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WO2011021678A1 - Composé à hétérocycles fusionnés - Google Patents

Composé à hétérocycles fusionnés Download PDF

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Publication number
WO2011021678A1
WO2011021678A1 PCT/JP2010/064042 JP2010064042W WO2011021678A1 WO 2011021678 A1 WO2011021678 A1 WO 2011021678A1 JP 2010064042 W JP2010064042 W JP 2010064042W WO 2011021678 A1 WO2011021678 A1 WO 2011021678A1
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Prior art keywords
mol
alkyl
compound
optionally substituted
substituted
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Japanese (ja)
Inventor
誠司 見渡
啓 海江田
昌志 高橋
広美 乾
玲 岡本
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • 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
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Definitions

  • the present invention relates to a fused heterocyclic compound having excellent pharmaceutical action such as p38 MAPK inhibitory action and TNF- ⁇ production inhibitory action, and a medicament containing the compound.
  • Cytokines such as TNF- ⁇ (tumor necrosis factor- ⁇ ) and IL-1 (interleukin-1) are organisms produced by various cells such as monocytes or macrophages in response to infection or other cellular stress. It is a chemical substance (see Non-Patent Document 1). Although these cytokines play an important role in immune responses when they are present in appropriate amounts, excessive production is considered to be involved in many inflammatory diseases (see Non-Patent Document 2).
  • P38 MAP kinase also referred to as p38 MAPK
  • MAP mitogen activated protein
  • MAPK mitogen activated protein
  • an inhibitor of p38 MAPK may be a therapeutic agent for inflammatory diseases (see Non-Patent Document 3).
  • heterocyclic compounds such as imidazole derivatives, oxazole derivatives, imidazopyrimidine derivatives, imidazopyridazine derivatives and imidazopyridine derivatives are known (see Patent Documents 1 to 8).
  • Patent Document 1 discloses the following compounds (for the definitions of the abbreviations in the structural formulas indicating the compounds of Patent Documents 1 to 12, see the specifications of each patent document).
  • Patent Document 2 discloses the following compounds.
  • Patent Document 3 discloses the following compounds.
  • Patent Document 4 discloses the following compounds.
  • Patent Document 5 discloses the following compounds.
  • Patent Document 6 discloses the following compounds.
  • Patent Document 7 discloses the following compounds.
  • Patent Document 8 discloses the following compounds.
  • Patent Document 9 discloses the following compounds.
  • Patent Document 10 discloses the following compounds.
  • Patent Document 11 discloses the following compounds.
  • Patent Document 12 discloses the following compounds.
  • Patent Document 13 discloses the following compounds.
  • Patent Document 14 discloses the following compounds.
  • Non-Patent Document 4 discloses the following compounds.
  • R 1 represents a hydrogen atom, an optionally substituted phenyl, an optionally substituted heterocyclic group, an optionally substituted C 1-8 alkyl, an optionally substituted C 3-6 cycloalkyl, Optionally substituted C 1-6 alkoxy or optionally substituted indanyl, R 2 is an optionally substituted aryl or an optionally substituted bicyclic heteroaryl.
  • compound (I) Or a salt thereof (hereinafter sometimes abbreviated as compound (I)), and the resulting compound (I) was unexpectedly superior based on its unique chemical structure. It was found to have a MAPK inhibitory action and a TNF- ⁇ production inhibitory action. The present inventors have completed the present invention based on these findings.
  • R 1 is optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, Or optionally substituted indanyl, The compound of the above-mentioned [1] or a salt thereof.
  • One of Y 1 and Y 2 is an N atom, the other is CH, One of X 1 and X 2 is CH, the other is CLR 2 , L is a bond or -NH-, R 1 is 1 selected from (1) (i) hydroxy, (ii) C 1-6 alkoxy, (iii) oxetanyl substituted with C 1-6 alkyl, and (iv) phenyl optionally substituted with a halogen atom C 1-6 alkyl optionally substituted with up to 3 substituents, (2) C 3-6 cycloalkyl substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) C 1-6 alkyl, (3) oxetanyl substituted with C 1-6 alkyl, (4) tetrahydropyranyl, or (5) phenyl substituted with a halogen atom, R 2 is (1) halogen atom, (2) C 1-6 alkyl, (3) (i) C 3-6
  • Compound (I) exhibits excellent p38 MAPK inhibitory action, TNF-alpha inhibitory action (TNF-alpha production inhibitory action, TNF-alpha action inhibitory action), etc., and is therefore used as a safe pharmaceutical based on these actions. be able to.
  • the medicament of the present invention comprising compound (I) has low toxicity and can be safely administered orally or parenterally.
  • examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • examples of “C 1-8 alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like
  • C 1 “ -6 alkyl” includes 1 to 6 carbon atoms in the above “C 1-8 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • examples of “C 5-6 cycloalkyl-carbonyl” include cyclopentylcarbonyl and cyclohexylcarbonyl.
  • examples of “C 3-6 cycloalkenyl-carbonyl” include cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl and the like.
  • examples of “C 6-10 aryloxy” include phenoxy, naphthyloxy and the like.
  • examples of “C 7-12 aralkyloxy” include benzyloxy, phenylethyloxy, naphthylmethyloxy and the like.
  • “C 1-6 alkoxy-carbonyl” includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. Is mentioned.
  • examples of the “di-C 1-6 alkyl-carbamoyl” include dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl and the like.
  • C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • C 1-6 alkyl-carbonyl includes acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl. , Hexanoyl, heptanoyl and the like.
  • examples of “C 2-6 alkenyl-carbonyl” include propenoyl, 2-methylpropenoyl, 2-butenoyl, 3-butenoyl, pentenoyl, 3-methylpentenoyl, hexenoyl and the like.
  • examples of “C 7-12 aralkyl-carbonyl” include phenylacetyl, phenylpropanoyl, phenylbutanoyl, naphthylacetyl, naphthylpropanoyl and the like.
  • examples of “C 7-12 aralkyl” include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, naphthylethyl and the like.
  • examples of “C 6-10 aryl” include phenyl, naphthyl and the like.
  • C 1-6 alkylamino examples include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino and the like.
  • diC 1-6 alkylamino includes dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ditert-butylamino and the like. Is mentioned.
  • C 1-6 alkylsulfanyl examples include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl and the like.
  • C 1-6 alkylsulfonyl examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl and the like.
  • C 1-6 alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
  • examples of “C 1-6 alkyl-carbamoyl” include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl and the like.
  • examples of the “cyclic amino” include aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino and the like.
  • examples of the “hydrocarbon group” include a chain or cyclic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc.) and the like. Of these, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferred.
  • Examples of “alkyl” include C 1-6 alkyl, and preferably C 1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl) and the like.
  • Alkenyl includes, for example, C 2-6 alkenyl (eg, vinyl, allyl, isopropenyl, buten-1-yl, buten-2-yl, buten-3-yl, 2-methylpropene-2 -Yl, 1-methylpropen-2-yl, 2-methylpropen-1-yl and the like.
  • alkynyl include C 2-6 alkynyl (eg, ethynyl, propargyl, butyn-1-yl, butyn-2-yl, butyn-3-yl, hexyn-1-yl) and the like.
  • Cycloalkyl includes, for example, C 3-6 cycloalkyl and the like.
  • aryl include C 6-10 aryl.
  • aralkyl include C 7-12 aralkyl.
  • examples of the “substituent” of “optionally substituted hydrocarbon group” include: (1) oxo; (2) a halogen atom; (3) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.); (4) Nitro; (5) Cyano; (6) (a) a halogen atom, (b) hydroxy, (c) C 1-6 alkoxy, (d) mono-C 1-6 alkylamino, (e) di-C 1-6 alkylamino, (f) Substituted with 1 to 3 substituents selected from C 3-6 cycloalkyl, and (g) (i) a halogen atom, (ii) C 1-6 alkyl and (iii) C 1-6 alkoxy C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from good heterocyclic groups; (7) C 2-6 alkenyl optionally having 1 to 3 halogen atoms; (8) Carboxy-
  • heterocyclic group is, for example, a 5- to 14-membered (monocyclic) containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • (Bicyclic or tricyclic) heterocycle preferably (i) 5-14 membered (preferably 5-10 membered, particularly preferably 5 or 6 membered) aromatic heterocycle, (ii) 5-10 membered (preferably Includes a monovalent group formed by removing any one hydrogen atom from a 5- to 7-membered) aliphatic heterocyclic ring or (iii) a 7- to 10-membered heterocyclic bridged ring.
  • Examples of the “(i) 5- to 14-membered (preferably 5- to 10-membered, particularly preferably 5- or 6-membered) aromatic heterocycle” include, for example, thiophene, benzo [b] thiophene, benzo [b] furan, benz Imidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H -Quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ⁇ -carboline, phenanthridine, acridine, phenazine,
  • Examples of the “(ii) 5- to 10-membered (preferably 5- to 7-membered) aliphatic heterocyclic ring” include pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, Oxadiazoline, oxadiazolidine, thiadiazoline, thiadiazolidine, triazoline, triazolidine, thiadiazoline, thiadiazolidine, tetrahydropyran, dihydropyran, tetrahydrothiopyran, dihydrothiopyran, tetrahydrofuran, tetrahydrothiophene, 3,4-dihydroquinoline, Examples include 1,2,3,4-tetrahydroquinoline, 3,4-dihydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, hexahydroazepine and the like.
  • heterocyclic group is preferably 5 to 14 containing 1 to 4 (preferably 1 to 3) 1 or 2 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • a membered (preferably 5 to 10 membered, particularly preferably 5 or 6 membered) heterocyclic group (monocyclic or bicyclic, preferably monocyclic).
  • the “substituent” of the “optionally substituted heterocyclic group” is a substituent selected from the substituent group B, among which (a) a halogen atom, (b) a C 1-6 alkyl (C) hydroxy, (d) C 1-6 alkoxy, (e) mono-C 1-6 alkylamino, (f) di-C 1-6 alkylamino, (g) C 3-6 cycloalkyl, and (h) a substituent selected from a heterocyclic group optionally substituted with 1 to 3 substituents selected from (i) a halogen atom, (ii) C 1-6 alkyl and (iii) C 1-6 alkoxy Groups and the like.
