＣｌ２、Ｐｄ（ＯＡｃ）２、Ｐｄ（ｄｂａ）２等）とホスフィン配位子（例：ＰＰｈ３、ＢＩＮＡＰ等）の存在下、使用する溶媒が還流する温度で０．５～１２時間反応させればよい。
マイクロウェーブを用いて反応を行う際は、８０～２００℃で５分～１時間反応させればよい。溶媒は上記記載の溶媒を用いることができる。
　式：Ｒ１－Ｂ（ＯＨ）２で示される化合物としては、たとえば、4-(メトキシカルボニルアミノ)フェニルボロン酸などが挙げられる。 Sixth Step A compound represented by the formula (I′-7) and a compound represented by the formula: R 3 —B (OH) 2 are reacted in the presence of a palladium catalyst to give a compound represented by the formula (I-1). It is a manufacturing process.
For the compound represented by the formula: R 3 —B (OH) 2 , a boronic ester may be used.
As the solvent, the solvent described in Step 1 can be used. Preferably, N, N-dimethylformamide, dimethylacetamide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) or ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) are used. Use it.
As the base, the base described in Step 5 can be used. Preferably, a metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.) or an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
The reaction is used in the presence of a palladium catalyst (eg Pd (PPh 3 ) 4 , PdCl 2 , Pd (OAc) 2 , Pd (dba) 2 etc.) and a phosphine ligand (eg PPh 3 , BINAP etc.) The reaction may be performed for 0.5 to 12 hours at a temperature at which the solvent to be refluxed.
When the reaction is performed using a microwave, the reaction may be performed at 80 to 200 ° C. for 5 minutes to 1 hour. The solvent described above can be used as the solvent.
Examples of the compound represented by the formula: R 1 —B (OH) 2 include 4- (methoxycarbonylamino) phenylboronic acid.
　式（Ｉ－２）で示される化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000043
（式中、各記号は前記と同意義であり、式（Ｉ’－８）で示される化合物は公知の化合物を用いてもよく、公知の化合物から常法により誘導された化合物を用いてもよい。「ａｋ」は炭素数１～３のアルキルを意味する。「Ｈａｌ」はハロゲン、「ＬＧ」は脱離基を意味し、ハロゲン、－ＯＭｓ、－ＯＴｓ、－ＯＴｆ、－ＯＮｓ等があげられる。ここで、「Ｍｓ」はメタンスルホニル基、「Ｔｓ」はパラトルエンスルホニル基、「Ｔｆ」はトリフルオロメタンスルホニル基、「Ｎｓ」はオルトニトロベンゼンスルホニル基を表す。ＰＧは保護基を意味し、保護基としてはtert-ブトキシカルボニルまたはベンジル等が挙げられる。） The compound represented by the formula (I-2) can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000043
Wherein each symbol is as defined above, and the compound represented by the formula (I′-8) may be a known compound or a compound derived from a known compound by a conventional method. “Ak” means alkyl having 1 to 3 carbon atoms, “Hal” means halogen, “LG” means leaving group, and examples thereof include halogen, —OMs, —OTs, —OTf, —ONs and the like. Here, “Ms” represents a methanesulfonyl group, “Ts” represents a paratoluenesulfonyl group, “Tf” represents a trifluoromethanesulfonyl group, “Ns” represents an orthonitrobenzenesulfonyl group, PG represents a protecting group, Examples of the protecting group include tert-butoxycarbonyl and benzyl.)
第７工程
　式（Ｉ’－８）で示される化合物のグリニヤ試薬を調整し、式：（Ｉ’－９）で示される化合物とを反応させ、式（Ｉ’－１０）で示される化合物を製造する工程である。
　溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、エーテル類（例、テトラヒドロフラン、ジエチルエーテル、ジオキサン、１，２－ジメトキシエタンなど）を用いればよい。
　－７８～５０℃、好ましくは０℃～室温で、０．５～２４時間反応させればよい。 Seventh Step A Grignard reagent of a compound represented by the formula (I′-8) is prepared and reacted with a compound represented by the formula: (I′-9) to give a compound represented by the formula (I′-10) It is a manufacturing process.
As the solvent, the solvent described in Step 1 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
The reaction may be performed at −78 to 50 ° C., preferably 0 ° C. to room temperature for 0.5 to 24 hours.
第８工程
　式（Ｉ’－１０）で示される化合物から式（Ｉ’－１１）で示される化合物を製造する工程である。
　臭化水素酸などの強酸中で行えばよい。
　室温～１１０℃で、０．５～２４時間反応させればよい。
Eighth step The eighth step is a step of producing a compound represented by the formula (I'-11) from a compound represented by the formula (I'-10).
It may be performed in a strong acid such as hydrobromic acid.
The reaction may be performed at room temperature to 110 ° C. for 0.5 to 24 hours.
第９工程
　式（Ｉ’－１１）で示される化合物の脱保護を行い式（Ｉ’－１２）で示される化合物を製造する工程である。
　上記第４工程と同様にして行えばよい。 Ninth step The ninth step is a step for producing a compound represented by the formula (I'-12) by deprotecting the compound represented by the formula (I'-11).
What is necessary is just to carry out like the said 4th process.
第１０工程
　式（Ｉ’－１２）で示される化合物と、式：ＬＧ－Ｒ８で示される化合物とを反応させ、式（Ｉ’－１３）で示される化合物を製造する工程である。
　上記第５工程と同様にして行えばよい。 A compound represented by the tenth step formula (I'-12), formula: and a compound represented by LG-R 8 is reacted, to produce a compound represented by the formula (I'-13).
What is necessary is just to carry out like the said 5th process.
第１１工程
　式（Ｉ’－１３）で示される化合物と、式：Ｒ３－Ｂ（ＯＨ）２で示される化合物とをパラジウム触媒下で反応させ、式（Ｉ－２）で示される化合物を製造する工程である。
　上記第６工程と同様にして行えばよい。 Eleventh Step A compound represented by the formula (I′-13) is reacted with a compound represented by the formula: R 3 —B (OH) 2 in the presence of a palladium catalyst to give a compound represented by the formula (I-2). It is a manufacturing process.
What is necessary is just to carry out like the said 6th process.
　式（ＩＩ）中、Ｙ３が－Ｏ－であり、かつ、Ｙ４が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｏ－または－Ｏ－である化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000044
（式中、各記号は前記と同意義であり、式（ＩＩ’－１）で示される化合物は公知の化合物を用いてもよく、公知の化合物から常法により誘導された化合物を用いてもよい。「ＬＧ」は脱離基を意味し、ハロゲン、－ＯＭｓ、－ＯＴｓ、－ＯＴｆ、－ＯＮｓ等があげられる。ここで、「Ｍｓ」はメタンスルホニル基、「Ｔｓ」はパラトルエンスルホニル基、「Ｔｆ」はトリフルオロメタンスルホニル基、「Ｎｓ」はオルトニトロベンゼンスルホニル基を表す。ＰＧは保護基を意味し、保護基としてはtert-ブトキシカルボニルまたはベンジル等が挙げられる。） In the formula (II), a compound in which Y 3 is —O— and Y 4 is —C (R 5 ) (R 5A ) —O— or —O— can be synthesized as follows. it can.
Figure JPOXMLDOC01-appb-C000044
(In the formula, each symbol is as defined above, and the compound represented by the formula (II′-1) may be a known compound or a compound derived from a known compound by a conventional method. “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc. Here, “Ms” is a methanesulfonyl group, and “Ts” is a paratoluenesulfonyl group. , “Tf” represents a trifluoromethanesulfonyl group, “Ns” represents an orthonitrobenzenesulfonyl group, PG represents a protecting group, and examples of the protecting group include tert-butoxycarbonyl and benzyl.)
第１２工程
　式（ＩＩ’－１）で示される化合物と、式：（Ｉ’－２）で示される化合物とを反応させ、式（ＩＩ’－２）で示される化合物を製造する工程である。
　式（ＩＩ’－１）で示される化合物は、市販の化合物を使用することもできるし、よく知られる有機合成反応を行いて製造することができる。環Ａ上に置換基を有する最終物を製造する場合は、そのような環Ａ上の置換基を有する式（ＩＩ’－１）で示される化合物を用いてもよいし、その代わりに、そのような置換基を第１２～１４工程の途中で環Ａに導入してもよいし、式（ＩＩ－１）で示される化合物まで導いた後に導入してよい。
反応溶媒としては、工程１記載の溶媒を用いることができる。好ましくは、芳香族炭化水素類（例、トルエン、ベンゼン、キシレンなど）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、１，２－ジクロロエタンなど）を用いればよい。
　使用する溶媒が還流する温度で０．５～２４時間反応させればよい。
　反応は、p-トルエンスルホン酸・1水和物などの酸触媒の存在下で行うのが好ましい。
　式：（Ｉ’－２）で示される化合物としては、たとえば、N-カルベトキシ-4-ピペリドンが挙げられる。 Twelfth step is a step of producing a compound represented by the formula (II'-2) by reacting a compound represented by the formula (II'-1) with a compound represented by the formula: (I'-2) .
As the compound represented by the formula (II′-1), a commercially available compound can be used, or it can be produced by performing a well-known organic synthesis reaction. In the case of producing a final product having a substituent on ring A, a compound represented by formula (II′-1) having such a substituent on ring A may be used. Such a substituent may be introduced into the ring A in the middle of the 12th to 14th steps, or after introduction to the compound represented by the formula (II-1).
As the reaction solvent, the solvent described in Step 1 can be used. Preferably, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) and halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) may be used.
The reaction may be performed at a temperature at which the solvent to be used is refluxed for 0.5 to 24 hours.
The reaction is preferably carried out in the presence of an acid catalyst such as p-toluenesulfonic acid monohydrate.
Examples of the compound represented by the formula: (I′-2) include N-carbethoxy-4-piperidone.
第１３工程
　式（ＩＩ’－２）で示される化合物の脱保護を行い式（ＩＩ’－３）で示される化合物を製造する工程である。
　上記第４工程と同様にして行えばよい。 Thirteenth step is a step of producing a compound represented by the formula (II'-3) by deprotecting the compound represented by the formula (II'-2).
What is necessary is just to carry out like the said 4th process.
第１４工程
　式（ＩＩ’－３）で示される化合物と、式：ＬＧ－Ｒ８で示される化合物とを反応させ、式（ＩＩ－１）で示される化合物を製造する工程である。
　上記第５工程と同様にして行えばよい。 And a compound represented by the 14 step formula (II'-3), wherein: the compound represented by LG-R 8 are reacted to a process for preparing a compound represented by formula (II-1).
What is necessary is just to carry out like the said 5th process.
　式（ＩＩ－２）で示される化合物は、以下のように合成することができる。
Figure JPOXMLDOC01-appb-C000045
 The compound represented by the formula (II-2) can be synthesized as follows.
Figure JPOXMLDOC01-appb-C000045
第１５工程
　式（ＩＩ’－４）で示される化合物と、式：ＬＧ－Ｒ８で示される化合物とを反応させ、式（ＩＩ－２）で示される化合物を製造する工程である。
　上記第５工程と同様にして行えばよい。
　式（ＩＩ’－４）で示される化合物は、市販の化合物を使用することもできるし、よく知られる有機合成反応を行いて製造することができる。
　Ｙ３が－Ｃ（Ｒ７）（Ｒ７Ａ）－である化合物は、実施例３７－４０を参考に合成することができる。 And a compound represented by the 15 step formula (II'-4), wherein: the compound represented by LG-R 8 are reacted to a process for preparing a compound of formula (II-2).
What is necessary is just to carry out like the said 5th process.
As the compound represented by the formula (II′-4), a commercially available compound can be used, or it can be produced by performing a well-known organic synthesis reaction.
A compound in which Y 3 is —C (R 7 ) (R 7A ) — can be synthesized with reference to Example 37-40.
　本発明化合物の各種の置換基は、（１）　Ａｌａｎ　Ｒ．Ｋａｔｒｉｓｚｌｙ　ｅｔ　ａｌ．，　Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍｉｓｔｒｙ　　（２）　Ａｌａｎ　Ｒ．Ｋａｔｒｉｓｚｌｙ　ｅｔ　ａｌ．，　Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍｉｓｔｒｙ　ＩＩ　　（３）　ＲＯＤＤ’Ｓ　ＣＨＥＭＩＳＴＲＹ　ＯＦ　ＣＡＲＢＯＮ　ＣＯＭＰＯＵＮＤＳ　ＶＯＬＵＭＥ　ＩＶ　ＨＥＴＥＲＯＣＹＣＬＩＣ　ＣＯＭＰＯＵＮＤＳ等を参考にして、導入することができる。 The various substituents of the compound of the present invention are (1) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry (2) Alan R. Katriszly et al. , Comprehensive Heterocyclic Chemistry II (3) RODD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYLIC COMPOUNDS etc.
　本発明化合物は、優れたＧＰＲ１１９アゴニスト活性を有する。従って、Ｉ型糖尿病、ＩＩ型糖尿病、インスリン抵抗性、代謝性疾患、高血糖および／または肥満などの疾患の治療または予防に用いることができる。特に、Ｉ型糖尿病およびＩＩ型糖尿病の治療または予防おいては有用である。 The compound of the present invention has excellent GPR119 agonist activity. Therefore, it can be used for the treatment or prevention of diseases such as type I diabetes, type II diabetes, insulin resistance, metabolic diseases, hyperglycemia and / or obesity. In particular, it is useful in the treatment or prevention of type I diabetes and type II diabetes.
　本発明に使用される化合物は、経口的又は非経口的に投与することができる。経口投与による場合、本発明に使用される化合物は通常の製剤、例えば、錠剤、散剤、顆粒剤、カプセル剤等の固形剤；水剤；油性懸濁剤；又はシロップ剤若しくはエリキシル剤等の液剤のいずれかの剤形としても用いることができる。非経口投与による場合、本発明に使用される化合物は、水性又は油性懸濁注射剤、点鼻液として用いることができる。その調製に際しては、慣用の賦形剤、結合剤、滑沢剤、水性溶剤、油性溶剤、乳化剤、懸濁化剤、保存剤、安定剤等を任意に用いることができる。特に、経口剤として使用する場合が好ましい。
　本発明に使用される化合物の製剤は、治療有効量の本発明に使用される化合物を製薬上許容される担体または希釈剤とともに組み合わせる（例：混合する）ことによって製造される。本発明に使用される化合物の製剤は、周知の、容易に入手できる成分を用いて既知の方法により製造される。
　本発明に使用される化合物の投与量は、投与方法、患者の年齢、体重、状態及び疾患の種類によっても異なるが、通常、経口投与の場合、成人１日あたり約０．０５ｍｇ～３０００ｍｇ、好ましくは、約０．１ｍｇ～１０００ｍｇを、要すれば分割して投与すればよい。また、非経口投与の場合、成人１日あたり約０．０１ｍｇ～１０００ｍｇ、好ましくは、約０．０５ｍｇ～５００ｍｇを投与する。また投与においては他の治療剤と併用することもできる。
　本発明には、以下の態様も含まれる。
　式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物による治療を受けている糖尿病患者に、他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法。
　式（Ｉ）または式（ＩＩ）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物と併用して他の糖尿病治療薬を投与することを特徴とする糖尿病の治療方法。
他の糖尿病治療薬としては、糖尿病治療効果を有する薬剤であれば特に限定されず、インスリン分泌刺激薬（たとえば、スルホニル尿素（SU）薬、速効型インスリン分泌促進薬、フェニルアラニン誘導体薬）、ビグアナイド系薬剤、インスリン抵抗性改善薬（たとえば、チアゾリジンジオン誘導体）、αグルコシダーゼ阻害薬、インスリン製剤、DPP-IV阻害薬、GLP-1受容体アゴニスト、2型ナトリウム依存性グルコース輸送体（SGLT2）阻害薬などが挙げられる。 The compound used in the present invention can be administered orally or parenterally. In the case of oral administration, the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can be used also as any dosage form. In the case of parenteral administration, the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. In particular, it is preferable to use it as an oral preparation.
Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent. The preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
The dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary. In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.
The following aspects are also included in the present invention.
Administration of another therapeutic agent for diabetes to a diabetic patient treated with a compound of formula (I) or formula (II), a pharmaceutically acceptable salt thereof or a solvate thereof How to treat diabetes.
A method for treating diabetes, comprising administering another therapeutic agent for diabetes in combination with a compound represented by formula (I) or formula (II), a pharmaceutically acceptable salt thereof, or a solvate thereof.
Other anti-diabetic drugs are not particularly limited as long as they have anti-diabetic effects, such as insulin secretagogues (for example, sulfonylurea (SU) drugs, fast-acting insulin secretagogues, phenylalanine derivative drugs), biguanides Drugs, insulin sensitizers (eg thiazolidinedione derivatives), α-glucosidase inhibitors, insulin preparations, DPP-IV inhibitors, GLP-1 receptor agonists, type 2 sodium-dependent glucose transporter (SGLT2) inhibitors, etc. Is mentioned.
　以下に実施例を示し、本発明をさらに詳しく説明するが、これらは本発明を限定するものではない。
　本発明化合物およびその中間体のＮＭＲスペクトルまたはＬＣ／ＭＳデータを示した。
各実施例で得られたＮＭＲ分析は３００ＭＨｚまたは４００MHｚで行い、ＣＤＣｌ３またはジメチルスルホキシド（ＤＭＳＯ）を用いて測定した。
ＬＣ／ＭＳは以下の条件で測定した。
method A：
測定には Luna 5μ C18(2) 100A, 50x4.6mm （Phenomenex社製）を使用し、流速3ml/分でアセト二トリル/水（ギ酸0.1%）　１０：９０～１００：０/3分　の直線勾配をかけて測定した。
method C：
測定には Shim-pack XR-ODS 50Lx3.0（Shimazu社製）を使用し、流速１．６ml/分でアセト二トリル/水（ギ酸0.1%）　 １０：９０～１００：０/3分　の直線勾配をかけて測定した。
method E： 
測定には Gemini-NX 5μm C18 110A, 50x4.6mm（ Phenomenex社製）を使用し、流速3ml/分でメタノール/水（炭酸アンモニウム 10mM）　５：９５～１００：０/3.5分　の直線勾配をかけて測定した。
method F： 
測定には Gemini-NX 5μm C18 110A, 50x4.6mm（ Phenomenex社製）を使用し、流速3ml/分でアセトニトリル/水（ギ酸0.1%）　５：９５～１００：０/3.5分　の直線勾配をかけて測定した。
method G： 
測定にはACQUITY UPLC(R)BEH C18 (1.7μm i.d. 2.1x50mm)(Waters)を使用し、流速0.8ml/分でアセトニトリル/水（炭酸アンモニウム 10mM）　５：９５～１００：０/3.5分　の直線勾配をかけて測定した
method H： 
測定にはACQUITY UPLC(R)BE C18 （1.7μm ｉ.d. 2.1ｘ50mm)(Ｗａｔｅｒｓ)を使用し、流速0.8ml/分でアセトニトリル/水（ギ酸0.1% ）　１０：９０～１００：０/3.5分　の直線勾配をかけて測定した

　なお、実施例中の各用語の意味は以下のとおりである。
HATU：　2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium
BINAP：　(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)
IBX：　2-iodoxybenzoic acid
1-Boc-4-ピペリドン：　1-tert-butoxycarbonyl-4-piperidone
The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
The NMR spectrum or LC / MS data of the compound of the present invention and its intermediate were shown.
The NMR analysis obtained in each example was performed at 300 MHz or 400 MHz and measured using CDCl 3 or dimethyl sulfoxide (DMSO).
LC / MS was measured under the following conditions.
method A:
Luna 5μ C18 (2) 100A, 50x4.6mm (manufactured by Phenomenex) was used for the measurement, and a straight line of acetonitrile / water (formic acid 0.1%) 10:90 to 100: 0/3 min at a flow rate of 3 ml / min. Measured with a gradient.
method C:
Shim-pack XR-ODS 50Lx3.0 (manufactured by Shimazu) was used for the measurement, and a straight line of acetonitrile / water (formic acid 0.1%) 10:90 to 100: 0/3 min at a flow rate of 1.6 ml / min. Measured with a gradient.
method E:
Use Gemini-NX 5μm C18 110A, 50x4.6mm (manufactured by Phenomenex) for measurement, and apply a linear gradient of methanol / water (ammonium carbonate 10 mM) 5:95 to 100: 0 / 3.5 min at a flow rate of 3 ml / min. Measured.
method F:
Use Gemini-NX 5μm C18 110A, 50x4.6mm (manufactured by Phenomenex) for measurement, and apply a linear gradient of acetonitrile / water (formic acid 0.1%) 5:95 to 100: 0 / 3.5 min at a flow rate of 3 ml / min. Measured.
method G:
ACQUITY UPLC (R) BEH C18 (1.7μm id 2.1x50mm) (Waters) is used for the measurement. Acetonitrile / water (ammonium carbonate 10 mM) at a flow rate of 0.8 ml / min 5:95 to 100: 0 / 3.5 min linear Measured with a gradient
method H:
ACQUITY UPLC® BE C18 (1.7 μm i.d. 2.1 × 50 mm) (Waters) was used for the measurement, and acetonitrile / water (formic acid 0.1%) 10:90 to 100: 0 / 3.5 at a flow rate of 0.8 ml / min. Measured with a linear gradient of minutes

In addition, the meaning of each term in an Example is as follows.
HATU: 2- (1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium
BINAP: (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl)
IBX: 2-iodoxybenzoic acid
1-Boc-4-piperidone: 1-tert-butoxycarbonyl-4-piperidone
Figure JPOXMLDOC01-appb-C000046
第１工程
　4-ブロモ-2-(ヒドロキシメチル)フェノール　１(20.0 g, 98.5 mmol)のクロロホルム(300 ml)懸濁液にN-カルベトキシ-4-ピペリドン(19.3 ml, 128 mmol)、p-トルエンスルホン酸・1水和物(1.87 g, 9.85 mmol)を加え、4時間加熱還流を行った。溶媒を留去し、酢酸エチルを加え、有機層を2N 水酸化ナトリウム水溶液、水の順に洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２(30.1 g, 86 %)を得た。
第２工程
　化合物２(5.0 g, 14.0 mmol)のエタノール(75 ml)溶液に6N 水酸化ナトリウム水溶液(18.7 ml, 112 mmol)を加え、4時間加熱還流を行った。溶媒を留去し、酢酸エチルを加え、水、飽和食塩水の順に洗浄した。硫酸マグネシウムで乾燥し、溶媒を留去し、化合物３(3.98 g, 100 %)を得た。
第３工程
　化合物３(3.98 g, 14.0 mmol)のテトラヒドロフラン(40 ml)溶液に、氷冷下、トリエチルアミン(3.88 ml, 28.0 mmol)、ベンジルクロロホルメート(1.99 ml, 14.0 mmol)を加え、30分撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物４(4.71 g, 80 %)を得た。
第４工程
　化合物４(4.5 g, 10.8 mmol)のジメチルホルムアミド(45 ml)溶液に4-(ジメチルカルボニル)フェニルボロン酸(2.49 g, 12.9 mmol)、2M 炭酸ナトリウム水溶液(10.8 ml, 21.5 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(622 mg, 0.538 mmol)を加え、マイクロウェーブ照射下、120℃で10分間反応を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１）(4.2 g, 80 %)を得た。
化合物（Ｉ－１－１）；
 1H-NMR (CDCl3) δ: 1.85-2.01 (4H, m), 3.08 (6H, d, J = 35.5 Hz), 3.55-3.75 (4H, m), 4.92 (2H, s), 5.16 (2H, s), 6.94 (1H, d, J = 8.6 Hz), 7.19-7.21 (1H, m), 7.30-7.56 (10H, m).
第５工程
　化合物（Ｉ－１－１）(4.1g, 8.43 mmol)のメタノール(80 ml)溶液に10%パラジウム炭素(410 mg)を加え、水素ガス気流下、2時間撹拌した。触媒をろ過し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物５(2.93 g, 99 %)を得た。
第６工程
　ピラジン-2-カルボン酸(16.9 mg, 0.136 mmol)に、HATU(56.1 mg, 0.148 mmol)のジメチルアセトアミド(400 μl)溶液、トリエチルアミン(20.5 μl, 0.148 mmol)、化合物５(40 mg, 0.113 mmol)のジメチルアセトアミド(400 μl)溶液を加え、室温で24時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２）(26.5 mg, 51.1 %)を得た。
化合物（Ｉ－１－２）；
ＬＣ／ＭＳ　Rt= 2.53min、MS：459、method：E

　同様にして、化合物Ｉ－１－５０、Ｉ－１－５１、Ｉ－１－１００、Ｉ－１－１０１、Ｉ－１－１０２、Ｉ－１－１０３、Ｉ－１－１０４、Ｉ－１－１０５、Ｉ－１－１０６、Ｉ－１－１０７、Ｉ－１－１０８、Ｉ－１－１０９、Ｉ－１－１１０、Ｉ－１－１１１、Ｉ－１－１１２、Ｉ－１－１１３、Ｉ－１－１１４、Ｉ－１－１１５、Ｉ－１－１１６、Ｉ－１－１１７、Ｉ－１－１１８、Ｉ－１－１１９、Ｉ－１－１２０、Ｉ－１－１２１、Ｉ－１－１２２、Ｉ－１－１２３、Ｉ－１－１２４、Ｉ－１－１２５、Ｉ－１－１２６、Ｉ－１－１２７、Ｉ－１－１２８、Ｉ－１－１２９、Ｉ－１－１３０、Ｉ－１－１３１、Ｉ－１－１３２、Ｉ－１－１３３、Ｉ－１－１３４、Ｉ－１－１３５、Ｉ－１－１３９およびＩ－１－１４３を合成した。
Figure JPOXMLDOC01-appb-C000046
First Step 4-Bromo-2- (hydroxymethyl) phenol 1 (20.0 g, 98.5 mmol) in chloroform (300 ml) suspension with N-carbethoxy-4-piperidone (19.3 ml, 128 mmol), p-toluene Sulfonic acid monohydrate (1.87 g, 9.85 mmol) was added, and the mixture was heated to reflux for 4 hours. The solvent was distilled off, ethyl acetate was added, and the organic layer was washed with 2N sodium hydroxide aqueous solution and water in this order. It dried with sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 2 (30.1 g, 86%).
Second Step 6N aqueous sodium hydroxide solution (18.7 ml, 112 mmol) was added to a solution of compound 2 (5.0 g, 14.0 mmol) in ethanol (75 ml), and the mixture was heated to reflux for 4 hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with water and saturated brine in this order. It dried with magnesium sulfate and the solvent was distilled off and the compound 3 (3.98 g, 100%) was obtained.
Step 3 To a solution of compound 3 (3.98 g, 14.0 mmol) in tetrahydrofuran (40 ml) was added triethylamine (3.88 ml, 28.0 mmol) and benzyl chloroformate (1.99 ml, 14.0 mmol) under ice-cooling for 30 minutes. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 4 (4.71 g, 80%).
Fourth Step To a solution of compound 4 (4.5 g, 10.8 mmol) in dimethylformamide (45 ml), 4- (dimethylcarbonyl) phenylboronic acid (2.49 g, 12.9 mmol), 2M aqueous sodium carbonate solution (10.8 ml, 21.5 mmol), Tetrakis (triphenylphosphine) palladium (622 mg, 0.538 mmol) was added, and the reaction was performed at 120 ° C. for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-1) (4.2 g, 80%).
Compound (I-1-1);
1H-NMR (CDCl3) δ: 1.85-2.01 (4H, m), 3.08 (6H, d, J = 35.5 Hz), 3.55-3.75 (4H, m), 4.92 (2H, s), 5.16 (2H, s ), 6.94 (1H, d, J = 8.6 Hz), 7.19-7.21 (1H, m), 7.30-7.56 (10H, m).
Step 5 To a solution of compound (I-1-1) (4.1 g, 8.43 mmol) in methanol (80 ml) was added 10% palladium carbon (410 mg), and the mixture was stirred under a hydrogen gas stream for 2 hours. The catalyst was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 5 (2.93 g, 99%).
Step 6: Pyrazine-2-carboxylic acid (16.9 mg, 0.136 mmol) was added to a solution of HATU (56.1 mg, 0.148 mmol) in dimethylacetamide (400 μl), triethylamine (20.5 μl, 0.148 mmol), compound 5 (40 mg, 0.113 mmol) in dimethylacetamide (400 μl) was added and stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-2) (26.5 mg, 51.1%).
Compound (I-1-2);
LC / MS Rt = 2.53min, MS: 459, method: E

Similarly, compounds I-1-50, I-1-51, I-1-100, I-1-101, I-1-102, I-1-103, I-1-104, I-1 -105, I-1-106, I-1-107, I-1-108, I-1-109, I-1-110, I-1-111, I-1-112, I-113 , I-1-114, I-1-115, I-1-116, I-1-117, I-1-118, I-1-119, I-1-120, I-1-121, I -1-122, I-1-123, I-1-124, I-1-125, I-1-126, I-1-127, I-1-128, I-1-129, I-1 -130, I-1-131, I-1-132, I-1-133, I-1-134, I-1-135, I-1-139 and I-1-143 were synthesized
Figure JPOXMLDOC01-appb-C000047
第１工程
　ベンゼンスルホニルクロリド(40.1 mg, 0.227 mmol)に、クロロホルム(500 μl)、化合物５(40 mg, 0.113 mmol)、ジイソプロピルエチルアミン(79 μl, 0.454 mmol)のクロロホルム(500 μl)溶液を加え、室温で一晩撹拌した。反応液に水を加え、クロロホルムで抽出した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３）(37.2 mg, 66.8 %)を得た。
化合物（Ｉ－１－３）；
ＬＣ／ＭＳ　Rt= 2.92min、MS：493、method：E

　同様にして、化合物Ｉ－１－７９、Ｉ－１－８０、Ｉ－１－８１、Ｉ－１－８２、Ｉ－１－８３、Ｉ－１－８４、Ｉ－１－８５、Ｉ－１－８６、Ｉ－１－８７、Ｉ－１－８８、Ｉ－１－８９、Ｉ－１－９０、Ｉ－１－９１、Ｉ－１－９２、Ｉ－１－９３、Ｉ－１－９４、Ｉ－１－９５、Ｉ－１－９６、Ｉ－１－９７、Ｉ－１－９８およびＩ－１－９９を合成した。
Figure JPOXMLDOC01-appb-C000047
First Step To benzenesulfonyl chloride (40.1 mg, 0.227 mmol), chloroform (500 μl), compound 5 (40 mg, 0.113 mmol), diisopropylethylamine (79 μl, 0.454 mmol) in chloroform (500 μl) were added, Stir at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-3) (37.2 mg, 66.8%).
Compound (I-1-3);
LC / MS Rt = 2.92min, MS: 493, method: E

Similarly, compounds I-1-79, I-1-80, I-1-81, I-1-82, I-1-83, I-1-84, I-1-85, I-1 -86, I-1-87, I-1-88, I-1-89, I-1-90, I-1-91, I-1-92, I-1-93, I-1-94 I-1-95, I-1-96, I-1-97, I-1-98 and I-1-99 were synthesized.
Figure JPOXMLDOC01-appb-C000048
第１工程
　化合物３(3.1 g, 10.9 mmol)のテトラヒドロフラン(31 ml)溶液に、氷冷下、トリエチルアミン(2.27 ml, 16.4 mmol)、ベンゾイルクロリド(1.39 ml, 12.0 mmol)を加え、室温で30分撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６(4.05 g, 96 %)を得た。
第２工程
　ピリジン-4-ボロン酸(30.4 mg, 0.247 mmol)に、化合物６(80 mg, 0.206 mmol)のエタノール(1 ml)溶液、2M 炭酸ナトリウム水溶液(206 μl, 0.412 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(23.8 mg, 0.021 mmol)を加え、マイクロウェーブ照射下、120℃で10分間反応を行った。反応液に水を加え、クロロホルムで抽出した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－４）(27.5 mg, 43 %)を得た。
化合物（Ｉ－１－４）；
ＬＣ／ＭＳ　Rt= 2.82min、MS：387、method：E

　同様にして、化合物Ｉ－１－４４、Ｉ－１－４５、Ｉ－１－４６、Ｉ－１－４７、Ｉ－１－４８、Ｉ－１－４９、Ｉ－１－５４、Ｉ－１－５５、Ｉ－１－５６、Ｉ－１－５７、Ｉ－１－５８、Ｉ－１－５９、Ｉ－１－６０、Ｉ－１－６１、Ｉ－１－６２、Ｉ－１－６３、Ｉ－１－６４、Ｉ－１－６５、Ｉ－１－６６、Ｉ－１－６７、Ｉ－１－６８、Ｉ－１－６９、Ｉ－１－７０、Ｉ－１－７１、Ｉ－１－７２、Ｉ－１－７３、Ｉ－１－７４、Ｉ－１－７５、Ｉ－１－７６、Ｉ－１－７７、Ｉ－１－７８、Ｉ－１－１３６、Ｉ－１－１３７、Ｉ－１－１３８、Ｉ－１－１４０、Ｉ－１－１４１、Ｉ－１－１４２およびＩ－１－１４４を合成した。
Figure JPOXMLDOC01-appb-C000048
Step 1 To a solution of compound 3 (3.1 g, 10.9 mmol) in tetrahydrofuran (31 ml) was added triethylamine (2.27 ml, 16.4 mmol) and benzoyl chloride (1.39 ml, 12.0 mmol) under ice-cooling, and 30 minutes at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 6 (4.05 g, 96%).
Second Step To pyridine-4-boronic acid (30.4 mg, 0.247 mmol), a solution of compound 6 (80 mg, 0.206 mmol) in ethanol (1 ml), 2M aqueous sodium carbonate solution (206 μl, 0.412 mmol), tetrakis (tri Phenylphosphine) palladium (23.8 mg, 0.021 mmol) was added, and the reaction was performed at 120 ° C. for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-4) (27.5 mg, 43%).
Compound (I-1-4);
LC / MS Rt = 2.82min, MS: 387, method: E

In the same manner, compounds I-1-44, I-1-45, I-1-46, I-1-47, I-1-48, I-1-49, I-1-54, I-1 -55, I-1-56, I-1-57, I-1-58, I-1-59, I-1-60, I-1-61, I-1-62, I-1-63 I-1-64, I-1-65, I-1-66, I-1-67, I-1-68, I-1-69, I-1-70, I-1-71, I -1-72, I-1-73, I-1-74, I-1-75, I-1-76, I-1-77, I-1-78, I-1-136, I-1 -137, I-1-138, I-1-140, I-1-141, I-1-142 and I-1-144 were synthesized.
Figure JPOXMLDOC01-appb-C000049
第１工程
　4-ブロモカテコール　７(0.5 g, 2.65 mmol)のトルエン(8 ml)溶液に、N-カルベトキシ-4-ピペリドン(0.52 ml, 3.44 mmol)、p-トルエンスルホン酸・1水和物(100 mg, 0.529 mmol)を加え、4時間加熱還流を行った。2N 水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物８(280 mg, 31 %)を得た。
第２工程
　化合物８(280 mg, 0.818 mmol)のエタノール(5 ml)溶液に6N 水酸化ナトリウム水溶液(1.1 ml, 6.55 mmol)を加え、6.5時間加熱還流を行った。溶媒を留去し、水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、化合物９(207 mg, 94 %)を得た。
第３工程
　化合物９(205 mg, 0.759 mmol)のテトラヒドロフラン(4 ml)溶液に、二炭酸ジ-tert-ブチル(182 mg, 0.835 mmol)を加え、室温で1.5時間撹拌した。溶媒を留去し、化合物１０(281 mg, 100%)を得た。
第４工程
　化合物１０(60 mg)をジメチルホルムアミド(0.7 ml)溶液に、4-(メチルスルホニル)フェニルボロン酸(42 mg, 0.211 mmol)、2M 炭酸ナトリウム水溶液(243 μl, 0.486 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(19 mg, 0.016 mmol)を加え、マイクロウェーブ照射下、105℃で15分間反応を行った。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－５）(30 mg, 42 %)を得た。
化合物（Ｉ－１－５）；
1H-NMR(CDCl3)δ 1.43(9H, s), 1.97(4H, bs), 3.34(3H, s), 3.63(4H, bs), 7.02(1H, d, J = 8.0 Hz), 7.24(1H, d, J =7.6 Hz), 7.33(1H, s), 7.86(2H, d, J = 7.6 Hz), 7.94(2H, d, J = 7.2 Hz).

　同様にして、化合物Ｉ－１－５２およびＩ－１－５３を合成した。
Figure JPOXMLDOC01-appb-C000049
Step 1 To a solution of 4-bromocatechol 7 (0.5 g, 2.65 mmol) in toluene (8 ml) was added N-carbethoxy-4-piperidone (0.52 ml, 3.44 mmol), p-toluenesulfonic acid monohydrate ( 100 mg, 0.529 mmol) was added, and the mixture was heated to reflux for 4 hours. 2N Aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 8 (280 mg, 31%).
Second Step 6N aqueous sodium hydroxide solution (1.1 ml, 6.55 mmol) was added to a solution of compound 8 (280 mg, 0.818 mmol) in ethanol (5 ml), and the mixture was heated to reflux for 6.5 hours. The solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off to obtain Compound 9 (207 mg, 94%).
Third Step To a solution of compound 9 (205 mg, 0.759 mmol) in tetrahydrofuran (4 ml) was added di-tert-butyl dicarbonate (182 mg, 0.835 mmol), and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off to obtain Compound 10 (281 mg, 100%).
Step 4 Compound 10 (60 mg) in a dimethylformamide (0.7 ml) solution, 4- (methylsulfonyl) phenylboronic acid (42 mg, 0.211 mmol), 2M aqueous sodium carbonate solution (243 μl, 0.486 mmol), tetrakis ( Triphenylphosphine) palladium (19 mg, 0.016 mmol) was added, and the reaction was performed at 105 ° C. for 15 minutes under microwave irradiation. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-5) (30 mg, 42%).
Compound (I-1-5);
1H-NMR (CDCl3) δ 1.43 (9H, s), 1.97 (4H, bs), 3.34 (3H, s), 3.63 (4H, bs), 7.02 (1H, d, J = 8.0 Hz), 7.24 (1H , d, J = 7.6 Hz), 7.33 (1H, s), 7.86 (2H, d, J = 7.6 Hz), 7.94 (2H, d, J = 7.2 Hz).

In the same manner, compounds I-1-52 and I-1-53 were synthesized.
Figure JPOXMLDOC01-appb-C000050
第１工程
　5-ブロモ-2-ヒドロキシアセトフェノン　１１(4.0 g, 18.6 mmol)、tert-ブトキシカルボニル-4-ピペリドン(4.45 g, 22.3mmol)、ピロリジン(1.85 g, 26.0 mmol)、メタノール(25 ml)の混合物を3時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１２(6.5 g, 88 %)を得た。
第２工程
　化合物１２(6.5 g, 16.4 mmol)のエタノール(65 ml)溶液に、氷冷下、水素化ほう素ナトリウム(0.62 g, 16.4 mmol)を加え、室温で45分間撹拌した。反応終了後、アセトン(5 ml)を加え15分間撹拌した後に、水を加えた。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。硫酸マグネシウムで乾燥し、溶媒を留去し、化合物１３(6.5 g, 99 %)を得た。
第３工程
　化合物１３(6.5 g, 16.3 mmol)にトリフルオロ酢酸(65 ml, 816 mmol)、トリエチルシラン(10.4 ml, 65.3 mmol)を加え、3.5時間加熱還流した。冷却し、反応液を水に注ぎ、2N 水酸化ナトリウム水溶液で中和した。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣にn-ヘキサンを加え結晶化を行い、化合物１４(4.61 g, 100 %)を得た。
第４工程
　化合物１４(500 mg, 1.77 mmol)の塩化メチレン(5 ml)溶液に、氷冷下、トリエチルアミン(368 μl, 2.66 mmol)、ベンゾイルクロリド(226 μl, 1.95 mmol)を加え、1時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１５(490 mg, 72 %)を得た。
第５工程
　化合物１５(80 mg, 0.207 mmol)のエタノール(1 ml)溶液に4-(メトキシカルボニルアミノ)フェニルボロン酸(48.5 mg, 0.249 mmol)、2M 炭酸ナトリウム水溶液(207 μl, 0.414 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(23.9 mg, 0.021 mmol)を加え、マイクロウェーブ照射下、120℃で10分間反応を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－６）(48.6 mg, 51 %)を得た。
化合物（Ｉ－１－６）；
 1H-NMR (CDCl3) δ: 1.49-2.04 (4H, m), 1.87 (2H, t, J = 6.8 Hz), 2.80-2.89 (2H, m), 3.26-3.65 (3H, m), 3.79 (3H, s), 4.50-4.58 (1H, m), 6.63 (1H, s), 6.91 (1H, d, J = 8.1 Hz), 7.32 (1H, dd, J = 8.4, 1.8 Hz), 7.38-7.50 (10H, m).

　同様にして、化合物Ｉ－１－１４５、Ｉ－１－１４６、Ｉ－１－１４７、Ｉ－１－１４８、Ｉ－１－１４９、Ｉ－１－１５０、Ｉ－１－１５５、Ｉ－１－１５６、Ｉ－１－１５７、Ｉ－１－１５８、Ｉ－１－１５９、Ｉ－１－１６３、Ｉ－１－２１０、Ｉ－１－２１１、Ｉ－１－２１２、Ｉ－１－２１３、Ｉ－１－２１４、Ｉ－１－２１５、Ｉ－１－２１８、Ｉ－１－２１９、Ｉ－１－２２０、Ｉ－１－２２１、Ｉ－１－２２２、Ｉ－１－２２３、Ｉ－１－２２４、Ｉ－１－２２５、Ｉ－１－２２６、Ｉ－１－２２７、Ｉ－１－２２８、Ｉ－１－２２９、Ｉ－１－２３０、Ｉ－１－２３２、Ｉ－１－２３３、Ｉ－１－２３５、Ｉ－１－２３６、Ｉ－１－２３７、Ｉ－１－２３８、Ｉ－１－２４０およびＩ－１－２４１を合成した。
Figure JPOXMLDOC01-appb-C000050
First Step 5-Bromo-2-hydroxyacetophenone 11 (4.0 g, 18.6 mmol), tert-butoxycarbonyl-4-piperidone (4.45 g, 22.3 mmol), pyrrolidine (1.85 g, 26.0 mmol), methanol (25 ml) The mixture was heated to reflux for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 12 (6.5 g, 88%).
Second Step Sodium borohydride (0.62 g, 16.4 mmol) was added to a solution of compound 12 (6.5 g, 16.4 mmol) in ethanol (65 ml) under ice cooling, and the mixture was stirred at room temperature for 45 minutes. After completion of the reaction, acetone (5 ml) was added and stirred for 15 minutes, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying with magnesium sulfate, the solvent was distilled off to obtain Compound 13 (6.5 g, 99%).
Third Step To compound 13 (6.5 g, 16.3 mmol), trifluoroacetic acid (65 ml, 816 mmol) and triethylsilane (10.4 ml, 65.3 mmol) were added and heated to reflux for 3.5 hours. After cooling, the reaction mixture was poured into water and neutralized with 2N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It dried with magnesium sulfate and the solvent was distilled off. The residue was crystallized by adding n-hexane to obtain Compound 14 (4.61 g, 100%).
Step 4 To a solution of compound 14 (500 mg, 1.77 mmol) in methylene chloride (5 ml) is added triethylamine (368 μl, 2.66 mmol) and benzoyl chloride (226 μl, 1.95 mmol) under ice cooling, and the mixture is stirred for 1 hour. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 15 (490 mg, 72%).
Step 5 To a solution of compound 15 (80 mg, 0.207 mmol) in ethanol (1 ml), 4- (methoxycarbonylamino) phenylboronic acid (48.5 mg, 0.249 mmol), 2M aqueous sodium carbonate solution (207 μl, 0.414 mmol), Tetrakis (triphenylphosphine) palladium (23.9 mg, 0.021 mmol) was added, and the reaction was performed at 120 ° C. for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-6) (48.6 mg, 51%).
Compound (I-1-6);
1H-NMR (CDCl3) δ: 1.49-2.04 (4H, m), 1.87 (2H, t, J = 6.8 Hz), 2.80-2.89 (2H, m), 3.26-3.65 (3H, m), 3.79 (3H , s), 4.50-4.58 (1H, m), 6.63 (1H, s), 6.91 (1H, d, J = 8.1 Hz), 7.32 (1H, dd, J = 8.4, 1.8 Hz), 7.38-7.50 ( 10H, m).

