WO2012086735A1 - Composé hétérocyclique condensé - Google Patents

Composé hétérocyclique condensé Download PDF

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WO2012086735A1
WO2012086735A1 PCT/JP2011/079745 JP2011079745W WO2012086735A1 WO 2012086735 A1 WO2012086735 A1 WO 2012086735A1 JP 2011079745 W JP2011079745 W JP 2011079745W WO 2012086735 A1 WO2012086735 A1 WO 2012086735A1
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substituted
alkyl
unsubstituted
group
cycloalkyl
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PCT/JP2011/079745
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Japanese (ja)
Inventor
綾子 坊野
大輔 松田
憲一 大嶽
浩行 柿沼
陽平 小橋
円 川村
史康 塩澤
憲一 川部
由紀 岩田
まこと 濱田
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大正製薬株式会社
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Priority to JP2012549862A priority Critical patent/JPWO2012086735A1/ja
Publication of WO2012086735A1 publication Critical patent/WO2012086735A1/fr

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    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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.
  • OOA oleylethanolamide
  • 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.
  • Patent Document 1 certain bipiperidinyl derivatives
  • Patent Document 2 and Non-Patent Document 4 pyrimidinyl derivatives
  • oxadiazolyl derivatives see Patent Document 3
  • thiazolyl derivatives see Patent Document 4
  • Patent Documents 5 to 12 A compound of the formula (A) shown below, which is structurally similar, has been reported, but the use of the compound of the present application is in that it is intended for diseases caused by the activation of p38 kinase such as rheumatoid arthritis. It is different from the use (Patent Document 13).
  • An object of the present invention is to provide an excellent GPR119 agonist.
  • Substituent A is phenyl or 5- or 6-membered heteroaryl (the phenyl and 5- or 6-membered heteroaryl are unsubstituted or selected from 1 to 3 selected from the following substituent group Z1 in the same or different manner: Substituted with 1 group.)
  • Indicate Substituent group Z1 is a halogen atom, carbamoyl, sulfamoyl, cyano, cyanamide, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or halogen atom, hydroxy, carbamoyl, sulfamoyl, C 3-8 Cycloalkyl, aryl, heteroaryl, partially saturated heteroaryl, saturated heterocyclyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, mono C 1-6 alkylaminocarbonyl, diC 1-6 alkylamino carbonyl, heterocyclylcarbonyl saturated, substituted with
  • C 1-6 alkylsulfonylamino C 1-6 alkylsulfonyl (wherein the C 1-6 alkylsulfonyl is one which is unsubstituted or selected from the group consisting of hydroxy, carbamoyl and C 1-6 alkoxy)
  • a mono-C 1-6 alkylaminosulfonyl the mono-C 1-6 alkylaminosulfonyl being unsubstituted or substituted with one hydroxy.
  • Show W represents a single bond, —O—, —NH—, —OCH 2 — or —CH 2 O—,
  • X represents a nitrogen atom or CR 21 ;
  • Y 1 represents a nitrogen atom or CR 22 ;
  • Y 2 represents a nitrogen atom or CR 23 ,
  • Y 3 represents a nitrogen atom or CR 24 ,
  • R 21 , R 22 , R 23 and R 24 are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
  • Substituent B is (A) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 groups selected from the group consisting of a halogen atom and hydroxy), C 3- 8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with 1 C 1-6
  • Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl)
  • B —COOR 31 (wherein R 31 is C 1-6 alkyl ⁇ the C 1-6 alkyl is unsubstituted, halogen atom, cyano, C 3-8 cycloalkyl (the C 3-8 cycloalkyl Is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (the C 1-6 alkoxy is Unsubstituted or substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is substituted) Or substituted with 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.], He
  • Substituent A is phenyl or 5- or 6-membered heteroaryl (the phenyl and 5- or 6-membered heteroaryl are unsubstituted or selected from 1 to 3 selected from the following substituent group Z2 in the same or different manner: Substituted with 1 group.)
  • Indicate Substituent group Z2 is a halogen atom, carbamoyl, cyano, cyanamide, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted, halogen atom, hydroxy, carbamoyl, C 1-6 alkoxy, and C Substituted with 1 to 3 groups identically or differently selected from the group consisting of 1-6 alkylsulfonyl), C 3-8 cycloalkyl, aryl, heteroaryl, partially saturated heteroaryl C 1-6 alkoxy (the C 1-6 alkoxy is unsubstituted or substituted with 1 to 3
  • C 1-6 alkylsulfonylamino C 1-6 alkylsulfonyl (wherein the C 1-6 alkylsulfonyl is one which is unsubstituted or selected from the group consisting of hydroxy, carbamoyl and C 1-6 alkoxy)
  • a mono-C 1-6 alkylaminosulfonyl the mono-C 1-6 alkylaminosulfonyl being unsubstituted or substituted with one hydroxy.
  • Show W represents a single bond, —O—, —OCH 2 — or —CH 2 O—, X represents a nitrogen atom or CR 21 ; Y 1 represents CR 22 Y 2 represents a nitrogen atom or CR 23 , Y 3 represents CR 24 , R 21 , R 22 , R 23 and R 24 are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
  • Substituent B is (A) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 groups selected from the group consisting of a halogen atom and hydroxy), C 3- 8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with 1 C 1-6 alkyl).
  • Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl)
  • B —COOR 31 (wherein R 31 is C 1-6 alkyl ⁇ the C 1-6 alkyl is unsubstituted, halogen atom, cyano, C 3-8 cycloalkyl (the C 3-8 cycloalkyl Is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (the C 1-6 alkoxy is Unsubstituted or substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is substituted) Or substituted with 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.], He
  • Substituent A is phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are 1 to 3 groups which are not substituted or are the same or different from the following substituent group Z3: Has been replaced.)
  • Indicate Substituent group Z3 is a halogen atom, carbamoyl, cyano, cyanamide, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkylsulfonyl).
  • the carbonyl is unsubstituted or substituted with 1 to 3 groups selected identically or differently from the group consisting of hydroxy, C 1-6 alkoxy and diC 1-6 alkylamino), di.
  • C 1-6 alkylaminocarbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted, is substituted with one hydroxy.), heterocyclylcarbonyl saturated [ Heterocyclylcarbonyl Saturated, unsubstituted or substituted with hydroxy, C 1-6 alkyl (said C 1-6 alkyl is unsubstituted or substituted with substituted with one hydroxy.), Di C 1- Substituted with one group selected from the group consisting of 6 alkylamino and C 1-6 alkylsulfonyl.
  • Substituent B is (A) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 groups selected from the group consisting of a halogen atom and hydroxy), C 3- 8 cycloalkyl or C 3-8 cycloalkyl C 1-6 alkyl, (B) -COOR 31 [wherein R 31 is C 1-6 alkyl or C 3
  • a 5- or 6-membered heteroaryl represented by the above is a non-substituted or halogen atom, C 1-6 alkyl (the C 1-6 Alkyl is unsubstituted or substituted with one hydroxy.), C 2-6 alkenyl, C 3-8 cycloalkyl, C 1-6 alkoxy and C 1-6 alkoxycarbonyl Substitution with 1 to 3 groups selected identically or differently. ] It is providing the compound as described in (1) which shows this, or its pharmaceutically acceptable salt.
  • Substituent B is (a) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 groups selected from the group consisting of a halogen atom and hydroxy).
  • Substituent B is (b) -COOR 31 (R 31 is C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, cyano, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (the C 1 -6 alkoxy is unsubstituted or substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl Is substituted or substituted with 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.], Heteroaryl (said heteroaryl is unsubstituted or substituted with a halogen atom and a C 1-6 a Substituted
  • Substituent B is (c) the following formula ( ⁇ )
  • Substituent B is (c) the following formula ( ⁇ )
  • a 5- or 6-membered heteroaryl represented by the above [5 or 6-membered heteroaryl represented by the formula ( ⁇ ) is a non-substituted or halogen atom, C 1-6 alkyl (the C 1-6 Alkyl is unsubstituted or substituted with one hydroxy.), C 2-6 alkenyl, C 3-8 cycloalkyl, C 1-6 alkoxy and C 1-6 alkoxycarbonyl Substitution with 1 to 3 groups selected identically or differently. ] (1), (2), (3), or a pharmaceutically acceptable salt thereof.
  • the object is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein Y 1 represents CH and Y 3 represents CH.
  • the object is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein Y 2 represents a nitrogen atom.
  • the object is to provide a compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof, wherein X represents a nitrogen atom.
  • 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, “i” is iso, “s” is secondary, “t” and “tert” are tertiary, “c” is cyclo, and “o” is ortho. , “M” represents meta, and “p” represents para.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like.
  • C 2-6 alkyl refers to a linear or branched alkyl having 2 to 6 carbon atoms. Examples include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like. “C 2-6 alkenyl” refers to a straight or branched alkenyl having 2 to 6 carbon atoms.
  • C 2-6 alkynyl refers to linear or branched alkynyl having 2 to 6 carbon atoms. Examples include ethynyl, n-propynyl, n-butynyl, n-pentynyl, n-hexynyl and the like.
  • C 3-8 cycloalkyl refers to a cyclic alkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Aryl refers to a monocyclic hydrocarbon aromatic ring or condensed polycyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms. For example, phenyl, naphthyl, anthryl and the like can be mentioned.
  • Heteroaryl is a 5- to 7-membered monocyclic group consisting of one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen and the same or different and 1 to 6 carbon atoms.
  • An aromatic heterocyclic ring or a condensed polycyclic aromatic heterocyclic ring composed of 9 to 14 atoms 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.
  • “5- or 6-membered 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 5 carbon atoms.
  • Examples include imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like.
  • “6-membered heteroaryl” is a single-membered 6-membered ring consisting of one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen and the same or different and 1 to 5 carbon atoms. A cyclic aromatic heterocycle is shown.
  • Partially saturated 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 7 carbon atoms.
  • An 8-membered partially saturated monocyclic aromatic heterocycle is shown. For example, oxazolinyl, thiazolinyl and the like can be mentioned.
  • “Saturated heterocyclyl” is a 4- to 7-membered monocyclic ring composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or one to six carbon atoms. A saturated heterocyclic ring is shown. Examples include azetidinyl, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, piperazinyl, pyrazolidinyl, quinuclidinyl, morpholinyl, oxetanyl, oxolanyl, oxanyl and the like.
  • C 3-8 cycloalkyl C 1-6 alkyl refers to a C 1-6 alkyl having a substituent "C 3-8 cycloalkyl” of the. Examples thereof include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl and the like.
  • Aryl C 1-6 alkyl refers to C 1-6 alkyl having the above “aryl” as a substituent. Examples include benzyl, phenethyl, naphthylmethyl and the like.
  • Heteroaryl C 1-6 alkyl refers to C 1-6 alkyl having the above-mentioned “heteroaryl” as a substituent.
  • heteroaryl C 1-6 alkyl refers to C 1-6 alkyl having the above-mentioned “heteroaryl” as a substituent.
  • 2-pyridylmethyl, 2-pyridylethyl, 2-quinolylmethyl and the like can be mentioned.
  • partially saturated heteroaryl C 1-6 alkyl refers to a C 1-6 alkyl having said a "partially saturated heteroaryl” as a substituent.
  • oxazolinylmethyl, thiazolinylmethyl and the like can be mentioned.
  • Heterocyclyl C 1-6 alkyl, saturated refers to a C 1-6 alkyl having a substituent “heterocyclyl saturation” of the. Examples thereof include 2-oxetanylmethyl, 2-tetrahydrofuranylmethyl, 2-tetrahydrofuranylethyl, 3-tetrahydrofuranylmethyl, 4-tetrahydropyranylmethyl and the like.
  • C 1-6 alkoxy refers to a linear or branched alkoxy having 1 to 6 carbon atoms.
  • C 1-6 alkoxycarbonyl refers to a group in which the above “C 1-6 alkoxy” is bonded to carbonyl. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl and the like.
  • “Mono C 1-6 alkylamino” refers to an amino having one “C 1-6 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, s-butylamino, t-butylamino, n-pentylamino, isopentylamino, neopentylamino, n-hexylamino , Isohexylamino and the like.