  • the “optionally substituted acyl” includes, for example, the formula: — (C ⁇ O) —R h , — (C ⁇ O) —NR i R i ′ or —SO 2 —R j
  • R h represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • R i and R i ′ are the same or different and each represents a hydrogen atom, a substituted A hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or R i and R i ′ may form a ring together with the nitrogen atom to which they are bonded
  • R j is The hydrocarbon group which may be substituted or the heterocyclic group which may be substituted is shown. The group etc. which are represented by these are mentioned.
  • acyl examples include, for example, (1) formyl; (2) C 1-6 alkyl-carbonyl optionally substituted with 1 to 3 substituents selected from the substituent group B; (3) C 3-6 cycloalkyl-carbonyl optionally substituted with 1 to 3 substituents selected from Substituent Group B (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); (4) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.) optionally substituted with 1 to 3 substituents selected from Substituent Group B; (5) C 6-10 aryl-carbonyl optionally substituted with 1 to 3 substituents selected from substituent group B (eg, benzoyl, naphthalen-1-ylcarbonyl, naphthalen-2-
  • substituent group B eg
  • examples of the “ring” formed together with the nitrogen atom include “optionally substituted 5- to 7-membered saturated cyclic amine”.
  • the “optionally substituted 5- to 7-membered saturated cyclic amine” is a substituted ring condensed with C 6-10 arene (eg, benzene ring etc.) etc. (eg, condensed with C 6-10 arene). In the form of a 5- to 7-membered saturated cyclic amine, etc.).
  • pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, piperazine optionally having a substituent at the 4-position 3,4-dihydroquinoline, 3,4-dihydroisoquinoline, 1,2, 3,4-tetrahydroquinoline, hexahydroazepine and the like can be mentioned, and particularly preferred are piperidine, 1,2,3,4-tetrahydroquinoline and the like.
  • the ring may be substituted, and as such a “substituent”, a substituent selected from Substituent Group B, among them (a) a halogen atom, (b) C 1-6 alkyl, (c) Hydroxy, (d) C 1-6 alkoxy, (e) mono-C 1-6 alkylamino, (f) di-C 1-6 alkylamino, (g) C 3-6 cycloalkyl, and (h) ( i) a halogen atom, (ii) a substituent selected from a heterocyclic group optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl and (iii) C 1-6 alkoxy It is done.
  • a substituent selected from Substituent Group B among them (a) a halogen atom, (b) C 1-6 alkyl, (c) Hydroxy, (d) C 1-6 alkoxy, (e) mono-C 1-6 alkylamino, (f) di-
  • R 1 is a hydrogen atom, an optionally substituted phenyl, an optionally substituted heterocyclic group, an optionally substituted C 1-8 alkyl, or an optionally substituted C. 3-6 cycloalkyl, optionally substituted C 1-6 alkoxy or optionally substituted indanyl.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R 1 is preferably a 5- or 6-membered monocyclic heterocyclic group, and in particular, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydro Pyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrofuryl, tetrahydrothienyl and the like are preferable.
  • an optionally substituted hydrocarbon group eg, optionally substituted (eg, optionally substituted with hydroxy, etc.) C 1-6 alkyl (eg, methyl, ethyl, isopropyl, etc.), Optionally substituted C 3-6 cycloalkyl (eg, cyclopropyl, etc.), optionally substituted C 7-12 aralkyl (eg, benzyl, etc.)];
  • optionally substituted amino eg, formula:
  • R d and R e are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl, Alternatively, R d and R e may form a ring together with the nitrogen atom to which they are bonded.
  • R f O—, R f —CO—O—, R f O—CO—O—, R f —NH—CO—O— or R f R f ′ A group represented by N—CO—O— (R f and R f ′ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group); .
  • sulfanyl selected from sulfanyl; a C 1-6 alkylsulfanyl optionally having 1 to 3 halogen atoms (eg, methylsulfanyl, etc.); a halogen atom, C 1-6 alkoxy and C 1-6 alkyl C 6-10 arylsulfanyl (eg, phenylsulfanyl, naphthalen-1-ylsulfanyl, naphthalen-2-ylsulfanyl, etc.) optionally substituted by 1 to 3 substituents as described above; halogen atom, C 1-6 C 7-12 aralkylsulfanyl optionally substituted with 1 to 3 substituents selected from alkyl and C 1-6 alkoxy (eg, benzylsulfanyl, phenylethylsulfanyl etc.) and the like]; (9) Carboxy; (10) optionally substituted acyl [eg, optionally substituted C 1-6
  • substituted sulfonyl [eg, C 1-6 alkylsulfonyl (eg, methylsulfonyl, etc.); substituted with 1 to 3 substituents selected from a halogen atom, C 1-6 alkoxy and C 1-6 alkyl C 6-10 arylsulfonyl (eg, phenylsulfonyl, naphthalen-1-ylsulfonyl, naphthalen-2-ylsulfonyl, etc.)] (16) substituted sulfinyl [eg, C 1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.); 1 to 3 substituents selected from a halogen atom, C 1-6 alkoxy and C 1-6 alkyl Optionally substituted C 6-10 arylsulfinyl (eg, phenylsulfinyl, n
  • An optionally substituted heterocyclic group (preferably C 1-6 alkyl (eg, methyl etc.), C 6-10 aryl, C 1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic ring Groups (eg, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl Yl, quinolin-5-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, indol-1-yl, indol-2-yl, Indol-3-yl, benzothiazol-2-yl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, be
  • R 1 is preferably a hydrogen atom, an optionally substituted phenyl, an optionally substituted heterocyclic group, an optionally substituted C 1-8 alkyl, an optionally substituted C 3-6.
  • Cycloalkyl, C 1-6 alkoxy or indanyl more preferably (1) a hydrogen atom; (2) (a) a halogen atom (preferably a fluorine atom, a chlorine atom), and (b) a C 1-6 alkyl optionally having 1 to 3 halogen atoms (preferably a fluorine atom) ( Preferably, methyl)
  • Phenyl optionally having 1 to 3 substituents selected from: (3) (a) C 1-6 alkyl (preferably methyl), (b) C 7-12 aralkyl (preferably benzyl), (c) C 1-6 alkyl-carbonyl (preferably acetyl), and (d) a 5- or 6-membered monocyclic heterocyclic group optionally having 1 to 3 substituents selected from o
  • R 1 is preferably Optionally substituted phenyl, optionally substituted heterocyclic group, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted Indanyl, It is.
  • one of Y 1 and Y 2 represents an N atom, and the other represents CH.
  • one of X 1 and X 2 represents CH, and the other represents CLR 2 .
  • R 2 represents an optionally substituted aryl or an optionally substituted bicyclic heteroaryl.
  • Examples of the “bicyclic heteroaryl” of the “optionally substituted bicyclic heteroaryl” represented by R 2 include benzofuryl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzo Isothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, indolyl, 1H-indazolyl, furopyridyl, thienopyridyl, 1H-pyrrolopyridyl, 1H-imidazolopyridyl, 1H-pyrazolopyridyl, oxa Zolopyridyl, isoxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, oxadiazolopyridyl, thiadiazolopyr
  • the “substituent” of the “optionally substituted aryl” and the “optionally substituted bicyclic heteroaryl” represented by R 2 is 1 to 3 substituents selected from the substituent group A Among them, (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) C 1-6 alkyl (preferably methyl) (3) C 1-6 alkoxy (preferably methoxy) (4) cyano, (5) Nitro, (6) Carboxy, (7) C 1-6 alkoxy-carbonyl (preferably methoxycarbonyl, ethoxycarbonyl), (8) (a) (i) 1 to 3 C 1-6 alkyl (preferably methyl) optionally having 1 to 3 halogen atoms (preferably a fluorine atom), (ii) a 5 or 6 membered aliphatic heterocyclic group (preferably morpholino), and (iii) 1 to 3 C 1-6 alkyl (preferably methyl) optionally 5 or 6 Membered aromatic heterocyclic group (
  • R 2 is preferably an optionally substituted aryl, more preferably an optionally substituted phenyl.
  • R 2 is preferably (1) a halogen atom (preferably a fluorine atom or a chlorine atom), (2) C 1-6 alkyl (preferably methyl), (3) C 1-6 alkoxy (preferably methoxy), (4) cyano, (5) Nitro, (6) Carboxy, (7) C 1-6 alkoxy-carbonyl (preferably methoxycarbonyl, ethoxycarbonyl), (8) (a) (i) 1 to 3 C 1-6 alkyl (preferably methyl) optionally having 1 to 3 halogen atoms (preferably a fluorine atom), (ii) a 5 or 6 membered aliphatic heterocyclic group (preferably morpholino), and (iii) 1 to 3 C 1-6 alkyl (preferably methyl) optionally 5 or 6 Membered aromatic heterocyclic group (preferably pyrrolyl) C 6-10 aryl-carbonyl (preferably be
  • R 2 is preferably an optionally substituted bicyclic heteroaryl, more preferably an optionally substituted benzoisoxazolyl.
  • R 2 is preferably (1) C 1-6 alkyl (preferably methyl), and (2) (a) C 1-6 alkyl (preferably methyl), and (b) C 3-6 cycloalkyl (preferably cyclopropyl)
  • a bicyclic heteroaryl preferably benzoisoxazolyl
  • R 2 is preferably having 1 to 3 substituents selected from amino optionally mono- or di-substituted with a substituent selected from .
  • L represents a bond, —NH—, —CH 2 — or —CO—.
  • L is preferably a bond or —NH—.
  • Suitable compounds (I) include the following compounds.
  • One of Y 1 and Y 2 is an N atom and the other is CH;
  • One of X 1 and X 2 is CH and the other is CLR 2 ;
  • L is a bond or —NH—;
  • R 1 is (1) a hydrogen atom; (2) (a) a halogen atom (preferably a fluorine atom, a chlorine atom), and (b) a C 1-6 alkyl optionally having 1 to 3 halogen atoms (preferably a fluorine atom) ( Preferably, methyl) Phenyl optionally having 1 to 3 substituents selected from: (3) (a) C 1-6 alkyl (preferably methyl), (b) C 7-12 aralkyl (preferably benzyl), (c) C 1-6 alkyl-carbonyl (preferably acetyl), and (d) a 5- or 6-membered monocyclic heterocyclic group optionally having 1 to 3 substituents selected from oxo (
  • R 1 is (1) (a) a halogen atom (preferably a fluorine atom, a chlorine atom), and (b) a C 1-6 alkyl which may have 1 to 3 halogen atoms (preferably a fluorine atom) ( Preferably, methyl) Phenyl optionally having 1 to 3 substituents selected from: (2) (a) C 1-6 alkyl (preferably methyl), (b) C 7-12 aralkyl (preferably benzyl), (c) C 1-6 alkyl-carbonyl (preferably acetyl), and (d) a 5- or 6-membered monocyclic heterocyclic group optionally having 1 to 3 substituents selected from oxo (Preferably pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, oxet
  • suitable compounds (I) include the following compounds.