Similarly, the compounds I-1-145, I-1-146, I-1-147, I-1-148, I-1-149, I-1-150, I-1-155, I-1 -156, I-1-157, I-1-158, I-1-159, I-1-163, I-1-210, I-1-211, I-1-212, I-1-213 I-214, I-215, I-218, I-219, I-1-220, I-221, I-122, I-1-223, I -1-224, I-1-225, I-1-226, I-1-227, I-1-228, I-1-229, I-1-230, I-1-232, I-1 -233, I-I-235, I-I-236, I-I-237, I-I-238, I-I-240 and I-I-241 were synthesized.
Figure JPOXMLDOC01-appb-C000051
第１工程
　化合物１４(500 mg, 1.77 mmol)の塩化メチレン(4 ml)溶液に、氷冷下、トリエチルアミン(246 μl, 1.77 mmol)、二炭酸ジ-tert-ブチル(425 mg, 1.95 mmol)を加え、1時間撹拌した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１６(514 mg, 76%)を得た。
第２工程
　化合物１６(80 mg, 0.209 mmol)のエタノール(1 ml)溶液に4-(メトキシカルボニルアミノ)フェニルボロン酸(49 mg, 0.251 mmol)、2M 炭酸ナトリウム水溶液(209 μl, 0.418 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(24.2 mg, 0.021 mmol)を加え、マイクロウェーブ照射下、120℃で10分間反応を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－７）(28.9 mg, 31 %)を得た。
化合物（Ｉ－１－７）；
 1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.50-1.59 (2H, m), 1.80-1.86 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.20-3.29 (2H, m), 3.79 (3H, s), 3.82-3.94 (2H, m), 6.62 (1H, s), 6.89 (1H, d, J = 8.6 Hz), 7.25-7.27 (1H, m), 7.31 (1H, dd, J = 8.1, 2.0 Hz), 7.39-7.49 (4H, m).

　同様にして、化合物Ｉ－１－１５１、Ｉ－１－１５２、Ｉ－１－１５３、Ｉ－１－１５４、Ｉ－１－１６０、Ｉ－１－１６１、Ｉ－１－１６２、Ｉ－１－１６３、Ｉ－１－１６４、Ｉ－１－１６５、Ｉ－１－１６６、Ｉ－１－１６７、Ｉ－１－１６８、Ｉ－１－１７３、Ｉ－１－１７４、Ｉ－１－１７５、Ｉ－１－１７６、Ｉ－１－１７７、Ｉ－１－１７８、Ｉ－１－１７９、Ｉ－１－１８０、Ｉ－１－１８１、Ｉ－１－１８２、Ｉ－１－１８４、Ｉ－１－１８５、Ｉ－１－１８９、Ｉ－１－１９２、Ｉ－１－２１０、Ｉ－１－２１１、Ｉ－１－２１２、Ｉ－１－２１３、Ｉ－１－２１４、Ｉ－１－２１５、Ｉ－１－２１８、Ｉ－１－２１９、Ｉ－１－２２０、Ｉ－１－２２１、Ｉ－１－２２２、Ｉ－１－２２３、Ｉ－１－２２４、Ｉ－１－２２５、Ｉ－１－２２６、Ｉ－１－２２７、Ｉ－１－２２８、Ｉ－１－２２９、Ｉ－１－２３０、Ｉ－１－２３２、Ｉ－１－２３３、Ｉ－１－２３４、Ｉ－１－２３５、Ｉ－１－２３６、Ｉ－１－２３７、Ｉ－１－２３８、Ｉ－１－２４０およびＩ－１－２４１を合成した。
Figure JPOXMLDOC01-appb-C000051
First Step To a methylene chloride (4 ml) solution of compound 14 (500 mg, 1.77 mmol), triethylamine (246 μl, 1.77 mmol) and di-tert-butyl dicarbonate (425 mg, 1.95 mmol) were added under ice cooling. It was added and stirred for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 16 (514 mg, 76%).
Second Step Compound 16 (80 mg, 0.209 mmol) in ethanol (1 ml) was added 4- (methoxycarbonylamino) phenylboronic acid (49 mg, 0.251 mmol), 2M aqueous sodium carbonate solution (209 μl, 0.418 mmol), Tetrakis (triphenylphosphine) palladium (24.2 mg, 0.021 mmol) was added, and the reaction was performed at 120 ° C. for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-7) (28.9 mg, 31%).
Compound (I-1-7);
1H-NMR (CDCl3) δ: 1.47 (9H, s), 1.50-1.59 (2H, m), 1.80-1.86 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.20-3.29 (2H , m), 3.79 (3H, s), 3.82-3.94 (2H, m), 6.62 (1H, s), 6.89 (1H, d, J = 8.6 Hz), 7.25-7.27 (1H, m), 7.31 ( 1H, dd, J = 8.1, 2.0 Hz), 7.39-7.49 (4H, m).

Similarly, the compounds I-1-151, I-1-152, I-1-153, I-1-154, I-1-160, I-1-161, I-1-162, I-1 -163, I-1-164, I-1-165, I-1-166, I-1-167, I-1-168, I-1-173, I-1-174, I-1-175 I-1-176, I-1-177, I-1-178, I-1-179, I-1-180, I-1-181, I-1-182, I-1-184, I -1-185, I-1-189, I-192, I-1-210, I-1-211, I-1-212, I-213, I-1-214, I-1 -215, I-218, I-219, I-1-220, I-221, I-122, I-223, I-1-224, I-1- 25, I-I-226, I-I-227, I-I-228, I-I-229, I-I-230, I-I-232, I-I-233, I-I-234, I-1-235, I-1-236, I-1-237, I-1-238, I-1-240 and I-1-241 were synthesized.
Figure JPOXMLDOC01-appb-C000052
第１工程
　化合物１６(200 mg, 0.523 mmol)にトルエン(3 ml)、1-メチルスルホニルピペラジン(86 mg, 0.523 mmol)、Pd2(dba)3(24 mg, 0.026 mmol)、ナトリウム tert-ブトキシド(101 mg, 1.05 mmol)、BINAP(33 mg, 0.052 mmol)を加え、100℃で30分撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－８）(75 mg, 31 %)を得た。
化合物（Ｉ－１－８）；
1H-NMR(CDCl3)δ1.46(9H, s), 1.45-1.56(2H, m), 1.76-1.88(4H, m), 2.77(2H, t, J = 7.1Hz), 2.83(3H, s), 3.18-3.25(4H, m), 3.18-3.28(2H, m), 3.38-3.47(4H, m), 3.85-3.96(2H, m),  6.65(1H, s), 6.79(2H, s).

　同様にして、化合物Ｉ－１－１６９、Ｉ－１－１７０、Ｉ－１－１７１、Ｉ－１－１７２、Ｉ－１－１８３、Ｉ－１－１９０、Ｉ－１－１９１、Ｉ－１－２１０、Ｉ－１－２１１、Ｉ－１－２１２、Ｉ－１－２１３、Ｉ－１－２１４、Ｉ－１－２１５、Ｉ－１－２１８、Ｉ－１－２１９、Ｉ－１－２２０、Ｉ－１－２２１、Ｉ－１－２２２、Ｉ－１－２２３、Ｉ－１－２２４およびＩ－１－２２５を合成した。
Figure JPOXMLDOC01-appb-C000052
Step 1 Compound 16 (200 mg, 0.523 mmol) to toluene (3 ml), 1-methylsulfonylpiperazine (86 mg, 0.523 mmol), Pd 2 (dba) 3 (24 mg, 0.026 mmol), sodium tert-butoxide (101 mg, 1.05 mmol) and BINAP (33 mg, 0.052 mmol) were added and stirred at 100 ° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-8) (75 mg, 31%).
Compound (I-1-8);
1H-NMR (CDCl3) δ1.46 (9H, s), 1.45-1.56 (2H, m), 1.76-1.88 (4H, m), 2.77 (2H, t, J = 7.1Hz), 2.83 (3H, s ), 3.18-3.25 (4H, m), 3.18-3.28 (2H, m), 3.38-3.47 (4H, m), 3.85-3.96 (2H, m), 6.65 (1H, s), 6.79 (2H, s ).

Similarly, the compounds I-1-169, I-1-170, I-1-171, I-1-172, I-1-183, I-1-190, I-1-191, I-1 -210, I-1-211, I-1-212, I-1-213, I-1-214, I-1-215, I-1-218, I-1-219, I-1-220 I-1-221, I-1-222, I-1-223, I-1-224 and I-1-225 were synthesized.
Figure JPOXMLDOC01-appb-C000053
第１工程
　化合物（Ｉ－１－８）(700 mg, 1.50 mmol)の酢酸エチル(10 ml)溶液に4N 塩酸-ジオキサン溶液(7.5 ml, 30.1 mmol)を加え、室温で3時間撹拌した。析出した結晶をろ取し、酢酸エチルで洗浄し、乾燥し、化合物１７(560 mg, 93 %)を得た。
第２工程
　化合物１７(100 mg, 0.249 mmol)の塩化メチレン(4 ml)溶液に、トリエチルアミン(103 μl, 0.746 mmol)、ベンゾイルクロリド(35 μl, 0.299 mmol)を加え、室温で1時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－９）(67 mg, 57 %)を得た。
化合物（Ｉ－１－９）；
1H-NMR(CDCl3)δ1.50-1.60(2H, m), 1.76-1.88(4H, m), 2.70-2.77(2H, m), 2.81(3H, s), 3.12-3.20(4H, m), 3.20-3.27(2H, m), 3.31-3.38(4H, m), 3.44-3.56(2H, m), 6.65(1H, s), 6.82(2H, s), 7.40(5H, m).

　同様にして、化合物Ｉ－１－１９３、Ｉ－１－１９４、Ｉ－１－１９５、Ｉ－１－１９６、Ｉ－１－１９７、Ｉ－１－１９８、Ｉ－１－２１０、Ｉ－１－２１１、Ｉ－１－２１２、Ｉ－１－２１３、Ｉ－１－２１４、Ｉ－１－２１５、Ｉ－１－２１８、Ｉ－１－２１９、Ｉ－１－２２０、Ｉ－１－２２１、Ｉ－１－２２２、Ｉ－１－２２３、Ｉ－１－２２４、Ｉ－１－２２５、Ｉ－１－２２７、Ｉ－１－２２８、Ｉ－１－２３０、Ｉ－１－２３２およびＩ－１－２３３を合成した。
Figure JPOXMLDOC01-appb-C000053
First Step To a solution of compound (I-1-8) (700 mg, 1.50 mmol) in ethyl acetate (10 ml) was added 4N hydrochloric acid-dioxane solution (7.5 ml, 30.1 mmol), and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to obtain Compound 17 (560 mg, 93%).
Second Step To a solution of compound 17 (100 mg, 0.249 mmol) in methylene chloride (4 ml) was added triethylamine (103 μl, 0.746 mmol) and benzoyl chloride (35 μl, 0.299 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-9) (67 mg, 57%).
Compound (I-1-9);
1H-NMR (CDCl3) δ1.50-1.60 (2H, m), 1.76-1.88 (4H, m), 2.70-2.77 (2H, m), 2.81 (3H, s), 3.12-3.20 (4H, m) , 3.20-3.27 (2H, m), 3.31-3.38 (4H, m), 3.44-3.56 (2H, m), 6.65 (1H, s), 6.82 (2H, s), 7.40 (5H, m).

Similarly, compounds I-1-193, I-1-194, I-1-195, I-1-196, I-1-197, I-1-198, I-1-210, I-1 -211, I-212, I-213, I-214, I-215, I-218, I-219, I-1-220, I-221 I-1-222, I-1-223, I-1-224, I-1-225, I-1-227, I-1-228, I-1-230, I-1-232 and I -1-233 was synthesized.
Figure JPOXMLDOC01-appb-C000054
第１工程
　化合物１７(100 mg, 0.249 mmol)にジメチルホルムアミド(2 ml)、炭酸カリウム(69 mg, 0.498 mmol)、ピペリジン-1-カルボニルクロリド(44 mg, 0.299 mmol)を加え、室温で8時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１０）(78 mg, 66 %)を得た。
化合物（Ｉ－１－１０）；
1H-NMR(CDCl3)δ1.45-1.70(6H, m), 1.76-1.88(4H, m), 1.90-1.98(2H., m), 2.77(2H, t, J = 7.0Hz), 2.81(3H, s), 3.09-3.20(8H, m), 3.20-3.27(2H, m), 3.40-3.48(4H, m), 3.46-3.56(2H, m), 6.65(1H, s), 6.82(2H, s).
Figure JPOXMLDOC01-appb-C000054
First Step To compound 17 (100 mg, 0.249 mmol) is added dimethylformamide (2 ml), potassium carbonate (69 mg, 0.498 mmol), piperidine-1-carbonyl chloride (44 mg, 0.299 mmol), and 8 hours at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-10) (78 mg, 66%).
Compound (I-1-10);
1H-NMR (CDCl3) δ1.45-1.70 (6H, m), 1.76-1.88 (4H, m), 1.90-1.98 (2H., M), 2.77 (2H, t, J = 7.0Hz), 2.81 ( 3H, s), 3.09-3.20 (8H, m), 3.20-3.27 (2H, m), 3.40-3.48 (4H, m), 3.46-3.56 (2H, m), 6.65 (1H, s), 6.82 ( 2H, s).
Figure JPOXMLDOC01-appb-C000055
第１工程
　化合物１７(100 mg, 0.249 mmol)に塩化メチレン(3 ml)、トリエチルアミン(138 μl, 0.995 mmol)を加え撹拌し、氷冷下、n-ブチルクロロホルメート(40.8 mg, 0.299 mmol)を加え、2時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１１）(75 mg, 65 %)を得た。
化合物（Ｉ－１－１１）；
1H-NMR(CDCl3)δ0.93(3H, t, J = 7.0Hz), 1.30-1.42(2H, m), 1.45-1.76(4H, m), 1.76-1.88(4H, m), 2.77(2H, t, J = 7.1Hz), 2.83(3H, s), 3.15-3.22(4H, m), 3.20-3.30(2H, m), 3.30-3.38(4H, m), 3.80-3.91(2H, m), 4.10(2H, t, J = 7.0Hz), 6.65(1H, s), 6.79(2H, s).

　同様にして、化合物Ｉ－１－１９９、Ｉ－１－２００、Ｉ－１－２０１、Ｉ－１－２０２、Ｉ－１－２０３、Ｉ－１－２０４、Ｉ－１－２０５、Ｉ－１－２０６、Ｉ－１－２０７、Ｉ－１－２０８、Ｉ－１－２０９、Ｉ－１－２１０、Ｉ－１－２１１、Ｉ－１－２１２、Ｉ－１－２１３、Ｉ－１－２１４、Ｉ－１－２１５、Ｉ－１－２１８、Ｉ－１－２１９、Ｉ－１－２２０、Ｉ－１－２２１、Ｉ－１－２２２、Ｉ－１－２２３、Ｉ－１－２２４、Ｉ－１－２２５、Ｉ－１－２２７、Ｉ－１－２２８、Ｉ－１－２３０、Ｉ－１－２３２およびＩ－１－２３３を合成した。
Figure JPOXMLDOC01-appb-C000055
First Step To compound 17 (100 mg, 0.249 mmol), methylene chloride (3 ml) and triethylamine (138 μl, 0.995 mmol) were added and stirred. Under ice cooling, n-butyl chloroformate (40.8 mg, 0.299 mmol) And stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-11) (75 mg, 65%).
Compound (I-1-11);
1H-NMR (CDCl3) δ0.93 (3H, t, J = 7.0Hz), 1.30-1.42 (2H, m), 1.45-1.76 (4H, m), 1.76-1.88 (4H, m), 2.77 (2H , t, J = 7.1Hz), 2.83 (3H, s), 3.15-3.22 (4H, m), 3.20-3.30 (2H, m), 3.30-3.38 (4H, m), 3.80-3.91 (2H, m ), 4.10 (2H, t, J = 7.0Hz), 6.65 (1H, s), 6.79 (2H, s).

Similarly, compounds I-1-199, I-1-200, I-1-201, I-1-202, I-1-203, I-1-204, I-1-205, I-1 -206, I-1-207, I-1-208, I-1-209, I-1-210, I-1-211, I-1-212, I-1-213, I-1-214 I-1-215, I-218, I-219, I-1-220, I-221, I-122, I-223, I-224, I -1-225, I-1-227, I-228, I-1-230, I-1-232 and I-1-233 were synthesized.
Figure JPOXMLDOC01-appb-C000056
第１工程
　化合物１４(500 mg, 1.77 mmol)のジメチルアセトアミド(5 ml)溶液に炭酸カリウム(490 mg, 3.54 mmol)、2-クロロ-5-エチルピリミジン(300 mg, 2.12 mmol)を加え、100℃で4時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１８(420 mg, 61 %)を得た。
第２工程
　化合物１８(200 mg, 0.515 mmol)にトルエン(2 ml)、1-メチルスルホニルピペラジン(85 mg, 0.515 mmol)、Pd2(dba)3(24 mg, 0.026 mmol)、ナトリウム tert-ブトキシド(99 mg, 1.03 mmol)、BINAP(32 mg, 0.052 mmol)を加え、100℃で7.5時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１２）(150 mg, 62 %)を得た。
化合物（Ｉ－１－１２）；
1H-NMR(CDCl3)δ1.18(3H, t, J = 7.5hz), 1.45-1.56(2H, m), 1.76-1.88(4H, m), 2.47(2H, q, J = 7.5Hz), 2.77(2H, t, J = 7.1Hz), 2.83(3H, s), 3.18-3.25(4H, m), 3.38-3.47(4H, m), 3.40-3.49(2H, m), 4.30-4.45(2H, m),  6.65(1H, s), 6.76-6.82(2H, m), 8.17(2H, s).
Figure JPOXMLDOC01-appb-C000056
Step 1 To a solution of compound 14 (500 mg, 1.77 mmol) in dimethylacetamide (5 ml) was added potassium carbonate (490 mg, 3.54 mmol) and 2-chloro-5-ethylpyrimidine (300 mg, 2.12 mmol). Stir at 4 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 18 (420 mg, 61%).
Second Step Compound 18 (200 mg, 0.515 mmol) was added to toluene (2 ml), 1-methylsulfonylpiperazine (85 mg, 0.515 mmol), Pd 2 (dba) 3 (24 mg, 0.026 mmol), sodium tert-butoxide (99 mg, 1.03 mmol) and BINAP (32 mg, 0.052 mmol) were added, and the mixture was stirred at 100 ° C. for 7.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-12) (150 mg, 62%).
Compound (I-1-12);
1H-NMR (CDCl3) δ 1.18 (3H, t, J = 7.5hz), 1.45-1.56 (2H, m), 1.76-1.88 (4H, m), 2.47 (2H, q, J = 7.5Hz), 2.77 (2H, t, J = 7.1Hz), 2.83 (3H, s), 3.18-3.25 (4H, m), 3.38-3.47 (4H, m), 3.40-3.49 (2H, m), 4.30-4.45 ( 2H, m), 6.65 (1H, s), 6.76-6.82 (2H, m), 8.17 (2H, s).
Figure JPOXMLDOC01-appb-C000057
第１工程
　化合物１４(2.0 g, 7.09 mmol)のジメチルホルムアミド(20 ml)溶液に、炭酸カリウム(1.95 g, 14.1 mmol)、ベンジルブロミド(716 μl, 6.02 mmol)を加え、室温で7時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１９(1.8 g, 68 %)を得た。
第２工程
　化合物１９(200 mg, 0.537 mmol)にトルエン(2 ml)、1-メチルスルホニルピペラジン(88 mg, 0.537 mmol)、Pd2(dba)3(25 mg, 0.027 mmol)、ナトリウム tert-ブトキシド(103 mg, 1.07 mmol)、BINAP(34 mg, 0.054 mmol)を加え、100℃で7.5時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１３）(74 mg, 30 %)を得た。
化合物（Ｉ－１－１３）；
1H-NMR(CDCl3)δ1.60-1.70(2H, m), 1.76-1.88(4H, m), 2.40-2.47(2H, m), 2.60-2.67(2H, m), 2.72(2H, t, J = 7.0Hz),  2.81(3H, s), 3.12-3.20(4H, m), 3.31-3.38(4H, m), 3.54(2H, s), 6.65(1H, s), 6.76-6.82(2H, s), 7.20-7.34(5H, m).
Figure JPOXMLDOC01-appb-C000057
First Step To a solution of compound 14 (2.0 g, 7.09 mmol) in dimethylformamide (20 ml) was added potassium carbonate (1.95 g, 14.1 mmol) and benzyl bromide (716 μl, 6.02 mmol), and the mixture was stirred at room temperature for 7 hours. . The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 19 (1.8 g, 68%).
Second Step Compound 19 (200 mg, 0.537 mmol) was added to toluene (2 ml), 1-methylsulfonylpiperazine (88 mg, 0.537 mmol), Pd 2 (dba) 3 (25 mg, 0.027 mmol), sodium tert-butoxide (103 mg, 1.07 mmol) and BINAP (34 mg, 0.054 mmol) were added, and the mixture was stirred at 100 ° C. for 7.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-13) (74 mg, 30%).
Compound (I-1-13);
1H-NMR (CDCl3) δ 1.60-1.70 (2H, m), 1.76-1.88 (4H, m), 2.40-2.47 (2H, m), 2.60-2.67 (2H, m), 2.72 (2H, t, J = 7.0Hz), 2.81 (3H, s), 3.12-3.20 (4H, m), 3.31-3.38 (4H, m), 3.54 (2H, s), 6.65 (1H, s), 6.76-6.82 (2H , s), 7.20-7.34 (5H, m).
Figure JPOXMLDOC01-appb-C000058
第１工程
　化合物１２(1.0 g, 2.52 mmol)のテトラヒドロフラン(20 ml)溶液を、-78℃に冷却し、窒素ガス気流下、ヘキサメチルジシラザンナトリウム(1.9 M テトラヒドロフラン溶液, 5.3 ml, 10.1 mmol)を加え0℃で30分撹拌した。-78℃に冷却し、N-フルオロベンゼンスルホンイミド(3.18 mmol, 10.1 mmol)を加え、室温で2.5時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２０(1.0 g, 92 %)を得た。
第２工程
　化合物２０(2.8 g, 6.48 mmol)のジオキサン(3 ml)溶液に4-アミノフェニルボロン酸ピナコールエステル(2.84 g, 13.0 mmol)、2M 炭酸ナトリウム水溶液(13.0 ml, 26.0 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(749 mg, 0.648 mmol)を加え、4時間加熱還流を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物２１を得た。精製せずに次の反応に用いた。
第３工程
　前工程で得られた化合物２１をジメチルホルムアミド(56 ml)に溶解し、炭酸カリウム(5.38 g, 38.9 mmol)、モルホリン-4-カルボニルクロリド(3.1 ml, 25.9 mmol)を加え、室温で4日間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２２(1.6 g, 44 %)を得た。
第４工程
　化合物２２(1.6 g, 2.87 mmol)のエタノール(32 ml)溶液に水素化ほう素ナトリウム(217 mg, 5.74 mmol)を加え、室温で30分間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２３(1.2 g, 75 %)を得た。
第５工程
　化合物２３(1.2 g, 2.14 mmol)の塩化メチレン(12 ml)溶液にトリエチルアミン(594 μl, 4.29 mmol)、メタンスルホニルクロリド(201 μl, 2.57 mmol)を加え、室温で1時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物２４を得た。精製することなく次の反応に用いた。
第６工程
　前工程で得られた化合物２４のエタノール(120 ml)溶液に10% パラジウム炭素(120 mg)を加え、水素ガス気流下、3時間撹拌した。触媒をろ過し、溶媒を留去し、化合物（Ｉ－１－１４）(1163 mg)を得た。
化合物（Ｉ－１－１４）；
1H-NMR(DMSO)δ1.42(9H, s), 1.60-1.88(2H, m), 1.99-2.04(2H, m), 2.90-3.10(3H, m), 3.42-3.46(4H, m), 3.60-3.63(4H, m), 3.71-3.74(2H, m), 3.80-4.00(2H, m), .7.01-7.04(1H, m), 7.49-7.62(6H, m), 8.61(1H, s).
第７工程
　化合物（Ｉ－１－１４）(168 mg, 0.309 mmol)に4N 塩酸-酢酸エチル溶液(4.0 ml, 16.0 mmol)を加え、室温で1日撹拌した。溶媒を留去し、化合物２５を得た。精製せずに次の反応に用いた。
第８工程
　前工程で得られた化合物２５に塩化メチレン(5 ml)、トリエチルアミン(128 μl, 0.924 mmol)を加え、0℃に冷却し、イソプロピルクロロホルメート(42 μl, 0.370 mmol)を滴下した。室温で1日撹拌し、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１５）(40 mg, 25 %)を得た。
化合物（Ｉ－１－１５）；
1H-NMR(DMSO)δ1.20(6H, d, J = 6.3Hz), 1.65-1.86(2H, m), 2.00-2.01(1H, m), 3.00-3.40(3H, m), 3.40-3.50(4H, m), 3.58-3.63(4H, m), 3.67-3.74(2H, m), 3.90-4.02(2H, m), 4.80-4.90(1H, m), .7.01-7.04(1H, m), 7.45-7.62(6H, m), 8.61(1H, s).

　同様にして、化合物Ｉ－１－２３１およびＩ－１－２３９を合成した。
Figure JPOXMLDOC01-appb-C000058
First Step A solution of compound 12 (1.0 g, 2.52 mmol) in tetrahydrofuran (20 ml) was cooled to -78 ° C., and under a nitrogen gas stream, sodium hexamethyldisilazane (1.9 M tetrahydrofuran solution, 5.3 ml, 10.1 mmol) And stirred at 0 ° C. for 30 minutes. The mixture was cooled to −78 ° C., N-fluorobenzenesulfonimide (3.18 mmol, 10.1 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 20 (1.0 g, 92%).
Second Step Compound 20 (2.8 g, 6.48 mmol) in dioxane (3 ml) was added 4-aminophenylboronic acid pinacol ester (2.84 g, 13.0 mmol), 2M aqueous sodium carbonate solution (13.0 ml, 26.0 mmol), tetrakis ( Triphenylphosphine) palladium (749 mg, 0.648 mmol) was added, and the mixture was heated to reflux for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 21. Used in the next reaction without purification.
Step 3 Compound 21 obtained in the previous step was dissolved in dimethylformamide (56 ml), potassium carbonate (5.38 g, 38.9 mmol) and morpholine-4-carbonyl chloride (3.1 ml, 25.9 mmol) were added, and at room temperature. Stir for 4 days. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 22 (1.6 g, 44%).
Fourth Step Sodium borohydride (217 mg, 5.74 mmol) was added to a solution of compound 22 (1.6 g, 2.87 mmol) in ethanol (32 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 23 (1.2 g, 75%).
Fifth Step To a solution of compound 23 (1.2 g, 2.14 mmol) in methylene chloride (12 ml) was added triethylamine (594 μl, 4.29 mmol) and methanesulfonyl chloride (201 μl, 2.57 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off to obtain Compound 24. Used in the next reaction without purification.
Step 6 To a solution of compound 24 obtained in the previous step in ethanol (120 ml) was added 10% palladium carbon (120 mg), and the mixture was stirred under a hydrogen gas stream for 3 hours. The catalyst was filtered off and the solvent was distilled off to obtain compound (I-1-14) (1163 mg).
Compound (I-1-14);
1H-NMR (DMSO) δ1.42 (9H, s), 1.60-1.88 (2H, m), 1.99-2.04 (2H, m), 2.90-3.10 (3H, m), 3.42-3.46 (4H, m) , 3.60-3.63 (4H, m), 3.71-3.74 (2H, m), 3.80-4.00 (2H, m), .7.01-7.04 (1H, m), 7.49-7.62 (6H, m), 8.61 (1H , s).
Step 7 4N Hydrochloric acid-ethyl acetate solution (4.0 ml, 16.0 mmol) was added to compound (I-1-14) (168 mg, 0.309 mmol), and the mixture was stirred at room temperature for 1 day. The solvent was distilled off to obtain Compound 25. Used in the next reaction without purification.
Step 8 Methylene chloride (5 ml) and triethylamine (128 μl, 0.924 mmol) were added to the compound 25 obtained in the previous step, cooled to 0 ° C., and isopropyl chloroformate (42 μl, 0.370 mmol) was added dropwise. . The mixture was stirred at room temperature for 1 day, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-15) (40 mg, 25%).
Compound (I-1-15);
1H-NMR (DMSO) δ 1.20 (6H, d, J = 6.3Hz), 1.65-1.86 (2H, m), 2.00-2.01 (1H, m), 3.00-3.40 (3H, m), 3.40-3.50 (4H, m), 3.58-3.63 (4H, m), 3.67-3.74 (2H, m), 3.90-4.02 (2H, m), 4.80-4.90 (1H, m), .7.01-7.04 (1H, m ), 7.45-7.62 (6H, m), 8.61 (1H, s).

In the same manner, compounds I-1-231 and I-1-239 were synthesized.
Figure JPOXMLDOC01-appb-C000059
第１工程
　マグネシウム(3.15 g, 130 mmol)をテトラヒドロフラン(20 ml)に懸濁し、ブロモエタン(1 ml)を加えた。内温を50～60℃に保ちながら2-ブロモ-4-クロロ-1-メトキシベンゼン　２６(22.1 g, 100 mmol)のテトラヒドロフラン(80 ml)溶液を25分間かけて滴下し、更に室温で80分間撹拌した。次に、臭化第1銅(716 mg, 4.99 mmol)を加え、1-オキサ-6-アザ-スピロ[2.5]オクタン-6-カルボン酸 tert-ブチル(21.3 g, 100 mmol)のテトラヒドロフラン(80 ml)溶液を20分かけて滴下した。室温で1時間撹拌した後に、反応液を飽和塩化アンモニウム水溶液に注ぎ、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、化合物２７(30.5 g, 86 %)を得た。
第２工程
　化合物２７(30 g, 84 mmol)の酢酸(80 ml)溶液に48%臭化水素酸(142 g, 843 mmol)を15分間かけて滴下し、50℃で30分、次に120℃で13時間撹拌した。反応液に3M 水酸化ナトリウム水溶液を加えアルカリ性とした後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、化合物２８(18.7 g, 99 %)を得た。
第３工程
　化合物２８(2.75 g, 12.3 mmol)の塩化メチレン(30 ml)溶液に、氷冷下、トリエチルアミン(3.41 ml, 24.6 mmol)とネオペンチルクロロホルメート(2.22 g, 14.7 mmol)を加え、1.5時間撹拌した。反応液を水に注ぎ、塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２９(3.65 g, 88 %)を得た。
第４工程
　化合物２９(80 mg, 0.237 mmol)をジメチルアセトアミド(2 ml)に溶解し、水(0.2 ml)、4-(メチルスルホニル)フェニルボロン酸(57 mg, 0.284 mmol)、PdCl2(dppf)(17.3 mg, 0.024 mmol)、炭酸カリウム(98 mg, 0.710 mmol)を加え、90℃で3時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１６）(80 mg, 74 %)を得た。
化合物（Ｉ－１－１６）；
1H-NMR(CDCl3)δ0.94(9H, s), 1.71-1.85(2H, m), 1.91-2.04(2H, m), 3.03(2H, s), 3.05(3H, s),  3.40-3.50(2H, m), 3.81(2H, s), 3.81-3.94(2H, m), 6.84(1H, d, J = 8.6Hz), 7.38(1H, d, J = 8.4Hz), 7.39(1H, s), 7.70(2H, d, J = 8.6Hz), 7.95(2H, d, J = 8.6Hz).

　同様にして、化合物Ｉ－１－２４７、Ｉ－１－３０４、Ｉ－１－３０８、Ｉ－１－３０９、Ｉ－１－３１０、Ｉ－１－３１１、Ｉ－１－３１７、Ｉ－１－３１８およびＩ－１－３２１を合成した。
Figure JPOXMLDOC01-appb-C000059
First Step Magnesium (3.15 g, 130 mmol) was suspended in tetrahydrofuran (20 ml), and bromoethane (1 ml) was added. While maintaining the internal temperature at 50 to 60 ° C., a solution of 2-bromo-4-chloro-1-methoxybenzene 26 (22.1 g, 100 mmol) in tetrahydrofuran (80 ml) was added dropwise over 25 minutes, and further at room temperature for 80 minutes. Stir. Next, cuprous bromide (716 mg, 4.99 mmol) was added and tert-butyl 1-oxa-6-aza-spiro [2.5] octane-6-carboxylate (21.3 g, 100 mmol) in tetrahydrofuran (80 ml) The solution was added dropwise over 20 minutes. After stirring at room temperature for 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain Compound 27 (30.5 g, 86%).
Second Step To a solution of compound 27 (30 g, 84 mmol) in acetic acid (80 ml), 48% hydrobromic acid (142 g, 843 mmol) was added dropwise over 15 minutes, 30 minutes at 50 ° C., then 120 Stir at 13 ° C. for 13 hours. The reaction mixture was made alkaline with 3M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain Compound 28 (18.7 g, 99%).
Step 3 To a solution of compound 28 (2.75 g, 12.3 mmol) in methylene chloride (30 ml) was added triethylamine (3.41 ml, 24.6 mmol) and neopentyl chloroformate (2.22 g, 14.7 mmol) under ice-cooling. Stir for 1.5 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 29 (3.65 g, 88%).
Step 4 Compound 29 (80 mg, 0.237 mmol) was dissolved in dimethylacetamide (2 ml), water (0.2 ml), 4- (methylsulfonyl) phenylboronic acid (57 mg, 0.284 mmol), PdCl 2 (dppf ) (17.3 mg, 0.024 mmol) and potassium carbonate (98 mg, 0.710 mmol) were added, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-16) (80 mg, 74%).
Compound (I-1-16);
1H-NMR (CDCl3) δ0.94 (9H, s), 1.71-1.85 (2H, m), 1.91-2.04 (2H, m), 3.03 (2H, s), 3.05 (3H, s), 3.40-3.50 (2H, m), 3.81 (2H, s), 3.81-3.94 (2H, m), 6.84 (1H, d, J = 8.6Hz), 7.38 (1H, d, J = 8.4Hz), 7.39 (1H, s), 7.70 (2H, d, J = 8.6Hz), 7.95 (2H, d, J = 8.6Hz).

Similarly, compounds I-1-247, I-1-304, I-1-308, I-1-309, I-1-310, I-1-311, I-1-317, I-1 -318 and I-1-321 were synthesized.
Figure JPOXMLDOC01-appb-C000060
第１工程
　化合物２９(2.1 g, 6.22 mmol)をジメチルアセトアミド(20 ml)に溶解し、水(2 ml)、4-(tert-ブトキシカルボニル)フェニルボロン酸(2.07 g, 9.32 mmol)、PdCl2(dtbpf)(203 mg, 0.311 mmol)、炭酸カリウム(1.71 g, 12.43 mmol)を加え、90℃で4時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物３０(0.97 g, 33 %)を得た。
第２工程
　化合物３０(0.95 g, 1.98 mmol)を塩化メチレン(5 ml)に溶解し、トリフルオロ酢酸(3.05 ml, 39.6 mmol)を加え、室温で2時間撹拌した。反応液を水に注ぎ、析出した結晶をろ取した。乾燥後、化合物３１(0.77 g, 92 %)を得た。
第３工程
　化合物３１(50 mg, 0.118 mmol)のジメチルアセトアミド(2 ml)溶液にHATU(67.3 mg, 0.177 mmol)、トリエチルアミン(82 μl, 0.590 mmol)、4-メトキシピペリジン(20.4 mg, 0.177 mmol)を加え、室温で80分間撹拌した。反応液に水を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１７）(45 mg, 73 %)を得た。
化合物（Ｉ－１－１７）；
1H-NMR(CDCl3)δ0.95(9H, s), 1.40-1.99(8H, m), 3.05(2H, s), 3.35(3H, s), 3.40-3.60(5H, m), 3.80(2H, s), 3.81-3.92(4H, m), 6.82(1H, d, J = 8.6Hz), 7.31(1H, J = 8.4Hz), 7.38(1H, s), 7.44(2H, d, J = 8.6Hz), 7.52(2H, d, J = 8.6Hz).

　同様にして、化合物Ｉ－１－２５０、Ｉ－１－２５１、Ｉ－１－２５２、Ｉ－１－２５３、Ｉ－１－２５４、Ｉ－１－２５５、Ｉ－１－２５６、Ｉ－１－２５７、Ｉ－１－２５８、Ｉ－１－２５９、Ｉ－１－２６０、Ｉ－１－２６１、Ｉ－１－２６２、Ｉ－１－２６３、Ｉ－１－２６４、Ｉ－１－２６５、Ｉ－１－２６６、Ｉ－１－２６７、Ｉ－１－２６８、Ｉ－１－２６９、Ｉ－１－２７０、Ｉ－１－２７１、Ｉ－１－２７２、Ｉ－１－３１２、Ｉ－１－３１３、Ｉ－１－３１４およびＩ－１－３１５を合成した。
Figure JPOXMLDOC01-appb-C000060
Step 1 Compound 29 (2.1 g, 6.22 mmol) was dissolved in dimethylacetamide (20 ml), water (2 ml), 4- (tert-butoxycarbonyl) phenylboronic acid (2.07 g, 9.32 mmol), PdCl 2 (dtbpf) (203 mg, 0.311 mmol) and potassium carbonate (1.71 g, 12.43 mmol) were added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 30 (0.97 g, 33%).
Second Step Compound 30 (0.95 g, 1.98 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (3.05 ml, 39.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration. Compound 31 (0.77 g, 92%) was obtained after drying.
Step 3 Compound 31 (50 mg, 0.118 mmol) in dimethylacetamide (2 ml) was added to HATU (67.3 mg, 0.177 mmol), triethylamine (82 μl, 0.590 mmol), 4-methoxypiperidine (20.4 mg, 0.177 mmol). And stirred at room temperature for 80 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-17) (45 mg, 73%).
Compound (I-1-17);
1H-NMR (CDCl3) δ0.95 (9H, s), 1.40-1.99 (8H, m), 3.05 (2H, s), 3.35 (3H, s), 3.40-3.60 (5H, m), 3.80 (2H , s), 3.81-3.92 (4H, m), 6.82 (1H, d, J = 8.6Hz), 7.31 (1H, J = 8.4Hz), 7.38 (1H, s), 7.44 (2H, d, J = 8.6Hz), 7.52 (2H, d, J = 8.6Hz).

In the same manner, compounds I-1-250, I-1-251, I-1-252, I-1-253, I-1-254, I-1-255, I-1-256, I-1 -257, I-1-258, I-1-259, I-260, I-261, I-262, I-263, I-264, I-265 I-1-266, I-1-267, I-268, I-1-269, I-1-270, I-271, I-272, I-1-312, I -1-313, I-1-314 and I-1-315 were synthesized.
Figure JPOXMLDOC01-appb-C000061
第１工程
　化合物２９(2.5 g, 7.40 mmol)をジメチルアセトアミド(40 ml)に溶解し、水(4 ml)、4-アミノフェニルボロン酸ピナコールエステル(2.43 g, 11.1 mmol)、PdCl2(dtbpf)(0.48 g, 0.74 mmol)、炭酸カリウム(3.07 g, 22.2 mmol)を加え、90℃で4時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物３２(2.0 g, 69 %)を得た。
第２工程
　化合物３２(50 mg, 0.127 mmol)のジメチルアセトアミド(2 ml)溶液にHATU(72.3 mg, 0.190 mmol)、トリエチルアミン(53 μl, 0.380 mmol)、2-エトキシ酢酸(19.8 mg, 0.190 mmol)を加え、室温で50分間撹拌した。反応液に水を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１８）(46 mg, 76 %)を得た。
化合物（Ｉ－１－１８）；
1H-NMR(CDCl3)δ0.94(9H, s), 1.34(3H, J = 7.0Hz), 1.76-1.87(2H, m), 1.95-2.05(2H, m), 3.03(2H, s), 3.40-3.55(2H, m), 3.69(2H, q, J = 7.0Hz), 3.81(2H, s), 3.81-3.95(2H, m), 4.09(2H, s), 6.80(1H, d, J = 8.6Hz), 7.30(1H, s), 7.31(1H, d, J = 8.6Hz), 7.43(2H, d, J = 8.6Hz), 7.62(2H, d, J = 8.6Hz), 8.34(1H, brs).

　同様にして、化合物Ｉ－１－２７３、Ｉ－１－２７４、Ｉ－１－２７５、Ｉ－１－２７６、Ｉ－１－２７７、Ｉ－１－２７９、Ｉ－１－２８０、Ｉ－１－２８１、Ｉ－１－２８３、Ｉ－１－２８４、Ｉ－１－２８５、Ｉ－１－２８６、Ｉ－１－２８７、Ｉ－１－２８８、Ｉ－１－２８９、Ｉ－１－２９０、Ｉ－１－２９１、Ｉ－１－２９２、Ｉ－１－２９３、Ｉ－１－２９４、Ｉ－１－２９５、Ｉ－１－２９６、Ｉ－１－２９７、Ｉ－１－２９８、Ｉ－１－２９９、Ｉ－１－３００、Ｉ－１－３０１およびＩ－１－３０２を合成した。
Figure JPOXMLDOC01-appb-C000061
First Step Compound 29 (2.5 g, 7.40 mmol) was dissolved in dimethylacetamide (40 ml), water (4 ml), 4-aminophenylboronic acid pinacol ester (2.43 g, 11.1 mmol), PdCl 2 (dtbpf) (0.48 g, 0.74 mmol) and potassium carbonate (3.07 g, 22.2 mmol) were added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 32 (2.0 g, 69%).
Step 2 Compound 32 (50 mg, 0.127 mmol) in dimethylacetamide (2 ml) was added to HATU (72.3 mg, 0.190 mmol), triethylamine (53 μl, 0.380 mmol), 2-ethoxyacetic acid (19.8 mg, 0.190 mmol). And stirred at room temperature for 50 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-18) (46 mg, 76%).
Compound (I-1-18);
1H-NMR (CDCl3) δ0.94 (9H, s), 1.34 (3H, J = 7.0Hz), 1.76-1.87 (2H, m), 1.95-2.05 (2H, m), 3.03 (2H, s), 3.40-3.55 (2H, m), 3.69 (2H, q, J = 7.0Hz), 3.81 (2H, s), 3.81-3.95 (2H, m), 4.09 (2H, s), 6.80 (1H, d, J = 8.6Hz), 7.30 (1H, s), 7.31 (1H, d, J = 8.6Hz), 7.43 (2H, d, J = 8.6Hz), 7.62 (2H, d, J = 8.6Hz), 8.34 (1H, brs).

Similarly, compounds I-1-273, I-1-274, I-1-275, I-1-276, I-1-277, I-1-279, I-1-280, I-1 -281, I-1-283, I-1-284, I-1-285, I-1-286, I-1-287, I-1-288, I-1-289, I-1-290 I-291, I-292, I-293, I-294, I-295, I-296, I-297, I-298, I -1-299, I-1-300, I-1-301 and I-1-302 were synthesized.
Figure JPOXMLDOC01-appb-C000062
第１工程
　化合物３２(50 mg, 0.127 mmol)のテトラヒドロフラン(2 ml)溶液に1,1'-カルボニルジイミダゾール(22.6 mg, 0.139 mmol)を加え、室温で50分間撹拌した。溶媒を留去し、残渣にジエチルアミン(40 μl, 0.380 mmol)のテトラヒドロフラン(2 ml)溶液を加え、室温で160分間撹拌した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－１９）(45 mg, 72 %)を得た。
化合物（Ｉ－１－１９）；
1H-NMR(CDCl3)δ0.94(9H, s), 1.24(6H, J = 7.5Hz), 1.70-1.82(2H, m), 1.95-2.05(2H, m), 3.04(2H, s), 3.41(4H, q, J = 7.5H), 3.41-3.50(2H, m), 3.81(2H, s) ,3.82-3.93(2H, m), 6.38(1H, brs), 6.79(1H, d, J = 8.6Hz), 7.30-7.37(2H, m), 7.39(4H, m).

