WO2012173174A1 - Composé azaspiroalcane - Google Patents

Composé azaspiroalcane Download PDF

Info

Publication number
WO2012173174A1
WO2012173174A1 PCT/JP2012/065201 JP2012065201W WO2012173174A1 WO 2012173174 A1 WO2012173174 A1 WO 2012173174A1 JP 2012065201 W JP2012065201 W JP 2012065201W WO 2012173174 A1 WO2012173174 A1 WO 2012173174A1
Authority
WO
WIPO (PCT)
Prior art keywords
azaspiro
nonane
propyl
carboxylate
phenoxy
Prior art date
Application number
PCT/JP2012/065201
Other languages
English (en)
Japanese (ja)
Inventor
円 川村
陽平 小橋
大輔 松田
史康 塩澤
洋一郎 須賀
啓子 伏木
浩行 柿沼
憲一 大嶽
Original Assignee
大正製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大正製薬株式会社 filed Critical 大正製薬株式会社
Publication of WO2012173174A1 publication Critical patent/WO2012173174A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/505—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a GPR119 agonist.
  • GPR119 is a G protein-coupled receptor (GPCR) having an endogenous ligand such as oleylethanolamide, which is a natural long chain fatty acid amide. It is known that this receptor is highly expressed in pancreatic ⁇ cells, which are insulin-producing cells of the pancreas, and small intestinal endocrine cells involved in incretin secretion. It has been reported that the pancreas is activated by stimulation with a GPR119 agonist and the like and enhances insulin secretion in a hyperglycemic-dependent manner.
  • GPCR G protein-coupled receptor
  • GLP-1 Glucagon-like peptide 1
  • pancreatic ⁇ cells has been reported to be enhanced.
  • the hypoglycemia risk is assumed to be extremely low because it exerts hyperglycemic-dependent insulin secretion and, in turn, a hypoglycemic action from both the direct action on the pancreas and the indirect action through incretin secretion from the small intestine.
  • GPR119 agonist can be a novel anti-diabetic drug having both pancreatic protective action and anti-obesity action (see Non-Patent Documents 1 to 3).
  • oleylethanolamide As the GPR119 agonist, oleylethanolamide (OEA), which is the aforementioned endogenous ligand, is known.
  • some compounds such as certain bipiperidinyl derivatives (see Patent Document 1), pyrimidinyl derivatives (see Patent Document 2 and Non-Patent Document 4), oxadiazolyl derivatives (see Patent Document 3), thiazolyl derivatives (see Patent Document 4), etc.
  • certain types of cyclopropane derivatives see Patent Documents 5 to 6 and Non-Patent Document 5
  • certain diazaspiroalkane derivatives see Patent Documents 7 to 8) have been reported. There is no disclosure.
  • combination of a certain kind of azaspiroalkane derivative (refer patent document 9) is suggested, there is no indication of the compound of this invention.
  • An object of the present invention is to provide an excellent GPR119 agonist.
  • m1 represents an integer of 0 to 2
  • m2 represents an integer of 1 to 2
  • the ring represented by A represents a benzene ring or a 6-membered heteroaromatic ring
  • R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z1;
  • Substituent group Z1 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C
  • a saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of hydroxy, halogen atom, carbamoyl, cyano and oxo, the same or different) Monosaturated heterocyclylaminocarbonyl, C 1-6 alkylsulfinyl (wherein the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) and C 1-6 Represents a group consisting of alkylsulfonyl groups, wherein the C 1-6 alkylsulfonyl is unsubstituted or substituted with one hydroxy;
  • X represents —O— or —NR 3 —;
  • R 3 represents a hydrogen atom or C 1-4 alkyl, Y represents C 1-6 alkanediyl;
  • R 2 is (A) C 1-6 alkyl [wherein the C 1-6 alkyl
  • Halo C 1-6 alkyl or C 3-8 cycloalkyl, (B) —COOR 21 ⁇ R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). ⁇ , (C) 5- or 6-membered heteroaryl represented by the following formula ( ⁇ )
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1.
  • R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z2;
  • Substituent group Z2 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl are unsubstituted or hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the
  • R 2 is (A) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or single C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or trifluoro Substituted with one group selected from the group consisting of methyl and C 1-6 alkyl.
  • Halo C 1-6 alkyl or C 3-8 cycloalkyl, (B) —COOR 21 ⁇ R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). ⁇ Or (c) 5- or 6-membered heteroaryl represented by the following formula ( ⁇ )
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different. Or a pharmaceutically acceptable salt thereof according to (1).
  • R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted) Or is substituted with 1 trifluoromethyl). ] Or a pharmaceutically acceptable salt thereof according to any one of (1) to (2), which represents halo C 1-6 alkyl.
  • R 2 is (b) -COOR 21 ⁇ R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 Cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups).
  • the compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
  • R 2 is (b) -COOR 21 ⁇ R 21 is methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl Is replaced by ], Isopropyl, isobutyl, tert-butyl (the tert-butyl is unsubstituted or substituted with 1 to 2 fluorine atoms), neopentyl, cyclopropyl (the cyclopropyl is not substituted) Or substituted with 1 methyl) or cyclopentyl.
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ )
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
  • the compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
  • R 2 represents (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ),
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted, fluorine atom, chlorine atom, methyl, ethyl , Substituted with one group selected from the group consisting of isopropyl and cyclopropyl.) (1) to (2) or (6), or a pharmaceutically acceptable salt thereof.
  • R 2 is (e) a C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl is unsubstituted or substituted with one C 3-8 cycloalkyl) or C 3-8 Cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with 1 C 1-6 alkyl)
  • the compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
  • m1 represents 1, m2 represents 1, X represents —O—, Y is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein C 3-4 alkanediyl.
  • the ring represented by A is to provide the compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9), wherein the ring represented by A represents a benzene ring or a pyridine ring.
  • R 11 is carbamoyl, mono C 1-6 alkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl is unsubstituted or is hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy Is unsubstituted or substituted with 1 hydroxy) and is substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino.
  • the ring represented by A represents a benzene ring;
  • R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [the ethylamino Carbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (wherein the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with 1 group.
  • N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), Shows an hydroxy
  • the ring represented by A represents a pyridine ring;
  • R 11 represents ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl;
  • R 12 represents a hydrogen atom,
  • R 13 is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (11), in which R 13 represents a hydrogen atom.
  • hypoglycemic agent containing the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a compound of the general formula (I) having an excellent GPR119 agonist activity or a pharmaceutically acceptable salt thereof.
  • n is normal, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” is ortho, “m” “Represents meta, and” p "represents para.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-4 alkyl refers to a linear or branched alkyl having 1 to 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl are shown.
  • C 3-6 alkyl refers to a linear or branched alkyl having 3 to 6 carbon atoms.
  • n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
  • C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
  • Halo C 1-4 alkyl refers to a linear or branched alkyl having 1 to 4 carbon atoms substituted with a halogen atom.
  • a preferred number of substitution of halogen atoms is 1 to 3.
  • Halo C 3-6 alkyl refers to a linear or branched alkyl having 3 to 6 carbon atoms substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 3. Examples include 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl and the like.
  • Halo C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms substituted with a halogen atom.
  • a preferred number of substitution of halogen atoms is 1 to 3.
  • C 3-6 cycloalkyl refers to a cyclic alkyl having 3 to 6 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3-8 cycloalkyl refers to cyclic alkyl having 3 to 8 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Aryl refers to a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples thereof include phenyl, naphthyl, anthryl and the like.
  • Heteroaryl is a 5- to 7-membered monocyclic fragrance consisting of one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or the same or different, and 1 to 6 carbon atoms.
  • a polycyclic aromatic heterocyclic group is shown.
  • Examples include imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, quinolyl and the like.
  • a group partially saturated in heteroaryl is also included in “heteroaryl”.
  • the “partially saturated group in heteroaryl” refers to one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1 to 6 carbon atoms.
  • oxazolidinyl, thiazolinyl and the like can be mentioned.
  • 6-membered heteroaromatic ring refers to a 6-membered monocyclic aromatic heterocycle composed of one or more nitrogen atoms and 1 to 5 carbon atoms. Examples include pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
  • “Saturated heterocyclyl” is a 3 to 8 membered monocyclic group consisting of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 7 carbon atoms.
  • a saturated heterocyclic group is shown. Examples include azetidinyl, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, piperazinyl, pyrazolidinyl, quinuclidinyl, morpholinyl, oxetanyl, oxolanyl, oxanyl and the like.
  • C 1-4 alkoxy refers to linear or branched alkoxy having 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 1-6 alkoxy represents linear or branched alkoxy having 1 to 6 carbon atoms.
  • Halo C 1-6 alkoxy refers to a straight or branched alkoxy having 1 to 6 carbon atoms substituted with a halogen atom.
  • a preferred number of substitution of halogen atoms is 1 to 3.
  • “Mono C 1-4 alkylamino” means amino having one “C 1-4 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino and the like can be mentioned.
  • “Mono C 1-6 alkylamino” refers to amino having one “C 1-6 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, neopentylamino, n-hexylamino , Isohexylamino and the like.
  • “DiC 1-4 alkylamino” refers to amino having two “C 1-4 alkyl” as the same or different as a substituent. For example, N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn- And propylamino, N-isopropyl-N-methylamino and the like.
  • “DiC 1-6 alkylamino” refers to an amino having the same or different two “C 1-6 alkyl” as the substituent. For example, N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn- And propylamino, N-isopropyl-N-methylamino and the like.
  • C 3-6 alkylcarbonyl refers to a group in which the above “C 3-6 alkyl” and carbonyl are bonded.
  • n-propylcarbonyl isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 2-methylbutylcarbonyl, n-hexylcarbonyl And isohexylcarbonyl.
  • C 1-6 alkylcarbonyl refers to a group in which the above “C 1-6 alkyl” is bonded to carbonyl.
  • Examples include carbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like.
  • C 3-6 cycloalkylcarbonyl refers to a group in which the above “C 3-6 cycloalkyl” is bonded to carbonyl. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.
  • C 3-8 cycloalkylcarbonyl refers to a group in which the above “C 3-8 cycloalkyl” is bonded to carbonyl. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, and cyclooctylcarbonyl.
  • C 1-6 alkoxycarbonyl refers to a group in which the above “C 1-6 alkoxy” is bonded to carbonyl.
  • C 1-6 alkylcarbonylamino refers to a group in which amino is bonded to a group in which the above “C 1-6 alkyl” is bonded to carbonyl.
  • “Mono C 1-4 alkylaminocarbonyl” refers to a group in which amino and carbonyl having one “mono C 1-4 alkyl” as a substituent is bonded. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl and the like.