  • One of Y 1 and Y 2 is an N atom and the other is CH;
  • One of X 1 and X 2 is CH and the other is CLR 2 ;
  • L is a bond or —NH—;
  • R 1 is C 1-6 alkyl (preferably tert-butyl); and
  • R 2 is (1) C 1-6 alkyl (preferably methyl), and (2) (a) C 1-6 alkyl (preferably methyl), and (b) C 3-6 cycloalkyl (preferably cyclopropyl)
  • a bicyclic heteroaryl preferably benzoisoxazolyl which may have 1 to 3 substituents selected from amino optionally mono- or di-substituted with a substituent selected from Compound (I).
  • suitable compound (I) includes the following compounds. [Compound A]
  • Suitable compounds (Ia) include the following compounds.
  • L is a bond or —NH—;
  • R 1 is (1) (a) a halogen atom (preferably a fluorine atom, a chlorine atom), and (b) a C 1-6 alkyl which may have 1 to 3 halogen atoms (preferably a fluorine atom) ( Preferably, methyl)
  • Phenyl optionally having 1 to 3 substituents selected from: (2) an optionally substituted 5- or 6-membered monocyclic heterocyclic group (preferably pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, Tetrahydrofuryl, tetrahydrothienyl); (3) (a) C 3-6 cycloalkyl (preferably cyclopropyl), (b) (i) a hal
  • Particularly preferred compounds (Ia) include the following compounds.
  • L is a bond;
  • R 1 is (1) (a) a hydroxy group, and (b) a 4- to 6-membered aliphatic heterocyclic group having 1 to 2 C 1-6 alkyls (preferably 3-oxetanyl) C 1-6 alkyl which may have a substituent selected from (preferably methyl, sec-butyl, tert-butyl, 1,1-dimethylethyl, 1,1-dimethylpropyl) (2) 4- to 6-membered aliphatic heterocyclic group (preferably 4-tetrahydropyranyl, 3-oxetanyl) optionally having C 1-6 alkyl (preferably methyl) (3) (a) a halogen atom (preferably a fluorine atom), and (b) a C 1-6 alkyl (preferably methyl) C 3-6 cycloalkyl having 1 to 3 substituents selected from (preferably cyclopropyl, cyclobutyl,
  • R 2 is (1) C 1-6 alkyl (preferably methyl), and (2) (a) C 3-6 cycloalkyl (preferably cyclopropyl) having C 1-6 alkyl (preferably methyl), and (b) 5-membered aromatic heterocycle (preferably 3-isoxazolyl) Having a carbamoyl monosubstituted with a substituent selected from Phenyl optionally having one halogen atom (preferably a fluorine atom), Is preferred.
  • Suitable compounds (Ib) include the following compounds.
  • L is a bond or —NH—;
  • R 1 is (1) C 1-6 alkyl (preferably isobutyl, sec-butyl, tert-butyl); or (2) an optionally substituted 5- or 6-membered monocyclic heterocyclic group (preferably pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, Tetrahydrofuryl, tetrahydrothienyl); and
  • R 2 is (1) C 1-6 alkyl (preferably methyl), (2) Nitro, (3) (a) C 6-10 aryl-carbonyl (preferably benzoyl), and (b) C 3-6 cycloalkyl-carbonyl (preferably cyclopropylcarbonyl) Amino optionally mono- or di-substituted with a
  • Suitable compounds (Ic) include the following compounds.
  • L is a bond or —NH—;
  • R 1 is (1) (a) a halogen atom (preferably a fluorine atom, a chlorine atom), and (b) a C 1-6 alkyl which may have 1 to 3 halogen atoms (preferably a fluorine atom) ( Preferably, methyl) Phenyl optionally having 1 to 3 substituents selected from: or (2) C 1-6 alkyl (preferably methyl) optionally having 1 to 3 C 6-10 aryl (preferably phenyl); or (3) an optionally substituted 5- or 6-membered monocyclic heterocyclic group (preferably pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, Tetrahydrofuryl, tetrahydrothienyl); and
  • suitable compounds (I) include the following compounds.
  • One of Y 1 and Y 2 is an N atom and the other is CH;
  • One of X 1 and X 2 is CH and the other is CLR 2 ;
  • L is a bond or —NH—;
  • R 1 is 1 to 3 selected from (1) (i) hydroxy, (ii) C 1-6 alkoxy, (iii) oxetanyl substituted with C 1-6 alkyl, and (iv) phenyl optionally substituted with a halogen atom C 1-6 alkyl optionally substituted by 3 substituents, (2) C 3-6 cycloalkyl substituted with 1 to 3 substituents selected from (i) a halogen atom and (ii) C 1-6 alkyl, (3) oxetanyl substituted with C 1-6 alkyl, (4) tetrahydropyranyl, or (5) phenyl substituted with a halogen atom; and R 2 is (1) halogen
  • One of Y 1 and Y 2 is an N atom and the other is CH; One of X 1 and X 2 is CH and the other is CLR 2 ; L is —NH—; R 1 is C 1-6 alkyl optionally substituted with a phenyl optionally substituted with a halogen atom, or phenyl substituted with a halogen atom; and R 2 is (1) halogen atom, (2) C 1-6 alkyl, (3) carbamoyl monosubstituted with C 3-6 cycloalkyl, (4) amino monosubstituted with C 3-6 cycloalkylcarbonyl, and (5) substituted with a substituent selected from (i) morpholinyl, (ii) pyrrolidyl, and (iii) C 3-6 cycloalkylamino Compound (I-3), which is phenyl substituted with 1 to 3 substituents selected from amino monosubstituted
  • One of Y 1 and Y 2 is an N atom and the other is CH; X 1 is CLR 2 ; X 2 is CH; L is —NH—; R 1 is C 1-6 alkyl optionally substituted with phenyl, or phenyl substituted with a halogen atom; and R 2 is (1) halogen atom, (2) C 1-6 alkyl, (3) carbamoyl monosubstituted with C 3-6 cycloalkyl, and (4) phenyl substituted with 1 to 3 substituents selected from amino monosubstituted with C 3-6 cycloalkylcarbonyl Compound (I-4); or Y 1 is an N atom; Y 2 is CH; X 1 is CH; X 2 is located at the C-L-R 2; L is —NH—; R 1 is C 1-6 alkyl; and R 2 is (1) C 1-6 alkyl, (2) carbamoyl monosubstituted with
  • Y 1 is an N atom
  • Y 2 is CH
  • X 1 is CLR 2
  • X 2 is CH
  • L is a bond
  • R 1 is C 1-6 alkyl, or oxetanyl substituted with C 1-6 alkyl
  • R 2 is (1) halogen atom, Compound (I-7), which is phenyl substituted with 1 to 3 substituents selected from (2) C 1-6 alkyl, and (3) carbamoyl monosubstituted with C 3-6 cycloalkyl or isoxazolyl ).
  • the compound (I) include the compounds of Examples, and the following compounds are particularly preferable.
  • examples of the salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • Compound (I) can also be produced by the method shown in the following reaction formulas 1 to 4 or a method analogous thereto.
  • the compounds in Reaction Formulas 1 to 4 include cases where a salt is formed. Examples of the salt include the same salts as the salt of compound (I).
  • Compound (I) can be produced by the methods shown in the following reaction formulas 1 and 2.
  • R represents an optionally substituted C 1-6 alkyl group, and other symbols are as defined above.
  • Compound (II) can be produced, for example, according to the method described in Reaction Scheme 2, a method known per se, or a method analogous thereto.
  • Compound (III) can be obtained by acid or alkali hydrolysis of compound (II).
  • the amount of the acid to be used is about 0.1 mol to about 10.0 mol, preferably about 0.1 mol to about 4.0 mol, per 1 mol of compound (II).
  • the “acid” include hydrochloric acid, sulfuric acid and the like.
  • the amount of the alkali to be used is about 1.0 mol to about 10.0 mol, preferably about 1.0 mol to about 5.0 mol, per 1 mol of compound (II).
  • Examples of the “alkali” include sodium hydroxide and lithium hydroxide. This reaction is advantageously performed in water or a mixed solvent of water and a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, etc.
  • alcohols eg, methanol, ethanol, etc.
  • aromatic hydrocarbons eg, benzene, toluene
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • Sulfoxides eg, dimethyl sulfoxide, etc. or a mixture of two or more of these.
  • the reaction temperature is about ⁇ 20 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes to about 14 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can be obtained by reacting compound (III) with an azide compound. This reaction is carried out in the presence of a base if desired.
  • the amount of the azide compound to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (III).
  • Examples of the “azide compound” include diphenylphosphoryl azide, sodium azide and the like.
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (III).
  • Examples of the “base” include triethylamine, diisopropylethylamine and the like.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons Eg, hexane
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide) Etc.
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Hal represents a halogen atom
  • R 3 represents a hydrogen atom or a C 1-6 alkyl group, or R 3 may combine with each other to form a ring. It is synonymous with.
  • Compound (IV) for example, when it is commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se, or a method analogous thereto.
  • Compound (V) for example, when it is commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se or a method analogous thereto.
  • compound (V) can be obtained by reacting an amine corresponding to compound (IV), optionally in the presence of a catalyst and a base.
  • the amount of the amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (IV).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (IV).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (IV).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, etc.
  • esters eg, ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • Aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • Sulfoxides eg, dimethyl sulfoxide, etc.
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (II) can be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (V) or the corresponding amine, optionally in the presence of a catalyst and a base.
  • the amount of the organometallic reagent or amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (V).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (V).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (V).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (VIII) can be obtained by reacting compound (V) with an organic boronic acid derivative such as bis (pinacolato) diboron, optionally in the presence of a catalyst and a base.