  • “DiC 1-6 alkylamino” refers to an amino having two of the above “C 1-6 alkyl” as the same or different substituents. Examples include dimethylamino, diethylamino, di (n-propyl) amino, di (isopropyl) amino, ethylmethylamino, methyl (n-propyl) amino and the like.
  • “C 1-6 alkylcarbonyl” refers to a group in which the above “C 1-6 alkyl” is bonded to carbonyl. Examples thereof include acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl and the like.
  • C 1-6 alkylcarbonylamino refers to a group in which the above “C 1-6 alkylcarbonyl” and amino are bonded. Examples include acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, valerylamino, isovalerylamino 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 3-8 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. “Mono-saturated heterocyclylaminocarbonyl” refers to a group in which amino and carbonyl having one “saturated heterocyclyl” as a substituent is bonded.
  • Examples include pyrrolidinylaminocarbonyl, piperidinylaminocarbonyl, tetrahydrofuranylaminocarbonyl, tetrahydropyranylaminocarbonyl, tetrahydrothiophenylaminocarbonyl, tetrahydrothiopyranylaminocarbonyl and the like.
  • DiC 1-6 alkylaminocarbonyl refers to a group in which the above “diC 1-6 alkylamino” is bonded to carbonyl.
  • Examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, di (n-propyl) aminocarbonyl, di (isopropyl) aminocarbonyl, ethylmethylaminocarbonyl, methyl (n-propyl) aminocarbonyl, isopropyl (methyl) aminocarbonyl and the like.
  • the “saturated heterocyclylcarbonyl” refers to a carbonyl having the above “saturated heterocyclyl” as a substituent.
  • C 1-6 alkylsulfanyl refers to a group in which linear or branched alkyl having 1 to 6 carbon atoms and sulfanyl are bonded. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, isobutylsulfanyl, n-hexylsulfanyl and the like.
  • C 1-6 alkylsulfonyl refers to a group in which linear or branched alkyl having 1 to 6 carbon atoms and sulfonyl are bonded. Examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, n-hexylsulfonyl and the like.
  • C 1-6 alkylsulfonylamino refers to a group in which the above “C 1-6 alkylsulfonyl” is linked to amino.
  • Examples include methylsulfonylamino, n-propylsulfonylamino, isobutylsulfonylamino, n-hexylsulfonylamino and the like.
  • “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 in the present invention include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 1,1-dioxidetetrahydrothio Phenyl, 1-oxidetetrahydro-2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2-oxo-1,3-oxazolidinyl, 6-oxo-1, 1-dihydropyridazinyl and the like can be mentioned.
  • “5- or 6-membered heteroaryl represented by the formula ( ⁇ )” means
  • 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 forms of the compound of the present invention are as follows. That is, Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Substituted with 1 to 3 groups selected from the group consisting of aminocarbonyl, saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl, the same or different; Further preferred substituent A is phenyl or 3-pyridyl (the phenyl and 3-pyridyl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, Substituted with 1 to 3 groups selected from the group consisting of saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl identically or
  • Preferred X is a nitrogen atom or CR 21 , Preferred R 21 at this time is a hydrogen atom;
  • Preferred Y 1 is CR 22 Preferred R 22 at this time is a hydrogen atom;
  • Preferred Y 2 is a nitrogen atom or CR 23 , Preferred R 23 at this time is a hydrogen atom;
  • Further preferred Y 2 is a nitrogen atom;
  • Preferred Y 3 is a nitrogen atom or CR 24 , Preferred R 24 at this time is a hydrogen atom;
  • One preferred substituent B is (b) -COOR 31 Preferred R 31 at this time is C 1-6 alkyl;
  • Another preferred substituent B is (c) a 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 6-membered heteroaryl represented by the formula ( ⁇ ) is not substituted or is a halogen atom) , Substituted with one group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy.
  • substituent B is 2-pyridyl or 2-pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are not substituted, halogen atoms, C 1-6 alkyl, C 2-6 alkenyl, C 3 Substituted with one group selected from the group consisting of -8 cycloalkyl and C 1-6 alkoxy.
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Aminocarbonyl (wherein the mono C 1-6 alkylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl, or the same or different; Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1- 6 alkylaminocarbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and C 1-6 alkoxy Substituted with one or two groups
  • Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1-6 alkylamino carbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and C 1-6 alkoxy Substituted with 1 to 2 groups more or less identically selected), saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy).
  • substituent A is phenyl (the phenyl is unsubstituted or halogen atom, carbamoyl, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl is Mono-saturated heterocyclyl which is unsubstituted or substituted with one or two groups selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl.
  • Aminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is substituted with substituted or not, 1-2 groups identical to or different selected from the group consisting of hydroxy and C 1-6 alkoxy Is.), Heterocyclylcarbonyl in heterocyclylcarbonyl (saturated in saturation and is not substituted is substituted with one hydroxy.) And the same or different from the group consisting of C 1-6 alkylsulfonyl Substituted with 1 to 3 groups selected from Preferred W is a single bond or —O—.
  • Further preferred W is a single bond;
  • Preferred X is a nitrogen atom or CR 21 , Preferred R 21 at this time is a hydrogen atom, Further preferred X is a nitrogen atom;
  • Preferred Y 1 is CR 22 Preferred R 22 at this time is a hydrogen atom;
  • Preferred Y 2 is a nitrogen atom or CR 23 , Preferred R 23 at this time is a hydrogen atom;
  • Further preferred Y 2 is a nitrogen atom;
  • Preferred Y 3 is a nitrogen atom or CR 24 , Preferred R 24 at this time is a hydrogen atom, Further preferred Y 3 is a nitrogen atom;
  • One preferred substituent B is (a) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 halogen atoms), C 3-8 Cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl) , Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl).
  • substituents B are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms), C 3-8 cycloalkyl.
  • Particularly preferred substituents B at this time are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with one halogen atom) or C 3-8 cycloalkyl C 1.
  • R 31 is preferably C 1-6 alkyl [the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted)] Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (wherein the C 1-6 alkoxy is not substituted, Substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or 1 to 3 And 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.
  • Heteroaryl (the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of halogen atoms and C 1-6 alkyl) and saturated heterocyclyl (the saturated heterocyclyl Is unsubstituted or substituted with 1 C 1-6 alkyl.) And is substituted with 1 to 6 groups selected from the group consisting of: ] C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl).
  • Aryl or saturated heterocyclyl [the saturated heterocyclyl is unsubstituted or substituted with 1 C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 aryl) Is replaced by ], R 31 is more preferably C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (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.), Aryl [the aryl is unsubstituted, halogen atom, C 1-6 Substituted with one group selected from the group consisting of alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms) and C 1-6 alkoxy.
  • 1-6 selected from the group consisting of heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with 1 group.
  • C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl) or aryl;
  • Particularly preferred R 31 at this time is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or Substituted with one C 1-6 alkyl), aryl, heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one halogen atom), and is selected from the group consisting of Substituted with one group.
  • Another preferred substituent B 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.
  • substituent B is 2-pyridyl or 2-pyrimidinyl [the 2-pyridyl and 2-pyrimidinyl are not substituted, halogen atoms, cyano, C 1-6 alkyl (the C 1-6 alkyl Is unsubstituted or substituted with 1 to 3 halogen atoms.), One selected from the group consisting of C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy Substituted with a group.
  • Particularly preferred substituent B in this case is 2-pyridyl or 2-pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are not substituted, or one selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with a group).
  • One preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (III).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Substituted with 1 to 3 groups selected from the group consisting of aminocarbonyl, saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl, the same or different; Further preferred substituent A is phenyl or 3-pyridyl (the phenyl and 3-pyridyl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, Substituted with 1 to 3 groups selected from the group consisting of saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl identically or differently; Preferred W is a single bond or —O—.
  • substituent B is (b) —COOR 31 , wherein preferred R 31 is C 1-6 alkyl;
  • Another preferred embodiment of the substituent B is (c) a 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 6-membered heteroaryl is an unsubstituted, halogen atom, C 1-6 alkyl) , C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy are substituted with one group selected from the group consisting of 2-pyridyl and 2- Pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are unsubstituted or selected from the group consisting of a halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy) Substituted with one group).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Aminocarbonyl (wherein the mono C 1-6 alkylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl, or the same or different; Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1- 6 alkylaminocarbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and
  • Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1-6 alkylamino carbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and C 1-6 alkoxy Substituted with 1 to 2 groups more or less identically selected), saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy).
  • substituent A is phenyl (the phenyl is unsubstituted or halogen atom, carbamoyl, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl is Mono-saturated heterocyclyl which is unsubstituted or substituted with one or two groups selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl.
  • Aminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is substituted with substituted or not, 1-2 groups identical to or different selected from the group consisting of hydroxy and C 1-6 alkoxy Is.), Heterocyclylcarbonyl in heterocyclylcarbonyl (saturated in saturation and is not substituted is substituted with one hydroxy.) And the same or different from the group consisting of C 1-6 alkylsulfonyl Substituted with 1 to 3 groups selected from Preferred W is a single bond or —O—.
  • Further preferred W is a single bond;
  • Preferred X is a nitrogen atom or CR 21 , Preferred R 21 at this time is a hydrogen atom, Further preferred X is a nitrogen atom;
  • Preferred Y 1 is CR 22 Preferred R 22 at this time is a hydrogen atom;
  • Preferred Y 2 is a nitrogen atom or CR 23 , Preferred R 23 at this time is a hydrogen atom;
  • Further preferred Y 2 is a nitrogen atom;
  • Preferred Y 3 is a nitrogen atom or CR 24 , Preferred R 24 at this time is a hydrogen atom, Further preferred Y 3 is a nitrogen atom;
  • One preferred substituent B is (a) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 halogen atoms), C 3-8 Cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl) , Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl).
  • substituents B are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms), C 3-8 cycloalkyl.
  • Particularly preferred substituents B at this time are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with one halogen atom) or C 3-8 cycloalkyl C 1.
  • R 31 is preferably C 1-6 alkyl [the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted)] Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (wherein the C 1-6 alkoxy is not substituted, Substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or 1 to 3 And 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.
  • Heteroaryl (the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of halogen atoms and C 1-6 alkyl) and saturated heterocyclyl (the saturated heterocyclyl Is unsubstituted or substituted with 1 C 1-6 alkyl.) And is substituted with 1 to 6 groups selected from the group consisting of: ] C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl).
  • Aryl or saturated heterocyclyl [the saturated heterocyclyl is unsubstituted or substituted with 1 C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 aryl) Is replaced by ], R 31 is more preferably C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (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.), Aryl [the aryl is unsubstituted, halogen atom, C 1-6 Substituted with one group selected from the group consisting of alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms) and C 1-6 alkoxy.
  • 1-6 selected from the group consisting of heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with 1 group.
  • C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl) or aryl;
  • Particularly preferred R 31 at this time is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or Substituted with one C 1-6 alkyl), aryl, heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one halogen atom), and is selected from the group consisting of Substituted with one group.
  • Another preferred substituent B 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.
  • substituent B is 2-pyridyl or 2-pyrimidinyl [the 2-pyridyl and 2-pyrimidinyl are not substituted, halogen atoms, cyano, C 1-6 alkyl (the C 1-6 alkyl Is unsubstituted or substituted with 1 to 3 halogen atoms.), One selected from the group consisting of C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy Substituted with a group.
  • Particularly preferred substituent B in this case is 2-pyridyl or 2-pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are not substituted, or one selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with a group).
  • Another preferred embodiment of the present invention is the compound shown below or a pharmaceutically acceptable salt thereof in the following formula (IV).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Substituted with 1 to 3 groups selected from the group consisting of aminocarbonyl, saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl, the same or different; Further preferred substituent A is phenyl or 3-pyridyl (the phenyl and 3-pyridyl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, Substituted with 1 to 3 groups selected from the group consisting of saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl identically or differently; Preferred W is a single bond or —O—.