  • “Mono C 1-6 alkylaminocarbonyl” refers to a group in which the above “mono C 1-6 alkylamino” is bonded to carbonyl.
  • Examples include carbonyl, neopentylaminocarbonyl, n-hexylaminocarbonyl, isohexylaminocarbonyl and the like.
  • “Mono C 3-6 cycloalkylaminocarbonyl” refers to a group in which amino having one “C 3-6 cycloalkyl” as a substituent and carbonyl are bonded. Examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, and cyclohexylaminocarbonyl.
  • “Mono C 3-8 cycloalkylaminocarbonyl” refers to a group in which amino having one “C 3-8 cycloalkyl” as a substituent and carbonyl are bonded. Examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, and cyclooctylaminocarbonyl.
  • “DiC 1-4 alkylaminocarbonyl” refers to a group in which the above “diC 1-4 alkylamino” and carbonyl are bonded.
  • “DiC 1-6 alkylaminocarbonyl” refers to a group in which the above “diC 1-6 alkylamino” is bonded to carbonyl.
  • C 1-4 alkyl C 3-6 cycloalkylaminocarbonyl is a combination of amino and carbonyl having one each of the above “C 1-4 alkyl” and “C 3-6 cycloalkyl” as substituents. Indicates a group. For example, N-cyclopropyl-N-methylaminocarbonyl, N-cyclopropyl-N-ethylaminocarbonyl, N-cyclobutyl-N-methylaminocarbonyl, N-cyclobutyl-N-ethylaminocarbonyl, N-cyclopentyl-N-methyl Aminocarbonyl, N-cyclohexyl-N-methylaminocarbonyl and the like can be mentioned.
  • C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl is a combination of amino and carbonyl having one each of the above “C 1-6 alkyl” and “C 3-8 cycloalkyl” as substituents. Indicates a group.
  • N-cyclopropyl-N-methylaminocarbonyl N-cyclopropyl-N-ethylaminocarbonyl, N-cyclobutyl-N-methylaminocarbonyl, N-cyclobutyl-N-ethylaminocarbonyl, N-cyclopentyl-N-methyl
  • Examples include aminocarbonyl, N-cyclohexyl-N-methylaminocarbonyl, N-cycloheptyl-N-methylaminocarbonyl, N-cyclooctyl-N-methylaminocarbonyl and the like.
  • “Saturated heterocyclylcarbonyl” refers to a group in which the above “saturated heterocyclylcarbonyl” and carbonyl are bonded. Examples include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-hexamethyleneiminylcarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl and the like.
  • “Mono-saturated heterocyclylaminocarbonyl” refers to a group in which amino and carbonyl having one “saturated heterocyclyl” as a substituent is bonded. Examples include oxetanylaminocarbonyl, oxolanylaminocarbonyl, oxanylaminocarbonyl, tetrahydrothiopyranylaminocarbonyl, pyrrolidinylaminocarbonyl, piperidinylaminocarbonyl and the like.
  • C 1-4 alkylsulfinyl refers to a group in which the above “C 1-4 alkyl” and sulfinyl are bonded. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, isobutylsulfinyl and the like.
  • C 1-6 alkylsulfinyl refers to a group in which the above “C 1-6 alkyl” and sulfinyl are bonded. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, n-hexylsulfinyl and the like.
  • C 1-4 alkylsulfonyl refers to a group in which the above “C 1-4 alkyl” and sulfonyl are bonded.
  • methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl and the like can be mentioned.
  • C 1-6 alkylsulfonyl refers to a group in which the above “C 1-6 alkyl” and sulfonyl are bonded. Examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, n-hexylsulfonyl and the like.
  • C 3-8 cycloalkylsulfonyl refers to a group in which the above “C 3-8 cycloalkyl” is bonded to sulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl.
  • C 1-6 alkylsulfonylamino refers to a group in which the above “C 1-6 alkylsulfonyl” is linked to amino.
  • “Mono C 1-6 alkylaminosulfonyl” refers to a group in which the above “mono C 1-6 alkylamino” is bonded to sulfonyl.
  • Oxo refers to a substituent ( ⁇ O) in which an oxygen atom is substituted via a double bond. Therefore, when oxo is substituted with a carbon atom, it forms a carbonyl together with the carbon atom, and when one oxo is substituted with one sulfur atom, it forms a sulfinyl together with the sulfur atom, When two oxos are substituted with one sulfur atom, they are combined with the sulfur atom to form a sulfonyl.
  • saturated heterocyclyl substituted with oxo when oxo is substituted with saturated heterocyclyl include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 3 -Oxopiperazinyl, 1,1-dioxidetetrahydrothiophenyl, 1-oxidetetrahydro-2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2- Examples thereof include oxo-1,3-oxazolidinyl, 6-oxo-1,1-dihydropyridazinyl and the like.
  • C 3-4 alkanediyl refers to a divalent saturated hydrocarbon group having 3 to 4 carbon atoms. Examples thereof include propane-1,3-diyl, butane-1,4-diyl and the like.
  • C 1-6 alkanediyl refers to a divalent hydrocarbon group having 1 to 6 carbon atoms.
  • methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl and the like can be mentioned.
  • a 5- or 6-membered monocyclic aromatic heterocyclic group composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 5 carbon atoms.
  • Examples include oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like.
  • Preferred embodiments of the compound of the present invention are as follows. That is, Of the azaspiro ring structure represented by the following formula ( ⁇ 1),
  • Preferred azaspiro ring structures are the following structures:
  • More preferred azaspiro ring structures are the following structures:
  • More preferred azaspiro ring structures are the following structures
  • a preferred ring represented by A is a benzene ring or a 6-membered heteroaromatic ring
  • a more preferable ring represented by A is a benzene ring, a pyridine ring, a pyrazine ring or a pyrimidine ring
  • a more preferable ring represented by A is a benzene ring, a pyridine ring or a pyrazine ring
  • a particularly preferred ring represented by A is a benzene ring;
  • R 11 , R 12 and R 13 are hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl may be unsubstituted, hydroxy, carbamoyl, cyano, C 1-6 alkoxy (wherein the C 1-6 alkoxy is unsubstituted or And substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino.
  • R 11 , R 12 and R 13 are more preferably hydrogen atom, halogen atom, carbamoyl, C 1-4 alkyl, mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, diC.
  • Saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 hydroxy), monosaturated heterocyclylaminocarbonyl or C 1-4 alkylsulfonyl;
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
  • R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylamino.
  • Carbonyl the ethylaminocarbonyl consists of unsubstituted, hydroxy, methoxy, ethoxy (the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino Substituted with one group selected from the group.
  • N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), It is o
  • R 11 is ethylaminocarbonyl [wherein the ethylaminocarbonyl is one group selected from the group consisting of hydroxy, methoxy and ethoxy (the ethoxy is substituted with one hydroxy).
  • R 11 , R 12 and R 13 are mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8.
  • Cycloalkylaminocarbonyl (the mono-C 1-6 alkylaminocarbonyl, mono-C 3-8 cycloalkylaminocarbonyl, di-C 1-6 alkylaminocarbonyl and C 1-6 alkyl-C 3-8 cycloalkylaminocarbonyl are mono- C 1-6 substituted with one group identical to or different selected from alkyl aminocarbonyl and the group consisting of di-C 1-6 alkylaminocarbonyl.), heterocyclylcarbonyl in heterocyclylcarbonyl (saturated saturated Substituted with 1 to 2 groups selected from the group consisting of halogen atom, carbamoyl, cyano and oxo, the same or different C 1-6 alkylsulfinyl (the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) or C 1-6 alkylsulfonyl (the C 1- 6 alkylsulfonyl is
  • R 11 , R 12 and R 13 are more preferably mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, di C 1-4 alkylaminocarbonyl, C 1-4 alkyl C 3. -6 cycloalkylaminocarbonyl (the mono-C 1-4 alkylaminocarbonyl, mono-C 3-6 cycloalkylaminocarbonyl, di-C 1-4 alkylaminocarbonyl and C 1-4 alkylC 3-6 cycloalkylaminocarbonyl are Substituted with one or two groups selected from the same or different from the group consisting of mono C 1-4 alkylaminocarbonyl and diC 1-4 alkylaminocarbonyl), saturated heterocyclylcarbonyl (the saturated The heterocyclylcarbonyl is substituted with 1 to 2 groups selected from the group consisting of a halogen atom, carbamoyl and oxo).
  • C 1-4 alkylsulfinyl (wherein the C 1-4 alkylsulfinyl is unsubstituted or substituted with one hydroxy) or C 1-4 alkylsulfonyl (wherein the C 1-4 alkylsulfonyl is Substituted with one hydroxy).
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of methylaminocarbonyl and N, N-dimethylaminocarbonyl), N, N-dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), azetidin-1-yl-carbonyl (The azetidin-1-yl-carbonyl is substituted with 2 fluorine atoms), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is either unsubstituted or 1 Substituted with oxo).
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl
  • R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of carbamoyl and cyano), N, N-dimethylaminocarbonyl (the N , N-dimethylaminocarbonyl is substituted with 1 cyano), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is substituted with oxo),
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • particularly preferred R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl, Wherein R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
  • Preferred X is —O— or —NH—, More preferred X is —O—;
  • Preferred Y is ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl; More preferred Y is propane-1,3-diyl or butane-1,4-diyl, More preferred Y is propane-1,3-diyl;
  • R 2 is (a) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted) Or is substituted with 1 trifluoromethyl).
  • R 2 is (a) methyl (the methyl is substituted with one C 3-6 cycloalkyl), C 3-6 alkyl or haloC 3-6 alkyl, In this case, more preferable R 2 is (a) methyl (the methyl is substituted with one cyclopentyl), neopentyl or isopropyl (the isopropyl is substituted with one fluorine atom). Is;
  • R 21 is C 1-6 alkyl [the C 1-6 alkyl is not substituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is substituted). Or is substituted with one C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is unsubstituted or substituted with one C 1-6 alkyl. In this case, more preferable R 21 is C 1-6 alkyl (the C 1-6 alkyl is not substituted or one C 3-6 cycloalkyl (the C 3-6 cycloalkyl is substituted).
  • R 21 is more preferably methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl). Has been replaced.
  • R 21 is methyl [the methyl is substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl).
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is not substituted. Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1-6 alkoxy Is)
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted or halogenated) Substituted with one group selected from the group consisting of an atom, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 alkoxy.
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) is oxadiazolyl (the oxadiazolyl is not substituted or substituted with one isopropyl) ), Pyridyl or pyrimidinyl (the pyridyl and pyrimidinyl are unsubstituted or substituted with one group selected from the group consisting of fluorine atom, chlorine atom, methyl, ethyl, isopropyl and cyclopropyl).
  • R 2 is (c) 5-oxadiazolyl of 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) (the 5-oxadiazolyl is substituted with one isopropyl). Or 2-pyrimidinyl (the 2-pyrimidinyl is substituted with 1 ethyl);
  • R 2 is (e) C 1-6 alkylcarbonyl or C 3-8 cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with one C 1-6 Substituted with alkyl).
  • R 2 is (e) C 3-6 alkylcarbonyl or C 3-6 cycloalkylcarbonyl (the C 3-6 cycloalkylcarbonyl is either unsubstituted or substituted with one C 1-4). Substituted with alkyl).
  • R 2 is (e) tert-butylcarbonyl, neopentylcarbonyl or cyclopropylcarbonyl (the cyclopropylcarbonyl is unsubstituted or substituted with one methyl).
  • particularly preferred R 2 is (e) tert-butylcarbonyl or neopentylcarbonyl.
  • One preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (II).
  • Preferred embodiments of the ring represented by A, R 11 , R 12 , R 13 , Y and R 2 are as described above.
  • Another preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (III).
  • Preferred embodiments of the ring represented by A, R 11 , R 12 , R 13 , Y and R 2 are as described above.
  • a preferred ring represented by A is a benzene ring
  • R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [ The ethylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with one selected group.