  • the amount of the organic boronic acid derivative to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (V).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (V).
  • an organometallic catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (V).
  • base examples include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate
  • sodium methoxide sodium ethoxide and potassium tert- Metal alkoxides
  • aromatic amines such
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • sulfoxides eg, dimethyl
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (II) can also be obtained by reacting the halide corresponding to compound (VIII), optionally in the presence of a catalyst and a base.
  • the amount of the halide to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (VIII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (VIII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (VIII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (VI) for example, when commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se, or a method analogous thereto. Alternatively, it can also be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (IV) or a corresponding amine in the presence of a catalyst and a base, if desired.
  • an organometallic reagent such as boronic acid corresponding to compound (IV) or a corresponding amine in the presence of a catalyst and a base, if desired.
  • the amount of the organometallic reagent or amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (IV).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (IV).
  • the “catalyst” include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane) A phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthy
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (IV).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (II) can also be obtained by reacting an amine corresponding to compound (VI) in the presence of a catalyst and a base, if desired.
  • the amount of the amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (VI).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (VI).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (VI).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (VII) can be obtained by reacting compound (IV) with an organic boronic acid derivative such as bis (pinacolato) diboron, optionally in the presence of a catalyst and a base.
  • the amount of the organic boronic acid derivative to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (IV).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (IV).
  • an organometallic catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (IV).
  • base examples include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate
  • sodium methoxide sodium ethoxide and potassium tert- Metal alkoxides
  • aromatic amines such
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • sulfoxides eg, dimethyl
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (VI) can also be obtained by reacting a halide corresponding to compound (VII) in the presence of a catalyst and a base, if desired.
  • the amount of the halide to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (VII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (VII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (VII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can be produced by the methods shown in Reaction Schemes 3 and 4 below.
  • Compounds (V) and (VIII) can be produced, for example, according to the method described in Reaction Scheme 2, a method known per se, or a method analogous thereto.
  • Compounds (IX) and (XI) are obtained by acid or alkali hydrolysis of compound (V) or (VIII), respectively.
  • the amount of the acid to be used is about 0.1 mol to about 10.0 mol, preferably about 0.1 mol to about 4.0 mol, per 1 mol of compound (V) or (VIII).
  • the “acid” include hydrochloric acid, sulfuric acid and the like.
  • the amount of the alkali to be used is about 1.0 mol to about 10.0 mol, preferably about 1.0 mol to about 5.0 mol, per 1 mol of compound (V) or (VIII).
  • Examples of the “alkali” include sodium hydroxide and lithium hydroxide. This reaction is advantageously performed in water or a mixed solvent of water and a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • alcohols eg, methanol, ethanol, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • Nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these are used.
  • the reaction temperature is about ⁇ 20 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes to about 14 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compounds (X) and (XII) can be obtained by reacting compound (IX) or (XI) with an azide compound, respectively. This reaction is carried out in the presence of a base if desired.
  • the amount of the azide compound to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (IX) or (XI).
  • Examples of the “azide compound” include diphenylphosphoryl azide, sodium azide and the like.
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (IX) or (XI).
  • Examples of the “base” include triethylamine, diisopropylethylamine and the like. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these e. diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol,
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (X), optionally in the presence of a catalyst and a base.
  • the amount of the organometallic reagent to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (X).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (X).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (X).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can also be obtained by reacting a halide corresponding to compound (XII), optionally in the presence of a catalyst and a base.
  • the amount of the halide to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIII) can be obtained by introducing a protecting group into compound (X). This reaction is carried out in the presence of a base if desired.
  • the amount of the protective reagent to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (X).
  • Examples of the “protecting reagent” include di-tert-butyl dicarbonate, tert-butoxycarbonyl chloride, benzyloxymethyl chloride and the like.
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (X).
  • Examples of the “base” include sodium carbonate, potassium carbonate, cesium carbonate and the like. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • esters eg, ethyl acetate etc.
  • aromatic hydrocarbons Eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these Eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • esters eg, ethyl acetate etc.
  • aromatic hydrocarbons Eg, benzene
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIV) can be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (XIII) or the corresponding amine, optionally in the presence of a catalyst and a base.
  • the amount of the organometallic reagent or amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XIII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XIII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XIII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can also be obtained by treating compound (XIV) with an acid or alkali, or hydrogenating it.
  • the amount of the acid or alkali to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XIV).
  • Examples of the “acid” include hydrochloric acid, sulfuric acid and the like.
  • Examples of the “alkali” include sodium hydroxide and lithium hydroxide.
  • the amount of the catalyst used for hydrogenation is about 5% to 1000% by weight, preferably about 10% to about 300% by weight, relative to compound (XIV).
  • Examples of the “catalyst” include palladium carbon, platinum oxide, Raney nickel, Raney cobalt and the like.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg,
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the hydrogen pressure is usually about 1 atmosphere to about 100 atmospheres.
  • the hydrogenation may be performed in the presence of an acid, if desired.
  • the amount of the acid to be used is about 0.8 mol to about 5.0 mol, preferably about 1.0 mol to about 3.0 mol, per 1 mol of compound (XIV).
  • the “acid” include Lewis acids such as aluminum chloride, organic acids such as acetic acid, and mineral acids such as hydrochloric acid.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XV) can be produced, for example, according to the method described in Reference Examples, a method known per se or a method analogous thereto.
  • Compound (XVI) can be obtained by reacting compound (XV) with an azide compound. This reaction is carried out in the presence of a base if desired.
  • the amount of the azide compound to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XV).
  • Examples of the “azide compound” include diphenylphosphoryl azide, sodium azide and the like.
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XV).
  • Examples of the “base” include triethylamine, diisopropylethylamine and the like.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • sulfoxides e
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XVII) can be obtained by introducing a protecting group into compound (XVI). This reaction is carried out in the presence of a base if desired.
  • the amount of the protective reagent to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XVI).
  • Examples of the “protecting reagent” include benzyloxycarbonyl chloride, benzyloxymethyl chloride and the like.
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XVI).
  • Examples of the “base” include sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • sulfoxides e
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XVIII) can be obtained by treating compound (XVII) with an acid or alkali.
  • the amount of the acid or alkali to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XVII).
  • Examples of the “acid” include trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and the like.
  • Examples of the “alkali” include sodium hydroxide and lithium hydroxide. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIII) can also be obtained by reacting compound (XVIII) with the corresponding halide. This reaction is carried out in the presence of a base if desired.
  • the amount of the halide to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XVIII).
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XVIII).
  • Examples of the “base” include sodium carbonate, potassium carbonate, cesium carbonate and the like. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • esters eg, ethyl acetate etc.
  • aromatic hydrocarbons Eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these Eg, acetonitrile, etc.
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIX) can be produced, for example, according to the method described in Reaction Scheme 6, a method known per se or a method analogous thereto.
  • Compound (XX) for example, when it is commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se or a method analogous thereto.
  • compound (XX) can be obtained by reducing compound (XIX) using a reducing agent.
  • the amount of the reducing agent to be used is about 0.25 mol to about 50 mol, preferably about 0.5 mol to 5 mol, per 1 mol of compound (XIX).
  • Examples of the “reducing agent” include metal hydrides such as aluminum hydride, diisobutylaluminum hydride, tributyltin hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium aluminum hydride
  • Metal-hydrogen complex compounds such as borane tetrahydrofuran complex, borane complexes such as borane dimethyl sulfide complex, alkylboranes such as texylborane and diciamylborane, metals such as diborane, zinc, aluminum, tin and iron, and alkali metals such as sodium and lithium / Liquid ammonia (Birch reduction) or the like is used.
  • This reaction is advantageously performed in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • alcohols eg, methanol, ethanol, etc.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • the reaction temperature is usually about ⁇ 20 ° C. to about 100 ° C., preferably about 0 ° C. to about 80 ° C.
  • the reaction time is usually about 10 minutes to about 100 hours, preferably about 30 minutes to about 50 hours.
  • the product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, chromatography, etc. can do.
  • Compound (XX) can be obtained by subjecting compound (XIX) to a hydrogenation reaction in the presence of a catalyst.
  • the amount of the catalyst to be used is about 1.0 to about 2000% by weight, preferably about 10 to about 300% by weight, based on compound (XIX).
  • the “catalyst” include catalysts such as palladium carbon, platinum oxide, Raney nickel, Raney cobalt, and the like.
  • Another source of hydrogen can be used instead of gaseous hydrogen.
  • the amount of the hydrogen source to be used is about 1.0 to about 10 mol, preferably about 1.0 to about 5.0 mol, per 1 mol of compound (XIX).
  • Examples of the “hydrogen source” include formic acid, ammonium formate, triethylammonium formate, sodium phosphinate, hydrazine and the like.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent inert for example, alcohols (eg, methanol, ethanol, etc.), ethers (eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), aliphatic hydrocarbons (Eg, hexane, etc.), amides (eg, N, N-dimethylformamide, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), esters (eg, ethyl acetate, etc.), organic acids (eg, Acetic acid etc.), sulfoxides (eg, dimethyl sulfoxide etc.), water or a mixture of two or more of these.
  • alcohols eg, methanol, ethanol, etc.
  • ethers eg, die
  • the reaction temperature is usually about ⁇ 20 ° C. to about 120 ° C., preferably about 0 ° C. to about 80 ° C. While the reaction time varies depending on the kind and amount of reducing agent used or the activity and amount of catalyst, it is generally about 30 minutes to about 100 hours, preferably about 1 hour to about 50 hours. When gaseous hydrogen is used, the hydrogen pressure is usually 1 to 100 atm.
  • the product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, chromatography, etc. can do.
  • Compound (I) can be obtained by reacting compound (XX) with a carbonylating reagent.
  • the amount of the carbonylating reagent to be used is about 1.0 mol to about 10.0 mol, preferably about 1.0 mol to about 3.0 mol, per 1 mol of compound (XX).
  • Examples of the “carbonylation reagent” include 1,1′-carbonylbis-1H-imidazole, diphosgene, triphosgene, phenyl chloroformate and the like. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds.
  • esters eg, ethyl acetate
  • ethers eg, diethyl ether, tetrahydrofuran, etc.
  • aromatic hydrocarbons eg, benzene, Toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile
  • Etc. sulfoxides (eg, dimethyl sulfoxide, etc.) or a mixture of two or more of these.