　同様にして、化合物Ｉ－１－２７８およびＩ－１－２８２を合成した。
Figure JPOXMLDOC01-appb-C000062
First Step 1,1′-carbonyldiimidazole (22.6 mg, 0.139 mmol) was added to a solution of compound 32 (50 mg, 0.127 mmol) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 50 minutes. The solvent was distilled off, a solution of diethylamine (40 μl, 0.380 mmol) in tetrahydrofuran (2 ml) was added to the residue, and the mixture was stirred at room temperature for 160 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-19) (45 mg, 72%).
Compound (I-1-19);
1H-NMR (CDCl3) δ0.94 (9H, s), 1.24 (6H, J = 7.5Hz), 1.70-1.82 (2H, m), 1.95-2.05 (2H, m), 3.04 (2H, s), 3.41 (4H, q, J = 7.5H), 3.41-3.50 (2H, m), 3.81 (2H, s), 3.82-3.93 (2H, m), 6.38 (1H, brs), 6.79 (1H, d, J = 8.6Hz), 7.30-7.37 (2H, m), 7.39 (4H, m).

In the same manner, compounds I-1-278 and I-1-282 were synthesized.
Figure JPOXMLDOC01-appb-C000063
第１工程
　化合物３２(50 mg, 0.127 mmol)のジクロロメタン(2 ml)溶液に、氷冷下、トリエチルアミン(53 μl, 0.380 mmol)、メタンスルホニルクロリド(10.9 μl, 0.139 mmol)を加え、同温度で30分間撹拌した。反応液を水に注ぎ、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２０）(44 mg, 74 %)を得た。
化合物（Ｉ－１－２０）；
1H-NMR(CDCl3)δ0.94(9H, s), 1.70-1.84(2H, m), 1.90-1.99(2H, m), 3.04(3H, s), 3.06(2H, s), 3.40-3.55(2H, m), 3.81(2H, s), 3.82-3.90(2H, m), 6.55(1H, brs), 6.82(1H, d, J = 8.6Hz), 7.30(1H, d, J = 8.6Hz), 7.31(1H, s), 7.33(2H, d, J = 8.6Hz), 7.50(2H, d, J = 8.6Hz).
Figure JPOXMLDOC01-appb-C000063
Step 1 To a solution of compound 32 (50 mg, 0.127 mmol) in dichloromethane (2 ml) was added triethylamine (53 μl, 0.380 mmol) and methanesulfonyl chloride (10.9 μl, 0.139 mmol) under ice-cooling. Stir for 30 minutes. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-20) (44 mg, 74%).
Compound (I-1-20);
1H-NMR (CDCl3) δ0.94 (9H, s), 1.70-1.84 (2H, m), 1.90-1.99 (2H, m), 3.04 (3H, s), 3.06 (2H, s), 3.40-3.55 (2H, m), 3.81 (2H, s), 3.82-3.90 (2H, m), 6.55 (1H, brs), 6.82 (1H, d, J = 8.6Hz), 7.30 (1H, d, J = 8.6 Hz), 7.31 (1H, s), 7.33 (2H, d, J = 8.6Hz), 7.50 (2H, d, J = 8.6Hz).
Figure JPOXMLDOC01-appb-C000064
第１工程
　化合物２８(18.7 g, 84 mmol)の塩化メチレン(200 ml)溶液に二炭酸ジ-tert-ブチル(18.24 g, 84 mmol)を加え、室温で2時間撹拌した。溶媒を留去後、酢酸エチルに溶解し、水、飽和食塩水の順に洗浄した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物３３(18.5 g, 68 %)を得た。
第２工程
　化合物３３(200 mg, 0.618 mmol)をジメチルアセトアミド(10 ml)に溶解し、水(1 ml)、4-(4-メチルピペラジン-1-カルボニル)ベンゼンボロン酸ピナコールエステル(224 mg, 0.679 mmol)、PdCl2(dtbpf)(20.1 mg, 0.031 mmol)、炭酸カリウム(256 mg, 1.85 mmol)を加え、90℃で3時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２１）(110 mg, 36 %)を得た。
化合物（Ｉ－１－２１）；
1H-NMR(CDCl3)δ1.48(9H, s), 1.65-1.76(2H, m), 1.85-1.96(2H, m), 2.32(3H, s), 2.30-2.45(4H, m), 3.05(2H, s), 3.40-3.50(4H, m), 3.50-3.83(4H, m), 6.82(1H, d, J = 8.6Hz), 7.34(2H, d, J = 8.6Hz), 7.36(1H, s), 7.44(2H, d, J = 8.6Hz), 7.53(2H, d, J = 8.6Hz).

　同様にして、化合物Ｉ－１－２４６およびＩ－１－３０３を合成した。
Figure JPOXMLDOC01-appb-C000064
First Step Di-tert-butyl dicarbonate (18.24 g, 84 mmol) was added to a solution of compound 28 (18.7 g, 84 mmol) in methylene chloride (200 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the residue was dissolved in ethyl acetate and washed with water and saturated brine in this order. It dried with magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 33 (18.5 g, 68%).
Second Step Compound 33 (200 mg, 0.618 mmol) was dissolved in dimethylacetamide (10 ml), water (1 ml), 4- (4-methylpiperazine-1-carbonyl) benzeneboronic acid pinacol ester (224 mg, 0.679 mmol), PdCl 2 (dtbpf) (20.1 mg, 0.031 mmol) and potassium carbonate (256 mg, 1.85 mmol) were added, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-21) (110 mg, 36%).
Compound (I-1-21);
1H-NMR (CDCl3) δ1.48 (9H, s), 1.65-1.76 (2H, m), 1.85-1.96 (2H, m), 2.32 (3H, s), 2.30-2.45 (4H, m), 3.05 (2H, s), 3.40-3.50 (4H, m), 3.50-3.83 (4H, m), 6.82 (1H, d, J = 8.6Hz), 7.34 (2H, d, J = 8.6Hz), 7.36 ( 1H, s), 7.44 (2H, d, J = 8.6Hz), 7.53 (2H, d, J = 8.6Hz).

Similarly, compounds I-1-246 and I-1-303 were synthesized.
Figure JPOXMLDOC01-appb-C000065
　化合物３３を用いて、実施例１６と同様の方法で化合物（Ｉ－１－２２）を合成した。
化合物（Ｉ－１－２２）；
1H-NMR(CDCl3)δ1.24(3H, J = 7.1Hz), 1.48(9H, s), 1.59-1.74(2H, m), 1.80-1.90(2H, m), 2.42(2H, q, J = 7.1H), 3.05(2H, s), 3.40-3.60(2H, m), 3.75-3.83(2H, m), 6.82(1H, d, J = 8.6Hz), 7.18(1H, brs), 7.30-7.40(2H, m), 7.44(2H, d, J = 8.6Hz), 7.52(2H, d, J = 8.6Hz).
Figure JPOXMLDOC01-appb-C000065
Using compound 33, compound (I-1-22) was synthesized in the same manner as in Example 16.
Compound (I-1-22);
1H-NMR (CDCl3) δ1.24 (3H, J = 7.1Hz), 1.48 (9H, s), 1.59-1.74 (2H, m), 1.80-1.90 (2H, m), 2.42 (2H, q, J = 7.1H), 3.05 (2H, s), 3.40-3.60 (2H, m), 3.75-3.83 (2H, m), 6.82 (1H, d, J = 8.6Hz), 7.18 (1H, brs), 7.30 -7.40 (2H, m), 7.44 (2H, d, J = 8.6Hz), 7.52 (2H, d, J = 8.6Hz).
Figure JPOXMLDOC01-appb-C000066
第１工程
　化合物３５(3.0 g, 6.1 mmol)の酢酸エチル(25 ml)溶液に4N 塩酸-ジオキサン溶液(15.2 ml, 60.8 mmol)を加え、室温で3時間撹拌した。反応液に2N 水酸化ナトリウム水溶液を加えてアルカリ性とした後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、溶媒を留去し、化合物３６(1.7 g, 71 %)を得た。
第２工程
　化合物３６(50.3 mg, 0.128 mmol)のジメチルホルムアミド(1.5 ml)溶液に炭酸カリウム(55.2 mg, 0.399 mmol)、2-クロロ-5-(トリフルオロメチル)ピリミジン(40.2 mg, 0.220 mmol)を加え、80℃で3時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２３）(40.4 mg, 59 %)を得た。
化合物（Ｉ－１－２３）；
1H-NMR(CDCl3) δ 1.77-1.87 (2H, m), 2.05-2.13 (2H, m), 3.10 (2H, s), 3.52 (4H, t, J = 4.9 Hz), 3.72-3.79 (2H, m), 3.78 (4H, t, J = 4.9 Hz), 4.49 (2H, td, J = 8.7, 4.9 Hz), 6.37 (1H, s), 6.86 (1H, d, J = 8.1 Hz), 7.35-7.51 (6H, m), 8.52 (2H, s).

　同様にして、化合物Ｉ－１－２４９、Ｉ－１－３０５、Ｉ－１－３０６、Ｉ－１－３０７、Ｉ－１－３１９およびＩ－１－３２０を合成した。
Figure JPOXMLDOC01-appb-C000066
First Step To a solution of compound 35 (3.0 g, 6.1 mmol) in ethyl acetate (25 ml) was added 4N hydrochloric acid-dioxane solution (15.2 ml, 60.8 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made alkaline by adding 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was distilled off to obtain Compound 36 (1.7 g, 71%).
Step 2 Compound 36 (50.3 mg, 0.128 mmol) in dimethylformamide (1.5 ml) was added potassium carbonate (55.2 mg, 0.399 mmol), 2-chloro-5- (trifluoromethyl) pyrimidine (40.2 mg, 0.220 mmol). And stirred at 80 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-23) (40.4 mg, 59%).
Compound (I-1-23);
1H-NMR (CDCl3) δ 1.77-1.87 (2H, m), 2.05-2.13 (2H, m), 3.10 (2H, s), 3.52 (4H, t, J = 4.9 Hz), 3.72-3.79 (2H, m), 3.78 (4H, t, J = 4.9 Hz), 4.49 (2H, td, J = 8.7, 4.9 Hz), 6.37 (1H, s), 6.86 (1H, d, J = 8.1 Hz), 7.35- 7.51 (6H, m), 8.52 (2H, s).

Similarly, compounds I-1-249, I-1-305, I-1-306, I-1-307, I-1-319, and I-1-320 were synthesized.
Figure JPOXMLDOC01-appb-C000067
第１工程
　化合物３６(218.2 mg, 0.555 mmol)のジクロロメタン(1 ml)懸濁液に、氷冷下、水(0.5 ml)、炭酸水素ナトリウム(97.3 mg, 1.16 mmol)、臭化シアン(222 μl, 0.666 mmol)を加え、室温で3時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２４）(259.2 mg)を得た。
化合物（Ｉ－１－２４）；
1H-NMR(CDCl3) δ 1.92-2.06 (4H, m), 3.08 (2H, s), 3.32-3.40 (2H, m), 3.51-3.60 (2H, m), 3.52 (4H, t, J = 4.9 Hz), 3.78 (4H, t, J = 4.9 Hz), 6.38 (1H, s), 6.82 (1H, d, J = 8.2 Hz), 7.34-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000067
First Step To a suspension of compound 36 (218.2 mg, 0.555 mmol) in dichloromethane (1 ml) under ice-cooling, water (0.5 ml), sodium bicarbonate (97.3 mg, 1.16 mmol), cyanogen bromide (222 μl) , 0.666 mmol) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-24) (259.2 mg).
Compound (I-1-24);
1H-NMR (CDCl3) δ 1.92-2.06 (4H, m), 3.08 (2H, s), 3.32-3.40 (2H, m), 3.51-3.60 (2H, m), 3.52 (4H, t, J = 4.9 Hz), 3.78 (4H, t, J = 4.9 Hz), 6.38 (1H, s), 6.82 (1H, d, J = 8.2 Hz), 7.34-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000068
第１工程
　化合物（Ｉ－１－２４）(151.2 mg, 0.361 mmol)の酢酸エチル(4 ml)懸濁液に(Z)-N'-hydroxy-2-methylpropanimidamide (50.2 mg, 0.491 mmol)、塩化亜鉛(0.5 M/L テトラヒドロフラン溶液, 867 μl, 0.434 mmol)を加え、室温で30分撹拌した。溶媒を留去し、残渣をエーテルで洗浄した後に、エタノール(4 ml)、濃塩酸(1 ml)を加え、60℃で4時間撹拌した。反応液に2M 水酸化ナトリウム水溶液(5 ml)を加え、 酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２５）(68.4 mg, 38 %)を得た。
化合物（Ｉ－１－２５）；
1H-NMR(CDCl3) δ 1.32 (6H, d, J = 6.9 Hz), 1.82-1.92 (2H, m), 2.03-2.11 (2H, m), 2.88-2.97 (1H, m), 3.09 (2H, s), 3.52 (4H, t, J = 4.9 Hz), 3.64-3.73 (2H, m), 3.77 (4H, t, J = 4.9 Hz), 3.97 (2H, dt, J = 13.4, 3.9 Hz), 6.48 (1H, s), 6.84 (1H, d, J = 8.1 Hz), 7.34-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000068
Step 1 (Z) -N'-hydroxy-2-methylpropanimidamide (50.2 mg, 0.491 mmol), chloride in a suspension of compound (I-1-24) (151.2 mg, 0.361 mmol) in ethyl acetate (4 ml) Zinc (0.5 M / L tetrahydrofuran solution, 867 μl, 0.434 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, the residue was washed with ether, ethanol (4 ml) and concentrated hydrochloric acid (1 ml) were added, and the mixture was stirred at 60 ° C. for 4 hr. To the reaction solution was added 2M aqueous sodium hydroxide solution (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-25) (68.4 mg, 38%).
Compound (I-1-25);
1H-NMR (CDCl3) δ 1.32 (6H, d, J = 6.9 Hz), 1.82-1.92 (2H, m), 2.03-2.11 (2H, m), 2.88-2.97 (1H, m), 3.09 (2H, s), 3.52 (4H, t, J = 4.9 Hz), 3.64-3.73 (2H, m), 3.77 (4H, t, J = 4.9 Hz), 3.97 (2H, dt, J = 13.4, 3.9 Hz), 6.48 (1H, s), 6.84 (1H, d, J = 8.1 Hz), 7.34-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000069
第１工程
　化合物３６(42.5 mg, 0.108 mmol)のアセトニトリル(1 ml)懸濁液に炭酸カリウム(45.1 mg, 0.326 mmol)、ブロモ酢酸 tert-ブチル(19 μl, 0.130 mmol)を加え、50℃で1.5時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２６）(30.3 mg, 55 %)を得た。
化合物（Ｉ－１－２６）；
1H-NMR(CDCl3) δ 1.51 (9H, s), 1.93 (2H, dd, J = 13.3, 6.5 Hz), 2.00-2.08 (2H, m), 2.74 (4H, t, J = 4.9 Hz), 3.05 (2H, s), 3.21 (2H, s), 3.50 (4H, t, J = 4.9 Hz), 3.75 (4H, t, J = 4.9 Hz), 6.52 (1H, s), 6.81 (1H, d, J = 8.1 Hz), 7.29-7.48 (6H, m).
Figure JPOXMLDOC01-appb-C000069
First Step To a suspension of compound 36 (42.5 mg, 0.108 mmol) in acetonitrile (1 ml) was added potassium carbonate (45.1 mg, 0.326 mmol) and tert-butyl bromoacetate (19 μl, 0.130 mmol) at 50 ° C. Stir for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-26) (30.3 mg, 55%).
Compound (I-1-26);
1H-NMR (CDCl3) δ 1.51 (9H, s), 1.93 (2H, dd, J = 13.3, 6.5 Hz), 2.00-2.08 (2H, m), 2.74 (4H, t, J = 4.9 Hz), 3.05 (2H, s), 3.21 (2H, s), 3.50 (4H, t, J = 4.9 Hz), 3.75 (4H, t, J = 4.9 Hz), 6.52 (1H, s), 6.81 (1H, d, J = 8.1 Hz), 7.29-7.48 (6H, m).
Figure JPOXMLDOC01-appb-C000070
第１工程
　化合物３６(43.5 mg, 0.111 mmol)のジクロロメタン(1 ml)懸濁液にトリエチルアミン(45 μl, 0.325 mmol)、tert-ブチルアセチルクロリド(18 μl, 0.130 mmol)を加え、室温で1.5時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、化合物（Ｉ－１－２７）(39.0 mg, 72 %)を得た。
化合物（Ｉ－１－２７）；
1H-NMR(CDCl3) δ 1.10 (9H, s), 1.70-1.80 (2H, m), 1.97-2.06 (2H, m), 2.33 (2H, dd, J = 25.9, 14.1 Hz), 3.07 (2H, s), 3.39 (1H, t, J = 11.5 Hz), 3.52 (4H, t, J = 4.9 Hz), 3.64 (1H, t, J = 10.7 Hz), 3.73-3.79 (1H, m), 3.78 (4H, t, J = 4.9 Hz), 4.26-4.33 (1H, m), 6.37 (1H, s), 6.83 (1H, d, J = 7.7 Hz), 7.33-7.50 (6H, m).
Figure JPOXMLDOC01-appb-C000070
Step 1 Triethylamine (45 μl, 0.325 mmol) and tert-butylacetyl chloride (18 μl, 0.130 mmol) were added to a suspension of compound 36 (43.5 mg, 0.111 mmol) in dichloromethane (1 ml), and the mixture was stirred at room temperature for 1.5 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain compound (I-1-27) (39.0 mg, 72%).
Compound (I-1-27);
1H-NMR (CDCl3) δ 1.10 (9H, s), 1.70-1.80 (2H, m), 1.97-2.06 (2H, m), 2.33 (2H, dd, J = 25.9, 14.1 Hz), 3.07 (2H, s), 3.39 (1H, t, J = 11.5 Hz), 3.52 (4H, t, J = 4.9 Hz), 3.64 (1H, t, J = 10.7 Hz), 3.73-3.79 (1H, m), 3.78 ( 4H, t, J = 4.9 Hz), 4.26-4.33 (1H, m), 6.37 (1H, s), 6.83 (1H, d, J = 7.7 Hz), 7.33-7.50 (6H, m).
Figure JPOXMLDOC01-appb-C000071
第１工程
　化合物３６(51.3 mg, 0.130 mmol)のテトラヒドロフラン(1 ml)懸濁液にトリエチルアミン(54 μl, 0.391 mmol)、tert-ブチルイソシアネート(18 μl, 0.154 mmol)を加え、室温で2時間撹拌した。結晶を濾取し、酢酸エチルで洗浄した。乾燥後、化合物（Ｉ－１－２８）(33.2 mg, 52 %)を得た。
化合物（Ｉ－１－２８）；
1H-NMR(CDCl3) δ 1.39 (9H, s), 1.73-1.83 (2H, m), 1.94-2.02 (2H, m), 3.06 (2H, s), 3.38-3.47 (2H, m), 3.52 (4H, t, J = 4.9 Hz), 3.62 (2H, dt, J = 13.1, 4.7 Hz), 3.78 (4H, t, J = 4.9 Hz), 4.39 (1H, s), 6.40 (1H, s), 6.82 (1H, d, J = 8.1 Hz), 7.33-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000071
Step 1 Triethylamine (54 μl, 0.391 mmol) and tert-butyl isocyanate (18 μl, 0.154 mmol) are added to a suspension of compound 36 (51.3 mg, 0.130 mmol) in tetrahydrofuran (1 ml) and stirred at room temperature for 2 hours. did. The crystals were collected by filtration and washed with ethyl acetate. After drying, compound (I-1-28) (33.2 mg, 52%) was obtained.
Compound (I-1-28);
1H-NMR (CDCl3) δ 1.39 (9H, s), 1.73-1.83 (2H, m), 1.94-2.02 (2H, m), 3.06 (2H, s), 3.38-3.47 (2H, m), 3.52 ( 4H, t, J = 4.9 Hz), 3.62 (2H, dt, J = 13.1, 4.7 Hz), 3.78 (4H, t, J = 4.9 Hz), 4.39 (1H, s), 6.40 (1H, s), 6.82 (1H, d, J = 8.1 Hz), 7.33-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000072
第１工程
　化合物３６(56.1 mg, 0.143 mmol)のジクロロメタン(1 ml)懸濁液にトリエチルアミン(59 μl, 0.426 mmol)、2,2-ジメチルプロパン-1-スルホニルクロリド(38.4 mg, 0.225 mmol)を加え、室温で2時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－２９）(32.7 mg, 44 %)を得た。
化合物（Ｉ－１－２９）；
1H-NMR(CDCl3) δ 1.23 (9H, s), 1.89-1.97 (2H, m), 2.04-2.12 (2H, m), 2.84 (2H, s), 3.08 (2H, s), 3.22-3.29 (2H, m), 3.53 (4H, t, J = 4.9 Hz), 3.64-3.71 (2H, m), 3.79 (4H, t, J = 4.9 Hz), 6.37 (1H, s), 6.83 (1H, d, J = 8.1 Hz), 7.33-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000072
Step 1 Triethylamine (59 μl, 0.426 mmol) and 2,2-dimethylpropane-1-sulfonyl chloride (38.4 mg, 0.225 mmol) were added to a suspension of compound 36 (56.1 mg, 0.143 mmol) in dichloromethane (1 ml). The mixture was further stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-29) (32.7 mg, 44%).
Compound (I-1-29);
1H-NMR (CDCl3) δ 1.23 (9H, s), 1.89-1.97 (2H, m), 2.04-2.12 (2H, m), 2.84 (2H, s), 3.08 (2H, s), 3.22-3.29 ( 2H, m), 3.53 (4H, t, J = 4.9 Hz), 3.64-3.71 (2H, m), 3.79 (4H, t, J = 4.9 Hz), 6.37 (1H, s), 6.83 (1H, d , J = 8.1 Hz), 7.33-7.49 (6H, m).
Figure JPOXMLDOC01-appb-C000073
第１工程
　化合物３６(54.4 mg, 0.138 mmol)のジメチルホルムアミド(1 ml)溶液にピリミジン-2-カルボン酸(29.5 mg, 0.238 mmol)、HATU(83.4 mg, 0.219 mmol)、トリエチルアミン(96 μl, 0.693 mmol)を加え、室温で2.5時間撹拌した。反応液に水を注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３０）(28.9 mg, 42 %)を得た。
化合物（Ｉ－１－３０）；
1H-NMR(CDCl3) δ 1.77-2.16 (4H, m), 3.08 (2H, s), 3.39-3.65 (3H, m), 3.51 (4H, t, J = 4.9 Hz), 3.75 (4H, t, J = 4.9 Hz), 4.50 (1H, dt, J = 12.9, 4.0 Hz), 6.69 (1H, s), 6.84 (1H, d, J = 8.4 Hz), 7.33-7.47 (7H, m), 8.85 (2H, d, J = 5.0 Hz).
Figure JPOXMLDOC01-appb-C000073
First Step A solution of compound 36 (54.4 mg, 0.138 mmol) in dimethylformamide (1 ml) was added pyrimidine-2-carboxylic acid (29.5 mg, 0.238 mmol), HATU (83.4 mg, 0.219 mmol), triethylamine (96 μl, 0.693). mmol) was added and stirred at room temperature for 2.5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-30) (28.9 mg, 42%).
Compound (I-1-30);
1H-NMR (CDCl3) δ 1.77-2.16 (4H, m), 3.08 (2H, s), 3.39-3.65 (3H, m), 3.51 (4H, t, J = 4.9 Hz), 3.75 (4H, t, J = 4.9 Hz), 4.50 (1H, dt, J = 12.9, 4.0 Hz), 6.69 (1H, s), 6.84 (1H, d, J = 8.4 Hz), 7.33-7.47 (7H, m), 8.85 ( (2H, d, J = 5.0 Hz).
Figure JPOXMLDOC01-appb-C000074
第１工程
　2-ピリミジンメタノール(149 mg, 1.35 mmol)のトルエン(2 ml)溶液にトリエチルアミン(562 μl, 4.06 mmol)、メタンスルホニルクロリド(211 μl, 2.71 mmol)を加え、室温で30分撹拌した。次に、化合物３６(53.2 mg, 0.135 mmol)、炭酸カリウム(63.7 mg, 0.461 mmol)を加え、室温で18時間撹拌した。反応液に水を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３１）(23 mg, 35 %)を得た。
化合物（Ｉ－１－３１）；
1H-NMR(CDCl3) δ 1.96-2.07 (4H, m), 2.70-2.84 (4H, m), 3.06 (2H, s), 3.51 (4H, t, J = 4.9 Hz), 3.76 (4H, t, J = 4.9 Hz), 3.92 (2H, s), 6.50 (1H, s), 6.83 (1H, d, J = 8.1 Hz), 7.22 (1H, t, J = 5.0 Hz), 7.31-7.48 (6H, m), 8.78 (2H, d, J = 4.9 Hz).

　同様にして、化合物Ｉ－１－３２２を合成した。
Figure JPOXMLDOC01-appb-C000074
First Step To a solution of 2-pyrimidinemethanol (149 mg, 1.35 mmol) in toluene (2 ml), triethylamine (562 μl, 4.06 mmol) and methanesulfonyl chloride (211 μl, 2.71 mmol) were added and stirred at room temperature for 30 minutes. . Next, compound 36 (53.2 mg, 0.135 mmol) and potassium carbonate (63.7 mg, 0.461 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-31) (23 mg, 35%).
Compound (I-1-31);
1H-NMR (CDCl3) δ 1.96-2.07 (4H, m), 2.70-2.84 (4H, m), 3.06 (2H, s), 3.51 (4H, t, J = 4.9 Hz), 3.76 (4H, t, J = 4.9 Hz), 3.92 (2H, s), 6.50 (1H, s), 6.83 (1H, d, J = 8.1 Hz), 7.22 (1H, t, J = 5.0 Hz), 7.31-7.48 (6H, m), 8.78 (2H, d, J = 4.9 Hz).

Similarly, Compound I-1-322 was synthesized.
Figure JPOXMLDOC01-appb-C000075
第１工程
　化合物３６(58.2 mg, 0.148 mmol)の塩化メチレン(1 ml)懸濁液に、トリエチルアミン(62 μl, 0.444 mmol)と2,2,2-トリフルオロエチルクロロホルメート(28.8 mg, 0.177 mmol)を加え、室温で1.5時間撹拌した。反応液に水を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３２）(74.4 mg, 97 %)を得た。
化合物（Ｉ－１－３２）；
1H-NMR(CDCl3) δ 1.73-1.84 (2H, m), 1.97-2.06 (2H, m), 3.06 (2H, s), 3.45-3.57 (2H, m), 3.51 (4H, t, J = 4.9 Hz), 3.76 (4H, t, J = 4.9 Hz), 3.87-3.99 (2H, m), 4.54 (2H, t, J = 8.0 Hz), 6.48 (1H, s), 6.83 (1H, d, J = 8.0 Hz), 7.33-7.48 (6H, m).

　同様にして、化合物Ｉ－１－２４８およびＩ－１－３１６を合成した。
Figure JPOXMLDOC01-appb-C000075
First Step To a suspension of compound 36 (58.2 mg, 0.148 mmol) in methylene chloride (1 ml) was added triethylamine (62 μl, 0.444 mmol) and 2,2,2-trifluoroethyl chloroformate (28.8 mg, 0.177). mmol) was added and stirred at room temperature for 1.5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-32) (74.4 mg, 97%).
Compound (I-1-32);
1H-NMR (CDCl3) δ 1.73-1.84 (2H, m), 1.97-2.06 (2H, m), 3.06 (2H, s), 3.45-3.57 (2H, m), 3.51 (4H, t, J = 4.9 Hz), 3.76 (4H, t, J = 4.9 Hz), 3.87-3.99 (2H, m), 4.54 (2H, t, J = 8.0 Hz), 6.48 (1H, s), 6.83 (1H, d, J = 8.0 Hz), 7.33-7.48 (6H, m).

In the same manner, compounds I-1-248 and I-1-316 were synthesized.
Figure JPOXMLDOC01-appb-C000076
第１工程
　化合物２９(380 mg, 1.13 mmol)にトルエン(5 ml)、1-メチルスルホニルピペラジン(185 mg, 1.13 mmol)、PdCl2(PCy3)2(83 mg, 0.112 mmol)、ナトリウム tert-ブトキシド(151 mg, 1.58 mmol)を加え、120℃で9時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３３）(110 mg, 21 %)を得た。
化合物（Ｉ－１－３３）；
1H-NMR(CDCl3)δ0.96(9H, s), 1.65-1.76(2H, m), 1.85-1.96(2H, m), 2.78(3H, s), 2.95(2H, s), 3.11-3.15(4H, m), 3.35-3.43(6H, m), 3.80(2H, s), 3.75-3.88(2H, m),  6.69(1H, d, J = 8.6Hz), 6.73(1H, d, J = 8.6Hz), 6.81(1H, s).
Figure JPOXMLDOC01-appb-C000076
First Step To compound 29 (380 mg, 1.13 mmol), toluene (5 ml), 1-methylsulfonylpiperazine (185 mg, 1.13 mmol), PdCl 2 (PCy 3 ) 2 (83 mg, 0.112 mmol), sodium tert- Butoxide (151 mg, 1.58 mmol) was added and stirred at 120 ° C. for 9 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-33) (110 mg, 21%).
Compound (I-1-33);
1H-NMR (CDCl3) δ0.96 (9H, s), 1.65-1.76 (2H, m), 1.85-1.96 (2H, m), 2.78 (3H, s), 2.95 (2H, s), 3.11-3.15 (4H, m), 3.35-3.43 (6H, m), 3.80 (2H, s), 3.75-3.88 (2H, m), 6.69 (1H, d, J = 8.6Hz), 6.73 (1H, d, J = 8.6Hz), 6.81 (1H, s).
Figure JPOXMLDOC01-appb-C000077
第１工程
　6-ブロモ-3-ヒドロキシピリジン-2-カルボニトリル　３７(8.3 g, 41.7 mmol)のテトラヒドロフラン(120 ml)溶液に、氷冷下、メチルマグネシウムブロミド(3M ジエチルエーテル溶液, 41.7 ml, 125 mmol)を滴下し、室温で30分間撹拌した。反応液に6N 塩酸水溶液を加え中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物３８を得た。精製することなく次の反応に用いた。
第２工程
　前工程で得られた化合物３８を用いて、実施例５の第１工程と同様に反応を行い、化合物３９(5.4 g, 33 %)を得た。
第３工程
　化合物３９(2.0 g, 5.03 mmol)のテトラヒドロフラン(40 ml)溶液に4-(ベンジルオキシカルボニルアミノ)フェニルボロン酸(2.73 g, 10.1 mmol)、2M 炭酸ナトリウム水溶液(10.1 ml, 20.2 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(582 mg, 0.503 mmol)を加え、4時間加熱還流を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物４０を得た。精製することなく、次の反応に用いた。
第４工程
　前工程で得られた化合物４０を用いて、実施例１３の第４工程と同様に反応を行い、化合物４１を得た。精製することなく、次の反応に用いた。
第５工程
　前工程で得られた化合物４１の塩化メチレン(27 ml)溶液にトリエチルアミン(4.18 ml, 30.2 mmol)、メタンスルホニルクロリド(1.88 ml, 24.1 mmol)を加え、室温で16時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物４２を得た。精製することなく、次の反応に用いた。
第６工程
　前工程で得られた化合物４２を用いて、実施例１３の第６工程と同様に反応を行い、化合物４３(1.55 g, 58 %)を得た。
第７工程
　化合物４３(1.5 g, 2.83 mmol)のメタノール(10 ml)溶液に40% 水酸化カリウム水溶液(10 ml)を加え、8時間加熱還流を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物４４(1.1 g, 98 %)を得た。精製することなく次の反応に用いた。
第８工程
　化合物４４(84.3 mg, 0.213 mmol)を用いて、実施例１３の第３工程と同様に反応を行い、化合物（Ｉ－１－３４）(30 mg, 28 %)を得た。
化合物（Ｉ－１－３４）；
1H-NMR(DMSO)δ1.41-1.75(13H, m), 1.94-2.00(2H, m), 2.88-2.92(2H, m), 3.10-3.30(2H, m), 3.42-3.46(4H, m), 3.60-3.80(6H, m), 7.23(1H, d, J = 8.4Hz), 7.54(2H, d, J = 8.7Hz),  7.63(1H, d, J = 8.4Hz), 7.87(2H, d, J = 8.7Hz), 8.63(1H, s).
Figure JPOXMLDOC01-appb-C000077
First Step 6-Bromo-3-hydroxypyridine-2-carbonitrile 37 (8.3 g, 41.7 mmol) in tetrahydrofuran (120 ml) was added with methylmagnesium bromide (3M diethyl ether solution, 41.7 ml, 125) under ice-cooling. mmol) was added dropwise and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 6N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 38. Used in the next reaction without purification.
Second Step Using compound 38 obtained in the previous step, the reaction was carried out in the same manner as in the first step of Example 5 to obtain compound 39 (5.4 g, 33%).
Step 3 To a solution of compound 39 (2.0 g, 5.03 mmol) in tetrahydrofuran (40 ml) was added 4- (benzyloxycarbonylamino) phenylboronic acid (2.73 g, 10.1 mmol), 2M aqueous sodium carbonate solution (10.1 ml, 20.2 mmol). , Tetrakis (triphenylphosphine) palladium (582 mg, 0.503 mmol) was added, and the mixture was heated to reflux for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 40. Used in the next reaction without purification.
Fourth Step Using compound 40 obtained in the previous step, the reaction was carried out in the same manner as in the fourth step of Example 13 to obtain compound 41. Used in the next reaction without purification.
Fifth Step Triethylamine (4.18 ml, 30.2 mmol) and methanesulfonyl chloride (1.88 ml, 24.1 mmol) were added to a methylene chloride (27 ml) solution of Compound 41 obtained in the previous step, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off to obtain Compound 42. Used in the next reaction without purification.
Step 6 Using compound 42 obtained in the previous step, the reaction was carried out in the same manner as in Step 6 of Example 13 to obtain compound 43 (1.55 g, 58%).
Step 7 To a solution of compound 43 (1.5 g, 2.83 mmol) in methanol (10 ml) was added 40% aqueous potassium hydroxide solution (10 ml), and the mixture was heated to reflux for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 44 (1.1 g, 98%). Used in the next reaction without purification.
Eighth Step Using compound 44 (84.3 mg, 0.213 mmol), the reaction was carried out in the same manner as in the third step of Example 13 to obtain compound (I-1-34) (30 mg, 28%).
Compound (I-1-34);
1H-NMR (DMSO) δ 1.41-1.75 (13H, m), 1.94-2.00 (2H, m), 2.88-2.92 (2H, m), 3.10-3.30 (2H, m), 3.42-3.46 (4H, m), 3.60-3.80 (6H, m), 7.23 (1H, d, J = 8.4Hz), 7.54 (2H, d, J = 8.7Hz), 7.63 (1H, d, J = 8.4Hz), 7.87 ( 2H, d, J = 8.7Hz), 8.63 (1H, s).
Figure JPOXMLDOC01-appb-C000078
第１工程
　5-ブロモ-2-ヒドロキシニコチン酸　４５(2.0 g, 9.17 mmol)のテトラヒドロフラン(20 ml)溶液に1,1'-カルボニルジイミダゾール(1.53 g, 9.45 mmol)を加え、8時間加熱還流を行った。冷却後、析出物をろ取し、ジエチルエーテルで洗浄した。ジオキサン(30 ml)に懸濁し、O,N-ジメチルヒドロキシアミン(1.79 g, 18.4 mmol)、トリエチルアミン(2.8 ml, 20.2 mmol)を加え、9時間加熱還流を行った。反応終了後、2N 塩酸水溶液を加え、塩化メチレンで抽出した。硫酸ナトリウムで乾燥し、溶媒を留去し、化合物４６を得た。精製することなく次の反応に用いた。
第２工程
　前工程で得られた化合物４６のテトラヒドロフラン(37 ml)溶液に、氷冷下、メチルマグネシウムブロミド(3M ジエチルエーテル溶液, 7.1 ml, 21.3 mmol)を滴下し、室温で1日撹拌した。反応液に6N 塩酸水溶液を加え中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物４７(1.25 g, 82 %)を得た。
第３工程
　化合物４７(1.25 g, 5.79 mmol)を用いて、実施例５の第１工程と同様に反応を行い、化合物４８(1.0 g, 44 %)を得た。
第４工程
　化合物４８(1.0 g, 2.52 mmol)を用いて、実施例３２の第３工程と同様に反応を行い、化合物４９を得た。精製せずに次の反応に用いた。
第５工程
　前工程で得られた化合物４９を用いて、実施例１３の第４工程と同様に反応を行い、化合物５０を得た。精製せずに次の反応に用いた。
第６工程
　前工程で得られた化合物５０を用いて、実施例３２の第５工程と同様に反応を行い、化合物５１を得た。精製せずに次の反応に用いた。
第７工程
　前工程で得られた化合物５１を用いて、実施例１３の第６工程と同様に反応を行い、化合物５２(865 mg, 65 %)を得た。
第８工程
　化合物５２(200 mg, 0.378 mmol)を用いて、実施例３２の第７工程と同様に反応を行い、化合物５３を得た。精製せずに次の反応に用いた。
第９工程
　前工程で得られた化合物５３を用いて、実施例１３の第３工程と同様に反応を行い、化合物（Ｉ－１－３５）(77 mg, 40 %)を得た。
化合物（Ｉ－１－３５）；
1H-NMR(DMSO)δ1.42(9H, s), 1.50-1.64(2H, m), 1.70-1.78(2H, m), 1.82-1.86(2H, m), 2.78-2.86(2H, m), 3.10-3.30 (2H, m), 3.42-3.46(4H, m), 3.60-3.63(4H, m), 3.69-3.74(2H, m), 7.50-7.60(4H, m), 7.80(1H, d, J = 2.7Hz),  8.27(1H, d, J = 2.7Hz), 8.61(1H, s).
Figure JPOXMLDOC01-appb-C000078
Step 1 Add 1,1'-carbonyldiimidazole (1.53 g, 9.45 mmol) to a solution of 5-bromo-2-hydroxynicotinic acid 45 (2.0 g, 9.17 mmol) in tetrahydrofuran (20 ml) and heat to reflux for 8 hours. Went. After cooling, the precipitate was collected by filtration and washed with diethyl ether. The mixture was suspended in dioxane (30 ml), O, N-dimethylhydroxyamine (1.79 g, 18.4 mmol) and triethylamine (2.8 ml, 20.2 mmol) were added, and the mixture was heated to reflux for 9 hours. After completion of the reaction, 2N aqueous hydrochloric acid solution was added, and the mixture was extracted with methylene chloride. It dried with sodium sulfate, the solvent was distilled off, and the compound 46 was obtained. Used in the next reaction without purification.
Second Step To a tetrahydrofuran (37 ml) solution of Compound 46 obtained in the previous step, methylmagnesium bromide (3M diethyl ether solution, 7.1 ml, 21.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 day. The reaction mixture was neutralized with 6N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 47 (1.25 g, 82%).
Third Step Using compound 47 (1.25 g, 5.79 mmol), the reaction was carried out in the same manner as in the first step of Example 5 to obtain compound 48 (1.0 g, 44%).
Fourth Step Using compound 48 (1.0 g, 2.52 mmol), the reaction was carried out in the same manner as in the third step of Example 32 to obtain compound 49. Used in the next reaction without purification.
Fifth Step Using compound 49 obtained in the previous step, the reaction was carried out in the same manner as in the fourth step of Example 13 to obtain compound 50. Used in the next reaction without purification.
Step 6 Using compound 50 obtained in the previous step, the reaction was carried out in the same manner as in Step 5 of Example 32 to obtain compound 51. Used in the next reaction without purification.
Step 7 Using compound 51 obtained in the previous step, the reaction was carried out in the same manner as in Step 6 of Example 13 to obtain compound 52 (865 mg, 65%).
Eighth Step Using compound 52 (200 mg, 0.378 mmol), the reaction was carried out in the same manner as in the seventh step of Example 32 to obtain compound 53. Used in the next reaction without purification.
Ninth Step Using compound 53 obtained in the previous step, the reaction was carried out in the same manner as in the third step of Example 13 to obtain compound (I-1-35) (77 mg, 40%).
Compound (I-1-35);
1H-NMR (DMSO) δ1.42 (9H, s), 1.50-1.64 (2H, m), 1.70-1.78 (2H, m), 1.82-1.86 (2H, m), 2.78-2.86 (2H, m) , 3.10-3.30 (2H, m), 3.42-3.46 (4H, m), 3.60-3.63 (4H, m), 3.69-3.74 (2H, m), 7.50-7.60 (4H, m), 7.80 (1H, d, J = 2.7Hz), 8.27 (1H, d, J = 2.7Hz), 8.61 (1H, s).
Figure JPOXMLDOC01-appb-C000079
第１工程
　2-ブロモ-5-ヒドロキシピリジン　５４(4.95 g, 28.4 mmol)のテトラヒドロフラン(50 ml)溶液に、氷冷下、水素化ナトリウム(60% oil suspension； 1.37 g, 34.1 mmol)を加えた。同温度で1.5時間撹拌した後、クロロメチルメチルエーテル(2.6 ml, 34.1 mmol)を加え、更に2時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物５５(4.77 g, 77 %)を得た。
第２工程
　ジイソプロピルアミン(6.1 ml, 43.3 mmol)のテトラヒドロフラン(35 ml)溶液に、氷冷下、n-ブチルリチウム(1.67 M n-ヘキサン溶液, 26 ml, 43.3 mmol)を滴下した。同温度で1時間撹拌した後、-60℃に冷却し、化合物５５(7.86 g, 36.0 mmol)のテトラヒドロフラン(35 ml)溶液を滴下した。-60℃で1時間撹拌した後、アセトアルデヒド(4.65 ml, 83mmol)を加え、更に1時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物５６(8.7 g, 92 %)を得た。
第３工程
　IBX(18.6 g, 49.6 mmol)のジメチルスルホキシド(200 ml)溶液に、化合物５６(8.66 g, 33 mmol)のテトラヒドロフラン(80 ml)を加え、室温で21時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物５７(8.54 g, 99 %)を得た。
第４工程
　化合物５７(8.5 g, 32.7 mmol)をテトラヒドロフラン(16 ml)、i-プロパノール(16 ml)に溶解し、濃塩酸(32 ml, 32.7 mmol)を加え、室温で30分撹拌した。反応終了後、冷却下、2N 水酸化ナトリウム水溶液を加えpH8に調製し、塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物５８(6.76 g, 96 %)を得た。
第５工程
　化合物５８(6.65 g, 30.8 mmol)のメタノール(100 ml)溶液に1-Boc-4-ピペリドン(6.13 g, 30.8 mmol)、ピロリジン(3.3 ml, 40.0 mmol)を加え、20分間加熱還流を行った。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物５９(11.18 g, 91 %)を得た。
第６工程
　化合物５９(1.0 g, 2.52 mmol)のジメトキシエタン(10 ml)溶液に4-メチルスルホニルフェニルボロン酸(604 mg, 3.02 mmol)、2M 炭酸ナトリウム水溶液(3.78 ml, 7.55 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(291 mg, 0.252 mmol)を加え、窒素気流下、4時間加熱還流を行った。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６０(950 mg, 80 %)を得た。
第７工程
　化合物６０(400 mg, 0.846 mmol)のエタノール(5 ml)溶液に水素化ほう素ナトリウム(32 mg, 0.846 mmol)を加え、室温で30分間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６１(334 mg, 83 %)を得た。
第８工程
　化合物６１(100 mg, 0.211 mmol)の塩化メチレン(5 ml)溶液にトリエチルアミン(61 μl, 0.443 mmol)、メタンスルホニルクロリド(26 μl, 0.337 mmol)を加え、室温で1時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６２(114 mg, 98 %)を得た。
第９工程
　化合物６２(108 mg, 0.195 mmol)のエタノール(10 ml)溶液に10% パラジウム炭素(11 mg)を加え、水素ガス気流下、3時間撹拌した。触媒をろ過し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３６）(21 mg, 23 %)を得た。
化合物（Ｉ－１－３６）；
1H-NMR(CDCl3)δ1.48(9H, s), 1.55-1.65(2H, m), 1.78-1.88(2H, m), 1.89(2H, t, J = 6.6 Hz), 2.87(3H, t, J = 6.6 Hz), 3.08(3H, s), 3.19-3.32(2H, m), 3.86-4.00(2H, m), 7.51(1H, s), 7.99(2H, d, J = 8.4 Hz), 8.11(2H, d, J = 8.4 Hz), 8.30(1H, s).