  • N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), It is o
  • R 11 is more preferably ethylaminocarbonyl [wherein the ethylaminocarbonyl is a group selected from the group consisting of hydroxy, methoxy and ethoxy (wherein the ethoxy is substituted with one hydroxy).
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of methylaminocarbonyl and N, N-dimethylaminocarbonyl), N, N— Dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), azetidin-1-yl-carbonyl (the Azetidin-1-yl-carbonyl is substituted with 2 fluorine atoms), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is either unsubstituted or Substituted with oxo).
  • R 11 is substituted at the para-position of the benzene ring
  • preferable R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
  • R 12 and R 13 are independently substituted at the ortho-position or meta-position of the benzene ring,
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of carbamoyl and cyano), N, N-dimethylaminocarbonyl (the N , N-dimethylaminocarbonyl is substituted with one cyano), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is substituted with oxo),
  • R 11 is substituted at the para-position of the benzene ring
  • R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
  • R 12 and R 13 are independently substituted at the ortho or meta position of the benzene ring.
  • a preferred ring represented by A is a pyridine ring
  • Preferred R 11 is ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl; In this case, more preferred R 11 is cyclopropylaminocarbonyl or methylsulfonyl; Preferred R 12 is a hydrogen atom; Preferred R 13 is a hydrogen atom.
  • a preferred ring represented by A is a pyrazine ring
  • R 11 is ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with one hydroxy), cyclopropylaminocarbonyl, N, N-dimethylaminocarbonyl (the N, N -Dimethylaminocarbonyl is unsubstituted or substituted with 1 cyano), pyrrolidin-1-yl-carbonyl (wherein the pyrrolidin-1-yl-carbonyl is unsubstituted or 1 Substituted with hydroxy)), morpholinocarbonyl or methylsulfonyl, In this case, more preferable R 11 is cyclopropylaminocarbonyl, N, N-dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is substituted with one cyano), morpholinocarbonyl or methylsulfonyl.
  • Preferred R 12 is a hydrogen atom or
  • Preferred azaspiro ring structures are the following structures:
  • More preferred azaspiro ring structures are the following structures
  • a preferred ring represented by A is a benzene ring or a 6-membered heteroaromatic ring, A more preferable ring represented by A is a benzene ring, a pyridine ring or a pyrimidine ring;
  • R 11 , R 12 and R 13 are hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl And C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl is unsubstituted, hydroxy, carbamoyl, cyano, C 1-6 alkoxy (wherein the C 1-6 alkoxy is unsubstituted or substituted with hydroxy.) and optionally substituted with one to two groups the same or different and selected from the group consisting of di-C 1-6 alkylamino .
  • Preferred X is -O-
  • Preferred Y is ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl; More preferred Y is propane-1,3-diyl;
  • R 21 is preferably C 1-6 alkyl (the C 1-6 alkyl is not substituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted) Substituted with 1 C 1-6 alkyl.)), Halo C 1-6 alkyl or C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted) Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, the same or different from each other);
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is not substituted) And substituted with one group selected from the group consisting of a halogen atom, C 1-6 alkyl and C 3-8 cycloalkyl).
  • R 2 is 5-oxadiazolyl (the 5-oxadiazolyl is unsubstituted or substituted with one C 1-6 alkyl), 2-pyridyl or 2-pyrimidinyl 2-pyridyl and 2-pyrimidinyl are unsubstituted or substituted with one group selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-8 cycloalkyl.
  • the compound of the present invention is an azaspiroalkane compound and may be a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention” as appropriate).
  • Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, mineral salts such as methanesulfonate, ethanesulfone, and the like.
  • Acid addition salts such as acid salts, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartic acid
  • Amino acid salts such as salts, or inorganic or ammonium salts such as lithium, sodium, potassium, calcium, and magnesium salts, triethylamine salts, Isopropylamine salt, salts with organic bases such as cyclohexylamine salts.
  • the salt includes a hydrated salt.
  • the compound of the present invention may have an asymmetric center, in which case various optical isomers exist.
  • the compounds of the present invention may exist as separate optically active forms of (R) and (S) and as racemates or (RS) mixtures.
  • diastereomers by respective optical isomerism also exist.
  • the compounds of the present invention also include those containing all these types in any proportion.
  • diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.
  • the compound of the present invention may have geometric isomers such as cis isomer and trans isomer.
  • the compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.
  • the compound of the present invention has GPR119 agonist activity. Therefore, the compound of the present invention causes pancreatic ⁇ cell GLP-1 receptor activation through direct activation of pancreatic ⁇ cell GPR119 or small intestine GLP-1 secretion, and increases insulin secretion from pancreatic ⁇ cells in a hyperglycemic manner Can correct hyperglycemia.
  • pancreatic ⁇ -cell dysfunction and exhaustion are alleviated or improved by pancreatic ⁇ -cell protective action through activation of pancreatic ⁇ -cell GPR119. Therefore, it can be used as a new drug therapy having a different mechanism of action from existing anti-diabetic drugs. Diabetes includes type I diabetes, type II diabetes, and other diabetes due to specific causes.
  • the compound of the present invention can also be used for the treatment or prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout. Since the compound of the present invention has a pancreatic ⁇ -cell protective action, it can be used to improve the prognosis at the time of islet transplantation. Furthermore, the compound of the present invention can be used for ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, peripheral artery occlusion, etc.), neuropathy (sensory nerve, motor Nerves, autonomic nerves, etc.), foot gangrene, infections and other diabetic complications.
  • diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout. Since the compound of the present invention has a pancreatic ⁇ -cell protective action, it can be used to improve the progno
  • the compound of the present invention can also be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension and the like having a different mechanism of action other than the GPR119 agonistic action.
  • a therapeutic agent for diabetes a therapeutic agent for diabetic complications
  • a therapeutic agent for hyperlipidemia a therapeutic agent for hypertension and the like having a different mechanism of action other than the GPR119 agonistic action.
  • Examples of antidiabetic drugs and diabetic complications that can be used in combination include insulin preparations, insulin fragments or derivatives (INS-1), oral insulin preparations, insulin resistance improving drugs (PPAR ⁇ agonists, PPAR ⁇ / ⁇ agonists, PPAR ⁇ ). Agonists, PPAR ⁇ / ⁇ / ⁇ agonists, etc.
  • ⁇ -glucosidase inhibitors eg, voglibose, acarbose, Miglitol
  • biguanide drugs eg, metformin, buformin, phenformin
  • insulin secretagogues eg, glibenclamide, glimepiride, repaglinide, nateglinide, mitiglinide
  • glucagon receptor antagonist Insulin receptor kinase promoter, dipeptidyl peptidase IV inhibitor (eg, vildagliptin, alogliptin, sitagliptin, linagliptin, saxagliptin), SGLT inhibitor (eg, sagliflozin, canagliflozin, dapagliflozin, TS-071,
  • drugs for diabetes-related diseases examples include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid adsorbents, IBAT inhibitors, CETP inhibitors, CPT inhibitors, fibrate drugs, ACAT Inhibitor, MGAT inhibitor, DGAT inhibitor, cholesterol absorption inhibitor, pancreatic lipase inhibitor, MTP inhibitor, nicotinic acid derivative, LXR agonist, LDL receptor promoter, angiotensin converting enzyme inhibitor, angiotensin II antagonist, diuretic , Calcium antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, appetite suppressants, uric acid production inhibitors, uric acid excretion promoters, and the like.
  • the compound of the present invention can be administered alone or together with a pharmaceutically or pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically or pharmaceutically acceptable carrier or diluent When the compound of the present invention is used as a GPR119 agonist or the like, the compound of the present invention may be orally or parenterally administered as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient.
  • Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. It is desirable to administer this amount once to three times a day.
  • the agonistic effect of GPR119 of the compound of the present invention can be evaluated according to a known method such as the method described in the test method.
  • the compound of the present invention represented by the general formula (I) has desirable properties as a pharmaceutical product. For example, it is advantageous in terms of effectiveness because it has good water solubility, and is advantageous in terms of safety because it exhibits no inhibitory activity against liver metabolic enzymes. .
  • the method for producing the compound according to the present compound will be described in detail, it is not particularly limited to those exemplified. Moreover, the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction.
  • Compound (I) can be produced by a method known per se, for example, the production methods 1 to 19 shown below or a method analogous thereto.
  • the raw material compound may be used as a salt, and examples thereof include the above-mentioned “pharmaceutically acceptable salts”.
  • the compound (I-2) in which X is —O— can be produced, for example, by the following production method 1 or a method analogous thereto.
  • Step 1-1 This step is a method for producing compound (I-2) using compound (I-1). This method can be performed using a known method, the so-called Mitsunobu reaction (Synthesis, 1981, 1-28).
  • the amount of compound (I-3) used in this step is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
  • Examples of the azo compound to be used include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide) and the like.
  • the amount of the azo compound used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
  • Examples of the phosphine compound used usually include triphenylphosphine and tributylphosphine.
  • the amount of the phosphine compound used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
  • Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, diethyl ether, chloroform, dichloromethane, toluene, N, N-dimethylformamide, dimethyl sulfoxide and the like, which are not involved in the reaction. You may mix and use by the ratio. These reactions can usually be performed at room temperature to reflux temperature for 1 to 4 hours.
  • this step can be performed using methods described in the literature (Tetrahedron Letters, 1995, 36, 2531-2534, Tetrahedron Letters, 1996, 37, 2463-2466).
  • the reagent used in this step include (cyanomethylene) trimethylphosphorane, (cyanomethylene) tributylphosphorane, and the like.
  • the amount of the reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-1).
  • the solvent used for the reaction include the same solvents as described above. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • the compound (I-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (II-2) in which the ring represented by A is a 6-membered heteroaromatic ring can be produced, for example, by the following production method 2 or a method analogous thereto. .
  • Ua represents a leaving group
  • a ′ represents a 6-membered heteroaromatic ring
  • m1, m2, R 11 , R 12 , R 13 , X, Y, and R 2 have the same meaning as described above.
  • Examples of the “leaving group” represented by Ua include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • the “6-membered heteroaromatic ring” represented by A ′ has the same meaning as described above.