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Hal represents a halogen atom
  • R 3 represents a hydrogen atom or a C 1-6 alkyl group, or R 3 may combine with each other to form a ring. Is synonymous with.
  • Compound (XXI) for example, when it is commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se or a method analogous thereto.
  • Compound (XXII) for example, when commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se, or a method analogous thereto.
  • compound (XXII) can be obtained by reacting an amine corresponding to compound (XXI), optionally in the presence of a catalyst and a base.
  • the amount of the amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXI).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXI).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXI).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • esters eg, ethyl acetate etc.
  • aromatic hydrocarbons Eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these e., dimethyl sulfoxide, etc.
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIX) can be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (XXII) or the corresponding amine, optionally in the presence of a catalyst and a base.
  • the amount of the organometallic reagent or amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XXIII) can be obtained by reacting compound (XXII) with an organic boronic acid derivative such as bis (pinacolato) diboron, optionally in the presence of a catalyst and a base.
  • the amount of the organic boronic acid derivative to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXII).
  • an organometallic catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXII).
  • base examples include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate
  • sodium methoxide sodium ethoxide and potassium tert- Metal alkoxides
  • aromatic amines such
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • sulfoxides eg, dimethyl
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIX) can also be obtained by reacting a halide corresponding to compound (XXIII), optionally in the presence of a catalyst and a base.
  • the amount of the halide to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXIII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXIII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXIII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XXIV) for example, when commercially available, can be used as it is, and can be produced according to the method described in Reference Examples, a method known per se, or a method analogous thereto. Alternatively, it can also be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (XXI) or the corresponding amine in the presence of a catalyst and a base, if desired.
  • the amount of the organometallic reagent or amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXI).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXI).
  • the “catalyst” include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane) A phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaph
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXI).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XIX) can also be obtained by reacting an amine corresponding to compound (XXIV), optionally in the presence of a catalyst and a base.
  • the amount of the amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXIV).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXIV).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXIV).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium carbonate, potassium carbonate, sodium acetate and potassium acetate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XXV) can be obtained by reacting compound (XXI) with an organic boronic acid derivative such as bis (pinacolato) diboron, optionally in the presence of a catalyst and a base.
  • the amount of the organic boronic acid derivative to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXI).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXI).
  • an organometallic catalyst such as [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXI).
  • base examples include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • alkali metal hydrides such as sodium hydride and potassium hydride
  • basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate
  • sodium methoxide sodium ethoxide and potassium tert- Metal alkoxides
  • aromatic amines such
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • sulfoxides eg, dimethyl
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XXIV) can also be obtained by reacting a halide corresponding to compound (XXV) in the presence of a catalyst and a base, if desired.
  • the amount of the halide to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXV).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXV).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXV).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compounds (XXII) and (XXIII) can be produced, for example, according to the method described in Reaction Scheme 6, a method known per se, or a method analogous thereto.
  • Compounds (XXVI) and (XXVIII) can be obtained by acid or alkaline hydrolysis of compound (XXII) or (XXIII), respectively.
  • the amount of the acid to be used is about 0.1 mol to about 10.0 mol, preferably about 0.1 mol to about 4.0 mol, per 1 mol of compound (XXII) or (XXIII).
  • Examples of the “acid” include hydrochloric acid, sulfuric acid and the like.
  • the amount of the alkali to be used is about 1.0 mol to about 10.0 mol, preferably about 1.0 mol to about 5.0 mol, per 1 mol of compound (XXII) or (XXIII).
  • Examples of the “alkali” include sodium hydroxide and lithium hydroxide. This reaction is advantageously performed in water or a mixed solvent of water and a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • alcohols eg, methanol, ethanol, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • Nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these are used.
  • the reaction temperature is about ⁇ 20 ° C. to about 150 ° C., preferably about 0 ° C. to about 100 ° C.
  • the reaction time is usually 5 minutes to about 24 hours, preferably about 10 minutes to about 14 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compounds (XXVII) and (XXIX) can be obtained by reacting compound (XXVI) or (XXVIII) with a carbonylating reagent, respectively.
  • the amount of the carbonylating reagent to be used is about 1.0 mol to about 10.0 mol, preferably about 1.0 mol to about 3.0 mol, per 1 mol of compound (XXVI) or (XXVIII).
  • Examples of the “carbonylation reagent” include 1,1′-carbonylbis-1H-imidazole, diphosgene, triphosgene, phenyl chloroformate and the like. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • esters eg, ethyl acetate
  • ethers eg, diethyl ether, tetrahydrofuran, etc.
  • aromatic hydrocarbons eg, benzene, Toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile
  • Etc. sulfoxides (eg, dimethyl sulfoxide, etc.) or a mixture of two or more of these.
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can be obtained by reacting an organometallic reagent such as boronic acid corresponding to compound (XXVII), optionally in the presence of a catalyst and a base.
  • the amount of the organometallic reagent to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXVII).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXVII).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXVII).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can also be obtained by reacting a halide corresponding to compound (XXIX) in the presence of a catalyst and a base, if desired.
  • the amount of the halide to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXIX).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXIX).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXIX).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a suitable solvent.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XXX) can be obtained by introducing a protecting group into compound (XXVII). This reaction is carried out in the presence of a base if desired.
  • the amount of the protective reagent to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XXVII).
  • Examples of the “protecting reagent” include di-tert-butyl dicarbonate, tert-butoxycarbonyl chloride, benzyloxymethyl chloride and the like.
  • the amount of the base to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XXVII).
  • Examples of the “base” include sodium carbonate, potassium carbonate, cesium carbonate and the like. This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • esters eg, ethyl acetate etc.
  • aromatic hydrocarbons Eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • a mixture of two or more of these Eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • esters eg, ethyl acetate etc.
  • aromatic hydrocarbons Eg, benzene
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (XXXI) can be obtained by reacting an organometallic reagent such as boronic acid corresponding to Compound (XXX) or the corresponding amine, optionally in the presence of a catalyst and a base.
  • the amount of the organometallic reagent or amine to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXX).
  • the amount of the catalyst to be used is about 0.01 mol to about 50 mol, preferably about 0.01 mol to about 0.1 mol, per 1 mol of compound (XXX).
  • Catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, Organometallic catalysts such as palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane)
  • a phosphine ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl is used.
  • the amount of the base to be used is about 1 mol to about 100 mol, preferably about 2 mol to about 50 mol, per 1 mol of compound (XXX).
  • the “base” include alkali metal hydrides such as sodium hydride and potassium hydride, basic salts such as sodium acetate, potassium acetate, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert- Metal alkoxides such as butoxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine Organic bases such as tertiary amines such as N-methylmorpholine are used.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg, acetic acid, etc.
  • aromatic amines eg,
  • the reaction time is usually about 10 minutes to about 50 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 0 ° C. to about 300 ° C., preferably about 20 ° C. to about 250 ° C.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • Compound (I) can also be obtained by treating compound (XXXI) with an acid or alkali, or by hydrogenation.
  • the amount of the acid or alkali to be used is about 1.0 mol to about 5.0 mol, preferably about 1.0 mol to about 2.0 mol, per 1 mol of compound (XXXI).
  • Examples of the “acid” include hydrochloric acid, sulfuric acid and the like.
  • Examples of the “alkali” include sodium hydroxide and lithium hydroxide.
  • the amount of the catalyst used for hydrogenation is about 5% to 1000% by weight, preferably about 10% to about 300% by weight, relative to compound (XXXI).
  • Examples of the “catalyst” include palladium carbon, platinum oxide, Raney nickel, Raney cobalt and the like.
  • This reaction is advantageously performed in the absence of a solvent or in the presence of a solvent inert to the reaction.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • ethers eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc.
  • alcohols eg, methanol, ethanol etc.
  • esters eg, , Ethyl acetate, etc.
  • aromatic hydrocarbons eg, benzene, toluene, etc.
  • aliphatic hydrocarbons eg, hexane, etc.
  • amides eg, N, N-dimethylformamide, etc.
  • halogenated hydrocarbons Eg, dichloromethane, chloroform, etc.
  • nitriles eg, acetonitrile, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • organic acids eg,
  • the reaction temperature is about ⁇ 5 ° C. to about 200 ° C., preferably about 5 ° C. to about 150 ° C.
  • the reaction time is usually about 0.5 hour to about 120 hours, preferably about 2 hours to about 72 hours.
  • the hydrogen pressure is usually about 1 atmosphere to about 100 atmospheres.
  • the hydrogenation may be performed in the presence of an acid, if desired.
  • the amount of the acid to be used is about 0.8 mol to about 5.0 mol, preferably about 1.0 mol to about 3.0 mol, per 1 mol of compound (XXXI).
  • the “acid” include Lewis acids such as aluminum chloride, organic acids such as acetic acid, and mineral acids such as hydrochloric acid.
  • the product can be used as it is in the reaction solution or as a crude product in the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be easily separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be purified.
  • the desired product When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method. You can also.
  • the compound (I) thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.
  • compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included.
  • compound (I) when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a mixture of crystal forms.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). Means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
  • a compound labeled or substituted with an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc. is also encompassed in compound (I).
  • the prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated eg, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylated compounds
  • compounds ( A compound wherein the hydroxy of I) is acylated, alkylated, phosphorylated or borated eg, the hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or Dimethylaminomethylcarbonylated compounds, etc.
  • Compound (I) and prodrugs thereof have excellent p38 MAPK inhibitory activity, TNF- ⁇ inhibitory activity (TNF- ⁇ production inhibitory activity, TNF- ⁇ inhibitory activity)
  • TNF- ⁇ inhibitory activity TNF- ⁇ production inhibitory activity, TNF- ⁇ inhibitory activity
  • the medicament of the present invention comprising the compound of the present invention is used for p38 MAPK-related diseases against mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.).
  • TNF- ⁇ -related diseases and more specifically, can be used as preventive or therapeutic agents for the diseases described in (1) to (8) below.
  • Inflammatory diseases eg, rheumatoid arthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, hepatitis Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia, hepatitis, nephritis, meningitis, cystitis, sore throat, gastric mucosal damage, meningitis, spondylitis, arthritis, dermatitis, Chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, etc.), (2) Autoimmune diseases (eg, rheumatoid arthritis, ankylosing spondylitis, psoriasis, multiple sclerosis (MS), polymyositis, dermatomyositis (DM), nodular polyarteritis (PN), mixed)
  • the medicament of the present invention is preferably an inflammatory disease, bone / joint disease, pain or neoplastic disease, particularly preferably rheumatoid arthritis, inflammatory bowel disease, psoriasis, ankylosing spondylitis, postoperative pain, ovarian cancer, It can be used as a preventive or therapeutic agent for non-small cell lung cancer, breast cancer, stomach cancer, head and neck cancer, prostate cancer or endometrial cancer.
  • “prevention” of the disease refers to, for example, a patient who has not developed the disease, which is expected to have a high risk of onset due to some factor related to the disease, or who has developed the subjective symptom. This means that a drug containing the compound of the present invention is administered to a patient who is not, or that a drug containing the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.
  • the medicament of the present invention has excellent pharmacokinetics (eg, blood drug half-life), low toxicity (eg, HERG inhibition, CYP inhibition, CYP induction), and reduction in drug interaction is observed.
  • the compound of the present invention is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se generally used in the preparation of pharmaceutical preparations to form a pharmaceutical composition, which is used as the pharmaceutical of the present invention. be able to.
  • the medicament of the present invention is given orally or parenterally to mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.). Safe to administer.
  • the medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • the content of the compound of the present invention in the medicament of the present invention is about 0.01% to about 100% by weight of the whole medicament.
  • the dose varies depending on the administration subject, administration route, disease, etc. For example, it is about 0. 0 as an active ingredient (compound (I)) per day as an oral agent for patients with rheumatoid arthritis (body weight: about 60 kg). 1 mg / kg body weight to about 30 mg / kg body weight, preferably about 1 mg / kg body weight to 20 mg / kg body weight may be administered once to several times a day.
  • the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials.
  • excipients and lubricants in solid preparations Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers and soothing agents.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of preservatives include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention can be used together with other drugs.
  • the pharmaceutical used when the compound of the present invention is used in combination with another drug is referred to as “the combination agent of the present invention”.
  • the combination agent of the present invention when the compound of the present invention is used as a p38 MAPK inhibitor or TNF- ⁇ production inhibitor, it can be used in combination with the following drugs.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (I) Classic NSAIDs Arcofenac, aceclofenac, sulindac, tolmetine, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, migrenin, aspirin, fefenamic acid, mefenamic acid Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, fructaphenine, piroxicam, epilisol, thiaramide hydrochloride, zal
  • cyclooxygenase inhibitor COX-1 selective inhibitor, COX-2 selective inhibitor, etc.
  • Salicylic acid derivatives eg, celecoxib, rofecoxib, aspirin
  • MK-663 e.g., celecoxib, rofecoxib, aspirin
  • MK-663 e.g., celecoxib, rofecoxib, aspirin
  • MK-663 eg., aspirin
  • valdecoxib eg., aspirin
  • SC-57666 eg., thylakoxib
  • S-2474 thylakoxib
  • diclofenac thylakoxib
  • indomethacin loxoprofen
  • loxoprofen etc.
  • Drugs mL-3000, p54 COX inhibition & 5-lipoxygenase inhibition having both COX inhibition and 5-lipoxygenase inhibition.
  • Anti-cytokine drugs Protein preparations (i) TNF inhibitors Etanercept, infliximab, D2E7, CDP-571, PASTNF- ⁇ , soluble TNF- ⁇ receptor, TNF- ⁇ binding protein, anti-TNF- ⁇ antibody, etc. . (Ii) Interleukin-1 inhibitor Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like. (Iii) Interleukin-6 inhibitor MRA (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody and the like. (Iv) Interleukin-10 drug Interleukin-10 etc. (V) Interleukin-12 inhibitor Anti-interleukin-12 antibody and the like.
  • (II) Non-protein preparation i) MAPK inhibitor PD-98059 and the like.
  • (Iv) TNF- ⁇ converting enzyme inhibitor (v) interleukin-1 ⁇ converting enzyme inhibitor HMR3480 / VX-740 and the like.
  • Ix Interleukin-2 receptor antagonist Denileukine, Diftitox, etc.
  • Gene therapy drug Gene therapy drug for the purpose of enhancing the expression of anti-inflammatory genes such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF- ⁇ receptor .
  • Immunomodulatory drugs Methotrexate, cyclophosphamide, MX-68, atiprimmod dihydrochloride, BMS-188667, CKD-461, limexolone, cyclosporine, tacrolimus, gusperimus, azathioprine, anti-lymphocera, dry sulfonated immunoglobulin, erythropoietin, colony stimulation Factors, interleukins, interferons, etc.
  • Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, estriol propionate, etc.
  • c-Jun N-terminal kinase (JNK) inhibitor Compounds described in WO00 / 35906, WO00 / 35909, WO00 / 35921, WO00 / 64872, or WO00 / 75118.
  • Angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
  • Angiotensin II receptor antagonist candesartan, cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan, and the like.
  • Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide and the like.
  • (11) ⁇ receptor antagonist carvedilol, metoprolol, atenolol and the like.
  • Contraceptive Sex hormone or derivative thereof Progesterone or derivative thereof (progesterone, 17 ⁇ -hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodrel, levonorgestrel , Norgestrel, etinodiol diacetate, desogestrel, norgestimate, guestden, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestron, chromadianone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or Progesterone or its derivative and follicular hormone or its derivative (estradiol, estradiol benzoate) Estradiol
  • T cell inhibitor IR-501 T cell receptor peptide
  • Ii Inosine monophosphate dehydrogenase
  • IMPDH Inosine monophosphate dehydrogenase
  • VX-497 Adhesion molecule inhibitor
  • ISIS-2302 Adhesion molecule inhibitor
  • selectin inhibitor ELAM-1
  • VCAM-1 VCAM-1
  • ICAM-1 Thalidomide
  • MMPs Matrix metalloproteinase
  • BB-3644 CGS-27023A, Bay-12-9566, KB-R7785, L-758354, POL-641 and the like.
  • Vii Glucose-6-phosphate dehydrogenase inhibitor CBF-BS2 and the like.
  • DHODH Dihydroorotate dehydrogenase
  • ix Phosphodiesterase IV (PDE IV) inhibitor CG-1088 and the like.
  • X Phospholipase A 2 inhibitor
  • xi iNOS inhibitor NOX-200 and the like.
  • Xii Microtuble stimulant paclitaxel and the like.
  • Xiii Microtuble inhibitor Rheumacon and the like.
  • Xiv MHC class II antagonist ZD-2315 and the like.
  • CD4 antagonist 4162W94, keriximab and the like CD23 antagonist
  • xviii LTB4 receptor antagonist CGS-25019C and the like.
  • Xix 5-lipoxygenase inhibitor zileuton and the like.
  • Xx Cholinesterase inhibitor galantamine and the like.
  • Xxi tyrosine kinase inhibitor YT-146 and the like.
  • Calepsin B inhibitor xxiii) Adenosine deaminase inhibitor Pentostatin and the like.
  • concomitant drugs other than the above include, for example, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, antihypertensive diuretics, anticoagulants Drugs, tranquilizers, antipsychotics, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs, vasodilators, vasoconstriction Drugs, antihypertensive diuretics, antidiabetics, narcotic antagonists, vitamins, vitamin derivatives, anti-asthma, frequent urinary and urinary incontinence, atopic dermatitis, allergic rhinitis, pressor, endotoxin antagonist Examples include drugs or antibodies, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitory antibodies, anti-
  • Antibacterial drugs sulfa drugs sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.
  • Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
  • Antituberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
  • Mycobacterial drugs Diaphenylsulfone, rifampicillin and the like.
  • Antiviral drugs idoxuridine, acyclovir, vitarabine, ganciclovir and the like.
  • Anti-HIV drugs zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir and the like.
  • Antispiro carte drugs (viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, cannendomycin, ribidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, doxycycline, ampicillin, piperacillin, ticacylin, ticaricin Cefapirin, cephaloridine, cefaclor, cephalexin, cefloxazine, cefadroxyl, cefamandol, cephalium, cefuroxime, cefothiam, cefotium hexetyl, cefuroxime acetyl,
  • Antifungal drugs Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin) (ii) Griseofulvin, pyrrolnitrin, etc. (iii) cytosine antimetabolite (eg, flucytosine) (iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) (v) Triazole derivatives (eg, fluconazole, itraconazole) (vi) Thiocarbamic acid derivatives (eg, trinaphthol) and the like. (3) Antiprotozoal drugs Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.
  • Ephedrine hydrochloride noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, aloclamide, chlorfedianol, picoperidamine, cloperastine, protochlorol , Isoproterenol, salbutamol, tereptaline, oxypetebanol, morphine hydrochloride, dextropetrphan hydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipipedin hibenzate, pentoxyberine citrate, clofedanol hydrochloride, benzonate, guaifenesin, Bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine,
  • Anesthetic (6-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein and the like.
  • Anti-ulcer drugs Histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesasein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, tepregone, prostaglandin, etc.
  • Arrhythmia drug (i) sodium channel blockers (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin), (ii) ⁇ -blockers (eg, propranolol, alprenolol, bufetrol, hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride), (iii) potassium channel blockers (eg, amiodarone), (iv) Calcium channel blockers (eg, verapamil, diltiazem) and the like.
  • sodium channel blockers eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin
  • ⁇ -blockers eg, prop
  • Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, cloxoxazone, eperisone, tizanidine and the like.
  • Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
  • Antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyraline, methoxyphenamine, cromoglycate sodium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine hydrochloride , Pranlukast hydrate, seratrodast, etc.
  • Vasodilators Oxyfedrine, diltiazem, tolazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.
  • Vasoconstricting agents dopamine, dobutamine denopamine and the like.
  • Antihypertensive diuretics Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
  • Antidiabetic drugs Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, grimidine, glipzide, phenformin, pformin, metformin, and the like.
  • Vitamin A Vitamin A 1 , Vitamin A 2 and retinol palmitate
  • Vitamin D Vitamin D 1 , D 2 , D 3 , D 4 and D 5
  • Vitamin E ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, dl- ⁇ -tocopherol nicotinate
  • Vitamin K Vitamin K 1 , K 2 , K 3 and K 4
  • Folic acid vitamin M
  • Vitamin derivatives Various derivatives of vitamins, for example, vitamin D 3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1- ⁇ -hydroxycholecalciferol, 5,6- Vitamin D 2 derivatives such as trans-ergocalciferol.
  • Anti-asthma drugs Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone hydrocolicone , Beclomethasone prop
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) obtained by separately formulating the compound of the present invention and the concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • the dose varies depending on the type of the compound of the present invention, administration route, symptoms, patient age, etc., but for example, when orally administered to a patient with rheumatoid arthritis (body weight of about 60 kg), the compound (kg per body weight per day) As I), about 0.1 mg / kg body weight to about 30 mg / kg body weight, preferably about 1 mg / kg body weight to 20 mg / kg body weight may be administered once to several times a day.
  • the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (for example, mouse, rat, hamster, guinea pig) Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.), depending on the purpose of administration, for example, when applied by parenteral administration, about 0.1 per week About 100 mg of Compound (I) may be released from the dosage formulation.
  • the animal to be administered for example, mouse, rat, hamster, guinea pig
  • Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.
  • about 100 mg of Compound (I) may be released from the dosage formulation.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg per kg body weight of the mammal by oral administration, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg. This is usually administered in 1 to 4 divided doses per day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, or may be administered with a time difference.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • a concomitant drug when administering a concomitant drug first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day after administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. Is mentioned.
  • sequence number in the sequence listing in the present specification indicates the following sequence.
  • Cesium fluoride (84.9 g, 559 mmol) was added to a solution of methyl 5-bromo-2-chloropyridine-3-carboxylate (100 g, 39.9 mmol) in dimethyl sulfoxide (1.33 L) at 45 ° C. Stir at ⁇ 50 ° C for 48 hours. After cooling to room temperature, ethyl acetate was added and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine. The extract was dried over sodium sulfate and concentrated under reduced pressure.
  • Reference example 3 According to Reference Example 2, the following Reference Example compounds 3-1 to 3-4 were synthesized using 3-methylaniline, benzylamine, 4-fluorobenzylamine or 4-chlorobenzylamine instead of aniline.
  • Methyl 5-bromo-2- (phenylamino) pyridine-3-carboxylate 300 mg, 0.977 mmol
  • 2,4-difluoroaniline 151 mg, 1.17 mmol
  • cesium carbonate 636 mg, obtained in Reference Example 2
  • 1.95 mmol) in toluene (10 mL) was added to 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (9.31 mg, 0.0195 mmol) and tris (dibenzylideneacetone) dipalladium ( 8.94 mg, 0.00977 mmol) was added at room temperature, and the mixture was stirred at 100 ° C.
  • Reference Example 7 According to Reference Example 6, instead of methyl 5-bromo-2- (phenylamino) pyridine-3-carboxylate, methyl 5-bromo-2-[(3-chlorophenyl) amino] pyridine-3-carboxylate (reference Example compound 4), methyl 2- (benzylamino) -5-bromopyridine-3-carboxylate (reference example compound 3-2), 5-bromo-2-[(3-methylphenyl) amino] pyridine-3- Methyl carboxylate (Reference Example Compound 3-1), methyl 5-bromo-2-[(2-phenylethyl) amino] pyridine-3-carboxylate (Reference Example Compound 5-1), 5-bromo-2-fluoro Methyl pyridine-3-carboxylate (Reference Example Compound 1), methyl 5-bromo-2-[(4-fluorobenzyl) amino] pyridine-3-carboxylate (Reference Example Compound 3-3) or 5 Bromo-2
  • Methyl 5-bromo-2-[(1-methylpropyl) amino] pyridine-3-carboxylate (5.00 g, 17.4 mmol) obtained in Reference Example 5-4 was added to tetrahydrofuran (5 mL) and methanol (35 mL). It melt
  • the obtained black oil (0.375 g) was dissolved in a mixed solution of tetrahydrofuran (7.5 mL), methanol (7.5 mL), and water (1.5 mL), and 1N aqueous sodium hydroxide solution (6 .6 mL) was added at room temperature and stirred for 15 hours.
  • 1N Hydrochloric acid (6.6 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Reference Example 13 According to Reference Example 12, the following Reference Example compounds 13-1 to 13-2 were synthesized using 2,4-dichloroaniline or 2-methyl-5-nitroaniline instead of 2,6-difluoroaniline.
  • Amine hydrochloride (1.90 g, 63.7 mmol), 1H-benzotriazol-1-ol (5.16 g, 38.2 mmol), N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (7.32 g, 38.2 mmol) and diisopropylethylamine (22.2 mL, 127 mmol) were added at room temperature, and the mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere and concentrated under reduced pressure. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane).
  • Reference Example 16 In accordance with Reference Example 15, the following Reference Example compounds 16-1 to 16-2 were synthesized using aniline or 2-aminopyridine instead of methylamine hydrochloride.
  • Reference Example 18 According to Reference Example 17, instead of 1,2-dimethylethyl [2-methyl-5- (methylaminocarbonyl) phenyl] carbamate, [2-methyl-5- (phenylaminocarbonyl) phenyl] carbamic acid 1, Using 1-dimethylethyl (Reference Example Compound 16-1) or [2-methyl-5- (pyridin-2-ylaminocarbonyl) phenyl] carbamate 1,1-dimethylethyl (Reference Example Compound 16-2) The following Reference Example compounds 18-1 to 18-2 were synthesized.
  • Reference Example 20 According to Reference Example 10, instead of methyl 5-bromo-2-[(2-methylpropyl) amino] pyridine-3-carboxylate, 5-bromo-2-[(1-methylpropyl) amino] pyridine-3-
  • the following Reference Example Compound 20 was synthesized using 3-amino-N, 4-dimethylbenzamide (Reference Example Compound 17) instead of methyl carboxylate (Reference Example Compound 5-4) and 2,4-difluoroaniline.
  • Reference Example 22 According to Reference Example 12, 3-amino-4-methyl-N-phenylbenzamide (Reference Example Compound 18-1) was used instead of 2,6-difluoroaniline, and ethylene glycol dimethyl ether was used instead of toluene. Reference Example Compound 22 was synthesized.
  • Reference Example 23 According to Reference Example 10, instead of methyl 5-bromo-2-[(2-methylpropyl) amino] pyridine-3-carboxylate, 5-bromo-2-[(1-methylpropyl) amino] pyridine-3-
  • Reference Example 24 According to Reference Example 12, N- (3-amino-4-methylphenyl) benzamide is used instead of 2,6-difluoroaniline, and 10: 1 of ethylene glycol dimethyl ether and N, N-dimethylformamide is used instead of toluene.
  • the following Reference Example compound 24 was synthesized using a mixed solvent.
  • Reference Example 26 According to Reference Example 25, instead of methyl 5-bromo-2-[(1,1-dimethylethyl) amino] pyridine-3-carboxylate, 5-bromo-2-[(cyclopropylmethyl) amino] pyridine- Methyl 3-carboxylate (Reference Example Compound 5-16), 5-bromo-2-[(2-methylpropyl) amino] pyridine-3-carboxylate methyl (Reference Example Compound 5-2), 5-bromo-2 -[(1-Ethylpropyl) amino] pyridine-3-carboxylate (Reference Example Compound 5-8), 5-bromo-2- ⁇ [1- (methoxymethyl) propyl] amino ⁇ pyridine-3-carboxylic acid Using methyl (reference compound 5-9) or methyl 5-bromo-2-[(2,6-difluorobenzyl) amino] pyridine-3-carboxylate (reference compound 5-17)
  • Example Compound 26-1 to 26-5 were synthesized
  • Methyl 5-bromo-2-chloropyridine-3-carboxylate (0.205 g, 0.822 mmol), N-cyclopropyl-4-methyl-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.248 g, 0.822 mmol) and potassium carbonate (0.284 g, 2.06 mmol) in ethylene glycol dimethyl ether (4.5 mL) and water (0 [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (33.6 mg, 0.0411 mmol) was added to the solution at room temperature, and 1 at 100 ° C.
  • Reference Example 31 According to Reference Example 30, the following Reference Example compounds 31-1 to 31-2 were synthesized using 2,6-dichloroaniline or 2-chloro-6-fluoroaniline instead of 2-fluoroaniline.
  • Reference compound 31-1 5- [5- (Cyclopropylaminocarbonyl) -2-methylphenyl] -2-[(2,6-dichlorophenyl) amino] pyridine-3-carboxylate methyl
  • Reference Example 34 According to Reference Example 33, instead of 5-bromo-2-[(1-methylpropyl) amino] pyridine-3-carboxylic acid, 5-bromo-2-[(1,2-dimethylpropyl) amino] pyridine- 3-carboxylic acid (Reference Example Compound 9-8), 5-bromo-2-[(2-methylbutyl) amino] pyridine-3-carboxylic acid (Reference Example Compound 9-9) or 5-bromo-2-[( The following Reference Example compounds 34-1 to 34-3 were synthesized using 1,3-dimethylbutyl) amino] pyridine-3-carboxylic acid (Reference Example Compound 9-10).
  • Reference Example 38 According to Reference Example 28, instead of 3-bromo-N-cyclopropyl-4-methylbenzamide, 6-bromo-3- (1,2-dimethylpropyl) -1,3-dihydro-2H-imidazo [4,5 -B] The following reference compound 38 was synthesized using pyridin-2-one (reference compound 34-1) and using potassium acetate instead of sodium acetate.
  • Reference Example 39 According to Reference Example 32, instead of methyl 5-bromo-2-[(1-methylpropyl) amino] pyridine-3-carboxylate, 6-bromo-3- (1-methylpropyl) -1,3-dihydro- 2H-imidazo [4,5-b] pyridin-2-one (Reference Example Compound 33) and (3-formyl-5-methylphenyl) boron instead of 2-methyl-5-nitrophenylboronic acid The following reference compounds 39-1 to 39-2 using acid or methyl 4-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate was synthesized.
  • Reference Example 41 According to Reference Example 10, methyl 5-bromo-2- (phenylamino) pyridine-3-carboxylate instead of methyl 5-bromo-2-[(2-methylpropyl) amino] pyridine-3-carboxylate (reference The following Reference Example compounds 41-1 to 41-2 were synthesized using Example Compound 2) and using 2-methylaniline or 3-methylaniline instead of 2,4-difluoroaniline.
  • Reference Example 43 In accordance with Reference Example 42, using 2,6-difluoroaniline or 3-amino-N, 4-dimethylbenzamide (Reference Example Compound 17) instead of 2,4-difluoroaniline, the following Reference Example Compound 43-1 ⁇ 43-2 were synthesized.
  • Reference Example 46 According to Reference Example 45, instead of methyl 2-chloro-5-[(2,6-difluorophenyl) amino] pyridine-3-carboxylate, 2-chloro-5- ⁇ [2-methyl-5- (methylamino)
  • the following Reference Example Compound 46 was synthesized using methyl carbonyl) phenyl] amino ⁇ pyridine-3-carboxylate (Reference Example Compound 43-2).
  • Reference compound 46 2-[(2-Fluorophenyl) amino] -5- ⁇ [2-methyl-5- (methylaminocarbonyl) phenyl] amino ⁇ pyridine-3-carboxylate methyl
  • Reference Example 47 According to Reference Example 45, instead of methyl 2-chloro-5-[(2,6-difluorophenyl) amino] pyridine-3-carboxylate, 2-chloro-5-[(2,4-difluorophenyl) amino]
  • the following Reference Example Compound 47 was synthesized using methyl pyridine-3-carboxylate (Reference Example Compound 42) and using 2,6-dichloroaniline instead of 2-fluoroaniline.
  • Reference Example 48 According to Reference Example 4, instead of methyl 5-bromo-2-fluoropyridine-3-carboxylate, methyl 2-fluoro-4-iodopyridine-3-carboxylate synthesized according to the method described in WO200810964 was used, and 3 The following Reference Example compounds 48-1 to 48-2 were synthesized using 2-methylpropylamine or 1-methylpropylamine instead of chloroaniline.
  • Reference Example 49 According to Reference Example 45, instead of methyl 2-chloro-5-[(2,6-difluorophenyl) amino] pyridine-3-carboxylate, 4-iodo-2-[(2-methylpropyl) amino] pyridine-
  • the following reference compound 49 was prepared using methyl 3-carboxylate (reference compound 48-1) and using 3-amino-N, 4-dimethylbenzamide (reference compound 17) instead of 2-fluoroaniline. Synthesized.
  • Reference Example 50 According to Reference Example 45, instead of methyl 2-chloro-5-[(2,6-difluorophenyl) amino] pyridine-3-carboxylate, 4-iodo-2-[(1-methylpropyl) amino] pyridine- Using methyl 3-carboxylate (Reference Example Compound 48-2) and using 2-methyl-5-nitroaniline or N- (3-amino-4-methylphenyl) benzamide instead of 2-fluoroaniline The following Reference Example compounds 50-1 to 50-2 were synthesized.
  • Reference compound 50-1 4-[(2-Methyl-5-nitrophenyl) amino] -2-[(1-methylpropyl) amino] pyridine-3-carboxylate methyl
  • Reference Example 51 According to Reference Example 10, instead of methyl 5-bromo-2-[(2-methylpropyl) amino] pyridine-3-carboxylate, 4-iodo-2-[(1-methylpropyl) amino] pyridine-3- Using methyl carboxylate (Reference Example Compound 48-2) and using N- (3-amino-4-methylphenyl) cyclopropanecarboxamide instead of 2,4-difluoroaniline, 2-dicyclohexylphosphino-2 ′, Substituting 1,1′-binaphthalene-2,2′-diylbis (diphenylphosphane) for 4 ′, 6′-triisopropylbiphenyl and palladium acetate for tris (dibenzylideneacetone) dipalladium The following Reference Example compound 51 was synthesized.
  • Reference compound 51 4-( ⁇ 5-[(Cyclopropylcarbonyl) amino] -2-methylphenyl ⁇ amino) -2-[(1-methylpropyl) amino] pyridine-3-carboxylic acid
  • Reference Example 52 According to Reference Example 8, instead of methyl 2-[(3-chlorophenyl) amino] -5-[(2,4-difluorophenyl) amino] pyridine-3-carboxylate, 5-[(2,4-difluoro Phenyl) amino] -2-[(2,6-difluorophenyl) amino] pyridine-3-carboxylate (Reference Example Compound 44), 5-[(2,6-difluorophenyl) amino] -2-[( 2-fluorophenyl) amino] pyridine-3-carboxylate methyl compound (Reference Example Compound 45), 2-[(2-fluorophenyl) amino] -5- ⁇ [2-methyl-5- (methylaminocarbonyl) phenyl] Amino ⁇ methyl 3-pyridine-3-carboxylate (Reference Example Compound 46), 2-[(2,6-dichlorophenyl) amino] -5-[(2,4-difluorophenyl) amino
  • Reference compound 52-5 4- ⁇ [2-Methyl-5- (methylaminocarbonyl) phenyl] amino ⁇ -2-[(2-methylpropyl) amino] pyridine-3-carboxylic acid
  • Reference compound 52-6 4-[(2-Methyl-5-nitrophenyl) amino] -2-[(1-methylpropyl) amino] pyridine-3-carboxylic acid
  • Reference Example 53 According to Reference Example 33, instead of 5-bromo-2-[(1-methylpropyl) amino] pyridine-3-carboxylic acid, 4-iodo-2-[(1-methylpropyl) amino] pyridine-3-.
  • carboxylic acid Reference Example Compound 52-8
  • Reference Example 55 According to Reference Example 42, instead of methyl 5-bromo-2-chloropyridine-3-carboxylate, 1-[(benzyloxy) methyl] -6-chloro-2-oxo-1,2-dihydro-3H-imidazo The following Reference Example Compound 55 was synthesized using 1,1-dimethylethyl [4,5-c] pyridine-3-carboxylate (Reference Example Compound 54).
  • Reference Example 57 1-[(Benzyl) instead of 1,1-dimethylethyl 6-chloro-2-oxo-1,2-dihydro-3H-imidazo [4,5-c] pyridine-3-carboxylate according to Reference Example 54 Oxy) methyl] -6-[(2,4-difluorophenyl) amino] -1,3-dihydro-2H-imidazo [4,5-c] pyridin-2-one (Reference Example Compound 56), and The following Reference Example compound 57 was synthesized using benzyl bromide instead of benzyl chloromethyl ether.
  • N-cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide (1.60 g, 3.01 mmol), bis (pinacolato) diboron (2.55 g, 10.0 mmol) and acetic acid obtained in Reference Example 65 [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane adduct (819 mg, 1.00 mmol) was added to a solution of potassium (1.65 g, 16.8 mmol) in ethylene glycol dimethyl ether (20 mL). The mixture was reacted at 80 ° C. for 24 hours under a nitrogen atmosphere.
  • the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.

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Abstract

L'invention porte sur un composé à hétérocycles fusionnés ayant d'excellentes activités médicales comprenant une activité inhibitrice de MAPK p38 et une activité inhibitrice de la production de TNF-a ; sur un agent médicinal comprenant le composé ; et autres. De façon spécifique, l'invention porte sur un composé représenté par la formule (I) [dans laquelle l'un parmi Y1 et Y2 représente un atome de N et l'autre représente CH ; l'un parmi X1 et X2 représente CH et l'autre représente C-L-R2 ; L représente une liaison, -NH-, -CH2- ou -CO- ; R1 représente un groupe phényle facultativement substitué, un groupe hétérocyclique facultativement substitué, un groupe alkyle en C1-6 facultativement substitué, un groupe cycloalkyle en C3-6 facultativement substitué ou un groupe indanyle facultativement substitué ; et R2 représente un groupe aryle facultativement substitué, ou un groupe hétéroaryle bicyclique facultativement substitué] ou un sel de ce composé. Le composé est utile comme inhibiteur de MAPK p38 et/ou inhibiteur de la production de TNF-a.
PCT/JP2010/064042 2009-08-21 2010-08-20 Composé à hétérocycles fusionnés Ceased WO2011021678A1 (fr)

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WO2014069510A1 (fr) * 2012-10-31 2014-05-08 富山化学工業株式会社 Nouveau dérivé d'amine ou sel correspondant
JP2016539976A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリジン誘導体
JP2016539981A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾピリジン誘導体
WO2018036469A1 (fr) * 2016-08-22 2018-03-01 南京明德新药研发股份有限公司 Inhibiteur de pde4
CN109563051A (zh) * 2016-08-22 2019-04-02 南京明德新药研发股份有限公司 作为pde4抑制剂的并环类化合物
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WO2019144970A1 (fr) * 2018-01-29 2019-08-01 石家庄智康弘仁新药开发有限公司 Forme cristalline d'un composé 1h-imidazo[4,5-b]pyridine-2(3h)-one et son procédé de préparation
JP2021529806A (ja) * 2018-07-06 2021-11-04 ギリアード サイエンシーズ， インコーポレイテッド 治療用複素環式化合物
US20210380573A1 (en) * 2018-12-11 2021-12-09 UCB Biopharma SRL Benzimidazolone Derivatives, and Analogues Thereof, as IL-17 Modulators
WO2022066917A1 (fr) * 2020-09-23 2022-03-31 Takeda Pharmaceutical Company Limited Dérivés de 3-(6-aminopyridin-3-yl)benzamide utilisés comme inhibiteurs de ripk2
WO2022064430A1 (fr) * 2020-09-24 2022-03-31 Auckland Uniservices Limited Nouvelles aminopyridines et leur utilisation dans le traitement du cancer
WO2022218296A1 (fr) * 2021-04-12 2022-10-20 Impact Therapeutics (Shanghai) , Inc Composés bicycliques condensés substitués servant d'inhibiteurs de parp et leur utilisation
RU2784538C2 (ru) * 2018-01-29 2022-11-28 Медшайн Дискавери Инк. Кристаллическая форма соединения 1h-имидазо[4,5-b]пиридин-2(3h)-она и способ ее получения
US11667651B2 (en) 2017-12-22 2023-06-06 Hibercell, Inc. Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors
JP2023526521A (ja) * 2020-05-21 2023-06-21 ステムシナジー セラピューティクス， インク． Ｎｏｔｃｈ阻害剤及びそれらの使用
CN116496270A (zh) * 2022-01-27 2023-07-28 四川大学华西医院 一类4-氨基哌啶衍生物及其制备方法和用途
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