　同様にして、化合物Ｉ－１－３２３、Ｉ－１－３２４、Ｉ－１－３２５およびＩ－１－３２６を合成した。
Figure JPOXMLDOC01-appb-C000079
First Step Sodium hydride (60% oil suspension; 1.37 g, 34.1 mmol) was added to a solution of 2-bromo-5-hydroxypyridine 54 (4.95 g, 28.4 mmol) in tetrahydrofuran (50 ml) under ice cooling. . After stirring at the same temperature for 1.5 hours, chloromethyl methyl ether (2.6 ml, 34.1 mmol) was added, and the mixture was further stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 55 (4.77 g, 77%).
Second Step n-Butyllithium (1.67 M n-hexane solution, 26 ml, 43.3 mmol) was added dropwise to a solution of diisopropylamine (6.1 ml, 43.3 mmol) in tetrahydrofuran (35 ml) under ice cooling. The mixture was stirred at the same temperature for 1 hour, cooled to −60 ° C., and a solution of compound 55 (7.86 g, 36.0 mmol) in tetrahydrofuran (35 ml) was added dropwise. After stirring at −60 ° C. for 1 hour, acetaldehyde (4.65 ml, 83 mmol) was added, and the mixture was further stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 56 (8.7 g, 92%).
Third Step To a solution of IBX (18.6 g, 49.6 mmol) in dimethyl sulfoxide (200 ml) was added compound 56 (8.66 g, 33 mmol) in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 21 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 57 (8.54 g, 99%).
Fourth Step Compound 57 (8.5 g, 32.7 mmol) was dissolved in tetrahydrofuran (16 ml) and i-propanol (16 ml), concentrated hydrochloric acid (32 ml, 32.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, 2N aqueous sodium hydroxide solution was added under cooling to adjust the pH to 8, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 58 (6.76 g, 96%).
Step 5 Add 1-Boc-4-piperidone (6.13 g, 30.8 mmol) and pyrrolidine (3.3 ml, 40.0 mmol) to a solution of compound 58 (6.65 g, 30.8 mmol) in methanol (100 ml) and heat to reflux for 20 minutes. Went. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 59 (11.18 g, 91%).
Step 6 To a solution of compound 59 (1.0 g, 2.52 mmol) in dimethoxyethane (10 ml) was added 4-methylsulfonylphenylboronic acid (604 mg, 3.02 mmol), 2M aqueous sodium carbonate solution (3.78 ml, 7.55 mmol), tetrakis ( Triphenylphosphine) palladium (291 mg, 0.252 mmol) was added, and the mixture was heated to reflux for 4 hours under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 60 (950 mg, 80%).
Step 7 Sodium borohydride (32 mg, 0.846 mmol) was added to a solution of compound 60 (400 mg, 0.846 mmol) in ethanol (5 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 61 (334 mg, 83%).
Step 8 To a solution of compound 61 (100 mg, 0.211 mmol) in methylene chloride (5 ml) was added triethylamine (61 μl, 0.443 mmol) and methanesulfonyl chloride (26 μl, 0.337 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 62 (114 mg, 98%).
Step 9 To a solution of compound 62 (108 mg, 0.195 mmol) in ethanol (10 ml) was added 10% palladium carbon (11 mg), and the mixture was stirred under a hydrogen gas stream for 3 hours. The catalyst was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-36) (21 mg, 23%).
Compound (I-1-36);
1H-NMR (CDCl3) δ1.48 (9H, s), 1.55-1.65 (2H, m), 1.78-1.88 (2H, m), 1.89 (2H, t, J = 6.6 Hz), 2.87 (3H, t , J = 6.6 Hz), 3.08 (3H, s), 3.19-3.32 (2H, m), 3.86-4.00 (2H, m), 7.51 (1H, s), 7.99 (2H, d, J = 8.4 Hz) , 8.11 (2H, d, J = 8.4 Hz), 8.30 (1H, s).

In the same manner, compounds I-1-323, I-1-324, I-1-325 and I-1-326 were synthesized.
Figure JPOXMLDOC01-appb-C000080
第１工程
　化合物５９(2.0 g, 5.03 mmol)のジメトキシエタン(20 ml)溶液に4-ニトロフェニルボロン酸(1.01 g, 6.04 mmol)、2M 炭酸ナトリウム水溶液(7.55 ml, 15.1 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(291 mg, 0.252 mmol)を加え、窒素気流下、1時間加熱還流を行った。反応液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６３(1.1 g, 50 %)を得た。
第２工程
　化合物６３(400 mg, 0.91 mmol)のテトラヒドロフラン(4 ml)溶液を-78℃に冷却し、リチウムヘキサメチルジシラザン(1.0 M テトラヒドロフラン溶液, 3.64 ml, 3.64 mmol)を加え、0℃で2時間撹拌した。再び-78℃に冷却し、N-フルオロベンゼンスルホンイミド(1.15 g, 0.91 mmol)のテトラヒドロフラン(10 ml)溶液を加え、室温で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６４(228 mg, 53 %)を得た。
第３工程～第４工程
　化合物６４(219 mg, 0.461 mmol)を用いて、実施例２１の第７工程～第８工程と同様に反応を行い、化合物６６(144 mg, 56 %)を得た。
第５工程
　化合物６６(128 mg, 0.230 mmol)を用いて、実施例２１の第９工程と同様に反応を行い、化合物６７(99 mg, 100 %)を得た。
第６工程
　化合物６７(99 mg, 0.229 mmol)のテトラヒドロフラン(5 ml)溶液に、ピリジン(56 μl, 0.688 mmol)、クロロギ酸フェニル(32 μl, 0.252 mmol)を加え、室温で45分撹拌した。次にモルホリン(120μl, 1.38 mmol)を加え、60℃で27時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３７）(52 mg, 42 %)を得た。
化合物（Ｉ－１－３７）；
1H-NMR(CDCl3)δ1.48(9H, s), 1.82-1.90(4H, m), 3.05-3.21(2H, m), 3.27(2H, t, J = 14.4 Hz), 3.50(4H, t, J = 4.8 Hz), 3.76(4H, t, J = 4.8 Hz), 4.03-4.17(2H, m), 6.42(1H, br), 7.40(1H, s), 7.46(2H, d, J = 8.4 Hz), 7.85(2H, d, J = 8.4 Hz), 8.36(1H, s).
第７工程
　化合物（Ｉ－１－３７）(40 mg, 0.073 mmol)の酢酸エチル(2 ml)溶液に4N 塩酸-酢酸エチル溶液(2 ml, 8.0 mmol)を加え、室温で2時間撹拌した。ジイソプロピルエーテルで希釈し、結晶をろ取した。乾燥し、化合物６８(36 mg, 95 %)を得た。
第８工程
　化合物６８(36 mg, 0.070 mmol)の塩化メチレン(5 ml)溶液に、トリエチルアミン(41 μl, 0.294 mmol)とネオペンチルクロロホルメート(14 μl, 0.095 mmol)を加え、0.5時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３８）(26 mg, 63 %)を得た。
化合物（Ｉ－１－３８）；
1H-NMR(CDCl3)δ0.96(9H, s), 1.82-1.93(4H, m), 3.10-3.35(4H, m), 3.51(4H, t, J = 4.8 Hz), 3.76(4H, t, J = 4.8 Hz), 3.81(2H, s), 4.08-4.24(2H, m), 6.43(1H, br), 7.41(1H, s), 7.46(2H, d, J = 8.4 Hz), 7.85(2H, d, J = 8.4 Hz), 8.37(1H, s).
Figure JPOXMLDOC01-appb-C000080
Step 1 Compound 59 (2.0 g, 5.03 mmol) in dimethoxyethane (20 ml) was added to 4-nitrophenylboronic acid (1.01 g, 6.04 mmol), 2M aqueous sodium carbonate solution (7.55 ml, 15.1 mmol), tetrakis (tri Phenylphosphine) palladium (291 mg, 0.252 mmol) was added, and the mixture was heated to reflux for 1 hour under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 63 (1.1 g, 50%).
Step 2 A solution of compound 63 (400 mg, 0.91 mmol) in tetrahydrofuran (4 ml) was cooled to −78 ° C., lithium hexamethyldisilazane (1.0 M tetrahydrofuran solution, 3.64 ml, 3.64 mmol) was added, and 0 ° C. Stir for 2 hours. The mixture was again cooled to −78 ° C., a solution of N-fluorobenzenesulfonimide (1.15 g, 0.91 mmol) in tetrahydrofuran (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 64 (228 mg, 53%).
Step 3 to Step 4 Using compound 64 (219 mg, 0.461 mmol), the reaction was carried out in the same manner as in Step 7 to Step 8 of Example 21 to obtain compound 66 (144 mg, 56%). .
Step 5 Using compound 66 (128 mg, 0.230 mmol), the reaction was carried out in the same manner as in Step 9 of Example 21 to obtain compound 67 (99 mg, 100%).
Step 6 To a solution of compound 67 (99 mg, 0.229 mmol) in tetrahydrofuran (5 ml) was added pyridine (56 μl, 0.688 mmol) and phenyl chloroformate (32 μl, 0.252 mmol), and the mixture was stirred at room temperature for 45 minutes. Next, morpholine (120 μl, 1.38 mmol) was added, and the mixture was stirred at 60 ° C. for 27 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-37) (52 mg, 42%).
Compound (I-1-37);
1H-NMR (CDCl3) δ1.48 (9H, s), 1.82-1.90 (4H, m), 3.05-3.21 (2H, m), 3.27 (2H, t, J = 14.4 Hz), 3.50 (4H, t , J = 4.8 Hz), 3.76 (4H, t, J = 4.8 Hz), 4.03-4.17 (2H, m), 6.42 (1H, br), 7.40 (1H, s), 7.46 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 8.36 (1H, s).
Step 7 To a solution of compound (I-1-37) (40 mg, 0.073 mmol) in ethyl acetate (2 ml) was added 4N hydrochloric acid-ethyl acetate solution (2 ml, 8.0 mmol), and the mixture was stirred at room temperature for 2 hours. Diluted with diisopropyl ether, and the crystals were collected by filtration. Drying gave Compound 68 (36 mg, 95%).
Step 8 To a solution of compound 68 (36 mg, 0.070 mmol) in methylene chloride (5 ml) was added triethylamine (41 μl, 0.294 mmol) and neopentyl chloroformate (14 μl, 0.095 mmol), and the mixture was stirred for 0.5 hour. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-38) (26 mg, 63%).
Compound (I-1-38);
1H-NMR (CDCl3) δ0.96 (9H, s), 1.82-1.93 (4H, m), 3.10-3.35 (4H, m), 3.51 (4H, t, J = 4.8 Hz), 3.76 (4H, t , J = 4.8 Hz), 3.81 (2H, s), 4.08-4.24 (2H, m), 6.43 (1H, br), 7.41 (1H, s), 7.46 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 8.37 (1H, s).
Figure JPOXMLDOC01-appb-C000081
第１工程
　5-ブロモ-2-フルオロフェノール(1.79 g, 9.38 mmol)、tert-ブチル 1-オキサ-6-アザスピロ[2.5]オクタン-6-カルボキシレート　６９(2.0 g, 9.38 mmol)、水酸化ナトリウム(38 mg, 0.938 mmol)を加え、150℃で3時間撹拌した。冷却し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７０(2.8 g, 74 %)を得た。
第２工程
　化合物７０(3.4 g, 8.41 mmol)の酢酸エチル(25 ml)溶液に4N 塩酸-ジオキサン溶液(21 ml, 84 mmol)を加え、室温で3時間撹拌した。析出した結晶をろ取し、酢酸エチルで洗浄し、乾燥し、化合物７１(2.8 g, 98 %)を得た。
第３工程
　化合物７１(2.85 g, 8.37 mmol)にジメチルホルムアミド(20 ml)、炭酸カリウム(2.31 g, 16.7 mmol)、ベンジルブロミド(1.43 g, 8.37 moml)を加え、室温で1日撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７２(2.9 g, 88 %)を得た。
第４工程
　化合物７２(2.9 g, 7.36 mmol)のジメチルアセトアミド(20 ml)溶液に、氷冷下、水素化ナトリウム(60% oil suspension; 353 mg, 8.83 mmol)を加え、150℃で18時間撹拌した。冷却し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７３(820 mg, 30 %)を得た。
第５工程
　化合物７３(800 mg, 2.14 mmol)のジオキサン(20 ml)溶液に4-アミノフェニルボロン酸ピナコールエステル(656 mg, 2.99 mmol)、2M 炭酸ナトリウム水溶液(2.14 ml, 4.18 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(123 mg, 0.107 mmol)を加え、3時間加熱還流を行った。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７４(520 mg, 63 %)を得た。
第６工程
　化合物７４(500 mg, 1.29 mmol)にジメチルアセトアミド(5 ml)、炭酸カリウム(536 mg, 3.88 mmol)、モルホリン-4-カルボニルクロリド(302 μl, 2.59 mmol)を加え、室温で6.5時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、得られた残渣をn-ヘキサンで洗浄し、化合物７５(400 mg, 62 %)を得た。
第７工程
　化合物７５(400 mg, 0.801 mmol)にクロロホルム(10 ml)、1-クロロエチルクロロホルメート(229 mg, 1.60 mmol)を加え、加熱還流した。その後、溶媒を留去し、メタノール(10 ml)を加え、更に2時間加熱還流した。反応終了後、溶媒を留去し、酢酸エチルを加え、析出物をろ取した。乾燥し、化合物７６(255 mg, 71 %)を得た。
第８工程
　化合物７６(100 mg, 0.224 mmol)に塩化メチレン(2 ml)、トリエチルアミン(93 μl, 0.673 mmol)、二炭酸ジ-tert-ブチル(73.4 mg, 0.336 mmol)を加え、20分間撹拌した。反応液に水を加え塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物（Ｉ－１－３９）(70 mg, 61 %)を得た。
化合物（Ｉ－１－３９）；
1H-NMR(CDCl3)δ1.46(9H, s), 1.50-1.65(2H, m), 1.80-1.90(2H, m), 3.20-3.30(2H, m), 3.47-3.52(4H, m), 3.75-3.81(4H, m), 3.93(2H, s), 3.92-4.05(2H, m), 6.40(1H, brs), 6.92(1H, d, J = 8.4Hz), 7.07(1H, d,d, J = 8.4, 1.8Hz), 7.11(1H, d, J = 1.8Hz), 7.40(2H, d, J = 8.6 Hz), 7.49(2H, d, J = 8.6 Hz).

　同様にして、化合物Ｉ－１－３３１を合成した。
Figure JPOXMLDOC01-appb-C000081
First Step 5-Bromo-2-fluorophenol (1.79 g, 9.38 mmol), tert-butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate 69 (2.0 g, 9.38 mmol), sodium hydroxide (38 mg, 0.938 mmol) was added, and the mixture was stirred at 150 ° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 70 (2.8 g, 74%).
Second Step To a solution of compound 70 (3.4 g, 8.41 mmol) in ethyl acetate (25 ml) was added 4N hydrochloric acid-dioxane solution (21 ml, 84 mmol), and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried to obtain Compound 71 (2.8 g, 98%).
Third Step To compound 71 (2.85 g, 8.37 mmol), dimethylformamide (20 ml), potassium carbonate (2.31 g, 16.7 mmol) and benzyl bromide (1.43 g, 8.37 moml) were added and stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 72 (2.9 g, 88%).
Step 4 To a solution of compound 72 (2.9 g, 7.36 mmol) in dimethylacetamide (20 ml), add sodium hydride (60% oil suspension; 353 mg, 8.83 mmol) under ice cooling, and stir at 150 ° C. for 18 hours did. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 73 (820 mg, 30%).
Step 5 To a solution of compound 73 (800 mg, 2.14 mmol) in dioxane (20 ml), 4-aminophenylboronic acid pinacol ester (656 mg, 2.99 mmol), 2M aqueous sodium carbonate solution (2.14 ml, 4.18 mmol), tetrakis ( Triphenylphosphine) palladium (123 mg, 0.107 mmol) was added, and the mixture was heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 74 (520 mg, 63%).
Step 6 To compound 74 (500 mg, 1.29 mmol) was added dimethylacetamide (5 ml), potassium carbonate (536 mg, 3.88 mmol), morpholine-4-carbonyl chloride (302 μl, 2.59 mmol), and 6.5 hours at room temperature. Stir. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue was washed with n-hexane to obtain Compound 75 (400 mg, 62%).
Step 7 Chloroform (10 ml) and 1-chloroethyl chloroformate (229 mg, 1.60 mmol) were added to compound 75 (400 mg, 0.801 mmol), and the mixture was heated to reflux. Thereafter, the solvent was distilled off, methanol (10 ml) was added, and the mixture was further heated to reflux for 2 hours. After completion of the reaction, the solvent was distilled off, ethyl acetate was added, and the precipitate was collected by filtration. Drying gave Compound 76 (255 mg, 71%).
Step 8 To compound 76 (100 mg, 0.224 mmol) was added methylene chloride (2 ml), triethylamine (93 μl, 0.673 mmol), di-tert-butyl dicarbonate (73.4 mg, 0.336 mmol), and the mixture was stirred for 20 minutes. . Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound (I-1-39) (70 mg, 61%).
Compound (I-1-39);
1H-NMR (CDCl3) δ1.46 (9H, s), 1.50-1.65 (2H, m), 1.80-1.90 (2H, m), 3.20-3.30 (2H, m), 3.47-3.52 (4H, m) , 3.75-3.81 (4H, m), 3.93 (2H, s), 3.92-4.05 (2H, m), 6.40 (1H, brs), 6.92 (1H, d, J = 8.4Hz), 7.07 (1H, d , d, J = 8.4, 1.8Hz), 7.11 (1H, d, J = 1.8Hz), 7.40 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz).

Similarly, Compound 1-1-331 was synthesized.
Figure JPOXMLDOC01-appb-C000082
第１工程
　ジイソプロピルアミン(1.56 ml, 11.0mmol)のテトラヒドロフラン(20 ml)溶液に、氷冷下、n-ブチルリチウム(1.57 M n-ヘキサン溶液, 7 ml, 11.0 mmol)を滴下した。同温度で15分間撹拌した後、-70℃に冷却し、1-tert-ブチル 4-エチル ピペリジン-1,4-ジカルボキシレート　７７(2.57 g, 9.99 mmol)のテトラヒドロフラン(20 ml)溶液を滴下した。-70℃で1時間撹拌した後、4-ブロモ-1-(ブロモエチル)-2-フルオロベンゼン(2.68 ml, 9.99mmol)を加え、更に1.5時間撹拌した。反応液を飽和塩化アンモニウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７８(3.4 g, 77 %)を得た。
第２工程
　化合物７８(3.4 g, 7.65 mmol)のテトラヒドロフラン(50 ml)溶液に、氷冷下、水素化リチウムアルミニウム(319 mg, 8.42 mmol)を加え、室温で1日撹拌した。反応終了後、0℃にて水を加え1時間撹拌した。不溶物をろ過し、テトラヒドロフランで洗浄した。ろ液と洗浄液をあわせて濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物７９(1.65 g, 54 %)を得た。
第３工程
　化合物７９(1.6 g, 3.98 mmol)のテトラヒドロフラン(40 ml)溶液に、氷冷下、水素化ナトリウム(60% oil suspension; 318 mg, 7.95 mmol)を加え、室温で2時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物８０(1.3 g, 86 %)を得た。
第４工程
　化合物８０(300 mg, 0.785 mmol)を用いて、実施例３６の第５工程と同様に反応を行い、化合物８１(130 mg, 42 %)を得た。
第５工程
　化合物８１(130 mg, 0.330 mmol)を用いて、実施例３６の第６工程と同様に反応を行い、化合物（Ｉ－１－４０）(110 mg, 66 %)を得た。
化合物（Ｉ－１－４０）；
1H-NMR(CDCl3)δ1.46(9H, s), 1.45-1.56(4H, m), 2.70(2H, s), 3.30-3.40(2H, m), 3.47-3.52(4H, m), 3.55-3.60(2H, m), 3.75-3.81(4H, m), 3.91(2H, s), 6.40(1H, brs), 7.02(1H, s), 7.07(2H, s), 7.38(2H, d, J = 8.6 Hz), 7.49(2H, d, J = 8.6 Hz).

　同様にして、化合物Ｉ－１－３２７を合成した。
Figure JPOXMLDOC01-appb-C000082
First Step n-Butyllithium (1.57 M n-hexane solution, 7 ml, 11.0 mmol) was added dropwise to a solution of diisopropylamine (1.56 ml, 11.0 mmol) in tetrahydrofuran (20 ml) under ice cooling. The mixture was stirred at the same temperature for 15 minutes, cooled to -70 ° C, and a solution of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate 77 (2.57 g, 9.99 mmol) in tetrahydrofuran (20 ml) was added dropwise. did. After stirring at −70 ° C. for 1 hour, 4-bromo-1- (bromoethyl) -2-fluorobenzene (2.68 ml, 9.99 mmol) was added, and the mixture was further stirred for 1.5 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 78 (3.4 g, 77%).
Second Step To a solution of compound 78 (3.4 g, 7.65 mmol) in tetrahydrofuran (50 ml) was added lithium aluminum hydride (319 mg, 8.42 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, water was added at 0 ° C. and stirred for 1 hour. The insoluble material was filtered and washed with tetrahydrofuran. The filtrate and washings were combined and concentrated, and the residue was purified by silica gel column chromatography to give compound 79 (1.65 g, 54%).
Third Step To a solution of compound 79 (1.6 g, 3.98 mmol) in tetrahydrofuran (40 ml) was added sodium hydride (60% oil suspension; 318 mg, 7.95 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 80 (1.3 g, 86%).
Fourth Step Using compound 80 (300 mg, 0.785 mmol), the reaction was carried out in the same manner as in the fifth step of Example 36 to obtain compound 81 (130 mg, 42%).
Step 5 Compound 81 (130 mg, 0.330 mmol) was used in the same manner as in Step 6 of Example 36 to give compound (I-1-40) (110 mg, 66%).
Compound (I-1-40);
1H-NMR (CDCl3) δ1.46 (9H, s), 1.45-1.56 (4H, m), 2.70 (2H, s), 3.30-3.40 (2H, m), 3.47-3.52 (4H, m), 3.55 -3.60 (2H, m), 3.75-3.81 (4H, m), 3.91 (2H, s), 6.40 (1H, brs), 7.02 (1H, s), 7.07 (2H, s), 7.38 (2H, d , J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz).

Similarly, Compound I-1-327 was synthesized.
Figure JPOXMLDOC01-appb-C000083
第１工程
　5-クロロ-2-メチル安息香酸　８２(5.8 g, 34.0 mmol)にチオニルクロリド(13.6 ml)を加え、1.5時間加熱還流を行った。次に、減圧下、チオニルクロリドを留去し、残渣を塩化メチレン(10 ml)に溶解した。氷冷下、この溶液に40%メチルアミン水溶液(7.92 g, 102 mmol)を滴下し、室温で10分撹拌した。反応終了後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物８３(5.94 g, 95 %)を得た。
第２工程
　化合物８３(5.94 g, 32.3 mmol)のテトラヒドロフラン(175 ml)溶液に、氷冷下、n-ブチルリチウム(1.66 M n-ヘキサン溶液, 39.3 ml, 65.3 mmol)を滴下した。同温度で1時間撹拌後、-78℃に冷却し、1-ベンジルピペリジン-4-オン(9.1 ml, 49.1 mmol)を加え、0.5時間撹拌した。その後、室温まで昇温し、水を加えた。クロロホルムで抽出し、硫酸ナトリウムで乾燥し、溶媒を留去した。残渣に水(15 ml)、酢酸(15 ml)を加え、氷冷下、濃硫酸(10 ml)を滴下した。4時間加熱還流後、反応液を水に注いだ。水層に水酸化カリウムを加えpH9～10に調製し、クロロホルムで抽出した。硫酸ナトリウムで乾燥し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製した。得られた目的物をエタノール(100 ml)に溶解し、4N 塩酸-酢酸エチル溶液(20 ml)を加えた。アセトンで希釈し、析出した塩酸塩をろ取し、アセトンで洗浄した。乾燥し、化合物８４(894 mg, 7 %)を得た。
第３工程
　水素化リチウムアルミニウム(126 mg, 3.31 mmol)のテトラヒドロフラン(10 ml)懸濁液を-10℃に冷却し、化合物８４(894 mg, 2.36 mmol)のテトラヒドロフラン(10 ml)溶液を滴下した。0℃で1時間撹拌し、その後、室温で9日間撹拌した。0℃に冷却し、水(2 ml)を加え、1時間撹拌した。溶媒を留去し、りん酸(85 %, 20ml)を加え、100℃で2時間撹拌した。反応終了後、水酸化ナトリウム水溶液を加えpH9～10に調製し、クロロホルムで抽出した。硫酸ナトリウムで乾燥し、溶媒を留去し、化合物８５(638 mg, 82 %)を得た。精製することなく次の反応に用いた。
第４工程
　化合物８５(638 mg, 1.95 mmol)を用いて、実施例３６の第５工程と同様に反応を行い、化合物８６(290 mg, 39 %)を得た。
第５工程
　化合物８６(290 mg, 0.754 mmol)を用いて、実施例３６の第６工程と同様に反応を行い、化合物８７(141 mg, 15 %)を得た。
第６工程
　化合物８７(141 mg, 0.284 mmol)を用いて、実施例３６の第７工程と同様に反応を行い、化合物８８を得た。精製することなく次の反応に用いた。
第７工程
　前工程で得られた化合物８８を用いて、実施例３６の第８工程と同様に反応を行い、化合物（Ｉ－１－４１）(14 mg, 10 %)を得た。
化合物（Ｉ－１－４１）；
1H-NMR(CDCl3)δ1.47-1.84(13H, m), 2.71(s, 2H), 3.20-3.30(2H, m), 3.49-3.52(2H, m), 3.74-3.78(6H, m), 4.81(2H, s), 6.39(1H, s), 7.12-7.52(7H, m)
Figure JPOXMLDOC01-appb-C000083
First Step Thionyl chloride (13.6 ml) was added to 5-chloro-2-methylbenzoic acid 82 (5.8 g, 34.0 mmol), and the mixture was heated under reflux for 1.5 hours. Next, thionyl chloride was distilled off under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). Under ice cooling, 40% aqueous methylamine solution (7.92 g, 102 mmol) was added dropwise to this solution, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It dried with sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 83 (5.94 g, 95%).
Second Step n-Butyllithium (1.66 M n-hexane solution, 39.3 ml, 65.3 mmol) was added dropwise to a solution of compound 83 (5.94 g, 32.3 mmol) in tetrahydrofuran (175 ml) under ice cooling. After stirring at the same temperature for 1 hr, the mixture was cooled to −78 ° C., 1-benzylpiperidin-4-one (9.1 ml, 49.1 mmol) was added, and the mixture was stirred for 0.5 hr. Then, it heated up to room temperature and added water. Extraction with chloroform, drying with sodium sulfate, and evaporation of the solvent. Water (15 ml) and acetic acid (15 ml) were added to the residue, and concentrated sulfuric acid (10 ml) was added dropwise under ice cooling. After heating at reflux for 4 hours, the reaction solution was poured into water. Potassium hydroxide was added to the aqueous layer to adjust to pH 9-10, and extracted with chloroform. It dried with sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography. The obtained target product was dissolved in ethanol (100 ml), and 4N hydrochloric acid-ethyl acetate solution (20 ml) was added. Diluted with acetone, the precipitated hydrochloride was collected by filtration and washed with acetone. Drying gave Compound 84 (894 mg, 7%).
Step 3 A suspension of lithium aluminum hydride (126 mg, 3.31 mmol) in tetrahydrofuran (10 ml) was cooled to −10 ° C., and a solution of compound 84 (894 mg, 2.36 mmol) in tetrahydrofuran (10 ml) was added dropwise. . The mixture was stirred at 0 ° C. for 1 hour, and then stirred at room temperature for 9 days. After cooling to 0 ° C., water (2 ml) was added and stirred for 1 hour. The solvent was distilled off, phosphoric acid (85%, 20ml) was added, and the mixture was stirred at 100 ° C for 2 hours. After completion of the reaction, an aqueous sodium hydroxide solution was added to adjust the pH to 9-10, and the mixture was extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off to obtain Compound 85 (638 mg, 82%). Used in the next reaction without purification.
Step 4 Compound 85 (638 mg, 1.95 mmol) was used in the same manner as in Step 5 of Example 36 to obtain compound 86 (290 mg, 39%).
Step 5 Using compound 86 (290 mg, 0.754 mmol), the reaction was carried out in the same manner as in Step 6 of Example 36 to obtain compound 87 (141 mg, 15%).
Step 6 Using compound 87 (141 mg, 0.284 mmol), the reaction was carried out in the same manner as in Step 7 of Example 36 to obtain compound 88. Used in the next reaction without purification.
Step 7 Using compound 88 obtained in the previous step, the reaction was carried out in the same manner as in Step 8 of Example 36 to obtain compound (I-1-41) (14 mg, 10%).
Compound (I-1-41);
1H-NMR (CDCl3) δ1.47-1.84 (13H, m), 2.71 (s, 2H), 3.20-3.30 (2H, m), 3.49-3.52 (2H, m), 3.74-3.78 (6H, m) , 4.81 (2H, s), 6.39 (1H, s), 7.12-7.52 (7H, m)
Figure JPOXMLDOC01-appb-C000084
第１工程
　1-tert-ブチル 4-エチル ピペリジン-1,4-ジカルボキシレート　７７(6.0 g, 22.6 mmol)と1-ブロモ-3-(2-ブロモエチル)ベンゼン(6.57 g, 24.9 mmol)を用いて、実施例３７の第１工程と同様に反応を行い、化合物８９(6.56 g, 66 %)を得た。
第２工程
　化合物８９(6.56 g, 14.9 mmol)にトリフルオロ酢酸(15 ml)を加え、室温で1時間撹拌した。トリフルオロ酢酸を留去し、残渣に1N 水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物９０を得た。精製することなく次の反応に用いた。
第３工程
　前工程で得られた化合物９０をアセトニトリル(50 ml)に溶解し、氷冷下、ジイソプロピルアミン(3.9 ml, 22.3 mmol)、ベンジルブロミド(1.8 ml, 14.9 mmol)を加え、1時間撹拌した。反応液を1N 水酸化ナトリウム水溶液中に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣シリカゲルカラムクロマトグラフィーで精製し、化合物９１(6.41 g, 100 %)を得た。
第４工程
　化合物９１(6.41 g, 14.9 mmol)にエタノール(149 ml)、2N 水酸化ナトリウム水溶液(149 ml, 298 mmol)を加え、17時間加熱還流を行った。エタノールを留去し、2N 塩酸水溶液を加えpH3に調製し、析出した粉末をろ取した。水洗した後、乾燥し、化合物９２を得た。精製することなく次の反応に用いた。
第５工程
　前工程で得られた化合物９２にイートン試薬(40 ml)を加え、110℃で1.5時間撹拌した。氷水に反応液を注ぎ、2N 水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣シリカゲルカラムクロマトグラフィーで精製し、化合物９３(4.29 g, 75 %)を得た。
第６工程
　前工程で得られた化合物９３(1.0 g, 2.60 mmol)を用いて、実施例５の第２工程と同様に反応を行い、化合物９４を得た。精製することなく次の反応に用いた。
第７工程
　前工程で得られた化合物９４を用いて、実施例５の第３工程と同様に反応を行い、化合物９５を得た。精製することなく次の反応に用いた。
第８工程
　前工程で得られた化合物９５を用いて、実施例３６の第５工程と同様に反応を行い、化合物９６を得た。精製することなく次の反応に用いた。
第９工程
　前工程で得られた化合物９６を用いて、実施例３６の第６工程と同様に反応を行い、化合物９７を得た。精製することなく次の反応に用いた。
第１０工程
　前工程で得られた化合物９７を用いて、実施例１の第５工程と同様に反応を行い、化合物９８を得た。精製することなく次の反応に用いた。
第１１工程
　前工程で得られた化合物９８を用いて、実施例３６の第８工程と同様に反応を行い、化合物（Ｉ－１－４２）(216.5 mg, 17 %)を得た。
化合物（Ｉ－１－４２）；
1H-NMR(DMSO)δ1.33-1.40(13H, m), 1.64-1.68(2H, m), 2.62(2H, s), 2.77-2.81(2H, m), 3.31-3.44(8H, m), 3.60-3.63(4H, m), 7.08-7.11(1H, m), 7.30-7.40(2H, brs),  7.49-7.55(4H, m), 8.58(1H, s).

　同様にして、化合物Ｉ－１－３２９、Ｉ－１－３３０およびＩ－１－３３２を合成した。
Figure JPOXMLDOC01-appb-C000084
First Step Using 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate 77 (6.0 g, 22.6 mmol) and 1-bromo-3- (2-bromoethyl) benzene (6.57 g, 24.9 mmol) Then, the reaction was carried out in the same manner as in Step 1 of Example 37 to obtain compound 89 (6.56 g, 66%).
Second Step To compound 89 (6.56 g, 14.9 mmol) was added trifluoroacetic acid (15 ml), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 90. Used in the next reaction without purification.
Step 3 Compound 90 obtained in the previous step was dissolved in acetonitrile (50 ml), diisopropylamine (3.9 ml, 22.3 mmol) and benzyl bromide (1.8 ml, 14.9 mmol) were added under ice cooling, and the mixture was stirred for 1 hour. did. The reaction mixture was poured into 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 91 (6.41 g, 100%).
Fourth Step Ethanol (149 ml) and 2N aqueous sodium hydroxide solution (149 ml, 298 mmol) were added to compound 91 (6.41 g, 14.9 mmol), and the mixture was heated to reflux for 17 hours. Ethanol was distilled off, 2N aqueous hydrochloric acid was added to adjust to pH 3, and the precipitated powder was collected by filtration. After washing with water and drying, Compound 92 was obtained. Used in the next reaction without purification.
Fifth Step Eaton's reagent (40 ml) was added to compound 92 obtained in the previous step, and the mixture was stirred at 110 ° C. for 1.5 hours. The reaction mixture was poured into ice water, neutralized with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 93 (4.29 g, 75%).
Step 6 Using the compound 93 (1.0 g, 2.60 mmol) obtained in the previous step, the reaction was carried out in the same manner as in the second step of Example 5 to obtain the compound 94. Used in the next reaction without purification.
Step 7 Using compound 94 obtained in the previous step, reaction was performed in the same manner as in step 3 of Example 5 to obtain compound 95. Used in the next reaction without purification.
Eighth Step Using compound 95 obtained in the previous step, the reaction was carried out in the same manner as in the fifth step of Example 36 to obtain compound 96. Used in the next reaction without purification.
Ninth Step Using compound 96 obtained in the previous step, the reaction was carried out in the same manner as in the sixth step of Example 36 to obtain compound 97. Used in the next reaction without purification.
Step 10 Using compound 97 obtained in the previous step, reaction was performed in the same manner as in step 5 of Example 1 to obtain compound 98. Used in the next reaction without purification.
Step 11 Using compound 98 obtained in the previous step, the reaction was carried out in the same manner as in Step 8 of Example 36 to obtain compound (I-1-42) (216.5 mg, 17%).
Compound (I-1-42);
1H-NMR (DMSO) δ1.33-1.40 (13H, m), 1.64-1.68 (2H, m), 2.62 (2H, s), 2.77-2.81 (2H, m), 3.31-3.44 (8H, m) , 3.60-3.63 (4H, m), 7.08-7.11 (1H, m), 7.30-7.40 (2H, brs), 7.49-7.55 (4H, m), 8.58 (1H, s).