  • Step 2-1 This step is a method for producing compound (II-2) by reacting compound (II-1) with compound (II-3) in the presence of a base.
  • a base examples include sodium hydride, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. Is equivalent.
  • the solvent used include N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and N-methyl-2-pyrrolidone. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • the compound (II-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (III-3) in which R 11 is R 14 R 15 NCO— can be produced, for example, by the following production method 3 or a method analogous thereto.
  • the starting compound (III-1) in which R 11 is a carboxylic acid precursor (for example, ethoxycarbonyl, methoxycarbonyl, cyano, etc.) can be obtained by, for example, the production method 1 or a method analogous thereto. Can be manufactured.
  • R 14 and R 15 are the same or different and each represents a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl or saturated heterocyclyl, or R 14 and R 15 are bonded nitrogen atoms. Together with m 1, m 2, A, R 12 , R 13 , X, Y and R 2 are as defined above. ]
  • Step 3-1 This step is a method for producing compound (III-2) from compound (III-1) by hydrolysis with a base.
  • the base used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • the amount of the base used is 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (III-1).
  • the solvent used in the reaction include solvents such as methanol, ethanol, tetrahydrofuran, and water, and these solvents may be mixed and used at an appropriate ratio. These reactions can usually be performed at room temperature to reflux temperature.
  • Step 3-2 This step is a method for producing compound (III-3) by condensing compound (III-2) and compound (III-4).
  • This reaction can be performed by a known method, for example, using a condensing agent in the presence or absence of a base and an activator in a solvent that does not participate in the reaction.
  • the amount of compound (III-4) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the condensing agent used in the reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, diethyl cyanophosphonate and the like.
  • the amount of the condensing agent to be used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the activator used in the reaction include 1-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide and the like.
  • the amount of the activator used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, and pyridine.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the solvent used for the reaction include N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, water and the like, which are not involved in the reaction. May be mixed and used at an appropriate ratio. These reactions can usually be performed at 0 to 100 ° C.
  • the compound (III-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • R 2 is (c) a compound (IV-3) which is a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) or a compound (IV-5) which is a substituted oxadiazolyl )
  • IV-3 which is a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) or a compound (IV-5) which is a substituted oxadiazolyl
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different. Production method 4:
  • compound (IV-6) represents a 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) having the leaving group Ub as a substituent
  • R 22 represents C 1 -6 alkyl or C 3-8 cycloalkyl, m1, m2, A, R 11 , R 12 , R 13 , X and Y are as defined above.
  • Examples of the “leaving group” represented by Ub include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • “C 1-6 alkyl” for R 22 is as defined above.
  • “C 3-8 cycloalkyl” represented by R 22 is as defined above.
  • Step 4-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
  • the acid used for the reaction usually include 4M hydrogen chloride / ethyl acetate solution, 4M hydrogen chloride / 1,4-dioxane solution, trifluoroacetic acid and the like.
  • the amount of the acid used is 5 to 50 equivalents, preferably 10 to 30 equivalents, relative to 1 equivalent of compound (IV-1).
  • Examples of the solvent used for the reaction include ethyl acetate, tetrahydrofuran, 1,4- Examples include solvents that do not participate in the reaction, such as dioxane, methanol, ethanol, water, chloroform, and dichloromethane, and these solvents may be mixed and used at an appropriate ratio. These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • Step 4-2 This step is a method for producing compound (IV-3) from compound (IV-2) and compound (IV-6).
  • Compound (IV-3) can be produced by reacting compound (IV-2) with compound (IV-6) in the presence or absence of a base.
  • Examples of the compound (IV-6) used in this reaction include 2-chloro-5-isopropylpyridine, 2-chloro-5-methylpyridine, 2,5-dichloropyridine and the like.
  • the amount of compound (IV-6) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate and potassium carbonate, and pyridine.
  • the amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
  • Examples of the solvent used in the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, tetrahydrofuran, 2-propanol and the like, which are not involved in the reaction. You may mix and use. These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
  • Compound (IV-3) can be produced by reacting compound (IV-2) with compound (IV-6) in the presence of a metal catalyst and a base. This reaction can be carried out in an inert gas atmosphere such as argon or nitrogen in a solvent that does not participate in the reaction in the presence of a palladium catalyst, a base, and in the presence or absence of a phosphine compound.
  • the amount of compound (IV-6) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the palladium catalyst used in the reaction include (1,3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] palladium.
  • the amount of the palladium catalyst to be used is generally 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IV-2).
  • Examples of the phosphine compound used in the reaction include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 1,1′-bis (diphenylphosphino) ferrocene, and 4,5′-bis (diphenyl). Phosphino) -9,9'-dimethylxanthene and the like.
  • the amount of the phosphine compound used is usually 0.02 to 2 equivalents, preferably 0.2 to 1 equivalent.
  • Examples of the base used in the reaction include alkali metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide and sodium phenoxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, potassium phosphate and the like And alkali metal phosphates.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used for the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like, which are not involved in the reaction.
  • Step 4-3 This step is a method for producing compound (IV-4) by reacting compound (IV-2) with cyanogen bromide in the presence of a base.
  • the amount of cyanogen bromide used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used in the reaction usually include sodium acetate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine and the like.
  • the amount of the base used is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, water, ethanol, methanol, and the like, and these solvents may be mixed and used at an appropriate ratio. These reactions are usually performed at 0 ° C. to reflux temperature, and can be performed in 1 to 24 hours.
  • Step 4-4 is a method for producing compound (IV-5) by reacting compound (IV-4) with compound (IV-7) in the presence of zinc chloride and then treating with hydrochloric acid.
  • This step can be performed by a known method, for example, the method described in WO200808204 or a method analogous thereto.
  • Examples of the compound (IV-7) used in this reaction include N′-hydroxy-2-methylpropanimidamide and the like.
  • the amount of compound (IV-7) to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-4).
  • the amount of zinc chloride to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-4).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, and ethyl acetate. These solvents may be mixed and used at an appropriate ratio. This reaction is usually carried out at 0 ° C. to 50 ° C. for 15 minutes to 24 hours.
  • Examples of the solvent used in the treatment with hydrochloric acid include solvents that do not participate in the reaction, such as ethanol, methanol, diethyl ether, tetrahydrofuran, and 1,4-dioxane. These solvents may be used by mixing at an appropriate ratio. good. This reaction is usually carried out at room temperature to reflux temperature for 1 to 24 hours.
  • the compound (IV-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • R 2 is (b) -COOR 21 ⁇ R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3- Substituted with 8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups).
  • ⁇ (V-1) can be produced, for example, by the following production method 5 or a method analogous thereto. Production method 5:
  • Uc is a leaving group, and m1, m2, A, R 11 , R 12 , R 13 , X, Y and R 21 are as defined above].
  • Examples of the “leaving group” represented by Uc include leaving groups such as chlorine atom, bromine atom, iodine atom, methylimidazolium and 4-nitrophenoxy.
  • Step 5-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 5-2 This step is a method for producing compound (V-1) from compound (IV-2).
  • Compound (V-1) can be produced by reacting compound (IV-2) with compound (V-2) in the presence of a base.
  • the amount of compound (V-2) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the compound (V-2) used in the reaction include isopropyl chloroformate, isobutyl chloroformate, 1-methylcyclopropyl chloroformate, 1- ⁇ [(1-fluoro-2-methylpropan-2-yl) oxy] Carbonyl ⁇ -3-methyl-4,5-dihydro-1H-imidazol-3-ium iodide, 1- ⁇ [(1,1-difluoro-2-methylpropan-2-yl) oxy] carbonyl ⁇ -3-methyl
  • Examples include -4,5-dihydro-1H-imidazol-3-ium iodide, 1-methylcyclopropyl 4-nitrophenyl carbonate, and N- (methylcyclopropyloxycarbonyloxy) succinimide.
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, sodium hydroxide and pyridine. N, N-dimethyl-4-aminopyridine and the like.
  • the amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
  • Examples of the solvent used in the reaction include chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, methanol, ethanol, water, ethyl acetate, acetonitrile, acetone, toluene, and other solvents that do not participate in the reaction. These solvents may be mixed and used at an appropriate ratio. These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • Compound (V-1) can be produced by reacting compound (IV-2) with compound (V-3) in the presence of triphosgene.
  • the amount of compound (V-3) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the compound (V-3) used in the reaction include cyclopropanemethanol, 1-methylcyclopropanemethanol, cyclopentanol, neopentyl alcohol and the like.
  • Examples of the base used in the reaction include tertiary aliphatic amines such as triethylamine, aromatic heterocyclic amines such as pyridine, and the like.
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as dichloromethane, chloroform, and tetrahydrofuran, and these solvents may be mixed and used at an appropriate ratio. These reactions can be usually performed at 0 ° C. to room temperature for 5 minutes to 24 hours.
  • the thus obtained compound (V-1) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-6 8 cycloalkyl is unsubstituted or substituted with 1 group selected from the group consisting of trifluoromethyl and C 1-6 alkyl. ]
  • Compounds (VI-1), (VI-2), (VI-4) and (VI-6) which are halo C 1-6 alkyl or C 3-8 cycloalkyl can be produced, for example, by the following production method 6 or It can manufacture by the method according to this. Production method 6:
  • Ud represents a leaving group
  • Ue represents a hydroxy or halogen atom
  • R 23 and R 24 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 3-8 cycloalkyl, or R 23 and R 24 together with the carbon atoms to which they are attached form C 3-8 cycloalkyl
  • R 25 represents a hydrogen atom, C 1-5 alkyl or C 3-8 cycloalkyl
  • R 26 and R 27 may be the same or different and represents a hydrogen atom, C 1-5 alkyl or C 3-8 cycloalkyl, or R 26 and R 27 together with the carbon atom to which they are attached represent C 3-8 cycloalkyl.
  • Examples of the “leaving group” represented by Ud include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • Examples of the “halogen atom” represented by Ue include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1-5 alkyl represented by R 23 , R 24 and R 25 represents linear or branched alkyl having 1 to 5 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl and the like.