  • substituent B is (b) —COOR 31 , wherein preferred R 31 is C 1-6 alkyl;
  • Another preferred embodiment of the substituent B is (c) a 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 6-membered heteroaryl is an unsubstituted, halogen atom, C 1-6 alkyl) , C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy are substituted with one group selected from the group consisting of 2-pyridyl and 2- Pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are unsubstituted or selected from the group consisting of a halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy) Substituted with one group).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Aminocarbonyl (wherein the mono C 1-6 alkylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl, or the same or different; Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1- 6 alkylaminocarbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and
  • Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1-6 alkylamino carbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and C 1-6 alkoxy Substituted with 1 to 2 groups more or less identically selected), saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy).
  • substituent A is phenyl (the phenyl is unsubstituted or halogen atom, carbamoyl, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl is Mono-saturated heterocyclyl which is unsubstituted or substituted with one or two groups selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl.
  • Aminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is substituted with substituted or not, 1-2 groups identical to or different selected from the group consisting of hydroxy and C 1-6 alkoxy Is.), Heterocyclylcarbonyl in heterocyclylcarbonyl (saturated in saturation and is not substituted is substituted with one hydroxy.) And the same or different from the group consisting of C 1-6 alkylsulfonyl Substituted with 1 to 3 groups selected from Preferred W is a single bond or —O—.
  • Further preferred W is a single bond;
  • Preferred X is a nitrogen atom or CR 21 , Preferred R 21 at this time is a hydrogen atom, Further preferred X is a nitrogen atom;
  • Preferred Y 1 is CR 22 Preferred R 22 at this time is a hydrogen atom;
  • Preferred Y 2 is a nitrogen atom or CR 23 , Preferred R 23 at this time is a hydrogen atom;
  • Further preferred Y 2 is a nitrogen atom;
  • Preferred Y 3 is a nitrogen atom or CR 24 , Preferred R 24 at this time is a hydrogen atom, Further preferred Y 3 is a nitrogen atom;
  • One preferred substituent B is (a) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 halogen atoms), C 3-8 Cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl) , Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl).
  • substituents B are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms), C 3-8 cycloalkyl.
  • Particularly preferred substituents B at this time are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with one halogen atom) or C 3-8 cycloalkyl C 1.
  • R 31 is preferably C 1-6 alkyl [the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted)] Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (wherein the C 1-6 alkoxy is not substituted, Substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or 1 to 3 And 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.
  • Heteroaryl (the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of halogen atoms and C 1-6 alkyl) and saturated heterocyclyl (the saturated heterocyclyl Is unsubstituted or substituted with 1 C 1-6 alkyl.) And is substituted with 1 to 6 groups selected from the group consisting of: ] C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl).
  • Aryl or saturated heterocyclyl [the saturated heterocyclyl is unsubstituted or substituted with 1 C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 aryl) Is replaced by ], R 31 is more preferably C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (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.), Aryl [the aryl is unsubstituted, halogen atom, C 1-6 Substituted with one group selected from the group consisting of alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms) and C 1-6 alkoxy.
  • 1-6 selected from the group consisting of heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with 1 group.
  • C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl) or aryl;
  • Particularly preferred R 31 at this time is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or Substituted with one C 1-6 alkyl), aryl, heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one halogen atom), and is selected from the group consisting of Substituted with one group.
  • Another preferred substituent B 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.
  • substituent B is 2-pyridyl or 2-pyrimidinyl [the 2-pyridyl and 2-pyrimidinyl are not substituted, halogen atoms, cyano, C 1-6 alkyl (the C 1-6 alkyl Is unsubstituted or substituted with 1 to 3 halogen atoms.), One selected from the group consisting of C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy Substituted with a group.
  • Particularly preferred substituent B in this case is 2-pyridyl or 2-pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are not substituted, or one selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with a group).
  • Another preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (V).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Substituted with 1 to 3 groups selected from the group consisting of aminocarbonyl, saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl, the same or different; Further preferred substituent A is phenyl or 3-pyridyl (the phenyl and 3-pyridyl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, Substituted with 1 to 3 groups selected from the group consisting of saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl identically or differently; Preferred W is a single bond or —O—.
  • substituent B is (b) —COOR 31 , wherein preferred R 31 is C 1-6 alkyl;
  • Another preferred embodiment of the substituent B is (c) a 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 6-membered heteroaryl is an unsubstituted, halogen atom, C 1-6 alkyl) , C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy are substituted with one group selected from the group consisting of 2-pyridyl and 2- Pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are unsubstituted or selected from the group consisting of a halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy) Substituted with one group).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Aminocarbonyl (wherein the mono C 1-6 alkylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl, or the same or different; Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1- 6 alkylaminocarbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and
  • Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1-6 alkylamino carbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and C 1-6 alkoxy Substituted with 1 to 2 groups more or less identically selected), saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy).
  • substituent A is phenyl (the phenyl is unsubstituted or halogen atom, carbamoyl, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl is Mono-saturated heterocyclyl which is unsubstituted or substituted with one or two groups selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl.
  • Aminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is substituted with substituted or not, 1-2 groups identical to or different selected from the group consisting of hydroxy and C 1-6 alkoxy Is.), Heterocyclylcarbonyl in heterocyclylcarbonyl (saturated in saturation and is not substituted is substituted with one hydroxy.) And the same or different from the group consisting of C 1-6 alkylsulfonyl Substituted with 1 to 3 groups selected from Preferred W is a single bond or —O—.
  • Further preferred W is a single bond;
  • Preferred X is a nitrogen atom or CR 21 , Preferred R 21 at this time is a hydrogen atom, Further preferred X is a nitrogen atom;
  • Preferred Y 1 is CR 22 Preferred R 22 at this time is a hydrogen atom;
  • Preferred Y 2 is a nitrogen atom or CR 23 , Preferred R 23 at this time is a hydrogen atom;
  • Further preferred Y 2 is a nitrogen atom;
  • Preferred Y 3 is a nitrogen atom or CR 24 , Preferred R 24 at this time is a hydrogen atom, Further preferred Y 3 is a nitrogen atom;
  • One preferred substituent B is (a) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 halogen atoms), C 3-8 Cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl) , Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl).
  • substituents B are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms), C 3-8 cycloalkyl.
  • Particularly preferred substituents B at this time are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with one halogen atom) or C 3-8 cycloalkyl C 1.
  • R 31 is preferably C 1-6 alkyl [the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted)] Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (wherein the C 1-6 alkoxy is not substituted, Substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or 1 to 3 And 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.
  • Heteroaryl (the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of halogen atoms and C 1-6 alkyl) and saturated heterocyclyl (the saturated heterocyclyl Is unsubstituted or substituted with 1 C 1-6 alkyl.) And is substituted with 1 to 6 groups selected from the group consisting of: ] C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl).
  • Aryl or saturated heterocyclyl [the saturated heterocyclyl is unsubstituted or substituted with 1 C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 aryl) Is replaced by ], R 31 is more preferably C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (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.), Aryl [the aryl is unsubstituted, halogen atom, C 1-6 Substituted with one group selected from the group consisting of alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms) and C 1-6 alkoxy.
  • 1-6 selected from the group consisting of heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with 1 group.
  • C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl) or aryl;
  • Particularly preferred R 31 at this time is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or Substituted with one C 1-6 alkyl), aryl, heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one halogen atom), and is selected from the group consisting of Substituted with one group.
  • Another preferred substituent B 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.
  • substituent B is 2-pyridyl or 2-pyrimidinyl [the 2-pyridyl and 2-pyrimidinyl are not substituted, halogen atoms, cyano, C 1-6 alkyl (the C 1-6 alkyl Is unsubstituted or substituted with 1 to 3 halogen atoms.), One selected from the group consisting of C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy Substituted with a group.
  • Particularly preferred substituent B in this case is 2-pyridyl or 2-pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are not substituted, or one selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with a group).
  • Another preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (VI).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Substituted with 1 to 3 groups selected from the group consisting of aminocarbonyl, saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl, the same or different; Further preferred substituent A is phenyl or 3-pyridyl (the phenyl and 3-pyridyl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, Substituted with 1 to 3 groups selected from the group consisting of saturated heterocyclylcarbonyl and C 1-6 alkylsulfonyl identically or differently; Preferred W is a single bond or —O—.
  • substituent B is (b) —COOR 31 , wherein preferred R 31 is C 1-6 alkyl;
  • Another preferred embodiment of the substituent B is (c) a 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 6-membered heteroaryl is an unsubstituted, halogen atom, C 1-6 alkyl) , C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy are substituted with one group selected from the group consisting of 2-pyridyl and 2- Pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are unsubstituted or selected from the group consisting of a halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy) Substituted with one group).
  • Preferred substituents A are phenyl or 6-membered heteroaryl (the phenyl and 6-membered heteroaryl are unsubstituted or halogen atoms, carbamoyl, C 1-6 alkyl, heteroaryl, mono C 1-6 alkyl Aminocarbonyl (wherein the mono C 1-6 alkylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl, or the same or different; Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1- 6 alkylaminocarbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and
  • Monosaturated heterocyclylaminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), di-C 1-6 alkylamino carbonyl (the di C 1-6 alkylaminocarbonyl, unsubstituted or substituted with hydroxy and C 1-6 alkoxy Substituted with 1 to 2 groups more or less identically selected), saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy).
  • substituent A is phenyl (the phenyl is unsubstituted or halogen atom, carbamoyl, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl is Mono-saturated heterocyclyl which is unsubstituted or substituted with one or two groups selected from the group consisting of hydroxy, carbamoyl, C 1-6 alkoxy and C 1-6 alkylsulfonyl.
  • Aminocarbonyl (the monosaturated heterocyclylaminocarbonyl is unsubstituted or substituted with 1 to 2 oxo), diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is substituted with substituted or not, 1-2 groups identical to or different selected from the group consisting of hydroxy and C 1-6 alkoxy Is.), Heterocyclylcarbonyl in heterocyclylcarbonyl (saturated in saturation and is not substituted is substituted with one hydroxy.) And the same or different from the group consisting of C 1-6 alkylsulfonyl Substituted with 1 to 3 groups selected from Preferred W is a single bond or —O—.
  • Further preferred W is a single bond;
  • Preferred X is a nitrogen atom or CR 21 , Preferred R 21 at this time is a hydrogen atom, Further preferred X is a nitrogen atom;
  • Preferred Y 1 is CR 22 Preferred R 22 at this time is a hydrogen atom;
  • Preferred Y 2 is a nitrogen atom or CR 23 , Preferred R 23 at this time is a hydrogen atom;
  • Further preferred Y 2 is a nitrogen atom;
  • Preferred Y 3 is a nitrogen atom or CR 24 , Preferred R 24 at this time is a hydrogen atom, Further preferred Y 3 is a nitrogen atom;
  • One preferred substituent B is (a) C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 halogen atoms), C 3-8 Cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl) , Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl).
  • substituents B are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms), C 3-8 cycloalkyl.
  • Particularly preferred substituents B at this time are C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with one halogen atom) or C 3-8 cycloalkyl C 1.
  • R 31 is preferably C 1-6 alkyl [the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted)] Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl), C 1-6 alkoxy (wherein the C 1-6 alkoxy is not substituted, Substituted with 1 aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or 1 to 3 And 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.
  • Heteroaryl (the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of halogen atoms and C 1-6 alkyl) and saturated heterocyclyl (the saturated heterocyclyl Is unsubstituted or substituted with 1 C 1-6 alkyl.) And is substituted with 1 to 6 groups selected from the group consisting of: ] C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl).
  • Aryl or saturated heterocyclyl [the saturated heterocyclyl is unsubstituted or substituted with 1 C 1-6 alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 aryl) Is replaced by ], R 31 is more preferably C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, C 3-8 cycloalkyl (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.), Aryl [the aryl is unsubstituted, halogen atom, C 1-6 Substituted with one group selected from the group consisting of alkyl (the C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogen atoms) and C 1-6 alkoxy.
  • 1-6 selected from the group consisting of heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with 1 group.
  • C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl) or aryl;
  • Particularly preferred R 31 at this time is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or Substituted with one C 1-6 alkyl), aryl, heteroaryl (wherein the heteroaryl is unsubstituted or substituted with one halogen atom), and is selected from the group consisting of Substituted with one group.
  • Another preferred substituent B 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.
