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WO2012077655A1 - Dérivé spiro présentant une activité agoniste de gpr119 - Google Patents

Dérivé spiro présentant une activité agoniste de gpr119 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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substituted
unsubstituted
compound
mmol
pharmaceutically acceptable
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English (en)
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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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Publication of WO2012077655A1 publication Critical patent/WO2012077655A1/fr
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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 or sparfloxacin
    • 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.

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Abstract

La présente invention concerne un composé répondant à la formule (I) (où X représente =C(R2)- ou =N- ; chacun des radicaux R1, R2 et R4 représente indépendamment un atome d'hydrogène, un atome d'halogène, un groupement hydroxy, etc. ; R3 représente un groupement aryle, un groupement hétéroaryle, etc. ; Y1 représente -C(R7)(R7A)- ou -O- ; Y2 représente -C(R5)(R5A)-C(R6)(R6A)- ou -C(R6)(R6A)- ; chacun des radicaux R5, R5A, R6, R6A, R7 et R7A représente indépendamment un atome d'hydrogène, un groupement hydroxy, un atome d'halogène, un groupement alkyle, etc. ; R8 représente une formule-(CR8AR8B)p-R8C, etc. (où chacun des radicaux R8A et R8B représente indépendamment un atome d'hydrogène, etc. ; p représente un entier compris entre 0 et 3 ; et R8C représente un groupement aryle, un groupement hétéroaryle, un groupement cycloalkyle, etc.) ; chacun des nombres m et n est indépendamment égal à 0, 1 ou 2 ; chacun des radicaux R9 représente indépendamment un atome d'halogène, etc. ; et r représente un entier compris entre 0 et 12, où, lorsque r est égal à 2 ou plus, deux radicaux R9 liés au même atome de carbone peuvent former ensemble un groupement oxo), un sel de qualité pharmaceutique du composé, ou un solvate du composé ou de son sel de qualité pharmaceutique.
PCT/JP2011/078125 2010-12-07 2011-12-06 Dérivé spiro présentant une activité agoniste de gpr119 Ceased WO2012077655A1 (fr)

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WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
JP2014508756A (ja) * 2011-02-18 2014-04-10 バーテックス ファーマシューティカルズ インコーポレイテッド イオンチャネルのモジュレーターとしてのクロマン−スピロ環式ピペリジンアミド
JP2015516001A (ja) * 2012-05-07 2015-06-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規な２，３−ジヒドロ−フロ［２，３−ｃ］ピリジン、Ｇタンパク質共役受容体ＧＰＲ１１９のモジュレーターとしてのそれらの使用、及びそれらを含む医薬組成物
WO2015124541A1 (fr) * 2014-02-20 2015-08-27 F. Hoffmann-La Roche Ag Spiro-oxazolones
WO2015179759A1 (fr) * 2014-05-22 2015-11-26 Genzyme Corporation Inhibiteurs de la nampt et procédés associés
CN105503725A (zh) * 2015-12-30 2016-04-20 天津药明康德新药开发有限公司 一种叔丁基1-羟基-8-氮杂螺烷[4,5]葵烷-8-羧酸酯的制备方法
JP2016538296A (ja) * 2013-11-26 2016-12-08 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのアミド誘導体
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CN109574970A (zh) * 2018-12-27 2019-04-05 上海毕得医药技术有限公司 一种5-溴苯并二氢吡喃的合成方法
WO2021174048A1 (fr) 2020-02-28 2021-09-02 Kallyope, Inc. Agonistes de gpr40
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
CN114846005A (zh) * 2020-01-21 2022-08-02 贝达药业股份有限公司 Shp2抑制剂及其应用
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US12344600B2 (en) 2022-03-16 2025-07-01 Anima Biotech Inc. c-Myc mRNA translation modulators and uses thereof in the treatment of cancer

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JP2014508756A (ja) * 2011-02-18 2014-04-10 バーテックス ファーマシューティカルズ インコーポレイテッド イオンチャネルのモジュレーターとしてのクロマン−スピロ環式ピペリジンアミド
JP2015516001A (ja) * 2012-05-07 2015-06-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規な２，３−ジヒドロ−フロ［２，３−ｃ］ピリジン、Ｇタンパク質共役受容体ＧＰＲ１１９のモジュレーターとしてのそれらの使用、及びそれらを含む医薬組成物
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
JP2016538296A (ja) * 2013-11-26 2016-12-08 チョン クン ダン ファーマシューティカル コーポレーション Ｇｐｒ１１９アゴニストとしてのアミド誘導体
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
US9828385B2 (en) 2014-02-20 2017-11-28 Hoffmann-La Roche Inc. Spiro-oxazolones
JP2017507144A (ja) * 2014-02-20 2017-03-16 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ スピロオキサゾロン
CN105793266A (zh) * 2014-02-20 2016-07-20 豪夫迈·罗氏有限公司 螺-噁唑酮
WO2015124541A1 (fr) * 2014-02-20 2015-08-27 F. Hoffmann-La Roche Ag Spiro-oxazolones
CN105793266B (zh) * 2014-02-20 2019-02-12 豪夫迈·罗氏有限公司 螺-噁唑酮
CN106661044B (zh) * 2014-05-22 2019-03-22 建新公司 Nampt抑制剂和方法
CN106661044A (zh) * 2014-05-22 2017-05-10 建新公司 Nampt抑制剂和方法
JP2017516774A (ja) * 2014-05-22 2017-06-22 ジェンザイム・コーポレーション Ｎａｍｐｔ阻害剤および方法
WO2015179759A1 (fr) * 2014-05-22 2015-11-26 Genzyme Corporation Inhibiteurs de la nampt et procédés associés
US10017523B2 (en) 2014-05-22 2018-07-10 Genzyme Corporation NAMPT inhibitors and methods
CN105503725A (zh) * 2015-12-30 2016-04-20 天津药明康德新药开发有限公司 一种叔丁基1-羟基-8-氮杂螺烷[4,5]葵烷-8-羧酸酯的制备方法
CN109574970A (zh) * 2018-12-27 2019-04-05 上海毕得医药技术有限公司 一种5-溴苯并二氢吡喃的合成方法
CN114846005A (zh) * 2020-01-21 2022-08-02 贝达药业股份有限公司 Shp2抑制剂及其应用
CN114846005B (zh) * 2020-01-21 2024-04-02 贝达药业股份有限公司 Shp2抑制剂及其应用
WO2021174048A1 (fr) 2020-02-28 2021-09-02 Kallyope, Inc. Agonistes de gpr40
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US12344600B2 (en) 2022-03-16 2025-07-01 Anima Biotech Inc. c-Myc mRNA translation modulators and uses thereof in the treatment of cancer

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