  • C 1-4 alkyl represented by R 26 and R 27 are as defined above.
  • Step 6-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 6-2 This reaction is a method for producing compound (VI-1) by reacting compound (IV-2) with compound (VI-7) in the presence or absence of a base.
  • Examples of the compound (VI-7) used in this reaction include 2,2-difluoropropyl 4-methylbenzenesulfonate.
  • the amount of compound (VI-7) to be used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, sodium hydroxide and pyridine. N, N-dimethyl-4-aminopyridine and the like.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used for the reaction include acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, ethanol and the like which do not participate in the reaction, and these solvents are mixed in an appropriate ratio. May be used. These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
  • the compound (VI-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 6-3 This reaction is a method for producing compound (VI-2) by carrying out reductive amination reaction from compound (IV-2) and compound (VI-8).
  • the reducing agent used in the reaction include sodium triacetoxyborohydride, sodium cyanoborohydride, borane-2-picoline complex, and the like.
  • the amount of the reducing agent used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • the solvent used for the reaction include N, N-dimethylformamide, chloroform, dichloromethane, methanol and the like. These reactions can usually be carried out at 0 ° C. to reflux temperature.
  • the compound (VI-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 6-4 This step is a method for producing compound (VI-3) by reacting compound (IV-2) with compound (VI-9).
  • Step 6-5 This step is a method for producing compound (VI-4) by reducing compound (VI-3).
  • the reducing agent used in this reaction include lithium aluminum hydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, and borane-dimethyl sulfide complex.
  • the amount of the reducing agent used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (VI-3).
  • the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, and these solvents may be used by mixing at an appropriate ratio.
  • the reaction can usually be carried out at 0 ° C. to reflux temperature.
  • the compound (VI-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 6-6 This reaction is a method for producing compound (VI-5) by reacting compound (IV-2) with compound (VI-10) in the presence or absence of a base.
  • the compound (VI-10) used in this reaction include isobutylene oxide.
  • the amount of compound (VI-10) used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, sodium hydroxide and pyridine.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • the solvent used in the reaction include N, N-dimethylformamide, acetonitrile, ethanol, methanol, 2-propanol, water, and other solvents that do not participate in the reaction, and these solvents are used by mixing at an appropriate ratio. Also good. These reactions can usually be performed at 0 to 100 ° C.
  • This reaction is a method for producing compound (VI-6) by reacting compound ((VI-5) with a fluorinating agent.
  • a fluorinating agent examples include bis (2-methoxyethyl) aminosulfur trifluoride, (diethylamino) sulfur trifluoride, and Ishikawa reagent.
  • the amount of the fluorinating agent to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (VI-5).
  • Examples of the solvent used in the reaction include dichloroethane, chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, and the like, which are not involved in the reaction. It may be used. These reactions can usually be performed at ⁇ 78 ° C. to 100 ° C.
  • the compound (VI-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (VII-1) in which R 2 is (d) C 1-6 alkylsulfonyl or C 3-8 cycloalkylsulfonyl is, for example, in accordance with the following production method 7 or the same. It can be manufactured by a method. Production method 7:
  • Uf represents a halogen atom
  • R 28 represents C 1-6 alkyl or C 3-8 cycloalkyl
  • m1, m2 A, R 11 , R 12 , R 13 , X and Y are as defined above. Indicates.
  • Examples of the “halogen atom” represented by Uf include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Step 7-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 7-2 This step is a method for producing compound (VII-1) by reacting compound (IV-2) with compound (VII-2) in the presence or absence of a base.
  • This step can be performed by a known method, for example, a method described in the literature (Journal of Medicinal Chemistry, 2008, 51, 2170-2177) or a method analogous thereto.
  • Examples of the compound (VII-2) used in the reaction include cyclopropanesulfonyl chloride.
  • the amount of compound (VII-2) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used usually include N, N-diisopropylethylamine, triethylamine, potassium carbonate and the like.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, water, and the like. These solvents may be mixed and used at an appropriate ratio. These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • the compound (VII-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Compound (I-1) which is a starting material in Production Method 1 Compound (II-1) which is a starting material in Production Method 2 (wherein Compound (II-1) wherein X is —O— is compound (I) -1) and X is —NR 3 — (II-1) is Compound (VIII-3)) and Compound (IV-1) which is the starting material in Production Methods 4 to 7 is
  • it can be produced by the following production method 8 or a method analogous thereto.
  • Ug represents hydroxy or a leaving group
  • Ua, A ′, m1, m2, A, R 11 , R 12 , R 13 , X, Y, and R 2 have the same meaning as described above.
  • Examples of the “leaving group” represented by Ug include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • Step 8-1 This step is a method for producing compound (VIII-2) by treating compound (VIII-1) under acidic conditions. This reaction can be carried out according to the method described in Process 4-1, Step 4-1.
  • Step 8-2 This step is a method for producing compound (I-1) from compound (VIII-2). This reaction can be carried out according to the methods described in Production Methods 4 to 7.
  • the compound (I-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 8-3 This step is a method for producing compound (VIII-3) from compound (I-1). This method can be performed using a known method, for example, a method described in WO2011 / 019538.
  • the thus obtained compound (VIII-3) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 8-4 This step is a method for producing compound (IV-1) from compound (VIII-1).
  • Method A When Ug of compound (VIII-4) is hydroxy, this reaction is carried out by reacting compound (VIII-1) with compound (VIII-4) using a so-called Mitsunobu reaction to give compound (IV-1) Can be manufactured. This reaction can be carried out according to the method described in Production Method 1.
  • Method B When Ug of compound (VIII-4) is a leaving group and the ring represented by A is a 6-membered heteroaryl, this reaction is carried out by reacting compound (VIII-1) with compound (VIII-) in the presence of a base. Compound (IV-1) can be produced by reacting with 4).
  • This reaction can be carried out according to the method described in Production Method 2.
  • the thus obtained compound (IV-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 8-5 This step is a method for producing compound (VIII-5) from compound (VIII-1). This can be carried out according to the method described in Step 8-3 of Production Method 8.
  • Step 8-6 This step is a method for producing compound (IV-1) from compound (VIII-5).
  • This step is a method for producing compound (IV-1) by reacting compound (VIII-5) with compound (II-3) in the presence of a base.
  • This reaction can be carried out according to the method described in Production Method 2.
  • the thus obtained compound (IV-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is the starting material in production method 8
  • compound (IX-6) wherein Y is propane-1,3-diyl is obtained, for example, from compound (IX-1) by the following production method 9 or It can manufacture by the method according to this.
  • Step 9-1 This step is a method for producing compound (IX-2) by reacting compound (IX-1) with (methoxymethyl) triphenylphosphonium chloride in the presence of a base.
  • the amount of (methoxymethyl) triphenylphosphonium chloride used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-1).
  • Examples of the base used in the reaction usually include n-butyl lithium, sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide and the like.
  • the amount of the base used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-1).
  • solvent used in the reaction examples include solvents that do not participate in the reaction, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, and benzene. These solvents are mixed in an appropriate ratio. It may be used. These reactions can be usually performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • Step 9-2 This step is a method for producing compound (IX-3) by treating compound (IX-2) under acidic conditions.
  • the acid used for the reaction usually include p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid and the like.
  • the amount of the acid used is 1 to 10 equivalents relative to 1 equivalent of compound (IX-2).
  • the solvent used for the reaction include acetonitrile, tetrahydrofuran, 1,4-dioxane, diethyl ether, water, chloroform, dichloromethane and the like, which are not involved in the reaction. These solvents are used in a mixture at an appropriate ratio. Also good.
  • These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • Step 9-3 This step is a method for producing compound (IX-4) by reacting compound (IX-3) with triethyl phosphonoacetate in the presence of a base.
  • the amount of triethyl phosphonoacetate used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-3).
  • Examples of the base used usually include n-butyllithium, sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide and the like.
  • the amount of the base used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-3).
  • solvent used in the reaction examples include solvents that do not participate in the reaction, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, and benzene. These solvents are mixed in an appropriate ratio. It may be used. These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • Step 9-4 This step is a method for producing compound (IX-5) by reducing compound (IX-4).
  • This reaction can be performed in the presence of a metal and hydrogen gas in a solvent that does not participate in the reaction.
  • the metal used include palladium, nickel, platinum and the like.
  • the amount of the metal used is 0.1 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IX-4).
  • the hydrogen pressure used in the reaction is from normal pressure to 10 atm, preferably from normal pressure to 4 atm.
  • Examples of the solvent used for the reaction include methanol, ethanol, water, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, and the like, which are not involved in the reaction, and these solvents may be used by mixing at an appropriate ratio. These reactions can usually be performed at room temperature to reflux temperature.
  • Step 9-5 This step is a method for producing compound (IX-6) by reducing compound (IX-5).
  • the reducing agent used in this reaction include lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, lithium aluminum hydride, diisobutylaluminum hydride and the like.
  • the amount of the reducing agent used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IX-5).
  • Examples of the solvent used in this reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, diethyl ether, 1,4-dioxane, ethanol, methanol, and the like, and these solvents may be used in an appropriate ratio. These reactions can be usually performed at 0 ° C. to reflux temperature for 30 minutes to 24 hours.
  • the thus obtained compound (IX-6) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (IX-1) which is the starting material in production method 9
  • compound (X-4) wherein m1 is 1 and m2 is 1 is obtained, for example, from compound (X-1) by the following production method 10 or Can be produced by a method according to the above.
  • the starting compound (X-1) can be produced by a method known per se. Production method 10:
  • Steps 10-1 to 10-3 This step is a method for producing compound (X-4) from compound (X-1).
  • This method can be carried out using a known method, for example, the method described in Chemical & Pharmaceutical Bulletin, 2004, 675-687.
  • the compound (X-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (IX-1) which is the starting material in production method 9
  • compound (XI-4) in which m1 is 1 and m2 is 2 is obtained, for example, from compound (XI-1) by the following production method 11 or Can be produced by a method according to the above.
  • the starting compound (XI-1) can be produced by a method known per se. Production method 11:
  • This step is a method for producing compound (XI-4) from compound (XI-1).
  • This step can be performed by a known method, for example, the method described in Chemistry-a European Journal, 2009, 9773-9784, or a method analogous thereto.
  • the compound (XI-4) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (IX-1) which is the starting material in production method 9
  • compound (XII-3) wherein m1 is 2 and m2 is 2 is obtained, for example, from compound (XII-1) by the following production method 12 or It can be manufactured by a method according to the above.
  • the starting compound (XII-1) can be produced by a method known per se. Production method 12:
  • Steps 12-1 to 12-2 This step is a method for producing compound (XII-3) from compound (XII-1).
  • This method can be performed using a known method, for example, a method described in WO2010 / 049146.
  • the thus obtained compound (XII-3) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (XIII-7) wherein Y is propane-1,3-diyl, m1 is 0 and m2 is 1, for example, the compound (XIII From 1) it can be produced by the following production method 13 or a method analogous thereto.
  • the starting compound (XIII-1) can be produced by a method known per se. Production method 13:
  • Step 13-1 This step is a method for producing compound (XIII-2) by reacting compound (XIII-1) with phosphonoacetic acid triethyl in the presence of a base. This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
  • Step 13-2 This step is a method for producing compound (XIII-3) by reacting compound (XIII-2) with trimethylsulfoxonium salt in the presence of a base. Examples of the trimethylsulfoxonium salt used in the reaction include trimethylsulfoxonium iodide, trimethylsulfoxonium bromide, trimethylsulfoxonium chloride, and the like.
  • the amount of the trimethylsulfoxonium salt to be used is generally 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (XIII-2).
  • the base used in the reaction include sodium hydride and potassium tert-butoxide.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (XIII-2).
  • the solvent used for the reaction include solvents that do not participate in the reaction, such as dimethyl sulfoxide, and these solvents may be mixed and used at an appropriate ratio. These reactions are usually carried out at room temperature to 100 ° C. for 5 to 72 hours. [Step 13-3] This step is a method for producing compound (XIII-4) by reducing compound (XIII-3).
  • This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
  • This step is a method for producing compound (XIII-5) by reacting compound (XIII-4) with triphenylphosphine and iodine in the presence of imidazole.
  • the amount of imidazole used in this reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (XIII-5).
  • the amount of triphenylphosphine used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (XIII-5).
  • the amount of iodine used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (XIII-5).
  • Step 13-5 This step is a method for producing compound (XIII-6) by reacting compound (XIII-5) with tert-butyl acetate and lithium diisopropylamide in the presence of N, N′-dimethylpropyleneurea.
  • the amount of tert-butyl acetate used in this reaction is usually 1 to 5 equivalents, preferably 1.5 to 4 equivalents, relative to 1 equivalent of compound (XIII-5).
  • the amount of lithium diisopropylamide used in this reaction is usually 1 to 5 equivalents, preferably 1.5 to 4 equivalents, per 1 equivalent of tert-butyl acetate.
  • substitute compounds for N, N′-dimethylpropyleneurea used in the reaction include hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, and tetramethylurea.
  • Step 13-6 This step is a method for producing compound (XIII-7) by reducing compound (XIII-6). This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
  • the thus obtained compound (VIII-7) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is the starting material in production method 8 compound (XIV-3) wherein Y is ethane-1,2-diyl is obtained, for example, from compound (IX-1) by the following production method 14 or It can manufacture by the method according to this.
  • Compound (IX-1) as a starting material can be produced by the method described in Production methods 10 to 12 or a method analogous thereto. Production method 14:
  • Step 14-1 This step is a method for producing compound (XIV-1) by reacting compound (IX-1) with triethyl phosphonoacetate in the presence of a base. This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
  • Step 14-2 This step is a method for producing compound (XIV-2) by reducing compound (XIV-1). This can be carried out according to the method described in Step 9-4 of Production Method 9.
  • Step 14-3 This step is a method for producing compound (XIV-3) from compound (XIV-2).
  • This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
  • the thus obtained compound (XIV-3) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is the starting material in production method 8
  • the starting compound (XIII-4) can be produced by the method described in Production Method 13 or a method analogous thereto.
  • This step is a method for producing compound (XV-1) by oxidizing compound (XIII-4).
  • This reaction can be performed using Dess-Martin oxidation or the like.
  • the oxidizing agent used in the reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (XIII-4).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform and dichloromethane, and these solvents may be used by mixing at an appropriate ratio.
  • These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • this reaction can be performed using a so-called Swan oxidation reaction (J. Org. Chem. 1976, 41, 3329.), 2-iodoxybenzoic acid (IBX) oxidation or the like.
  • Step 15-2 This step is a method for producing compound (XV-2) by reacting compound (XV-1) with (methoxymethyl) triphenylphosphonium chloride in the presence of a base. This can be carried out according to the method described in Step 9-1 of Production Method 9.
  • Step 15-3 This step is a method for producing compound (XV-3) by treating compound (XV-2) under acidic conditions. This can be carried out according to the method described in Step 9-2 of Production Method 9.
  • Step 15-4 This step is a method for producing compound (XV-4) by reducing compound (XV-3). This can be carried out according to the method described in Step 9-5 of Production Method 9.
  • the thus obtained compound (XV-4) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is a starting material in production method 8
  • compound (XVI-5) wherein Y is butane-1,4-diyl is synthesized, for example, from compound (XVI-1) by the following production method 16 or It can manufacture by the method according to this.
  • the starting compound (XVI-1) can be produced by the method described in Production Methods 14 to 15 or a method analogous thereto.
  • Step 16-1 This step is a method for producing compound (XVI-2) by oxidizing compound (XVI-1). This can be carried out according to the method described in Step 15-1 of Production Method 15.
  • Step 16-2 This step is a method for producing compound (XVI-3) by reacting compound (XVI-2) with triethyl phosphonoacetate in the presence of a base. This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
  • Step 16-3 This step is a method for producing compound (XVI-4) by reducing compound (XVI-3). This can be carried out according to the method described in Step 9-4 of Production Method 9.
  • Step 16-4 This step is a method for producing compound (XVI-5) by reducing compound (XVI-4). This can be carried out according to the method described in Step 9-5 of Production Method 9.
  • the compound (XVI-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (XVII-1) in which R 2 is (e) C 1-6 alkylcarbonyl or C 3-8 cycloalkylcarbonyl is, for example, in accordance with the following Production method 17 or the like. It can be manufactured by a method. Production method 17:
  • Step 17-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 17-2 This step is a method for producing compound (XVII-1) by reacting compound (IV-2) with compound (XVII-2). This reaction can be carried out using the method described in Step 6-4 of Production Method 6.
  • R 2 is di-C 1-6 alkylamino carbonyl
  • compound (XVIII-1) and C 1-6 compound alkylaminocarbonyl (XVIII-2) is, for example, the following It can be produced by production method 18 or a method analogous thereto.
  • Step 18-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 18-2 This step is a reaction for obtaining compound (XVIII-1) by reacting compound (IV-2) with compound (XVIII-3) in the presence of a carbonylating reagent.
  • the carbonylation reagent used here is 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, triphosgene, etc.
  • the amount of reagent used is usually 1 to 3 equivalents, preferably 1 Is equivalent.
  • a base such as triethylamine, pyridine or N-methylmorpholine may coexist.
  • the solvent used in the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these solvents may be used by mixing at an appropriate ratio. These reactions are usually carried out at room temperature to 80 ° C. for 30 minutes to 48 hours.
  • Step 18-3 This step is a reaction for obtaining the compound (XVIII-2) by reacting the compound (IV-2) with the compound (XVIII-4).
  • a base such as triethylamine, pyridine or N-methylmorpholine may coexist.
  • the solvent used in the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these solvents may be used by mixing at an appropriate ratio. These reactions are usually carried out at room temperature to 80 ° C. for 30 minutes to 24 hours.
  • Ud is a leaving group
  • Z is a single bond or C 1-3 alkanediyl
  • R 32 is C 1-3 alkyl
  • A, R 11 , R 12 , R 13 , R 2 and R 3 are as defined above.
  • Examples of the “leaving group” represented by Ud include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • C 1-3 alkyl represented by R 32 is linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl and isopropyl.
  • C 1-3 alkanediyl represented by Z represents a divalent hydrocarbon group having 1 to 3 carbon atoms, and examples thereof include methanediyl, ethane-1,2-diyl, and propane-1,3-diyl. Can be mentioned.
  • Step 19-1 This step is a reaction in which the compound (XIX-9) is obtained from the compound (XIX-10) by hydrolysis with a base. This reaction can be carried out using the method described in Process 3-1, Step 3-1.
  • Step 19-2 This step is a method for producing compound (XIX-7) by condensing compound (XIX-9) and compound (XIX-8). This reaction can be carried out using the method described in Step 3-2 of Production Method 3.
  • Step 19-3 This step is a method for producing compound (XIX-2) by reacting compound (XIX-7) with a reducing agent. This reaction can be carried out using the method described in Process 9-5 of Production Method 9.
  • Step 19-4 This step is a method for producing compound (XIX-1) by reacting compound (XIX-2) with R 32 —CHO or R 3 —Ud. This reaction can be carried out using the method described in Step 6-2 or 6-3 of Production Method 6.
  • Step 19-5 This step is a method for producing compound (XIX-6) by treating compound (XIX-7) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 19-6 This step is a method for producing compound (XIX-5) from compound (XIX-6). This reaction can be carried out according to the methods described in Production Methods 4 to 7.
  • the compound (XIX-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 19-7 This step is a method for producing compound (XIX-4) by allowing a reducing agent to act on compound (XIX-5).
  • This reaction can be carried out using the method described in Process 9-5 of Production Method 9.
  • Step 19-8 This step is a method for producing compound (XIX-3) by allowing R 32 —CHO or R 3 —Ud to act on compound (XIX-4). This reaction can be carried out using the method described in Step 6-2 or 6-3 of Production Method 6.