  • substituent B is 2-pyridyl or 2-pyrimidinyl [the 2-pyridyl and 2-pyrimidinyl are not substituted, halogen atoms, cyano, C 1-6 alkyl (the C 1-6 alkyl Is unsubstituted or substituted with 1 to 3 halogen atoms.), One selected from the group consisting of C 2-6 alkenyl, C 3-8 cycloalkyl and C 1-6 alkoxy Substituted with a group.
  • Particularly preferred substituent B in this case is 2-pyridyl or 2-pyrimidinyl (the 2-pyridyl and 2-pyrimidinyl are not substituted, or one selected from the group consisting of a halogen atom and C 1-6 alkyl) Substituted with a group).
  • the compound of the present invention is a compound having a condensed heterocyclic ring, 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 organic acid salts such as acid salts, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartic acid
  • Amino acid salts such as salts, or inorganic or ammonium salts such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, triethylamine salts Diisopropylamine salts, 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 a GPR119 agonistic action. 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 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 12 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”.
  • compound (I-2) in which X is CR 21 and W is a single bond can be produced, for example, by the following production method 1, production method 2, or a method analogous thereto.
  • Ua and Ud are halogen atoms, Ub is a leaving group or hydroxy, Uc is a boronic acid ester or boronic acid, and other symbols are as defined above.
  • Examples of the “halogen atom” represented by Ua and Ud include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • 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.
  • Step 1 This step is a method for producing compound (1-b) from compound (1-a).
  • This step is carried out by a known method such as Bioorganic & Medicinal Chemistry Letters, 2007, 15, 2441-2452, Tetrahedron Letters, 2002, 43, 2695-2697, Synthesis, 2006, 20, 3506-3514, WO 2008/088692, and the like. It can carry out by the method of description or a method according to it.
  • the reagent used in this step include alkali metal nitrites such as sodium nitrite, nitrites such as t-butyl nitrite and isoamyl nitrite.
  • the amount of the reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-a).
  • the solvent used in the reaction include an acetic acid-water mixed solvent, a trifluoroacetic acid-water mixed solvent, an acidic solvent such as hydrochloric acid and an aqueous sulfuric acid solution, and these solvents may be used by mixing at an appropriate ratio. These reactions can be usually performed at ⁇ 30 ° C. to reflux temperature for 1 to 24 hours.
  • Step 2 This step is a method for producing compound (1-d) by reacting compound (1-b) with compound (1-c).
  • Ub of compound (1-c) is a leaving group
  • this reaction can be carried out in the presence of a base.
  • the amount of (1-c) in the compound used in this step is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-b).
  • Examples of the base used are usually tertiary aliphatic amines such as triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [4,3,0] undec-7-ene, and hydrogen such as sodium hydride.
  • alkali metal hydroxides such as alkali metal halides and potassium hydroxide
  • alkali metal carbonates such as cesium carbonate, potassium carbonate and sodium carbonate
  • alkali metal alkoxides such as potassium t-butoxide.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-b).
  • the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone. May be used as a mixture. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • the amount of (1-c) in the compound used in this step is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-b).
  • 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 (1-b).
  • 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 (1-b).
  • 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 be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • this step can be performed using a method 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-b).
  • 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.
  • Step 3 This step is a method for producing compound (I-2) by reacting compound (1-d) with compound (1-e).
  • This reaction is a so-called Suzuki-Miyaura coupling reaction in the presence of a palladium catalyst and a base (Tetrahedron Letters, 1979, 20, 3437-3440, Chemical reviews, 1995, 95, 2457-2483) or It can carry out by the method according to it.
  • the amount of (1-e) in the compound used in this step is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-d).
  • Examples of the palladium catalyst used include tetrakis (triphenylphosphine) palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, bis (triphenylphosphine) palladium (II ) Dichloride and the like.
  • the amount of the palladium catalyst to be used is generally 0.01 to 0.5 equivalent, preferably 0.05 to 0.3 equivalent, relative to 1 equivalent of compound (1-d).
  • Examples of the base to be used include alkali metal carbonates such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate and aqueous solutions thereof, potassium fluoride, cesium fluoride, triethylamine 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 (1-d).
  • Examples of the solvent used in the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethanol and the like, which are not involved in the reaction. May be mixed and used at an appropriate ratio.
  • the reaction 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 (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.
  • Step 4 This step is a method for producing compound (1-f) from compound (1-d).
  • Uc of compound (1-f) is a boronic ester
  • this reaction can be carried out by a known method (Journal of Organic Chemistry, 1995, 60, 7508-7510) or a method analogous thereto.
  • the amount of bis (pinacolato) diboron used in this step is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-d).
  • the palladium catalyst to be used for example, tetrakis (triphenylphosphine) palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex and the like can be mentioned.
  • the amount of the palladium catalyst to be used is generally 0.01 to 1 equivalent, preferably 0.05 to 0.5 equivalent, relative to 1 equivalent of compound (1-d).
  • Examples of the base used usually include potassium acetate and triethylamine.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-d).
  • Examples of the solvent used in the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylacetamide and the like 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 room temperature to 120 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation. Alternatively, this reaction can be performed by a known method (Journal of the American Chemical Society, 2002, 124, 13179-13184) or a method analogous thereto.
  • the amount of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane used in this step is 1 to 5 equivalents relative to 1 equivalent of compound (1-d), Preferably 1.1 to 2.5 equivalents.
  • the base used usually include n-butyl lithium and t-butyl lithium.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1.1 to 2.5 equivalents, relative to 1 equivalent of compound (1-d).
  • the solvent used in this reaction include solvents that do not participate in the reaction, such as tetrahydrofuran and 1,2-dimethoxyethane, and these solvents may be mixed and used at an appropriate ratio. These reactions can usually be performed at ⁇ 78 ° C.
  • Examples of the solvent used in this reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, 1,2-dimethoxyethane, and diethyl ether, and these solvents may be used in a mixture at an appropriate ratio. These reactions can be carried out usually at ⁇ 78 ° C. to room temperature for 0.5 to 5 hours.
  • Step 5 This step is a method for producing compound (I-2) by reacting compound (1-f) with compound (1-g). This reaction is performed according to the Suzuki-Miyaura coupling reaction described in Step 3 of Production Method 1.
  • 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.
  • Step 1 This step is a method for producing compound (2-b) by reacting compound (2-a) with di-tert-butyl dicarbonate in the presence of a base.
  • the amount of di-tert-butyl dicarbonate used in this reaction is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (2-a).
  • Examples of the base used usually include triethylamine, pyridine, N, N-dimethyl-4-aminopyridine, N, N-diisopropylethylamine, aqueous sodium hydroxide, aqueous sodium bicarbonate, 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 (2-a).
  • solvent used in the reaction examples include solvents that do not participate in the reaction such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate, acetonitrile, and the like. You may mix and use. These reactions are usually carried out at 0 to 100 ° C. for 1 to 24 hours.
  • Step 2 This step is a method for producing compound (2-c) by reacting compound (2-b) with trifluoromethanesulfonic anhydride in the presence of a base.
  • the amount of trifluoromethanesulfonic anhydride used in this reaction is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (2-b).
  • Examples of the base used include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, and pyridine.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (2-b).
  • solvents that do not participate in the reaction such as chloroform, diethyl ether, tetrahydrofuran, and 1,4-dioxane, and these solvents may be used in a mixture at an appropriate ratio. These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • Step 3 is a method for producing compound (2-d) by reacting compound (2-c) under acidic conditions.
  • an acid such as a 4M hydrogen chloride / ethyl acetate solution, a 4M hydrogen chloride / 1,4-dioxane solution, or trifluoroacetic acid is usually used.
  • the amount of the acid used is 5 to 50 equivalents, preferably 10 to 30 equivalents, relative to 1 equivalent of compound (2-c).
  • the solvent used for the reaction include ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water, chloroform, dichloromethane and the like, which are not involved in the reaction. These solvents are mixed in an appropriate ratio. It may be used.
  • These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • This step is a method for producing compound (2-e) from compound (2-d). This reaction can be carried out according to the method described in Process 1 of Production Method 1.
  • This step is a method for producing compound (2-f) by reacting compound (2-e) with compound (1-e). This reaction can be carried out according to the Suzuki-Miyaura coupling reaction described in Step 3 of Production Method 1.
  • Step 6 This step is a method for producing compound (I-2) by reacting compound (2-f) with compound (1-c). This reaction can be performed according to the method described in Step 2 of Production Method 1.
  • 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 (2-a) used as a raw material compound in the above production method 2 can be obtained by a method known per se.
  • the compound (I-3) wherein X is a nitrogen atom and W is a single bond can be produced, for example, by the following production method 3 or a method analogous thereto.
  • Uf represents a halogen atom, and other symbols are as defined above.
  • Examples of the “halogen atom” represented by Uf include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Step 1 This step is a method for producing compound (3-c) by reacting compound (3-a) with compound (3-b) in the presence of a base.
  • the amount of (3-b) in the compound used in this step is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (3-a).
  • the base used include tertiary aliphatic amines such as triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [4,3,0] undec-7-ene, cesium carbonate, potassium carbonate, Examples thereof include alkali metal carbonates such as sodium carbonate and alkali metal alkoxides such as potassium t-butoxide.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (3-a).
  • the solvent used in the reaction include dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like, which are not involved in the reaction. You may mix and use. These reactions can be usually performed at room temperature to 100 ° C. for 1 to 24 hours.
  • Step 2 This step is a method for producing compound (3-d) by reducing compound (3-c).
  • This reaction is carried out using a method that is carried out in the presence of a metal and an acid in a solvent that does not participate in the reaction.
  • the metal used usually include iron, zinc, indium, tin chloride and the like.
  • the amount of the metal used is 1 to 50 equivalents, preferably 3 to 30 equivalents, relative to 1 equivalent of compound (3-c).
  • the acid used include ammonium chloride, acetic acid, hydrochloric acid and the like.
  • the amount of the acid used is 0.01 to 500 equivalents, preferably 0.1 to 300 equivalents, relative to 1 equivalent of compound (3-c).
  • Examples of the solvent used for the reaction include water, ethanol, methanol, tetrahydrofuran, ethyl acetate, and the like. These solvents may be used by mixing at an appropriate ratio, or may be solventless. These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours. Or this reaction is performed using the method performed in the solvent which does not participate in reaction in presence of a metal and a hydrogen source. Examples of 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 (3-c).
  • Examples of the hydrogen source used in the reaction include hydrogen gas, and the hydrogen pressure at that time is from normal pressure to 10 atm, and preferably from normal pressure to 4 atm. Further, formic acid, ammonium formate, cyclohexene, or the like may be used as a hydrogen source.
  • Examples of the solvent used in the reaction include methanol, ethanol, water, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, and the like. These solvents may be mixed and used at an appropriate ratio. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • Step 3 This step is a method for producing compound (3-e) from compound (3-d).
  • This reaction can be carried out by a known method such as described in Tetrahedron Letters, 2006, 47, 8661-8665, European Journal of Organic Chemistry, 2005, 15, 3271-3278, Bioorganic & Medicinal Chemistry, 2006, 14668, etc. It can carry out by the method of or the method according to it.
  • the reagent used in this step include alkali metal nitrites such as sodium nitrite, nitrites such as t-butyl nitrite and isoamyl nitrite.
  • the amount of the reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (3-d).
  • the solvent used in the reaction include an acetic acid-water mixed solvent, a trifluoroacetic acid-water mixed solvent, an acidic solvent such as hydrochloric acid and a sulfuric acid aqueous solution, and the like, and these solvents may be mixed and used at an appropriate ratio. . These reactions can be usually performed at ⁇ 30 ° C. to reflux temperature for 1 to 24 hours.
  • Step 4 is a method for producing compound (I-3) by reacting compound (3-e) with compound (1-e) in the presence of a palladium catalyst and a base.
  • This reaction can be carried out according to the Suzuki-Miyaura coupling reaction described in Step 3 of Production Method 1.
  • Step 5 This step is a method for producing compound (3-f) from compound (3-e). This reaction can be performed according to the method described in Process 4 of Production Method 1.
  • Step 6 is a method for producing compound (I-3) by reacting compound (3-f) with compound (1-g) in the presence of a palladium catalyst and a base.