In the same manner, compounds I-1-329, I-1-330 and I-1-332 were synthesized.
Figure JPOXMLDOC01-appb-C000085
第１工程
　1-tert-ブチル 4-エチル 4-(4-クロロベンジル)ピペリジン-1,4-ジカルボキシレート　９９(620 mg, 1.62 mmol)に4N 塩酸-酢酸エチル溶液(10.2 ml, 40.8 mmol)を加え、室温で1時間撹拌した。溶媒を留去し、残渣をジイソプロピルエーテルで粉末とした。ろ取した後に乾燥し、化合物１００を得た。精製することなく次の反応に用いた。
第２工程
　前工程で得られた化合物１００の塩化メチレン(5 ml)懸濁液に、トリエチルアミン(676 μl, 4.87 mmol)とネオペンチルクロロホルメート(293 μl, 1.95 mmol)を加え、16.5時間撹拌した。反応液に2N 塩酸水溶液を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１０１(463 mg, 72 %)を得た。
第３工程　
　化合物１０１(452 mg, 1.14 mmol)のエタノール(6 ml)溶液に2N 水酸化ナトリウム水溶液(5.7 ml, 11.4 mmol)を加え、70℃で2日間撹拌した。溶媒を留去し、2N 塩酸水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、化合物１０２(391 mg, 93 %)を得た。
第４工程
　化合物１０２(384 mg, 1.04 mmol)にイートン試薬(3 ml)を加え、110℃で1時間撹拌した。氷水を加え、2N 水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣に塩化メチレン(5 ml)、トリエチルアミン(676 μl, 4.87 mmol)、ネオペンチルクロロホルメート(293 μl, 1.95 mmol)を加え、0.5時間撹拌した。反応液に2N 塩酸水溶液を注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１０３(105 mg, 29 %)を得た。
第５工程
　化合物１０３(93 mg, 0.266 mmol)のエタノール(2 ml)溶液に、水素化ほう素ナトリウム(50 mg, 0.266 mmol)を加え、室温で50分間撹拌した。反応終了後、2N 塩酸水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去し、化合物１０４(97 mg)を得た。精製することなく次の反応に用いた。
第６工程
　化合物１０４(97 mg, 0.276 mmol)にトリフルオロ酢酸(637 μl, 8.27 mmol)、トリエチルシラン(176 μl, 1.10 mmol)を加え、50℃で40分間撹拌した。冷却し、反応液に氷水を加え、2N 水酸化ナトリウム水溶液で中和した。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１０５(85 mg, 92 %)を得た。
第７工程
　化合物１０５(82 mg, 0.244 mmol)のジメチルアセトアミド(2 ml)溶液に4-アミノフェニルボロン酸ピナコールエステル(80 mg, 0.366 mmol)、PdCl2(dtbpf)(16 mg, 0.024 mmol)、炭酸カリウム水溶液(101 mg, 0.732 mmol)、水(0.2 ml)を加え、90℃で3.5時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物１０６(76 mg, 79 %)を得た。
第８工程
　化合物１０６(68 mg, 0.173 mmol)をジメチルアセトアミド(2 ml)に溶解し、炭酸カリウム(72 mg, 0.520 mmol)、モルホリン-4-カルボニルクロリド(61 μl, 0.520 mmol)を加え、室温で2日間撹拌した。反応液に2N 塩酸水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣を再結晶（酢酸エチル、n-ヘキサン）し、化合物（Ｉ－１－４３）(70 mg, 80 %)を得た。
化合物（Ｉ－１－４３）；
1H-NMR(CDCl3)δ0.95(9H, s), 1.58-1.68(4H, m), 2.86(4H, d, J = 5.1 Hz), 3.46-3.56(8H, m), 3.74-3.78(4H, m), 3.79(2H, s), 6.38(1H, br), 7.22(1H, d, J = 7.8 Hz), 7.32-7.42(2H, m), 7.41(2H, d, J = 8.7 Hz), 7.51(2H, d, J = 8.7 Hz).
Figure JPOXMLDOC01-appb-C000085
1st step 1-tert-butyl 4-ethyl 4- (4-chlorobenzyl) piperidine-1,4-dicarboxylate 99 (620 mg, 1.62 mmol) in 4N hydrochloric acid-ethyl acetate solution (10.2 ml, 40.8 mmol) And stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was powdered with diisopropyl ether. The compound 100 was obtained by drying after filtration. Used in the next reaction without purification.
Step 2 Triethylamine (676 μl, 4.87 mmol) and neopentyl chloroformate (293 μl, 1.95 mmol) were added to a suspension of compound 100 obtained in the previous step in methylene chloride (5 ml) and stirred for 16.5 hours. did. A 2N aqueous hydrochloric acid solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 101 (463 mg, 72%).
Third step
To a solution of compound 101 (452 mg, 1.14 mmol) in ethanol (6 ml) was added 2N aqueous sodium hydroxide solution (5.7 ml, 11.4 mmol), and the mixture was stirred at 70 ° C. for 2 days. The solvent was distilled off, 2N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off to obtain Compound 102 (391 mg, 93%).
Fourth Step Eaton's reagent (3 ml) was added to compound 102 (384 mg, 1.04 mmol), and the mixture was stirred at 110 ° C. for 1 hour. Ice water was added, neutralized with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and methylene chloride (5 ml), triethylamine (676 μl, 4.87 mmol) and neopentyl chloroformate (293 μl, 1.95 mmol) were added to the residue and stirred for 0.5 hours. A 2N aqueous hydrochloric acid solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 103 (105 mg, 29%).
Step 5 To a solution of compound 103 (93 mg, 0.266 mmol) in ethanol (2 ml) was added sodium borohydride (50 mg, 0.266 mmol), and the mixture was stirred at room temperature for 50 minutes. After completion of the reaction, 2N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off to obtain Compound 104 (97 mg). Used in the next reaction without purification.
Sixth Step To compound 104 (97 mg, 0.276 mmol) was added trifluoroacetic acid (637 μl, 8.27 mmol) and triethylsilane (176 μl, 1.10 mmol), and the mixture was stirred at 50 ° C. for 40 minutes. After cooling, ice water was added to the reaction solution and neutralized with 2N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It dried with sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain compound 105 (85 mg, 92%).
Step 7 To a solution of compound 105 (82 mg, 0.244 mmol) in dimethylacetamide (2 ml), 4-aminophenylboronic acid pinacol ester (80 mg, 0.366 mmol), PdCl 2 (dtbpf) (16 mg, 0.024 mmol), An aqueous potassium carbonate solution (101 mg, 0.732 mmol) and water (0.2 ml) were added, and the mixture was stirred at 90 ° C. for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain compound 106 (76 mg, 79%).
Step 8 Compound 106 (68 mg, 0.173 mmol) was dissolved in dimethylacetamide (2 ml), potassium carbonate (72 mg, 0.520 mmol) and morpholine-4-carbonyl chloride (61 μl, 0.520 mmol) were added, and room temperature was added. For 2 days. 2N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over sodium sulfate. The solvent was distilled off, and the residue was recrystallized (ethyl acetate, n-hexane) to obtain Compound (I-1-43) (70 mg, 80%).
Compound (I-1-43);
1H-NMR (CDCl3) δ0.95 (9H, s), 1.58-1.68 (4H, m), 2.86 (4H, d, J = 5.1 Hz), 3.46-3.56 (8H, m), 3.74-3.78 (4H , m), 3.79 (2H, s), 6.38 (1H, br), 7.22 (1H, d, J = 7.8 Hz), 7.32-7.42 (2H, m), 7.41 (2H, d, J = 8.7 Hz) , 7.51 (2H, d, J = 8.7 Hz).
Figure JPOXMLDOC01-appb-C000086
第１工程
　窒素雰囲気下、化合物１０７（２５ｇ、１４５ｍｍｏｌ）のテトラヒドロフラン（５００ｍｌ）溶液をドライアイス－アセトンで－６０℃に冷却した。これに１．９ｍｏｌ／Ｌナトリウムヘキサメチルジシラジド（８０ｍｌ、１５３ｍｍｏｌ）を加え、－１５℃で1時間攪拌した。－６０℃に冷却し、三ふっ化ほう素エーテル錯塩（４０．５ｍｌ、３２０ｍｍｏｌ）、次に１－Ｂｏｃ－４－ピペリドン（３４．７ｇ、１７４ｍｍｏｌ）のテトラヒドロフラン溶液（１００ｍｌ）を加え、同温度にて3時間攪拌した。飽和塩化アンモニウム水溶液を加え室温で1時間攪拌し、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物１０８（２５．２ｇ、収率４７％）を得た。
第２工程
　化合物１０８（１．１８ｇ、３．１８ｍｍｏｌ）をトルエン（３０ｍｌ）に溶解し、炭酸セシウム（２．０７ｇ、６．３６ｍｍｏｌ）、よう化銅（Ｉ）（６０．５ｍｇ、０．３１８ｍｍｏｌ）、８－キノリノール（９２ｍｇ、０．６３６ｍｍｏｌ）を加え、１４時間還流した。室温に冷却し、水で希釈し、飽和塩化アンモニウム水溶液と飽和炭酸水素ナトリウム水溶液を加えた。酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製し、化合物１０９（８３５ｍｇ、収率９１％）を得た。
第３工程
　化合物１０９（１６．２ｇ、５５．８ｍｍｏｌ）をジクロロメタン（１６２ｍｌ）に溶解し、氷冷下、ｍ－クロロ過安息香酸（７０％、１５．８２ｇ、６４．１７ｍｍｏｌ）を加え、２０℃で２．５時間攪拌した。０℃に冷却し、１０％亜硫酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、化合物１１０（１７．０ｇ、収率１００％）を得た。
第４工程
　化合物１１０（８．５ｇ、２７．７ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（４２５ｍｌ）に溶解し、オキシ塩化リン（１０．３１ｍｌ、１１．１ｍｍｏｌ）を加え、５０℃で４．５時間攪拌した。０℃に冷却し、１５％炭酸カリウム水溶液（２３０ｍｌ）を加え室温で１０分間攪拌した。水を加え、トルエンで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製し、化合物１１１（４．８９ｇ、収率５４％）を得た。
第５工程
　化合物１１１（５．０ｇ、１５．３９ｍｍｏｌ）をジオキサン（７０ｍｌ）に懸濁し、４－メトキシカルボニルフェニルボロン酸（３．７４ｇ、２０．７８ｍｍｏｌ）、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（３８．５ｍｌ、７６．９９ｍｍｏｌ）、［１，１‘－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリドジクロロメタン付加物（６２９ｍｇ、０．７７ｍｍｏｌ）を加え、１００℃で３．５時間攪拌した。室温に冷却し、水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製した。メタノールを加え、固体を析出させた後、濾取することにより化合物１１２（４．６２ｇ、収率７１％）を得た。
第６工程
　化合物１１２（５．１６ｇ、１２．１６ｍｍｏｌ）をジオキサン（３５ｍｌ）とメタノール（２６ｍｌ）の混合液に懸濁し、４ｍｏｌ／Ｌ塩酸ジオキサン溶液（１５．２ｍｌ）を加え、５０℃で１時間攪拌した。室温に冷却し、ジエチルエーテル（７７ｍｌ）を加え室温で１５分間攪拌した。固体を濾取し、ジエチルエーテルで洗浄後、乾燥して化合物１１３（４．７４ｇ、収率９８％）を得た。
第７工程
　化合物１１３（４．５４ｇ、１１．４３ｍｍｏｌ）をテトラヒドロフラン（６８ｍｌ）と水（４５ｍｌ）に溶解し、炭酸水素ナトリウム（３．８４ｇ、４５．７ｍｍｏｌ）、２－クロロ－３－トリフルオロメチルピラジン（９０％、２．５５ｇ、１２．５７ｍｍｏｌ）を加え、６０℃で５時間攪拌した。室温に冷却し、水を加え３０分間攪拌した。析出した固体を濾取し、１０％メタノール水溶液で洗浄後、乾燥して化合物１１４（５．１４ｇ、収率９６％）を得た。
第８工程
　化合物１１４（５．３６ｇ、１１．３９ｍｍｏｌ）をテトラヒドロフラン（２５ｍｌ）とメタノール（２５ｍｌ）の混合液に懸濁し、４ｍｏｌ／Ｌ水酸化リチウム水溶液（１５ｍｌ）を加え、５０℃で4時間攪拌した。０℃に冷却し、１０％クエン酸水溶液を加えｐＨ４～５に調製し、水を加え室温で３０分間攪拌した。析出した固体を濾取し、水洗後、乾燥して化合物１１５（５．１９ｇ、収率１００％）を得た。
第９工程
　化合物１１５（４．１９ｇ、９．１８ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（８０ｍｌ）に懸濁し、３－ピロリジノール（８８０ｍｇ、１０．１０ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール一水和物（１．５５ｇ、１０．１０ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（１．９４ｇ、１０．１０ｍｍｏｌ）を加え、室温で4時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣を酢酸エチルに加熱溶解した。ヘキサンを加え、固体を析出させた後、濾取することにより化合物（Ｉ－２－１）（４．３ｇ、収率８９％）を得た。
化合物（Ｉ－２－１）；
1H-NMR (CDCl3) δ: 1.70-1.76 (1H, m), 1.83-1.90 (2H, m), 2.00-2.14 (4H, m), 3.12 (2H, s), 3.45-3.69 (4H, m), 3.74-3.86 (2H, m), 4.23-4.29 (2H, m), 4.48-4.61 (1H, br m), 7.59-7.64 (3H, m), 7.93 (2H, d, J = 7.6 Hz), 8.21 (1H, s), 8.27 (1H, s), 8.39 (1H, s).
Figure JPOXMLDOC01-appb-C000086
First Step Under a nitrogen atmosphere, a solution of compound 107 (25 g, 145 mmol) in tetrahydrofuran (500 ml) was cooled to −60 ° C. with dry ice-acetone. To this was added 1.9 mol / L sodium hexamethyldisilazide (80 ml, 153 mmol), and the mixture was stirred at −15 ° C. for 1 hour. Cool to −60 ° C., add boron trifluoride etherate (40.5 ml, 320 mmol), and then add 1-Boc-4-piperidone (34.7 g, 174 mmol) in tetrahydrofuran (100 ml) at the same temperature. And stirred for 3 hours. Saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine in that order and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 108 (25.2 g, yield 47%).
Second Step Compound 108 (1.18 g, 3.18 mmol) was dissolved in toluene (30 ml), cesium carbonate (2.07 g, 6.36 mmol), copper (I) iodide (60.5 mg, 0.318 mmol) 8-quinolinol (92 mg, 0.636 mmol) was added and refluxed for 14 hours. Cool to room temperature, dilute with water, and add saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 109 (835 mg, yield 91%).
Third Step Compound 109 (16.2 g, 55.8 mmol) was dissolved in dichloromethane (162 ml), and m-chloroperbenzoic acid (70%, 15.82 g, 64.17 mmol) was added under ice cooling, followed by 20 ° C. For 2.5 hours. The mixture was cooled to 0 ° C., 10% aqueous sodium bisulfite solution was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 110 (17.0 g, yield 100%).
Step 4 Compound 110 (8.5 g, 27.7 mmol) was dissolved in N, N-dimethylformamide (425 ml), phosphorus oxychloride (10.31 ml, 11.1 mmol) was added and the mixture was stirred at 50 ° C. for 4.5 hours. Stir. The mixture was cooled to 0 ° C., 15% aqueous potassium carbonate solution (230 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Water was added and extracted with toluene. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 111 (4.89 g, yield 54%).
Step 5 Compound 111 (5.0 g, 15.39 mmol) was suspended in dioxane (70 ml), 4-methoxycarbonylphenylboronic acid (3.74 g, 20.78 mmol), 2 mol / L aqueous sodium carbonate solution (38.5 ml). , 76.99 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (629 mg, 0.77 mmol) was added, and the mixture was stirred at 100 ° C. for 3.5 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol). Methanol was added to precipitate a solid, which was then collected by filtration to obtain Compound 112 (4.62 g, yield 71%).
Step 6 Compound 112 (5.16 g, 12.16 mmol) was suspended in a mixture of dioxane (35 ml) and methanol (26 ml), 4 mol / L dioxane hydrochloride solution (15.2 ml) was added, and the mixture was stirred at 50 ° C. for 1 hour. Stir. The mixture was cooled to room temperature, diethyl ether (77 ml) was added, and the mixture was stirred at room temperature for 15 minutes. The solid was collected by filtration, washed with diethyl ether, and dried to give compound 113 (4.74 g, yield 98%).
Step 7 Compound 113 (4.54 g, 11.43 mmol) was dissolved in tetrahydrofuran (68 ml) and water (45 ml), sodium bicarbonate (3.84 g, 45.7 mmol), 2-chloro-3-trifluoromethyl. Pyrazine (90%, 2.55 g, 12.57 mmol) was added and stirred at 60 ° C. for 5 hours. After cooling to room temperature, water was added and stirred for 30 minutes. The precipitated solid was collected by filtration, washed with a 10% aqueous methanol solution, and dried to obtain Compound 114 (5.14 g, yield 96%).
Step 8 Compound 114 (5.36 g, 11.39 mmol) was suspended in a mixture of tetrahydrofuran (25 ml) and methanol (25 ml), 4 mol / L aqueous lithium hydroxide solution (15 ml) was added, and the mixture was stirred at 50 ° C. for 4 hr. did. After cooling to 0 ° C., 10% aqueous citric acid solution was added to adjust to pH 4-5, water was added, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with water, and dried to obtain Compound 115 (5.19 g, yield 100%).
Step 9 Compound 115 (4.19 g, 9.18 mmol) was suspended in N, N-dimethylformamide (80 ml), and 3-pyrrolidinol (880 mg, 10.10 mmol), 1-hydroxybenzotriazole monohydrate (1 0.55 g, 10.10 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.94 g, 10.10 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated ammonium chloride aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate with heating. Hexane was added to precipitate a solid, which was then collected by filtration to obtain compound (I-2-1) (4.3 g, yield 89%).
Compound (I-2-1);
1H-NMR (CDCl3) δ: 1.70-1.76 (1H, m), 1.83-1.90 (2H, m), 2.00-2.14 (4H, m), 3.12 (2H, s), 3.45-3.69 (4H, m) , 3.74-3.86 (2H, m), 4.23-4.29 (2H, m), 4.48-4.61 (1H, br m), 7.59-7.64 (3H, m), 7.93 (2H, d, J = 7.6 Hz), 8.21 (1H, s), 8.27 (1H, s), 8.39 (1H, s).
Figure JPOXMLDOC01-appb-C000087
第１工程　
　化合物１１２（１．３６ｇ、３．２０ｍｍｏｌ）を四塩化炭素（６０ｍｌ）に懸濁し、アゾビスイソブチロニトリル（５２．６ｍｇ、０．３２０ｍｍｏｌ）を加え、続けてN-ブロモコハク酸イミド（８５５ｍｇ、４．８１ｍｍｏｌ）を加えた後、９０℃で１時間還流した。室温に冷却し、飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで３回抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物１１６（７７２ｍｇ、収率４８％）を得た。
第２工程　
　化合物１１６（７３７ｍｇ、１．４６ｍｍｏｌ）をジメチルスルホキシド（１５ｍｌ）に溶解し、炭酸水素ナトリウム（６１５ｍｇ、７．３２ｍｍｏｌ）と、予め活性化させた粉末状モレキュラーシーブ４Ａ（１．５ｇ）を室温で加え、１２０℃で２．５時間撹拌した。室温に冷却し、酢酸エチルを加え、セライトろ過した後、ろ液を水で洗浄した。水層をさらに酢酸エチルで２回抽出した後、有機層を合わせて、水、飽和食塩水の順で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物１１７（４８５ｍｇ、収率７６％）を得た。
第３工程
　化合物１１７（２０５ｍｇ、０．４６８ｍｍｏｌ）をテトラヒドロフラン（３ｍｌ）とメタノール（１．５ｍｌ）の混合溶媒に溶解し、２M水酸化リチウム水溶液（３２７μｌ、０．６５５ｍｍｏｌ）を加え、５０℃で３時間撹拌した。室温に冷却し、水を加え、続いて１０％クエン酸水溶液でｐＨ４～５にして、酢酸エチルで３回抽出した。有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１１８（１７３ｍｇ、収率８７％）を得た。
第４工程
　化合物１１８（３２ｍｇ、０．０７５ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（１ｍｌ）に溶解し、３－ピロリジノール（７．９ｍｇ、０．０９０ｍｍｏｌ）、ジイソプロピルエチルアミン（４０μｌ、０．２２６ｍｍｏｌ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート（４３ｍｇ、０．１１３ｍｍｏｌ）を加え、室温で３０分間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。有機層を合わせて、水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物（Ｉ－２－２）（３６ｍｇ、収率９７％）を得た。
化合物（Ｉ－２－２）；
1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.64-1.74 (3H, m), 1.94-2.13 (4H, m), 3.24-3.30 (2H, br m), 3.45-3.85 (4H, m), 4.18 (2H, br s), 4.49-4.62 (1H, br m), 7.62-7.68 (2H, m), 7.95 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.82 (1H, s).
第５工程
　化合物（Ｉ－２－２）（２９ｍｇ、０．０５９ｍｍｏｌ）をジオキサン（１．２ｍｌ）とメタノール（０．６ｍｌ）の混合液に懸濁し、４ｍｏｌ／Ｌ塩酸ジオキサン溶液（２９４μｌ）加え、室温で２．５時間攪拌した。反応混合液を減圧下濃縮した後、残渣にジエチルエーテルを加え減圧下濃縮する操作を３回繰り返し、化合物１１９を粗生成物として得た。
第６工程
第５工程で得た化合物１１９をＮ－メチルピロリドン（１ｍｌ）に溶解し、炭酸カリウム（２４．４ｍｇ、０．１７６ｍｍｏｌ）、２－クロロ－３－トリフルオロメチルピラジン（１１．８ｍｇ、０．０６５ｍｍｏｌ）およびジイソプロピルエチルアミン（２６μｌ、０．１４７ｍｍｏｌ）を加え、５０℃で１．５時間攪拌した。室温に冷却し、水を加え、酢酸エチルで３回抽出した。有機層合わせて、水で２回、飽和食塩水で１回洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物（Ｉ－２－３）（２３ｍｇ、収率７３％）を得た。
化合物（Ｉ－２－３）；
1H-NMR (CDCl3) δ: 1.63-1.71 (1H, br m), 1.82-1.85 (2H, br m), 2.01-2.14 (4H, m), 3.46-3.86 (6H, m), 4.50-4.62 (3H, m), 7.63-7.69 (2H, m), 7.97 (1H, s), 8.01 (2H, d, J = 8.1 Hz), 8.24 (1H, s), 8.42 (1H, s), 8.86 (1H, s).
Figure JPOXMLDOC01-appb-C000087
First step
Compound 112 (1.36 g, 3.20 mmol) was suspended in carbon tetrachloride (60 ml) and azobisisobutyronitrile (52.6 mg, 0.320 mmol) was added followed by N-bromosuccinimide (855 mg, (4.81 mmol), and then refluxed at 90 ° C. for 1 hour. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 116 (772 mg, yield 48%).
Second step
Compound 116 (737 mg, 1.46 mmol) is dissolved in dimethyl sulfoxide (15 ml), sodium bicarbonate (615 mg, 7.32 mmol) and pre-activated powdered molecular sieve 4A (1.5 g) are added at room temperature. , And stirred at 120 ° C. for 2.5 hours. After cooling to room temperature, ethyl acetate was added, and the mixture was filtered through celite, and the filtrate was washed with water. The aqueous layer was further extracted twice with ethyl acetate, and the organic layers were combined, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 117 (485 mg, yield 76%).
Third Step Compound 117 (205 mg, 0.468 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 ml) and methanol (1.5 ml), 2M aqueous lithium hydroxide solution (327 μl, 0.655 mmol) was added, and 3 ° C. was added at 50 ° C. Stir for hours. After cooling to room temperature, water was added, followed by 10% aqueous citric acid solution to pH 4-5 and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 118 (173 mg, yield 87%).
Step 4 Compound 118 (32 mg, 0.075 mmol) was dissolved in N, N-dimethylformamide (1 ml), 3-pyrrolidinol (7.9 mg, 0.090 mmol), diisopropylethylamine (40 μl, 0.226 mmol), O -(7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (43 mg, 0.113 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-2-2) (36 mg, yield 97%).
Compound (I-2-2);
1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.64-1.74 (3H, m), 1.94-2.13 (4H, m), 3.24-3.30 (2H, br m), 3.45-3.85 (4H, m ), 4.18 (2H, br s), 4.49-4.62 (1H, br m), 7.62-7.68 (2H, m), 7.95 (1H, s), 8.00 (2H, d, J = 8.1 Hz), 8.82 ( 1H, s).
Step 5 Compound (I-2-2) (29 mg, 0.059 mmol) was suspended in a mixture of dioxane (1.2 ml) and methanol (0.6 ml), 4 mol / L dioxane hydrochloride solution (294 μl) was added, Stir at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then the operation of adding diethyl ether to the residue and concentrating under reduced pressure was repeated three times to obtain compound 119 as a crude product.
Step 6 Compound 119 obtained in Step 5 was dissolved in N-methylpyrrolidone (1 ml), potassium carbonate (24.4 mg, 0.176 mmol), 2-chloro-3-trifluoromethylpyrazine (11.8 mg, 0.065 mmol) and diisopropylethylamine (26 μl, 0.147 mmol) were added and stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, water was added and extracted three times with ethyl acetate. The organic layers were combined, washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-2-3) (23 mg, yield 73%).
Compound (I-2-3);
1H-NMR (CDCl3) δ: 1.63-1.71 (1H, br m), 1.82-1.85 (2H, br m), 2.01-2.14 (4H, m), 3.46-3.86 (6H, m), 4.50-4.62 ( 3H, m), 7.63-7.69 (2H, m), 7.97 (1H, s), 8.01 (2H, d, J = 8.1 Hz), 8.24 (1H, s), 8.42 (1H, s), 8.86 (1H , s).
Figure JPOXMLDOC01-appb-C000088
第１工程
　化合物１１８（１２４ｍｇ、０．２９２ｍｍｏｌ）をテトラヒドロフラン（５．６ｍｌ）に懸濁し、１ｍｏｌ／Ｌ（トリメチルシリル）メチルマグネシウムクロリドのテトラヒドロフラン溶液（１．４６ｍｌ、１．４６ｍｍｏｌ）を０℃で滴下し、３０分間撹拌した。飽和塩化アンモニウム水溶液を加え、１０％クエン酸水溶液でｐＨ４～５にして、酢酸エチルで３回抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１２０（１５０ｍｇ）を粗生成物として得た。
第２工程
　第１工程で得た化合物１２０の粗生成物（１５０ｍｇ）をテトラヒドロフラン（１０ｍｌ）に溶解し、０．５ｍｏｌ／Ｌカリウムヘキサメチルジシラジドのトルエン溶液（２．３４ｍｌ、１．１７ｍｍｏｌ）を０℃で滴下し、４５分間撹拌した。飽和塩化アンモニウム水溶液を加え、１０％クエン酸水溶液でｐＨ４～５にして、酢酸エチルで３回抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１２１（１２４ｍｇ）を粗生成物として得た。
第３工程
　化合物１２１の粗生成物（６５ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１ｍｌ）に溶解し、（Ｒ）－３－ピロリジノール（１６．１ｍｇ、０．１８５ｍｍｏｌ）、トリエチルアミン（５３μｌ、０．３８５ｍｍｏｌ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート（８８ｍｇ、０．２３１ｍｍｏｌ）を加え、室温で３０分間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。有機層を水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物１２２（６２ｍｇ、収率８２％）を得た。
第４工程
化合物１２２（６０ｍｇ、０．１２２ｍｍｏｌ）をテトラヒドロフラン（４ｍｌ）とメタノール（０．５ｍｌ）の混合溶媒に溶解し、５％パラジウム/硫酸バリウム（１８ｍｇ）を加え、常圧水素雰囲気下、室温で５０分間攪拌した。さらに５％パラジウム/硫酸バリウム（１２ｍｇ）を加え、常圧水素雰囲気下、室温で３．５時間攪拌した。反応混合液をセライト濾過し、減圧下溶媒を留去し、化合物１２３（６０ｍｇ、収率１００％）を得た。
第５工程
　化合物１２３（６０ｍｇ）を用いて、実施例４２の第５工程に従い、化合物１２４（５７ｍｇ）を粗生成物として得た。
第６工程
　第５工程で得た化合物１２４（２９ｍｇ）の粗生成物を用いて、実施例４２の第６工程に従い、化合物（Ｉ－２－４）（２２ｍｇ、収率６６％）を得た。
化合物（Ｉ－２－４）；
1H-NMR (CDCl3) δ: 1.31 (3H, d, J = 7.1 Hz), 1.73-2.14 (7H, m), 3.23 (1H, q, J = 7.1 Hz), 3.45-3.84 (6H, m), 4.39-4.61 (3H, m), 7.57-7.65 (3H, m), 7.95 (2H, d, J = 7.6 Hz), 8.20 (1H, s), 8.28 (1H, s), 8.38 (1H, s).
Figure JPOXMLDOC01-appb-C000088
Step 1 Compound 118 (124 mg, 0.292 mmol) was suspended in tetrahydrofuran (5.6 ml), and 1 mol / L (trimethylsilyl) methylmagnesium chloride in tetrahydrofuran (1.46 ml, 1.46 mmol) was added dropwise at 0 ° C. And stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added, the pH was adjusted to 4-5 with 10% aqueous citric acid solution, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 120 (150 mg) as a crude product.
Second Step The crude product (150 mg) of the compound 120 obtained in the first step was dissolved in tetrahydrofuran (10 ml), and a 0.5 mol / L potassium hexamethyldisilazide solution in toluene (2.34 ml, 1.17 mmol). Was added dropwise at 0 ° C. and stirred for 45 minutes. Saturated aqueous ammonium chloride solution was added, the pH was adjusted to 4-5 with 10% aqueous citric acid solution, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 121 (124 mg) as a crude product.
Third Step The crude product of compound 121 (65 mg) was dissolved in N, N-dimethylformamide (1 ml), (R) -3-pyrrolidinol (16.1 mg, 0.185 mmol), triethylamine (53 μl, 0.385 mmol). ), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (88 mg, 0.231 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 122 (62 mg, yield 82%).
Fourth Step Compound 122 (60 mg, 0.122 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and methanol (0.5 ml), 5% palladium / barium sulfate (18 mg) was added, and room temperature was found under atmospheric hydrogen atmosphere. For 50 minutes. Further, 5% palladium / barium sulfate (12 mg) was added, and the mixture was stirred at room temperature for 3.5 hours under a normal pressure hydrogen atmosphere. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain Compound 123 (60 mg, yield 100%).
Step 5 Compound 124 (57 mg) was obtained as a crude product according to Step 5 of Example 42 using compound 123 (60 mg).
Step 6 Using the crude product of compound 124 (29 mg) obtained in Step 5, according to Step 6 of Example 42, compound (I-2-4) (22 mg, yield 66%) was obtained. .
Compound (I-2-4);
1H-NMR (CDCl3) δ: 1.31 (3H, d, J = 7.1 Hz), 1.73-2.14 (7H, m), 3.23 (1H, q, J = 7.1 Hz), 3.45-3.84 (6H, m), 4.39-4.61 (3H, m), 7.57-7.65 (3H, m), 7.95 (2H, d, J = 7.6 Hz), 8.20 (1H, s), 8.28 (1H, s), 8.38 (1H, s) .
Figure JPOXMLDOC01-appb-C000089
第１工程
　化合物１２１の粗生成物（６２ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１ｍｌ）に溶解し、（Ｓ）－ピロリジン－２－カルボキサミド（２０．１ｍｇ、０．１７６ｍｍｏｌ）、トリエチルアミン（５１μｌ、０．３６７ｍｍｏｌ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート（８４ｍｇ、０．２２０ｍｍｏｌ）を加え、室温で１時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。有機層を水２回、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物（Ｉ－２－５）（５９ｍｇ、収率７８％）を得た。
化合物（Ｉ－２－５）；
1H-NMR (CDCl3) δ: 1.51 (9H, s), 1.67-1.89 (5H, m), 2.03-2.11 (2H, m), 2.47-2.52 (1H, m), 3.19-3.24 (2H, br m), 3.52-3.65 (2H, m), 4.17 (2H, br s), 4.81-4.84 (1H, m), 5.13 (1H, s), 5.39 (1H, s), 5.74 (1H, s), 6.99 (1H, s), 7.62 (2H, d, J = 8.1 Hz), 7.74 (1H, s), 7.99 (2H, d, J = 8.1 Hz), 8.40 (1H, s).
Figure JPOXMLDOC01-appb-C000089
First Step The crude product of compound 121 (62 mg) was dissolved in N, N-dimethylformamide (1 ml), and (S) -pyrrolidine-2-carboxamide (20.1 mg, 0.176 mmol), triethylamine (51 μl, 0 .367 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (84 mg, 0.220 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water twice and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-2-5) (59 mg, yield 78%).
Compound (I-2-5);
1H-NMR (CDCl3) δ: 1.51 (9H, s), 1.67-1.89 (5H, m), 2.03-2.11 (2H, m), 2.47-2.52 (1H, m), 3.19-3.24 (2H, br m ), 3.52-3.65 (2H, m), 4.17 (2H, br s), 4.81-4.84 (1H, m), 5.13 (1H, s), 5.39 (1H, s), 5.74 (1H, s), 6.99 (1H, s), 7.62 (2H, d, J = 8.1 Hz), 7.74 (1H, s), 7.99 (2H, d, J = 8.1 Hz), 8.40 (1H, s).
Figure JPOXMLDOC01-appb-C000090
第１工程
　化合物１１６（５３ｍｇ、０．１０５ｍｍｏｌ）をメタノール（２ｍｌ）に溶解し、２８％ナトリウムメトキシドのメタノール溶液（５１ｍｇ、０．２６３ｍｍｏｌ）を加え、合計１８時間加熱還流した。室温に冷却し、水を加え、１０％クエン酸水溶液でｐＨ４～５にして、酢酸エチルで３回抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１２５（４６ｍｇ）を粗生成物として得た。
第２工程
　第１工程で得た化合物１２５の粗生成物（４６ｍｇ）を用いて、実施例４３の第３工程に従い、化合物（Ｉ－２－６）（４７ｍｇ、収率８８％）を得た。
化合物（Ｉ－２－６）；
1H-NMR (CDCl3) δ: 1.49 (9H, s), 1.63-2.12 (7H, m), 3.33-3.94 (11H, m), 4.47-4.61 (2H, m), 7.60-7.65 (2H, m), 7.77 (1H, s), 7.95 (2H, d, J = 8.1 Hz), 8.37 (1H, s).
第３工程
　化合物（Ｉ－２－６）（４３ｍｇ、０．０８４ｍｍｏｌ）を用いて、実施例４２の第５工程に従い、化合物１２６（４１ｍｇ）を粗生成物として得た。
第４工程
　第３工程で得た化合物１２６（２０ｍｇ）の粗生成物をＮ－メチルピロリドン（１ｍｌ）に溶解し、２－クロロ－３－トリフルオロメチルピラジン（８．３ｍｇ、０．０４６ｍｍｏｌ）およびジイソプロピルエチルアミン（４３μｌ、０．２４９ｍｍｏｌ）を加え、５０℃で１．５時間攪拌した。室温に冷却し、水を加え、酢酸エチルで３回抽出した。有機層合わせて、水で２回、飽和食塩水で１回洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物（Ｉ－２－７）（１０ｍｇ、収率４３％）を得た。
化合物（Ｉ－２－７）；
1H-NMR (CDCl3) δ: 1.68-2.21 (7H, m), 3.45-3.87 (9H, m), 4.25-4.35 (2H, m), 4.49-4.62 (2H, m), 7.61-7.67 (2H, m), 7.80 (1H, s), 7.96 (2H, d, J = 8.2 Hz), 8.21 (1H, s), 8.40 (2H, d, J = 4.5 Hz).
Figure JPOXMLDOC01-appb-C000090
First Step Compound 116 (53 mg, 0.105 mmol) was dissolved in methanol (2 ml), methanol solution of 28% sodium methoxide (51 mg, 0.263 mmol) was added, and the mixture was heated to reflux for a total of 18 hours. After cooling to room temperature, water was added, the pH was adjusted to 4-5 with 10% aqueous citric acid solution, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 125 (46 mg) as a crude product.
Second Step Using the crude product of compound 125 (46 mg) obtained in the first step and according to the third step of Example 43, compound (I-2-6) (47 mg, yield 88%) was obtained. .
Compound (I-2-6);
1H-NMR (CDCl3) δ: 1.49 (9H, s), 1.63-2.12 (7H, m), 3.33-3.94 (11H, m), 4.47-4.61 (2H, m), 7.60-7.65 (2H, m) , 7.77 (1H, s), 7.95 (2H, d, J = 8.1 Hz), 8.37 (1H, s).
Third Step Using compound (I-2-6) (43 mg, 0.084 mmol) and following the fifth step of Example 42, compound 126 (41 mg) was obtained as a crude product.
Step 4 The crude product of Compound 126 (20 mg) obtained in Step 3 was dissolved in N-methylpyrrolidone (1 ml) to give 2-chloro-3-trifluoromethylpyrazine (8.3 mg, 0.046 mmol) and Diisopropylethylamine (43 μl, 0.249 mmol) was added, and the mixture was stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, water was added and extracted three times with ethyl acetate. The organic layers were combined, washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-2-7) (10 mg, yield 43%).
Compound (I-2-7);
1H-NMR (CDCl3) δ: 1.68-2.21 (7H, m), 3.45-3.87 (9H, m), 4.25-4.35 (2H, m), 4.49-4.62 (2H, m), 7.61-7.67 (2H, m), 7.80 (1H, s), 7.96 (2H, d, J = 8.2 Hz), 8.21 (1H, s), 8.40 (2H, d, J = 4.5 Hz).
Figure JPOXMLDOC01-appb-C000091
第１工程
　窒素雰囲気下、トリメチルスルホキソニウムブロミド（４９．２ｍｇ、０．２８４ｍｍｏｌ）をジメチルスルホキシド（０．９ｍｌ）とテトラヒドロフラン（０．６ｍｌ）の混合溶媒に懸濁し、カリウムtert-ブトキシド（３１．９ｍｇ、０．２８４ｍｍｏｌ）を０℃で加え、室温下３０分間撹拌した。化合物１２１（３０ｍｇ、０．０７１ｍｍｏｌ）のテトラヒドロフラン（０．６ｍｌ）溶液を加え、室温下３０分間撹拌した後、６０℃で反応が収束するまで撹拌した。反応終了後、飽和塩化アンモニウム水溶液を加え、１０％クエン酸水溶液でｐＨ４～５にして、酢酸エチルで３回抽出した。有機層を合わせて水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１２７（３１ｍｇ）を粗生成物として得た。
第２工程
　第１工程で得た化合物１２７の粗生成物（３１ｍｇ）を用いて、実施例４３の第３工程に従い、化合物１２８（２５．５ｍｇ）を不純物が含まれる状態で得た。
第３工程
　第２工程で得た化合物１２８の粗生成物（２５．５ｍｇ）を用いて、実施例４２の第５工程に従い、化合物１２９（２４ｍｇ）を粗生成物として得た。
第４工程
　第３工程で得た化合物１２９の粗生成物（２４ｍｇ）を用いて、実施例４５の第４工程に従い、化合物（Ｉ－２－８）（８ｍｇ）を得た。
化合物（Ｉ－２－８）；
1H-NMR (CDCl3) δ: 1.07-1.12 (2H, m), 1.14-1.19 (2H, m), 1.47-1.74 (3H, m), 1.97-2.14 (4H, m), 3.43-3.86 (6H, m), 4.45-4.61 (3H, m), 7.08 (1H, s), 7.58-7.63 (2H, m), 7.91 (2H, d, J = 8.1 Hz), 8.18 (1H, s), 8.26 (1H, s), 8.37 (1H, s).
Figure JPOXMLDOC01-appb-C000091
First Step Under a nitrogen atmosphere, trimethylsulfoxonium bromide (49.2 mg, 0.284 mmol) was suspended in a mixed solvent of dimethylsulfoxide (0.9 ml) and tetrahydrofuran (0.6 ml), and potassium tert-butoxide (31.31). 9 mg, 0.284 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. A solution of compound 121 (30 mg, 0.071 mmol) in tetrahydrofuran (0.6 ml) was added and stirred at room temperature for 30 minutes, and then stirred at 60 ° C. until the reaction converged. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, the pH was adjusted to 4-5 with a 10% aqueous citric acid solution, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 127 (31 mg) as a crude product.
Second Step Using the crude product of compound 127 (31 mg) obtained in the first step, compound 128 (25.5 mg) was obtained in a state containing impurities, according to the third step of Example 43.
Third Step According to the fifth step of Example 42, compound 129 (24 mg) was obtained as a crude product using the crude product (25.5 mg) of compound 128 obtained in the second step.
Fourth Step Compound (I-2-8) (8 mg) was obtained according to the fourth step of Example 45 using the crude product (24 mg) of compound 129 obtained in the third step.
Compound (I-2-8);
1H-NMR (CDCl3) δ: 1.07-1.12 (2H, m), 1.14-1.19 (2H, m), 1.47-1.74 (3H, m), 1.97-2.14 (4H, m), 3.43-3.86 (6H, m), 4.45-4.61 (3H, m), 7.08 (1H, s), 7.58-7.63 (2H, m), 7.91 (2H, d, J = 8.1 Hz), 8.18 (1H, s), 8.26 (1H , s), 8.37 (1H, s).
Figure JPOXMLDOC01-appb-C000092
第１工程
　アジ化ナトリウム（２０．７ｍｇ、０．３１８ｍｍｏｌ）をジメチルスルホキシド（２ｍｌ）に懸濁し、化合物１１６（８０ｍｇ、０．１５９ｍｍｏｌ）を加え、６０℃で２時間撹拌した。室温に冷却し、水を加え、酢酸エチルで３回抽出した。有機層を合わせて水で２回、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１３０（８０ｍｇ）を粗生成物として得た。
第２工程
　化合物１３０（８０ｍｇ、０．１７２ｍｍｏｌ）をテトラヒドロフラン（３．４ｍｌ）に溶解し、水（３．４ｍｌ）およびトリフェニルホスフィン（５０ｍｇ、０．１９１ｍｍｏｌ）を加え、８０℃で２時間加熱還流した。室温に冷却し、水を加え、酢酸エチルで３回抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、化合物１３１（１３６ｍｇ）をトリフェニルホスフィンオキシドが不純物として含まれる状態で得た。
第３工程
　第２工程で得た化合物１３１の粗生成物（６８ｍｇ）をジクロロメタン（１ｍｌ）に溶解し、無水酢酸（１０μｌ、０．１０６ｍｍｏｌ）を室温下加え、１時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。有機層を合わせて水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）で精製し、化合物１３２（３０ｍｇ）を得た。
第４工程
　化合物１３２（３０ｍｇ、０．０６２ｍｍｏｌ）を用いて、実施例４２の第３工程に従い、化合物１３３（２９ｍｇ、１００％）を得た。
第５工程
　化合物１３３（２９ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１ｍｌ）に溶解し、２－アミノエタノール（４．６ｍｇ、０．０７５ｍｍｏｌ）、ジイソプロピルエチルアミン（３３μｌ、０．１８６ｍｍｏｌ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート（３５．４ｍｇ、０．０９３ｍｍｏｌ）を加え、室温で３０分間攪拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで３回抽出した。有機層を水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物（Ｉ－２－９）（３０ｍｇ、収率９５％）を得た。
第６および第７工程
　窒素雰囲気下、化合物（Ｉ－２－９）（２５ｍｇ、０．０４９ｍｍｏｌ）をジオキサン（１ｍｌ）に溶解し、４ｍｍｏｌ／Ｌ塩酸のジオキサン溶液（４２８μｌ）を加え、続けてメタノール（０．５ｍｌ）を加え、３時間室温で撹拌した。減圧下溶媒を留去し、得た残渣にジエチルエーテルを加え減圧下溶媒を留去することを２回繰り返した。得た残渣にＮ－メチルピロリドン（１ｍｌ）と炭酸カリウム（２３．７ｍｇ、０．１７１ｍｍｏｌ）、ジイソプロピルエチルアミン（１７μｌ、０．０９８ｍｍｏｌ）を加えた後、３－ｔｅｒｔブチルー５－クロロー１，２，４－チアジアゾール（１０．４ｍｇ、０．０５９ｍｍｏｌ）を加え、５０℃で３時間撹拌した。室温に冷却し、水を加え、酢酸エチルで３回抽出した。有機層を合わせて水で２回、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）で精製し、化合物（Ｉ－２－１０）（７．６ｍｇ、収率２８％）を得た。
化合物（Ｉ－２－１０）；
1H-NMR (CDCl3) δ: 1.36 (9H, s), 1.91-1.97 (3H, br m), 2.06-2.11 (4H, m), 2.54 (1H, br s), 3.54-3.68 (4H, m), 3.82-3.94 (4H, m), 5.45 (1H, d, J = 9.1 Hz), 6.13 (1H, d, J = 8.9 Hz), 6.66 (1H, t, J = 5.8 Hz), 7.68 (1H, s), 7.80 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.33 (1H, s).
Figure JPOXMLDOC01-appb-C000092
First Step Sodium azide (20.7 mg, 0.318 mmol) was suspended in dimethyl sulfoxide (2 ml), compound 116 (80 mg, 0.159 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. After cooling to room temperature, water was added and extracted three times with ethyl acetate. The organic layers were combined, washed twice with water and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 130 (80 mg) as a crude product.
Second Step Compound 130 (80 mg, 0.172 mmol) was dissolved in tetrahydrofuran (3.4 ml), water (3.4 ml) and triphenylphosphine (50 mg, 0.191 mmol) were added, and the mixture was heated to reflux at 80 ° C. for 2 hours. did. After cooling to room temperature, water was added and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 131 (136 mg) in a state where triphenylphosphine oxide was contained as an impurity.
Third Step The crude product of compound 131 (68 mg) obtained in the second step was dissolved in dichloromethane (1 ml), acetic anhydride (10 μl, 0.106 mmol) was added at room temperature, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 132 (30 mg).
Fourth Step Compound 133 (29 mg, 100%) was obtained according to the third step of Example 42 using Compound 132 (30 mg, 0.062 mmol).
Step 5 Compound 133 (29 mg) was dissolved in N, N-dimethylformamide (1 ml), and 2-aminoethanol (4.6 mg, 0.075 mmol), diisopropylethylamine (33 μl, 0.186 mmol), O- (7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (35.4 mg, 0.093 mmol) was added and stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-2-9) (30 mg, yield 95%).
Steps 6 and 7 Under a nitrogen atmosphere, compound (I-2-9) (25 mg, 0.049 mmol) was dissolved in dioxane (1 ml), 4 mmol / L hydrochloric acid in dioxane (428 μl) was added, and then methanol was added. (0.5 ml) was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the resulting residue and the solvent was distilled off under reduced pressure twice. N-methylpyrrolidone (1 ml), potassium carbonate (23.7 mg, 0.171 mmol) and diisopropylethylamine (17 μl, 0.098 mmol) were added to the resulting residue, and then 3-tertbutyl-5-chloro-1,2,4. Add thiadiazole (10.4 mg, 0.059 mmol) and stir at 50 ° C. for 3 hours. After cooling to room temperature, water was added and extracted three times with ethyl acetate. The organic layers were combined, washed twice with water and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-2-10) (7.6 mg, yield 28%).
Compound (I-2-10);
1H-NMR (CDCl3) δ: 1.36 (9H, s), 1.91-1.97 (3H, br m), 2.06-2.11 (4H, m), 2.54 (1H, br s), 3.54-3.68 (4H, m) , 3.82-3.94 (4H, m), 5.45 (1H, d, J = 9.1 Hz), 6.13 (1H, d, J = 8.9 Hz), 6.66 (1H, t, J = 5.8 Hz), 7.68 (1H, s), 7.80 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.4 Hz), 8.33 (1H, s).