  • NH silica gel column chromatography refers to column chromatography separation and purification using NH 2 type silica gel (Chromatolex NH 2 type, Fuji Silysia Chemical Ltd.). The ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • MS mass spectrum
  • PlatformMLC Waters
  • LCMS-2010EV Shiadzu
  • LCMS-IT-TOF Shiadzu
  • ESI Electron-ray Ionization
  • APCI Admospheric Pressure Chemical Ionization
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (—Boc), a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated is observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment peak. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
  • Compound name is ACD / Name ver. It was named using 12.01 (trade name) or the like.
  • Dess-Martin periodinane (1.1 g) was added to a chloroform (10 ml) solution of the compound (526 mg) obtained in Reference Example 3-3 under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature.
  • the reaction mixture was diluted with chloroform, washed with a mixed solution of saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate.
  • n-butyllithium (2.76 M hexane solution, 3.9 mL) was added dropwise to a tetrahydrofuran (27 ml) solution of diisopropylamine (1.5 ml) under ice cooling, and the mixture was stirred for 30 minutes.
  • the reaction mixture was cooled at ⁇ 78 ° C., tert-butyl acetate (1.5 ml) was added, and the mixture was stirred for 30 min.
  • Dess-Martin periodinane (1.3 g) was added to a chloroform solution of the compound (600 mg) obtained in Reference Example 5-3 under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature.
  • the reaction mixture was diluted with chloroform, washed with a mixed solution of saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 1-formyl-6-azaspiro [2.5] octane-6-carboxylate.
  • tert-butyl 1- (2-oxoethyl) -6-azaspiro [2.5] octane-6-carboxylate was obtained.
  • the obtained tert-butyl 1- (2-oxoethyl) -6-azaspiro [2.5] octane-6-carboxylate was dissolved in methanol (5 ml). The reaction mixture was ice-cooled, sodium borohydride (38 mg) was added, and the mixture was stirred for 2 hr while warming to room temperature.
  • Lithium borohydride (87 mg) was added to a toluene-tetrahydrofuran (1: 1, 14 ml) solution of the compound (470 mg) obtained in Reference Example 8-4, and the mixture was stirred at 60 ° C. for 16 hours.
  • the reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off.
  • Triethylamine (4.9 ml) was added to a chloroform (90 ml) solution of ethyl 3- (7-azaspiro [3.5] non-2-yl) propanoate obtained, and isopropyl chloroformate (2. 4 ml) in chloroform (24 ml) was added dropwise. The reaction was stirred for 4 hours while warming to room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off.
  • 2-Fluoro-4-hydroxybenzoic acid 1.0 g is dissolved in N, N-dimethylformamide (32 ml), and azetidine (560 ⁇ l), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 1.6 g) and 1-hydroxybenzotriazole monohydrate (1.28 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off.
  • Methyl 5-chloropyrazine-2-carboxylate (2.4 g) was dissolved in methanol (140 mL), and 28% sodium methoxide methanol solution (2.7 mL) was added under ice cooling. The ice bath was removed and the mixture was stirred for 1 hour, and the reaction solution was evaporated under reduced pressure. Saturated aqueous ammonium chloride was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and then evaporated under reduced pressure to obtain the title compound (2.1 g).
  • Examples 2-2 to 2-6 also show the compounds obtained in Reference Examples 2-4 and 11-2 and the compounds obtained in Reference Examples 36-1, 37-1, 38-1, and 39-1.
  • synthesis was performed according to the method described in Example 2-1 using 2-bromo-5- (1H-1,2,3-triazol-1-yl) pyridine.
  • the structures, NMR data, and MS data of these compounds are shown in Tables 2-1 and 2-2.
  • Examples 3-2 to 3-96 below also refer to Reference Examples 10-2, 11-4, 12-4, 13-2, 14-2, 15-2, 16-2, 18-3, 19-3. 20-2, 21-2, 22-3, 23-2, 24-2, 25-3, 26-2, 27-2, 28-2, 29-2, 30-2, 31-2, 32 -3, 40-8, 41-2, 42-2, 43-1, 44-2, 45-2, 50-4, 51-2 and the corresponding amine compound Synthesized according to the method described in Example 3-1. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 to 3-17.
  • Examples 4-2 to 4-19 below are also the same as Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9. 1-11, 2-1 and 2-2 and the corresponding chloropyrimidine compound were synthesized according to the method described in Example 4-1.
  • the structures, NMR data, and MS data of these compounds are shown in Tables 4-1 to 4-3.
  • Examples 5-2 to 5-3 were also synthesized according to the method described in Example 5-1 using the compound obtained in Example 1-3 and the corresponding pyridine compound. .
  • the structure, NMR data and MS data of these compounds are shown in Table 5-1.
  • Example 6-1 1-methylcyclopropyl 2- ⁇ 3- [4- (methylsulfonyl) phenoxy] propyl ⁇ -7-azaspiro [3.5] nonane-7-carboxylate
  • Examples 6-2 to 6-17 below also correspond to the compounds obtained in Examples 1-1, 1-3, 1-9, 1-11, 1-12, 1-18, and 12-1. This was synthesized according to the method described in Example 6-1 using the carbamate reagent or sulfonyl chloride. The structures, NMR data, and MS data of these compounds are shown in Tables 6-1 to 6-3.
  • Example 7-2 to 7-14 below are also described in Example 7-1 using the compounds obtained in Examples 1-1, 1-3, 1-9 and the corresponding alcohol compounds. Synthesized according to the method. The structures, NMR data, and MS data of these compounds are shown in Tables 7-1 and 7-2.
  • reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure.
  • Example 1-11 The compound (515 mg) obtained in Example 1-11 was used for reaction and purification in the same manner as in Reference Example 12-2 to give 2- (3- ⁇ [6- (methylsulfonyl) pyridin-3-yl]. Oxy ⁇ propyl) -7-azaspiro [3.5] nonane (485 mg) was obtained.
  • Examples 15-2 to 15-3 below were also synthesized according to the method described in Example 15-1 using the compound obtained in Reference Example 33-1 and the corresponding amine compound. .
  • Table 8-1 shows the structures, NMR data, and MS data of these compounds.
  • the compound (500 mg) obtained above was dissolved in a mixed solution of tetrahydrofuran and N, N-dimethylformamide (1: 1) (20 mL), and sodium hydride (60%, dispersed in liquid paraffin) under ice-cooling. (102 mg) was added. After stirring for 10 minutes, 2- (2-chloroethoxy) tetrahydro-2H-pyran (375 ⁇ L) was added, the ice bath was removed, and the mixture was stirred for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off.
  • the compound (54 mg) obtained above was dissolved in ethanol (1 mL), p-toluenesulfonic acid monohydrate (4 mg) was added, and the mixture was stirred overnight at room temperature.
  • Example 18-1 The compound (37 mg) obtained in Example 18-1 was dissolved in N, N-dimethylformamide (850 ⁇ L), sodium hydride (60% w / w) (5.1 mg) was added, and the mixture was stirred for 20 minutes. To this was added iodomethane (11 ⁇ L) and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and the aqueous layer was extracted with a mixed solvent of ethyl acetate and normal hexane. Combined with the previous organic layer, the solvent was distilled off under reduced pressure through a phase separator, and the resulting residue was purified by preparative HPLC to obtain the title compound (18 mg).
  • Example 3-1 The compound (80 mg) obtained in Example 3-1 was used for reaction and purification in the same manner as in Reference Example 12-2 to give 4- [3- (7-azaspiro [3.5] non-2- Yl) propoxy] -2-fluoro-N- (2-hydroxyethyl) benzamide (74 mg). Further, sodium triacetoxyborohydride (75 mg) was added to a dimethyl sulfoxide-tetrahydrofuran solution (1: 1, 2 mL) of the compound obtained above (50 mg), pivalaldehyde (25 mg), and acetic acid (25 ⁇ L) for 3 hours. Stir.
  • the compound (88 mg) obtained above was dissolved in dimethyl sulfoxide (1 mL), sodium methanesulfinate (45 mg), N, N′-dimethylethylenediamine (9 ⁇ L) and copper trifluoromethanesulfonate (I) benzene complex ( 12 mg) was added and the mixture was stirred at 110 ° C. for 5 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the aqueous layer was extracted with a mixed solvent of ethyl acetate and normal hexane.
  • Test example 1 The compound of the present invention was added to human GPR119-expressing cells, and GPR119 agonist activity was evaluated using the amount of cAMP produced by the cells as an index.
  • Human GPR119 (NM — 178471) was amplified by polymerase chain reaction (PCR) using KOD-plus polymerase using human MTC multi-tissue cDNA panel (Clontech) as a template.
  • PCR polymerase chain reaction
  • a human GPR119 amplification product was inserted into pcDNA5 / FRT / TO (Invitrogen) as an insert, and a cell line capable of inducing expression of the human GPR119 gene in a tetracycline dose-dependent manner using the Flp-In T-Rex system was prepared.
  • Tetracycline having a final concentration of 10 ng / ml was added to the cell line to induce expression of human GPR119.
  • Cells were collected 24 hours after the expression-inducing stimulation and suspended in assay buffer (D-MEM (Invitrogen), 1 mM 3-Isobutyl-1-methylxantine (Sigma), 0.01% bovine serum albumin (Sigma)). Later, it was seeded on a 96-well half area plate (Corning) at 5000 cells / 15 ⁇ l. 15 ⁇ l of a test compound solution dissolved in assay buffer was added to each well, incubated at 37 ° C.
  • the compound concentration that activates 50% of the maximum activated GPR119 activity as 100% from the value obtained by subtracting the cAMP concentration in the presence of DMSO from the maximum cAMP concentration (Emax) under the high dose of the test compound (EC 50 ) was calculated.
  • Emax maximum activation rate of the test compound
  • cAMP concentration increase rate (% stimulation) in the presence of the test compound was calculated with the cAMP concentration in the presence of DMSO as 100%.
  • Results Tables 10-1 to 10-3 show the GPR119 agonist activities calculated based on the measurement results obtained by conducting the above tests on the compounds of the present invention.
  • Formulation examples of the compound of the present invention are shown below.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Component Compound represented by formula (I) 10mg Lactose 700mg Corn starch 274mg HPC-L 16mg 1000mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulated pore diameter: 0.5 to 1 mm), and then dried.
  • the obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.
  • HPC-L low-viscosity hydroxypropylcellulose
  • Formulation Example 2 A powder for capsule filling containing the following components is produced.
  • Component Compound represented by formula (I) 10mg Lactose 79mg Corn starch 10mg Magnesium stearate 1mg 100mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.
  • Formulation Example 3 A capsule filling granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 15mg Lactose 90mg Cornstarch 42mg HPC-L 3mg 150mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried.
  • the obtained dried granule is sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.
  • HPC-L low-viscosity hydroxypropylcellulose
  • Formulation Example 4 A tablet containing the following ingredients is produced.
  • a compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.
  • Formulation Example 5 The intravenous formulation is produced as follows. 100 mg of the compound represented by formula (I) 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 of the present invention has an excellent GPR119 agonist activity, and according to the present invention, it is possible to provide a pharmaceutical effective for the prevention or treatment of diseases derived from diabetes, thereby reducing the burden on the patient and contributing to the development of the pharmaceutical industry. Is expected to do.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Communicable Diseases (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule générale (I) et ayant une excellente activité agoniste de GPR119, ou un sel pharmaceutiquement acceptable de celui-ci. [Dans la formule générale (I), m1 représente un entier de 0-2 ; m2 représente un entier de 1-2 ; le noyau représenté par A représente un noyau benzène ou un noyau hétéroaromatique à 6 éléments ; X représente -O- ou -NR3- ; et Y représente un alcanediyle en C1-6].
PCT/JP2012/065201 2011-06-17 2012-06-14 Composé azaspiroalcane WO2012173174A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-134927 2011-06-17
JP2011134927A JP2014159376A (ja) 2011-06-17 2011-06-17 アザスピロアルカン化合物