  • This reaction can be carried out according to the Suzuki-Miyaura coupling reaction described in Step 3 of Production Method 1.
  • the compound (I-3) 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 (3-a) and the compound (3-b) used as raw material compounds in the above production method 3 can be produced by a method known per se.
  • the compound (I-3) can also be produced, for example, by the following production method 4 or a method analogous thereto.
  • Step 1 This step is a method for producing compound (4-c) by reacting compound (4-a) with compound (4-b) in the presence of a reducing reagent.
  • This reaction can be performed in the presence or absence of an acid in a solvent that does not participate in the reaction.
  • the amount of compound (4-b) used in this reaction is 0.5 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (4-a).
  • Examples of the reducing reagent used in this reaction include sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminum hydride and the like.
  • the amount of the reagent used is 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents, relative to 1 equivalent of compound (4-a). These reactions can be usually performed at 0 to 0 ° C. for 1 to 48 hours. Alternatively, this reaction can be carried out using a catalytic reduction reaction using a hydrogen source such as hydrogen gas in the presence of a metal catalyst such as palladium, instead of using the above-described reducing reagent. This catalytic reduction reaction can be carried out according to the method described in Step 2 of Production Method 3.
  • Step 2 This step is a method for producing a compound (4-d) by cyclizing the compound (4-c). This reaction can be carried out according to the method described in Step 3 of Production Method 3.
  • Step 3 is a method for producing compound (I-3) by reacting compound (4-d) with compound (1-e) in the presence of a palladium catalyst and a base.
  • This reaction can be carried out according to the Suzuki-Miyaura coupling reaction described in Step 3 of Production Method 1.
  • the compound (I-3) 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 (4-a) used as a raw material compound in the production method 4 can be obtained by a method known per se.
  • the compound (I-4) in which W is —OCH 2 — can be produced, for example, by the following production method 5 or a method analogous thereto.
  • Step 1 This step is a method for producing compound (5-b) by reacting compound (5-a) with compound (1-c). This reaction can be performed according to the method described in Step 2 of Production Method 1.
  • Step 2 This step is a method for producing compound (5-c) by reducing compound (5-b).
  • the reducing agent used in this reaction include lithium aluminum hydride, lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, 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 (5-b).
  • 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 0.5 to 24 hours.
  • Step 3 This step is a method for producing compound (I-4) by reacting compound (5-c) with compound (5-d).
  • This reaction can be performed according to the Mitsunobu reaction described in Step 2 of Production Method 1.
  • the compound (I-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.
  • the compound (5-a) used as a raw material compound in the above production method 5 can be obtained by a method known per se.
  • the compound (I-5) in which W is —O— or the compound (I-6) in which —NH— is produced, for example, by the following production method 6 or a method analogous thereto. be able to.
  • Ug represents a halogen atom or a boronic acid, and other symbols are as defined above.
  • Examples of the halogen atom represented by Ug include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • This production method is a method for producing compound (I-5) or compound (I-6) by reacting compound (6-a) with compound (5-d) or compound (6-b). is there.
  • this reaction can be carried out by a known method, for example, the method described in Journal of Organic Chemistry, 2010, 75, 1791-1794, or a method analogous thereto.
  • the amount of compound (5-d) and compound (6-b) used in this reaction is 0.5 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (6-a).
  • Examples of the copper reagent used in this reaction include copper, copper (I) iodide, copper (I) bromide, copper (I) chloride, copper (II) acetate, copper (I) oxide, and copper (II) oxide. Is mentioned.
  • the amount of the copper reagent is usually 0.01 to 10 equivalents, preferably 0.05 to 5 equivalents.
  • Examples of the ligand used include trans-cyclohexanediamine, trans-1,2-bis (methylamino) cyclohexane, N, N′-dimethylethylenediamine, 1,10-phenanthroline, 8-hydroxyquinoline, picolinic acid, Examples include proline, 2-isobutyrylcyclohexanone, N, N-dimethylglycine, and pyrrole-2-carboxylic acid.
  • the amount of the ligand is usually 0.01 to 10 equivalents, preferably 0.05 to 5 equivalents. Or it is not necessary to use a ligand.
  • Examples of the base include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, and sodium hydrogen carbonate, alkali metal phosphates such as tripotassium phosphate, cesium acetate, and the like.
  • the amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents. Alternatively, a base may not be used.
  • Examples of the solvent used for the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, dioxane, N-methylpyrrolidone and the like, which are not involved in the reaction. Also good. These reactions can usually be performed at room temperature to 200 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
  • this reaction can be carried out by a method performed in the presence of a palladium catalyst and a base, and in the presence or absence of a ligand.
  • the amount of compound (5-d) and compound (6-b) used in this reaction is 0.5 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (6-a). .
  • Examples of the palladium catalyst used in this reaction include palladium acetate (II), tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), [ 1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex and the like.
  • the amount of the palladium catalyst is usually 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of the compound (6-a).
  • Examples of the ligand used include 2- (di-t-butylphosphino) biphenyl, triphenylphosphine, 2- (di-t-butylphosphino) -1,1′-binaphthyl, 2-dicyclohexylphosphino- And 2 ′-(N, N-dimethylamino) biphenyl.
  • the amount of the ligand used is usually 0.02 to 2 equivalents, preferably 0.2 to 1 equivalent, relative to 1 equivalent of the compound (6-a).
  • Examples of the base include alkali metal alkoxides such as potassium t-butoxide, sodium t-butoxide and sodium phenoxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, and alkali metal phosphorus such as potassium phosphate. Examples thereof include acid salts and lithium chloride.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (6-a).
  • Examples of the solvent used in 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. You may mix and use by the ratio. These reactions can usually be performed at room temperature to 200 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation. When Ug is boronic acid, known methods such as Tetrahedron Letters, 1998, 39, 2933-2936, ibid. 1998, 39, 2937-2940 or a method analogous thereto.
  • the amount of compound (5-d) and compound (6-b) used in this reaction is 0.5 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (6-a).
  • the metal salt used in this reaction include copper (II) acetate.
  • the amount of copper (II) acetate used in the reaction is 0.5 to 3 equivalents, preferably 1 to 2 equivalents.
  • the base used in this reaction include triethylamine, pyridine and the like.
  • the amount of the base used is 3 to 15 equivalents, preferably 5 to 10 equivalents, relative to 1 equivalent of compound (6-a).
  • 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 usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • the thus obtained compound (I-5) and compound (I-6) are 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. be able to.
  • the compound (6-a) used as the raw material compound in the production method 6 can be produced by the production method 1, the production method 3, the production method 4, or a method analogous thereto.
  • compound (I-7) in which W is —CH 2 O— can be produced, for example, by the following production method 7 or a method analogous thereto.
  • Uh represents a halogen atom or hydroxy, and other symbols are as defined above.
  • Examples of the “halogen atom” represented by Uh include a chlorine atom, a bromine atom, and an iodine atom.
  • This step is a method for producing compound (7-b) from compound (7-a).
  • This reaction is carried out by a known method, for example, the method described in Journal of Organic Chemistry, 2005, 70, 7353-7363, Synlett, 2009, 4, 615-619 or a method analogous thereto. Hydrogen peroxide etc. are mentioned as an oxidizing agent used for this process.
  • the amount of the reagent used is 1 to 500 equivalents, preferably 5 to 300 equivalents, relative to 1 equivalent of compound (7-a).
  • Examples of the solvent used in the reaction include water, methanol, tetrahydrofuran, diethyl ether, dimethyl sulfoxide, dichloromethane, chloroform, and other solvents that do not participate in the reaction, and these solvents may be mixed and used at an appropriate ratio. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • This step is a method for producing compound (I-7) by reacting compound (7-b) with compound (7-c).
  • this reaction can be carried out by a known method, for example, in the presence of a base, in a solvent that does not participate in the reaction.
  • the amount of compound (7-c) used in this reaction is 0.5 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7-b).
  • Examples of the base used in this reaction include alkali metal carbonates such as potassium carbonate, cesium carbonate and sodium carbonate, alkali metal alkoxides such as potassium t-butoxide, and sodium hydride.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (7-b).
  • the solvent used in the reaction include N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, acetonitrile, and the like, which are not involved in the reaction. These solvents are used by mixing at an appropriate ratio. May be. These reactions can usually be performed at room temperature to 200 ° C. for 1 to 24 hours. When Uh is hydroxy, this reaction can be carried out according to the method described in Step 2 of Production Method 1.
  • the compound (I-7) 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 (7-a) used as the starting compound in the above production method 7 can be obtained by the above production method 1, production method 3, or a method analogous thereto.
  • the compound (I-10) in which the substituent B is R 1 can be produced, for example, by the following production method 8 or a method analogous thereto.
  • R 1 is C 2-6 alkyl (the C 2-6 alkyl is unsubstituted or substituted with 1 to 6 groups selected from the group consisting of a halogen atom and hydroxy), C 3- 8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl (wherein the C 3-8 cycloalkyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl). ), Aryl C 1-6 alkyl or saturated heterocyclyl C 1-6 alkyl (the saturated heterocyclyl C 1-6 alkyl is unsubstituted or substituted with one C 1-6 alkyl). Indicates.
  • R 11 is C 1-5 alkyl (the C 1-5 alkyl is unsubstituted or substituted with 1 to 6 groups selected from the group consisting of a halogen atom and hydroxy), C 3- 8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with one C 1-6 alkyl), aryl or saturated heterocyclyl (the saturated heterocyclyl is substituted Or is substituted with one C 1-6 alkyl).
  • R 12 represents a hydrogen atom or C 1-4 alkyl; R 11 and R 12 together with adjacent carbon atoms are C 3-8 cycloalkyl or saturated heterocyclyl (the saturated heterocyclyl is unsubstituted or substituted with one C 1-6 alkyl)
  • the other symbols have the same meanings as described above.
  • Examples of the “halogen atom” represented by Ui include a chlorine atom, a bromine atom, and an iodine atom.
  • C 1-5 alkyl” represented by R 11 represents linear or branched alkyl having 1 to 5 carbon atoms
  • C 1-4 alkyl represented by R 12 represents carbon atoms. A linear or branched alkyl having 1 to 4 is shown.
  • This step is a method for producing compound (8-a) by reacting compound (I-9) under acidic conditions. This reaction can be performed according to the method described in Step 3 of Production Method 2.
  • This step is a process for producing compound (I-10) by reacting compound (8-a) with compound (8-b) in the presence of a base and in the presence or absence of potassium iodide. It is.
  • the amount of compound (8-b) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (8-a).
  • Examples of the compound (8-b) used in this reaction include 1-iodopropane, 1-iodo-2-methylpropane, 1-iodo-2-methylbutane, cyclopropylmethyl bromide, cyclopentylmethyl iodide, cyclohexylmethyl.
  • Examples of the solvent used in the reaction include acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, and the like, which are not involved in the reaction. These solvents are used by mixing at an appropriate ratio. May be. These reactions can be usually performed at room temperature to 100 ° C. for 1 to 24 hours. This step can also be carried out by a reductive amination reaction of compound (8-a) and compound (8-c). In this case, it can be performed according to the method described in Step 1 of Production Method 4.
  • the compound (I-10) 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 (I-9) used as the starting compound in the above production method 8 can be produced by the above production method 1 to production method 7 or a method analogous thereto.
  • the compound (I-11) in which the substituent B is —COOR 31 can be produced, for example, by the following production method 9 or a method analogous thereto.
  • R 31 is C 1-6 alkyl ⁇ the C 1-6 alkyl is not substituted or is a halogen atom, cyano, C 3-8 cycloalkyl (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), C 1-6 alkoxy (the C 1-6 alkoxy is substituted) Or substituted with one aryl), aryl [the aryl is unsubstituted or halogen atom, C 1-6 alkyl (the C 1-6 alkyl is unsubstituted, Substituted with 1 to 3 halogen atoms) and 1 to 3 groups selected from the group consisting of C 1-6 alkoxy.
  • Heteroaryl (the heteroaryl is unsubstituted or substituted with one group selected from the group consisting of a halogen atom and C 1-6 alkyl), saturated heterocyclyl (the saturated heterocyclyl Is unsubstituted or substituted with one C 1-6 alkyl.), Mono C 1-6 alkylamino, diC 1-6 alkylamino, C 1-6 alkylsulfanyl and C 1- Substituted with 1 to 6 groups selected from the group consisting of 6 alkylsulfonyl.
  • This production method is a method for producing compound (I-11) by reacting compound (8-a) with a carbamation reagent corresponding to substituent B.
  • the amount of the carbamate reagent used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (8-a).
  • the carbamate reagent can be obtained commercially or prepared from the corresponding alcohol (R 31 OH) and a condensing agent in the presence of a base.
  • the condensing agent in this case include triphosgene, phosgene, p-nitrophenyl chloroformate, 1,1′-carbonyldiimidazole and the like.
  • the amount of the condensing agent is 0.5 to 3 equivalents, preferably 1 equivalent, with respect to the corresponding alcohol.
  • 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.
  • Solvents used in the reaction include N, N-dimethylformamide, chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, methanol, ethanol, water, ethyl acetate, acetonitrile, acetone, toluene, etc. Solvents that do not participate in the reaction are mentioned, and these solvents may be mixed and used at an appropriate ratio. These reactions are usually carried out at 0 to 100 ° C. for 1 to 12 hours.
  • the compound (I-11) 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 (8-a) used as the starting compound in the above production method 9 can be produced by the above-mentioned production method 8, step 1 or a method analogous thereto.
  • the compound (I-12) which is a 5- or 6-membered heteroaryl represented by the formula can be produced, for example, by the following production method 10 or a method analogous thereto.
  • Uj represents a leaving group. Other symbols are as defined above.
  • Examples of the “leaving group” represented by Uj include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • This production method is a method for producing compound (I-12) from compound (8-a) and compound (10-a).
  • This reaction can be carried out in the presence or absence of a base in a solvent that does not participate in the reaction.
  • the amount of compound (10-a) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (8-a).
  • the compound (10-a) used in this reaction is a halogenated 5- or 6-membered heteroaryl corresponding to the substituent B, for example, 2-chloro-5-ethylpyrimidine, 2-chloro-5- Methylpyrimidine, 2,5-dichloropyrimidine, 2-chloro-5-fluoropyrimidine, 2-chloro-5-methoxypyrimidine, methyl 2-chloropyrimidin-5-ylcarboxylate, 2,5-dibromopyridine, 3,6- Examples include dichloropyrazine.
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, and alkali metal carbonates such as pyridine, cesium carbonate and potassium carbonate.
  • 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.
  • Method B This reaction can be carried out in a solvent that does not participate in the reaction in the presence of a palladium catalyst and a base in an atmosphere of an inert gas such as argon or nitrogen.
  • the compound (10-a) used in this reaction is a halide described in (Method A).
  • the amount of compound (10-a) used in the reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (8-a).
  • 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 used is usually 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent.
  • a ligand may coexist.
  • the ligand include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, and 2- (dicyclohexylphosphino) -2 ′. 4,4 ′, 6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl, and the like.
  • the amount of the ligand used is usually from 0.01 to 1 equivalent, preferably from 0.1 to 0.5 equivalent.
  • the base used in the reaction include alkali metal alkoxides such as potassium t-butoxide, sodium t-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, lithium chloride and the like.
  • the amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
  • 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. You may mix and use by a ratio. 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 (I-12) 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 (8-a) used as the starting compound in the production method 10 can be obtained by the above-mentioned production method 8, step 1 or a method analogous thereto.
  • the compound (I-13) having R a R b NCO— on the substituent A can be produced, for example, by the following production method 11 or a method analogous thereto.
  • the compound (11-b) represented by R a R b NH is a mono C 1-6 alkylamine (the mono C 1-6 alkylamine is not substituted, hydroxy, carbamoyl, C ( Substituted by 1 to 3 groups selected from the group consisting of 3-8 cycloalkyl, C 1-6 alkoxy, diC 1-6 alkylamino and C 1-6 alkylsulfonyl).
  • Mono C 3-8 cycloalkylamine monosaturated heterocyclylamine (the monosaturated heterocyclylamine is unsubstituted or substituted with 1 to 2 oxo), diC 1-6 alkyl Amine (the di-C 1-6 alkylamine is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of hydroxy, cyano and C 1-6 alkoxy, the same or different.
  • At least one in the ring A saturated heterocyclyl containing at least one nitrogen atom in the ring is unsubstituted or substituted with hydroxy, C 1-6 alkyl (wherein the C 1-6 alkyl is substituted Or substituted with one hydroxy), selected from the group consisting of mono-C 1-6 alkylamino, di-C 1-6 alkylamino and C 1-6 alkylsulfonyl, identically or differently Substituted with 1 to 2 groups. And other symbols are as defined above.
  • This production method is a method for producing compound (I-13) from compound (11-a) and compound (11-b).
  • 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 (11-b) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (11-a).
  • the condensing agent used in the reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, diethyl cyanophosphonate, propylphosphonic anhydride 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 (11-a).
  • the activator used in the reaction include N-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 (11-a).
  • 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 (11-a).
  • Examples of the solvent used in the reaction include N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, water, and the like, which are not involved in the reaction. These solvents are mixed at an appropriate ratio. May be used. These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • the thus obtained compound (I-13) 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.
  • the compound (11-a) used as a starting compound in the above production method 11 can be produced by the above production method 1 to production method 10 or a method analogous thereto.
  • the compound (I-14) in which W is a single bond, —O— or —NH— can be produced, for example, by the following production method 12 or a method analogous thereto.
  • W ′ represents a single bond, —O— or —NH—, and the other symbols are as defined above.
  • Step 1 This step is a method for producing compound (12-b) by bonding substituent B to compound (12-a). This reaction can be carried out according to the method described in Production Method 8, Production Method 9, or Production Method 10.
  • Step 2 This step is a method for producing compound (I-14) by bonding substituent A to compound (12-b).
  • This reaction can be carried out according to the method described in Process 3 of Production Method 1 or Production Method 6.
  • the compound (12-a) used as the starting compound in the above production method 12 includes the compound (1-d) in the production method 1, the compound (3-e) in the production method 3, and the compound (3-e) in the production method 4 ( 4-d), or in the compound (6-a) of production method 6, when the substituent B is, for example, a t-butyloxycarbonyl group, this substituent is converted according to the method described in step 3 of production method 2. It can be obtained by deprotection.
  • NH silica gel column chromatography refers to column chromatography separation and purification using NH 2 type silica gel (Chromatolex (registered trademark) NH 2 type, Fuji Silysia Chemical Ltd.).
  • the ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • MS mass spectrum
  • LCMS-2010EV Shiadzu
  • LCMS-IT-TOF Shiadzu
  • Agilent 6150 Alent
  • LCQ Deca XP ThermoFisher Scientific
  • ESI Electronpray 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.
  • phase separator used in the text was ISOLUTE (registered trademark) Phase Separator manufactured by Biotage.
  • Compound name is ACD / Name ver. It was named using 12.01 (trade name) or the like.
  • Triethylamine (21 ml) and mesyl chloride (6.9 ml) were added to a solution of 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (10.0 g) in chloroform (250 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. did. Water was added to the reaction mixture, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.
  • 1-bromo-4-iodobenzene (6.20 g), 1H-1,2,3-triazole (1.03 g), copper iodide (2.76 g), N, N′-dimethylethylenediamine ( 4.7 ml), sodium tert-butoxide (4.20 g), and 1-methyl-2-pyrrolidone (29 ml) were stirred at 130 ° C. for 3.5 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (20 ml) and 28% aqueous ammonia (5 ml) were added, and the mixture was vigorously stirred, and then filtered through Celite (registered trademark).
  • lithium hexamethyldisilazane 1.0 M tetrahydrofuran solution, 6.4 ml
  • 4-bromophenylmethylsulfone 1.0 g
  • tetrahydrofuran 43 ml
  • acetone 6.2 ml
  • methanol was added and the temperature was raised to room temperature.
  • N, N, N ′, N′-tetramethylethylenediamine (4.85 g) was added to a commercially available solution of 3,5-difluorobenzoic acid (3.00 g) in tetrahydrofuran (94.9 ml) at ⁇ 78 ° C.
  • 1.02M s-butyllithium cyclohexane-hexane mixed solution (44.7 ml) was added, and the mixture was stirred at the same temperature for 80 minutes.
  • Trimethyl borate (4.15 g) was added and stirred at room temperature for 2 hours.
  • n-butyllithium (2.64 M hexane solution, 1.50 ml) was further added dropwise, stirred for 30 minutes, and dry ice was added. After stirring for 1 hour while raising the temperature to ⁇ 40 ° C., 1M aqueous sulfuric acid solution was added. After raising the temperature to room temperature, ethyl acetate was added to carry out a liquid separation operation. The obtained aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.
  • Triphenylphosphine (5.48 g) was added to a mixed solution of 4-bromo-2,5-difluorobenzenesulfonyl chloride (2.03 g) in N, N-dimethylformamide (0.4 ml) -chloroform (15 ml) at room temperature. Stir for 3 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with chloroform. After concentration of the organic layer, 1M aqueous sodium hydroxide solution was added to the resulting residue, the suspension was filtered through Celite (registered trademark), and the filtrate was extracted and washed with diethyl ether.
  • the resulting aqueous layer was neutralized with 1M hydrochloric acid, and then extracted twice with diethyl ether.
  • the obtained organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • Acetic acid (4.7 ml) and pinacol (10.5 g) were added, and the mixture was stirred at room temperature for 2 hr.
  • To the reaction solution was added 10% aqueous potassium dihydrogen phosphate solution, and the mixture was extracted with chloroform. Further, 3M hydrochloric acid was added to the aqueous layer and the mixture was extracted with chloroform.
  • the organic layer obtained previously was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • N-Butyllithium (2.64 M hexane solution, 14.6 ml) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (5.70 g) in tetrahydrofuran (38.4 ml) at ⁇ 30 ° C. Stir at 0 ° C. for 15 minutes.
  • a solution of 3-cyanopyridine (2.00 g) in tetrahydrofuran (19.2 ml) was added at ⁇ 78 ° C., and the mixture was stirred for 30 minutes.
  • Triisopropyl borate (7.22 g) was added at the same temperature and stirred for 15 minutes. The temperature was raised to room temperature, and water was added to the reaction solution.
  • Pinacol (304 mg) and magnesium sulfate (1.55 g) were added to a suspension of the compound (380 mg) obtained in Reference Example E-16 (1) in toluene (12.8 ml), and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (110 mg) as a light brown powder.
  • n-butyllithium (2.64 M hexane solution, 3.7 ml) was added dropwise to a solution of 2,5-dibromo-4-fluorotoluene (2.5 g) in tetrahydrofuran (47 ml) at ⁇ 78 ° C. After stirring for minutes, dry ice was added. After raising the temperature to room temperature, a 1M aqueous sodium hydroxide solution and ethyl acetate were added to carry out a liquid separation operation. The organic layer was further extracted with 1M aqueous sodium hydroxide solution, and the aqueous layer was neutralized with saturated aqueous ammonium chloride solution.
  • n-butyllithium (2.64 M hexane solution, 3.7 ml) was added dropwise to a solution of 2,5-dibromo-4-fluorotoluene (2.5 g) in tetrahydrofuran (15 ml) at ⁇ 78 ° C.
  • n-butyllithium (2.64 M hexane solution, 3.9 ml) was further added dropwise, stirred for 30 minutes, and dry ice was added.
  • a 1M aqueous sodium hydroxide solution and ethyl acetate were added to carry out a liquid separation operation.
  • the organic layer was further extracted with 1M aqueous sodium hydroxide solution, and the aqueous layer was neutralized with saturated aqueous ammonium chloride solution.
  • the aqueous layer was extracted twice with chloroform.
  • 5-Bromopyridine-2-carboxylic acid 500 mg
  • 28% aqueous ammonia 200 ⁇ l
  • N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride 618 mg
  • 1-hydroxybenzotriazole monohydrate A solution of the Japanese product (493 mg) in N, N-dimethylformamide (10 ml) was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate.
  • 5-bromopyridine-2-carboxylic acid 500 mg
  • 40% aqueous methylamine solution 250 ⁇ L
  • N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride 618 mg
  • 1-hydroxybenzotriazole A solution of hydrate (493 mg) in N, N-dimethylformamide (10 ml) was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate.
  • 1,4-dioxane 25 ml solution of 2-chloro-5-iodopyridine (1.0 g), tributylvinyltin (1.5 g), bis (triphenylphosphine) palladium (II) dichloride (150 mg) under an argon atmosphere was stirred at 80 ° C. for 5 hours.
  • 3,4-Dihydro-2Hpyran (661 mg) and pyridinium p-toluenesulfonate (132 mg) were added to a solution of 4-bromo-3-fluorophenol (1.00 g) in chloroform (5.24 ml) at room temperature. Stir for 15 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • the organic layer obtained previously was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • the reaction mixture was cooled to room temperature, 1M aqueous sodium hydroxide solution was added, and the aqueous layer was washed with diethyl ether.
  • the obtained aqueous layer was extracted with chloroform, and the organic layer was washed successively with a 10% aqueous citric acid solution and water.
  • the desiccant was filtered off and the solvent was distilled off under reduced pressure.
  • the obtained residue was recrystallized with a mixed solution of hexane-ethyl acetate, and the powder was collected by filtration and washed with hexane.
  • the filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized with a hexane-ethyl acetate mixed solution, and the powder was collected by filtration and washed with hexane.
  • the obtained powders were combined and dried under reduced pressure to give the title compound (40.5 g) as an orange powder.
  • Example 11-1 A 4M hydrogen chloride / 1,4-dioxane solution (15.2 ml) was added to a suspension of the compound obtained in Example 11-1 (694 mg) in methanol (5.07 ml), and the mixture was added at room temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure, and the obtained powder was washed with ethyl acetate to give the title compound (610 mg) as a pale pink powder.
  • 1,2-Dimethoxyethane of the compound obtained in Reference Example 9 (100 mg), 4-bromo-3-fluorobenzoic acid (77 mg), tetrakis (triphenylphosphine) palladium (10 mg), 2M aqueous sodium carbonate solution (350 ⁇ l)
  • the suspension (2.4 ml) was stirred at 130 ° C. for 30 minutes under microwave irradiation using a microwave reactor (Initiator Sixty TM (trade name) manufactured by Biotage). After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off.
  • Triethylamine (1.98 ml) and isopropyl chloroformate (1.22 ml) were added to a chloroform (70 ml) solution of the compound (2.00 g) obtained in Reference Example 22 (1), and the mixture was stirred at room temperature for 1 hour.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the obtained organic layer was passed through a phase separator, and the solvent was distilled off under reduced pressure.
  • Example 8-1 (4) described below Using the compound (2.0 g) obtained in Reference Example 25 described later and the compound (2.2 g) synthesized in Reference Example G-5, the same procedure as in Example 8-1 (4) described below was performed. The reaction and purification were carried out to obtain the title compound (2.0 g).
  • Triphosgene (2.67 g) was added to a solution of 2,2-dimethyl-1-propanol (2.26 g) in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was ice-cooled and triethylamine (7.14 ml) was added.
  • the compound (3.61 g) obtained in Reference Example 25 described below was added into the reaction solution, and the mixture was further stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
  • Acetic acid (306 ml) and 1-benzylpiperidin-4-one (69.5 g) were added to a solution of 6-chloro-3,4-pyridinediamine (44 g) in 1,2-dichloroethane (306 ml) at 0 ° C.
  • Sodium triacetoxyborohydride (77.8 g) was added, and the mixture was stirred at room temperature for 1 hour.
  • Chloroform was added to the reaction solution and neutralized by adding a 10% aqueous sodium hydroxide solution. Extraction was performed with chloroform, and the organic layer was concentrated under reduced pressure.
  • the obtained residue was purified by NH silica gel column chromatography (developing solvent: ethyl acetate), and the obtained residue was recrystallized from a hexane-ethyl acetate mixed solution to obtain the title compound (41 g) as a colorless powder.
  • the aqueous layer was acidified with 1M hydrochloric acid and extracted with a chloroform-methanol (10: 1) mixed solution.
  • the obtained organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • the obtained residue powder was washed with a mixed solution of hexane-ethyl acetate to give the title compound (290 mg) as a colorless powder.
  • Sodium triacetoxyborohydride (2.2 g) was added to the solution at room temperature, stirred overnight, and then stirred at 60 ° C. for 1 hour.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with chloroform. Thereafter, the organic layer was washed with 5% brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • Reference Example 35-G The same procedure as Reference Example 31 was carried out using the compound (0.28 g) obtained in G (1) and 4- (dihydroxyboranyl) -2,3-difluorobenzoic acid (0.28 g). And purification was performed to obtain a crude title compound (0.42 g).
  • Example 1-2 to 1-3 were also synthesized according to the method described in Example 1-1 using the compound obtained in Reference Example 1 (2) and the corresponding boronic acid. .
  • the structure, NMR data, and MS data of these compounds are shown in Table 1-1.
  • Example 2-1 is also described in Example 2-1 using the compound obtained in Reference Example 2 and the compound obtained in Reference Example C or the corresponding halogen compound. Synthesized according to the method. The structure, NMR data and MS data of these compounds are shown in Table 2-1.
  • Example 1-1 To a solution of the compound obtained in Example 1-1 (239 mg) in methanol (30 ml) was added 4M hydrogen chloride / 1,4-dioxane solution (10 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 8M aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • Examples 3-3 to 3-14 were also prepared using the halogen compounds corresponding to the compounds obtained in Examples 1-1 to 1-3 and Examples 2-1 and 2-2. Synthesis was performed according to the method described in 1 and 3-2. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 and 3-2.
  • Example 4-1 4- ⁇ 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -1H-indazol-5-yl ⁇ -N-methylbenzamide
  • Example 4-1 The following Examples 4-2 to 4-5 were also synthesized according to the method described in Example 4-1, using the compound obtained in Reference Example 3 and the corresponding boronic acid. The structure, NMR data, and MS data of these compounds are shown in Table 4-1.
  • Examples 5-2 and 5-3 were also synthesized using the compound obtained in Reference Example 4 and the corresponding amine according to the method described in Example 5-1.
  • the structure, NMR data and MS data of these compounds are shown in Table 5-1.
  • Example 6-1 4- ⁇ 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -1H-indazol-5-yl ⁇ -N- (propan-2-yl) benzamide
  • Example 5-1 To a solution of the compound obtained in Example 5-1 (88 mg) in methanol (2 ml) was added 4M hydrogen chloride / 1,4-dioxane solution (2 ml), and the mixture was stirred at room temperature for 3 hours. After concentration of the reaction solution, cesium carbonate (310 mg) and 2-chloro-5-ethylpyrimidine (55 mg) were added to a solution of the obtained residue in N, N-dimethylformamide (2 ml), and the mixture was stirred at 80 ° C. for 2 days. did. Water was added to the reaction solution, and the precipitated crystals were collected by filtration.
  • Example 7-2 was also synthesized according to the method described in Example 5-1 using the compound obtained in Reference Example 5 and N-isopropylmethylamine.
  • the structure, NMR data, and MS data of the compound are shown in Table 6-1.
  • Example 8-1 [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -6-methyl-5- [4- (methylsulfonyl) phenyl] -1H-indazole (1) 6-methyl-5- [4- (Methylsulfonyl) phenyl] -1H-indazole
  • Example 8-1 (2) To a suspension of the compound (200 mg) obtained in Example 8-1 (2) in methanol (0.85 ml) was added 4M hydrogen chloride / 1,4-dioxane solution (2.1 ml), and 13 hours at room temperature. Stir. The reaction mixture was concentrated under reduced pressure to give the title compound (176 mg) as a pale yellow powder.
  • Example 8-1 To a solution of the compound obtained in Example 8-1 (3) (82 mg) in dimethyl sulfoxide (2.0 ml), 2-chloro-5-ethylpyrimidine (43 mg) and cesium carbonate (329 mg) were added, and the mixture was heated to 120 ° C. And stirred for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the resulting organic layer was washed twice with water. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.
  • Example 8-2 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -4-methyl-5- [4- (methylsulfonyl) phenyl] -1H-indazole (1) 4-methyl-5 [4- (Methylsulfonyl) phenyl] -1H-indazole
  • Example 8-2 (1) The compound (300 mg) obtained in Example 8-2 (1) was subjected to reaction and purification in the same manner as in Reference Example 8-1 (2) to give the title compound (335 mg) as a colorless powder.
  • Example 8-2 (2) The compound (330 mg) obtained in Example 8-2 (2) was synthesized in the same manner as in Reference Example 8-1 (3) to give the title compound (305 mg) as a colorless powder.
  • Example 8-2 (3) Using the compound (100 mg) obtained in Example 8-2 (3), the reaction and purification were conducted in the same manner as in Reference Example 8-1 (4) to obtain the title compound (42 mg) as a colorless powder. .
  • 1 H NMR (300 MHz, CHLOROFORM-d) ⁇ ppm 1.22 (t, J 7.6 Hz, 3 H) 2.07-2.18 (m, 2 H) 2.24-2.41 (m, 2 H) 2.44-2.56 (m, 5 H) 3.07-3.21 (m, 5 H) 4.65-4.79 (m, 1 H) 4.91-5.02 (m, 2 H) 7.23-7.30 (m, 1 H) 7.37-7.44 (m, 1 H) 7.53-7.60 (m, 2 H) 7.98-8.04 (m, 2 H) 8.08 (s, 1 H) 8.21 (s, 2 H).
  • Example 9-2 below also conforms to the method described in Example 7-1 using the compound obtained in Reference Example 7 (2) and the compound obtained in Reference Example B-1. Synthesized. Table 7-1 shows the structures, NMR data, and MS data of these compounds.
  • Example 10-1 [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5- ⁇ [4- (methylsulfonyl) phenoxy] methyl ⁇ -1H-indazole
  • Example 9-1 To a solution of the compound obtained in Example 9-1 (67 mg) in methanol (6 ml), 4M hydrogen chloride / 1,4-dioxane solution (3 ml) was added and stirred at room temperature for 3 hours. To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to remove 5- ⁇ [4- (methylsulfonyl) phenoxy] methyl ⁇ -1- (piperidin-4-yl). -1H-indazole (56 mg) was obtained.
  • Example 10-2 was also synthesized according to the method described in Example 10-1 using the compound obtained in Example 9-2 and 2-chloro-5-ethylpyrimidine.
  • Table 8-1 shows the structures, NMR data, and MS data of these compounds.
  • Examples 11-2 to 11-8 were also synthesized according to the method described in Example 1-1, using the compound obtained in Reference Example 8 (3) and the corresponding boronic acid. .
  • the structures, NMR data, and MS data of these compounds are shown in Tables 9-1 to 9-2.
  • Example 12-2 was also synthesized according to the method described in Example 12-1 using the compound obtained in Reference Example 9 and the compound obtained in Reference Example B-2.
  • the structures, NMR data, and MS data of these compounds are shown in Table 10-1.
  • Triethylamine (258 mg) and isopropyl chloroformate (46.8 mg) were added to a solution of the compound (100 mg) obtained in Reference Example 12 in chloroform (2.55 ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and extracted with chloroform. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.
  • Examples 13-3 to 13-6 and 13-16 to 13-20 are also the compounds obtained in Reference Example 12, the compounds obtained in Reference Example G-2 and Reference Example G-3, or the corresponding halogens.
  • the compounds were synthesized according to the method described in Example 13-2, and 13-7 to 13-15 were compounds obtained in Examples 11-2 to 11-6 and Example 12-1. Were synthesized in accordance with the methods described in Reference Example 12 and Example 13-2. The structures, NMR data, and MS data of these compounds are shown in Tables 11-1 to 11-3.
  • Example 13-21 (4- ⁇ 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -1H-benzotriazol-5-yl ⁇ phenyl) cyanamide (1) 1- (piperidin-4-yl ) -5- [4- (1H-tetrazol-1-yl) phenyl] -1H-benzotriazole hydrochloride
  • Example 14-1 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5- (2-methylpyridin-3-yl) -1H-benzotriazole
  • Example 14-1 The following Examples 14-2 to 14-9 were also prepared in Example 14-1 using the compound obtained in Reference Example 10 (2) and the compound obtained in Reference Example E-7 or the corresponding boronic acid. Synthesized according to the method described. The structures, NMR data and MS data of these compounds are shown in Table 12-1.
  • Example 14-10 1- [1- (5-Methylpyrimidin-2-yl) piperidin-4-yl] -5- [4- (methylaminocarbonyl) phenyl] -1H-benzotriazole
  • Example 14-12 below was also synthesized according to the method described in Example 14-11 using the boronic acid corresponding to the compound obtained in Reference Example 10 (1).
  • the structures, NMR data and MS data of these compounds are shown in Table 12-2.
  • Example 15-1 [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -5- [4- (1H-tetrazol-1-yl) phenyl] -1H-benzotriazole
  • Examples 15-2 to 15-10 were also carried out using the compound obtained in Reference Example 11 and the compounds obtained in Reference Examples D-1 to D-4 and Reference Examples F-1 to F-5. Synthesized according to the method described in Example 15-1. The structures, NMR data, and MS data of these compounds are shown in Tables 13-1 to 13-2.
  • Examples 16-2 to 16-11 were also synthesized according to the method described in Example 16-1 using the compound obtained in Reference Example 12 and the corresponding alkyl halide.
  • the structures, NMR data, and MS data of these compounds are shown in Tables 14-1 to 14-2.
  • Examples 17-2 to 17-5 were also synthesized in accordance with the method described in Example 17-1 using the compound obtained in Reference Example 13 or 13-B and the corresponding amine.
  • the structures, NMR data and MS data of these compounds are shown in Table 15-1.
  • Example 18-1 4- ⁇ 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -1H-benzotriazol-5-yl ⁇ -N- (propan-2-yl) benzamide
  • Example 17-1 To a suspension of the compound (80 mg) obtained in Example 17-1 in methanol (0.575 ml) was added 4M hydrogen chloride / 1,4-dioxane solution (1.73 ml), and the mixture was stirred at room temperature for 3 hours. . The reaction solution was concentrated under reduced pressure to give 4- [1- (piperidin-4-yl) -1H-benzotriazol-5-yl] -N- (propan-2-yl) benzamide hydrochloride (69 mg) as a colorless powder. Obtained.
  • Examples 18-2 to 18-8 below are also the methods described in Example 18-1 using the halogen compounds corresponding to the compounds obtained in Examples 17-1, 17-4, and 17-5. Synthesized according to The structures, NMR data, and MS data of these compounds are shown in Tables 16-1 to 16-2.
  • Example 18-9 4- ⁇ 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -1H-benzotriazol-5-yl ⁇ -N- (2-hydroxyethyl) benzamide
  • Examples 18-11 to 18-14 were also obtained from N- (2-hydroxyethyl) -4- [1- (piperidin-4-yl) -1H-benzotriazole-- obtained in Example 18-9.
  • 5-yl] benzamide was synthesized according to the method described in Examples 18-9 and 18-10 using the corresponding halogen compound with hydrochloride. The structures, NMR data, and MS data of these compounds are shown in Tables 16-3 to 16-4.
  • Example 19-1 4- ⁇ 1- [1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl] -1H-benzotriazol-5-yl ⁇ -N, N-dimethylbenzamide
  • Example 5-1 The reaction and purification were conducted in the same manner as in Example 5-1 using the compound (102 mg) obtained in Reference Example 14-A, dimethylamine hydrochloride (29 mg) and triethylamine (50 ⁇ l) to give the title compound (94 mg ) Was obtained as a colorless powder.
  • Examples 19-2 to 19-68 are also based on the method described in Example 5-1 using the compounds obtained in Reference Examples 14-A to 14-H and the corresponding amines. Synthesized. The structures, NMR data, and MS data of these compounds are shown in Tables 17-1 to 17-11.
  • Example 20-1 [1- (5-Ethylpyridin-2-yl) piperidin-4-yl] -5- [4- (methylsulfonyl) phenyl] -1H-benzotriazole (1) 1- [1- (5-bromo Pyridin-2-yl) piperidin-4-yl] -5- [4- (methylsulfonyl) phenyl] -1H-benzotriazole
  • Example 20-1 The compound obtained in Example 20-1 (1) (142 mg), tributyl (vinyl) tin (96 ⁇ l), bis (triphenylphosphine) palladium (II) dichloride (9.7 mg) of 1,4-dioxane (1 0.5 ml) The suspension was stirred at 150 ° C. for 30 minutes using a microwave reactor (Initiator Sixty TM (trade name) manufactured by Biotage). The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure.
  • Example 20-1 (2) A suspension of the compound obtained in Example 20-1 (2) (33 mg) and palladium hydroxide (II) (6.6 mg) in 1,4-dioxane (2m1) was stirred overnight at room temperature under a hydrogen atmosphere. did. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from chloroform-hexane to give the title compound (23 mg).
  • Example 20-2 1- [1- (6-Ethylpyridazin-3-yl) piperidin-4-yl] -5- [4- (methylsulfonyl) phenyl] -1H-benzotriazole (1) 1- [1- (6-E Tenylpyridazin-3-yl) piperidin-4-yl] -5- [4- (methylsulfonyl) phenyl] -1H-benzotriazole
  • Example 20-4 [2- (4- ⁇ 5- [4- (Methylsulfonyl) phenyl] -1H-benzotriazol-1-yl ⁇ piperidin-1-yl) pyrimidin-5-yl] methanol
  • Example 20-3 A chloroform (4 ml) suspension of the compound (80 mg) obtained in Example 20-3 was cooled in an ice bath, methylmagnesium chloride (3M diethyl ether solution, 1.1 ml) was added, and the mixture was stirred at room temperature for 2 hours. Further, methylmagnesium chloride (3M diethyl ether solution, 1.0 ml) was added and stirred for 1 hour. A 6M aqueous sodium hydroxide solution and chloroform were added to the reaction solution, followed by filtration through Celite (registered trademark). The organic layer of the filtrate was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • methylmagnesium chloride (3M diethyl ether solution, 1.1 ml) was added, and the mixture was stirred at room temperature for 2 hours. Further, methylmagnesium chloride (3M diethyl ether solution, 1.0 ml) was added and stir
  • Example 20-6 5- [4- (Methylsulfonyl) phenyl] -1- ⁇ 1- [5- (prop-1-en-2-yl) pyrimidin-2-yl] piperidin-4-yl ⁇ -1H-benzotriazole
  • Example 20-3 To a suspension of the compound (100 mg) obtained in Example 20-3 in tetrahydrofuran (2 ml) was added methylmagnesium chloride (3M diethyl ether solution, 1.36 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour at 60 ° C. for 3 hours. Stir for hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure.
  • methylmagnesium chloride 3M diethyl ether solution, 1.36 ml
  • Example 20-7 5- [4- (Methylsulfonyl) phenyl] -1- ⁇ 1- [5- (propan-2-yl) pyrimidin-2-yl] piperidin-4-yl ⁇ -1H-benzotriazole
  • Example 20-6 The compound (90 mg) obtained in Example 20-6 was subjected to reaction and purification in the same manner as in Reference Example 20-1 (3) to give the title compound (62 mg) as a colorless powder.
  • 1 H NMR (300 MHz, CHLOROFORM-d) ⁇ ppm 1.22-1.30 (m, 6 H) 2.25-2.35 (m, 2 H) 2.37-2.52 (m, 2 H) 2.75-2.89 (m, 1 H) 3.12 (s, 3 H) 3.15-3.27 (m, 2 H) 4.95-5.06 (m, 3 H) 7.67-7.76 (m, 2 H) 7.81-7.86 (m, 2 H) 8.03-8.08 (m, 2 H ) 8.26 (s, 2 H) 8.29 (dd, J 1.6, 0.9 Hz, 1 H).
  • Example 13-20 The compound (90 mg) obtained in Example 13-20 was subjected to reaction and purification in the same manner as in Reference Example 20-1 (3) to give the title compound (16 mg) as a colorless powder.
  • Example 21-1 To a solution of the compound obtained in Example 21-1 (62.4 mg) in N-methylpyrrolidone (2 ml), sodium cyanide (42.8 mg), 1,4-diazabicyclo [2.2.2] octane (16 3 mg) and stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.

Abstract

La présente invention concerne un composé présentant une remarquable activité d'agoniste du récepteur GPR119. L'invention concerne plus particulièrement un composé représenté par la formule générale (I) ou l'un de ses sels pharmaceutiquement admis. Dans la formule (I), le substituant A est phényle ou hétéroaryle à 5 ou 6 segments. W est liaison simple, -O-, -NH-, -OCH2- ou -CH2O-. X est atome d'azote ou CR21. Y1 est atome d'azote ou CR22. Y2 est atome d'azote ou CR23. Y3 est atome d'azote ou CR24. R21, R22, R23 et R24, qui peuvent être identiques ou différents, sont atome d'hydrogène ou C1-C6 alkyle. Enfin, le substituant B est, soit (a) C2-C6 alkyle, C3-C8 cycloalkyle, (C3-C8 cycloalkyle)C1-C6 alkyle, (aryl)C1-C6 alkyle, ou (hétérocyclyle saturé)C1-C6 alkyle, soit (b) -COOR31 (R31 étant C1-C6 alkyle, C3-C8 cycloalkyle, aryle ou hétérocyclyle saturé), soit enfin (c) hétéroaryle à 5 ou 6 segments représenté par la formule générale (β). Toutefois une structure représentée par la formule (A) est exclue.
PCT/JP2011/079745 2010-12-22 2011-12-21 Composé hétérocyclique condensé WO2012086735A1 (fr)

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EP2670746A1 (fr) * 2011-01-31 2013-12-11 Centaurus Biopharma Co., Ltd. Composés hétéroaryles bicycliques en tant qu'agonistes du récepteur gpr119
CN104529881A (zh) * 2014-12-08 2015-04-22 苏州施亚生物科技有限公司 一种2-氯-5-乙基吡啶的制备方法
EP2860177A3 (fr) * 2013-09-20 2015-06-10 Bayer Intellectual Property GmbH Synthèse d'arènes fonctionnalisés
WO2017045955A1 (fr) * 2015-09-14 2017-03-23 Basf Se Composés hétérobicycliques
US9908885B2 (en) * 2015-04-15 2018-03-06 Celgene Quanticel Research, Inc. Bromodomain inhibitors
WO2018068759A1 (fr) 2016-10-14 2018-04-19 江苏恒瑞医药股份有限公司 Dérivé d'anneau ponté à cycle hétéroaryle à cinq chaînons, son procédé de préparation et son utilisation médicale
CN108997224A (zh) * 2018-08-28 2018-12-14 韶远科技（上海)有限公司 一种2-氯-5-氰基含氮六元杂环化合物的制备方法

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CN110845426A (zh) * 2019-11-29 2020-02-28 都创(上海)医药科技有限公司 一种2-氯-5-氰基嘧啶化合物制备方法

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EP2670746A1 (fr) * 2011-01-31 2013-12-11 Centaurus Biopharma Co., Ltd. Composés hétéroaryles bicycliques en tant qu'agonistes du récepteur gpr119
EP2670746A4 (fr) * 2011-01-31 2014-07-30 Centaurus Biopharma Co Ltd Composés hétéroaryles bicycliques en tant qu'agonistes du récepteur gpr119
EP2860177A3 (fr) * 2013-09-20 2015-06-10 Bayer Intellectual Property GmbH Synthèse d'arènes fonctionnalisés
CN104529881A (zh) * 2014-12-08 2015-04-22 苏州施亚生物科技有限公司 一种2-氯-5-乙基吡啶的制备方法
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US10494371B2 (en) 2015-04-15 2019-12-03 Celgene Quanticel Research, Inc. Bromodomain inhibitors
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CN108997224A (zh) * 2018-08-28 2018-12-14 韶远科技（上海)有限公司 一种2-氯-5-氰基含氮六元杂环化合物的制备方法
CN108997224B (zh) * 2018-08-28 2023-04-28 韶远科技（上海)有限公司 一种2-氯-5-氰基含氮六元杂环化合物的制备方法

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