　以下に示した化合物も同様にして合成した。各化合物については、ＮＭＲまたはＬＣ／ＭＳの測定結果を示した。
　なお、構造式中、Ａｂｓは立体異性を示す。 The following compounds were synthesized in the same manner. About each compound, the measurement result of NMR or LC / MS was shown.
In the structural formula, Abs represents stereoisomerism.
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000143
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000260
Figure JPOXMLDOC01-appb-T000260
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000317
（試験例１）
ヒトGPR119受容体アゴニストの探索
　本化合物のGPR119受容体応答性は、ヒトGPR119受容体遺伝子をCHO-K1細胞に導入して作製したヒトGPR119受容体発現細胞株 GPR119/CHO-K1細胞を用いて細胞内cAMPの産生を指標として測定した。ヒトGPR119受容体をコードする遺伝子の塩基配列は、NM_178471 (GenBank)に記載されている。10％ FBSを添加したα-MEM培地にて増殖させたGPR119/CHO-K1細胞をPBS(phosphate buffered saline)(-)で一回洗浄後、トリプシン/EDTAを用いて細胞懸濁液にし、384穴マイクロプレートに3×103個/ウェルになるように細胞を播種して、5％ CO2雰囲気下で37℃、オーバーナイト培養した。翌日、0.1％ Bovine serum albumin (BSA)を含むHanks’Balanced Salt Solution (HBSS)、20 mM HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)で構成される洗浄バッファー 20 μlで2回 各ウェルを洗浄後、0.1 mM isobutylmethylxanthine（IBMX），0.2 mM RO 20-1724を含む0.1％ BSA，HBSS，20mM HEPESで構成されるアッセイバッファーを5 μl添加した。さらに、アッセイバッファーに溶解調整した化合物を5 μl添加し、5％ CO2雰囲気下で37℃、1時間反応した。細胞内cAMPの産生を市販のアッセイキットで測定し、その用量反応曲線より化合物の50％ 活性濃度(EC50値)を求めた。 (Test Example 1)
Search for a human GPR119 receptor agonist The GPR119 receptor responsiveness of this compound is determined by using the human GPR119 receptor-expressing cell line GPR119 / CHO-K1 cells prepared by introducing the human GPR119 receptor gene into CHO-K1 cells. Production of internal cAMP was measured as an index. The base sequence of the gene encoding the human GPR119 receptor is described in NM_178471 (GenBank). GPR119 / CHO-K1 cells grown in α-MEM medium supplemented with 10% FBS were washed once with PBS (phosphate buffered saline) (−), and made into a cell suspension using trypsin / EDTA. Cells were seeded in a well microplate at 3 × 10 3 cells / well and cultured at 37 ° C. overnight in a 5% CO 2 atmosphere. The next day, twice each with 20 μl of washing buffer consisting of Hanks' Balanced Salt Solution (HBSS) containing 0.1% Bovine serum albumin (BSA) and 20 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) After washing the wells, 5 μl of an assay buffer composed of 0.1% BSA, HBSS, and 20 mM HEPES containing 0.1 mM isobutylmethylxanthine (IBMX) and 0.2 mM RO 20-1724 was added. Further, 5 μl of the compound adjusted to be dissolved in the assay buffer was added and reacted at 37 ° C. for 1 hour in a 5% CO 2 atmosphere. Intracellular cAMP production was measured with a commercially available assay kit, and a 50% active concentration (EC50 value) of the compound was determined from the dose-response curve.
　試験例１の結果を以下に示す。
化合物（Ｉ－１－７）：　ＥＣ５０＝４２８ｎＭ
化合物（Ｉ－１－１４）：　ＥＣ５０＝１７４ｎＭ
化合物（Ｉ－１－１５）：　ＥＣ５０＝４１３ｎＭ
化合物（Ｉ－１－１８）：　ＥＣ５０＝２１９ｎＭ
化合物（Ｉ－１－１９）：　ＥＣ５０＝２８８ｎＭ
化合物（Ｉ－１－２１）：　ＥＣ５０＝４８０ｎＭ
化合物（Ｉ－１－２２）：　ＥＣ５０＝１３０ｎＭ
化合物（Ｉ－１－２３）：　ＥＣ５０＝１１５ｎＭ
化合物（Ｉ－１－２５）：　ＥＣ５０＝４２ｎＭ
化合物（Ｉ－１－２６）：　ＥＣ５０＝１９８ｎＭ
化合物（Ｉ－１－２９）：　ＥＣ５０＝８２ｎＭ
化合物（Ｉ－１－３６）：　ＥＣ５０＝１２６ｎＭ
化合物（Ｉ－１－３７）：　ＥＣ５０＝４５ｎＭ
化合物（Ｉ－１－３８）：　ＥＣ５０＝１５ｎＭ
化合物（Ｉ－１－４２）：　ＥＣ５０＝２９２ｎＭ
化合物（Ｉ－１－４７）：　ＥＣ５０＝４８８ｎＭ
化合物（Ｉ－１－６５）：　ＥＣ５０＝３７１ｎＭ
化合物（Ｉ－１－６８）：　ＥＣ５０＝２５４ｎＭ
化合物（Ｉ－１－１４８）：　ＥＣ５０＝４０５ｎＭ
化合物（Ｉ－１－１５１）：　ＥＣ５０＝２５１ｎＭ
化合物（Ｉ－１－１５２）：　ＥＣ５０＝３３２ｎＭ
化合物（Ｉ－１－１６０）：　ＥＣ５０＝２８８ｎＭ
化合物（Ｉ－１－１６１）：　ＥＣ５０＝３１８ｎＭ
化合物（Ｉ－１－１６２）：　ＥＣ５０＝３８１ｎＭ
化合物（Ｉ－１－１６３）：　ＥＣ５０＝３７９ｎＭ
化合物（Ｉ－１－１６４）：　ＥＣ５０＝１６２ｎＭ
化合物（Ｉ－１－１６５）：　ＥＣ５０＝４７０ｎＭ
化合物（Ｉ－１－１６６）：　ＥＣ５０＝１６０ｎＭ
化合物（Ｉ－１－１６７）：　ＥＣ５０＝１７４ｎＭ
化合物（Ｉ－１－１７６）：　ＥＣ５０＝３５３ｎＭ
化合物（Ｉ－１－１９０）：　ＥＣ５０＝２４４ｎＭ
化合物（Ｉ－１－１９８）：　ＥＣ５０＝１８５ｎＭ
化合物（Ｉ－１－１９９）：　ＥＣ５０＝３９３ｎＭ
化合物（Ｉ－１－２０６）：　ＥＣ５０＝４９９ｎＭ
化合物（Ｉ－１－２１０）：　ＥＣ５０＝１８９ｎＭ
化合物（Ｉ－１－２１３）：　ＥＣ５０＝１６３ｎＭ
化合物（Ｉ－１－２１４）：　ＥＣ５０＝１１３ｎＭ
化合物（Ｉ－１－２１８）：　ＥＣ５０＝２５３ｎＭ
化合物（Ｉ－１－２１９）：　ＥＣ５０＝１４４ｎＭ
化合物（Ｉ－１－２２６）：　ＥＣ５０＝４４７ｎＭ
化合物（Ｉ－１－２２７）：　ＥＣ５０＝２３９ｎＭ
化合物（Ｉ－１－２２８）：　ＥＣ５０＝３５５ｎＭ
化合物（Ｉ－１－２２９）：　ＥＣ５０＝３３８ｎＭ
化合物（Ｉ－１－２３０）：　ＥＣ５０＝３１６ｎＭ
化合物（Ｉ－１－２３１）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－１－２３２）：　ＥＣ５０＝２８０ｎＭ
化合物（Ｉ－１－２３６）：　ＥＣ５０＝２１４ｎＭ
化合物（Ｉ－１－２４１）：　ＥＣ５０＝４３９ｎＭ
化合物（Ｉ－１－２４６）：　ＥＣ５０＝９９ｎＭ
化合物（Ｉ－１－２４７）：　ＥＣ５０＝１９８ｎＭ
化合物（Ｉ－１－２４８）：　ＥＣ５０＝３８１ｎＭ
化合物（Ｉ－１－２４９）：　ＥＣ５０＝１７６ｎＭ
化合物（Ｉ－１－２５１）：　ＥＣ５０＝３９０ｎＭ
化合物（Ｉ－１－２５３）：　ＥＣ５０＝１６７ｎＭ
化合物（Ｉ－１－２６１）：　ＥＣ５０＝４４３ｎＭ
化合物（Ｉ－１－２６３）：　ＥＣ５０＝２９２ｎＭ
化合物（Ｉ－１－２６４）：　ＥＣ５０＝２２３ｎＭ
化合物（Ｉ－１－２６５）：　ＥＣ５０＝４８４ｎＭ
化合物（Ｉ－１－２６７）：　ＥＣ５０＝２７７ｎＭ
化合物（Ｉ－１－２７３）：　ＥＣ５０＝１５８ｎＭ
化合物（Ｉ－１－２７４）：　ＥＣ５０＝４３９ｎＭ
化合物（Ｉ－１－２７８）：　ＥＣ５０＝１６０ｎＭ
化合物（Ｉ－１－２８５）：　ＥＣ５０＝４７５ｎＭ
化合物（Ｉ－１－２８７）：　ＥＣ５０＝３１１ｎＭ
化合物（Ｉ－１－２９０）：　ＥＣ５０＝１２７ｎＭ
化合物（Ｉ－１－２９２）：　ＥＣ５０＝４４０ｎＭ
化合物（Ｉ－１－２９３）：　ＥＣ５０＝１５５ｎＭ
化合物（Ｉ－１－２９４）：　ＥＣ５０＝１１９ｎＭ
化合物（Ｉ－１－２９８）：　ＥＣ５０＝２６１ｎＭ
化合物（Ｉ－１－３０３）：　ＥＣ５０＝２４５ｎＭ
化合物（Ｉ－１－３０５）：　ＥＣ５０＝８９ｎＭ
化合物（Ｉ－１－３０６）：　ＥＣ５０＝２６６ｎＭ
化合物（Ｉ－１－３１０）：　ＥＣ５０＝２９９ｎＭ
化合物（Ｉ－１－３１２）：　ＥＣ５０＝３８２ｎＭ
化合物（Ｉ－１－３１３）：　ＥＣ５０＝２５６ｎＭ
化合物（Ｉ－１－３１５）：　ＥＣ５０＝１８７ｎＭ
化合物（Ｉ－１－３１７）：　ＥＣ５０＝３３０ｎＭ
化合物（Ｉ－１－３１８）：　ＥＣ５０＝５４ｎＭ
化合物（Ｉ－１－３２１）：　ＥＣ５０＝７１ｎＭ
化合物（Ｉ－１－３２２）：　ＥＣ５０＝９７ｎＭ
化合物（Ｉ－１－３２３）：　ＥＣ５０＝２１６ｎＭ
化合物（Ｉ－１－３２５）：　ＥＣ５０＝９９ｎＭ
化合物（Ｉ－１－３２６）：　ＥＣ５０＝２５９ｎＭ
化合物（Ｉ－１－３３０）：　ＥＣ５０＝５００ｎＭ
化合物（Ｉ－２－１２）：　ＥＣ５０＝１７７ｎＭ
化合物（Ｉ－２－１３）：　ＥＣ５０＝１８４ｎＭ
化合物（Ｉ－２－１４）：　ＥＣ５０＝１０２ｎＭ
化合物（Ｉ－２－１５）：　ＥＣ５０＝４２ｎＭ
化合物（Ｉ－２－１６）：　ＥＣ５０＝３４３ｎＭ
化合物（Ｉ－２－１７）：　ＥＣ５０＝５０ｎＭ
化合物（Ｉ－２－１８）：　ＥＣ５０＝６２ｎＭ
化合物（Ｉ－２－１９）：　ＥＣ５０＝４６ｎＭ
化合物（Ｉ－２－２０）：　ＥＣ５０＝１３８ｎＭ
化合物（Ｉ－２－２２）：　ＥＣ５０＝２６０ｎＭ
化合物（Ｉ－２－２３）：　ＥＣ５０＝２３８ｎＭ
化合物（Ｉ－２－２５）：　ＥＣ５０＝３４６ｎＭ
化合物（Ｉ－２－２７）：　ＥＣ５０＝４１３ｎＭ
化合物（Ｉ－２－２８）：　ＥＣ５０＝１７５ｎＭ
化合物（Ｉ－２－２９）：　ＥＣ５０＝１３２ｎＭ
化合物（Ｉ－２－３０）：　ＥＣ５０＝１６７ｎＭ
化合物（Ｉ－２－３２）：　ＥＣ５０＝２１２ｎＭ
化合物（Ｉ－２－３３）：　ＥＣ５０＝１６６ｎＭ
化合物（Ｉ－２－３４）：　ＥＣ５０＝３０７ｎＭ
化合物（Ｉ－２－３７）：　ＥＣ５０＝１８９ｎＭ
化合物（Ｉ－２－４３）：　ＥＣ５０＝４９９ｎＭ
化合物（Ｉ－２－５１）：　ＥＣ５０＝２０６ｎＭ
化合物（Ｉ－２－５２）：　ＥＣ５０＝８２ｎＭ
化合物（Ｉ－２－５４）：　ＥＣ５０＝４１９ｎＭ
化合物（Ｉ－２－５５）：　ＥＣ５０＝２３１ｎＭ
化合物（Ｉ－２－５９）：　ＥＣ５０＝２８ｎＭ
化合物（Ｉ－２－６０）：　ＥＣ５０＝１４ｎＭ
化合物（Ｉ－２－６１）：　ＥＣ５０＝＜１．５ｎＭ
化合物（Ｉ－２－６２）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－６３）：　ＥＣ５０＝２８ｎＭ
化合物（Ｉ－２－６４）：　ＥＣ５０＝９．９ｎＭ
化合物（Ｉ－２－６５）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－６６）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－６８）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－６９）：　ＥＣ５０＝１１６ｎＭ
化合物（Ｉ－２－７０）：　ＥＣ５０＝１４ｎＭ
化合物（Ｉ－２－７２）：　ＥＣ５０＝１０１ｎＭ
化合物（Ｉ－２－７４）：　ＥＣ５０＝４５３ｎＭ
化合物（Ｉ－２－７５）：　ＥＣ５０＝２２６ｎＭ
化合物（Ｉ－２－７６）：　ＥＣ５０＝１３０ｎＭ
化合物（Ｉ－２－８３）：　ＥＣ５０＝１７ｎＭ
化合物（Ｉ－２－８４）：　ＥＣ５０＝１１０ｎＭ
化合物（Ｉ－２－８５）：　ＥＣ５０＝１２２ｎＭ
化合物（Ｉ－２－８６）：　ＥＣ５０＝１０５ｎＭ
化合物（Ｉ－２－８７）：　ＥＣ５０＝１９１ｎＭ
化合物（Ｉ－２－８８）：　ＥＣ５０＝２２６ｎＭ
化合物（Ｉ－２－８９）：　ＥＣ５０＝１８５ｎＭ
化合物（Ｉ－２－９０）：　ＥＣ５０＝２８９ｎＭ
化合物（Ｉ－２－９１）：　ＥＣ５０＝２９４ｎＭ
化合物（Ｉ－２－９２）：　ＥＣ５０＝１４８ｎＭ
化合物（Ｉ－２－９３）：　ＥＣ５０＝１８１ｎＭ
化合物（Ｉ－２－９４）：　ＥＣ５０＝４６０ｎＭ
化合物（Ｉ－２－９５）：　ＥＣ５０＝１０２ｎＭ
化合物（Ｉ－２－９６）：　ＥＣ５０＝２０７ｎＭ
化合物（Ｉ－２－９７）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－１０１）：　ＥＣ５０＝３５５ｎＭ
化合物（Ｉ－２－１０３）：　ＥＣ５０＝３０３ｎＭ
化合物（Ｉ－２－１０４）：　ＥＣ５０＝２１２ｎＭ
化合物（Ｉ－２－１０６）：　ＥＣ５０＝３１８ｎＭ
化合物（Ｉ－２－１０７）：　ＥＣ５０＝２８０ｎＭ
化合物（Ｉ－２－１０８）：　ＥＣ５０＝３８４ｎＭ
化合物（Ｉ－２－１１２）：　ＥＣ５０＝１５４ｎＭ
化合物（Ｉ－２－１１３）：　ＥＣ５０＝４ｎＭ
化合物（Ｉ－２－１１９）：　ＥＣ５０＝４０７ｎＭ
化合物（Ｉ－２－１２１）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－１２４）：　ＥＣ５０＝１９０ｎＭ
化合物（Ｉ－２－１２５）：　ＥＣ５０＝２９８ｎＭ
化合物（Ｉ－２－１２６）：　ＥＣ５０＝２３２ｎＭ
化合物（Ｉ－２－１２７）：　ＥＣ５０＝１５６ｎＭ
化合物（Ｉ－２－１２８）：　ＥＣ５０＝３０８ｎＭ
化合物（Ｉ－２－１２９）：　ＥＣ５０＝２１０ｎＭ
化合物（Ｉ－２－１３０）：　ＥＣ５０＝１７１ｎＭ
化合物（Ｉ－２－１３１）：　ＥＣ５０＝３１１ｎＭ
化合物（Ｉ－２－１３２）：　ＥＣ５０＝３２３ｎＭ
化合物（Ｉ－２－１３３）：　ＥＣ５０＝９２ｎＭ
化合物（Ｉ－２－１３５）：　ＥＣ５０＝１２９ｎＭ
化合物（Ｉ－２－１３６）：　ＥＣ５０＝３２４ｎＭ
化合物（Ｉ－２－１３７）：　ＥＣ５０＝４０１ｎＭ
化合物（Ｉ－２－１３９）：　ＥＣ５０＝１８３ｎＭ
化合物（Ｉ－２－１４０）：　ＥＣ５０＝１８４ｎＭ
化合物（Ｉ－２－１４２）：　ＥＣ５０＝２１８ｎＭ
化合物（Ｉ－２－１４４）：　ＥＣ５０＝１５８ｎＭ
化合物（Ｉ－２－１４５）：　ＥＣ５０＝２１４ｎＭ
化合物（Ｉ－２－１４６）：　ＥＣ５０＝２５３ｎＭ
化合物（Ｉ－２－１４７）：　ＥＣ５０＝２０９ｎＭ
化合物（Ｉ－２－１４８）：　ＥＣ５０＝２０９ｎＭ
化合物（Ｉ－２－１４９）：　ＥＣ５０＝２３２ｎＭ
化合物（Ｉ－２－１５０）：　ＥＣ５０＝２３４ｎＭ
化合物（Ｉ－２－１５１）：　ＥＣ５０＝３３６ｎＭ
化合物（Ｉ－２－１５２）：　ＥＣ５０＝２１８ｎＭ
化合物（Ｉ－２－１５３）：　ＥＣ５０＝２５４ｎＭ
化合物（Ｉ－２－１５４）：　ＥＣ５０＝４１９ｎＭ
化合物（Ｉ－２－１５５）：　ＥＣ５０＝３２６ｎＭ
化合物（Ｉ－２－１５６）：　ＥＣ５０＝３５８ｎＭ
化合物（Ｉ－２－１５７）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－１５８）：　ＥＣ５０＝４０ｎＭ
化合物（Ｉ－２－１５９）：　ＥＣ５０＝６９ｎＭ
化合物（Ｉ－２－１６０）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－１６１）：　ＥＣ５０＝４１ｎＭ
化合物（Ｉ－２－１６２）：　ＥＣ５０＝７ｎＭ
化合物（Ｉ－２－１６３）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－１６４）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－１６５）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－１６６）：　ＥＣ５０＝６０ｎＭ
化合物（Ｉ－２－１６７）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－１６８）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－１６９）：　ＥＣ５０＝２０ｎＭ
化合物（Ｉ－２－１７０）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－１７１）：　ＥＣ５０＝４４ｎＭ
化合物（Ｉ－２－１７２）：　ＥＣ５０＝７ｎＭ
化合物（Ｉ－２－１７３）：　ＥＣ５０＝４６ｎＭ
化合物（Ｉ－２－１７４）：　ＥＣ５０＝９５ｎＭ
化合物（Ｉ－２－１７５）：　ＥＣ５０＝５ｎＭ
化合物（Ｉ－２－１７６）：　ＥＣ５０＝８ｎＭ
化合物（Ｉ－２－１７７）：　ＥＣ５０＝３８ｎＭ
化合物（Ｉ－２－１７８）：　ＥＣ５０＝１０６ｎＭ
化合物（Ｉ－２－１７９）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－１８０）：　ＥＣ５０＝７．９ｎＭ
化合物（Ｉ－２－１８１）：　ＥＣ５０＝４３ｎＭ
化合物（Ｉ－２－１８２）：　ＥＣ５０＝６８ｎＭ
化合物（Ｉ－２－１８３）：　ＥＣ５０＝３８１ｎＭ
化合物（Ｉ－２－１８４）：　ＥＣ５０＝４０ｎＭ
化合物（Ｉ－２－１８５）：　ＥＣ５０＝９．１ｎＭ
化合物（Ｉ－２－１８６）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－１８７）：　ＥＣ５０＝８．５ｎＭ
化合物（Ｉ－２－１８８）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－１８９）：　ＥＣ５０＝９６ｎＭ
化合物（Ｉ－２－１９０）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－１９１）：　ＥＣ５０＝１６３ｎＭ
化合物（Ｉ－２－１９２）：　ＥＣ５０＝７８ｎＭ
化合物（Ｉ－２－１９３）：　ＥＣ５０＝１７１ｎＭ
化合物（Ｉ－２－１９４）：　ＥＣ５０＝３２ｎＭ
化合物（Ｉ－２－１９５）：　ＥＣ５０＝４１ｎＭ
化合物（Ｉ－２－１９６）：　ＥＣ５０＝１４８ｎＭ
化合物（Ｉ－２－１９７）：　ＥＣ５０＝３４ｎＭ
化合物（Ｉ－２－１９８）：　ＥＣ５０＝７０ｎＭ
化合物（Ｉ－２－１９９）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－２００）：　ＥＣ５０＝３２ｎＭ
化合物（Ｉ－２－２０１）：　ＥＣ５０＝４５ｎＭ
化合物（Ｉ－２－２０２）：　ＥＣ５０＝２６１ｎＭ
化合物（Ｉ－２－２０３）：　ＥＣ５０＝４６ｎＭ
化合物（Ｉ－２－２０４）：　ＥＣ５０＝３０ｎＭ
化合物（Ｉ－２－２０５）：　ＥＣ５０＝１５６ｎＭ
化合物（Ｉ－２－２０６）：　ＥＣ５０＝７６ｎＭ
化合物（Ｉ－２－２０７）：　ＥＣ５０＝９ｎＭ
化合物（Ｉ－２－２０８）：　ＥＣ５０＝５３ｎＭ
化合物（Ｉ－２－２０９）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－２１０）：　ＥＣ５０＝１６ｎＭ
化合物（Ｉ－２－２１１）：　ＥＣ５０＝５７ｎＭ
化合物（Ｉ－２－２１２）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－２１４）：　ＥＣ５０＝５０ｎＭ
化合物（Ｉ－２－２１５）：　ＥＣ５０＝９３ｎＭ
化合物（Ｉ－２－２１６）：　ＥＣ５０＝１０２ｎＭ
化合物（Ｉ－２－２１７）：　ＥＣ５０＝１０８ｎＭ
化合物（Ｉ－２－２１８）：　ＥＣ５０＝２０２ｎＭ
化合物（Ｉ－２－２１９）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－２２０）：　ＥＣ５０＝１２５ｎＭ
化合物（Ｉ－２－２２１）：　ＥＣ５０＝１１３ｎＭ
化合物（Ｉ－２－２２２）：　ＥＣ５０＝１２８ｎＭ
化合物（Ｉ－２－２２３）：　ＥＣ５０＝６．６ｎＭ
化合物（Ｉ－２－２２４）：　ＥＣ５０＝１２１ｎＭ
化合物（Ｉ－２－２２５）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－２２６）：　ＥＣ５０＝７５ｎＭ
化合物（Ｉ－２－２２７）：　ＥＣ５０＝２５１ｎＭ
化合物（Ｉ－２－２２８）：　ＥＣ５０＝３９ｎＭ
化合物（Ｉ－２－２２９）：　ＥＣ５０＝１３１ｎＭ
化合物（Ｉ－２－２３０）：　ＥＣ５０＝５７ｎＭ
化合物（Ｉ－２－２３１）：　ＥＣ５０＝７７ｎＭ
化合物（Ｉ－２－２３２）：　ＥＣ５０＝１９５ｎＭ
化合物（Ｉ－２－２３３）：　ＥＣ５０＝４４ｎＭ
化合物（Ｉ－２－２３４）：　ＥＣ５０＝７８ｎＭ
化合物（Ｉ－２－２３５）：　ＥＣ５０＝２４ｎＭ
化合物（Ｉ－２－２３６）：　ＥＣ５０＝７３ｎＭ
化合物（Ｉ－２－２３７）：　ＥＣ５０＝１１０ｎＭ
化合物（Ｉ－２－２３８）：　ＥＣ５０＝１４２ｎＭ
化合物（Ｉ－２－２３９）：　ＥＣ５０＝６０ｎＭ
化合物（Ｉ－２－２４０）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－２４１）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－２４２）：　ＥＣ５０＝１６１ｎＭ
化合物（Ｉ－２－２４３）：　ＥＣ５０＝３４ｎＭ
化合物（Ｉ－２－２４４）：　ＥＣ５０＝３７ｎＭ
化合物（Ｉ－２－２４５）：　ＥＣ５０＝２２４ｎＭ
化合物（Ｉ－２－２４６）：　ＥＣ５０＝４８ｎＭ
化合物（Ｉ－２－２４７）：　ＥＣ５０＝１２１ｎＭ
化合物（Ｉ－２－２４８）：　ＥＣ５０＝４２ｎＭ
化合物（Ｉ－２－２４９）：　ＥＣ５０＝７８ｎＭ
化合物（Ｉ－２－２５０）：　ＥＣ５０＝１８７ｎＭ
化合物（Ｉ－２－２５１）：　ＥＣ５０＝１１９ｎＭ
化合物（Ｉ－２－２５２）：　ＥＣ５０＝２０６ｎＭ
化合物（Ｉ－２－２５３）：　ＥＣ５０＝５７ｎＭ
化合物（Ｉ－２－２５４）：　ＥＣ５０＝１９８ｎＭ
化合物（Ｉ－２－２５５）：　ＥＣ５０＝４３１ｎＭ
化合物（Ｉ－２－２５６）：　ＥＣ５０＝８４ｎＭ
化合物（Ｉ－２－２５７）：　ＥＣ５０＝１２１ｎＭ
化合物（Ｉ－２－２５８）：　ＥＣ５０＝５７ｎＭ
化合物（Ｉ－２－２５９）：　ＥＣ５０＝１０６ｎＭ
化合物（Ｉ－２－２６０）：　ＥＣ５０＝８７ｎＭ
化合物（Ｉ－２－２６１）：　ＥＣ５０＝７３ｎＭ
化合物（Ｉ－２－２６２）：　ＥＣ５０＝１８９ｎＭ
化合物（Ｉ－２－２６３）：　ＥＣ５０＝１０１ｎＭ
化合物（Ｉ－２－２６４）：　ＥＣ５０＝１５５ｎＭ
化合物（Ｉ－２－２６５）：　ＥＣ５０＝１４７ｎＭ
化合物（Ｉ－２－２６６）：　ＥＣ５０＝１１６ｎＭ
化合物（Ｉ－２－２６７）：　ＥＣ５０＝４３ｎＭ
化合物（Ｉ－２－２６８）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－２６９）：　ＥＣ５０＝１４８ｎＭ
化合物（Ｉ－２－２７０）：　ＥＣ５０＝５８ｎＭ
化合物（Ｉ－２－２７１）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－２７２）：　ＥＣ５０＝４２ｎＭ
化合物（Ｉ－２－２７３）：　ＥＣ５０＝１１３ｎＭ
化合物（Ｉ－２－２７４）：　ＥＣ５０＝１３７ｎＭ
化合物（Ｉ－２－２７５）：　ＥＣ５０＝９５ｎＭ
化合物（Ｉ－２－２７６）：　ＥＣ５０＝４２４ｎＭ
化合物（Ｉ－２－２７７）：　ＥＣ５０＝１３３ｎＭ
化合物（Ｉ－２－２７８）：　ＥＣ５０＝３１２ｎＭ
化合物（Ｉ－２－２７９）：　ＥＣ５０＝８３ｎＭ
化合物（Ｉ－２－２８０）：　ＥＣ５０＝１４８ｎＭ
化合物（Ｉ－２－２８１）：　ＥＣ５０＝４５ｎＭ
化合物（Ｉ－２－２８２）：　ＥＣ５０＝１１８ｎＭ
化合物（Ｉ－２－２８３）：　ＥＣ５０＝３３ｎＭ
化合物（Ｉ－２－２８４）：　ＥＣ５０＝８２ｎＭ
化合物（Ｉ－２－２８５）：　ＥＣ５０＝３０ｎＭ
化合物（Ｉ－２－２８６）：　ＥＣ５０＝３０ｎＭ
化合物（Ｉ－２－２８７）：　ＥＣ５０＝１１５ｎＭ
化合物（Ｉ－２－２８８）：　ＥＣ５０＝９７ｎＭ
化合物（Ｉ－２－２８９）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－２９０）：　ＥＣ５０＝８２ｎＭ
化合物（Ｉ－２－２９１）：　ＥＣ５０＝９３ｎＭ
化合物（Ｉ－２－２９２）：　ＥＣ５０＝３１０ｎＭ
化合物（Ｉ－２－２９３）：　ＥＣ５０＝９６ｎＭ
化合物（Ｉ－２－２９４）：　ＥＣ５０＝５５ｎＭ
化合物（Ｉ－２－２９５）：　ＥＣ５０＝３４ｎＭ
化合物（Ｉ－２－２９６）：　ＥＣ５０＝７．１ｎＭ
化合物（Ｉ－２－２９７）：　ＥＣ５０＝７．５ｎＭ
化合物（Ｉ－２－２９８）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－２９９）：　ＥＣ５０＝２６ｎＭ
化合物（Ｉ－２－３００）：　ＥＣ５０＝１２６ｎＭ
化合物（Ｉ－２－３０１）：　ＥＣ５０＝１４ｎＭ
化合物（Ｉ－２－３０２）：　ＥＣ５０＝７．９ｎＭ
化合物（Ｉ－２－３０３）：　ＥＣ５０＝８３ｎＭ
化合物（Ｉ－２－３０４）：　ＥＣ５０＝８４ｎＭ
化合物（Ｉ－２－３０５）：　ＥＣ５０＝６９ｎＭ
化合物（Ｉ－２－３０６）：　ＥＣ５０＝６９ｎＭ
化合物（Ｉ－２－３０７）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－３０８）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－３０９）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－３１０）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－３１１）：　ＥＣ５０＝３２ｎＭ
化合物（Ｉ－２－３１２）：　ＥＣ５０＝２６ｎＭ
化合物（Ｉ－２－３１３）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－３１４）：　ＥＣ５０＝７９ｎＭ
化合物（Ｉ－２－３１５）：　ＥＣ５０＝５６ｎＭ
化合物（Ｉ－２－３１６）：　ＥＣ５０＝６ｎＭ
化合物（Ｉ－２－３１８）：　ＥＣ５０＝１６ｎＭ
化合物（Ｉ－２－３１９）：　ＥＣ５０＝１３５ｎＭ
化合物（Ｉ－２－３２０）：　ＥＣ５０＝１０２ｎＭ
化合物（Ｉ－２－３２１）：　ＥＣ５０＝５１ｎＭ
化合物（Ｉ－２－３２２）：　ＥＣ５０＝１５ｎＭ
化合物（Ｉ－２－３２３）：　ＥＣ５０＝２２ｎＭ
化合物（Ｉ－２－３２４）：　ＥＣ５０＝１７ｎＭ
化合物（Ｉ－２－３２５）：　ＥＣ５０＝２９ｎＭ
化合物（Ｉ－２－３２６）：　ＥＣ５０＝１６ｎＭ
化合物（Ｉ－２－３２７）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－３２８）：　ＥＣ５０＝４３９ｎＭ
化合物（Ｉ－２－３２９）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－３３０）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－３３１）：　ＥＣ５０＝６８ｎＭ
化合物（Ｉ－２－３３２）：　ＥＣ５０＝６１ｎＭ
化合物（Ｉ－２－３３４）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－３３６）：　ＥＣ５０＝３３０ｎＭ
化合物（Ｉ－２－３３７）：　ＥＣ５０＝１４０ｎＭ
化合物（Ｉ－２－３３８）：　ＥＣ５０＝７９ｎＭ
化合物（Ｉ－２－３３９）：　ＥＣ５０＝１００ｎＭ
化合物（Ｉ－２－３４０）：　ＥＣ５０＝１３０ｎＭ
化合物（Ｉ－２－３４１）：　ＥＣ５０＝６０ｎＭ
化合物（Ｉ－２－３４２）：　ＥＣ５０＝６．５ｎＭ
化合物（Ｉ－２－３４３）：　ＥＣ５０＝４７ｎＭ
化合物（Ｉ－２－３４４）：　ＥＣ５０＝２２ｎＭ
化合物（Ｉ－２－３４５）：　ＥＣ５０＝１５ｎＭ
化合物（Ｉ－２－３４６）：　ＥＣ５０＝２６２ｎＭ
化合物（Ｉ－２－３４７）：　ＥＣ５０＝８３ｎＭ
化合物（Ｉ－２－３４８）：　ＥＣ５０＝１０ｎＭ
化合物（Ｉ－２－３４９）：　ＥＣ５０＝＜１．５ｎＭ
化合物（Ｉ－２－３５０）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－３５１）：　ＥＣ５０＝６４ｎＭ
化合物（Ｉ－２－３５２）：　ＥＣ５０＝８５ｎＭ
化合物（Ｉ－２－３５３）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－３５６）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－３５７）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－３５８）：　ＥＣ５０＝７．５ｎＭ
化合物（Ｉ－２－３５９）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－３６０）：　ＥＣ５０＝８．４ｎＭ
化合物（Ｉ－２－３６１）：　ＥＣ５０＝１５ｎＭ
化合物（Ｉ－２－３６２）：　ＥＣ５０＝７．１ｎＭ
化合物（Ｉ－２－３６３）：　ＥＣ５０＝５．９ｎＭ
化合物（Ｉ－２－３６４）：　ＥＣ５０＝８０ｎＭ
化合物（Ｉ－２－３６５）：　ＥＣ５０＝１３５ｎＭ
化合物（Ｉ－２－３６６）：　ＥＣ５０＝５２ｎＭ
化合物（Ｉ－２－３６７）：　ＥＣ５０＝２６ｎＭ
化合物（Ｉ－２－３６８）：　ＥＣ５０＝６２ｎＭ
化合物（Ｉ－２－３６９）：　ＥＣ５０＝８０ｎＭ
化合物（Ｉ－２－３７０）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－３７１）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－３７２）：　ＥＣ５０＝１．０ｎＭ
化合物（Ｉ－２－３７３）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－３７４）：　ＥＣ５０＝３３ｎＭ
化合物（Ｉ－２－３７５）：　ＥＣ５０＝３４ｎＭ
化合物（Ｉ－２－３７６）：　ＥＣ５０＝２４６ｎＭ
化合物（Ｉ－２－３７７）：　ＥＣ５０＝１５８ｎＭ
化合物（Ｉ－２－３７８）：　ＥＣ５０＝５２ｎＭ
化合物（Ｉ－２－３７９）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－３８０）：　ＥＣ５０＝５２ｎＭ
化合物（Ｉ－２－３８１）：　ＥＣ５０＝９８ｎＭ
化合物（Ｉ－２－３８２）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－３８３）：　ＥＣ５０＝１６ｎＭ
化合物（Ｉ－２－３８４）：　ＥＣ５０＝２２ｎＭ
化合物（Ｉ－２－３８５）：　ＥＣ５０＝２６ｎＭ
化合物（Ｉ－２－３８６）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－３８７）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－３８８）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－３８９）：　ＥＣ５０＝１３１ｎＭ
化合物（Ｉ－２－３９０）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－３９１）：　ＥＣ５０＝３７ｎＭ
化合物（Ｉ－２－３９２）：　ＥＣ５０＝２０ｎＭ
化合物（Ｉ－２－３９３）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－３９４）：　ＥＣ５０＝３７８ｎＭ
化合物（Ｉ－２－３９５）：　ＥＣ５０＝１６５ｎＭ
化合物（Ｉ－２－３９６）：　ＥＣ５０＝１３１ｎＭ
化合物（Ｉ－２－３９７）：　ＥＣ５０＝３ｎＭ
化合物（Ｉ－２－３９８）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－３９９）：　ＥＣ５０＝７．６ｎＭ
化合物（Ｉ－２－４００）：　ＥＣ５０＝３．９ｎＭ
化合物（Ｉ－２－４０１）：　ＥＣ５０＝１３６ｎＭ
化合物（Ｉ－２－４０２）：　ＥＣ５０＝７２ｎＭ
化合物（Ｉ－２－４０３）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－４０４）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－４０５）：　ＥＣ５０＝１１０ｎＭ
化合物（Ｉ－２－４０６）：　ＥＣ５０＝４９ｎＭ
化合物（Ｉ－２－４０７）：　ＥＣ５０＝３０ｎＭ
化合物（Ｉ－２－４０８）：　ＥＣ５０＝２９９ｎＭ
化合物（Ｉ－２－４０９）：　ＥＣ５０＝１００ｎＭ
化合物（Ｉ－２－４１０）：　ＥＣ５０＝４．９ｎＭ
化合物（Ｉ－２－４１１）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－４１２）：　ＥＣ５０＝１７ｎＭ
化合物（Ｉ－２－４１３）：　ＥＣ５０＝７．１ｎＭ
化合物（Ｉ－２－４１４）：　ＥＣ５０＝１４６ｎＭ
化合物（Ｉ－２－４１５）：　ＥＣ５０＝２０ｎＭ
化合物（Ｉ－２－４１６）：　ＥＣ５０＝２４ｎＭ
化合物（Ｉ－２－４１９）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－４２０）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－４２１）：　ＥＣ５０＝１２０ｎＭ
化合物（Ｉ－２－４２２）：　ＥＣ５０＝２２ｎＭ
化合物（Ｉ－２－４２３）：　ＥＣ５０＝３９ｎＭ
化合物（Ｉ－２－４２４）：　ＥＣ５０＝１９１ｎＭ
化合物（Ｉ－２－４２５）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－４２６）：　ＥＣ５０＝１５８ｎＭ
化合物（Ｉ－２－４２７）：　ＥＣ５０＝１１５ｎＭ
化合物（Ｉ－２－４２８）：　ＥＣ５０＝６４ｎＭ
化合物（Ｉ－２－４２９）：　ＥＣ５０＝１７ｎＭ
化合物（Ｉ－２－４３０）：　ＥＣ５０＝２７１ｎＭ
化合物（Ｉ－２－４３１）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－４３２）：　ＥＣ５０＝２４ｎＭ
化合物（Ｉ－２－４３３）：　ＥＣ５０＝５３ｎＭ
化合物（Ｉ－２－４３４）：　ＥＣ５０＝１４１ｎＭ
化合物（Ｉ－２－４３５）：　ＥＣ５０＝７３ｎＭ
化合物（Ｉ－２－４３６）：　ＥＣ５０＝３３６ｎＭ
化合物（Ｉ－２－４３７）：　ＥＣ５０＝２２９ｎＭ
化合物（Ｉ－２－４３８）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－４３９）：　ＥＣ５０＝１２４ｎＭ
化合物（Ｉ－２－４４０）：　ＥＣ５０＝１５７ｎＭ
化合物（Ｉ－２－４４１）：　ＥＣ５０＝３０２ｎＭ
化合物（Ｉ－２－４４２）：　ＥＣ５０＝２３３ｎＭ
化合物（Ｉ－２－４４３）：　ＥＣ５０＝３９ｎＭ
化合物（Ｉ－２－４４４）：　ＥＣ５０＝９５ｎＭ
化合物（Ｉ－２－４４６）：　ＥＣ５０＝１０８ｎＭ
化合物（Ｉ－２－４５３）：　ＥＣ５０＝１３６ｎＭ
化合物（Ｉ－２－４５７）：　ＥＣ５０＝２０４ｎＭ
化合物（Ｉ－２－４５９）：　ＥＣ５０＝６６ｎＭ
化合物（Ｉ－２－４６２）：　ＥＣ５０＝６１ｎＭ
化合物（Ｉ－２－４７０）：　ＥＣ５０＝３０ｎＭ
化合物（Ｉ－２－４７１）：　ＥＣ５０＝１１８ｎＭ
化合物（Ｉ－２－４８２）：　ＥＣ５０＝３２ｎＭ
化合物（Ｉ－２－４８３）：　ＥＣ５０＝４４７ｎＭ
化合物（Ｉ－２－４８８）：　ＥＣ５０＝２７ｎＭ
化合物（Ｉ－２－４８９）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－４９０）：　ＥＣ５０＝３４ｎＭ
化合物（Ｉ－２－４９１）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－４９２）：　ＥＣ５０＝２０ｎＭ
化合物（Ｉ－２－４９３）：　ＥＣ５０＝４９ｎＭ
化合物（Ｉ－２－４９４）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－４９５）：　ＥＣ５０＝２９ｎＭ
化合物（Ｉ－２－４９６）：　ＥＣ５０＝１４ｎＭ
化合物（Ｉ－２－４９７）：　ＥＣ５０＝１５ｎＭ
化合物（Ｉ－２－４９８）：　ＥＣ５０＝２３４ｎＭ
化合物（Ｉ－２－４９９）：　ＥＣ５０＝４５０ｎＭ
化合物（Ｉ－２－５００）：　ＥＣ５０＝２９ｎＭ
化合物（Ｉ－２－５０１）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－５０２）：　ＥＣ５０＝２６４ｎＭ
化合物（Ｉ－２－５０３）：　ＥＣ５０＝３４７ｎＭ
化合物（Ｉ－２－５０４）：　ＥＣ５０＝３９ｎＭ
化合物（Ｉ－２－５０５）：　ＥＣ５０＝１２７ｎＭ
化合物（Ｉ－２－５０６）：　ＥＣ５０＝５０ｎＭ
化合物（Ｉ－２－５０７）：　ＥＣ５０＝１１３ｎＭ
化合物（Ｉ－２－５０８）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－５０９）：　ＥＣ５０＝３２ｎＭ
化合物（Ｉ－２－５１０）：　ＥＣ５０＝２８ｎＭ
化合物（Ｉ－２－５１２）：　ＥＣ５０＝２４２ｎＭ
化合物（Ｉ－２－１）：　ＥＣ５０＝４９ｎＭ
化合物（Ｉ－２－５１３）：　ＥＣ５０＝１４０ｎＭ
化合物（Ｉ－２－５１４）：　ＥＣ５０＝２９６ｎＭ
化合物（Ｉ－２－５１５）：　ＥＣ５０＝７９ｎＭ
化合物（Ｉ－２－５１６）：　ＥＣ５０＝６．７ｎＭ
化合物（Ｉ－２－５１８）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－５１９）：　ＥＣ５０＝１０９ｎＭ
化合物（Ｉ－２－５２０）：　ＥＣ５０＝８２ｎＭ
化合物（Ｉ－２－５２１）：　ＥＣ５０＝８．５ｎＭ
化合物（Ｉ－２－５２２）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－２）：　ＥＣ５０＝５５ｎＭ
化合物（Ｉ－２－３）：　ＥＣ５０＝１６ｎＭ
化合物（Ｉ－２－５２３）：　ＥＣ５０＝２９ｎＭ
化合物（Ｉ－２－５２５）：　ＥＣ５０＝３８２ｎＭ
化合物（Ｉ－２－５２６）：　ＥＣ５０＝２７６ｎＭ
化合物（Ｉ－２－５２７）：　ＥＣ５０＝１７４ｎＭ
化合物（Ｉ－２－５２８）：　ＥＣ５０＝９９ｎＭ
化合物（Ｉ－２－５２９）：　ＥＣ５０＝２７ｎＭ
化合物（Ｉ－２－５３０）：　ＥＣ５０＝３９ｎＭ
化合物（Ｉ－２－５３１）：　ＥＣ５０＝４６ｎＭ
化合物（Ｉ－２－５３２）：　ＥＣ５０＝１５１ｎＭ
化合物（Ｉ－２－５３３）：　ＥＣ５０＝４３ｎＭ
化合物（Ｉ－２－５３４）：　ＥＣ５０＝２２０ｎＭ
化合物（Ｉ－２－５３５）：　ＥＣ５０＝６９ｎＭ
化合物（Ｉ－２－５３６）：　ＥＣ５０＝１４０ｎＭ
化合物（Ｉ－２－５３８）：　ＥＣ５０＝５９ｎＭ
化合物（Ｉ－２－４）：　ＥＣ５０＝４１ｎＭ
化合物（Ｉ－２－５３９）：　ＥＣ５０＝１６４ｎＭ
化合物（Ｉ－２－５４０）：　ＥＣ５０＝８．７ｎＭ
化合物（Ｉ－２－５４１）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－５４２）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－５４３）：　ＥＣ５０＝４８ｎＭ
化合物（Ｉ－２－５４４）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－５）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－５４６）：　ＥＣ５０＝２２ｎＭ
化合物（Ｉ－２－７）：　ＥＣ５０＝２０７ｎＭ
化合物（Ｉ－２－５４７）：　ＥＣ５０＝１２ｎＭ
化合物（Ｉ－２－５４８）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－５４９）：　ＥＣ５０＝４１ｎＭ
化合物（Ｉ－２－５５０）：　ＥＣ５０＝６４ｎＭ
化合物（Ｉ－２－５５２）：　ＥＣ５０＝２１ｎＭ
化合物（Ｉ－２－８）：　ＥＣ５０＝５５ｎＭ
化合物（Ｉ－２－５５３）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－５５４）：　ＥＣ５０＝１５ｎＭ
化合物（Ｉ－２－５５５）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－５５６）：　ＥＣ５０＝８５ｎＭ
化合物（Ｉ－２－５５７）：　ＥＣ５０＝３０ｎＭ
化合物（Ｉ－２－５５８）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－５５９）：　ＥＣ５０＝１７３ｎＭ
化合物（Ｉ－２－５６０）：　ＥＣ５０＝４７ｎＭ
化合物（Ｉ－２－５６１）：　ＥＣ５０＝４０ｎＭ
化合物（Ｉ－２－５６２）：　ＥＣ５０＝８７ｎＭ
化合物（Ｉ－２－５６３）：　ＥＣ５０＝１１４ｎＭ
化合物（Ｉ－２－５６４）：　ＥＣ５０＝１０９ｎＭ
化合物（Ｉ－２－５６５）：　ＥＣ５０＝８６ｎＭ
化合物（Ｉ－２－５６６）：　ＥＣ５０＝４２９ｎＭ
化合物（Ｉ－２－５６７）：　ＥＣ５０＝７２ｎＭ
化合物（Ｉ－２－５６８）：　ＥＣ５０＝１３８ｎＭ
化合物（Ｉ－２－５６９）：　ＥＣ５０＝１５６ｎＭ
化合物（Ｉ－２－５７１）：　ＥＣ５０＝３４５ｎＭ
化合物（Ｉ－２－５７２）：　ＥＣ５０＝７２ｎＭ
化合物（Ｉ－２－５７６）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－５７７）：　ＥＣ５０＝４１０ｎＭ
化合物（Ｉ－２－５７８）：　ＥＣ５０＝６８ｎＭ
化合物（Ｉ－２－５８０）：　ＥＣ５０＝２０ｎＭ
化合物（Ｉ－２－５８３）：　ＥＣ５０＝５３ｎＭ
化合物（Ｉ－２－５８４）：　ＥＣ５０＝６８ｎＭ
化合物（Ｉ－２－５８５）：　ＥＣ５０＝１８６ｎＭ
化合物（Ｉ－２－５８６）：　ＥＣ５０＝３０４ｎＭ
化合物（Ｉ－２－５８７）：　ＥＣ５０＝６７ｎＭ
化合物（Ｉ－２－５８８）：　ＥＣ５０＝１５５ｎＭ
化合物（Ｉ－２－５８９）：　ＥＣ５０＝３１９ｎＭ
化合物（Ｉ－２－５９０）：　ＥＣ５０＝９４ｎＭ
化合物（Ｉ－２－５９１）：　ＥＣ５０＝４０８ｎＭ
化合物（Ｉ－２－５９３）：　ＥＣ５０＝１８３ｎＭ
化合物（Ｉ－２－５９４）：　ＥＣ５０＝２２ｎＭ
化合物（Ｉ－２－６０４）：　ＥＣ５０＝２９７ｎＭ
化合物（Ｉ－２－６１１）：　ＥＣ５０＝４２６ｎＭ
化合物（Ｉ－２－６１６）：　ＥＣ５０＝３４０ｎＭ
化合物（Ｉ－２－６１９）：　ＥＣ５０＝３９３ｎＭ
化合物（Ｉ－２－６２０）：　ＥＣ５０＝２５ｎＭ
化合物（Ｉ－２－６２１）：　ＥＣ５０＝１６ｎＭ
化合物（Ｉ－２－６２４）：　ＥＣ５０＝６２ｎＭ
化合物（Ｉ－２－６２５）：　ＥＣ５０＝２３ｎＭ
化合物（Ｉ－２－６２９）：　ＥＣ５０＝２０７ｎＭ
化合物（Ｉ－２－６３０）：　ＥＣ５０＝３００ｎＭ
化合物（Ｉ－２－６３１）：　ＥＣ５０＝１２９ｎＭ
化合物（Ｉ－２－６３２）：　ＥＣ５０＝２０８ｎＭ
化合物（Ｉ－２－６３３）：　ＥＣ５０＝１０２ｎＭ
化合物（Ｉ－２－６３４）：　ＥＣ５０＝５９ｎＭ
化合物（Ｉ－２－６３５）：　ＥＣ５０＝４１ｎＭ
化合物（Ｉ－２－６３６）：　ＥＣ５０＝５９ｎＭ
化合物（Ｉ－２－６３７）：　ＥＣ５０＝８４ｎＭ
化合物（Ｉ－２－６３８）：　ＥＣ５０＝９２ｎＭ
化合物（Ｉ－２－６３９）：　ＥＣ５０＝３７ｎＭ
化合物（Ｉ－２－６４０）：　ＥＣ５０＝２１６ｎＭ
化合物（Ｉ－２－６４１）：　ＥＣ５０＝２２８ｎＭ
化合物（Ｉ－２－６４２）：　ＥＣ５０＝３５７ｎＭ
化合物（Ｉ－２－６４３）：　ＥＣ５０＝２５２ｎＭ
化合物（Ｉ－２－６４４）：　ＥＣ５０＝７７ｎＭ
化合物（Ｉ－２－６４５）：　ＥＣ５０＝４７ｎＭ
化合物（Ｉ－２－６４６）：　ＥＣ５０＝１２８ｎＭ
化合物（Ｉ－２－６４７）：　ＥＣ５０＝３９ｎＭ
化合物（Ｉ－２－６４８）：　ＥＣ５０＝２０８ｎＭ
化合物（Ｉ－２－６４９）：　ＥＣ５０＝６７ｎＭ
化合物（Ｉ－２－６５０）：　ＥＣ５０＝３５９ｎＭ
化合物（Ｉ－２－６５１）：　ＥＣ５０＝４６９ｎＭ
化合物（Ｉ－２－６５２）：　ＥＣ５０＝２１０ｎＭ
化合物（Ｉ－２－６５４）：　ＥＣ５０＝９４ｎＭ
化合物（Ｉ－２－６５５）：　ＥＣ５０＝５６ｎＭ
化合物（Ｉ－２－６５６）：　ＥＣ５０＝１１ｎＭ
化合物（Ｉ－２－６５７）：　ＥＣ５０＝１３９ｎＭ
化合物（Ｉ－２－６５８）：　ＥＣ５０＝１４４ｎＭ
化合物（Ｉ－２－６５９）：　ＥＣ５０＝６８ｎＭ
化合物（Ｉ－２－６６０）：　ＥＣ５０＝３６ｎＭ
化合物（Ｉ－２－６６１）：　ＥＣ５０＝５．６ｎＭ
化合物（Ｉ－２－６６２）：　ＥＣ５０＝２８ｎＭ
化合物（Ｉ－２－６６３）：　ＥＣ５０＝１０ｎＭ
化合物（Ｉ－２－６６４）：　ＥＣ５０＝５５ｎＭ
化合物（Ｉ－２－６６５）：　ＥＣ５０＝３１ｎＭ
化合物（Ｉ－２－６６６）：　ＥＣ５０＝５６ｎＭ
化合物（Ｉ－２－６６７）：　ＥＣ５０＝２０ｎＭ
化合物（Ｉ－２－６６８）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－６８３）：　ＥＣ５０＝１８０ｎＭ
化合物（Ｉ－２－６８４）：　ＥＣ５０＝２３８ｎＭ
化合物（Ｉ－２－６８５）：　ＥＣ５０＝４９ｎＭ
化合物（Ｉ－２－６８９）：　ＥＣ５０＝９１ｎＭ
化合物（Ｉ－２－６９１）：　ＥＣ５０＝４３９ｎＭ
化合物（Ｉ－２－６９３）：　ＥＣ５０＝１０５ｎＭ
化合物（Ｉ－２－６９７）：　ＥＣ５０＝１７４ｎＭ
化合物（Ｉ－２－６９８）：　ＥＣ５０＝３０９ｎＭ
化合物（Ｉ－２－７０１）：　ＥＣ５０＝２１０ｎＭ
化合物（Ｉ－２－７０４）：　ＥＣ５０＝４７３ｎＭ
化合物（Ｉ－２－７０５）：　ＥＣ５０＝７２ｎＭ
化合物（Ｉ－２－７０６）：　ＥＣ５０＝３１７ｎＭ
化合物（Ｉ－２－７０７）：　ＥＣ５０＝４５ｎＭ
化合物（Ｉ－２－７０８）：　ＥＣ５０＝２４０ｎＭ
化合物（Ｉ－２－７０９）：　ＥＣ５０＝２６１ｎＭ
化合物（Ｉ－２－７１０）：　ＥＣ５０＝３０２ｎＭ
化合物（Ｉ－２－７１１）：　ＥＣ５０＝６２ｎＭ
化合物（Ｉ－２－７１２）：　ＥＣ５０＝４６２ｎＭ
化合物（Ｉ－２－７１４）：　ＥＣ５０＝３７５ｎＭ
化合物（Ｉ－２－７１５）：　ＥＣ５０＝２７ｎＭ
化合物（Ｉ－２－７１８）：　ＥＣ５０＝３５７ｎＭ
化合物（Ｉ－２－７１９）：　ＥＣ５０＝３９６ｎＭ
化合物（Ｉ－２－７２０）：　ＥＣ５０＝３５ｎＭ
化合物（Ｉ－２－７２２）：　ＥＣ５０＝８ｎＭ
化合物（Ｉ－２－７２３）：　ＥＣ５０＝３６２ｎＭ
化合物（Ｉ－２－７２４）：　ＥＣ５０＝４１０ｎＭ
化合物（Ｉ－２－７２５）：　ＥＣ５０＝１２７ｎＭ
化合物（Ｉ－２－７２６）：　ＥＣ５０＝６５ｎＭ
化合物（Ｉ－２－７３０）：　ＥＣ５０＝９２ｎＭ
化合物（Ｉ－２－７３９）：　ＥＣ５０＝４３０ｎＭ
化合物（Ｉ－２－７４１）：　ＥＣ５０＝４６９ｎＭ
化合物（Ｉ－２－７４２）：　ＥＣ５０＝１４０ｎＭ
化合物（Ｉ－２－７４３）：　ＥＣ５０＝１０８ｎＭ
化合物（Ｉ－２－７４５）：　ＥＣ５０＝９４ｎＭ
化合物（Ｉ－２－７４７）：　ＥＣ５０＝３０９ｎＭ
化合物（Ｉ－２－７４８）：　ＥＣ５０＝３０８ｎＭ
化合物（Ｉ－２－７５０）：　ＥＣ５０＝１８１ｎＭ
化合物（Ｉ－２－７５１）：　ＥＣ５０＝１５２ｎＭ
化合物（Ｉ－２－７５２）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－７５３）：　ＥＣ５０＝１７２ｎＭ
化合物（Ｉ－２－７５４）：　ＥＣ５０＝１５７ｎＭ
化合物（Ｉ－２－７５６）：　ＥＣ５０＝２６０ｎＭ
化合物（Ｉ－２－７５８）：　ＥＣ５０＝７０ｎＭ
化合物（Ｉ－２－７５９）：　ＥＣ５０＝１５５ｎＭ
化合物（Ｉ－２－７６４）：　ＥＣ５０＝６３ｎＭ
化合物（Ｉ－２－７６５）：　ＥＣ５０＝１４ｎＭ
化合物（Ｉ－２－７６７）：　ＥＣ５０＝１９ｎＭ
化合物（Ｉ－２－７６８）：　ＥＣ５０＝１３ｎＭ
化合物（Ｉ－２－７７０）：　ＥＣ５０＝５ｎＭ
化合物（Ｉ－２－７７２）：　ＥＣ５０＝５ｎＭ
化合物（Ｉ－２－７７３）：　ＥＣ５０＝７ｎＭ
化合物（Ｉ－２－７７４）：　ＥＣ５０＝２４７ｎＭ
化合物（Ｉ－２－７７５）：　ＥＣ５０＝１８ｎＭ
化合物（Ｉ－２－７７６）：　ＥＣ５０＝６４ｎＭ
化合物（Ｉ－２－７７７）：　ＥＣ５０＝９４ｎＭ
化合物（Ｉ－２－７７８）：　ＥＣ５０＝１７７ｎＭ
化合物（Ｉ－２－７７９）：　ＥＣ５０＝２０５ｎＭ
化合物（Ｉ－２－７８０）：　ＥＣ５０＝２０５ｎＭ
化合物（Ｉ－２－７８１）：　ＥＣ５０＝３２ｎＭ
化合物（Ｉ－２－７８２）：　ＥＣ５０＝２１０ｎＭ
化合物（Ｉ－２－７８３）：　ＥＣ５０＝５７ｎＭ
化合物（Ｉ－２－７８４）：　ＥＣ５０＝２１０ｎＭ
化合物（Ｉ－２－７８５）：　ＥＣ５０＝１１２ｎＭ
化合物（Ｉ－２－７８６）：　ＥＣ５０＝２５６ｎＭ
化合物（Ｉ－２－７８７）：　ＥＣ５０＝３２８ｎＭ
化合物（Ｉ－２－７９０）：　ＥＣ５０＝１６９ｎＭ
化合物（Ｉ－２－７９６）：　ＥＣ５０＝４４ｎＭ
化合物（Ｉ－２－８０３）：　ＥＣ５０＝３０２ｎＭ
化合物（Ｉ－２－８０６）：　ＥＣ５０＝２２３ｎＭ
化合物（Ｉ－２－８０７）：　ＥＣ５０＝２１１ｎＭ
化合物（Ｉ－２－８０８）：　ＥＣ５０＝４１０ｎＭ
化合物（Ｉ－２－８１０）：　ＥＣ５０＝２９５ｎＭ
化合物（Ｉ－２－８１１）：　ＥＣ５０＝３３８ｎＭ
化合物（Ｉ－２－８１４）：　ＥＣ５０＝１２２ｎＭ
The results of Test Example 1 are shown below.
Compound (I-1-7): EC50 = 428 nM
Compound (I-1-14): EC50 = 174 nM
Compound (I-1-15): EC50 = 413 nM
Compound (I-1-18): EC50 = 219 nM
Compound (I-1-19): EC50 = 288 nM
Compound (I-1-21): EC50 = 480 nM
Compound (I-1-22): EC50 = 130 nM
Compound (I-1-23): EC50 = 115 nM
Compound (I-1-25): EC50 = 42 nM
Compound (I-1-26): EC50 = 198 nM
Compound (I-1-29): EC50 = 82 nM
Compound (I-1-36): EC50 = 126 nM
Compound (I-1-37): EC50 = 45 nM
Compound (I-1-38): EC50 = 15 nM
Compound (I-1-42): EC50 = 292 nM
Compound (I-1-47): EC50 = 488 nM
Compound (I-1-65): EC50 = 371 nM
Compound (I-1-68): EC50 = 254 nM
Compound (I-1-148): EC50 = 405 nM
Compound (I-1-151): EC50 = 251 nM
Compound (I-1-152): EC50 = 332 nM
Compound (I-1-160): EC50 = 288 nM
Compound (I-1-161): EC50 = 318 nM
Compound (I-1-162): EC50 = 381 nM
Compound (I-1-163): EC50 = 379 nM
Compound (I-1-164): EC50 = 162 nM
Compound (I-1-165): EC50 = 470 nM
Compound (I-1-166): EC50 = 160 nM
Compound (I-1-167): EC50 = 174 nM
Compound (I-1-176): EC50 = 353 nM
Compound (I-1-190): EC50 = 244 nM
Compound (I-1-198): EC50 = 185 nM
Compound (I-1-199): EC50 = 393 nM
Compound (I-1-206): EC50 = 499 nM
Compound (I-1-210): EC50 = 189 nM
Compound (I-213): EC50 = 163 nM
Compound (I-1-214): EC50 = 113 nM
Compound (I-218): EC50 = 253 nM
Compound (I-1-219): EC50 = 144 nM
Compound (I-1-226): EC50 = 447 nM
Compound (I-1-227): EC50 = 239 nM
Compound (I-1-228): EC50 = 355 nM
Compound (I-1-229): EC50 = 338 nM
Compound (I-1-230): EC50 = 316 nM
Compound (I-1-231): EC50 = 21 nM
Compound (I-1-232): EC50 = 280 nM
Compound (I-1-236): EC50 = 214 nM
Compound (I-1-241): EC50 = 439 nM
Compound (I-1-246): EC50 = 99 nM
Compound (I-1-247): EC50 = 198 nM
Compound (I-1-248): EC50 = 381 nM
Compound (I-1-249): EC50 = 176 nM
Compound (I-1-251): EC50 = 390 nM
Compound (I-1-253): EC50 = 167 nM
Compound (I-261): EC50 = 443 nM
Compound (I-1-263): EC50 = 292 nM
Compound (I-1-264): EC50 = 223 nM
Compound (I-1-265): EC50 = 484 nM
Compound (I-1-267): EC50 = 277 nM
Compound (I-1-273): EC50 = 158 nM
Compound (I-1-274): EC50 = 439 nM
Compound (I-1-278): EC50 = 160 nM
Compound (I-1-285): EC50 = 475 nM
Compound (I-1-287): EC50 = 311 nM
Compound (I-1-290): EC50 = 127 nM
Compound (I-1-292): EC50 = 440 nM
Compound (I-1-293): EC50 = 155 nM
Compound (I-1-294): EC50 = 119 nM
Compound (I-1-298): EC50 = 261 nM
Compound (I-1-303): EC50 = 245 nM
Compound (I-1-305): EC50 = 89 nM
Compound (I-1-306): EC50 = 266 nM
Compound (I-1-310): EC50 = 299 nM
Compound (I-1-312): EC50 = 382 nM
Compound (I-1-313): EC50 = 256 nM
Compound (I-1-315): EC50 = 187 nM
Compound (I-1-317): EC50 = 330 nM
Compound (I-1-318): EC50 = 54 nM
Compound (I-1-321): EC50 = 71 nM
Compound (I-1-322): EC50 = 97 nM
Compound (I-1-323): EC50 = 216 nM
Compound (I-1-325): EC50 = 99 nM
Compound (I-1-326): EC50 = 259 nM
Compound (I-1-330): EC50 = 500 nM
Compound (I-2-12): EC50 = 177 nM
Compound (I-2-13): EC50 = 184 nM
Compound (I-2-14): EC50 = 102 nM
Compound (I-2-15): EC50 = 42 nM
Compound (I-2-16): EC50 = 343 nM
Compound (I-2-17): EC50 = 50 nM
Compound (I-2-18): EC50 = 62 nM
Compound (I-2-19): EC50 = 46 nM
Compound (I-2-20): EC50 = 138 nM
Compound (I-2-22): EC50 = 260 nM
Compound (I-2-23): EC50 = 238 nM
Compound (I-2-25): EC50 = 346 nM
Compound (I-2-27): EC50 = 413 nM
Compound (I-2-28): EC50 = 175 nM
Compound (I-2-29): EC50 = 132 nM
Compound (I-2-30): EC50 = 167 nM
Compound (I-2-32): EC50 = 212 nM
Compound (I-2-33): EC50 = 166 nM
Compound (I-2-34): EC50 = 307 nM
Compound (I-2-37): EC50 = 189 nM
Compound (I-2-43): EC50 = 499 nM
Compound (I-2-51): EC50 = 206 nM
Compound (I-2-52): EC50 = 82 nM
Compound (I-2-54): EC50 = 419 nM
Compound (I-2-55): EC50 = 231 nM
Compound (I-2-59): EC50 = 28 nM
Compound (I-2-60): EC50 = 14 nM
Compound (I-2-61): EC50 = <1.5 nM
Compound (I-2-62): EC50 = 31 nM
Compound (I-2-63): EC50 = 28 nM
Compound (I-2-64): EC50 = 9.9 nM
Compound (I-2-65): EC50 = 12 nM
Compound (I-2-66): EC50 = 23 nM
Compound (I-2-68): EC50 = 36 nM
Compound (I-2-69): EC50 = 116 nM
Compound (I-2-70): EC50 = 14 nM
Compound (I-2-72): EC50 = 101 nM
Compound (I-2-74): EC50 = 453 nM
Compound (I-2-75): EC50 = 226 nM
Compound (I-2-76): EC50 = 130 nM
Compound (I-2-83): EC50 = 17 nM
Compound (I-2-84): EC50 = 110 nM
Compound (I-2-85): EC50 = 122 nM
Compound (I-2-86): EC50 = 105 nM
Compound (I-2-87): EC50 = 191 nM
Compound (I-2-88): EC50 = 226 nM
Compound (I-2-89): EC50 = 185 nM
Compound (I-2-90): EC50 = 289 nM
Compound (I-2-91): EC50 = 294 nM
Compound (I-2-92): EC50 = 148 nM
Compound (I-2-93): EC50 = 181 nM
Compound (I-2-94): EC50 = 460 nM
Compound (I-2-95): EC50 = 102 nM
Compound (I-2-96): EC50 = 207 nM
Compound (I-2-97): EC50 = 36 nM
Compound (I-2-101): EC50 = 355 nM
Compound (I-2-103): EC50 = 303 nM
Compound (I-2-104): EC50 = 212 nM
Compound (I-2-106): EC50 = 318 nM
Compound (I-2-107): EC50 = 280 nM
Compound (I-2-108): EC50 = 384 nM
Compound (I-2-112): EC50 = 154 nM
Compound (I-2-113): EC50 = 4 nM
Compound (I-2-119): EC50 = 407 nM
Compound (I-2-121): EC50 = 35 nM
Compound (I-2-124): EC50 = 190 nM
Compound (I-2-125): EC50 = 298 nM
Compound (I-2-126): EC50 = 232 nM
Compound (I-2-127): EC50 = 156 nM
Compound (I-2-128): EC50 = 308 nM
Compound (I-2-129): EC50 = 210 nM
Compound (I-2-130): EC50 = 171 nM
Compound (I-2-131): EC50 = 311 nM
Compound (I-2-132): EC50 = 323 nM
Compound (I-2-133): EC50 = 92 nM
Compound (I-2-135): EC50 = 129 nM
Compound (I-2-136): EC50 = 324 nM
Compound (I-2-137): EC50 = 401 nM
Compound (I-2-139): EC50 = 183 nM
Compound (I-2-140): EC50 = 184 nM
Compound (I-2-142): EC50 = 218 nM
Compound (I-2-144): EC50 = 158 nM
Compound (I-2-145): EC50 = 214 nM
Compound (I-2-146): EC50 = 253 nM
Compound (I-2-147): EC50 = 209 nM
Compound (I-2-148): EC50 = 209 nM
Compound (I-2-149): EC50 = 232 nM
Compound (I-2-150): EC50 = 234 nM
Compound (I-2-151): EC50 = 336 nM
Compound (I-2-152): EC50 = 218 nM
Compound (I-2-153): EC50 = 254 nM
Compound (I-2-154): EC50 = 419 nM
Compound (I-2-155): EC50 = 326 nM
Compound (I-2-156): EC50 = 358 nM
Compound (I-2-157): EC50 = 18 nM
Compound (I-2-158): EC50 = 40 nM
Compound (I-2-159): EC50 = 69 nM
Compound (I-2-160): EC50 = 25 nM
Compound (I-2-161): EC50 = 41 nM
Compound (I-2-162): EC50 = 7 nM
Compound (I-2-163): EC50 = 23 nM
Compound (I-2-164): EC50 = 23 nM
Compound (I-2-165): EC50 = 21 nM
Compound (I-2-166): EC50 = 60 nM
Compound (I-2-167): EC50 = 25 nM
Compound (I-2-168): EC50 = 11 nM
Compound (I-2-169): EC50 = 20 nM
Compound (I-2-170): EC50 = 13 nM
Compound (I-2-171): EC50 = 44 nM
Compound (I-2-172): EC50 = 7 nM
Compound (I-2-173): EC50 = 46 nM
Compound (I-2-174): EC50 = 95 nM
Compound (I-2-175): EC50 = 5 nM
Compound (I-2-176): EC50 = 8 nM
Compound (I-2-177): EC50 = 38 nM
Compound (I-2-178): EC50 = 106 nM
Compound (I-2-179): EC50 = 18 nM
Compound (I-2-180): EC50 = 7.9 nM
Compound (I-2-181): EC50 = 43 nM
Compound (I-2-182): EC50 = 68 nM
Compound (I-2-183): EC50 = 381 nM
Compound (I-2-184): EC50 = 40 nM
Compound (I-2-185): EC50 = 9.1 nM
Compound (I-2-186): EC50 = 23 nM
Compound (I-2-187): EC50 = 8.5 nM
Compound (I-2-188): EC50 = 12 nM
Compound (I-2-189): EC50 = 96 nM
Compound (I-2-190): EC50 = 35 nM
Compound (I-2-191): EC50 = 163 nM
Compound (I-2-192): EC50 = 78 nM
Compound (I-2-193): EC50 = 171 nM
Compound (I-2-194): EC50 = 32 nM
Compound (I-2-195): EC50 = 41 nM
Compound (I-2-196): EC50 = 148 nM
Compound (I-2-197): EC50 = 34 nM
Compound (I-2-198): EC50 = 70 nM
Compound (I-2-199): EC50 = 31 nM
Compound (I-2-200): EC50 = 32 nM
Compound (I-2-201): EC50 = 45 nM
Compound (I-2-202): EC50 = 261 nM
Compound (I-2-203): EC50 = 46 nM
Compound (I-2-204): EC50 = 30 nM
Compound (I-2-205): EC50 = 156 nM
Compound (I-2-206): EC50 = 76 nM
Compound (I-2-207): EC50 = 9 nM
Compound (I-2-208): EC50 = 53 nM
Compound (I-2-209): EC50 = 31 nM
Compound (I-2-210): EC50 = 16 nM
Compound (I-2-211): EC50 = 57 nM
Compound (I-2-212): EC50 = 23 nM
Compound (I-2-214): EC50 = 50 nM
Compound (I-2-215): EC50 = 93 nM
Compound (I-2-216): EC50 = 102 nM
Compound (I-2-217): EC50 = 108 nM
Compound (I-2-218): EC50 = 202 nM
Compound (I-2-219): EC50 = 18 nM
Compound (I-2-220): EC50 = 125 nM
Compound (I-2-221): EC50 = 113 nM
Compound (I-222): EC50 = 128 nM
Compound (I-2-223): EC50 = 6.6 nM
Compound (I-2-224): EC50 = 121 nM
Compound (I-2-225): EC50 = 31 nM
Compound (I-2-226): EC50 = 75 nM
Compound (I-2-227): EC50 = 251 nM
Compound (I-2-228): EC50 = 39 nM
Compound (I-2-229): EC50 = 131 nM
Compound (I-2-230): EC50 = 57 nM
Compound (I-2-231): EC50 = 77 nM
Compound (I-2-232): EC50 = 195 nM
Compound (I-2-233): EC50 = 44 nM
Compound (I-2-234): EC50 = 78 nM
Compound (I-2-235): EC50 = 24 nM
Compound (I-2-236): EC50 = 73 nM
Compound (I-2-237): EC50 = 110 nM
Compound (I-2-238): EC50 = 142 nM
Compound (I-2-239): EC50 = 60 nM
Compound (I-2-240): EC50 = 25 nM
Compound (I-2-241): EC50 = 21 nM
Compound (I-2-242): EC50 = 161 nM
Compound (I-2-243): EC50 = 34 nM
Compound (I-2-244): EC50 = 37 nM
Compound (I-2-245): EC50 = 224 nM
Compound (I-2-246): EC50 = 48 nM
Compound (I-2-247): EC50 = 121 nM
Compound (I-2-248): EC50 = 42 nM
Compound (I-2-249): EC50 = 78 nM
Compound (I-2-250): EC50 = 187 nM
Compound (I-2-251): EC50 = 119 nM
Compound (I-2-252): EC50 = 206 nM
Compound (I-2-253): EC50 = 57 nM
Compound (I-2-254): EC50 = 198 nM
Compound (I-2-255): EC50 = 431 nM
Compound (I-2-256): EC50 = 84 nM
Compound (I-2-257): EC50 = 121 nM
Compound (I-2-258): EC50 = 57 nM
Compound (I-2-259): EC50 = 106 nM
Compound (I-2-260): EC50 = 87 nM
Compound (I-2-261): EC50 = 73 nM
Compound (I-2-262): EC50 = 189 nM
Compound (I-2-263): EC50 = 101 nM
Compound (I-2-264): EC50 = 155 nM
Compound (I-2-265): EC50 = 147 nM
Compound (I-2-266): EC50 = 116 nM
Compound (I-2-267): EC50 = 43 nM
Compound (I-2-268): EC50 = 36 nM
Compound (I-2-269): EC50 = 148 nM
Compound (I-2-270): EC50 = 58 nM
Compound (I-2-271): EC50 = 36 nM
Compound (I-2-272): EC50 = 42 nM
Compound (I-2-273): EC50 = 113 nM
Compound (I-2-274): EC50 = 137 nM
Compound (I-2-275): EC50 = 95 nM
Compound (I-2-276): EC50 = 424 nM
Compound (I-2-277): EC50 = 133 nM
Compound (I-2-278): EC50 = 312 nM
Compound (I-2-279): EC50 = 83 nM
Compound (I-2-280): EC50 = 148 nM
Compound (I-2-281): EC50 = 45 nM
Compound (I-2-282): EC50 = 118 nM
Compound (I-2-283): EC50 = 33 nM
Compound (I-2-284): EC50 = 82 nM
Compound (I-2-285): EC50 = 30 nM
Compound (I-2-286): EC50 = 30 nM
Compound (I-2-287): EC50 = 115 nM
Compound (I-2-288): EC50 = 97 nM
Compound (I-2-289): EC50 = 23 nM
Compound (I-2-290): EC50 = 82 nM
Compound (I-2-291): EC50 = 93 nM
Compound (I-2-292): EC50 = 310 nM
Compound (I-2-293): EC50 = 96 nM
Compound (I-2-294): EC50 = 55 nM
Compound (I-2-295): EC50 = 34 nM
Compound (I-2-296): EC50 = 7.1 nM
Compound (I-2-297): EC50 = 7.5 nM
Compound (I-2-298): EC50 = 25 nM
Compound (I-2-299): EC50 = 26 nM
Compound (I-2-300): EC50 = 126 nM
Compound (I-2-301): EC50 = 14 nM
Compound (I-2-302): EC50 = 7.9 nM
Compound (I-2-303): EC50 = 83 nM
Compound (I-2-304): EC50 = 84 nM
Compound (I-2-305): EC50 = 69 nM
Compound (I-2-306): EC50 = 69 nM
Compound (I-2-307): EC50 = 21 nM
Compound (I-2-308): EC50 = 25 nM
Compound (I-2-309): EC50 = 25 nM
Compound (I-2-310): EC50 = 19 nM
Compound (I-2-311): EC50 = 32 nM
Compound (I-2-312): EC50 = 26 nM
Compound (I-2-313): EC50 = 31 nM
Compound (I-2-314): EC50 = 79 nM
Compound (I-2-315): EC50 = 56 nM
Compound (I-2-316): EC50 = 6 nM
Compound (I-2-318): EC50 = 16 nM
Compound (I-2-319): EC50 = 135 nM
Compound (I-2-320): EC50 = 102 nM
Compound (I-2-321): EC50 = 51 nM
Compound (I-2-322): EC50 = 15 nM
Compound (I-2-323): EC50 = 22 nM
Compound (I-2-324): EC50 = 17 nM
Compound (I-2-325): EC50 = 29 nM
Compound (I-2-326): EC50 = 16 nM
Compound (I-2-327): EC50 = 12 nM
Compound (I-2-328): EC50 = 439 nM
Compound (I-2-329): EC50 = 19 nM
Compound (I-2-330): EC50 = 21 nM
Compound (I-2-331): EC50 = 68 nM
Compound (I-2-332): EC50 = 61 nM
Compound (I-2-334): EC50 = 35 nM
Compound (I-2-336): EC50 = 330 nM
Compound (I-2-337): EC50 = 140 nM
Compound (I-2-338): EC50 = 79 nM
Compound (I-2-339): EC50 = 100 nM
Compound (I-2-340): EC50 = 130 nM
Compound (I-2-341): EC50 = 60 nM
Compound (I-2-342): EC50 = 6.5 nM
Compound (I-2-343): EC50 = 47 nM
Compound (I-2-344): EC50 = 22 nM
Compound (I-2-345): EC50 = 15 nM
Compound (I-2-346): EC50 = 262 nM
Compound (I-2-347): EC50 = 83 nM
Compound (I-2-348): EC50 = 10 nM
Compound (I-2-349): EC50 = <1.5 nM
Compound (I-2-350): EC50 = 35 nM
Compound (I-2-351): EC50 = 64 nM
Compound (I-2-352): EC50 = 85 nM
Compound (I-2-353): EC50 = 13 nM
Compound (I-2-356): EC50 = 12 nM
Compound (I-2-357): EC50 = 19 nM
Compound (I-2-358): EC50 = 7.5 nM
Compound (I-2-359): EC50 = 11 nM
Compound (I-2-360): EC50 = 8.4 nM
Compound (I-2-361): EC50 = 15 nM
Compound (I-2-362): EC50 = 7.1 nM
Compound (I-2-363): EC50 = 5.9 nM
Compound (I-2-364): EC50 = 80 nM
Compound (I-2-365): EC50 = 135 nM
Compound (I-2-366): EC50 = 52 nM
Compound (I-2-367): EC50 = 26 nM
Compound (I-2-368): EC50 = 62 nM
Compound (I-2-369): EC50 = 80 nM
Compound (I-2-370): EC50 = 36 nM
Compound (I-2-371): EC50 = 18 nM
Compound (I-2-372): EC50 = 1.0 nM
Compound (I-2-373): EC50 = 21 nM
Compound (I-2-374): EC50 = 33 nM
Compound (I-2-375): EC50 = 34 nM
Compound (I-2-376): EC50 = 246 nM
Compound (I-2-377): EC50 = 158 nM
Compound (I-2-378): EC50 = 52 nM
Compound (I-2-379): EC50 = 18 nM
Compound (I-2-380): EC50 = 52 nM
Compound (I-2-381): EC50 = 98 nM
Compound (I-2-382): EC50 = 11 nM
Compound (I-2-383): EC50 = 16 nM
Compound (I-2-384): EC50 = 22 nM
Compound (I-2-385): EC50 = 26 nM
Compound (I-2-386): EC50 = 21 nM
Compound (I-2-387): EC50 = 23 nM
Compound (I-2-388): EC50 = 18 nM
Compound (I-2-389): EC50 = 131 nM
Compound (I-2-390): EC50 = 31 nM
Compound (I-2-391): EC50 = 37 nM
Compound (I-2-392): EC50 = 20 nM
Compound (I-2-393): EC50 = 18 nM
Compound (I-2-394): EC50 = 378 nM
Compound (I-2-395): EC50 = 165 nM
Compound (I-2-396): EC50 = 131 nM
Compound (I-2-397): EC50 = 3 nM
Compound (I-2-398): EC50 = 12 nM
Compound (I-2-399): EC50 = 7.6 nM
Compound (I-2-400): EC50 = 3.9 nM
Compound (I-2-401): EC50 = 136 nM
Compound (I-2-402): EC50 = 72 nM
Compound (I-2-403): EC50 = 21 nM
Compound (I-2-404): EC50 = 12 nM
Compound (I-2-405): EC50 = 110 nM
Compound (I-2-406): EC50 = 49 nM
Compound (I-2-407): EC50 = 30 nM
Compound (I-2-408): EC50 = 299 nM
Compound (I-2-409): EC50 = 100 nM
Compound (I-2-410): EC50 = 4.9 nM
Compound (I-2-411): EC50 = 13 nM
Compound (I-2-412): EC50 = 17 nM
Compound (I-2-413): EC50 = 7.1 nM
Compound (I-2-414): EC50 = 146 nM
Compound (I-2-415): EC50 = 20 nM
Compound (I-2-416): EC50 = 24 nM
Compound (I-2-419): EC50 = 11 nM
Compound (I-2-420): EC50 = 31 nM
Compound (I-2-421): EC50 = 120 nM
Compound (I-2-422): EC50 = 22 nM
Compound (I-2-423): EC50 = 39 nM
Compound (I-2-424): EC50 = 191 nM
Compound (I-2-425): EC50 = 13 nM
Compound (I-2-426): EC50 = 158 nM
Compound (I-2-427): EC50 = 115 nM
Compound (I-2-428): EC50 = 64 nM
Compound (I-2-429): EC50 = 17 nM
Compound (I-2-430): EC50 = 271 nM
Compound (I-2-431): EC50 = 23 nM
Compound (I-2-432): EC50 = 24 nM
Compound (I-2-433): EC50 = 53 nM
Compound (I-2-434): EC50 = 141 nM
Compound (I-2-435): EC50 = 73 nM
Compound (I-2-436): EC50 = 336 nM
Compound (I-2-437): EC50 = 229 nM
Compound (I-2-438): EC50 = 19 nM
Compound (I-2-439): EC50 = 124 nM
Compound (I-2-440): EC50 = 157 nM
Compound (I-2-441): EC50 = 302 nM
Compound (I-2-442): EC50 = 233 nM
Compound (I-2-443): EC50 = 39 nM
Compound (I-2-444): EC50 = 95 nM
Compound (I-2-446): EC50 = 108 nM
Compound (I-2-453): EC50 = 136 nM
Compound (I-2-457): EC50 = 204 nM
Compound (I-2-459): EC50 = 66 nM
Compound (I-2-462): EC50 = 61 nM
Compound (I-2-470): EC50 = 30 nM
Compound (I-2-471): EC50 = 118 nM
Compound (I-2-482): EC50 = 32 nM
Compound (I-2-483): EC50 = 447 nM
Compound (I-2-488): EC50 = 27 nM
Compound (I-2-489): EC50 = 19 nM
Compound (I-2-490): EC50 = 34 nM
Compound (I-2-491): EC50 = 19 nM
Compound (I-2-492): EC50 = 20 nM
Compound (I-2-493): EC50 = 49 nM
Compound (I-2-494): EC50 = 18 nM
Compound (I-2-495): EC50 = 29 nM
Compound (I-2-496): EC50 = 14 nM
Compound (I-2-497): EC50 = 15 nM
Compound (I-2-498): EC50 = 234 nM
Compound (I-2-499): EC50 = 450 nM
Compound (I-2-500): EC50 = 29 nM
Compound (I-2-501): EC50 = 23 nM
Compound (I-2-502): EC50 = 264 nM
Compound (I-2-503): EC50 = 347 nM
Compound (I-2-504): EC50 = 39 nM
Compound (I-2-505): EC50 = 127 nM
Compound (I-2-506): EC50 = 50 nM
Compound (I-2-507): EC50 = 113 nM
Compound (I-2-508): EC50 = 13 nM
Compound (I-2-509): EC50 = 32 nM
Compound (I-2-510): EC50 = 28 nM
Compound (I-2-512): EC50 = 242 nM
Compound (I-2-1): EC50 = 49 nM
Compound (I-2-513): EC50 = 140 nM
Compound (I-2-514): EC50 = 296 nM
Compound (I-2-515): EC50 = 79 nM
Compound (I-2-516): EC50 = 6.7 nM
Compound (I-2-518): EC50 = 18 nM
Compound (I-2-519): EC50 = 109 nM
Compound (I-2-520): EC50 = 82 nM
Compound (I-2-521): EC50 = 8.5 nM
Compound (I-2-522): EC50 = 11 nM
Compound (I-2-2): EC50 = 55 nM
Compound (I-2-3): EC50 = 16 nM
Compound (I-2-523): EC50 = 29 nM
Compound (I-2-525): EC50 = 382 nM
Compound (I-2-526): EC50 = 276 nM
Compound (I-2-527): EC50 = 174 nM
Compound (I-2-528): EC50 = 99 nM
Compound (I-2-529): EC50 = 27 nM
Compound (I-2-530): EC50 = 39 nM
Compound (I-2-531): EC50 = 46 nM
Compound (I-2-532): EC50 = 151 nM
Compound (I-2-533): EC50 = 43 nM
Compound (I-2-534): EC50 = 220 nM
Compound (I-2-535): EC50 = 69 nM
Compound (I-2-536): EC50 = 140 nM
Compound (I-2-538): EC50 = 59 nM
Compound (I-2-4): EC50 = 41 nM
Compound (I-2-539): EC50 = 164 nM
Compound (I-2-540): EC50 = 8.7 nM
Compound (I-2-541): EC50 = 23 nM
Compound (I-2-542): EC50 = 11 nM
Compound (I-2-543): EC50 = 48 nM
Compound (I-2-544): EC50 = 35 nM
Compound (I-2-5): EC50 = 19 nM
Compound (I-2-546): EC50 = 22 nM
Compound (I-2-7): EC50 = 207 nM
Compound (I-2-547): EC50 = 12 nM
Compound (I-2-548): EC50 = 13 nM
Compound (I-2-549): EC50 = 41 nM
Compound (I-2-550): EC50 = 64 nM
Compound (I-2-552): EC50 = 21 nM
Compound (I-2-8): EC50 = 55 nM
Compound (I-2-553): EC50 = 35 nM
Compound (I-2-554): EC50 = 15 nM
Compound (I-2-555): EC50 = 19 nM
Compound (I-2-556): EC50 = 85 nM
Compound (I-2-557): EC50 = 30 nM
Compound (I-2-558): EC50 = 11 nM
Compound (I-2-559): EC50 = 173 nM
Compound (I-2-560): EC50 = 47 nM
Compound (I-2-561): EC50 = 40 nM
Compound (I-2-562): EC50 = 87 nM
Compound (I-2-563): EC50 = 114 nM
Compound (I-2-564): EC50 = 109 nM
Compound (I-2-565): EC50 = 86 nM
Compound (I-2-566): EC50 = 429 nM
Compound (I-2-567): EC50 = 72 nM
Compound (I-2-568): EC50 = 138 nM
Compound (I-2-569): EC50 = 156 nM
Compound (I-2-571): EC50 = 345 nM
Compound (I-2-572): EC50 = 72 nM
Compound (I-2-576): EC50 = 36 nM
Compound (I-2-577): EC50 = 410 nM
Compound (I-2-578): EC50 = 68 nM
Compound (I-2-580): EC50 = 20 nM
Compound (I-2-583): EC50 = 53 nM
Compound (I-2-584): EC50 = 68 nM
Compound (I-2-585): EC50 = 186 nM
Compound (I-2-586): EC50 = 304 nM
Compound (I-2-587): EC50 = 67 nM
Compound (I-2-588): EC50 = 155 nM
Compound (I-2-589): EC50 = 319 nM
Compound (I-2-590): EC50 = 94 nM
Compound (I-2-591): EC50 = 408 nM
Compound (I-2-593): EC50 = 183 nM
Compound (I-2-594): EC50 = 22 nM
Compound (I-2-604): EC50 = 297 nM
Compound (I-2-611): EC50 = 426 nM
Compound (I-2-616): EC50 = 340 nM
Compound (I-2-619): EC50 = 393 nM
Compound (I-2-620): EC50 = 25 nM
Compound (I-2-621): EC50 = 16 nM
Compound (I-2-624): EC50 = 62 nM
Compound (I-2-625): EC50 = 23 nM
Compound (I-2-629): EC50 = 207 nM
Compound (I-2-630): EC50 = 300 nM
Compound (I-2-631): EC50 = 129 nM
Compound (I-2-632): EC50 = 208 nM
Compound (I-2-633): EC50 = 102 nM
Compound (I-2-634): EC50 = 59 nM
Compound (I-2-635): EC50 = 41 nM
Compound (I-2-636): EC50 = 59 nM
Compound (I-2-637): EC50 = 84 nM
Compound (I-2-638): EC50 = 92 nM
Compound (I-2-639): EC50 = 37 nM
Compound (I-2-640): EC50 = 216 nM
Compound (I-2-641): EC50 = 228 nM
Compound (I-2-642): EC50 = 357 nM
Compound (I-2-643): EC50 = 252 nM
Compound (I-2-644): EC50 = 77 nM
Compound (I-2-645): EC50 = 47 nM
Compound (I-2-646): EC50 = 128 nM
Compound (I-2-647): EC50 = 39 nM
Compound (I-2-648): EC50 = 208 nM
Compound (I-2-649): EC50 = 67 nM
Compound (I-2-650): EC50 = 359 nM
Compound (I-2-651): EC50 = 469 nM
Compound (I-2-652): EC50 = 210 nM
Compound (I-2-654): EC50 = 94 nM
Compound (I-2-655): EC50 = 56 nM
Compound (I-2-656): EC50 = 11 nM
Compound (I-2-657): EC50 = 139 nM
Compound (I-2-658): EC50 = 144 nM
Compound (I-2-659): EC50 = 68 nM
Compound (I-2-660): EC50 = 36 nM
Compound (I-2-661): EC50 = 5.6 nM
Compound (I-2-662): EC50 = 28 nM
Compound (I-2-663): EC50 = 10 nM
Compound (I-2-664): EC50 = 55 nM
Compound (I-2-665): EC50 = 31 nM
Compound (I-2-666): EC50 = 56 nM
Compound (I-2-667): EC50 = 20 nM
Compound (I-2-668): EC50 = 18 nM
Compound (I-2-683): EC50 = 180 nM
Compound (I-2-684): EC50 = 238 nM
Compound (I-2-685): EC50 = 49 nM
Compound (I-2-689): EC50 = 91 nM
Compound (I-2-691): EC50 = 439 nM
Compound (I-2-693): EC50 = 105 nM
Compound (I-2-697): EC50 = 174 nM
Compound (I-2-698): EC50 = 309 nM
Compound (I-2-701): EC50 = 210 nM
Compound (I-2-704): EC50 = 473 nM
Compound (I-2-705): EC50 = 72 nM
Compound (I-2-706): EC50 = 317 nM
Compound (I-2-707): EC50 = 45 nM
Compound (I-2-708): EC50 = 240 nM
Compound (I-2-709): EC50 = 261 nM
Compound (I-2-710): EC50 = 302 nM
Compound (I-2-711): EC50 = 62 nM
Compound (I-2-712): EC50 = 462 nM
Compound (I-2-714): EC50 = 375 nM
Compound (I-2-715): EC50 = 27 nM
Compound (I-2-718): EC50 = 357 nM
Compound (I-2-719): EC50 = 396 nM
Compound (I-2-720): EC50 = 35 nM
Compound (I-2-722): EC50 = 8 nM
Compound (I-2-723): EC50 = 362 nM
Compound (I-2-724): EC50 = 410 nM
Compound (I-2-725): EC50 = 127 nM
Compound (I-2-726): EC50 = 65 nM
Compound (I-2-730): EC50 = 92 nM
Compound (I-2-739): EC50 = 430 nM
Compound (I-2-741): EC50 = 469 nM
Compound (I-2-742): EC50 = 140 nM
Compound (I-2-743): EC50 = 108 nM
Compound (I-2-745): EC50 = 94 nM
Compound (I-2-747): EC50 = 309 nM
Compound (I-2-748): EC50 = 308 nM
Compound (I-2-750): EC50 = 181 nM
Compound (I-2-751): EC50 = 152 nM
Compound (I-2-752): EC50 = 13 nM
Compound (I-2-753): EC50 = 172 nM
Compound (I-2-754): EC50 = 157 nM
Compound (I-2-756): EC50 = 260 nM
Compound (I-2-758): EC50 = 70 nM
Compound (I-2-759): EC50 = 155 nM
Compound (I-2-764): EC50 = 63 nM
Compound (I-2-765): EC50 = 14 nM
Compound (I-2-767): EC50 = 19 nM
Compound (I-2-768): EC50 = 13 nM
Compound (I-2-770): EC50 = 5 nM
Compound (I-2-772): EC50 = 5 nM
Compound (I-2-773): EC50 = 7 nM
Compound (I-2-774): EC50 = 247 nM
Compound (I-2-775): EC50 = 18 nM
Compound (I-2-776): EC50 = 64 nM
Compound (I-2-777): EC50 = 94 nM
Compound (I-2-778): EC50 = 177 nM
Compound (I-2-779): EC50 = 205 nM
Compound (I-2-780): EC50 = 205 nM
Compound (I-2-781): EC50 = 32 nM
Compound (I-2-782): EC50 = 210 nM
Compound (I-2-783): EC50 = 57 nM
Compound (I-2-784): EC50 = 210 nM
Compound (I-2-785): EC50 = 112 nM
Compound (I-2-786): EC50 = 256 nM
Compound (I-2-787): EC50 = 328 nM
Compound (I-2-790): EC50 = 169 nM
Compound (I-2-796): EC50 = 44 nM
Compound (I-2-803): EC50 = 302 nM
Compound (I-2-806): EC50 = 223 nM
Compound (I-2-807): EC50 = 211 nM
Compound (I-2-808): EC50 = 410 nM
Compound (I-2-810): EC50 = 295 nM
Compound (I-2-811): EC50 = 338 nM
Compound (I-2-814): EC50 = 122 nM
　なお、本発明化合物は、試験例１に示すようにＧＰＲ１１９アゴニスト作用を有し、優れた薬効の持続性を示す。薬効の持続性については、以下の試験により調べた。
（試験例２）
経口耐糖能試験
　雄性Ｃ５７ＢＬ／６Ｊマウス（８～１０週齢、日本クレア）に、対照群には２０％ヒドロキシプロピル-β-シクロデキストリン水溶液を１０ｍL／ｋｇの割合で、化合物群には２０％ヒドロキシプロピル-β-シクロデキストリン水溶液に懸濁した化合物を１～３０ｍｇ／ｋｇの用量で経口投与し、１２～１４時間後に２ｇ／ｋｇのグルコース水溶液を経口投与した。グルコース投与直前（０分）および投与後２０、４０、６０、１２０分に尾静脈から採血を行い、血糖値をグルコカード（アークレイ）にて測定した。グルコース投与直前から投与後１２０分までの血糖値変化量を血糖値‐時間曲線下面積（ＡＵＣ）として台形法により算出した。対照群のＡＵＣを１００％とし、化合物群のＡＵＣを変化率として算出した。 The compound of the present invention has a GPR119 agonist activity as shown in Test Example 1, and exhibits excellent drug efficacy. The durability of the drug effect was examined by the following test.
(Test Example 2)
Oral glucose tolerance test Male C57BL / 6J mice (8-10 weeks old, CLEA Japan, Inc.), 20% hydroxypropyl-β-cyclodextrin aqueous solution in the control group at a rate of 10 mL / kg, and 20% hydroxy in the compound group A compound suspended in a propyl-β-cyclodextrin aqueous solution was orally administered at a dose of 1 to 30 mg / kg, and after 12 to 14 hours, a 2 g / kg aqueous glucose solution was orally administered. Blood was collected from the tail vein immediately before administration of glucose (0 minutes) and 20, 40, 60, and 120 minutes after administration, and blood glucose levels were measured with a glucocard (ARKRAY). The amount of change in blood glucose level from immediately before glucose administration to 120 minutes after administration was calculated as the area under the blood glucose level-time curve (AUC) by the trapezoidal method. The AUC of the control group was taken as 100%, and the AUC of the compound group was calculated as the rate of change.
　医薬としての有用性については、以下の試験などで調べた。 The usefulness as a medicine was examined by the following tests.
試験例３：ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による本発明化合物のＣＹＰ３Ａ４阻害の増強を調べる試験である。ＣＹＰ３Ａ４酵素（大腸菌発現酵素）により７－ベンジルオキシトリフルオロメチルクマリン（７－ＢＦＣ）が脱ベンジル化されて、蛍光を発する代謝物７－ハイドロキシトリフルオロメチルクマリン（７－ＨＦＣ）が生じる。７－ＨＦＣ生成反応を指標としてＣＹＰ３Ａ４阻害を評価した。 Test Example 3: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition was evaluated using 7-HFC production reaction as an index.
　反応条件は以下のとおり：基質、５．６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ、反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；本発明化合物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止した。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始した。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止した。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定した。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ） The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction was stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed. (Ex = 420nm, Em = 535nm)
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。ＩＣ５０値の差が５μｍｏｌ／Ｌ以上の場合を（＋）とし、３μｍｏｌ／Ｌ以下の場合を（－）とした。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. The IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 μmol / L or more was designated as (+), and the case where it was 3 μmol / L or less was designated as (−).
試験例４：ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価した。 Test Example 4: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始した。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止した。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量した。 As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction Started. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。 The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. Calculated.
試験例５：ＦＡＴ試験
　凍結保存しているネズミチフス菌（Salmonella typhimurium TA98株、TA100株）20 μLを10 mL液体栄養培地（2.5% Oxoid nutrient broth No.2）に接種し37℃にて10 時間、振盪前培養した。TA98株は9mLの菌液を遠心（2000×g、10 分間）して培養液を除去し、9mLのMicro F緩衝液(K2HPO4：3.5 g/L、 KH2PO4：1 g/L、 (NH4)2SO4：1g/L、 クエン酸三ナトリウム二水和物：0.25 g/L、 MgSO4・7H20：0.1g/L)に菌を懸濁し、110 mLのExposure培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、 グルコース：8 mg/mLを含むMicroF緩衝液)に添加し、TA100株は3.16mL菌液に対しExposure培地120mLに添加し試験菌液を調製した。被験物質DMSO溶液（最高用量50mg/mLから2倍公比で8段階希釈)、陰性対照としてDMSO、陽性対照として非代謝活性化条件ではTA98株に対しては50 μg/mLの4-ニトロキノリン-1-オキシドDMSO溶液、 TA100株に対しては0.25 μg/mLの2-(2-フリル)-3-(5-ニトロ-2-フリル)アクリルアミド DMSO溶液、 代謝活性化条件ではTA98株に対して40μg/mLの2-アミノアントラセンDMSO溶液、 TA100株に対しては20 μg/mLの2-アミノアントラセンDMSO溶液それぞれ12 μL と試験菌液588μL（代謝活性化条件では試験菌液498 μLとS9 mix 90 μLの混合液）を混和し、37℃にて90分間、振盪培養した。被験物質を暴露した菌液460 μLを、Indicator培地(ビオチン：8 μg/mL、ヒスチジン：0.2 μg/mL、グルコース：8 mg/mL、ブロモクレゾールパープル：37.5 μg/mLを含むMicroF緩衝液)2300μLに混和し50 μLずつマイクロプレート48ウェル/用量に分注し、37℃にて 3日間、 静置培養した。アミノ酸(ヒスチジン)合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、pH変化により紫色から黄色に変色するため、1用量あたり48ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価した。変異原性が陰性のものを（－）、陽性のものを（＋）として示した。 Test Example 5: FAT test 20 ml of Salmonella typhimurium TA98 strain, TA100 strain frozen and stored in 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) at 37 ° C for 10 hours, Incubated before shaking. For TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L), 110 mL of Exposure Add to medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: MicroF buffer containing 8 mg / mL), TA100 strain to 3.16 mL bacterial solution, add 120 mL of exposure medium to test medium Was prepared. Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 μg / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 μg / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 μg / mL 2-aminoanthracene DMSO solution each 12 μL and test bacterial solution 588 μL (under metabolic activation conditions, test bacterial solution 498 μL and S9 mix 90 μL of the mixture), and cultured with shaking at 37 ° C. for 90 minutes. 2300 μL of 460 μL of bacterial solution exposed to the test substance in Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) 50 μL aliquots were dispensed into 48 wells / dose of the microplate and incubated at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutations in the amino acid (histidine) synthase gene turn from purple to yellow due to pH change, count the number of bacterial growth wells that turn yellow in 48 wells per dose. Evaluation was made in comparison with the negative control group. The negative mutagenicity was indicated as (−), and the positive one was indicated as (+).
試験例６：溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定した。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液６　μＬをｐＨ６．８人工腸液（０．２ｍｏｌ／Ｌ　リン酸二水素カリウム試液　２５０ｍＬに０．２ｍｏｌ／Ｌ　ＮａＯＨ試液１１８ｍＬ、水を加えて１０００ｍＬとした）５９４μＬに添加した。２５℃で１６時間静置させた後、混液を吸引濾過した。濾液をメタノール／水＝１／１（Ｖ／Ｖ）にて２倍希釈し、絶対検量線法によりＨＰＬＣまたはＬＣ／ＭＳ／ＭＳを用いて濾液中濃度を測定した。
Test Example 6: Solubility test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) To 594 μL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate was measured by HPLC or LC / MS / MS by the absolute calibration curve method.
試験例７：代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価した。 Test Example 7: Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. did.
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させた（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心した。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の本発明化合物の残存量を０分反応時の化合物量を１００％として計算した。なお、加水分解反応はＮＡＤＰＨ非存在下で、グルクロン酸抱合反応はＮＡＤＰＨに換えて５ｍｍｏｌ／Ｌ　ＵＤＰ－グルクロン酸の存在下で反応を行い、以後同じ操作を実施する。 In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction was calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.
試験例８：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャネルを発現させたＨＥＫ２９３細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討した。
　全自動パッチクランプシステム（ＰａｔｃｈＸｐｒｅｓｓ　７０００Ａ、ＡｘｏｎＩｎｓｔｒｕｍｅｎｔｓ　Ｉｎｃ．）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持し、－５０ｍＶのリーク電位を与えた後、＋４０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録した。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１３５　ｍｍｏｌ／Ｌ、ＫＣｌ：５．４　ｍｍｏｌ／Ｌ、ＮａＨ２ＰＯ４：０．３ｍｍｏｌ／Ｌ、ＣａＣｌ２・２Ｈ２Ｏ：１．８ｍｍｏｌ／Ｌ、ＭｇＣｌ２・６Ｈ２Ｏ：１ｍｍｏｌ／Ｌ、グルコース：１０ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－１－ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｅｓｕｌｆｏｎｉｃ　ａｃｉｄ、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温条件下で、１０分間細胞に適用させた。得られたＩＫｒから、解析ソフト（ＤａｔａＸｐｒｅｓｓ　ｖｅｒ．２、Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ　Ｃｏｒｐｏｒａｔｉｏｎ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測した。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価した。 Test Example 8: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, HEK293 cells expressing a human ether-a-go-go related gene (hERG) channel are used in the ventricular repolarization process. The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role, was investigated.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cell was held at a membrane potential of −80 mV by the whole cell patch clamp method, a leak potential of −50 mV was applied, and then a depolarization stimulus of +40 mV was applied. I Kr elicited when 2 seconds of additional -50 mV repolarization stimulation was applied for 2 seconds was recorded. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH 2 PO 4 : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl 2 · 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine etheric acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
試験例９：粉末溶解度試験
　適当な容器に本発明化合物を適量入れ、各容器にＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとした）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加えた）、２０ｍｍｏｌ／Ｌ　タウロコール酸ナトリウム（ＴＣＡ）／ＪＰ－２液（ＴＣＡ１．０８ｇにＪＰ－２液を加え１００ｍＬとした）を２００μＬずつ添加した。試験液添加後に全量溶解した場合には、適宜、本発明化合物を追加した。密閉して３７℃で１時間振とう後に濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行った。希釈倍率は、必要に応じて変更した。気泡および析出物がないかを確認し、密閉して振とうした。絶対検量線法によりＨＰＬＣを用いて本発明化合物を定量した。 Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution in each container. 200 μL of 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution was added to 1.08 g of TCA to make 100 mL) Added in increments. When the entire amount was dissolved after adding the test solution, the compound of the present invention was appropriately added. After sealing and shaking at 37 ° C. for 1 hour, the mixture was filtered, and 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. The compound of the present invention was quantified using HPLC by an absolute calibration curve method.
試験例１０：ＢＡ試験
　経口吸収性の検討実験材料と方法
（１）使用動物：ＳＤラットを使用した。
（２）飼育条件：ＳＤラットは、固形飼料および水道水を自由摂取させた。
（３）投与量、群分けの設定：経口投与、静脈内投与を所定の投与量により投与した。以下のように群を設定した。
　経口投与　１ｍｇ／ｋｇ（ｎ＝２）
　静脈内投与　０．５ｍｇ／ｋｇ（ｎ＝２）
（４）投与液の調製：経口投与は溶液または懸濁液として投与した。静脈内投与は可溶化して投与した。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与した。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与した。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定した。
（７）統計解析：血漿中本発明化合物濃度推移について、薬物動態解析ソフトＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群のＡＵＣから本発明化合物のバイオアベイラビリティ（ＢＡ）を算出した。 Test Example 10: BA test Examination of oral absorbability Experimental materials and methods (1) Animals used: SD rats were used.
(2) Breeding conditions: SD rats were allowed to freely take solid feed and tap water.
(3) Setting of dose and grouping: Oral administration and intravenous administration were administered at a predetermined dose. Groups were set up as follows.
Oral administration 1 mg / kg (n = 2)
Intravenous administration 0.5 mg / kg (n = 2)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) was calculated using the pharmacokinetic analysis software WinNonlin (registered trademark) for the plasma compound concentration transition in plasma, and the oral administration group and the intravenous administration group The bioavailability (BA) of the compound of the present invention was calculated from the AUC.
試験例１１：Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価した。
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養した。ＴＡ９８株は９ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去した。９ｍＬのＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１１０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加した。ＴＡ１００株は３．１６ｍＬ菌液に対しＥｘｐｏｓｕｒｅ培地１２０ｍＬに添加し試験菌液を調製した。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養した。本発明化合物を暴露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し、５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養した。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価した。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。 Test Example 11: Fluctuation Ames Test
The mutagenicity of the compounds of the present invention was evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L) Buffer). The TA100 strain was added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under the metabolic activation conditions, 498 μL of the test bacterial solution and S9 (mix solution of 90 μL of mix) was mixed and incubated at 37 ° C. for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each was dispensed into 48 wells / dose of a microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation was made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).
（製剤例１）
　硬質ゼラチンカプセルは次の成分を用いて製造する：
　　　　　　　　　　　　　　　　　　　　　　　用量
　　　　　　　　　　　　　　　　　　　（ｍｇ／カプセル）
　　　活性成分　　　　　　　　　　　　　　２５０
　　　デンプン（乾燥）　　　　　　　　　　２００
　　　ステアリン酸マグネシウム　　　　　　　１０　　　　
　　　合計　　　　　　　　　　　　　　　　４６０ｍｇ (Formulation example 1)
Hard gelatin capsules are manufactured using the following ingredients:
Dose (mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg
（製剤例２）
　錠剤は下記の成分を用いて製造する：
　　　　　　　　　　　　　　　　　　　　　　　用量
　　　　　　　　　　　　　　　　　　　（ｍｇ／錠剤）
　　　活性成分　　　　　　　　　　　　　　２５０
　　　セルロース（微結晶）　　　　　　　　４００
　　　二酸化ケイ素（ヒューム）　　　　　　　１０
　　　ステアリン酸　　　　　　　　　　　　　　５　　　
　　　合計　　　　　　　　　　　　　　　　６６５ｍｇ
　成分を混合し、圧縮して各重量６６５ｍｇの錠剤にする。 (Formulation example 2)
Tablets are manufactured using the following ingredients:
Dose (mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.
（製剤例３）
　以下の成分を含有するエアロゾル溶液を製造する：
　　　　　　　　　　　　　　　　　　　　　　　　　　　　重量　　　
　　　活性成分　　　　　　　　　　　　　　　　　　　　　０．２５
　　　エタノール　　　　　　　　　　　　　　　　　　　２５．７５
　　　プロペラント２２（クロロジフルオロメタン）　　　７４．００　
　　　合計　　　　　　　　　　　　　　　　　　　　　１００．００
　活性成分とエタノールを混合し、この混合物をプロペラント２２の一部に加え、－３０℃に冷却し、充填装置に移す。ついで必要量をステンレススチール容器へ供給し、残りのプロペラントで希釈する。バブルユニットを容器に取り付ける。 (Formulation example 3)
An aerosol solution is prepared containing the following ingredients:
weight
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to −30 ° C. and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
（製剤例４）
　活性成分６０ｍｇを含む錠剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　　６０ｍｇ
　　　デンプン　　　　　　　　　　　　　　　　　　　　　４５ｍｇ
　　　微結晶性セルロース　　　　　　　　　　　　　　　　３５ｍｇ
　　　ポリビニルピロリドン（水中１０％溶液）　　　　　　　４ｍｇ
　　　ナトリウムカルボキシメチルデンプン　　　　　　　　　４．５ｍｇ
　　　ステアリン酸マグネシウム　　　　　　　　　　　　　　０．５ｍｇ
　　　滑石　　　　　　　　　　　　　　　　　　　　　　　　１ｍｇ　　
　　　合計　　　　　　　　　　　　　　　　　　　　　　１５０ｍｇ
　活性成分、デンプン、およびセルロースはＮｏ．４５メッシュＵ．Ｓ．のふるいにかけて、十分に混合する。ポリビニルピロリドンを含む水溶液を得られた粉末と混合し、ついで混合物をＮｏ．１４メッシュＵ．Ｓ．ふるいに通す。このようにして得た顆粒を５０℃で乾燥してＮｏ．１８メッシュＵ．Ｓ．ふるいに通す。あらかじめＮｏ．６０メッシュＵ．Ｓ．ふるいに通したナトリウムカルボキシメチルデンプン、ステアリン酸マグネシウム、および滑石をこの顆粒に加え、混合した後、打錠機で圧縮して各重量１５０ｍｇの錠剤を得る。 (Formulation example 4)
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.V. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
（製剤例５）
　活性成分８０ｍｇを含むカプセル剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　　８０ｍｇ
　　　デンプン　　　　　　　　　　　　　　　　　　　　　５９ｍｇ
　　　微結晶性セルロース　　　　　　　　　　　　　　　　５９ｍｇ
　　　ステアリン酸マグネシウム　　　　　　　　　　　　　　２ｍｇ　　
　　　合計　　　　　　　　　　　　　　　　　　　　　　２００ｍｇ
　活性成分、デンプン、セルロース、およびステアリン酸マグネシウムを混合し、Ｎｏ．４５メッシュＵ．Ｓ．のふるいに通して硬質ゼラチンカプセルに２００ｍｇずつ充填する。 (Formulation example 5)
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.V. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
（製剤例６）
　活性成分２２５ｍｇを含む坐剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　２２５ｍｇ
　　　飽和脂肪酸グリセリド　　　　　　　　　　　　　２０００ｍｇ　　
　　　合計　　　　　　　　　　　　　　　　　　　　　２２２５ｍｇ
　活性成分をＮｏ．６０メッシュＵ．Ｓ．のふるいに通し、あらかじめ必要最小限に加熱して融解させた飽和脂肪酸グリセリドに懸濁する。ついでこの混合物を、みかけ２ｇの型に入れて冷却する。 (Formulation example 6)
A suppository containing 225 mg of active ingredient is prepared as follows:
Active ingredient 225mg
Saturated fatty acid glyceride 2000mg
Total 2225mg
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
（製剤例７）
　活性成分５０ｍｇを含む懸濁剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　　５０ｍｇ
　　　ナトリウムカルボキシメチルセルロース　　　　　　　５０ｍｇ
　　　シロップ　　　　　　　　　　　　　　　　　　　１．２５ｍｌ
　　　安息香酸溶液　　　　　　　　　　　　　　　　　０．１０ｍｌ
　　　香料　　　　　　　　　　　　　　　　　　　　　　　　ｑ．ｖ．
　　　色素　　　　　　　　　　　　　　　　　　　　　　　　ｑ．ｖ．
　　　精製水を加え合計　　　　　　　　　　　　　　　　　　５ｍｌ
　活性成分をＮｏ．４５メッシュＵ．Ｓ．のふるいにかけ、ナトリウムカルボキシメチルセルロースおよびシロップと混合して滑らかなペーストにする。安息香酸溶液および香料を水の一部で希釈して加え、攪拌する。ついで水を十分量加えて必要な体積にする。 (Formulation example 7)
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.V. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add benzoic acid solution and perfume diluted with a portion of water and stir. Then add a sufficient amount of water to the required volume.
（製剤例８）
　静脈用製剤は次のように製造する：
　　　活性成分　　　　　　　　　　　　　　　　　　　　１００ｍｇ
　　　飽和脂肪酸グリセリド　　　　　　　　　　　　　１０００ｍｌ
　上記成分の溶液は通常、１分間に１ｍｌの速度で患者に静脈内投与される。 (Formulation Example 8)
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
　以上の試験例から明らかなように、本発明に係る化合物はＧＰＲ１１９アゴニスト作用を示す。従って、本発明に係る化合物は、Ｉ型糖尿病治療薬、ＩＩ型糖尿病治療薬、インスリン抵抗性治療薬、代謝性疾患治療薬、高血糖治療薬および肥満治療薬として非常に有用である。 As is clear from the above test examples, the compound according to the present invention exhibits a GPR119 agonistic action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for type I diabetes, a therapeutic agent for type II diabetes, a therapeutic agent for insulin resistance, a therapeutic agent for metabolic diseases, a therapeutic agent for hyperglycemia, and a therapeutic agent for obesity.

Claims (38)

  1. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    Ｘは＝Ｃ（Ｒ２）－または＝Ｎ－であり、
    Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノであり、
    Ｒ３は置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
    Ｙ１は－Ｃ（Ｒ７）（Ｒ７Ａ）－または－Ｏ－であり、
    Ｙ２は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－または－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、
    Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
    Ｒ６とＲ６Ａは一緒になってオキソまたは置換もしくは非置換のイミノを形成してもよく、
    Ｒ６とＲ６Ａは隣接する炭素原子と一緒になって置換もしくは非置換の環または置換もしくは非置換のアルキリデンを形成してもよく、
    Ｒ８はシアノ、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、Ｒ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８ＥおよびＲ８Ｆは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２である。）で示される基または
    式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基であり、
    ｍおよびｎは各々独立して０、１または２であり、
    ｒは０～１２の整数であり、
    Ｒ９は各々独立してハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルであり、
    ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、および／または、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。
    但し、Ｘが＝ＣＨ－であり、Ｙ１が－Ｏ－であり、Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃで示される基であり、かつ、Ｒ８Ｃが置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のヘテロサイクリルである化合物、および以下に示される化合物：
    Figure JPOXMLDOC01-appb-C000002
    を除く。）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    X is ═C (R 2 ) — or ═N—,
    R 1 , R 2 and R 4 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl Substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkyl Kenyloxycarbonyl or substituted or unsubstituted amino;
    R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;
    Y 1 is —C (R 7 ) (R 7A ) — or —O—,
    Y 2 is —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) — or —C (R 6 ) (R 6A ) —
    R 5 , R 5A , R 6 , R 6A , R 7 and R 7A are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
    R 6 and R 6A may together form an oxo or substituted or unsubstituted imino;
    R 6 and R 6A may be taken together with adjacent carbon atoms to form a substituted or unsubstituted ring or substituted or unsubstituted alkylidene;
    R 8 is cyano,
    Formula:-(CR 8A R 8B ) p-R 8C wherein R 8A is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, and R 8B is independently And hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer of 0 to 3, and R 8C is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.),
    Formula: — (CR 8A R 8B ) pC (═O) OR 8D (wherein R 8A , R 8B and p are as defined above, and R 8D is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by
    Formula: — (CR 8A R 8B ) pC (═O) NR 8E R 8F (wherein R 8A , R 8B and p are as defined above, and R 8E and R 8F are each independently hydrogen) Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkenyl or a substituted or unsubstituted heterocyclyl).
    Formula: — (CR 8A R 8B ) pC (═O) R 8G (wherein R 8A , R 8B and p are as defined above, and R 8G is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by
    Formula: —S (═O) q—R 8H where R 8H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, q is 1 or 2.) (═O) q—NR 8I R 8J (wherein q is as defined above, R 8I and R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted) Or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloal Le, a group represented by a heterocyclyl cycloalkenyl or substituted or unsubstituted substituted or unsubstituted.),
    m and n are each independently 0, 1 or 2,
    r is an integer from 0 to 12,
    Each R 9 is independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl;
    When r is 2 or more, two R 9 bonded to the same carbon atom may be combined to form oxo and / or two R 9 bonded to different carbon atoms are May be combined with the carbon atom to which is bonded to form a substituted or unsubstituted ring.
    However, X is ═CH—, Y 1 is —O—, R 8 is a group represented by the formula: — (CR 8A R 8B ) p—R 8C , and R 8C is substituted or non-substituted. Compounds that are substituted cycloalkyl or substituted or unsubstituted heterocyclyl, and compounds shown below:
    Figure JPOXMLDOC01-appb-C000002
    except for. ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
  2. Ｙ１が－Ｏ－である、請求項１記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound of claim 1, wherein Y 1 is -O-, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  3. Ｘが＝Ｎ－である、請求項１または２記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to claim 1 or 2, wherein X is = N-, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  4. Ｘが＝Ｃ（Ｒ２）－である、請求項１または２記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to claim 1, wherein X is ═C (R 2 ) —, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  5. Ｙ２が－Ｃ（Ｒ６）（Ｒ６Ａ）－である、請求項１～４のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 4, wherein Y 2 is -C (R 6 ) (R 6A )-.
  6. Ｙ２が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である、請求項１～４のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 1 to 4, wherein Y 2 is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-, a pharmaceutically acceptable salt thereof or a salt thereof Solvate.
  7. Ｒ６およびＲ６Ａが水素である、請求項１～６のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 1 to 6, wherein R 6 and R 6A are hydrogen, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  8. Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである、請求項１～６のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl.
  9. Ｒ３が置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のヘテロサイクリルである、請求項１～８のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 1 to 8, wherein R 3 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl. Their solvates.
  10. Ｒ３が置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルであり、該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であり、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
    またはＲ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよく、
    Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
    Ｒ１０Ｄは水素または置換もしくは非置換のアルキルである、請求項１～８のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。     R 3 is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl, and at least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is —C (= O) NR 10A R 10B , -NR 10D -C (= O) -R 10C , -NR 10D -C (= O) -NR 10A R 10B , -NR 10D -S (= O) 2 -NR 10A R 10B , —SO 2 NR 10A R 10B , —NR 10D SO 2 —R 10C and —SO 2 —R 10C are groups selected from the group consisting of R 10A and R 10B each independently hydrogen, substituted Or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Properly is unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, cycloalkenyl, substituted or unsubstituted, or a substituted or unsubstituted heterocyclyl,
    Or R 10A and R 10B may form a substituted or unsubstituted ring together with the adjacent nitrogen atom;
    R 10C is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
    The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 8, wherein R 10D is hydrogen or substituted or unsubstituted alkyl.
  11. Ｒ３が置換アリールまたは置換ヘテロアリールであり、該アリールまたはヘテロアリール上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂで示される基であり、Ｒ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成する、請求項１～８のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 R 3 is substituted aryl or substituted heteroaryl, and at least one of the substituents on the aryl or heteroaryl is a group represented by —C (═O) NR 10A R 10B , and R 10A and R 10B are adjacent to each other The compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a solvate thereof, which forms a substituted or unsubstituted ring together with a nitrogen atom.
  12. ｍが１であり、かつ、ｎが１である、請求項１～１１のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 11, wherein m is 1 and n is 1.
  13. Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは請求項１と同意義である。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは請求項１と同意義である。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｇは請求項１と同意義である。）で示される基または
    式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは請求項１と同意義である。）で示される基である、請求項１～１２のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。     R 8 is a group represented by the formula:-(CR 8A R 8B ) p-R 8C (wherein R 8A , R 8B , p and R 8C are as defined in claim 1),
    A group represented by the formula: — (CR 8A R 8B ) pC (═O) OR 8D (wherein R 8A , R 8B , p and R 8D are as defined in claim 1);
    A group represented by the formula: — (CR 8A R 8B ) pC (═O) R 8G (wherein R 8A , R 8B , p and R 8G are as defined in claim 1) or a group represented by the formula: The compound according to any one of claims 1 to 12, which is a group represented by -S (= O) q-R 8H (wherein R 8H and q are as defined in claim 1), A pharmaceutically acceptable salt or a solvate thereof.
  14. Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは請求項１と同意義である。）で示される基である、請求項１～１３のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 Claim 8 wherein R 8 is a group represented by the formula:-(CR 8A R 8B ) p-R 8C (wherein R 8A , R 8B , p and R 8C are as defined in claim 1). 14. The compound according to any one of 1 to 13, its pharmaceutically acceptable salt, or a solvate thereof.
  15. ｐが０である、請求項１３または１４記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 15. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
  16. Ｒ８Ｃが置換もしくは非置換のヘテロアリールである、請求項１５記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to claim 15, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 8C is substituted or unsubstituted heteroaryl.
  17. ｒが０である、請求項１～１６のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 16, wherein r is 0.
  18. 請求項１～１７のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 17, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  19. 請求項１～１７のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of claims 1 to 17, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  20. 式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000003
    （式中、破線は結合の存在または不存在を示し、
    環Ａは
    Figure JPOXMLDOC01-appb-C000004
    であり、
    Ｒ１、Ｒ２およびＲ４は各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニルまたは置換もしくは非置換のアミノであり、
    Ｒ３Ａは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のヘテロサイクリル、置換もしくは非置換のアリールオキシ、置換もしくは非置換のヘテロアリールオキシ、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換のヘテロサイクリルオキシ、置換もしくは非置換のアリールチオ、置換もしくは非置換のヘテロアリールチオ、置換もしくは非置換のシクロアルキルチオ、置換もしくは非置換のシクロアルケニルチオ、置換もしくは非置換のヘテロサイクリルチオ、置換もしくは非置換のアリールスルフィニル、置換もしくは非置換のヘテロアリールスルフィニル、置換もしくは非置換のシクロアルキルスルフィニル、置換もしくは非置換のシクロアルケニルスルフィニル、置換もしくは非置換のヘテロサイクリルスルフィニル、置換もしくは非置換のアリールスルホニル、置換もしくは非置換のヘテロアリールスルホニル、置換もしくは非置換のシクロアルキルスルホニル、置換もしくは非置換のシクロアルケニルスルホニル、置換もしくは非置換のヘテロサイクリルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
    Ｙ３は－Ｃ（Ｒ７）（Ｒ７Ａ）－、－Ｃ（＝Ｏ）－または－Ｏ－であり、
    Ｙ４は－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｏ－、－Ｏ－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｃ（Ｒ６）（Ｒ６Ａ）－、－Ｏ－または－Ｃ（Ｒ５）＝Ｃ（Ｒ６）－であり、
    Ｒ５、Ｒ５Ａ、Ｒ６、Ｒ６Ａ、Ｒ７およびＲ７Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアシル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のアミノであり、
    Ｒ６とＲ６Ａは一緒になってオキソまたは置換もしくは非置換のイミノを形成してもよく、
    Ｒ６とＲ６Ａは隣接する炭素原子と一緒になって置換もしくは非置換の環または置換もしくは非置換のアルキリデンを形成してもよく、
    Ｒ８はシアノ、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、Ｒ８Ｂは各々独立して水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、カルボキシまたは置換もしくは非置換のアルキルであり、ｐは０～３の整数であり、Ｒ８Ｃは置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｄは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＮＲ８ＥＲ８Ｆ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８ＥおよびＲ８Ｆは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂおよびｐは上記と同意義であり、Ｒ８Ｇは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基、
    式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、ｑは１または２である。）で示される基または
    式：－Ｓ（＝Ｏ）ｑ－ＮＲ８ＩＲ８Ｊ（式中、ｑは上記と同意義であり、Ｒ８ＩおよびＲ８Ｊは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルである。）で示される基であり、
    ｍおよびｎは各々独立して０、１または２であり、
    ｒは０～１２の整数であり、
    Ｒ９は各々独立してハロゲン、ヒドロキシ、シアノ、カルボキシまたは置換もしくは非置換のアルキルであり、
    ｒが２以上である場合、同一の炭素原子に結合した２個のＲ９が一緒になってオキソを形成してもよく、異なる炭素原子に結合した２個のＲ９がそれらが結合している炭素原子と一緒になって置換もしくは非置換の環を形成してもよい。
    但し、環Ａが
    Figure JPOXMLDOC01-appb-C000005
    であり、
    Ｙ３が－Ｏ－であり、Ｙ４が－Ｃ（Ｒ６）（Ｒ６Ａ）－であり、ｍが１であり、ｎが１であり、Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃで示される基であり、かつ、Ｒ８Ｃが置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のヘテロサイクリルである化合物を除く。）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。     Formula (II):
    Figure JPOXMLDOC01-appb-C000003
    (Where the dashed line indicates the presence or absence of a bond,
    Ring A is
    Figure JPOXMLDOC01-appb-C000004
    And
    R 1 , R 2 and R 4 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl Substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkyl Kenyloxycarbonyl or substituted or unsubstituted amino;
    R 3A is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted Or unsubstituted heterocyclyloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted Telocyclylthio, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted heteroarylsulfinyl, substituted or unsubstituted cycloalkylsulfinyl, substituted or unsubstituted cycloalkenylsulfinyl, substituted or unsubstituted heterocyclylsulfinyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl Substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
    Y 3 is —C (R 7 ) (R 7A ) —, —C (═O) — or —O—,
    Y 4 represents —C (R 5 ) (R 5A ) —C (R 6 ) (R 6A ) —, —C (R 5 ) (R 5A ) —O—, —O—C (R 6 ) (R 6A )-, -C (R 6 ) (R 6A )-, -O- or -C (R 5 ) = C (R 6 )-
    R 5 , R 5A , R 6 , R 6A , R 7 and R 7A are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl Sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino,
    R 6 and R 6A may together form an oxo or substituted or unsubstituted imino;
    R 6 and R 6A may be taken together with adjacent carbon atoms to form a substituted or unsubstituted ring or substituted or unsubstituted alkylidene;
    R 8 is cyano,
    Formula:-(CR 8A R 8B ) p-R 8C wherein R 8A is independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, and R 8B is independently And hydrogen, halogen, hydroxy, cyano, nitro, carboxy or substituted or unsubstituted alkyl, p is an integer of 0 to 3, and R 8C is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.),
    Formula: — (CR 8A R 8B ) pC (═O) OR 8D (wherein R 8A , R 8B and p are as defined above, and R 8D is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by
    Formula: — (CR 8A R 8B ) pC (═O) NR 8E R 8F (wherein R 8A , R 8B and p are as defined above, and R 8E and R 8F are each independently hydrogen) Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A cycloalkenyl or a substituted or unsubstituted heterocyclyl).
    Formula: — (CR 8A R 8B ) pC (═O) R 8G (wherein R 8A , R 8B and p are as defined above, and R 8G is substituted or unsubstituted alkyl, substituted or non-substituted) Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl A group represented by
    Formula: —S (═O) q—R 8H where R 8H is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl, q is 1 or 2.) (═O) q—NR 8I R 8J (wherein q is as defined above, R 8I and R 8J are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted) Or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloal Le, a group represented by a heterocyclyl cycloalkenyl or substituted or unsubstituted substituted or unsubstituted.),
    m and n are each independently 0, 1 or 2,
    r is an integer from 0 to 12,
    Each R 9 is independently halogen, hydroxy, cyano, carboxy or substituted or unsubstituted alkyl;
    When r is 2 or more, two R 9 bonded to the same carbon atom may form together oxo to form two R 9 bonded to different carbon atoms. A substituted or unsubstituted ring may be formed together with the carbon atom.
    However, ring A is
    Figure JPOXMLDOC01-appb-C000005
    And
    Y 3 is —O—, Y 4 is —C (R 6 ) (R 6A ) —, m is 1, n is 1, and R 8 is of the formula: — (CR 8A R 8B ) Excluded are compounds represented by p-R 8C and wherein R 8C is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl. ), A pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition having GPR119 receptor agonist activity.
  21. 環Ａが
    Figure JPOXMLDOC01-appb-C000006
    （ここで、Ｒ１、Ｒ２、Ｒ３ＡおよびＲ４は請求項２０と同意義である。）である、請求項２０記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。     Ring A is
    Figure JPOXMLDOC01-appb-C000006
    (Wherein R 1 , R 2 , R 3A and R 4 have the same meaning as in claim 20), the compound according to claim 20, a pharmaceutically acceptable salt thereof or a solvate thereof A pharmaceutical composition having GPR119 receptor agonist activity.
  22. Ｙ３が－Ｏ－である、請求項２０または２１記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 Y 3 is -O-, and claim 20 or 21 compound as described, pharmaceutical compositions comprising a pharmaceutically acceptable salt thereof or GPR119 receptor agonist activity containing solvate thereof.
  23. Ｙ４が－Ｃ（Ｒ６）（Ｒ６Ａ）－である、請求項２０～２２のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 The GPR119 receptor agonist containing a compound according to any one of claims 20 to 22, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Y 4 is -C (R 6 ) (R 6A )-. A pharmaceutical composition having activity.
  24. Ｙ４が－Ｃ（Ｒ５）（Ｒ５Ａ）－Ｃ（Ｒ６）（Ｒ６Ａ）－である、請求項２０～２２のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 The compound according to any one of claims 20 to 22, a pharmaceutically acceptable salt thereof, or a compound thereof, wherein Y 4 is -C (R 5 ) (R 5A ) -C (R 6 ) (R 6A )-. A pharmaceutical composition having GPR119 receptor agonist activity comprising a solvate.
  25. Ｒ６およびＲ６Ａが水素である、請求項２０～２４のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of claims 20 to 24, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 6 and R 6A are hydrogen.
  26. Ｒ６およびＲ６Ａの少なくともいずれか一方がハロゲンまたは置換もしくは非置換のアルキルである、請求項２０～２４のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 The compound according to any one of claims 20 to 24, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein at least one of R 6 and R 6A is halogen or substituted or unsubstituted alkyl. A pharmaceutical composition having GPR119 receptor agonist activity.
  27. Ｒ３Ａが置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたは置換もしくは非置換のヘテロサイクリルである、請求項２０～２６のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 The compound according to any one of claims 20 to 26, its pharmaceutically acceptable salt, or R 3A, which is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. A pharmaceutical composition having GPR119 receptor agonist activity, comprising these solvates.
  28. Ｒ３Ａが置換アリール、置換ヘテロアリール、置換シクロアルキル、置換シクロアルケニルまたは置換ヘテロサイクリルであり、該アリール、ヘテロアリール、シクロアルキル、シクロアルケニルまたはヘテロサイクリル上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－Ｒ１０Ｃ、－ＮＲ１０Ｄ－Ｃ（＝Ｏ）－ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０Ｄ－Ｓ（＝Ｏ）２－ＮＲ１０ＡＲ１０Ｂ、－ＳＯ２ＮＲ１０ＡＲ１０Ｂ、－ＮＲ１０ＤＳＯ２－Ｒ１０Ｃおよび－ＳＯ２－Ｒ１０Ｃからなる群から選択される基であり、Ｒ１０ＡおよびＲ１０Ｂは各々独立して水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、またはＲ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成していてもよく、
    Ｒ１０Ｃは置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニルまたは置換もしくは非置換のヘテロサイクリルであり、
    Ｒ１０Ｄは水素または置換もしくは非置換のアルキルである、請求項２０～２６のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。     R 3A is substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkenyl or substituted heterocyclyl, and at least one of the substituents on the aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl is —C (= O) NR 10A R 10B , -NR 10D -C (= O) -R 10C , -NR 10D -C (= O) -NR 10A R 10B , -NR 10D -S (= O) 2 -NR 10A R 10B , —SO 2 NR 10A R 10B , —NR 10D SO 2 —R 10C and —SO 2 —R 10C are groups selected from the group consisting of R 10A and R 10B each independently hydrogen, substituted Or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, heterocyclyl cycloalkenyl or substituted or unsubstituted substituted or unsubstituted, or R 10A and R 10B are adjacent It may form a substituted or unsubstituted ring together with the nitrogen atom,
    R 10C is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted cycloalkenyl or substituted or unsubstituted heterocyclyl,
    R 10D has a GPR119 receptor agonist activity comprising a compound according to any one of claims 20 to 26, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 10D is hydrogen or substituted or unsubstituted alkyl. Pharmaceutical composition.
  29. Ｒ３Ａが置換アリールまたは置換ヘテロアリールであり、該アリールまたはヘテロアリール上の置換基の少なくとも一つが－Ｃ（＝Ｏ）ＮＲ１０ＡＲ１０Ｂで示される基であり、Ｒ１０ＡとＲ１０Ｂは隣接する窒素原子と一緒になって置換もしくは非置換の環を形成する、請求項２０～２８のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 R 3A is substituted aryl or substituted heteroaryl, and at least one of the substituents on the aryl or heteroaryl is a group represented by —C (═O) NR 10A R 10B , and R 10A and R 10B are adjacent to each other A GPR119 receptor agonist comprising a compound according to any one of claims 20 to 28, a pharmaceutically acceptable salt thereof, or a solvate thereof, which forms a substituted or unsubstituted ring together with a nitrogen atom. A pharmaceutical composition having activity.
  30. ｍが１であり、かつ、ｎが１である、請求項２０～２９のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 A GPR119 receptor agonist activity comprising a compound according to any one of claims 20 to 29, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1 and n is 1. Pharmaceutical composition.
  31. Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは請求項２０と同意義である。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）ＯＲ８Ｄ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｄは請求項２０と同意義である。）で示される基、
    式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｃ（＝Ｏ）Ｒ８Ｇ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｇは請求項２０と同意義である。）で示される基または
    式：－Ｓ（＝Ｏ）ｑ－Ｒ８Ｈ（式中、Ｒ８Ｈおよびｑは請求項２０と同意義である。）で示される基である、請求項２０～３０のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。     R 8 is a group represented by the formula:-(CR 8A R 8B ) p-R 8C (wherein R 8A , R 8B , p and R 8C are as defined in claim 20),
    A group represented by the formula: — (CR 8A R 8B ) pC (═O) OR 8D (wherein R 8A , R 8B , p and R 8D are as defined in claim 20);
    A group represented by the formula: — (CR 8A R 8B ) pC (═O) R 8G (wherein R 8A , R 8B , p and R 8G are as defined in claim 20) or a group represented by the formula: The compound according to any one of claims 20 to 30, which is a group represented by -S (= O) q-R 8H (wherein R 8H and q are as defined in claim 20), A pharmaceutical composition having GPR119 receptor agonist activity comprising a pharmaceutically acceptable salt or a solvate thereof.
  32. Ｒ８が式：－（ＣＲ８ＡＲ８Ｂ）ｐ－Ｒ８Ｃ（式中、Ｒ８Ａ、Ｒ８Ｂ、ｐおよびＲ８Ｃは請求項２０と同意義である。）で示される基である、請求項２０～３１のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 Claim 8 wherein R 8 is a group represented by the formula:-(CR 8A R 8B ) p-R 8C (wherein R 8A , R 8B , p and R 8C are as defined in claim 20). A pharmaceutical composition having GPR119 receptor agonist activity comprising the compound according to any one of 20 to 31, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  33. ｐが０である、請求項３１または３２記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 33. A pharmaceutical composition having GPR119 receptor agonist activity, comprising a compound according to claim 31 or 32, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein p is 0.
  34. Ｒ８Ｃが置換もしくは非置換のヘテロアリールである、請求項３３記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 R 8C is a substituted or unsubstituted heteroaryl, A compound according claim 33, a pharmaceutical composition having a pharmaceutically acceptable salt or GPR119 receptor agonist activity containing solvate thereof.
  35. ｒが０である、請求項２０～３４のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＧＰＲ１１９受容体アゴニスト活性を有する医薬組成物。 A pharmaceutical composition having GPR119 receptor agonist activity, comprising the compound according to any one of claims 20 to 34, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r is 0.
  36. 糖尿病の治療および／または予防のための、請求項１９～３５のいずれかに記載の記載の医薬組成物。 The pharmaceutical composition according to any one of claims 19 to 35, for the treatment and / or prevention of diabetes.
  37. 請求項１～３５のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、糖尿病の予防または治療方法。 A method for preventing or treating diabetes, comprising administering the compound according to any one of claims 1 to 35, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  38. 糖尿病の治療および／または予防のための、請求項１～３５のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 The compound according to any one of claims 1 to 35, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the treatment and / or prevention of diabetes.
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