Publications (1)

Publication Number Publication Date
WO2012173174A1 true WO2012173174A1 (fr) 2012-12-20

Family

ID=47357156

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/065201 WO2012173174A1 (fr) 2011-06-17 2012-06-14 Composé azaspiroalcane

Country Status (3)

Country Link
JP (1) JP2014159376A (fr)
TW (1) TW201313684A (fr)
WO (1) WO2012173174A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN103787839A (zh) * 2014-01-21 2014-05-14 苏州昊帆生物科技有限公司 合成2, 3, 4, 5, 6-五氟苯酚的方法
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
US9845301B2 (en) 2015-07-31 2017-12-19 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
US10329308B2 (en) 2017-01-20 2019-06-25 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors
US10858373B2 (en) 2017-01-23 2020-12-08 Pfizer Inc. Heterocyclic spiro compounds as MAGL inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008033460A2 (fr) * 2006-09-15 2008-03-20 Schering Corporation Procédé de traitement de la douleur, du diabète et des troubles du métabolisme lipidique
WO2010009195A1 (fr) * 2008-07-16 2010-01-21 Schering Corporation Dérivés hétérocycliques bicycliques et leur utilisation comme modulateurs du gpr119
WO2010123018A1 (fr) * 2009-04-24 2010-10-28 日本ケミファ株式会社 Dérivé de diazaspiroalcane
WO2012041158A1 (fr) * 2010-09-29 2012-04-05 上海恒瑞医药有限公司 Composé tricyclique, procédé de préparation et utilisation pharmaceutique associés
WO2012047703A2 (fr) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008033460A2 (fr) * 2006-09-15 2008-03-20 Schering Corporation Procédé de traitement de la douleur, du diabète et des troubles du métabolisme lipidique
WO2010009195A1 (fr) * 2008-07-16 2010-01-21 Schering Corporation Dérivés hétérocycliques bicycliques et leur utilisation comme modulateurs du gpr119
WO2010123018A1 (fr) * 2009-04-24 2010-10-28 日本ケミファ株式会社 Dérivé de diazaspiroalcane
WO2012041158A1 (fr) * 2010-09-29 2012-04-05 上海恒瑞医药有限公司 Composé tricyclique, procédé de préparation et utilisation pharmaceutique associés
WO2012047703A2 (fr) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-pipéridines utiles comme bloqueurs des canaux sodiques

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN103787839A (zh) * 2014-01-21 2014-05-14 苏州昊帆生物科技有限公司 合成2, 3, 4, 5, 6-五氟苯酚的方法
CN103787839B (zh) * 2014-01-21 2015-12-02 苏州昊帆生物科技有限公司 合成2,3,4,5,6-五氟苯酚的方法
US9845301B2 (en) 2015-07-31 2017-12-19 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
US10428034B2 (en) 2015-07-31 2019-10-01 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
US10723711B2 (en) 2015-07-31 2020-07-28 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
US10329308B2 (en) 2017-01-20 2019-06-25 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors
US10626125B2 (en) 2017-01-20 2020-04-21 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors
US10858373B2 (en) 2017-01-23 2020-12-08 Pfizer Inc. Heterocyclic spiro compounds as MAGL inhibitors

Also Published As

Publication number Publication date
TW201313684A (zh) 2013-04-01
JP2014159376A (ja) 2014-09-04

Similar Documents

Publication Publication Date Title
TWI606039B (zh) Ａｐｊ受體之三唑激動劑
WO2012173174A1 (fr) Composé azaspiroalcane
US11548871B2 (en) Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
JP2022545359A (ja) 嚢胞性線維症膜コンダクタンス制御因子モジュレーター
JP2011529483A (ja) フッ素化ヘテロアリール
WO2007037534A1 (fr) Derive indole substitue en position 2 par un groupe heteroaryle
JP2010138073A (ja) ピコリン酸アミド化合物
JP2021526123A (ja) オートタキシン阻害剤とその使用
WO2017001812A1 (fr) Composés et leur utilisation en tant qu'inhibiteurs de la n-myristoyl transférase
CN115942972A (zh) Lpa受体拮抗剂及其用途
WO2012086735A1 (fr) Composé hétérocyclique condensé
CN109153664B (zh) 吡啶基衍生物、药物组合物及其作为含铜胺氧化酶3抑制剂的用途
KR20240007233A (ko) Lpa 수용체 길항제 및 이의 용도
KR20240005892A (ko) Lpa 수용체 길항제 및 이의 용도
JP2014118368A (ja) アザスピロアルカン化合物を有効成分として含有する血糖低下作用薬
TWI591064B (zh) ２－吡啶酮化合物
KR20190036550A (ko) 폐 섬유증 치료용 조성물
TW201625545A (zh) 取代唑化合物及糖尿病治療藥
JP2014024838A (ja) 縮合複素環化合物を有効成分として含有する血糖低下作用薬
US11999717B2 (en) Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
JP6048533B2 (ja) ２−ピリドン化合物を含有する医薬
WO2024054840A1 (fr) Composés macrocycliques, compositions et procédés d'utilisation associés
CN113015736A (zh) 用于诱导软骨发生以治疗关节损害的6-羟基-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12800302

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12800302

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP