(19)
(11)EP 3 395 804 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
13.05.2020 Bulletin 2020/20

(21)Application number: 17849145.2

(22)Date of filing:  08.09.2017
(51)Int. Cl.: 
C07D 265/14  (2006.01)
A23L 33/10  (2016.01)
C07C 317/46  (2006.01)
C07C 235/28  (2006.01)
A61K 31/537  (2006.01)
C07C 255/57  (2006.01)
C07C 235/16  (2006.01)
C07C 235/38  (2006.01)
(86)International application number:
PCT/KR2017/009909
(87)International publication number:
WO 2018/048261 (15.03.2018 Gazette  2018/11)

(54)

NOVEL SPIROQUINONE DERIVATIVE COMPOUND, PRODUCTION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING NEUROLOGICAL DISORDERS WHICH CONTAINS SAME AS ACTIVE INGREDIENT

NEUARTIGE SPIROCHINONDERIVATVERBINDUNG, HERSTELLUNGSVERFAHREN DAFÜR UND PHARMAZEUTISCHE ZUSAMMENSETZUNG DAMIT ALS WIRKSTOFF ZUR VORBEUGUNG ODER BEHANDLUNG VON NEUROLOGISCHEN ERKRANKUNGEN

NOUVEAU COMPOSÉ DÉRIVÉ DE SPIROQUINONE, SON PROCÉDÉ DE PRODUCTION, ET COMPOSITION PHARMACEUTIQUE LE CONTENANT EN TANT QUE PRINCIPE ACTIF POUR PRÉVENIR OU TRAITER DES TROUBLES NEUROLOGIQUES


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 08.09.2016 KR 20160115468

(43)Date of publication of application:
31.10.2018 Bulletin 2018/44

(73)Proprietors:
  • Gachon University of Industry-Academic Cooperation Foundation
    Seongnam-si, Gyeonggi-do 13120 (KR)
  • Gil Medical Center
    Incheon 21565 (KR)

(72)Inventors:
  • KIM, Mi-hyun
    Incheon 21936 (KR)
  • KIM, Sun Yeou
    Incheon 21936 (KR)
  • LEE, Sang-Yoon
    Incheon 21572 (KR)
  • ARRAMSHETTI, Venkanna
    Incheon 21936 (KR)
  • KIM, Kang
    Incheon 21936 (KR)
  • CHO, Kyohee
    Incheon 21936 (KR)
  • LAMA, Prema Dhorma
    Incheon 21936 (KR)

(74)Representative: Office Freylinger 
P.O. Box 48
8001 Strassen
8001 Strassen (LU)


(56)References cited: : 
WO-A1-2008/129007
CN-A- 105 085 433
KR-A- 20020 040 160
CN-A- 102 850 337
JP-A- H10 268 489
US-A1- 2010 056 613
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    BACKGROUND OF THE INVENTION


    1. Field of the Invention



    [0001] The present invention relates to a novel spiroquinone derivative compound, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient for use in the prevention or treatment of neurological disease.

    2. Description of the Related Art



    [0002] Among the astrocytes composing the central nervous system, microglia are known to perform self-defense functions such as phagocytosis to eat up degenerated neurons and foreign substances. However, when TNF(tumor necrosis factor)-a produced for defense purposes or inflammation-inducing substances such as reactive oxygen species (ROS) or nitrogen compounds are excessively secreted or the cells themselves remain activated for a long time, the undesired side effect such as neuronal damage can be caused.

    [0003] Recently, it has been found that not only degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease but also neuronal damage due to trauma and ischemic conditions are involved in hypersensitization of microglia. Accordingly, studies have been undergoing to develop a therapeutic agent or a treatment method to inhibit the hypersensitized microglia or to suppress the functions of inflammation inducing substances secreted by microglia (Gonzalez-Scarano F and Baltuch G, Annu. Rev. Neurosci., 1999, 22, 219-240).

    [0004] It is also known that the inhibition of acetylcholine esterase brings the neuroprotective effect. However, even though acetylcholine inhibitors could be effective in preventing and treating neurological disease, there is no fundamental disease modifying drugs (DMD) to control Alzheimer's disease, yet. Such clinical drugs as donepezil, galatamine and tacrine are only effective in delaying the prognosis of a disease but cannot eliminate or solve the cause of a disease.

    [0005] In the meantime, JNK knock-out mice showed a higher dopamine level and a lower loss of dopaminergic neurons, confirming that JNK played a certain role in the development of Parkinson's disease. However, JNK still needs to be studied as a drug for neurological disease.

    [0006] The libraries of the conventional drugs and drug candidates and active substances and compounds are composed basically with such materials that display a structural similarity with the structure of an endogenous ligand in vivo based on the heteroaromatic ring structure. Studies have been made so far to develop drugs and industrially available materials but continuous research and development are still requested.

    [0007] The spiroquinone structure itself is a compound used as an intermediate for total synthesis of Spirooliganones A and B, which are natural products, and is known to be used as a drug medicine such as an anticancer agent (see CN102850337) or an infectious disease drug. In the previous studies, methods of synthesizing spiroquinone compounds through an oxidative cyclization reaction using a metal reagent such as cerium (CAN) or an oxidizing agent such as hypervalent iodine have reported. The conventional spiroquinone compound shows the structure in which single or one hetero atom is contained in the ring (Carnesi S et al., Angew. Chem. Int. Ed., 2004, 43, 4336-4338; Yasuyuki K et al., Angew. Chem. Int. Ed., 2008, 47, 3787-3790).

    [0008] Under these circumstances, the present inventors tried to develop a novel spiroquinone derivative compound having excellent activity in the prevention or treatment of neurological disease. As a result, the inventors developed a method of introducing an amide group, which is frequently observed in the structure of medicines, into the spiroquinone skeleton and introducing an oxygen atom into the spiro position via oxidative cyclization, so that a novel spiroquinone derivative having three heteroatoms could be efficiently synthesized. It was first confirmed that an aminal structure could be introduced into the spiroquinone skeleton.

    [0009] In addition, the present inventors confirmed that the novel spiroquinone derivative above was very useful in the prevention or treatment of neurological disease by inhibiting LPS (lipid polysaccharide) induced microglial activation and by suppressing cell death. It was also confirmed that the novel spiroquinone derivative not only inhibited acetylcholine esterase, JNK1, JNK2, and JNK3 significantly but also suppressed the enzyme activity of the neurological disease related enzyme group including RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, and TLK1. Accordingly, the present inventors confirmed that the novel spiroquinone derivative compound of the present invention could be effectively used as an active ingredient for a pharmaceutical composition for use in the prevention or treatment of neurological disease or a health functional food composition for use in the prevention or improvement of neurological disease, leading to the completion of the present invention.

    SUMMARY OF THE INVENTION



    [0010] It is an object of the present invention to provide a novel spiroquinone derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

    [0011] It is another object of the present invention to provide a preparation method of the novel spiroquinone derivative compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof.

    [0012] It is also an object of the present invention to provide a pharmaceutical composition comprising the novel spiroquinone derivative compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for use in the prevention or treatment of neurological disease.

    [0013] It is further an object of the present invention to provide a health functional food composition comprising the novel spiroquinone derivative compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for use in the prevention or improvement of neurological disease.

    [0014] It is also an object of the present disclosure to describe a method for the prevention or treatment of neurological disease comprising the step of administering a pharmaceutically effective dose of the pharmaceutical composition above to a subject in need.

    [0015] It is also an object of the present disclosure to describe a method for the prevention or treatment of neurological disease comprising the step of administering a pharmaceutically effective dose of the novel spiroquinone derivative compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof to a subject in need.

    [0016] It is also an object of the present disclosure to describe a use of the novel spiroquinone derivative compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for the prevention or treatment of neurological disease.

    [0017] To achieve the above objects, the present invention provides a compound represented by formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.



    [0018] In formula 1 above,
    R1 is nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,
    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano;
    R2 is hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,
    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano; and
    R3 and R4 are the same or different. They are independently hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted alkyl or alkoxy is independently substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, nitro, and cyano.

    [0019] The present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 from the compound represented by formula 2 (step 1), as shown in reaction formula 1 below.



    [0020] In reaction formula 1,
    R1, R2, R3, and R4 are as defined in formula 1 above.

    [0021] The present invention also provides a pharmaceutical composition comprising the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for use in the prevention or treatment of neurological disease.

    [0022] The present invention also provides a health functional food comprising the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for use in the prevention or improvement of neurological disease.

    [0023] The present disclosure also describes a method for the prevention or treatment of neurological disease comprising the step of administering a therapeutically effective dose of the pharmaceutical composition to a subject in need.

    [0024] In addition, the present disclosure describes a use of the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for the prevention or treatment of neurological disease.

    ADVANTAGEOUS EFFECT



    [0025] The novel spiroquinone derivative compound of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof is not only excellent in inhibiting the microglial activation and the activities of acetylcholine esterase, JNK1, JNK2, and JNK3 but also displays the significant enzyme activity suppressive effect on the neurological disease related enzyme group including RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, and TLK1, in addition to the cell death suppressive effect. Therefore, the novel spiroquinone derivative compound of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of neurological disease or as an active ingredient of a health functional food for the prevention or improvement of neurological disease.

    BRIEF DESCRIPTION OF THE DRAWINGS



    [0026] 

    Figure 1 is a set of graphs illustrating the nitrite generation from the comparison of nitric oxide measured in the neuronal cell line (murine microglial BV-2 cells) treated with a neurotoxicant (LPS) according to the different concentrations (0.01 µM, 0.1 µM, and 1 µM) of the compound of the present invention.

    Figure 2 is a set of graphs illustrating the cell survival rate (%) of the neuronal cell line (murine microglial BV-2 cells) treated with a neurotoxicant (LPS) according to the different concentrations (0.01 µM, 0.1 µM, and 1 µM) of the compound of the present invention.

    Figure 3 is a graph illustrating the nitrite generation from the comparison of nitric oxide measured in the neuronal cell line (murine microglial BV-2 cells) treated with a neurotoxicant (LPS) according to the different concentrations (1 µM, 5 µM, and 10 µM) of the compound of the present invention.

    Figure 4 is a graph illustrating the cell survival rate (%) of the neuronal cell line (murine microglial BV-2 cells) treated with a neurotoxicant (LPS) according to the different concentrations (1 µM, 5 µM, and 10 µM) of the compound of the present invention.

    Figure 5 is a graph illustrating the IC50 value calculated from the detection results of the nitric oxide generation measured by concentration gradient of the compound of the present invention (horizontal axis: example number, longitudinal axis: IC50(µM)).

    Figure 6 is a graph illustrating the acetylcholine esterase residual activity (%) after the treatment of the compound of the present invention at two different concentrations of 10 µM and 30 µM.

    Figure 7 is a graph illustrating the ratio (%) of spontaneous alternation behavior by memory damage induced by scopolamine (1 mg/kg, i.p.) in the test mouse after the treatment of donepezil (5 mg/kg, p.o.), 10% Tween 80 solution, and the compound of the present invention (10 mg/kg, p.o.).


    DESCRIPTION OF THE PREFERRED EMBODIMENTS



    [0027] Hereinafter, the present invention is described in detail.

    [0028] The present invention provides a compound represented by formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.



    [0029] In formula 1 above,
    R1 is nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,
    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano;
    R2 is hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,
    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano; and
    R3 and R4 are the same or different. They are independently hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted alkyl or alkoxy is independently substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, nitro, and cyano.

    [0030] In one aspect of the present invention,
    R1 is nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,
    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano.

    [0031] In another aspect of the present invention,
    R2 is hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,
    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted phenylsulfonyl, substituted or nonsubstituted phenylsulfonyl C1-5 alkyl, substituted or nonsubstituted phenyl, substituted or nonsubstituted phenyl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,
    wherein, the substituted phenylsulfonyl, phenylsulfonyl C1-5 alkyl, phenyl, phenyl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano.

    [0032] In another aspect of the present invention,
    R1 is

    and





    or



    [0033] The following compounds are preferred examples of the compound represented by formula 1 according to the present invention.
    1. (1) 5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    2. (2) 3-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    3. (3) 3-allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    4. (4) 3-(2-methyl-allyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    5. (5) 3-(3-butenyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    6. (6) 3-benzyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    7. (7) 3-(4-fluoro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    8. (8) 3-(4-chloro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    9. (9) 3-(3-bromo-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    10. (10) 3-(4-bromo-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    11. (11) 3-(4-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    12. (12) 3-(4-nitro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    13. (13) 3-(2-(phenylsulfonylmethyl)-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    14. (14) 3-(3,5-ditrifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    15. (15) 3-(3,5-dimethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    16. (16) 3-(2-nitro-4-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    17. (17) 3-(2-fluoro-6-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    18. (18) 3-(2-chloro-5-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    19. (19) 3-benzyl-5-(pyridine-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    20. (20) 3-methyl-5-(pyridine-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    21. (21) 3-hydroxy-2-methyl-N-(4-oxocyclohexa-2,5-diethyl)-N-(pyridine-3-yl)propanamide;
    22. (22) 3-methyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    23. (23) 3-allyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    24. (24) 3-benzyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    25. (25) 3,8-dimethyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    26. (26) 3-allyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    27. (27) 3-(2-methyl-allyl)-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    28. (28) 3-benzyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    29. (29) 3,5-dimethyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    30. (30) 3-allyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    31. (31) 3-(3-butenyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    32. (32) 3-(2-methyl-allyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    33. (33) 3-benzyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    34. (34) 3-(4-fluoro-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    35. (35) 3-(4-bromo-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    36. (36) 3-(4-cyano-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    37. (37) 3-(2-(phenylsulfonylmethyl)-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    38. (38) 3-allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    39. (39) 3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    40. (40) 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    41. (41) 3-methyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    42. (42) 3-allyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    43. (43) 3-(4-fluoro-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    44. (44) 3-(4-trifluoromethyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    45. (45) 3-(4-cyano-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    46. (46) 3-(2-fluoro-6-trifluoromethyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    47. (47) 3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;
    48. (48) 3-(3-bromobenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione; and
    49. (49) 5-isopropyl-3-(4-nitrobenzyl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione.


    [0034] In one aspect of the present invention, the present invention provides a compound represented by formula 2 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.



    [0035] In reaction formula 2,
    R1, R2, R3, and R4 are as defined in formula 1.

    [0036] The compound represented by formula 1, or formula 2 of the present invention can be used as a form of a pharmaceutically acceptable salt, in which the salt is preferably acid addition salt formed by pharmaceutically acceptable free acids. The acid addition salt herein can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic mono/dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate, alkandioate, aromatic acids, and aliphatic/aromatic sulfonic acids; or organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. The pharmaceutically non-toxic salts are exemplified by sulfate, pyrosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, maliate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, hydroxybutylate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

    [0037] The acid addition salt in this invention can be prepared by the conventional method known to those in the art. For example, the derivative represented by formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, and acetonitrile, to which organic acid or inorganic acid is added to induce precipitation. Then, the precipitate is filtered and dried to give the salt. Or the solvent and the excessive acid are distillated under reduced pressure, and dried to give the salt. Or the precipitate is crystallized in an organic solvent to give the same.

    [0038] A pharmaceutically acceptable metal salt can be prepared by using a base. Alkali metal or alkali earth metal salt is obtained by the following processes: dissolving the compound in excessive alkali metal hydroxide or alkali earth metal hydroxide solution; filtering non-soluble compound salt; evaporating the remaining solution and drying thereof. At this time, the metal salt is preferably prepared in the pharmaceutically suitable form of sodium, potassium, or calcium salt. And the corresponding silver salt is prepared by the reaction of alkali metal or alkali earth metal salt with proper silver salt (ex; silver nitrate).

    [0039] The present invention includes not only the compound represented by formula 1 but also a pharmaceutically acceptable salt thereof, and a solvate, a stereoisomer, or a hydrate possibly produced from the same.

    [0040] The pharmaceutically acceptable salt of the novel spiroquinone derivative compound of the present invention is not limited as long as a candidate compound salt displays the equal preventive or therapeutic effect to the novel spiroquinone derivative compound of the invention.

    [0041] The present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 from the compound represented by formula 2 (step 1), as shown in reaction formula 1 below.





    [0042] In reaction formula 1,
    R1, R2, R3, and R4 are as defined in formula 1 of claim 1.

    [0043] Hereinafter, the preparation method of the compound represented by formula 1 of the present invention is described in more detail, step by step.

    [0044] In the preparation method of the compound represented by formula 1 of the present invention, step 1 of reaction formula 1 is to prepare the compound represented by formula 1 from the compound represented by formula 2.

    [0045] At this time, step 1 can include any method that can produce the compound represented by formula 1 from the compound represented by formula 2, but is preferably understood as oxidative cyclization herein.

    [0046] Herein, the oxidative cyclization is the reaction induced to produce 3,5-substituted oxazaspiroquinone that can performed by using a hypervalent iodine oxidizing agent.

    [0047] As the hypervalent iodine oxidizing agent, BAIB (bis(acetoxy)iodobenzene) or PIFA (phenyliodinebis(trifluoroacetate)) is preferably used, but any oxidizing agent capable of performing the oxidative cyclization reaction of step 1 can be used without limitation and is included in the scope of the present invention.

    [0048] The usable solvent in step 1 above is exemplified by H2O, ethanol, tetrahydrofuran (THF), dichloromethane, toluene, acetonitrile, dimethylformamide, and hexafluoro isopropanol, and is preferably hexafluoro isopropanol herein.

    [0049] As shown in reaction formula 2 below, the compound represented by formula 2 can be prepared by the preparation method of the compound represented by formula 2 comprising the following steps:

    preparing the compound represented by formula 7 from the compound represented by formula 8 (step 1);

    preparing the compound represented by formula 6 from the compound represented by formula 7 prepared in step 1 above (step 2);

    preparing the compound represented by formula 5 from the compound represented by formula 6 prepared in step 2 above (step 3);

    preparing the compound represented by formula 4 from the compound represented by formula 5 prepared in step 3 above (step 4);

    preparing the compound represented by formula 3 from the compound represented by formula 4 prepared in step 4 above (step 5); and

    preparing the compound represented by formula 2 from the compound represented by formula 3 prepared in step 5 above (step 6).

    (In reaction formula 2,
    R1, R2, R3, and R4 are as defined in formula 1 of claim 1.)



    [0050] Hereinafter, the preparation method of the compound represented by formula 2 is described in more detail, step by step.

    [0051] In the preparation method of the compound represented by formula 2 of the present invention, step 1 of reaction formula 2 is to prepare the compound represented by formula 7 from the compound represented by formula 8.

    [0052] At this time, step 1 of reaction formula 2 is the step of introducing a protecting group into the hydroxy group of the compound represented by formula 8.

    [0053] As shown in reaction formula 2, the protecting group can be MOM (methoxymethyl ether), but methyl ether, methoxymethyl ether, methoxyethyl ether, or benzyloxymethyl ether can also be used. In addition, any protecting group generally used in this field can be used without limitation, and this is included in the scope of the present invention.

    [0054] In the preparation method of the compound represented by formula 2 above, step 2 of reaction formula 2 is to prepare the compound represented by formula 6 from the compound represented by formula 7.

    [0055] At this time, step 2 of reaction formula 2 can be understood as the step of introducing NH2R1. This reaction is preferably induced in the presence of amine, a ligand such as Pd2(dba)3, NaOtBu, BINAP, or X-Phos, and anhydrous toluene, and the present invention includes any general modification possibly accepted for the inducement of the reaction above.

    [0056] The temperature for carrying out the reaction is not particularly limited, but can be preferably performed at 20°C ∼ 120°C.

    [0057] In the preparation method of the compound represented by formula 2 above, step 3 of reaction formula 2 is to prepare the compound represented by formula 5 from the compound represented by formula 6.

    [0058] At this time, step 3 of reaction formula 2 above can be understood as the step of obtaining N,N-substituted malonamide ester by inducing acyl substitution of malonic acid monoester. As an example, this reaction can be induced with the compound represented by formula 6 in the presence of methylmalonyl chloride. Any modification generally accepted in this field can be included in the scope of the present invention.

    [0059] The temperature for carrying out the reaction is not particularly limited, but can be preferably performed at 0°C ∼ 30°C.

    [0060] In the preparation method of the compound represented by formula 2 above, step 4 of reaction formula 2 is to prepare the compound represented by formula 4 from the compound represented by formula 5.

    [0061] At this time, step 4 of reaction formula 2 above is understood as the step of obtaining 2-substituted malonamide ester by introducing R2 in the 2-position of N,N-substituted malonamide ester. As an example, this reaction can be induced with the compound represented by formula 5 in the presence of KOH (aqueous solution or solid), TBAl, R2-X (halogen), and a proper solvent or in the presence of NaH, R2-X (halogen) and an anhydrous solvent. Any modification generally accepted in this field can be included in the scope of the present invention.

    [0062] The temperature for carrying out the reaction is not particularly limited, but can be preferably performed at 0°C ∼ 30°C.

    [0063] In the preparation method of the compound represented by formula 2 above, step 5 of reaction formula 2 is to prepare the compound represented by formula 3 from the compound represented by formula 4.

    [0064] At this time, step 5 of reaction formula 2 above is understood as the step of reducing the ester group of the compound represented by formula 4. As an example, this reaction can be induced with the compound represented by formula 4 in the presence of Li(OtBu)3H. Any modification generally accepted in this field can be included in the scope of the present invention.

    [0065] The temperature for carrying out the reaction is not particularly limited, but can be preferably performed at -40°C ∼ 0°C.

    [0066] In the preparation method of the compound represented by formula 2 above, step 6 of reaction formula 2 is to prepare the compound represented by formula 2 from the compound represented by formula 3.

    [0067] At this time, step 6 of reaction formula 2 is understood as the deprotection reaction to remove the protecting group introduced in step 1 above. Any modification generally accepted in this field can be included in the scope of the present invention.

    [0068] Alternatively, when R2 is C1-C6 alkyl, the compound represented by formula 2 can be obtained by reducing the ester group of N,N-substituted malonamide ester having a substituent at the 2-position introduced according to a literature (non-patent reference 3) by chemoselective reduction and removing the hydroxy protecting group of the protected phenol of the N,N-substituent.

    [0069] The present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 from the compound represented by formula 2 (step 1), as shown in reaction formula 1 below.

    [0070] In another aspect of the present invention, step 1 of reaction formula 1 is composed of the following steps, as shown in reaction formula 1':

    preparing the compound represented by formula 1" from the compound represented by formula 2' (step 2); and

    preparing the compound represented by formula 1 from the compound represented by formula 1" (step 3).





    [0071] In reaction formula 1',
    R1, R3, and R4 are as defined in formula 1;
    R2' is C1-5 straight or branched alkynyl containing one or more triple bonds; and
    R2 is preferably

    Wherein, Ra is C1-5 straight or branched alkylene,
    Rb is hydrogen, substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, or cyano,
    Wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano.

    [0072] Further, the present invention provides a pharmaceutical composition comprising the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for use in the prevention or treatment of neurological disease.

    [0073] The compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof can be effectively used for the prevention or treatment of neurological disease by inhibiting the cell death by suppressing the microglial activation, which can be an example of the industrial usage of the same, or by suppressing significantly the activities of acetylcholine esterase, JNK1, JNK2 and JNK3, and the neurological disease related enzyme group including RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, and TLK1.

    [0074] Particularly, the pharmaceutical composition above can be used to treat injury, symptoms or disease caused by neurotoxic substances such as LPS (lipid polysaccharide) or by the over-activation of microglial cells or to prevent or treat neurological disease requiring the inhibition of the activity of acetylcholine esterase, JNK1, JNK2, JNK3, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, or TLK1.

    [0075] At this time, the neurological disease herein indicates any nerve disorder requiring the inhibition of the microglial activation or the suppression of the activity of acetylcholine esterase, JNK1, JNK2, JNK3, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, or TLK1. The neurological disease can include, in particular, cerebral nervous system disease and central nervous system disease.

    [0076] More particularly, the neurological disease can be one or more diseases selected from the group consisting of multiple sclerosis, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, HIV-associated dementia, Huntington's disease, Lou Gehrig's disease, amyotrophic lateral sclerosis, myasthenia gravis, and Creutzfeldt-Jakob disease.

    [0077] In another aspect of the present invention, the neurological disease can be one or more diseases selected from the group consisting of attention deficit disorder, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment, schizophrenia, age-associated memory impairment (AAMI), senile dementia, AIDS dementia, peak disease, Lewy body dementia, Down's syndrome related dementia, amyotrophic lateral sclerosis, Huntington's disease, smoking cessation, nicotine withdrawal symptoms, schizoaffective disorder, bipolar disorder and manic-depressive illness, CNS dysfunction associated with traumatic brain injury, acute pain, postoperative pain, chronic pain, inflammatory pain, and neuropathic pain.

    [0078] In another aspect of the present invention, the neurological disease can be one or more diseases selected from the group consisting of Alzheimer's disease, Huntington's disease, Dandy-walker syndrome, Parkinson's disease, Parkinson-plus disease, amyotrophic lateral sclerosis (ALS), ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, brain barrier disorder, trigeminal neuralgia, tongue pharyngeal pain, Bell's palsy, myasthenia gravis, dystrophy, progressive muscular dystrophy, primary lateral sclerosis (PLS), false medulla oblongata palsy, progressive medulla oblongata palsy, progressive supranuclear palsy, spinal muscular atrophy, hereditary muscular dystrophy, invertebral disc syndrome, plexus disorder, cervical spondylosis, plexus disorder, chest exit syndrome, peripheral neuropathy, porphyria, multiple system atrophy, progressive supranuclear palsy, cortical basal degeneration, Lewy body dementia, anterior temporal dementia, dehydration disease, Guillain-Barre syndrome, multiple sclerosis, Charcot-Marie-Tooth disease, prion disease, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, AIDS dementia complex; nerve damage due to exposure to toxic compounds selected from the group consisting of heavy metals, industrial solvents, drugs and chemotherapeutic agents; nervous system damage caused by physical, mechanical, or chemical trauma; glaucoma, lattice dystrophy, retinal pigment degeneration, agerelated macular degeneration (AMD), photoreceptor degeneration associated with habit or dry AMD, other retinal degeneration, optic nerve drusen, optic neuropathy and optic neuritis.

    [0079] To treat the diseases listed above, the pharmaceutical composition of the present invention brings the preventive and therapeutic effect on neurological disease by inhibiting the over-activation of microglia. The pharmaceutical composition of the present invention can also be efficient in preventing and treating neurological disease by protecting cells from neurotoxicity induced by LPS. Also, the pharmaceutical composition of the present invention can prevent and treat neurological disease by suppressing the activity of acetylcholine esterase. Further, the pharmaceutical composition of the present invention can prevent and treat neurological disease by suppressing the activity of JNK1, JNK2 or JNK3. In addition, the pharmaceutical composition of the present invention can prevent or treat neurological disease by suppressing the activity of RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, or TLK1.

    [0080] The pharmacological effect of the compound represented by formula 1 of the present invention on the above-mentioned diseases have been demonstrated in the following experimental examples using the compounds of the examples of the present invention.

    [0081] Particularly, the present inventors confirmed the protective effect of the compounds of the example of the present invention on nerve injury induced by LPS, and also confirmed the cell death suppression effect of the compounds resulted from inhibiting acetylcholine esterase activity and microglia.

    [0082] In the experiment using a mouse model, drug-induced memory cognitive impairment was induced, and the recovery following the treatment with the compound of the present invention was investigated. The compound represented by formula 1 of the present invention was also efficient as an active ingredient for a pharmaceutical composition for use in the prevention or treatment of the disease or for a health functional food composition for use in the prevention or improvement of the disease.

    [0083] The compound represented by formula 1 of the present invention, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof itself displays the cytoprotective activity, and it is also possible to bring a pharmacological effect by the specific internal environment or by the products of the metabolic process as an agonist.

    [0084] Therefore, the pharmaceutical form for the administration of the compound represented by formula 1 of the present invention, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof or the solvate thereof can be any pharmaceutically acceptable salt or the solvate.

    [0085] The present invention also provides a health functional food composition comprising the compound represented by formula 1, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient for use in the prevention or improvement of neurological disease.

    [0086] At this time, the health functional food composition can be prepared and used as a general health functional food composition containing the compound represented by formula 1 of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient.

    [0087] Any formulation, food type, or administration pathway known to those in the art can be included in the scope of the present invention, and any health functional food composition can be included in the criteria of the health functional food composition of the present invention.

    [0088] The term "prevention" in this invention indicates any activity to inhibit or delay the development of neurological disease by administering the pharmaceutical composition of the present invention to a subject.

    [0089] The term "treatment" in this invention indicates any activity that is helpful for the improvement of the symptoms of neurological disease by administering the pharmaceutical composition of the present invention to a subject.

    [0090] The pharmaceutical composition of the present invention can additionally include a pharmaceutically acceptable carrier, an excipient, or a diluent.

    [0091] When the composition of the present invention is used as a medicinal drug, the pharmaceutical composition comprising the compound represented by formula 1, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient can be formulated for oral or parenteral administration.

    [0092] The formulations for oral administration are exemplified by tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and troches, etc. These formulations can include diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine) and lubricants (for example, silica, talc, stearate and its magnesium or calcium salt, and/or polyethylene glycol) in addition to the active ingredient. Tablets can include binding agents such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrolidone, and if necessary disintegrating agents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents, coloring agents, flavors, and sweeteners can be additionally included thereto.

    [0093] The pharmaceutical composition comprising the compound represented by formula 1 of the present invention can be administered by parenterally and the parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

    [0094] To prepare the composition as a formulation for parenteral administration, the compound represented by formula 1, the stereoisomer thereof or the pharmaceutically acceptable salt thereof of the present invention is mixed with a stabilizer or a buffering agent to produce a solution or suspension, which is then formulated as ampoules or vials. The composition herein can be sterilized and additionally contains preservatives, stabilizers, wettable powders or emulsifiers, salts and/or buffers for the regulation of osmotic pressure, and other therapeutically useful materials, and the composition can be formulated by the conventional mixing, granulating or coating method.

    [0095] The effective dose of the pharmaceutical composition comprising the compound represented by formula 1 as an active ingredient of the present invention can be adjusted according to age, weight, gender and health condition of patient, administration form, and severity of disease. The dose is preferably 0.01 to 1000 mg/kg/day, which can be administered orally or parenterally several times a day or preferably 1 ∼ 3 times a day according to the judgment of a physician or a pharmacist.

    [0096] Hereinafter, the preparation method of the compound represented by formula 1 is described in more detail with preparative examples or examples. The following examples are the examples to describe the preparation method of the compound represented by formula 1. The preparation method described by the following examples can be accomplished by using proper reagents and synthesis conditions well-known in the field of organic synthesis.

    [0097] The pharmaceutical composition of the present invention can be used as a single agent. It can also be formulated as a combined agent by including one or more other neurological disease therapeutic agents.

    [0098] In another aspect of the present invention, the present invention provides a method for the prevention or treatment of neurological disease comprising the step of administering a therapeutically effective dose of the pharmaceutical composition to a subject in need.

    [0099] The pharmaceutical composition indicates a pharmaceutical composition for use in the prevention or treatment of neurological disease, which comprises the compound represented by formula 1, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient.

    [0100] The neurological disease herein indicates any nerve disorder requiring the inhibition of the microglial activation or the suppression of the activity of acetylcholine esterase, JNK1, JNK2, JNK3, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, or TLK1. The neurological disease can include, in particular, cerebral nervous system disease and central nervous system disease.

    [0101] The neurological disease herein includes all the nerve disorders listed above. Particularly, the neurological disease includes the nerve disorders requiring the treatment based on the suppression of the microglial activation and the nerve disorders requiring the treatment based on the inhibition of the activity of acetylcholine esterase, JNK1, JNK2, JNK3, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, or TLK1, which are exemplified by one or more diseases selected from the group consisting of multiple sclerosis, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, HIV-associated dementia, Huntington's disease, Lou Gehrig's disease, amyotrophic lateral sclerosis, myasthenia gravis, Creutzfeldt-Jakob disease, Dandy-walker syndrome, and progressive supranuclear palsy.

    [0102] To treat the diseases listed above, the pharmaceutical composition of the present invention brings the preventive and therapeutic effect on neurological disease by inhibiting the over-activation of microglia. The pharmaceutical composition of the present invention can also be efficient in preventing and treating neurological disease by protecting cells from neurotoxicity induced by LPS.

    [0103] The term "therapeutically effective dose" can be understood by the minimum amount of the composition which shows the improvement, recovery and preferably the preventive or therapeutic effect on the disease in a subject when the compound of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof is administered to the subject.

    [0104] The term "administration" in this invention indicates the introduction of the pharmaceutical composition of the present invention into a subject via a proper pathway. The administration pathway for the pharmaceutical composition of the present invention can include any general pathway so long as it can reach the target tissue, which is exemplified by intraperitoneal administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intra-uterine administration, or intracerbroventricular injection.

    [0105] The term "subject" used in this invention indicates all the animals such as mammals including humans, mammals not including humans, and livestock wherein a neurological disease is developed or possibly occur. By administering the pharmaceutical composition of the present invention to a subject, the neurological disease can be effectively prevented or treated.

    [0106] Next, the following experiments were performed in this invention in order to evaluate and examine the pharmacological activity and the therapeutic effect of the compound represented by formula 1 of the invention (the novel spiroquinone derivative compound) on disease.

    [0107] First, an experiment was performed to evaluate the neuronal cell protection activity of the compound represented by formula 1 of the present invention (the novel spiroquinone derivative compound). As a result, it was shown that the production of nitrite was significantly inhibited in the LPS-treated neuronal cell line (murine microglial BV-2 cells) dose-dependently (see Experimental Example 1 Figure 1 and Experimental Example 2 Figure 3).

    [0108] The compound of the present invention was also confirmed to increase the cell survival rate (%) significantly in the LPS-treated neuronal cell line (murine microglial BV-2 cells) dose-dependently (see Experimental Example 1 Figure 2 and Experimental Example 2 Figure 4).

    [0109] Therefore, the compound of the present invention represented by formula 1 of the present invention was confirmed to have excellent neuroprotective effects (protective effect from oxidation caused by neurotoxic substances and stress) and significant inhibitory effects on microglial over-activation.

    [0110] Further, the acetylcholine esterase inhibition activity of the compound of the present invention was also investigated and as a result a significant inhibition activity was confirmed.

    [0111] Therefore, it was confirmed that the compound represented by formula 1 of the present invention was efficient in treating one or more diseases selected from the group consisting of the acetylcholine inhibition related diseases, for example the neurological diseases described in this specification and more specifically Alzheimer's disease, intractable epilepsy, stroke, cerebral infarct, head trauma, cerebral arteriosclerosis, Parkinson disease Huntington's disease, Creutzfeldt-Jakob disease, Pick's disease, Lewy body disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic brain disease, cerebrovascular disease, cranial nerve disease, cognitive disease or disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), central nervous system (CNS) or peripheral nervous system (PNS) disease, Guillain-Barre syndrome, progressive dementia due to gradual killing of neurons, and progressive ataxia (see Experimental Example 3).

    [0112] Another experiment was performed in order to investigate which kinases, among 369 kinases, were inhibited significantly by the compound of the present invention. As a result, the compound of the present invention significantly inhibited the enzyme activities of JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, and JNK3, indicating that the compound of the present invention can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, and JNK3 related diseases.

    [0113] More precisely, the diseases related to each kinase are listed in Table 1 below.
    [Table 1]
    KinaseDiseaseReference
    JNK 1 Neurodegenerative disease, Ischemia, AD, PD Neurobiology of Disease 54 (2013) 432-444Nat Rev Drug Discov. 2003 Jul;2(7):554-65.Journal of Neuroinflammation 2012, 9:175Brain, Behavior, and Immunity 24 (2010) 800.811
    CDK2/cyclin 0 Neurodegenerative disease Journal of Neurochemistry, 2005, 93, 538.548 Neuroscience 146 (2007) 350-365
    DAPK1 AD, Ischemia Prog Neurobiol. 2014 Apr;115:157-88.Cell Death Dis. 2014 May 22;5:e1237.
    PKCa Brain microvascular endothelial cell barrier disorder Journal of Neuroinflammation 2011, 8:28
    CDK1/cyclin B Neurodegenerative disease Neuroscience 146 (2007) 350-365
    MST3/ST K24 AD PLoS Biol. 2010 Jan; 8(1): e1000294
    JNK2 Neurodegenerative disease, AD, PD Neurobiology of Disease 54 (2013) 432-444Nat Rev Drug Discov. 2003 Jul;2(7):554-65.Journal of Neuroinflammation 2012, 9:175Brain, Behavior, and Immunity 24 (2010) 800.811
    RIPK5 Alzheimer's disease, Down syndrome J. Med. Chem. 2012, 55, 9312.9330
    CDK3/cy clin E Neurodegenerative disease Neuroscience 146 (2007) 350-365
    PKCb2 Brain microvascular endothelial cell barrier disorder Journal of Neuroinflammation 2011, 8:28
    JNK3 Neurodegenerative disease, AD, PD Neurobiology of Disease 54 (2013) 432-444Nat Rev Drug Discov. 2003 Jul;2(7):554-65.Journal of Neuroinflammation 2012, 9:175Brain, Behavior, and Immunity 24 (2010) 800.811
    (*Alzheimer's disease: AD, Parkinson's disease: PD)


    [0114] Therefore, it was confirmed that the compound represented by formula 1 of the present invention was effective in treating the kinase-related neurological diseases described above (see Experimental Example 4).

    [0115] Further, it was confirmed from the animal model experiment (Y tube mouse experiment) using the compound represented by formula 1 (the novel spiroquinone derivative compound) that the treatment of the compound of the invention to the mouse induced with memory impairment resulted in the recovery of memory impairment almost close to the level induced by donepezil.

    [0116] Thus, it was confirmed that the compound of the present invention showed the neuroprotective effect and accordingly could be effectively used as a pharmaceutical composition for the prevention or treatment of all the neurological diseases described in this specification which are specifically exemplified by cerebral neurological diseases and central nervous system diseases (see Experimental Example 5).

    [0117] Practical and presently preferred embodiments of the present invention are illustrative as shown in the following Examples.

    [0118] However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modifications and improvements within the spirit and scope of the present invention.

    Preparative Example 1: Preparation of 2-benzyl-3-hydroxy-N-(4-hydroxyphenyl)-N-(pyridine-3-yl)propanamide



    [0119] 


    Step 1: Preparation of 1-bromo-4-(methoxymethoxy)benzene



    [0120] 50 mL of 4-bromophenol (5 g, 28.9 mmol) was dissolved in anhydrous tetrahydropyran, to which bromo(methoxy)methane (MOM-Br, 2.8 mL, 34.68 mmol) and sodium hydride (1.387 g, 34.68 mmol) were added, followed by stirring for 12 hours. The reaction was terminated by using methanol drop and distilled water. The reaction mixture was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by using silica gel column chromatography (flash column chromatography) using EtOAc:Hex (1:9) as a moving phase to give the target compound (5.35 g, 85%).
    1H NMR (600 Hz, CDCl3) : δ 7.41 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 8.24 Hz, 2 H), 5.17 (s, 2H), 3.49 (s, 3H)

    Step 2: Preparation of N-(4-(methoxymethoxyphenyl)pyridine-3-amine



    [0121] The compound prepared in step 1 (1.4 g, 11.53 mmol), pyridine-3-amine (0.92 mL, 9.61 mmol), Pd2(bda)3 (0.437 g, 0.321 mmol), X-Phos (1.364 g, 1.364 mmol) and NaOtBu (1.318 g, 9.61 mmol) were dissolved in 10 mL of anhydrous toluene, which was added in a seal tube filled with argon gas, followed by stirring at 100 ∼ 120°C for 18 hours. The temperature was lowered to room temperature and the reaction was terminated with distilled water. The generated reaction mixture was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by using silica gel column chromatography (flash column chromatography) using EtOAc:Hex (1:4) as a moving phase to give the target compound.
    1H NMR (600 Hz, CDCl3) : δ 8.27 (d, J = 2.6 Hz, 1 H), 8.08 (dd, J = 4.5, 0.94 Hz, 1 H), 7.26-7.23 (m, 1 H), 7.12-7.09 (m, 1 H), 7.06 (d, J = 9.0 Hz, 2 H), 7.01 (d, J = 9.0 Hz, 2 H), 5.87-5.85 (bs, 1 H), 5.15 (s, 2 H), 3.49 (s, 3 H), 13C NMR (125 MHz, CDCl3) : δ 153.0, 141.2, 140.6, 138.5, 135.7, 123.6, 121.8 (3 C), 121.4, 117.4 (2 C), 94.8, 55.9 ppm.

    [0122] The target compound of step 2 having an aromatic substituent substituted with heteroatoms such as pyridine can be prepared from pyridine-3-amine and 1-bromo-4-(methoxymethoxy)benzene as described in step 2 above. In addition to this method, the target compound of step 2 can be prepared by reacting 4-(methoxymethoxy)aniline and 3-bromopyridine as shown in reaction formula 3 below.


    Step 2: Preparation of N-(4-(methoxymethoxy)phenyl)pyridine-3-amine



    [0123] The oven-dried seal tube was filled with tri(dibenzylidineacetone)dipalladium (0.437 g, 0.321 mmol), (XPhos)palladium(2) phenethylamin chloride (1.364 g, 1.364 mmol), and sodium tert-butoxide (1.318 g, 9.61 mmol), to which degassed toluene anhydride (10 mL) was added. Then, 3-bromopyridine (0.92 mL, 9.61 mmol) and 4-(methoxymethoxy)aniline (1.4 g, 11.53 mmol) were added thereto after degassing with argon gas. The tube was filled with argon gas again. The mixture was stirred at room temperature for 5 ∼ 10 minutes. After sealing with a Teflon screw cap, the mixture was stirred at 100 ∼ 120°C for 18 hours. The reaction progression was monitored by TLC. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with dichloromethane (25 mL) and filtered with celite. Concentration was performed under reduced pressure. The crude product was purified by using silica gel column chromatography (flash column chromatography) using EtOAc:Hex (3:7) as a moving phase to give the target compound as a light brown solid (1.92 g, 87%).
    1H NMR (600 Hz, CDCl3) : δ 8.27 (d, J = 2.6 Hz, 1 H), 8.08 (dd, J = 4.5, 0.94 Hz, 1 H), 7.26-7.23 (m, 1 H), 7.12-7.09 (m, 1 H), 7.06 (d, J = 9.0 Hz, 2 H), 7.01 (d, J = 9.0 Hz, 2 H), 5.87-5.85 (bs, 1 H), 5.15 (s, 2 H), 3.49 (s, 3 H)

    Step 3: Preparation of methyl 3-((4-(methoxymethoxy)phenyl)(pyridine-3-yl)amino)-3-oxopropanoate



    [0124] 1.12 mL of 3-methoxy-3-oxopropanoic acid (9.08 mmol) was dissolved in 12 mL of anhydrous dichloromethane. The mixture was cooled to 0°C with stirring. Then, EDCI·HCl (1.90 g, 9.91 mmol) and anhydrous HOBt (1.51 g, 9.91 mmol) were added thereto stepwise. The compound prepared in step 2 (1.9 g, 8.26 mmol) was added to the mixture at 0°C. The temperature was raised to room temperature. After 12 hours of stirring, the reaction was terminated with a saturated aqueous sodium bicarbonate solution. The generated reaction mixture was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc:Hex (3:7) as a moving phase to give the target compound (1.85 g, 68%).

    [0125] 1.23 mL of methylmalonyl chloride was dissolved in 30 mL of anhydrous dichloromethane by another method. The mixture was cooled to 0°C with stirring. Then, 5.5 mL of triethylamine was added thereto at 0°C. N-(4-(methoxymethoxyphenyl)pyridine-3-amine (1.9 g, 8.26 mmol) was added to the mixture at 0°C, and then the temperature was raised to room temperature slowly. After 12 hours of stirring, the reaction was terminated with a saturated aqueous sodium bicarbonate solution. The generated reaction mixture was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc:Hex (3:7) as a moving phase to give the target compound (2.4 g, 86%).
    1H NMR(600 Hz, CDCl3) : δ 8.52 (s, 1 H), 8.41 (s, 1 H), 7.72 (d, J = 6.9 Hz, 1 H), 7.27-7.20 (m, 3 H), 7.10 (d, J = 7.3 Hz, 2 H), 5.19 (s, 2 H), 3.71 (s, 3 H), 3.49 (s, 3 H), 3.42 (s, 2 H), 13C NMR (125 MHz, CDCl3): δ 167.6, 166.5, 157.4, 146.9, 146.8, 138.9, 134.9, 132.9, 129.8 (2 C), 123.3, 117.6 (2 C), 94.3, 56.2, 52.4, 42.3 ppm.

    Step 4: Preparation of methyl 2-benzyl-3-((4-(methoxymethoxy)phenyl)(pyridine-3-yl)amino)-3-oxopropanoate



    [0126] The compound prepared in step 3 (0.500 g, 1.515 mmol) was dissolved in toluene, to which tetra-n-butylammonium bromide (TBAB) (0.049 g, 0.1515 mmol) and 50% aqueous potassium hydroxide solution (0.54 mL, 19.61 mmol) were added stepwise at room temperature, followed by stirring. Benzylbromide (0.18 mL, 1.15 mmol) was added to the stirred solution, followed by stirring at room temperature until the substrate (the compound prepared in step 3) disappeared completely. The reaction was terminated with water and ethyl acetate. The reaction mixture was diluted with ethyl acetate and then washed with water and saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc:Hex (1:4) as a moving phase to give the target compound (0.458 g, 72%).
    1H NMR(600 Hz, CDCl3) : δ 8.37 (d, J = 4.1 Hz, 1 H), 8.31 (d, J = 1.7 Hz, 1 H), 7.48 (d, J = 8.1 Hz, 1 H), 7.36-7.27 (m, 4 H), 7.23-7.19 (m, 1 H), 7.14 (d, J = 6.9 Hz, 3 H), 6.97-6.89 (m, 2 H), 5.16 (s, 2 H), 3.83-3.78 (m, 1 H), 3.77 (s, 3 H), 3.48 (s, 3 H), 3.33 (t, J = 13.7 Hz, 1 H), 3.20 (dd, J = 13.1, 4.3 Hz, 1 H), 13C NMR (125 MHz, CDCl3): δ 169.4, 169.1, 157.1, 147.2, 146.8, 138.9, 137.9, 134.7, 133.1, 129.9, 129.4 (3 C), 128.5 (2 C), 126.9, 123.2, 117.1 (2 C), 94.3, 56.1, 52.6, 51.3, 35.4 ppm.

    Step 5: Preparation of 2-benzyl-3-hydroxy-N-(4-(methoxymethoxy)phenyl)-N-(pyridine-3-yl)procainamide



    [0127] The compound prepared in step 4 (0.340 g, 0.8095 mmol) was dissolved in anhydrous THF (6 mL), to which LiAl(O-t-Bu)3H (30% in THF, 8.9 mL, 10.523 mmol) was slowly added under argon atmosphere at -40°C. After stirring the mixture at -40°C for 30 minutes, the temperature was slowly raised to room temperature with stirring. After confirming that the substrate (the compound prepared in step 4) disappeared completely, the reaction was quenched with a saturated sodium potassium tartrate aqueous solution. The reaction mixture was diluted with ethyl acetate and then stirred until the water layer and the organic layer became clear. The organic layer was separated and then washed with saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc:Hex (6:4) as a moving phase to give the target compound (0.269 g, 85%).
    1H NMR(600 Hz, CDCl3) : δ 8.37 (d, J = 4.1 Hz, 1 H), 8.36 (d, J = 1.8 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.33-7.27 (m, 3 H), 7.24-7.20 (m, 1 H), 7.08-7.05 (m, 3 H), 6.98-6.91 (m, 3 H), 5.17 (s, 2 H), 3.86-3.81 (m, 1 H), 3.79-3.76 (m, 1 H), 3.49 (s, 3 H), 3.07-3.01 (m, 1 H), 2.78-2.74 (m, 1 H).
    13C NMR (125 MHz, CDCl3) : δ 175.4, 156.9, 147.5, 146.8, 139.1, 138.6, 134.9, 133.3, 130.0, 129.2 (2 C), 128.4 (2 C), 126.6, 123.3, 117.1 (2 C), 94.3, 63.8, 56.1, 46.7, 35.7 ppm.
    HRMS (ESI): calcd. For C23H25N2O4 [M + H]+ 393.1814; found 393.1814.

    Step 6: Preparation of 2-benzyl-3-hydroxy-N-(4-hydroxyphenyl)-N-(pyridine-3-yl)propanamide



    [0128] The compound prepared in step 5 (0.180 g, 0.4591 mmol) was dissolved in 15 mL of acetonitrile and 15 mL of dichloromethane, followed by stirring. Sodium iodide (0.688 g, 4.591 mmol) was added thereto at 0°C, to which chlorotrimethylsilane (0.6 mL, 4.591 mmol) was added stepwise. After stirring the mixture for 1 hour, the reaction was terminated with a saturated aqueous sodium bisulfate solution. The organic layer obtained by extraction with dichloromethane (2 x 50 mL) was washed with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc:Hex (4:1) as a moving phase to give the target compound (0.111 g, 70%).
    1H NMR (600 Hz, CDCl3) : δ 9.14 (d, J = 3.9 Hz, 1 H), 9.1 (s, 1 H), 8.25 (d, J = 7.9 Hz, 1 H), 8.17-8.05 (m, 5 H), 7.85 (d, J = 7.3 Hz, 2 H), 7.67-7.61 (m, 1 H), 7.51-7.44 (m, 2 H), 5.69-5.62 (bs, 1 H), 4.50 (t, J = 8.4 Hz, 1 H), 4.24-4.18 (m, 1 H), 3.74-3.68 (m, 1 H), 3.55-3.44 (m, 2 H), 13C NMR (125 MHz, MeOD): δ 183.6, 157.0, 155.9, 149.3, 148.8, 143.0, 138.5 (4 C), 137.7 (3 C), 135.8 (2 C), 133.2, 128.4 (2 C), 72.4, 57.0, 44.9 ppm.
    HRMS (ESI): calcd. For C21H21N2O3 [M + H]+ 349.1552; found 349.1548.

    Preparative Example 2: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-2-methyl-N-(pyridine-3-yl)propanamide



    [0129] 



    [0130] The target compound was prepared by the same manner as described in Preparative Example 1 except that iodomethane was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 Hz, MeOD) : δ 8.43 (s, 1 H), 8.24 (s, 1 H), 7.71-7.52 (m, 1 H), 7.42-7.33 (m, 1 H), 7.22-7.04 (m, 2 H), 6.81-6.64 (m, 2 H), 3.72-3.63 (m, 1 H), 3.38-3.34 (m, 1 H), 2.73-2.92 (m, 1 H), 0.87 (d, J = 1.7 Hz, 3 H); 13C NMR (125 MHz, MeOD): 177.15, 157.75, 146.90, 145.78, 140.40, 134.47, 132.99, 129.82 (2 C), 123.93, 116.20 (2 C), 64.53, 39.92, 13.12 ppm.

    Preparative Example 3: Preparation of 2-benzyl-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0131] 



    [0132] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.39 - 7.23 (m, 6H), 7.19 (t, J = 7.3 Hz, 1H), 7.15 - 7.06 (m, 4H), 6.92 (d, J = 8.7 Hz, 1H), 6.78 - 6.61 (m, 2H), 3.92 - 3.86 (m, 1H), 3.63 - 3.59 (m, 1H), 3.16 - 3.03 (m, 1H), 2.87 - 2.80 (m, 1H), 2.78 - 2.70 (m, 1H); 13C NMR (151 MHz, MeOD) δ 175.24, 156.99, 143.11, 139.21, 133.77, 129.68, 129.11, 129.09, 129.00, 128.53, 128.41, 128.12, 127.81, 127.36, 126.47, 126.23, 126.20, 115.43, 115.15, 63.61, 48.10, 35.57 ppm.

    Preparative Example 4: Preparation of 2-benzyl-3-hydroxy-N-(4-hydroxyphenyl)-N-methylpropanamide



    [0133] 



    [0134] The secondary amine compound with the substitution of an alkyl group instead of an aromatic substituent can be prepared by the same manner as described in Preparation Example 4 as shown in reaction formula 4 below, unlike Preparation Examples 1-3 and 5-13.




    Step 1: Preparation of benzyl(4-hydroxyphenyl)carbamate



    [0135] 4-aminophenol (8.0 g, 73.3 mmol) was mixed with distilled water (91.5 mL) and tetrahydrofuran (91.5 mL) mixture (1:1), followed by stirring. After lowering the temperature of the mixture to 0°C, sodium carbonate (15.58 g, 146.7 mmol) was added thereto dropwise. A solution of benzyl chloroformate (12.5 mL, 76.2 mmol) in tetrahydrofuran (30 mL) was added thereto slowly. The temperature of the solution with brown floats was slowly raised to room temperature, followed by stirring for 1 hour. Then, tetrahydrofuran was removed in vacuo. The brown solution was diluted with distilled water (200 mL), followed by extraction with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The crude product was subjected to recrystallization from ethyl acetate to give the target compound (14.4 g, 61.6 mmol, 90%) as white crystals protected with a carboxybenzyl group.
    1H NMR (600 MHz, DMSO-d6) δ δ 5.12 (s, 2 H), 6.66-7.00 (m, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.31-7.47 (m, 5H), 9.12 (s, 1 H), 9.44 (br s, 1 H) ppm.

    Step 2: Preparation of benzyl(4-(methoxyketoxy)phenyl)carbamate



    [0136] Sodium hydride (1.604 g, 66.87 mmol, dispersed in 60% paraffin oil) was mixed with anhydrous dimethylformamide (10 mL), to which the compound prepared in step 1 (13.8 g, 60.78 mmol) dissolved in anhydrous dimethylformamide (10 mL) was added slowly in the condition of nitrogen gas filled therein at 0°C. 30 minutes later when hydrogen gas was not generated anymore, the loading was stopped. Bromomethylmethylether (5.45 mL, 66.87 mmol) was slowly added thereto at 0°C, followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the red solution was concentrated in vacuo. The residue was washed with ethyl acetate (250 mL), 10% citric acid (2 × 100 mL), 1 M sodium hydroxide (aq) (2 × 150 mL), and brine, followed by drying over sodium sulfate. The solvent was removed under reduced pressure. The crude product was subjected to recrystallization from ethanol to give the target compound (9.3 g, 56.8%) as white crystals.
    1H NMR (600 Hz, CDCl3) : δ 7.17-7.29 (m, 7 H), 6.98 (d, J = 9.0 Hz, 2 H), 5.19 (s, 2 H), 5.13 (s, 2 H), 3.47 (s, 3 H), 13C NMR (125 MHz, CDCl3) : δ 153.5, 136.0, 131.9, 128.5 (4 C), 128.29 (2 C), 128.26 (2 C), 120.4, 116.8 (2 C), 94.78, 66.9, 55.8 ppm.

    Step 3: Preparation of benzyl(4-(methoxymethoxy)phenyl)(methyl)carbamate



    [0137] Sodium hydride (0.93 g, 37.63 mmol, dispersed in 60% paraffin oil) was mixed with anhydrous dimethylformamide (15 mL), to which the compound prepared in step 2 (7.2 g, 25.08 mmol) dissolved in anhydrous dimethylformamide (20 mL) was added slowly in the condition of nitrogen gas filled therein at 0°C, followed by stirring for 30 minutes. 30 minutes later when hydrogen gas was not generated anymore, the loading was stopped. Methyl iodide (2.3 mL, 37.63 mmol) was slowly added thereto at 0°C, followed by stirring at room temperature for 6 hours. The reaction was terminated with cold ice cubes and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced the pressure. The crude product was purified by silica gel column chromatography (flash column chromatography) to give the brown target compound (6.5 g, 86%).
    1H NMR (600 Hz, CDCl3) : δ 7.38-7.27 (m, 5 H), 7.16-7.24 (m, 2 H), 7.04 (d, J = 8.3 Hz, 2 H), 5.19 (s, 4 H), 3.51 (s, 3 H), 3.30 (s, 3 H) ppm.

    Step 4: Preparation of 4-(methoxymethoxy)-N-methylalanine



    [0138] The compound prepared in step 3 (6.0 g, 35.01 mmol) was dissolved in methanol, to which palladium (3.4 g, 5% activated carbon powder) filled with argon gas was added thereto. Argon gas was replaced with hydrogen gas, followed by stirring until the starting substrates were reacted completely. Upon completion of the reaction, the reaction mixture was filtered with a diatomite pad. The solvent was removed under reduced the pressure. The crude product was purified by silica gel column chromatography (flash column chromatography) to give the target compound (2.88 g, 86%) as yellow oil.
    1H NMR (600 Hz, CDCl3) : δ 7.28-7.25 (m, 4 H), 5.04 (s, 2 H), 2.77 (s, 3 H) ppm.

    Step 5: Preparation of methyl-3-((4-(methoxymethoxy)phenyl) (methyl)amino)-3-oxopropanoate



    [0139] Cooled methylmalonylchloride (1.57 mL, 14.65 mmol) was dissolved in dimethylformamide (10 mL), to which the compound prepared in step 4 (2.69 g, 16.11 mmol) dissolved in dimethylformamide (20 mL) was slowly added at 0°C, followed by stirring for 1 hour. The reaction was terminated with ice cubes and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced the pressure. The crude product was purified by silica gel column chromatography (flash column chromatography) to give the target compound (3.8 g, 89%) as colorless liquid.
    1H NMR (600 Hz, CDCl3) : δ 7.13-7.06 (m, 4 H), 5.2 (s, 2 H), 3.69 (s, 3 H), 3.50 (s, 3 H), 3.28 (s, 3 H), 3.23 (s, 3 H) ppm.

    Step 6: Preparation of 2-benzyl-3-hydroxy-N-(4-hydroxyphenyl)-N-methylpropanamide



    [0140] After step 5, the target compound was prepared by the same manner as described in step 4, step 5 and step 6 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.29 - 7.22 (m, 3H), 7.04 - 6.97 (m, 2H), 6.81 - 6.55 (m, 4H), 3.78 (dd, J = 10.6, 8.2 Hz, 1H), 3.51 (dd, J = 10.6, 5.8 Hz, 1H), 3.10 (d, J = 3.8 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.76 (dd, J = 12.8, 10.2 Hz, 1H), 2.63 (dd, J = 12.9, 4.8 Hz, 1H); 13C NMR (150 MHz, MeOD) δ 174.80, 156.85, 139.33, 134.68, 128.77 (2 C), 128.34, 128.01(2 C), 126.02(2 C), 115.46 (2 C), 63.36, 47.67, 36.61, 35.31 ppm.

    Preparative Example 5: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-2-methyl--N-phenylpropanamide



    [0141] 



    [0142] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and iodomethane was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.51 - 7.06 (m, 7H), 6.91-6.67 (m, 2H), 3.79 (dd, J = 10.4, 8.5 Hz, 1H), 3.44 (dd, J = 10.0, 5.5 Hz, 1H), 2.87 (dd, J = 16.7, 10.2 Hz, 1H), 1.05 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz, MeOD) δ 178.16, 158.57, 144.51, 135.54, 130.83, 129.89, 129.51, 129.27, 128.88, 127.82, 127.40, 117.21, 116.54, 65.85, 41.23, 14.56 ppm.

    Preparative Example 6: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-phenylpent-4-enamide



    [0143] 



    [0144] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and allylbromide was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.45 - 7.30 (m, 3H), 7.26 (s, 1H), 7.19 (d, J = 7.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.78-5.67 (m, 1H), 5.11-5.04 (t, J = 12.4 Hz, 2H), 3.80 (dd, J = 10.5, 8.5 Hz, 1H), 3.53 (dd, J = 10.4, 5.4 Hz, 1H), 3.02 - 2.86 (m, 1H), 2.38-2.26 (m, 1H), 2.21-2.13 (m, 1H); 13C NMR (151 MHz, MeOD) δ 176.79, 158.51, 144.57, 136.51, 135.38, 131.25, 130.62, 129.88 (2 C), 129.27, 127.87 (2 C), 117.41, 117.06, 116.53, 64.49, 46.45, 35.14 ppm.

    Preparative Example 7: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-2-(4-(trifluoromethyl)benzyl)propanamide



    [0145] 



    [0146] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 4-trifluoromethylbenzylbromide was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.65 (d, J = 6.9 Hz, 2H), 7.38-7.24 (m, 5H), 7.19 (t, J = 7.1 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.76 - 6.60 (m, 3H), 3.91 (t, J = 9.0 Hz, 1H), 3.66 - 3.61 (m, 1H), 3.19 - 3.06 (m, 1H), 2.98 - 2.80 (m, 2H); 13C NMR (150 MHz, MeOD) δ 176.09, 158.44, 145.38, 144.31, 135.68, 134.95, 131.02, 130.82, 130.44, 129.93, 129.55, 129.07, 128.82, 127.70, 127.60, 126.34, 126.31, 124.89, 116.88, 116.55, 64.79, 49.22, 36.57 ppm.

    Preparative Example 8: Preparation of 2-(4-fluorobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0147] 



    [0148] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 4-fluorobenzylbromide was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.32-7.24 (m, 3H), 7.17 (t, J = 7.2 Hz, 1H), 7.13-6.98 (m, 6H), 6.91 (d, J = 8.3 Hz, 1H), 6.75 - 6.58 (m, 2H), 3.86 (t, J = 8.9 Hz, 1H), 3.58 (t, J = 8.9 Hz, 1H), 3.12-2.99 (m, 1H), 2.85-2.77 (m, 1H), 2.74-7.68 (m, 1H); 13C NMR (150 MHz, MeOD) δ 176.40, 163.96, 158.40, 144.36, 136.50, 136.43, 135.74, 135.06, 132.04, 131.99, 130.41, 129.89, 129.11, 127.75, 127.55, 116.84, 116.52, 116.06, 115.92, 64.80, 49.39, 35.94 ppm.

    Preparative Example 9: Preparation of 2-(4-bromobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0149] 



    [0150] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 4-bromobenzylbromide was used instead of benzylbromide in step 4.
    1H NMR (600 Hz, MeOD): δ 7.58 (s, 1 H), 7.47 (d, J = 7.2 Hz, 2 H), 7.31-7.26 (m, 3 H), 7.19-7.15 (m, 1 H), 7.09-7.07 (m, 2 H), 7.06-6.96 (m, 2 H), 7.09-7.07 (m, 2 H), 6.92-6.88 (m, 1 H), 6.73-6.66 (m, 2 H), 3.86 (t, J = 8.9 Hz, 1 H), 3.58 (s, 1 H), 3.09-3.01 (m, 1 H), 2.82-2.71 (m, 2 H) ppm.

    Preparative Example 10: Preparation of 2-benzyl-3-hydroxy-N-(4-hydroxy-3-methylphenyl)-N-phenylpropanamide



    [0151] 



    [0152] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-methylphenyl was used instead of 4-bromophenol in step 1 and aniline was used instead of pyridine-3-amine in step 2.
    1H NMR (600 Hz, MeOD): δ 7.37-7.21 (m, 5 H), 7.19-7.13 (t, J = 1.9Hz, 1 H), 7.13-7.05 (m, 3 H), 6.79-6.67 (m, 1 H), 6.66-6.55 (m, 1 H), 3.90-3.82 (m, 1 H), 3.62-3.54 (m, 1 H), 2.86-2.76 (m, 1 H) 2.75-2.66 (m, 1 H), 2.13-1.95 (m, 3H); 13C NMR (150 Hz, MeOD): δ 176.76, 156.62, 144.73, 140.89, 130.68, 130.51, 130.05, 129.92, 129.68, 128.85, 128.34, 128.01, 127.83, 127.75, 127.75, 127.69, 126.51, 115.93, 115.82, 65.21, 37.15, 30.82, 16.32 ppm.

    Preparative Example 11: Preparation of N-(4-hydroxy-3-methylphenyl)-2-(hydroxymethyl)-N-phenylpent-4-enamide



    [0153] 



    [0154] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-methylphenyl was used instead of 4-bromophenol in step 1, aniline was used instead of pyridine-3-amine in step 2, and allylbromide was used instead of benzylbromide.
    1H NMR (600 Hz, MeOD): δ 7.45-7.36 (m, 1 H), 7.35-7.27 (m, 2 H), 7.26-7.24 (m, 2 H), 7.05-6.86 (m, 2 H), 6.76-6.61 (m, 1 H), 5.78-5.53 (m, 1 H), 5.42-5.29 (m, 1 H), 5.13-5.02 (m, 2H), 3.83-3.70 (m, 2 H), 2.93-2.80 (m, 2 H), 2.50-2.39 (m, 1 H), 2.36-2.26 (m, 1 H), 2.25-2.12 (m, 3 H); 13C NMR (150 Hz, MeOD): δ 178.60, 140.45, 139.06, 136.41, 133.35, 132.50, 131.52, 129.98, 129.17, 127.90, 124.97, 122.49, 120.97, 110.36, 110.02, 77.93, 38.97, 30.89, 21.16 ppm.

    Preparative Example 12: Preparation of 3-hydroxy-N-(4-hydroxy-3-methylphenyl)-2-methyl-N-phenylpropanamide



    [0155] 



    [0156] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-methylphenyl was used instead of 4-bromophenol in step 1, aniline was used instead of pyridine-3-amine in step 2, and methyliodide was used instead of benzylbromide.
    1H NMR (600 Hz, MeOD): δ 7.47-7.14 (m, 5 H), 7.11-6.95 (m, 2 H), 6.80-6.66 (m, 1 H), 3.82-3.75 (t, J = 1.7Hz, 1 H), 3.46-3.38 (m, 1 H), 2.92-2.82 (m, 1 H), 2.21-2.09 (m, 3 H), 1.06-1.02 (d, J = 1.1Hz, 3 H); 13C NMR (150 Hz, MeOD): δ 174.30, 147.54, 144.84, 144.22, 143.62, 130.96, 130.08 (2 C), 128.16, 128.03, 127.56, 126.61, 122.96, 66.07, 41.45, 16.32, 14.80 ppm.

    Preparative Example 13: Preparation of 2-benzyl-N-(3-fluoro-4-hydroxyphenyl)-3-hydroxy-N-phenylpropanamide



    [0157] 



    [0158] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-fluorophenol was used instead of 4-bromophenol in step 1 and aniline was used instead of pyridine-3-amine in step 2.
    1H NMR (600 Hz, MeOD): δ 7.75-7.69 (m, 1 H), 7.64-7.59 (m, 1 H), 7.37-7.25 (m, 5 H), 7.23-7.17 (m, 1 H), 7.14-7.02 (m, 3 H), 6.80-6.78 (m, 2 H), 4.28 (t, J = 6.6 Hz, 1 H), 3.88 (t, J = 5.8 Hz, 1 H), 3.63-3.55 (m, 1 H), 2.85-2.76 (m, 1 H), 2.75-2.70 (m, 1 H) ppm.

    Preparative Example 14: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0159] 



    [0160] Unlike Preparative Examples 1∼ 13, when R2 in reaction formula 1 was hydrogen, the target compound was prepared by the same method until step 3 of Preparative Example 1 and thereafter the preparation continued by the following reaction formula A, as shown in Preparative Example 14.



    [0161] The compound of Preparative Example 14 was prepared as follows as shown in reaction formula A.

    Step 1: Preparation of 3-hydroxy-N-(4-(methoxymethoxy)phenyl)-N-phenylpropanamide



    [0162] The compound prepared in step 3 of Preparative Example 1 (0.175g, 0.53 mmol) was dissolved in anhydrous tetrahydrofuran, to which sodium borohydride (0.022 g, 0.58 mmol) was added at 0°C. The temperature was slowly raised to room temperature, during which the mixture was stirred for 24 hours. After confirming the complete consumption of the starting materials, the reaction mixture was filtered and then diluted with dichloromethane, followed by washing with water and saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc: Hex (1:1) as a moving phase to give the target compound (0.124 g, 78%).
    1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 49.2 Hz, 2H), 7.29 (s, 1H), 7.11 (s, 2H), 6.84-6.57 (m, 3H), 3.88 (t, J = 5.4Hz, 2H), 3.64-3.47 (bs 1H), 2.52 (t, J = 5.3 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 173.53, 156.11, 142.40, 134.40, 129.94, 129.69, 128.99, 128.15, 127.85, 126.41, 126.09, 116.65, 116.18, 58.79, 37.08 ppm.

    Step 2: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0163] The final target compound was prepared by the method of step 6 of Preparative Example 1 by using the compound prepared in step 1 above.
    1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 49.2 Hz, 2H), 7.29 (s, 1H), 7.11 (s, 2H), 6.84-6.57 (m, 3H), 3.88 (t, J = 5.4Hz, 2H), 3.64-3.47 (bs 1H), 2.52 (t, J = 5.3 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 173.53, 156.11, 142.40, 134.40, 129.94, 129.69, 128.99, 128.15, 127.85, 126.41, 126.09, 116.65, 116.18, 58.79, 37.08 ppm.

    Preparative Example 15: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-4-methyl-N-phenylpent-4-enamide



    [0164] 



    [0165] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 4-bromo-2-methylbut-1-ene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.44 - 7.36 (m, 1H), 7.34- 7.29 (m, 2H), 7.26 - 7.13 (m, 3H), 7.07 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.82 - 4.78 (m, 1H), 4.75 (d, J = 8.0 Hz, 1H), 3.81 (t, J = 9.5 Hz, 1H), 3.52-3.48 (m, 1H), 3.11 - 3.01 (m, 1H), 2.42-3.24 (m, 1H), 2.12 - 2.02 (m, 1H), 1.49 (d, J = 33.9 Hz, 3H); 13C NMR (150 MHz, MeOD) δ 177.32, 158.66, 144.81, 144.10, 135.54, 131.43, 130.81, 130.09, 129.50, 128.98, 128.10, 127.68, 117.27, 116.74, 113.58, 64.83, 45.09, 39.22, 22.63 ppm.

    Preparative Example 16: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-phenylhex-5-enamide



    [0166] 



    [0167] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 4-bromobut-1-ene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, CDCl3) δ 7.33 - 7.29 (m, 3H), 7.07 - 7.02 (m, 2H), 7.01 (dd, J = 10.2, 3.2 Hz, 1H), 6.95 (dd, J = 10.2, 3.2 Hz, 1H), 6.11-6.02 (m, 2H), 5.88-5.80 (m, 1H), 5.13 - 5.09 (m, 1H), 5.06-5.03 (m, 1H), 4.32 (dd, J = 12.0, 5.3 Hz, 1H), 4.11 (dd, J = 12.1, 6.9 Hz, 1H), 2.79 (m, 1H), 2.32 - 2.19 (m, 2H), 2.17 - 2.07 (m, 1H), 1.83-1.75 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.76, 170.25, 143.88, 143.47, 137.22, 136.31, 129.74 (2 C), 129.55, 129.51, 128.87 (2 C), 128.74, 115.60, 82.97, 63.78, 41.13, 30.94, 27.80 ppm.

    Preparative Example 17: Preparation of 2-(4-chlorobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0168] 



    [0169] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1-(bromomethyl)-4-chlorobenzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.36 - 7.26 (m, 4H), 7.18 (t, J = 7.3 Hz, 1H), 7.13 - 7.02 (m, 4H), 6.90 (d, J = 8.5 Hz, 1H), 6.76 - 6.57 (m, 3H), 3.86 (t, J = 9.2 Hz, 1H), 3.62 - 3.53 (m, 1H), 3.14 - 3.01 (m, 1H), 2.84-2.76 (m, 1H), 2.75 - 2.67 (m, 1H); 13C NMR (150 MHz, MeOD) δ 176.35, 158.50, 144.42, 139.45, 135.09, 133.46, 132.05 (2 C), 131.00, 130.50, 129.98, 129.54 (2 C), 129.17, 128.86, 127.81, 127.63, 116.93, 116.60, 49.31, 36.15, 20.84 ppm.

    Preparative Example 18: Preparation of 2-(3-bromobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0170] 



    [0171] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1,3-dibromobenzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.53 - 7.47 (m, 1H), 7.34 - 7.24 (m, 5H), 7.20 (t, J = 7.4 Hz, 1H), 7.14 - 7.06 (m, 3H), 6.94 - 6.88 (m, 1H), 6.75 - 6.71 (m, 2H), 3.93 - 3.86 (m, 1H), 3.62 (dd, J = 10.6, 6.0 Hz, 1H), 3.16 - 3.01 (m, 1H), 2.83 - 2.70 (m, 2H); 13C NMR (150 MHz, MeOD) δ 176.26, 158.52, 144.43, 143.34, 135.07, 133.53, 131.40, 130.74, 130.53, 130.02 (2C), 129.75, 129.45, 129.27, 127.93 (2C), 123.52, 116.97, 116.63, 64.93, 49.29, 36.58 ppm.

    Preparative Example 19: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-2-(4-nitrobenzyl)-N-phenylpropanamide



    [0172] 



    [0173] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1-bromo-4-nitrobenzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 8.20 (d, J = 8.3 Hz, 2H), 7.39 - 7.25 (m, 5H), 7.17 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.78 - 6.62 (m, 3H), 3.89 (t, J = 9.1 Hz, 1H), 3.65-3.57 (m, 1H), 3.20-3.07 (m, 1H), 3.00-2.93 (m, 1H), 2.92-2.82 (m, 1H); 13C NMR (150 MHz, MeOD) δ 175.89, 158.64, 148.81, 148.31, 144.33, 134.99, 131.54, 130.95, 130.66, 130.04, 129.67, 129.16, 129.03, 127.78, 127.71, 124.62 (2 C), 117.08, 116.66, 64.80, 48.75, 36.56 ppm.

    Preparative Example 20: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-phenyl-2-(2-((phenylsulfonyl)methyl)benzyl)propanamide



    [0174] 



    [0175] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1-(bromomethyl)-2-((phenylsulfonyl)methyl)benzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.89 (s, 1H), 7.75 - 7.58 (m, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.29 - 7.20 (m, 4H), 7.15 (d, J = 7.2 Hz, 2H), 7.08 (dd, J = 20.8, 7.5 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.71 - 6.55 (m, 3H), 4.59 (s, 1H), 4.44 (dd, J = 30.1, 14.2 Hz, 1H), 4.28 (dd, J = 32.0, 14.2 Hz, 1H), 3.79 (t, J = 8.9 Hz, 1H), 3.52 (dd, J = 9.8, 6.8 Hz, 1H), 3.04 - 2.90 (m, 1H), 2.76 - 2.59 (m, 2H); 13C NMR (150 MHz, MeOD) δ 176.21, 158.43, 144.23, 141.19, 139.66, 135.12, 134.94, 133.98, 132.21, 130.87, 130.48, 130.23 (2 C), 129.98, 129.64 (2 C), 129.58, 129.05, 128.87, 128.38, 127.90, 127.71, 127.67, 116.90, 116.59, 64.81, 59.88, 48.84, 33.20 ppm.

    Preparative Example 21: Preparation of 2- (3,5-bis(trifluoromethyl)benzyl)3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0176] 



    [0177] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.93 (s, 1H), 7.73 (s, 1H), 7.69 (s, 1H), 7.27 (dd, J = 10.7, 4.9 Hz, 3H), 7.17 (t, J = 7.4 Hz, 1H), 7.05 - 6.95 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.73-6.57 (m, 3H), 3.94-3.88 (m, 1H), 3.64 (dd, J = 10.6, 6.1 Hz, 1H), 3.21 - 3.06 (m, 1H), 3.03 - 2.90 (m, 2H); 13C NMR (150 MHz, MeOD) δ 175.64, 158.76, 144.18, 144.16, 134.87, 132.99, 132.77, 131.07, 130.71, 130.00 (2 C), 129.47, 129.05, 127.80, 127.69 (2 C), 125.82, 124.02, 121.55, 117.13, 116.61, 64.78, 49.18, 36.39 ppm.

    Preparative Example 22: Preparation of 2- (3,5-dimethylbenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0178] 



    [0179] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1-bromo-3,5-dimethylbenzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.31 - 7.14 (m, 4H), 7.06 (d, J = 7.9 Hz, 1H), 6.94 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 22.0 Hz, 5H), 3.86 (dd, J = 15.9, 7.2 Hz, 1H), 3.58 (dd, J = 10.3, 5.7 Hz, 1H), 3.11 - 2.99 (m, 1H), 2.73 - 2.59 (m, 2H), 2.30 (d, J = 4.3 Hz, 6H) ; 13C NMR (150 MHz, MeOD) δ 175.41, 156.95, 143.17, 138.87, 137.66, 133.79, 129.77, 128.80, 128.51 (2 C), 127.85, 127.60, 127.55, 127.00, 126.98, 126.52 (2 C), 115.25, 115.12, 63.63, 48.10, 35.59, 20.02 (2 C) ppm.

    Preparative Example 23: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-2-(2-nitro-4-(trifluoromethyl)benzyl)-N-phenylpropanamide



    [0180] 



    [0181] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 1-(bromomethyl)-2-nitro-4-(trifluoromethyl)benzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 8.31 (d, J = 7.1 Hz, 1H), 8.05 - 8.01 (m, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.24 (m, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.76-6.53 (m, 3H), 3.89 (dd, J = 10.6, 8.2 Hz, 1H), 3.66 (dd, J = 10.6, 5.6 Hz, 1H), 3.37 - 3.31 (m, 1H), 3.30-3.24 (m, 1H), 3.08 (dd, J = 12.7, 10.4 Hz, 1H); 13C NMR (150 MHz, MeOD) δ 175.71, 158.61, 150.82, 144.26, 140.07, 135.77, 134.84, 130.67, 130.04, 129.11, 129.03, 127.74 (2 C), 125.46, 123.66, 123.42, 117.11, 116.66, 65.11, 48.76, 48.61, 47.50, 33.83 ppm.

    Preparative Example 24: Preparation of 2-(2-fluoro-6-(trifluoromethyl)benzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0182] 



    [0183] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.89 (s, 1H), 7.53 - 7.47 (m, 2H), 7.43 - 7.39 (m, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.24 - 7.14 (m, 4H), 7.03 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 3.93 (m, 1H), 3.54 (m, 1H), 3.27 - 3.21 (m, 1H), 3.20 - 3.13 (m, 1H), 2.83 (t, J = 10.9 Hz, 1H); 13C NMR (150 MHz, MeOD) δ 175.88, 163.88, 158.01, 157.04, 144.17, 134.77, 130.13, 129.71, 129.58 (2 C), 128.76, 128.35, 127.38 (2 C), 127.18, 123.09, 120.33, 120.17, 116.58, 116.22, 64.80, 46.55, 26.15 ppm.

    Preparative Example 25: Preparation of 2-(2-chloro-5-(trifluoromethyl)benzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-phenylpropanamide



    [0184] 



    [0185] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 2-(bromomethyl)-1-chloro-4-(trifluoromethyl)benzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.61-7.58 (m, 3H), 7.32 - 7.26 (m, 3H), 7.17 (dd, J = 9.3, 1H), 7.09 - 7.04 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 3.97 - 3.85 (m, 1H), 3.73 - 3.51 (m, 1H), 3.39 - 3.31 (m, 1H), 3.04 (m, 1H), 2.97 - 2.86 (m, 1H); 13C NMR (150 MHz, MeOD) δ 174.52, 157.17, 156.12, 142.84, 138.12, 133.48, 130.30, 129.22, 128.87, 128.52 (2 C), 128.11, 127.68, 127.51, 126.34 (2 C), 126.31, 124.88, 115.65, 115.12, 63.49, 44.81, 33.30 ppm.

    Preparative Example 26: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-2-methyl-N-(pyrodi-3-nyl)propanamide



    [0186] 



    [0187] The target compound was prepared by the same manner as described in Preparative Example 1 except that iodomethane was used instead of benzylbromide in step 4.
    1H NMR (600 Hz, MeOD): δ 8.43 (s, 1 H), 8.24 (s, 1 H), 7.71-7.52 (m, 1 H), 7.42-7.33 (m, 1 H), 7.22-7.04 (m, 2 H), 6.81-6.64 (m, 2 H), 3.72-3.63 (m, 1 H), 3.38-3.34 (m, 1 H), 2.73-2.92 (m, 1 H), 0.87 (d, J = 1.7 Hz, 3 H); 13C NMR (125 MHz, MeOD) : 177.15, 157.75, 146.90, 145.78, 140.40, 134.47, 132.99, 129.82 (2 C), 123.93, 116.20 (2 C), 64.53, 39.92, 13.12 ppm.

    Preparative Example 27: Preparation of N-(4-hydroxy-3-methylphenyl)-2-(hydroxymethyl)-4-methyl-N-phenylpent-4-enamide



    [0188] 



    [0189] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-fluorophenol was used instead of 4-bromophenol in step 1, aniline was used instead of pyridine-3-amine in step 2, and 2-methyl-allylbromide was used instead of benzylbromide in step 4.
    1H NMR (600 Hz, MeOD): δ 7.44-7.16 (m, 5 H), 7.12-6.95 (m, 2 H), 6.79-6.67 (m, 1 H), 4.82-4.79 (s, 1 H), 4.76-4.72 (m, 1 H), 3.83-3.76 (m, 1 H), 3.52-3.46 (m, 1 H), 3.09-3.02 (m, 1 H),2.41-2.34 (m, 1 H), 2.18-2.12 (m, 3 H), 2.09-2.05(m, 1 H), 1.54-1.45 (m, 3 H); 13C NMR (150 Hz, MeOD): δ 177.35, 145.03, 144.23, 138.88, 138.52, 130.79, 130.12, 130.06 (2 C), 128.09 (2 C), 127.62, 116.22, 113.58 (2 C), 64.88, 45.15, 39.22, 22.57, 16.31 ppm.

    Preparative Example 28: Preparation of N-(3-fluoro-4-hydroxyphenyl)-2-(hydroxymethyl)-N-phenylpent-4-enamide



    [0190] 



    [0191] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-fluorophenol was used instead of 4-bromophenol in step 1, aniline was used instead of pyridine-3-amine in step 2, and 4-bromo-butyl-1-ene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.47 - 7.26 (m, 3H), 7.24 (s, 1H), 7.21 (d, J = 7.6 Hz, 2H), 6.83 -6.74 (m, 2H), 5.80-5.77 (m, 1H), 5.08-5.06 (t, J = 12.6 Hz, 2H), 3.79-3.76 (m, 1H), 3.52 (dd, J = 10.2, 5.5 Hz, 1H), 3.01 - 2.88 (m, 1H), 2.39-2.27 (m, 1H), 2.20-2.14 (m, 1H); 13C NMR (150 MHz, MeOD) δ 177.54, 154.62, 158.46, 144.75, 136.54, 135.36, 131.24, 130.60, 130.08 (2 C), 129.36, 128.09 (2 C), 116.61, 116.54, 64.52, 46.54, 35.12 ppm.

    Preparative Example 29: Preparation of N-(4-hydroxy-3-methylphenyl)-2-(hydroxymethyl)-N-phenylpent-4-enamide



    [0192] 



    [0193] The target compound was prepared by the same manner as described in Preparative Example 1 except that 4-bromo-2-methylphenyl was used instead of 4-bromophenol in step 1, aniline was used instead of pyridine-3-amine in step 2, and 4-bromo-butyl-1-ene was used instead of benzylbromide in step 4.
    1H NMR (600 Hz, MeOD): δ 7.45-7.36 (m, 1 H), 7.35-7.27 (m, 2 H), 7.26-7.24 (m, 2 H), 7.05-6.86 (m, 2 H), 6.76-6.61 (m, 1 H), 5.78-5.53 (m, 1 H), 5.42-5.29 (m, 1 H), 5.13-5.02 (m, 2H), 3.83-3.70 (m, 2 H), 2.93-2.80 (m, 2 H), 2.50-2.39 (m, 1 H), 2.36-2.26 (m, 1 H), 2.25-2.12 (m, 3 H); 13C NMR (150 Hz, MeOD): δ 178.60, 140.45, 139.06, 136.41, 133.35, 132.50, 131.52, 129.98, 129.17, 127.90, 124.97, 122.49, 120.97, 110.36, 110.02, 77.93, 38.97, 30.89, 21.16 ppm.

    Preparative Example 30: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N,2-dimethylpropanamide



    [0194] 



    [0195] The target compound was prepared by the same manner as described in step 5 and step 6 except that iodomethane was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.13 - 7.11 (m, 2H), 6.86 (d, J = 8.9 Hz, 2H), 3.71 (dd, J = 10.5, 8.3 Hz, 1H), 3.37 (dd, J = 10.5, 5.8 Hz, 1H), 3.22 (s, 3H), 2.74 - 2.68 (m, 1H), 0.96 (d, J = 6.9 Hz, 3H); 13C NMR (150 MHz, MeOD) δ 176.43, 157.13, 135.14, 128.20 (2 C), 115.86 (2 C), 64.37, 39.08, 36.65, 13.13 ppm.

    Preparative Example 31: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-methylpent-4-enamide



    [0196] 



    [0197] The target compound was prepared by the same manner as described in step 5 and step 6 except that 3-bromo-pro-1-pene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.10 (d, J = 8.5 Hz, 2H), 6.87 - 6.83 (m, 2H), 5.66 - 5.59 (m, 1H), 5.03 - 4.97 (m, 2H), 3.71 (dd, J = 10.6, 8.3 Hz, 1H), 3.49 - 3.44 (m, 1H), 3.22 (s, 3H), 2.79 - 2. 74 (m, 1H), 2.25 - 2.20 (m, 1H), 2.13 - 2.08 (m, 1H); 13C NMR (150 MHz, MeOD) δ 175.02, 157.08, 135.26 (2 C), 134.99, 128.63, 115.74, 115.72 (2 C), 63.08, 44.67, 36.72, 33.47 ppm.

    Preparative Example 32: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-methylhex-5-enamide



    [0198] 



    [0199] The target compound was prepared by the same manner as described in step 5 and step 6 except that 4-bromo-butyl-1-ene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, CDCl3) δ 7.05 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.61 - 5.54 (m, 1H), 4.91 - 4.85 (m, 2H), 3.74 - 3.66 (m, 1H), 3.27 (s, J = 4.6 Hz, 3H), 2.69 - 2.65 (m, 1H), 1.95 - 1.88 (m, 2H), 1.70 - 1.55 (m, 2H) ; 13C NMR (150 MHz, CDCl3) δ 176.34, 156.20, 137.55, 135.52, 128.68, 116.50 (2 C), 115.10 (2 C), 63.27, 42.61, 37.79, 31.59, 31.12 ppm.

    Preparative Example 33: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N,4-dimethylpent-4-enamide



    [0200] 



    [0201] The target compound was prepared by the same manner as described in step 5 and step 6 except that 3-bromo-2-methylpro-1-pene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.09 (d, J = 7.5 Hz, 2H), 6.85 - 6.82 (m, 2H), 4.70 (s, 1H), 4.63 (s, 1H), 3.73 - 3.68 (m, 1H), 3.42 (dd, J = 10.5, 5.4 Hz, 1H), 3.20 (s, 3H), 2.90 - 2.84 (m, 1H), 2.23 (dd, J = 13.4, 8.1 Hz, 1H), 1.99 (dd, J = 13.4, 6.2 Hz, 1H), 1.45 (s, 3H) ; 13C NMR (150 MHz, MeOD) δ 174.11, 155.79, 141.30, 133.70, 127.35, 114.45 (2C), 110.44 (2C), 61.86, 41.89, 36.05, 35.46, 19.70 ppm.

    Preparative Example 34: Preparation of 2-(4-fluorobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-methylpropanamide



    [0202] 



    [0203] The target compound was prepared by the same manner as described in step 5 and step 6 except that 1-(bromomethyl)-4-fluorobenzene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.03 - 6.99 (m, 4H), 6.83 - 5.86 (m, 4H), 3.77 (dd, J = 10.6, 8.1 Hz, 1H), 3.50 (dd, J = 10. 6, 5.9 Hz, 1H), 3.11 (s, 3H), 2.92 - 2.88 (m, 1H), 2.74 (dd, J = 13.1, 10.1 Hz, 1H), 2.63 (dd, J = 13.1, 4.9 Hz, 1H) ; 13C NMR (150 MHz, MeOD) δ 174.64, 162.51, 160.90, 156.94, 135.29, 135.27, 134.65, 130.40, 130.35, 128.33, 115.51, 114.62, 114.48, 63.25, 47.46, 36.60, 34.38 ppm.

    Preparative Example 35: Preparation of 2-(4-bromobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-methylpropanamide



    [0204] 



    [0205] The target compound was prepared by the same manner as described in step 5 and step 6 except that 1-(bromomethyl)-4-bromobenzene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.47 - 7.36 (m, 2H), 6.96 - 6.92 (m, 2H), 6.85 - 6.47 (bs, 3H), 5.97 (bs, 1H), 3.77 (dd, J = 10.6, 8.0 Hz, 1H), 3.50 (dd, J = 10.6, 5.9 Hz, 1H), 3.11 (s, 3H), 2.91 - 2.86 (m, 1H), 2.73 (dd, J = 13.0, 10.2 Hz, 1H), 2.62 (dd, J = 13.0, 4.8 Hz, 1H) ; 13C NMR (150 MHz, MeOD) δ 174.49, 156.94, 138.64, 134.59, 131.07 (2C), 130.73 (2C), 128.27, 119.71 (2C), 115.52 (2C), 78.07, 63.25, 36.62, 34.61 ppm.

    Preparative Example 36: Preparation of 2-(4-cyanobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-methylpropanamide



    [0206] 



    [0207] The target compound was prepared by the same manner as described in step 5 and step 6 except that 1-(bromomethyl)-4-thianobenzene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.65 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.86 - 6.57 (bs, 4H), 3.81 - 3.76 (m, 1H), 3.52 (dd, J = 10.6, 6.0 Hz, 1H), 3.11 (s, 3H), 2.96 - 2.91 (m, 1H), 2.85 (dd, J = 12.8, 10.1 Hz, 1H), 2.75 (dd, J = 12.8, 4.7 Hz, 1H); 13C NMR (150 MHz, MeOD) δ 174.07, 157.03, 145.50, 134.47, 131.91 (2 C), 129.84 (2 C), 128.23, 118.36 (2 C), 115.59 (2 C), 109.88, 63.18, 47.14, 36.61, 35.23 ppm.

    Preparative Example 37: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-methyl-2-(2-((phenylsulfonyl)methyl)benzyl)propanamide



    [0208] 



    [0209] The target compound was prepared by the same manner as described in step 5 and step 6 except that 1-(chloromethyl)-2-(phenylsulfonyl)benzene was used instead of benzylbromide in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.77 - 7.64 (m, 4H), 7.57 - 7.51 (m, 2H), 7.31 - 7.17 (m, 3H), 7.11 (dd, J = 13.0, 6.2 Hz, 1H), 7.01 (dd, J = 28.5, 7.6 Hz, 1H), 6.78 - 6.49 (m, 2H), 4.46 (d, J = 14.2, 6.2 Hz, 1H), 4.29 (d, J = 14.2 Hz, 1H), 3.70 (dd, J = 10.5, 7.5 Hz, 1H), 3.45 (dd, J = 10.6, 6.4 Hz, 1H), 3.04 (s, J = 4.8 Hz, 3H), 2.82 - 2.76 (m, 1H), 2.66 (dd, J = 13.8, 10.6 Hz, 1H), 2.58 (dd, J = 13.8, 4.2 Hz, 1H); 13C NMR (150 MHz, MeOD) δ 174.42, 156.87, 139.94, 138.33, 134.46, 133.71, 132.47, 130.51, 128.85 (2 C), 128.75(2C), 128.26 (2 C), 126.82, 126.29 (2 C), 115.52 (2 C), 63.23, 58.33, 46.82, 36.57, 31.63 ppm.

    Preparative Example 38: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-phenylpen-4-tinamide



    [0210] 



    [0211] The target compound was prepared by the same manner as described in Preparative Example 1 except that aniline was used instead of pyridine-3-amine in step 2 and 2-(bromomethyl)-1-chloro-4-(trifluoromethyl)benzene was used instead of benzylbromide in step 4.
    1H NMR (600 MHz, MeOD) δ 7.51 - 7.43 (m, 1H), 7.40 - 7.27 (m, 4H), 7.22 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 3.80 (dd, J = 10.6, 7.7 Hz, 1H), 3.69 - 3.50 (m, 1H), 3.18 - 2.99 (m, 1H), 2.48 (dd, J = 16.5, 9.1 Hz, 1H), 2.44 (d, J = 16.7 Hz, 1H), 2.39 - 2.29 (m, 1H); 13C NMR (150 MHz, MeOD) δ 174.41, 157.25, 143.18, 133.97 (2 C), 129.96 (2 C), 128.60, 127.61, 126.53, 126.23, 115.80, 115.24, 80.96, 69.91, 62.72, 44.53, 18.14 ppm.

    Preparative Example 39: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-isopropyl-2-methylpropanamide



    [0212] 



    [0213] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and iodomethane was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.06 - 7.00 (m, 2H), 6.89 - 6.85 (m, 2H), 4.94 - 4.91 (m, 1H), 3.71 (dd, J = 10.5, 8.1 Hz, 1H), 3.35 (dd, J = 10.5, 5.9 Hz, 1H), 2.52 - 2.45 (m, 1H), 1.05 (dd, J = 9.3, 6.8 Hz, 6H), 0.94 (d, J = 6.9 Hz, 3H) ; 13C NMR (150 MHz, MeOD) δ 175.88, 157.47, 131.60, 130.61, 129.06, 115.49, 115.17, 64.35, 45.97, 40.04, 19.86, 19.79, 13.23 ppm.

    Preparative Example 40: Preparation of 2-(hydroxymethyl)-N-(4-hydroxyphenyl)-N-isopropylpent-4-enamide



    [0214] 



    [0215] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 3-bromopro-1-pane was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.05 - 7.02 (m, 1H), 6.98 - 6.96 (m, 1H), 6.88 - 6.84 (m, 2H), 5.66 - 5.59 (m, 1H), 5.02 - 4.97 (m, 2H), 4.95 - 4.91 (m, 1H), 3.70 (dd, J = 10.6, 8.1 Hz, 1H), 3.43 (dd, J = 10.6, 5.8 Hz, 1H), 2.56 - 2.52 (m, 1H), 2.25 - 2.19 (m, 1H), 2.12 - 2.06 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, MeOD) δ 174.36, 157.43, 135.35, 131.84, 131.24, 128.90, 115.71, 115.38, 114.95, 63.08, 46.15, 45.52, 33.57, 20.10, 19.72 ppm.

    Preparative Example 41: Preparation of 2-(4-fluorobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-isopropylpropanamide



    [0216] 



    [0217] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 1-bromo-4-fluorobenzene was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.06 - 6.92 (m, 5H), 6.79 (dd, J = 8.5, 2.8 Hz, 1H), 6.57 (dd, J = 8.5, 2.8 Hz, 1H), 5.70 (dd, J = 8.5, 2.6 Hz, 1H), 4.88 - 4.86 (m, 1H).3.74 (dd, J = 10.5, 7.5 Hz, 1H), 3.48 (dd, J = 10.6, 5.8 Hz, 1H), 2.78 - 2.72 (m, 1H), 2.70 - 2.59 (m, 2H), 0.96 - 0.87 (m, 6H) ; 13C NMR (150 MHz, MeOD) δ 173.94, 162.54, 160.93, 157.27, 135.39, 131.65, 130.80, 130.66, 128.48, 115.16, 114.71, 114.56, 114.42, 63.35, 48.55, 46.00, 34.44, 19.82, 19.63 ppm.

    Preparative Example 42: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-isopropyl-2-(4-(trifluoromethyl)benzyl)propanamide



    [0218] 



    [0219] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 1-bromo-4-(trifluoromethyl)benzene was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.59 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.95 (dd, J = 8.5, 2.6 Hz, 1H), 6.79 (dd, J = 8.5, 2.9 Hz, 1H), 6.51 (dd, J = 8.5, 2.9 Hz, 1H), 5.57 (dd, J = 8.5, 2.6 Hz, 1H), 4.89 - 4.85 (m, 1H), 3.79 - 3.75 (m, 1H), 3.53 - 3.50 (m, 1H), 2.88 - 2.83 (m, 1H), 2.76 - 2.72 (m, 1H), 2.72 - 2.66 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H); 13C NMR (150 MHz, MeOD) δ 173.62, 157.31, 144.26, 131.69, 130.49, 129.65 (2 C), 128.55, 128.37, 128.34, 124.84, 124.81, 115.24, 114.66, 63.34, 48.37, 46.11, 35.06, 19.80, 19.58 ppm.

    Preparative Example 43: Preparation of 2-(4-cyanobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-isopropylpropanamide



    [0220] 



    [0221] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 4-bromobenzonitrile was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.68 - 7.65 (m, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.97 (dd, J = 8.5, 2.6 Hz, 1H), 6.80 (dd, J = 8.5, 2.9 Hz, 1H), 6.59 (dd, J = 8.5, 2.9 Hz, 1H), 5.73 (dd, J = 8.5, 2.6 Hz, 1H), 4.86 (dd, J = 13.6, 6.8 Hz, 1H), 3.76 (dd, J = 10.6, 7.5 Hz, 1H), 3.50 (dd, J = 10.6, 6.3 Hz, 1H), 2.86 (dd, J = 12.7, 10.4 Hz, 1H), 2.77 - 2.67 (m, 2H), 0.94 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H) ; 13C NMR (150 MHz, MeOD) δ 173.40, 157.40, 145.63, 131.85 (2 C), 131.69, 130.50, 130.10 (2 C), 128.37, 118.35, 115.31, 114.78, 109.87, 63.26, 48.09, 46.17, 35.28, 19.87, 19.59 ppm.

    Preparative Example 44: Preparation of 2-(2-fluoro-6-(trifluoromethyl)benzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-isopropylpropanamide



    [0222] 



    [0223] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 2-bromo-1-fluoro-3-(trifluoromethyl)benzene was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.54 - 7.49 (m, 2H), 7.38 - 7.34 (m, 1H), 6.93 (dd, J = 8.5, 2.6 Hz, 1H), 6.78 (dd, J = 8.5, 2.9 Hz, 1H), 6.41 (dd, J = 8.5, 2.9 Hz, 1H), 5.68 (dd, J = 8.5, 2.6 Hz, 1H), 4.94 -4.91 (m, 1H), 3.84 (dd, J = 10.4, 9.1 Hz, 1H), 3.47 (dd, J = 10.6, 5.5 Hz, 1H), 3.08 (dd, J = 13.8, 9.7 Hz, 1H), 2.87 - 2.82 (m, 1H), 2.75 (d, J = 14.0 Hz, 1H), 0.96 (dd, J = 6.7, 5.4 Hz, 6H) ; 13C NMR (150 MHz, MeOD) δ 173.87, 162.86, 161.22, 157.10, 131.92, 130.11, 128.46, 128.39, 125.60, 121.81, 119.15, 118.99, 115.24, 114.57, 63.72, 46.14, 45.89, 24.99, 19.78, 19.51 ppm.

    Preparative Example 45: Preparation of 2-(3-bromobenzyl)-3-hydroxy-N-(4-hydroxyphenyl)-N-isopropylamide



    [0224] 



    [0225] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 1,3-dibromobenzene was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 7.45 (dd, J = 8.0, 0.9 Hz, 1H), 7.23 - 7.20 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 (dd, J = 8.5, 2.6 Hz, 1H), 6.79 (dd, J = 8.5, 2.9 Hz, 1H), 6.59 (dd, J = 8.5, 2.9 Hz, 1H), 5.57 (dd, J = 8.5, 2.6 Hz, 2H), 4.86 - 4.85 (m, 1H), 4.84 - 4.81 (m, 1H), 3.75 (dd, J = 10.6, 7.4 Hz, 2H), 3.50 (dd, J = 10.6, 5.9 Hz, 2H), 2.77 - 2.70 (m, 1H), 2.69 - 2.62 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H) ; 13C NMR (150 MHz, MeOD) δ 173.65, 157.30, 142.14, 132.02, 131.61, 130.77, 129.81, 129.09, 128.34, 127.95, 121.90, 115.17, 114.72, 63.41, 48.43, 46.03, 34.92, 19.93, 19.59 ppm.

    Preparative Example 46: Preparation of 3-hydroxy-N-(4-hydroxyphenyl)-N-isopropyl-2-(4-nitrobenzyl)propanamide



    [0226] 



    [0227] The target compound was prepared by the same manner as described in step 5 and step 6 except that 2-iodopropane was used instead of iodomethane in step 3 of reaction formula 4 of Preparative Example 4 and 1-bromo-4-nitrobenzene was used instead of benzylbromode in step 4 of Preparative Example 1.
    1H NMR (600 MHz, MeOD) δ 8.18 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.98 (dd, J = 8.5, 2.6 Hz, 1H), 6.81 (dd, J = 8.5, 2.9 Hz, 1H), 6.57 (dd, J = 8.5, 2.9 Hz, 1H), 5.76 (dd, J = 8.5, 2.6 Hz, 1H), 4.87 - 4.84 (m, 1H), 3.77 (dd, J = 10.6, 7.5 Hz, 1H), 3.51 (dd, J = 10.6, 6.3 Hz, 1H), 2.91 (dd, J = 12.8, 10.4 Hz, 1H), 2.80 (dd, J = 12.8, 4.5 Hz, 1H), 2.76 - 2.69 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H) ; 13C NMR (150 MHz, MeOD) δ 173.34, 157.42, 147.63, 146.76, 131.69, 130.48, 130.09 (2 C), 128.37, 123.03 (2 C), 115.35, 114.81, 63.25, 48.08, 46.22, 34.97, 19.88, 19.58 ppm.

    [0228] Based on the above Preparative Examples 1 ∼ 46, the compounds of Examples 1 ∼ 49 were prepared by cyclization.

    Example 1: Preparation of 5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0229] 



    [0230] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 14 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.37 - 7.29 (m, 3H), 7.09-7.04 (m, 2H), 7.02 - 6.93 (m, 2H), 6.09 (d, J = 10.2 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 183.94, 167.19, 143.71 (2 C), 136.32, 129.87 (2 C), 129.81 (2 C), 129.14, 129.09, 129.02, 83.07, 60.26, 32.82 ppm.

    Example 2: Preparation of 3-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0231] 



    [0232] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 5 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.11 - 7.05 (m, 2H), 6.94 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.2, 2.0 Hz, 1H), 6.08 (dd, J = 10.2, 2.0 Hz, 1H), 4.32 (dd, J = 11.9, 5.5 Hz, 1H), 4.06 (dd, J = 11.9, 7.8 Hz, 1H), 2.98 - 2.88 (m, 1H), 1.39 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 184.09, 171.21, 144.51, 143.52, 136.60, 130.05, 129.81, 129.79, 129.17, 129.11, 129.05, 120.02, 83.53, 66.14, 37.29, 13.72 ppm.

    Example 3: Preparation of 3-allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0233] 



    [0234] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 6 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.34 - 7.29 (m, 3H), 7.06 - 7.03 (m, 2H), 7.01 (dd, J = 10.2, 3.2 Hz, 1H), 6.95 (dd, J = 10.2, 3.2 Hz, 1H), 6.12-6.03 (m, 2H), 5.91 - 5.80 (m, 1H), 5.23-5.14 (m, 2H), 4.29 (dd, J = 12.2, 5.5 Hz, 1H), 4.13 (dd, J = 12.2, 7.0 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.75 - 2.69 (m, 1H), 2.57 - 2.50 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.84, 169.72, 143.89, 143.52, 136.34, 135.13, 134.44, 129.76, 129.64, 128.97, 128.87, 124.29, 119.91, 118.19, 117.60, 83.11, 63.33, 41.24, 33.09 ppm.

    Example 4: Preparation of 3-(2-methyl-allyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0235] 



    [0236] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 15 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.32 - 7.29 (m, 3H), 7.06 - 7.02 (m, 2H), 7.01 (dd, J = 10.0, 3.2 Hz, 1H), 6.97 (dd, J = 10.0, 3.1 Hz, 1H), 6.11 - 6.05 (m, 2H), 4.86 (d, J = 44.8 Hz, 2H), 4.25 (dd, J = 12.2, 5.2 Hz, 1H), 4.08 (dd, J = 12.2, 6.6 Hz, 1H), 2.95 - 2.88 (m, 1H), 2.78 (dd, J = 14.1, 3.7 Hz, 1H), 2.41 (dd, J = 14.0, 11.0 Hz, 1H), 1.79 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.95, 170.25, 143.97, 143.73, 141.82, 136.49, 129.90, 129.75, 129.06, 128.94, 113.59, 83.23, 77.25, 77.04, 76.83, 63.35, 39.85, 37.10, 21.92 ppm.

    Example 5: Preparation of 3-(3-butenyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0237] 



    [0238] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 16 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.33 - 7.29 (m, 3H), 7.07 - 7.02 (m, 2H), 7.01 (dd, J = 10.2, 3.2 Hz, 1H), 6.95 (dd, J = 10.2, 3.2 Hz, 1H), 6.11-6.02 (m, 2H), 5.88-5.80 (m, 1H), 5.13 - 5.09 (m, 1H), 5.06-5.03 (m, 1H), 4.32 (dd, J = 12.0, 5.3 Hz, 1H), 4.11 (dd, J = 12.1, 6.9 Hz, 1H), 2.79 (m, 1H), 2.32 - 2.19 (m, 2H), 2.17 - 2.07 (m, 1H), 1.83-1.75 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.76, 170.25, 143.88, 143.47, 137.22, 136.31, 129.74 (2 C), 129.55, 129.51, 128.87 (2 C), 128.74, 115.60, 82.97, 63.78, 41.13, 30.94, 27.80 ppm.

    Example 6: Preparation of 3-benzyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0239] 



    [0240] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 3 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.39 - 7.26 (m, 8H), 7.05 - 7.01 (m, 2H), 6.92 (dd, J = 10.4, 3.2 Hz, 1H), 6.66 (dd, J = 10.4, 3.2 Hz, 1H), 6.05-5.99 (m, 1H), 4.18 (dd, J = 12.2, 5.2 Hz, 1H), 4.06 (dd, J = 12.2, 6.4 Hz, 1H), 3.29 (dd, J = 13.2, 3.5 Hz, 1H), 3.16 - 3.01 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 183.87, 169.67, 143.76, 143.57, 138.02, 136.42, 129.84, 129.72, 129.68, 129.40, 129.06, 128.97, 128.93, 128.90, 128.78, 128.67, 126.87, 120.08, 83.16, 63.10, 43.37, 34.94 ppm.

    Example 7: Preparation of 3-(4-fluoro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0241] 



    [0242] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 8 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.34-7.29 (m, 3H), 7.27-7.21 (m, 2H), 7.08-6.97 (m, 4H), 6.92 (dd, J = 10.3, 2.9 Hz, 1H), 6.73 - 6.68 (m, 1H), 6.04 (d, J = 10.2 Hz, 2H), 4.18 (dd, J = 12.2, 5.2 Hz, 1H), 4.04 (dd, J = 12.2, 6.5 Hz, 1H), 3.25 (dd, J = 13.7, 3.8 Hz, 1H), 3.11-3.05 (m, 1H), 3.04-2.98 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.65, 169.37, 162.46, 160.84, 143.51, 143.24, 136.16, 133.49, 130.72, 130.67, 129.66 (2 C), 129.60, 128.93 (2 C), 128.87, 115.42, 115.28, 83.05, 62.81, 43.28, 33.89 ppm.

    Example 8: Preparation of 3-(4-chloro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0243] 



    [0244] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 17 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.

    1H NMR (600 MHz, CDCl3) δ 7.38-7.29 (bs, 5H), 7.22 (d, J = 7.8 Hz, 2H), 7.04-6.94 (bs, 2H), 6.92 (d, J = 9.8 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H), 6.05 (d, J = 10.1 Hz, 2H), 4.18 (dd, J = 12.2, 4.2 Hz, 1H), 4.02 (dd, J = 11.8, 6.3 Hz, 1H), 3.25 (d, J = 13.2 Hz, 1H), 3.08-2.97 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 183.86, 169.54, 143.70, 143.41, 136.55, 136.34, 132.80, 130.76 (2 C), 129.90, 129.87 (2 C), 129.84, 129.16 (2 C), 129.11, 128.87 (2 C), 83.30, 62.99, 43.39, 34.23 ppm.

    Example 9: Preparation of 3-(3-bromo-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0245] 



    [0246] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 18 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.2 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.33 - 7.29 (m, 3H), 7.24 - 7.19 (m, 2H), 7.04 - 7.01 (m, 2H), 6.93 (dd, J = 10.4, 3.2 Hz, 1H), 6.69 (dd, J = 10.4, 3.2 Hz, 1H), 4.19 (dd, J = 12.3, 5.1 Hz, 1H), 4.03 (dd, J = 12.3, 6.3 Hz, 1H), 3.25 (dd, J = 12.7, 3.0 Hz, 1H), 3.09 - 2.99 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 183.81, 169.37, 143.62, 143.37, 140.47, 136.29, 132.28, 130.25, 130.06, 129.88 (2C), 129.85, 129.80, 129.11 (2C), 129.06, 128.06, 122.75, 83.25, 63.00, 43.21, 34.58 ppm.

    Example 10: Preparation of 3-(4-bromo-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0247] 



    [0248] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 9 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H-NMR (600 MHz, CDCl3) δ 7.54 -7.49 (m, 1 H), 7.47 -7.43 (m, 1 H), 7.42-7.35 (m, 5 H), 7.31-7.26 (m, 2 H), 7.14-7.06 (m, 2 H), 6.72 (d, J = 10.5 Hz 1 H), 6.03 (d, J = 10.3 Hz 1 H), 4.21-4.13 (m, 1 H), 4.07-3.96 (m, 2 H), 3.08-2.99 (m, 2 H), 2.87 -2.78 (m, 1 H) ppm.

    Example 11: Preparation of 3-(4-trifluoromethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0249] 



    [0250] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 7 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.3 Hz, 2H), 7.32 (bs, 3H), 7.16 (d, J = 7.5 Hz, 2H), 7.02 (bs, 2H), 6.92 (d, J = 10.4 Hz, 1H), 6.74 (d, J = 10.0 Hz, 1H), 6.05 (d, J = 10.1 Hz, 2H), 4.17 (d, J = 11.0 Hz, 1H), 4.05-3.99 (m, 1H), 3.24 (d, J = 12.2 Hz, 1H), 3.09 - 2.97 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 183.84, 169.49, 143.68, 143.38, 137.07, 136.63, 136.32, 131.82 (2 C), 131.12 (2 C), 129.89, 129.86 (2 C), 129.84, 129.15 (2 C), 129.10, 120.82, 83.29, 62.98, 43.33, 34.27 ppm.

    Example 12: Preparation of 3-(4-nitro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0251] 



    [0252] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 19 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.40-7.29 (m, 3H), 7.02 (d, J = 3.4 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 9.7 Hz, 1H), 6.07 (d, J = 10.1 Hz, 2H), 4.21 (dd, J = 12.1, 5.0 Hz, 1H), 4.02 (dd, J = 12.1, 6.8 Hz, 1H), 3.41 (dd, J = 13.6, 3.9 Hz, 1H), 3.17 (dd, J = 13.4, 9.3 Hz, 1H), 3.14-3.07 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 183.73, 169.13, 146.05, 143.50, 143.05, 136.16, 130.24 (2 C), 130.07, 130.03, 129.94, 129.84 (2 C), 129.25, 129.24, 129.09, 123.97 (2 C), 83.44, 63.00, 43.30, 34.65 ppm.

    Example 13: Preparation of 3-(2-((phenylsulfonyl)methyl)-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0253] 



    [0254] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 20 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.0 Hz, 2H), 7.63 (t, J = 6.5 Hz, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.41 - 7.27 (m, 5H), 7.25 - 7.16 (m, 2H), 7.05 (s, 2H), 6.98 (d, J = 10.1 Hz, 1H), 6.91 (d, J = 10.0 Hz, 1H), 6.10 - 6.06 (m, 2H), 4.53 (s, 2H), 4.20 (d, J = 11.9 Hz, 1H), 4.03 (d, J = 11.5 Hz, 1H), 3.31 (d, J = 12.4 Hz, 1H), 3.04 - 2.92 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 183.88, 169.82, 143.87, 143.35, 138.89, 138.63, 136.32, 133.88, 132.93, 130.58, 129.95 (3 C), 129.85, 129.31, 129.14 (2 C), 129.10 (2 C), 128.54 (2 C), 127.20 (2 C), 126.82, 83.37, 62.91, 59.33, 43.46, 31.61 ppm.

    Example 14: Preparation of 3-(3,5-ditrifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0255] 



    [0256] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 21 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.76 (s, 2H), 7.36 - 7.29 (m, 3H), 7.05 - 6.98 (m, 2H), 6.94 (dd, J = 10.0, 3.1 Hz, 1H), 6.74 (dd, J = 10.0, 2.8 Hz, 1H), 6.07 (t, J = 10.3 Hz, 2H), 4.23 (dd, J = 12.3, 5.1 Hz, 1H), 4.03 (dd, J = 12.2, 6.7 Hz, 1H), 3.43 (dd, J = 14.0, 4.3 Hz, 1H), 3.21 (dd, J = 14.0, 8.8 Hz, 1H), 3.15 - 3.07 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.68, 168.93, 143.36, 142.95, 140.91, 136.08, 132.38, 132.16, 131.94, 131.72, 130.05, 129.81, 129.48, 129.46, 129.23, 129.21, 125.92, 124.11, 122.30, 121.03, 83.43, 62.93, 43.23, 34.55 ppm.

    Example 15: Preparation of 3-(3,5-dimethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0257] 



    [0258] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 22 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.34 (s, 3H), 7.05 (d, J = 1.6 Hz, 2H), 6.98 - 6.86 (m, 4H), 6.75 (d, J = 10.3 Hz, 1H), 6.06 (d, J = 9.9 Hz, 2H), 4.19 (d, J = 12.2 Hz, 1H), 4.10 - 4.05 (m, 1H), 3.25 (d, J = 11.4 Hz, 1H), 3.07 - 2.98 (m, 2H), 2.34 (s, 6H) ; 13C NMR (150 MHz, CDCl3) δ 183.94, 169.63, 143.89, 143.77, 138.25, 137.94, 136.52, 129.92 (2C), 129.74, 129.70, 129.09 (2C), 129.00, 128.47 (2 C), 127.19 (2C), 83.20, 63.12, 43.45, 34.79, 21.29 (2C) ppm.

    Example 16: Preparation of 3-(2-nitro-4-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0259] 



    [0260] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 23 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 0.9 Hz, 1H), 7.82 (dd, J = 8.1, 1.5 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.37 - 7.31 (m, 3H), 7.09 (dd, J = 10.3, 3.2 Hz, 1H), 7.06-70.2 (m, 2H), 6.94 (d, J = 3.2 Hz, 1H), 6.15 (dd, J = 10.3, 2.0 Hz, 1H), 6.09 (dd, J = 10.2, 2.0 Hz, 1H), 4.43 (dd, J = 12.1, 5.1 Hz, 1H), 4.21 (dd, J = 12.1, 6.9 Hz, 1H), 3.74 (dd, J = 13.5, 8.0 Hz, 1H), 3.26 (dd, J = 13.5, 5.9 Hz, 1H), 3.23 - 3.13 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.78, 169.20, 149.09, 143.51, 143.22, 138.41, 136.00, 134.36, 130.79, 130.57, 130.07, 130.05, 129.90, 129.61, 129.58, 129.20, 129.17, 122.46, 122.44, 83.53, 64.10, 43.41, 32.16 ppm.

    Example 17: Preparation of 3-(2-fluoro-6-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0261] 



    [0262] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 24 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 1H), 7.35 (m, 1H), 7.31 - 7.26 (m, 4H), 7.11 - 7.03 (m, 3H), 6.95 (dd, J = 10.2, 3.2 Hz, 1H), 6.10 (dd, J = 10.2, 2.0 Hz, 1H), 6.06 (dd, J = 10.2, 2.0 Hz, 1H), 4.15 (m, 2H), 3.74 (m, 1H), 3.22 - 3.15 (m, 1H), 3.07 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 183.96, 168.85, 161.22, 143.79, 136.30, 130.09 (2 C), 129.88 (2 C), 129.04 (3 C), 129.00, 128.65, 128.59, 124.70, 122.19, 119.23, 119.07, 83.44, 63.97, 42.36, 25.26 ppm.

    Example 18: Preparation of 3-(2-chloro-5-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0263] 



    [0264] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 25 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.37 - 7.31 (m, 3H), 7.08 - 7.05 (m, 2H), 6.94 (dd, J = 10.3, 3.2 Hz, 1H), 6.89 (dd, J = 10.4, 3.2 Hz, 1H), 6.12 - 6.07 (m, 2H), 4.23 (dd, J = 12.2, 5.0 Hz, 1H), 4.13 (dd, J = 12.2, 6.9 Hz, 1H), 3.62 (dd, J = 12.7, 3.7 Hz, 1H), 3.24 - 3.15 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 183.95, 169.35, 143.91, 143.30, 138.37, 137.55, 136.36, 130.53, 130.09, 130.09, 130.06 (2 C), 129.29 (2 C), 129.14, 128.39, 125.34, 124.87, 120.38, 83.56, 63.37, 42.67, 32.21 ppm.

    Example 19: Preparation of 3-benzyl-5-(pyridine-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0265] 



    [0266] The compound prepared in Preparative Example 1 (0.010 g, 0.028 mmol) was dissolved in anhydrous hexafluoroisopropanol (1 mL), to which potassium carbonate (0.008 g, 0.057 mmol) was slowly added under a stream of argon at 0°C. The mixture was stirred at the same temperature as the above for 30 minutes, to which PIFA (phenyliodinebis(trifluoroacetate)) (0.012 g, 0.043 mmol) dissolved in anhydrous hexafluoroisopropanol was slowly added at the same temperature. After stirring the mixture at the same temperature for 1 hour, the temperature was raised slowly to room temperature with stirring. After confirming by TLC that the substrate (the compound prepared in Preparative Example 1) was completely consumed, the mixture was quenched with water and diluted with ethyl acetate, followed by stirring until the water layer and the organic layer became clear. The organic layer was separated and washed with saturated brine. The organic phase was dried over sodium sulfate, followed by concentration in vacuo. The crude product was purified by silica gel column chromatography (flash column chromatography) using EtOAc:Hex (3:7) as a moving phase to give the target compound (0.018 g, 76%).
    1H NMR (600 Hz, CDCl3): δ 8.61-8.55 (m, 1 H), 8.46-8.42 (bs, ½ H), 7.5 (d, J = 7.9 Hz, 1/2 H), 7.35-7.22 (m, 3 H), 7.17-7.14 (m, ½ H), 7.11-7.01 (m, ½ H), 7.01-6.97 (m, 2 H), 6.87-6.83 (m, ½ H), 6.77-6.69 (m, 1 H), 6.66-6.62 (m, ½ H), 6.39-6.33 (m, 2 H), 6.11-6.07 (m, ½ H), 4.11-4.06 (m, 1 H), 3.84-3.75 (m, 1 H), 3.66-3.89 (m, 1 H), 2.84-2.78 (m, 1 H), 2.60-2.55 (m, 1 H); 13C NMR (125 MHz, CDCl3): 183.91, 175.06, 151.89, 150.20, 141.85, 140.69, 138.83, 138.31, 130.94, 130.59, 129.52 (2 C), 129.28, 128.73 (2 C), 128.42, 127.03, 86.04, 64.40, 49.05, 35.84 ppm.
    HRMS (ESI): calcd. For C21H19N2O3 [M + H]+ 347.1396; found 347.1380.

    Example 20: Preparation of 3-methyl-5-(pyridine-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0267] 



    [0268] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 2 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 Hz, CDCl3): δ 8.55-8.52 (m, 1 H), 8.45-8.31 (m, 1 H), 7.46-7.32 (m, 1 H), 7.29-7.27 (m, 1 H), 7.15-7.02 (m, 2 H), 6.92-6.79 (m, 2 H), 4.33-4.25 (m, 1 H), 4.09-4.031 (m, 1 H), 2.96-2.85 (m, 1 H), 1.38 (d, J = 1.68 Hz, 3 H); 183.45, 171.37, 150.98, 149.76, 143.67, 142.50 (2 C), 137.73, 130.27, 130.20, 123.87, 83.78, 65.91, 37.27, 13.39 ppm.
    HRMS (ESI): calcd. For C15H15N2O3 [M + H]+ 271.1083; found 271.1079.

    Example 21: Preparation of 3-hydroxy-2-methyl-N-(4-oxocyclohexa-2,5-diethyl)-N-(pyridine-3-yl)propanamide



    [0269] 



    [0270] The compound of Example 21 was obtained by the same manner as described in Example 20 as a by-product.
    1H NMR (600 Hz, CDCl3) : δ 8.63 (q, J = 7.5, 3.9 Hz, 1 H), 8.49 (d, J = 7.4 Hz, 1 H), 7.59 (d, J = 7.2 Hz, 1 H), 7.42-7.36 (m, 1 H), 6.85-6.74 (m, 2 H), 6.33 (d, J = 8.2 Hz, 2 H), 4.25-4.18 (m, 1 H), 3.59-3.67(m, 1 H), 3.48-3.36 (m, 1 H), 2.28-2.36 (m, 1H), 0.88 (d, J = 1.68 Hz, 3 H); 13C NMR (150 Hz, CDCl3) :183.92, 176.66, 152.06, 151.14, 150.51, 141.94, 140.57, 131.59, 130.10, 124.198, 123.86, 69.91, 65.10, 41.12, 13.86 ppm.

    Example 22: Preparation of 3-methyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0271] 



    [0272] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 27 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.52 - 7.37 (m, 4H), 7.11 -7.04 (m, 2H), 6.64 (dd, J = 11.9, 2.9 Hz, 1H), 6.12 - 6.06 (m, 1H), 4.25 - 4.18 (m, 1H), 4.13 (dd, J = 14.8, 7.8 Hz, 1H), 3.07-2.96 (m, 1H), 1.38 (d, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 175.63, 168.68, 155.16, 145.24, 142.82, 129.91, 129.26, 129.02, 128.95, 128.28 (2 C), 118.94, 82.95, 64.95, 43.35, 13.94 ppm.

    Example 23: Preparation of 3-allyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0273] 



    [0274] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 28 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.38 - 7.27 (m, 4H), 7.04 - 7.01 (m, 2H), 6.98 (dd, J = 10.1, 3.4 Hz, 1H), 6.94 (dd, J = 10.2, 3.1 Hz, 1H), 5.94 - 5.78 (m, 1H), 5.22-5.11 (m, 2H), 3.78-3.76 (m, 1H), 3.54 (dd, J = 10.2, 5.5 Hz, 1H), 3.04 - 2.89 (m, 1H), 2.37-2.27 (m, 1H), 2.18-2.15 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 176.93, 168.69, 155.36, 144.59, 135.86, 135.34, 131.12, 130.59, 129.92, 129.89, 129.36, 128.04 (2 C), 116.57, 116.56, 64.53, 46.49, 35.14 ppm.

    Example 24: Preparation of 3-benzyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0275] 



    [0276] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 13 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.44 - 7.36 (m, 6H), 7.10 - 7.06 (m, 3H), 6.67 (d, J = 9.4 Hz, 1H), 6.53 (d, J = 12.0 Hz, 1H), 6.14 - 6.03 (m, 2H), 4.16 (dd, J = 12.0, 5.4 Hz, 1H), 4.08 (dd, J = 12.1, 5.8 Hz, 1H), 3.36-3.32 (m, 1H), 3.18 - 3.07 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 176.78, 168.72, 155.38, 143.74, 143.62, 138.08, 136.32, 127.89, 129.70, 129.48, 129.16, 129.04, 128.94, 128.80, 128.64, 126.84, 120.16, 118.72, 82.38, 63.08, 43.42, 34.96 ppm.

    Example 25: Preparation of 3,8-dimethyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0277] 



    [0278] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 12 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 Hz, CDCl3) : δ 7.33-7.26 (m, 3H), 7.05-7.00 (m, 2.5H), 6.91-6.86 (m, 1/2 H), 6.82-6.79(s, 1/2H), 6.71-6.66(s, 1/2H), 6.10-6.01 (m, 1 H), 4.32-4.25 (m, 1 H), 4.06-3.99 (m, 1 H), 2.93-2.84 (m, 1 H), 1.82-1.74 (dd, J = 0.8, 4 Hz, 3 H), 1.40-1.33 (m, 3 H); 13C NMR (150 Hz, CDCl3) : δ 184.99, 172.47, 144.29, 143.29, 140.25, 139.22, 137.03, 137.00, 130.23, 129.98, 129.19, 129.07, 84.40, 66.20, 37.43, 15.57, 13.85 ppm.

    Example 26: Preparation of 3-allyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0279] 



    [0280] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 11 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) : δ 7.34 - 7.28 (m, 3H), 7.05 - 7.01 (m, 2H), 6.99 (dd, J = 10.1, 3.2 Hz, 1H), 6.71 (dd, J = 3.1, 1.5 Hz, 1H), 6.07 (t, J = 6.7 Hz, 1H), 5.87-5.82 (m, 1H), 5.23 - 5.15 (m, 2H), 4.28 (dd, J = 12.1, 5.5 Hz, 1H), 4.15 - 4.09 (m, 1H), 2.85 (dtt, J = 12.5, 11.1, 5.6 Hz, 1H), 2.75 - 2.69 (m, 1H), 2.52 (dt, J = 14.2, 8.6 Hz, 1H), 1.77 (d, J = 1.5 Hz, 3H); 13C NMR (150 Hz, CDCl3): δ 184.88, 170.09, 143.39, 139.75, 137.00, 136.87, 134.88, 130.08 (2 C), 129.98, 129.14(2 C), 129.03, 118.40, 84.115, 63.56, 41.52, 33.38, 15.53 ppm.

    Example 27: Preparation of 3-(2-methyl-allyl)-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0281] 



    [0282] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 29 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) : δ 7.34 - 7.28 (m, 3H), 7.05 - 7.01 (m, 2H), 6.99 (dd, J = 10.1, 3.2 Hz, 1H), 6.71 (dd, J = 3.1, 1.5 Hz, 1H), 6.07 (t, J = 6.7 Hz, 1H), 5.87-5.82 (m, 1H), 5.23 - 5.15 (m, 2H), 4.28 (dd, J = 12.1, 5.5 Hz, 1H), 4.15 - 4.09 (m, 1H), 2.85 (dtt, J = 12.5, 11.1, 5.6 Hz, 1H), 2.75 - 2.69 (m, 1H), 2.52 (dt, J = 14.2, 8.6 Hz, 1H), 1.77 (d, J = 1.5 Hz, 3H); 13C NMR (150 Hz, CDCl3) : δ 184.88, 170.09, 143.39, 139.75, 137.00, 136.87, 134.88, 130.08 (2 C), 129.98, 129.14(2 C), 129.03, 118.40, 84.115, 63.56, 41.52, 33.38, 15.53 ppm.

    Example 28: Preparation of 3-benzyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0283] 



    [0284] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 10 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 Hz, CDCl3): δ 7.39-7.26 (m, 9 H), 7.04-6.96 (s, 1 H), 6.69-6.62 (d, J = 3 Hz, 2 H), 6.3-5.97 (d, J = 2.5 Hz, 1H), 4.20-4.10 (m 1H), 4.08-4.02 (m 1H), 3.31-3.25 (d, J = 2.8 Hz 1 H), 3.13-3.00 (m, 2 H), 1.61-1.53 (s, 3H); 13C NMR (150 Hz, CDCl3): δ 184.86, 170.05, 143.38, 139.53, 138.35, 136.97, 136.87, 130.08 (2 C), 129.98, 129.64 (2 C), 129.15 (2 C), 129.07, 128.90 (2 C), 127.07, 84.09, 63.21, 43.56, 35.13, 15.50 ppm.

    Example 29: Preparation of 3,5-dimethyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0285] 



    [0286] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 30 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 6.88 - 6.84 (m, 1H), 6.76 - 6.74 (m, 1H), 6.37 - 6.35 (m, 2H), 4.16 (dd, J = 11.8, 5.3 Hz, 1H), 3.87 (dd, J = 11.7, 7.6 Hz, 1H), 2.79 (s, 3H), 2.77 - 2.71 (m, 1H), 1.30 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 183.98, 170.84, 144.54, 143.50, 130.58, 130.50, 82.31, 65.72, 36.89, 28.43, 13.46 ppm.

    Example 30: Preparation of 3-allyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0287] 



    [0288] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 31 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 6.83 - 6.77 (m, 2H), 6.36 (d, J = 10.0, 1.8 Hz, 2H), 5.85 - 5.78 (m, 1H), 5.18 - 5.13 (m, 2H), 4.14 (dd, J = 12.0, 5.0 Hz, 1H), 3.97 (dd, J = 12.0, 6.5 Hz, 1H), 2.79 (s, 3H), 2.72 - 2.65 (m, 2H), 2.45 - 2.38 (m, 1H) ; 13C NMR (150 MHz, CDCl3) δ 183.95, 169.58, 144.06, 143.79, 134.71, 130.63, 130.59, 118.05, 82.12, 63.08, 41.25, 33.04, 28.47.

    Example 31: Preparation of 3-(3-butenyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0289] 



    [0290] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 32 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 6.81 - 6.75 (m, 2H), 6.37 - 6.32 (m, 2H), 5.85 - 5.78 (m, 1H), 5.11 - 5.01 (m, 2H), 4.16 (dd, J = 11.9, 4.9 Hz, 1H), 3.94 (dd, J = 11.9, 6.4 Hz, 1H), 2.77 (s, 3H), 2.62 - 2.58 (m, 1H), 2.27 - 2.13 (m, 2H), 2.08 - 2.02 (m, 1H), 1.71 - 1.65 (m, 1H) ; 13C NMR (150 MHz, CDCl3) δ 183.96, 170.22, 144.08, 143.88, 137.38, 130.58 (2 C), 115.69, 82.06, 63.57, 41.19, 31.14, 28.45, 27.86 ppm.

    Example 32: Preparation of 3-(2-methyl-allyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0291] 



    [0292] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 33 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 6.81 - 6.77 (m, 2H), 6.37 - 6.33 (m, 2H), 4.86 (s, 1H), 4.77 (s, 1H), 4.09 (dd, J = 11.9, 4.8 Hz, 1H), 3.92 - 3.88 (m, 1H), 2.78 (s, 3H), 2.75 - 2.69 (m, 2H), 2.32 - 2.26 (m, 1H), 1.77 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 183.96, 170.05, 143.96, 143.92, 141.86, 130.61 (2 C), 113.45, 82.11, 62.95, 39.63, 36.99, 21.84 ppm.

    Example 33: Preparation of 3-benzyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0293] 



    [0294] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 4 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.36 - 7.32 (m, 2H), 7.27 - 7.24 (m, 3H), 6.80 - 6.77 (m, 1H), 6.63 - 6.60 (m, 1H), 6.36 - 6.32 (m, 2H), 4.01 (dd, J = 12.0, 4.6 Hz, 1H), 3.88 (dd, J = 12.0, 5.7 Hz, 1H), 3.33 (dd, J = 13.3, 3.5 Hz, 1H), 2.91 (dd, J = 13.3, 10.4 Hz, 1H), 2.89 - 2.83 (m, 1H), 2.81 (s, 3H) ; 13C NMR (150 MHz, CDCl3) δ 183.94, 169.63, 143.94, 143.74, 138.23, 130.63, 130.61, 129.16 (2 C), 128.70 (2 C), 126.77, 82.12, 62.69, 43.52, 34.95, 28.54 ppm.

    Example 34: Preparation of 3-(4-fluoro-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0295] 



    [0296] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 34 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.22 - 7.19 (m, 2H), 7.04 - 7.00 (m, 2H), 6.80 - 6.76 (m, 1H), 6.64 - 6.61 (m, 1H), 6.35 - 6.32 (m, 2H), 4.01 (dd, J = 12.0, 4.7 Hz, 1H), 3.85 (dd, J = 12.0, 5.9 Hz, 1H), 3.27 (dd, J = 13.8, 3.9 Hz, 1H), 2.89 (dd, J = 13.8, 10.1 Hz, 1H), 2.83 - 2.80 (m, 1H), 2.79 (s, 3H) ; 13C NMR (150 MHz, CDCl3) δ 183.87, 169.39, 160.93, 143.79, 143.64, 133.88, 133.86, 130.69, 130.65, 130.64, 115.59, 115.45, 82.14, 62.56, 43.54, 34.07, 28.53 ppm.

    Example 35: Preparation of 3-(4-bromo-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0297] 



    [0298] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 35 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.77 (dd, J = 10.3, 3.1 Hz, 1H), 6.63 (dd, J = 10.3, 3.1 Hz, 1H), 6.34 (d, J = 10.4 Hz, 2H), 4.00 (dd, J = 12.0, 4.6 Hz, 1H), 3.84 (dd, J = 12.0, 5.8 Hz, 1H), 3.25 (dd, J = 13.5, 3.7 Hz, 1H), 2.87 (dd, J = 13.5, 10.2 Hz, 1H), 2.83 - 2.81 (m, 1H), 2.79 (s, 3H) ; 13C NMR (150 MHz, CDCl3) δ 183.84, 169.26, 143.72, 143.62, 137.23, 131.78 (2C), 130.89 (2C), 130.72, 130.68, 120.67, 82.16, 62.54, 43.34, 34.27, 28.55 ppm.

    Example 36: Preparation of 3-(4-cyano-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0299] 



    [0300] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 36 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.79 - 6.76 (m, 1H), 6.66 - 6.61 (m, 1H), 6.37 - 6.34 (m, 2H), 4.03 (dd, J = 12.1, 4.7 Hz, 1H), 3.83 (dd, J = 12.1, 6.1 Hz, 1H), 3.36 (dd, J = 13.8, 4.3 Hz, 1H), 2.97 (dd, J = 13.8, 9.9 Hz, 1H), 2.89 - 2.85 (m, 1H), 2.80 (s, 3H) ; 13C NMR (150 MHz, CDCl3) δ 183.74, 168.89, 144.02, 143.42 (2 C), 132.49 (2 C), 130.84, 130.81, 129.97 (2 C), 118.67, 110.83, 82.23, 62.55, 43.16, 34.93 ppm.

    Example 37: Preparation of 3-(2-(phenylsulfonylmethyl)-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0301] 



    [0302] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 37 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.80 - 7.78 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.5, 1.4 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.21 - 7.15 (m, 2H), 6.79 (dd, J = 10.0, 3.2 Hz, 1H), 6.73 (dd, J = 10.0, 3.2 Hz, 1H), 6.37 - 6.33 (m, 2H), 4.53 (s, 2H), 4.01 (dd, J = 12.1, 4.2 Hz, 1H), 3.82 (dd, J = 12.1, 4.9 Hz, 1H), 3.25 (dd, J = 14.3, 3.6 Hz, 1H), 2.84 (dd, J = 14.2, 10.7 Hz, 1H), 2.79 (s, 3H), 2.78 - 2.77 (m, 1H) ; 13C NMR (150 MHz, CDCl3) δ 183.88, 169.47, 144.12, 143.26, 138.99, 138.64, 133.89, 132.82, 130.81, 130.70, 130.46, 129.30, 129.13 (2 C), 128.53 (2 C), 127.12, 126.79, 82.21, 62.39, 59.27, 43.38, 31.54 ppm.

    Example 38: Preparation of 3-(2-propynyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0303] 



    [0304] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 38 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H-NMR (600 MHz, CDCl3) δ 7.30 -7.33 (m, 3 H), 7.02 -7.05 (m, 2 H), 7.00 (dd, J = 2.1, 10.2 Hz 1 H), 6.96 (dd, J = 2.6, 10.8 Hz 1 H), 6.09 (dd, J = 3.2, 10.1 Hz 1 H), 6.06 (dd, J = 2.7, 10.6 Hz 1 H), 5.82 - 5.89 (m, 1 H), 5.16 -5.21 (m, 2 H), 4.27 -4.30 (m, 1 H), 4.12 -4.15 (m, 1 H), 2.87 -2.83 (m, 1 H), 2.70 - 2.74 (m, 1 H), 2.50 -2.55 (m, 1 H) ppm.

    Example 39: Preparation of 3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0305] 



    [0306] The target compound was obtained according to reaction formula B below by using the compound of Example 38 as a starting material.


    Step 1: Preparation of 3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0307] The compound of Example 38 (1 mmol) was dissolved in the mixed solvent comprising tetrahydrofuran and distilled water at the ratio of 1:1 at 5°C, to which 1-azido-4-methoxybenzene (1.5 mmol) and copper sulfate pentahydrate (CuSO4. 5 H2O) (2 mmol) were added. Thereafter, sodium ascorbate (1 mmol) was added thereto and the temperature was raised slowly to room temperature with stirring. After confirming by TLC that the starting material was completely consumed, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (flash column chromatography) to give the target compound.
    1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.32 - 7.28 (m, 3H), 7.19 (dd, J = 10.3, 3.2 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 6.98 (dd, J = 7.7, 1.5 Hz, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.67 (dd, J = 12.2, 9.7 Hz, 1H), 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.90 (s, 3H), 3.44 (dd, J = 15.0, 6.9 Hz, 1H), 3.40 - 3.31 (m, 1H), 3.18 (dd, J = 15.0, 3.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 184.02, 169.59, 159.83, 144.78, 142.96, 136.47, 130.44, 129.83, 129.80 (3 C), 129.07 (2 C), 128.97 (2 C), 122.02 (2 C), 121.11, 114.80 (2 C), 83.43, 63.74, 55.65, 41.54, 31.94 ppm.

    Example 40: Preparation of 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0308] 



    [0309] The target compound was obtained by the same manner as described in Example 39 except that 1-azido-4-benzylbenzene was used instead of 1-azido-4-methoxybenzene in step 1 of reaction formula B.
    1H NMR (600 MHz, CDCl3) δ 7.44 - 7.36 (m, 4H), 7.35 - 7.30 (m, 3H), 7.25 (t, J = 7.4 Hz, 2H), 6.92 (dd, J = 10.3, 3.2 Hz, 1H), 6.83 (d, J = 7.3 Hz, 2H), 6.78 (dd, J = 10.2, 3.2 Hz, 1H), 6.06 (dd, J = 10.3, 2.0 Hz, 1H), 5.99 (dd, J = 10.2, 2.0 Hz, 1H), 5.59 (d, J = 14.8 Hz, 1H), 5.46 (d, J = 14.8 Hz, 1H), 4.49 (dd, J = 12.1, 9.8 Hz, 1H), 4.33 (dd, J = 12.2, 6.7 Hz, 1H), 3.38 (dd, J = 15.0, 6.5 Hz, 1H), 3.30 - 3.21 (m, 1H), 3.06 (dd, J = 15.0, 3.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 183.99, 177.33, 169.45, 144.71, 142.85, 136.39, 134.79, 130.50, 129.73, 129.67 (3 C), 129.18 (2 C), 129.04 (2 C), 128.90, 128.86, 128.06 (2 C), 83.27, 63.60, 54.20, 41.29, 23.61 ppm.

    Example 41: Preparation of 3-methyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0310] 



    [0311] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 39 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 6.92 - 6.89 (m, 1H), 6.82 - 6.79 (m, 1H), 6.36 - 6.34 (m, 2H), 4.09 (dd, J = 11.7, 5.3 Hz, 1H), 3.80 (dd, J = 11.7, 7.6 Hz, 1H), 3.09 - 3.05 (m, 1H), 2.69 - 2.063 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.39 (d, 3H), 1.26 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 184.21, 170.45, 144.99, 144.01, 130.32, 130.22, 82.89, 65.41, 49.63, 37.77, 20.53, 20.45, 13.36 ppm.

    Example 42: Preparation of 3-allyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0312] 



    [0313] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 40 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 6.88 - 6.80 (m, 2H), 6.36 - 6.34 (m, 2H), 5.84 - 5.76 (m, 1H), 5.16 - 5.11 (m, 2H), 4.06 (dd, J = 11.9, 5.1 Hz, 1H), 3.90 (dd, J = 11.9, 6.7 Hz, 1H), 3.09 - 3.05k (m, 1H), 2.65 - 2.59 (m, 2H), 2.46 - 2.41 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H) ; 13C NMR (150 MHz, CDCl3) δ 184.18, 169.11, 144.63, 144.21, 134.78, 130.34 (2 C), 117.92, 82.68, 62.80, 49.75, 42.01, 33.00, 20.48, 20.46 ppm.

    Example 43: Preparation of 3-(4-fluoro-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0314] 



    [0315] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 41 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.21 (dd, J = 8.4, 5.4 Hz, 2H), 7.02 (t, J = 8.6 Hz, 2H), 6.82 (dd, J = 10.0, 3.1 Hz, 1H), 6.59 (dd, J = 10.0, 3.1 Hz, 1H), 6.35 - 6.30 (m, 2H), 3.97 (dd, J = 12.0, 4.9 Hz, 1H), 3.80 (dd, J = 12.0, 6.2 Hz, 1H), 3.19 (dd, J = 13.9, 4.1 Hz, 1H), 3.08 - 3.04 (m, 1H), 2.97 (dd, J = 13.9, 9.4 Hz, 1H), 2.78 - 2.75 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H) ; 13C NMR (150 MHz, CDCl3) δ 184.08, 168.87, 162.54, 144.14 (2 C), 133.97, 130.79, 130.74, 130.45, 130.40, 115.49, 115.35, 82.68, 62.37, 49.80, 44.23, 34.05, 20.46 (2 C) ppm.

    Example 44: Preparation of 3-(4-trifluoromethylbenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0316] 



    [0317] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 42 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.82 (dd, J = 10.0, 3.1 Hz, 1H), 6.59 (dd, J = 10.0, 3.1 Hz, 1H), 6.35 - 6.31(m, 2H), 3.97 (dd, J = 12.0, 4.8 Hz, 1H), 3.79 (dd, J = 12.0, 6.1 Hz, 1H), 3.32 - 3.28 (m, 1H), 3.08 -3.01 (m, 2H), 2.83 - 2.79 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 184.00, 168.58, 143.98 (2 C), 142.62, 130.51, 130.47, 129.62 (2 C), 129.23, 129.02, 125.55, 125.52, 82.72, 62.32, 49.85, 44.06, 34.67, 20.45, 20.42 ppm.

    Example 45: Preparation of 3-(4-cyano-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0318] 



    [0319] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 43 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 6.83 - 6.80 (m, 1H), 6.60 - 6.57 (m, 1H), 6.35 - 6.31 (m, 2H), 3.98 (dd, J = 12.0, 4.9 Hz, 1H), 3.76 (dd, J = 12.0, 6.2 Hz, 1H), 3.27 (dd, J = 13.8, 4.4 Hz, 1H), 3.09 - 3.00 (m, 2H), 2.83 - 2.79 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H) ; 13C NMR (150MHz, CDCl3) δ 183.94, 168.30, 144.17, 143.88, 143.79, 132.38 (2 C), 130.60, 130.53, 130.10 (2 C), 118.72, 110.74, 82.74, 62.32, 49.88, 43.89, 34.97, 20.45, 20.39 ppm.

    Example 46: Preparation of 3-(2-fluoro-6-trifluoromethyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0320] 



    [0321] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 44 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 13.5, 8.0 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.92 (dd, J = 10.1, 3.1 Hz, 1H), 6.85 (dd, J = 10.1, 3.1 Hz, 1H), 6.39 - 6.34 (m, 2H), 3.98 (dd, J = 11.8, 4.2 Hz, 1H), 3.90 (dd, J = 11.8, 5.4 Hz, 1H), 3.64 (dd, J = 13.5, 6.0 Hz, 1H), 3.10 - 3.06 (m, 1H), 2.99 - 2.92 (m, 2H), 1.39 (dd, J = 6.8, 2.9 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 184.20, 168.02, 161.17, 144.51, 144.13, 130.43 (2 C), 128.51, 128.45, 125.11, 122.13, 119.09, 118.94, 82.77, 63.34, 49.78, 43.01, 25.24, 20.36, 20.21 ppm.

    Example 47: Preparation of 3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0322] 



    [0323] The target compound was obtained by the same manner as described in Example 39 except that 4-azido-1,1'biphenyl was used instead of 1-azido-4-methoxybenzene in step 1 of reaction formula B.
    1H NMR (600 MHz, CDCl3) δ 7.89 (s, 1H), 7.74 (dd, J = 8.6, 1.1 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.49 - 7.45 (m, 1H), 7.33 - 7.26 (m, 3H), 7.18 (dd, J = 10.3, 3.2 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.65 (dd, J = 12.2, 9.6 Hz, 1H), 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.45 (dd, J = 15.0, 6.9 Hz, 1H), 3.41 - 3.31 (m, 1H), 3.19 (dd, J = 15.0, 3.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 184.02, 169.61, 144.74, 142.93, 136.97, 136.43, 129.84, 129.81 (4 C), 129.08 (3 C), 128.99, 128.80 (2 C), 121.00, 120.40 (2 C), 83.44, 63.71, 41.55, 23.65 ppm.

    Example 48: Preparation of 3-(3-bromobenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0324] 



    [0325] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 45 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 7.42 - 7.38 (m, 2H), 7.21 - 7.15 (m, 2H), 6.81 (dd, J = 10.1, 3.2 Hz, 1H), 6.57 (dd, J = 10.1, 3.1 Hz, 1H), 6.34 - 6.30 (m, 2H), 3.97 (dd, J = 12.0, 5.0 Hz, 1H), 3.80 (dd, J = 12.0, 6.2 Hz, 1H), 3.18 (dd, J = 13.8, 4.2 Hz, 1H), 3.07 - 2.95 (m, 1H), 2.97 (dd, J = 13.8, 9.3 Hz, 1H), 2.80 - 2.76(m, 1H), 1.41 (dd, J = 15.3, 6.8 Hz, 6H) ; 13C NMR (150 MHz, CDCl3) δ 184.06, 168.62, 144.11, 144.07, 140.73, 132.26, 130.46, 130.42, 130.15, 129.87, 127.96, 122.65, 82.69, 62.39, 49.87, 43.96, 34.48, 20.50, 20.45 ppm.

    Example 49: Preparation of 5-isopropyl-3-(4-nitrobenzyl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione



    [0326] 



    [0327] The target compound was obtained by cyclization performed by the same manner as described in Example 19 except that the compound of Preparative Example 46 was used instead of the compound of Preparative Example 1 as the starting material in Example 19.
    1H NMR (600 MHz, CDCl3) δ 8.21 - 8.17 (m, 2H), 7.42 (d, J = 8.7 Hz, 2H), 6.83 - 6.80 (m, 1H), 6.64 - 6.60 (m, 1H), 6.36 - 6.31 (m, 2H), 3.99 (dd, J = 12.0, 4.9 Hz, 1H), 3.78 (dd, J = 12.0, 6.3 Hz, 1H), 3.32 (dd, J = 13.9, 4.5 Hz, 1H), 3.11 - 3.05 (m, 2H), 2.86 - 2.82 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H) ; 13C NMR (150 MHz, CDCl3) δ 183.92, 168.21, 146.92, 146.33, 143.88, 143.72, 130.63, 130.56, 130.14 (2 C), 123.83 (2 C), 82.78, 62.31, 49.91, 43.91, 34.65, 20.47, 20.39 ppm.

    [0328] The chemical structures of the compounds prepared in Examples 1 ∼ 49 are shown in Table 2 below.
    [Table 2]
    ExampleChemical StructureExampleChemical Structure
    1

    26

    2

    27

    3

    28

    4

    29

    5

    30

    6

    31

    7

    32

    8

    33

    9

    34

    10

    35

    11

    36

    12

    37

    13

    38

    14

    39

    15

    40

    16

    41

    17

    42

    18

    43

    19

    44

    20

    45

    21

    46

    22

    47

    23

    48

    24

    49

    25

       

    Experimental Example 1: Evaluation of nerve cell line protective activity



    [0329] The following experiment was performed to evaluate the nerve cell line protective activity of the compound represented by formula 1 of the present invention (novel spiroquinone derivative compound).

    [0330] Particularly, mouse microglial BV2 cells were cultured in Dulbecco's modified Eagle's medium (DMEM; Hyclone) supplemented with 10% heat-inactivated fetal bovine serum (Hyclone, USA) in a 5% CO2 incubator with 95% humidity at 37°C. To induce cell damage, LPS (lipid polysaccharide) was used as a toxic substance. To investigate the cell protective activity in the cell damage model, 6-shogaol was used as for the positive control. When the cell confluence reached 70% ∼ 80%, the cells were treated with the compound of the present invention at different concentrations of 0.01 µM, 0.1 µM and 1 µM, or 1 µM, 5 µM and 10 µM in serum-free condition. 30 minutes later, a toxic substance (100 mg/mL of LPS) was treated to the cells. All the chemicals treated were dissolved in dimethylsulfoxide (DMSO) before the treatment and the final DMSO concentration was 0.2%. 24 hours later, MTT assay was performed in BV2 cells and the results are shown in Figure 2 and Figure 4 (Con: DMSO treated group (not treated with the compound of the invention and LPS), LPS: LPS treated group (treated with the compound of the invention)).

    [0331] As shown in Figure 2, the cell survival rate of the LPS treated nerve cell line (murine microglial BV-2 cells) was significantly increased by the compound of the example of the present invention dose-dependently.

    [0332] As shown in Figure 4, the cell survival rate of the LPS treated nerve cell line (murine microglial BV-2 cells) was significantly increased by the compound of the example of the present invention dose-dependently.

    [0333] Therefore, the compound represented by formula 1 of the present invention can protect the nerve cell line excellently so that it can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of neurological disease.

    Experimental Example 2: Quantitative evaluation of nitrite generation



    [0334] The following experiment was performed to quantify the nitrite generated in the nerve cell line by the compound represented by formula 1 of the present invention (the novel spiroquinone derivative compound).

    [0335] Particularly, in order to quantify the nitrite generation in the LPS treated nerve cell line, nitrite generated from nitric oxide secreted therein was quantified. With the quantified nitrite, the inhibition of microglial activation and the neuron protection effect thereby were examined. The nerve cell line (BV2) was treated with LPS (100 mg/mL), and then treated with the compound of the present invention at different concentrations of 0.01 µM, 0.1 µM and 1 µM, or 1 µM, 5 µM and 10 µM (Con: DMSO treated group (not treated with the compound of the invention and LPS), LPS: LPS treated group (treated with the compound of the invention)).

    [0336] Further, IC50 was calculated from the quantification of nitric oxide measured by concentration gradient in Figures 1 and 3, and the results are shown in Figure 5.

    [0337] As shown in Figure 1, the compound of the example of the present invention significantly inhibited the generation of nitrite in the LPS treated nerve cell line (murine microglial BV-2 cells) dose-dependently (0.01, 0.1, and 1 µM).

    [0338] As shown in Figure 3, the compound of the example of the present invention significantly inhibited the generation of nitric oxide in the LPS treated nerve cell line (murine microglial BV-2 cells) dose-dependently (1, 5, and 10 µM).

    [0339] As shown in Figure 5, all the compounds of the examples of the invention exhibited excellent inhibitory effect at the level of micromole based on the IC50 of the compound of the invention for nitric oxide. In particular, the compound of example 14 showed as excellent nitric oxide inhibitory effect as about up to 0.3 µM, indicating excellent nerve cell protection effect.

    [0340] Inflammatory response in the central nervous system plays a key role in degenerative brain diseases and the inflammatory response mediated by the over-activation of microglial cells induces the death of neurons. Therefore, the inhibition of the microglial activation can be a pharmacological target for the treatment of degenerative brain diseases. Considering that the studies on the relationship between the microglial activation and the diseases like Parkinson's disease and Alzheimer's disease confirmed the microglial activation is induced by the treatment of LPS and then iNOS (nitric oxide synthase) is expressed to secret nitric oxide (NO), the compound represented by formula 1 (the novel spiroquinone derivative compound) of the present invention which displays excellent protective effect on nerve cells can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of neurological disease.

    Experimental Example 3: Evaluation of acetylcholine esterase inhibition activity



    [0341] The following experiment was performed to evaluate the acetylcholine esterase inhibition activity of the compound represented by formula 1 of the present invention.

    [0342] Particularly, a quantitative kit (ACh quantification colorimetric assay kit from BioVision) was prepared in order to quantify acetylcholine esterase (eeAChE, EC 3.1.1.7) and acetylcholine chloride (ACh) of Electrophorus electricus and acetylcholine. To measure the enzyme inhibition activity of the compound of the example of the invention, the following experiment was performed based on the standardized method of the manufacturer of the Ach kit (Draczkowski, P. et al. Bba-Gen Subjects 1860, 967-974, doi:10.1016/j.bbagen.2015.11.006 (2016)).

    [0343] First, acetylcholine esterase (eeAChE, EC 3.1.1.7) was dissolved in 20 µM Tris-HCL buffer at the concentration of 5 µM. Acetylcholine chloride was dissolved in 20 mM Tris-HCL buffer, resulting in the preparation of a Tris-HCL aqueous solution containing 10 µM acetylcholine chloride. The compound of the example was prepared in different concentrations of 10 µM and 30 µM. The prepared acetylcholine chloride solution and the compound solution were mixed in 20 µM acetylcholine esterase. 20 minutes and 30 minutes after mixing, the color change of the quantitative kit was measured at 570 nm in order to evaluate the inhibitory effect of the compound particularly to inhibit acetylcholine esterase that decomposes acetylcholine into choline.

    [0344] All the experiments were repeated at least twice, from which the mean values and the standard deviations were calculated. The results are shown in Table 3 and Figure 6.

    [0345] Based on the data obtained from the experiments above performed respectively with 10 µM and 30 µM of the compound, IC50 was calculated and the results are shown in Table 3.
    [Table 3]
    ExampleResidual activity of acetylcholine esterase (%)IC50 (µM)
    10 µM30 µM
    2 29.73 7.03 16.01±0.94
    3 30.32 -2.03 13.76±1.17
    6 40.19 6.07 13.62±1.05
    7 46.73 4.74 14.44±0.33
    10 27.26 12.95 15.25±0.64
    11 69.43 22.06 17.47±2.84
    19 66.08 8.07 13.61±0.72
    22 51.63 2.47 18.76±2.96
    23 38.07 5.64 20.6±4.47
    24 35.63 8.89 16.70±0.7
    25 20.92 8.15 15.75±0.72
    28 55.43 3.08 12.85±0.74
    33 50.53 2.08 14.22±0.72


    [0346] As shown in Table 3, all the compounds of the examples of the invention inhibited acetylcholine esterase activity significantly. As confirmed with the IC50 values calculated, the inhibition activity was as excellent as the level of micromol unit. Therefore, it was confirmed that all the compounds of the examples were excellent in inhibiting the activity of acetylcholine esterase.

    [0347] Therefore, the compound of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of acetylcholine esterase related disease such as neurological disease due to the excellent acetylcholine esterase inhibitory activity of the compound.

    Experimental Example 4: Evaluation of enzyme inhibition activity selectivity



    [0348] The following experiment was performed in order to evaluate the selectivity of the enzyme inhibition activity of the compound of the present invention represented by formula 1.

    [0349] The selectivity of the compound of the present invention to 369 kinase panels (Reaction Biology Corp) was investigated. Using the radio-labeled ATP ([γ-33P] ATP), the extent of the substitution of the substrate with 33P-phosphorylated substrate was measured, by which the changes in kinase activity was investigated. At this time, 30 µM of the compound of the example, 10 µM of ATP and 10 µM of substrate were used. As for the control, staurosporine was used in a 10-dose IC50 mode with 4-fold step dilution starting at 20 or 100 µM. The example compounds were tested in a 10-dose IC50 mode with 3 or 4-fold continuous dilution starting at 10, 20 or 100 µM. Curve fitting of the control compound with enzyme activity of less than 65% was performed at the highest concentration of the compound. DMSO concentration was regulated. Based on the raw data, the enzyme activity for the DMSO control group was calculated. Among the calculated inhibitory activity of the compound of the example against 369 enzymes, the enzymes affected significantly and the inhibitory activities (%) against the enzymes are shown in Table 4.
    [Table 4]
    KinaseResidual enzyme activity (%) (Values calculated to DMSO control)
    1st2nd
    JNK 1 36.03 35.58
    CDK/cyclin O 43.80 42.33
    DAPK 1 45.43 45.32
    PKCa 46.47 44.81
    CKD 1/cyclin B 46.54 45.38
    MST3/STK24 58.19 57.62
    TLK 1 58.62 57.28
    JNK 2 58.79 57.84
    RIPK 5 59.94 58.59
    CDK 3/cyclin E 60.20 58.48
    PKN 2/PRK 2 64.75 62.16
    Haspin 66.80 66.06
    STK25/YSK1 66.95 66.88
    ARK5/NUAK1 70.84 70.70
    PKCb 2 71.17 67.73
    JNK 3 73.42 70.58


    [0350] As shown in Table 4, the compound of the present invention displayed a significant enzyme inhibition activity on JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, and JNK3. Therefore, the compound of the present invention can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of the diseases relating to JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, and JNK3.

    Experimental Example 5: animal model experiment



    [0351] The following experiment was performed to investigate the neuroprotective effect of the compound of the present invention in an animal model.

    [0352] Particularly, Y-maze test was performed with an animal model (mice) to evaluate the effect of the compound of the present invention. The spatial recognition ability of the mouse was evaluated. A Y-type maze in the size of 20 cm (length) x 5 cm (width) x 10 cm (height) was prepared. The floor and the walls of the maze were made of dark opaque polyvinyl plastic, and the three arms of the maze were named A, B and C (the arms were arranged symmetrically at the angle of 120° to each other). The mice were immersed in the Y-maze for 2 minutes, followed by the 8-minute observation to record the number of times completely entered each arm (from the nose to the tail). When the mouse was continuously entered three different arms, one point was given to each arm. If the entry was not made serially, the point was not given. The alternation behavior was defined as three consecutive inputs to three different arms of the maze. The spatial recognition ability was calculated according to the following formula.

    (Nalternation number is the number of times the alternation movement is observed (1 point) and Ntotal number of entry is the total number of arm entry)

    [0353] Particularly, sequence (for example, ABCCAB, etc) and the number of arm entry were recorded manually for 8 minutes for each mouse. Real alternation was accepted only three consecutive selections (that is, includes ABC, CAB, or BCA but not BAB).

    [0354] One hour before the experiment, the mouse was administered with donepezil (5 mg/kg, p.o.), 10% Tween 80 solution and the compound of the example of the present invention (10 mg/kg, p.o.). Scopolamine (1 mg/kg, i.p.) was administered to induce memory impairment 30 minutes before the experiment.

    [0355] The results of the spontaneous alternation behavior ratio (%) obtained from the experiment above are shown in Figure 7.

    [0356] As shown in Figure 7, after the memory impairment was induced, the spatial recognition function of the mouse was significantly reduced. In the meantime, when the compound of the example of the present invention was treated to the mouse, the memory impairment of the mouse was recovered to the similar level to the control group treated with donepezil.

    [0357] Therefore, as confirmed in the animal model test, the compound of the example of the present invention can be effectively used for the pharmaceutical composition for the prevention or treatment of neurological disease, preferably cerebral nervous system disease and central nervous system disease, due to the neuroprotective activity of the compound.

    INDUSTRIAL APPLICABILITY



    [0358] The novel spiroquinone derivative compound of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof is not only excellent in inhibiting the microglial activation and the activities of acetylcholine esterase, JNK1, JNK2, and JNK3 but also displays the significant enzyme activity suppressive effect on the neurological disease related enzyme group including RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, and TLK1, in addition to the cell death suppressive effect. Therefore, the novel spiroquinone derivative compound of the present invention, the stereoisomer thereof or the pharmaceutically acceptable salt thereof can be effectively used as an active ingredient of a pharmaceutical composition for the prevention or treatment of neurological disease or as an active ingredient of a health functional food for use in the prevention or improvement of neurological disease.


    Claims

    1. A compound represented by formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

    wherein in formula 1 above,

    R1 is nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,

    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,

    wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano;

    R2 is hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S,

    wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,

    wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano; and

    R3 and R4 are the same or different and are independently hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano,

    wherein, the substituted alkyl or alkoxy is independently substituted with one or more substituents selected from the group consisting of hydroxy, halogen, amino, nitro, and cyano.


     
    2. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the R1 is nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano.
     
    3. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the R2 is hydrogen, nonsubstituted or substituted C1-6 straight or branched alkyl, nonsubstituted or substituted C1-6 straight or branched unsaturated alkyl containing one or more double bonds or triple bonds, nonsubstituted or substituted C3-10 cycloalkyl, nonsubstituted or substituted C3-10 heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S, nonsubstituted or substituted C6-10 aryl C1-3 alkyl, nonsubstituted or substituted C6-10 aryl, nonsubstituted or substituted 5-10 membered heteroaryl C1-3 alkyl containing one or more heteroatoms selected from the group consisting of N, O, and S, or nonsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, wherein, the substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroarylalkyl, or heteroaryl is independently substituted with one or more substituents selected from the group consisting of substituted or nonsubstituted phenylsulfonyl, substituted or nonsubstituted phenylsulfonyl C1-5 alkyl, substituted or nonsubstituted phenyl, substituted or nonsubstituted phenyl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano, wherein, the substituted phenylsulfonyl, phenylsulfonyl C1-5 alkyl, phenyl, phenyl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano.
     
    4. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the R1 is

    or

    and R2 is








     
    5. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula 1 is selected from the group consisting of the following compounds:

    (1) 5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (2) 3-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (3) 3-allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (4) 3-(2-methyl-allyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (5) 3-(3-butenyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (6) 3-benzyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (7) 3-(4-fluoro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (8) 3-(4-chloro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (9) 3-(3-bromo-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (10) 3-(4-bromo-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (11) 3-(4-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (12) 3-(4-nitro-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (13) 3-(2-(phenylsulfonylmethyl)-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (14) 3-(3,5-ditrifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (15) 3-(3,5-dimethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (16) 3-(2-nitro-4-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (17) 3-(2-fluoro-6-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (18) 3-(2-chloro-5-trifluoromethyl-benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (19) 3-benzyl-5-(pyridine-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (20) 3-methyl-5-(pyridine-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (21) 3-methyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (22) 3-allyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (23) 3-benzyl-8-fluoro-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (24) 3,8-dimethyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (25) 3-allyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (26) 3-(2-methyl-allyl)-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (27) 3-benzyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (28) 3,5-dimethyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (29) 3-allyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (30) 3-(3-butenyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (31) 3-(2-methyl-allyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (32) 3-benzyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (33) 3-(4-fluoro-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (34) 3-(4-bromo-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (35) 3-(4-cyano-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (36) 3-(2-(phenylsulfonylmethyl)-benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (37) 3-allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (38) 3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (39) 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (40) 3-methyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (41) 3-allyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (42) 3-(4-fluoro-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (43) 3-(4-trifluoromethyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (44) 3-(4-cyano-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (45) 3-(2-fluoro-6-trifluoromethyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (46) 3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione;

    (47) 3-(3-bromobenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione; and

    (48) 5-isopropyl-3-(4-nitrobenzyl)-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione.


     
    6. A preparation method of the compound represented by formula 1 of claim 1 comprising the step of preparing the compound represented by formula 1 from the compound represented by formula 2 (step 1), as shown in reaction formula 1 below:

    Wherein in reaction formula 1, R1, R2, R3, and R4 are as defined in formula 1 of claim 1.
     
    7. The preparation method according to claim 6, wherein the step 1 is composed of the following substeps, as shown in reaction formula 1':

    preparing the compound represented by formula 1" from the compound represented by formula 2' (step 2); and

    preparing the compound represented by formula 1 from the compound represented by formula 1" (step 3)

    wherein in reaction formula 1',

    R1, R3, and R4 are as defined in formula 1 of claim 1;

    R2' is C1-5 straight or branched alkynyl containing one or more triple bonds; and

    R2 is preferably

    wherein, Ra is C1-5 straight or branched alkylene,

    Rb is hydrogen, substituted or nonsubstituted C6-10 arylsulfonyl, substituted or nonsubstituted C6-10 arylsulfonyl C1-5 alkyl, substituted or nonsubstituted C6-10 aryl, substituted or nonsubstituted C6-10 aryl C1-5 alkyl, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted 5-10 membered heteroarylsulfonyl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted 5-10 membered heteroaryl C1-5 alkyl containing one or more heteroatoms selected from the group consisting of, N, O and S, substituted or nonsubstituted C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, or cyano, wherein, the substituted C6-10 arylsulfonyl, C6-10 arylsulfonyl C1-5 alkyl, C6-10 aryl, C6-10 aryl C1-5 alkyl, 5-10 membered heteroarylsulfonyl, 5-10 membered heteroarylsulfonyl C1-5 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl C1-5 alkyl, or C1-6 straight or branched alkyl is independently substituted with one or more substituents selected from the group consisting of C1-6 straight or branched alkyl, C1-6 straight or branched alkoxy, hydroxy, halogen, amino, nitro, and cyano.


     
    8. A compound represented by formula 2 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof

    wherein in reaction formula 2, R1, R2, R3, and R4 are as defined in formula 1 of claim 1.
     
    9. A pharmaceutical composition for use in prevention or treatment of neurological disease comprising the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.
     
    10. The pharmaceutical composition for use according to claim 9, wherein the pharmaceutical composition is characterized by being effective in preventing or treating neurological disease by suppressing the over-activation of microglial cells.
     
    11. The pharmaceutical composition for use according to claim 9, wherein the pharmaceutical composition is characterized by being effective in preventing or treating neurological disease by suppressing the activity of acetylcholine esterase.
     
    12. The pharmaceutical composition for use according to claim 9, wherein the pharmaceutical composition is characterized by being effective in preventing or treating neurological disease by suppressing the activity of JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, or JNK3.
     
    13. The pharmaceutical composition for use according to claim 9, wherein the neurological disease is Alzheimer's disease, dementia, stroke, or neurological inflammation.
     
    14. The pharmaceutical composition for use according to claim 9, wherein the neurological disease is one or more diseases selected from the group consisting of Alzheimer's disease, Huntington's disease, Dandy-walker syndrome, Parkinson's disease, Parkinson-plus disease, amyotrophic lateral sclerosis (ALS), ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, brain barrier disorder, trigeminal neuralgia, tongue pharyngeal pain, Bell's palsy, myasthenia gravis, dystrophy, progressive muscular dystrophy, primary lateral sclerosis (PLS), false medulla oblongata palsy, progressive medulla oblongata palsy, progressive supranuclear palsy, spinal muscular atrophy, hereditary muscular dystrophy, invertebral disc syndrome, plexus disorder, cervical spondylosis, plexus disorder, chest exit syndrome, peripheral neuropathy, porphyria, multiple system atrophy, progressive supranuclear palsy, cortical basal degeneration, Lewy body dementia, anterior temporal dementia, dehydration disease, Guillain-Barre syndrome, multiple sclerosis, Charcot-Marie-Tooth disease, prion disease, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, AIDS dementia complex; nerve damage due to exposure to toxic compounds selected from the group consisting of heavy metals, industrial solvents, drugs and chemotherapeutic agents; nervous system damage caused by physical, mechanical, or chemical trauma; glaucoma, lattice dystrophy, retinal pigment degeneration, age-related macular degeneration (AMD), photoreceptor degeneration associated with habit or dry AMD, other retinal degeneration, optic nerve drusen, optic neuropathy and optic neuritis.
     
    15. A health functional food composition for use in prevention or improvement of neurological disease comprising the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.
     
    16. The health functional food composition for use according to claim 15, wherein the neurological disease is Alzheimer's disease, dementia, stroke, or neurological inflammation.
     


    Ansprüche

    1. Verbindung, die durch die folgende Formel 1 dargestellt ist, ein Stereoisomer davon oder ein pharmazeutisch akzeptables Salz davon:

    wobei in der Formel 1 oben

    R1 nichtsubstituiertes oder substituiertes gerades oder verzweigtes C1-6-Alkyl, nichtsubstituiertes oder substituiertes gerades oder verzweigtes ungesättigtes C1-6-Alkyl, das eine oder mehrere Doppelbindungen oder Dreifachbindungen enthält, nichtsubstituiertes oder substituiertes C3-10-Cycloalkyl, nichtsubstituiertes oder substituiertes C3-10-Heterocycloalkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, nichtsubstituiertes oder substituiertes C6-10-Aryl-C1-3-alkyl, nichtsubstituiertes oder substituiertes C6-10-Aryl, nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl-C1-3alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, oder nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, ist,

    wobei das substituierte Alkyl, Alkenyl, Cycloalkyl, Heterocycloalkyl, Arylalkyl, Aryl, Heteroarylalkyl oder Heteroaryl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus substituiertem oder nichtsubstituiertem C6-16-Arylsulfonyl, substituiertem oder nichtsubstituiertem C6-10-Arylsulfonyl-C1-5-alkyl, substituiertem oder nichtsubstituiertem C6-16-Aryl, substituiertem oder nichtsubstituiertem C6-16-Aryl-C1-5-alkyl, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroarylsulfonyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroarylsulfonyl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroaryl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind,

    wobei das substituierte C6-16-Arylsulfonyl, C6-10-Arylsulfonyl-C1-5-alkyl, C6-16-Aryl, C6-10-Aryl-C1-5-alkyl, 5- bis 10-gliedrige Heteroarylsulfonyl, 5- bis 10-gliedrige Heteroarylsulfonyl-C1-5-alkyl, 5- bis 10-gliedrige Heteroaryl, 5- bis 10-gliedrige Heteroaryl-C1-5-alkyl oder gerade oder verzweigte C1-6-Alkyl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind;

    R2 Wasserstoff, nichtsubstituiertes oder substituiertes gerades oder verzweigtes C1-6-Alkyl, nichtsubstituiertes oder substituiertes gerades oder verzweigtes ungesättigtes C1-6-Alkyl, das eine oder mehrere Doppelbindungen oder Dreifachbindungen enthält, nichtsubstituiertes oder substituiertes C3-10-Cycloalkyl, nichtsubstituiertes oder substituiertes C3-16-Heterocycloalkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, nichtsubstituiertes oder substituiertes C6-10-Aryl-C1-3-alkyl, nichtsubstituiertes oder substituiertes C6-16-Aryl, nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl-C1-3-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, oder nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, ist,

    wobei das substituierte Alkyl, Alkenyl, Cycloalkyl, Heterocycloalkyl, Arylalkyl, Aryl, Heteroarylalkyl oder Heteroaryl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus substituiertem oder nichtsubstituiertem C6-16-Arylsulfonyl, substituiertem oder nichtsubstituiertem C6-10-Arylsulfonyl-C1-5-alkyl, substituiertem oder nichtsubstituiertem C6-16-Aryl, substituiertem oder nichtsubstituiertem C6-16-Aryl-C1-5-alkyl, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroarylsulfonyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroarylsulfonyl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigen Heteroaryl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind,

    wobei das substituierte C6-16-Arylsulfonyl, C6-10-Arylsulfonyl-C1-5-alkyl, C6-16-Aryl, C6-10-Aryl-C1-5-alkyl, 5- bis 10-gliedrige Heteroarylsulfonyl, 5- bis 10-gliedrige Heteroarylsulfonyl-C1-5-alkyl, 5- bis 10-gliedrige Heteroaryl, 5- bis 10-gliedrige Heteroaryl-C1-5-alkyl oder gerade oder verzweigte C1-6-Alkyl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind; und

    R3 und R4 gleich oder verschieden sind und unabhängig Wasserstoff, nichtsubstituiertes oder substituiertes gerades oder verzweigtes C1-6-Alkyl,

    nichtsubstituiertes oder substituiertes gerades oder verzweigtes C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano sind,

    wobei das substituierte Alkyl oder Alkoxy unabhängig mit einem oder mehreren Substituenten ausgewählt ist, die aus der Gruppe bestehend aus Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind.


     
    2. Verbindung, das Stereoisomer davon oder das pharmazeutisch akzeptable Salz davon nach Anspruch 1, wobei das R1 nichtsubstituiertes oder substituiertes gerades oder verzweigtes C1-6-Alkyl, nichtsubstituiertes oder substituiertes gerades oder verzweigtes ungesättigtes C1-6-Alkyl, das eine oder mehrere Doppelbindungen oder Dreifachbindungen enthält, nichtsubstituiertes oder substituiertes C3-10-Cycloalkyl, nichtsubstituiertes oder substituiertes C3-10-Heterocycloalkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, nichtsubstituiertes oder substituiertes C6-16-Aryl oder nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, ist, wobei das substituierte Alkyl, Alkenyl, Cycloalkyl, Heterocycloalkyl, Aryl oder Heteroaryl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind.
     
    3. Verbindung, das Stereoisomer davon oder das pharmazeutisch akzeptable Salz davon nach Anspruch 1, wobei das R2 Wasserstoff, nichtsubstituiertes oder substituiertes gerades oder verzweigtes C1-6-Alkyl, nichtsubstituiertes oder substituiertes gerades oder verzweigtes ungesättigtes C1-6-Alkyl, das eine oder mehrere Doppelbindungen oder Dreifachbindungen enthält, nichtsubstituiertes oder substituiertes C3-10-Cycloalkyl, nichtsubstituiertes oder substituiertes C3-10-Heterocycloalkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, nichtsubstituiertes oder substituiertes C6-10-Aryl-C1-3-alkyl, nichtsubstituiertes oder substituiertes C6-10-Aryl, nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl-C1-3-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, oder nichtsubstituiertes oder substituiertes 5- bis 10-gliedriges Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, ist, wobei das substituierte Alkyl, Alkenyl, Cycloalkyl, Heterocycloalkyl, Arylalkyl, Aryl, Heteroarylalkyl oder Heteroaryl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus substituiertem oder nichtsubstituiertem Phenylsulfonyl, substituiertem oder nichtsubstituiertem Phenylsulfonyl-C1-5-alkyl, substituiertem oder nichtsubstituiertem Phenyl, substituiertem oder nichtsubstituiertem Phenyl-C1-5-alkyl, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigem Heteroarylsulfonyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigem Heteroarylsulfonyl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigem Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem 5- bis 10-gliedrigem Heteroaryl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertem oder nichtsubstituiertem geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind, wobei das substituierte Phenylsulfonyl, Phenylsulfonyl-C1-5-alkyl, Phenyl, Phenyl-C1-5-alkyl, 5- bis 10-gliedrige Heteroarylsulfonyl, 5- bis 10-gliedrige Heteroarylsulfonyl-C1-5-alkyl, 5-bis 10-gliedrige Heteroaryl, 5- bis 10-gliedrige Heteroaryl-C1-5-alkyl oder gerade oder verzweigte C1-6-Alkyl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind.
     
    4. Verbindung, das Stereoisomer davon oder das pharmazeutisch akzeptable Salz davon nach Anspruch 1, wobei das R1

    ist und R2







    ist.
     
    5. Verbindung, das Stereoisomer davon oder das pharmazeutisch akzeptable Salz davon nach Anspruch 1, wobei die Verbindung, die durch die Formel 1 dargestellt ist, aus der Gruppe bestehend aus den folgenden Verbindungen ausgewählt ist:

    (1) 5-Phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (2) 3-Methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (3) 3-Allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (4) 3-(2-Methylallyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (5) 3-(3-Butenyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (6) 3-Benzyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (7) 3-(4-Fluorbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (8) 3-(4-Chlorbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (9) 3-(3-Brombenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (10) 3-(4-Brombenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (11) 3-(4-Trifluormethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (12) 3-(4-Nitrobenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (13) 3-(2-(Phenylsulfonylmethyl)benzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (14) 3-(3,5-Ditrifluormethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (15) 3-(3,5-Dimethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (16) 3-(2-Nitro-4-trifluormethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (17) 3-(2-Fluor-6-trifluormethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (18) 3-(2-Chlor-5-trifluormethylbenzyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (19) 3-Benzyl-5-(pyridin-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion,

    (20) 3-Methyl-5-(pyridin-3-yl)-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (21) 3-Methyl-8-fluor-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (22) 3-Allyl-8-fluor-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (23) 3-Benzyl-8-fluor-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (24) 3,8-Dimethyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (25) 3-Allyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (26) 3-(2-Methylallyl)-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (27) 3-Benzyl-8-methyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (28) 3,5-Dimethyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (29) 3-Allyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (30) 3-(3-Butenyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (31) 3-(2-Methylallyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (32) 3-Benzyl-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (33) 3-(4-Fluorbenzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (34) 3-(4-Brombenzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (35) 3-(4-Cyanobenzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (36) 3-(2-(Phenylsulfonylmethyl)benzyl)-5-methyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (37) 3-Allyl-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (38) 3-((1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (39) 3-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (40) 3-Methyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (41) 3-Allyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (42) 3-(4-Fluorbenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (43) 3-(4-Trifluormethylbenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (44) 3-(4-Cyanobenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (45) 3-(2-Fluor-6-trifluormethylbenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (46) 3-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion;

    (47) 3-(3-Brombenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion und

    (48) 5-Isopropyl-3-(4-nitrobenzyl)-1-oxa-5-azaspiro[5,5]undeca-7,10-dien-4,9-dion.


     
    6. Herstellungsverfahren für die Verbindung, die durch die Formel 1 nach Anspruch 1 dargestellt ist, umfassend den Schritt eines Herstellens der Verbindung, die durch die Formel 1 dargestellt ist, aus der Verbindung, die durch die Formel (2) dargestellt ist (Schritt 1), wie in der folgenden Reaktionsformel 1 gezeigt:

    wobei in der Reaktionsformel 1 R1, R2, R3 und R4 wie in der Formel 1 nach Anspruch 1 definiert sind.
     
    7. Herstellungsverfahren nach Anspruch 6, wobei der Schritt 1 sich aus den folgenden Unterschritten zusammensetzt, wie in der Reaktionsformel 1' gezeigt:

    Herstellen der Verbindung, die durch die Formel 1" dargestellt ist, aus der Verbindung, die durch die Formel 2' dargestellt ist (Schritt 2); und

    Herstellen der Verbindung, die durch die Formel 1 dargestellt ist, aus der Verbindung, die durch die Formel 1" dargestellt ist (Schritt 3):

    wobei in der Reaktionsformel 1'

    R1, R3 und R4 wie in der Formel 1 nach Anspruch 1 definiert sind;

    R2' gerades oder verzweigtes C1-5-Alkinyl ist, das eine oder mehrere Dreifachbindungen enthält; und

    R2 vorzugsweise

    ist,

    wobei Ra gerades oder verzweigtes C1-5-Alkylen ist,

    Rb Wasserstoff, substituiertes oder nichtsubstituiertes C6-10-Arylsulfonyl, substituiertes oder nichtsubstituiertes C6-10-Arylsulfonyl-C1-5-alkyl, substituiertes oder nichtsubstituiertes C6-16-Aryl, substituiertes oder nichtsubstituiertes C6-10-Aryl-C1-5-alkyl, substituiertes oder nichtsubstituiertes 5- bis 10-gliedriges Heteroarylsulfonyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertes oder nichtsubstituiertes 5- bis 10-gliedriges Heteroarylsulfonyl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertes oder nichtsubstituiertes 5- bis 10-gliedriges Heteroaryl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertes oder nichtsubstituiertes 5- bis 10-gliedriges Heteroaryl-C1-5-alkyl, das ein oder mehrere Heteroatome enthält, die aus der Gruppe bestehend aus N, O und S ausgewählt sind, substituiertes oder nichtsubstituiertes gerades oder verzweigtes C1-6-Alkyl, gerades oder verzweigtes C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro oder Cyano ist, wobei das substituierte C6-16-Arylsulfonyl, C6-10-Arylsulfonyl-C1-5-alkyl, C6-16-Aryl, C6-10-Aryl-C1-5-alkyl, 5- bis 10-gliedrige Heteroarylsulfonyl, 5- bis 10-gliedrige Heteroarylsulfonyl-C1-5-alkyl, 5- bis 10-gliedrige Heteroaryl, 5- bis 10-gliedrige Heteroaryl-C1-5-alkyl oder gerade oder verzweigte C1-6-Alkyl unabhängig mit einem oder mehreren Substituenten substituiert ist, die aus der Gruppe bestehend aus geradem oder verzweigtem C1-6-Alkyl, geradem oder verzweigtem C1-6-Alkoxy, Hydroxy, Halogen, Amino, Nitro und Cyano ausgewählt sind.


     
    8. Verbindung, die durch die folgende Formel 2 dargestellt ist, ein Stereoisomer davon oder ein pharmazeutisch akzeptables Salz davon:

    wobei in der Reaktionsformel 2 R1, R2, R3 und R4 wie in der Formel 1 nach Anspruch 1 definiert sind.
     
    9. Pharmazeutische Zusammensetzung zur Verwendung bei der Verhinderung oder Behandlung einer neurologischen Krankheit, umfassend die Verbindung, die durch die Formel 1 dargestellt ist, das Stereoisomer davon oder das pharmazeutisch akzeptable Salz davon nach Anspruch 1 als einen Wirkbestandteil.
     
    10. Pharmazeutische Zusammensetzung zur Verwendung nach Anspruch 9, wobei die pharmazeutische Zusammensetzung dadurch gekennzeichnet ist, dass sie beim Verhindern oder Behandeln einer neurologischen Krankheit durch Unterdrücken der Überaktivierung von Mikrogliazellen wirksam ist.
     
    11. Pharmazeutische Zusammensetzung zur Verwendung nach Anspruch 9, wobei die pharmazeutische Zusammensetzung dadurch gekennzeichnet ist, dass sie beim Verhindern oder Behandeln einer neurologischen Krankheit durch Unterdrücken der Aktivität von Acetylcholinesterase wirksam ist.
     
    12. Pharmazeutische Zusammensetzung zur Verwendung nach Anspruch 9, wobei die pharmazeutische Zusammensetzung dadurch gekennzeichnet ist, dass sie beim Verhindern oder Behandeln einer neurologischen Krankheit durch Unterdrücken der Aktivität von JNK1, CDK2/Cyclin O, DAPK1, PKCa, CDK1/Cyclin B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/Cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2 oder JNK3 wirksam ist.
     
    13. Pharmazeutische Zusammensetzung zur Verwendung nach Anspruch 9, wobei die neurologische Krankheit Alzheimer-Krankheit, Demenz, ein Schlaganfall oder eine neurologische Entzündung ist.
     
    14. Pharmazeutische Zusammensetzung zur Verwendung nach Anspruch 9, wobei es sich bei der neurologischen Krankheit um eine oder mehrere Krankheiten handelt, die aus der Gruppe bestehend aus Alzheimer-Krankheit, Morbus Huntington, Dandy-Walker-Fehlbildung, Parkinson-Krankheit, Parkinson-Plus-Syndrom, amyotropher Lateralsklerose (ALS), Ischämie, Schlaganfall, intrakranieller Blutung, Hirnblutung, Störung der Blut-Hirn-Schranke, Trigeminusneuralgie, Zungen-Rachen-Schmerzen, Bell-Lähmung, Erb-Goldflam-Syndrom, Dystrophie, progressiver Muskeldystrophie, primärer Lateralsklerose (PLS), falscher Medulla-oblongata-Lähmung, progressiver Medulla-oblongata-Lähmung, progressiver supranukleärer Lähmung, spinaler Muskelatrophie, hereditärer Muskeldystrophie, Bandscheibensyndrom, Plexusstörung, zervikaler Spondolyse, Plexusstörung, Brustaustrittssyndrom, peripherer Neuropathie, Porphyrie, multipler Systematrophie, progressiver supranukleärer Lähmung, kortikobasaler Degeneration, Lewy-Körper-Demenz, frontotemporaler Demenz, Dehydratationsstörung, Guillain-Barre-Syndrom, multipler Sklerose, Charcot-Marie-Tooth -Krankheit, Prionenkrankheit, Creutzfeldt-Jakob-Krankheit, Gerstmann-Straussler-Scheinker-Syndrom (GSS), letaler familiärer Insomnie (FFI), boviner spongiformer Enzephalopathie, Pick-Krankheit, Epilepsie, AIDS-Demenz-Komplex; Nervenschädigung aufgrund einer Aussetzung gegenüber toxischen Verbindungen, die aus der Gruppe bestehend aus Schwermetallen, gewerblichen Lösungsmitteln, Wirkstoffen und Chemotherapeutika ausgewählt sind; Nervensystemschädigung, die von einem physikalischen, mechanischen oder chemischen Trauma verursacht wird; Glaukom, Haab-Dimmer-Dystrophie, retinaler Pigmentdegeneration, altersbedingter Makuladegeneration (AMD), Photorezeptordegeneration, die mit feuchter oder trockener AMD assoziiert ist, anderer Retinadegeneration, Sehnervdrusen, optischer Neuropathie und optischer Neuritis ausgewählt sind.
     
    15. Reformkostzusammensetzung zur Verwendung bei der Verhinderung oder Behandlung einer neurologischen Krankheit, umfassend die Verbindung, die durch die Formel 1 dargestellt ist, das Stereoisomer davon oder das pharmazeutisch akzeptable Salz davon nach Anspruch 1 als einen Wirkstoff.
     
    16. Reformkostzusammensetzung zur Verwendung nach Anspruch 15, wobei die neurologische Krankheit Alzheimer-Krankheit, Demenz, ein Schlaganfall oder eine neurologische Entzündung ist.
     


    Revendications

    1. Composé représenté par la formule 1 ci-dessous, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci :

    dans lequel dans la formule 1 ci-dessus,

    R1 est un alkyle en C1-6 linéaire ou ramifié non substitué ou substitué, un alkyle insaturé en C1-6 linéaire ou ramifié non substitué ou substitué contenant une ou plusieurs doubles liaisons ou triples liaisons, un cycloalkyle en C3-10 non substitué ou substitué, un hétérocycloalkyle en C3-10 non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un aryl en C6-10 alkyle en C1-3 non substitué ou substitué, un aryle en C6-10 non substitué ou substitué, un hétéroaryl alkyle en C1-3 de 5 à 10 chaînons non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, ou un hétéroaryle de 5 à 10 chaînons non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S,

    dans lequel, l'alkyle, l'alcényle, le cycloalkyle, l'hétérocycloalkyle, l'arylalkyle, l'aryle, l'hétéroarylalkyle ou l'hétéroaryle substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un arylsulfonyle en C6-10 substitué ou non substitué, un arylsulfonyl en C6-10 alkyle en C1-5 substitué ou non substitué, un aryle en C6-10 substitué ou non substitué, un aryl en C6-10 alkyle en C1-5 substitué ou non substitué, un hétéroarylsulfonyle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un alkyle en C1-6 linéaire ou ramifié substitué ou non substitué, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro et un cyano,

    dans lequel l'arylsulfonyle en C6-10, l'arylsulfonyl en C6-10 alkyle en C1-5, l'aryle en C6-10, l'aryl en C6-10 alkyle en C1-5, l'hétéroarylsulfonyle de 5 à 10 chaînons, l'hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons, l'hétéroaryle de 5 à 10 chaînons, l'hétéroaryl alkyle en C1-5 de 5 à 10 chaînons, ou l'alkyle en C1-6 linéaire ou ramifié substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un alkyle en C1-6 linéaire ou ramifié, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène , un amino, un nitro et un cyano ;

    R2 est un atome d'hydrogène, un alkyle en C1-6 linéaire ou ramifié non substitué ou substitué, un alkyle en C1-6 insaturé linéaire ou ramifié non substitué ou substitué contenant une ou plusieurs doubles liaisons ou triples liaisons, un cycloalkyle en C3-10 non substitué ou substitué, un hétérocycloalkyle en C3-10 non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un aryl en C6-10 alkyle en C1-3 non substitué ou substitué, un aryle en C6-10 non substitué ou substitué, un hétéroaryl alkyle en C1-3 de 5 à 10 chaînons non substitué ou substitué contenant un ou plus hétéroatomes choisis dans le groupe constitué par N, O et S, ou un hétéroaryle de 5 à 10 chaînons non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S,

    dans lequel, l'alkyle, l'alcényle, le cycloalkyle, l'hétérocycloalkyle, l'arylalkyle, l'aryle, l'hétéroarylalkyle ou l'hétéroaryle substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un arylsulfonyle en C6-10 substitué ou non substitué, un arylsulfonyl en C6-10 alkyle en C1-5 substitué ou non substitué, un aryle en C6-10 substitué ou non substitué, un aryl en C6-10 alkyle en C1-5 substitué ou non substitué, un hétéroarylsulfonyle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un alkyle en C1-6 linéaire ou ramifié substitué ou non substitué, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro et un cyano,

    dans lequel l'arylsulfonyle en C6-10, l'arylsulfonyl en C6-10 alkyle en C1-5, l'aryle en C6-10, l'aryl en C6-10 alkyle en C1-5, l'hétéroarylsulfonyle de 5 à 10 chaînons, l'hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons, l'hétéroaryle de 5 à 10 chaînons, l'hétéroaryl alkyle en C1-5 de 5 à 10 chaînons, ou l'alkyle en C1-6 linéaire ou ramifié substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un alkyle en C1-6 linéaire ou ramifié, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro et un cyano ; et

    R3 et R4 sont identiques ou différents et sont indépendamment un atome d'hydrogène, un alkyle en C1-6 linéaire ou ramifié non substitué ou substitué, un alcoxy en C1-6 linéaire ou ramifié non substitué ou substitué, un hydroxy, un atome d'halogène , un amino, un nitro et un cyano,

    dans lesquels, l'alkyle ou l'alcoxy substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un hydroxy, un atome d'halogène, un amino, un nitro et un cyano.


     
    2. Composé, stéréoisomère de celui-ci, ou sel pharmaceutiquement acceptable de celui-ci selon la revendication 1, dans lequel le R1 est un alkyle en C1-6 linéaire ou ramifié non substitué ou substitué, un alkyle en C1-6 insaturé linéaire ou ramifié non substitué ou substitué contenant une ou plusieurs doubles liaisons ou triples liaisons, un cycloalkyle en C3-10 non substitué ou substitué, un hétérocycloalkyle en C3-10 non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un aryle en C6-16 non substitué ou substitué, ou un hétéroaryle de 5 à 10 chaînons non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, dans lequel, l'alkyle, l'alcényle, le cycloalkyle, l'hétérocycloalkyle, l'aryle, ou l'hétéroaryle substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un alkyle en C1-6 linéaire ou ramifié, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro et un cyano.
     
    3. Composé, stéréoisomère de celui-ci, ou sel pharmaceutiquement acceptable de celui-ci selon la revendication 1, dans lequel le R2 est un atome d'hydrogène, un alkyle en C1-6 linéaire ou ramifié non substitué ou substitué, un alkyle en C1-6 insaturé linéaire ou ramifié non substitué ou substitué contenant une ou plusieurs doubles liaisons ou triples liaisons, un cycloalkyle en C3-10 non substitué ou substitué, un hétérocycloalkyle en C3-10 non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un aryl en C6-10 alkyle en C1-3 non substitué ou substitué, un aryle en C6-10 non substitué ou substitué, un hétéroaryl alkyle en C1-3 de 5 à 10 chaînons non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, ou un hétéroaryle de 5 à 10 chaînons non substitué ou substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, dans lequel, l'alkyle, l'alcényle, le cycloalkyle, l'hétérocycloalkyle, l'arylalkyle, l'aryle, l'hétéroarylalkyle ou l'hétéroaryle substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un phénylsulfonyle substitué ou non substitué, un phénylsulfonyl alkyle en C1-5 substitué ou non substitué, un phényle substitué ou non substitué, un phényl alkyle en C1-5 substitué ou non substitué, un hétéroarylsulfonyle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un alkyle en C1-6 linéaire ou ramifié substitué ou non substitué, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro et un cyano, dans lequel le phénylsulfonyle, le phénylsulfonyl alkyle en C1-5, le phényle, le phényl alkyle en C1-5, l'hétéroarylsulfonyle de 5 à 10 chaînons, l'hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons, l'hétéroaryle de 5 à 10 chaînons, l'hétéroaryl alkyle en C1-5 de 5 à 10 chaînons, ou l'alkyle en C1-6 linéaire ou ramifié substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un alkyle en C1-6 linéaire ou ramifié, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro et un cyano.
     
    4. Composé, stéréoisomère de celui-ci, ou sel pharmaceutiquement acceptable de celui-ci selon la revendication 1, dans lequel le R1 est

    ou

    et R2 est








     
    5. Composé, stéréoisomère de celui-ci, ou sel pharmaceutiquement acceptable de celui-ci selon la revendication 1, dans lequel le composé représenté par la formule 1 est choisi dans le groupe constitué par les composés suivants :

    (1) la 5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione;

    (2) la 3-méthyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (3) la 3-allyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (4) la 3-(2-méthyl-allyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (5) la 3-(3-butényl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione;

    (6) la 3-benzyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (7) la 3-(4-fluoro-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (8) la 3-(4-chloro-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (9) la 3-(3-bromo-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (10) la 3-(4-bromo-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (11) la 3-(4-trifluorométhyl-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (12) la 3-(4-nitro-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (13) la 3-(2-(phénylsulfonylméthyl)-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (14) la 3-(3,5-ditrifluorométhyl-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (15) la 3-(3,5-diméthyl-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione;

    (16) la 3-(2-nitro-4-trifluorométhyl-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (17) la 3-(2-fluoro-6-trifluorométhyl-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (18) la 3-(2-chloro-5-trifluorométhyl-benzyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (19) la 3-benzyl-5-(pyridin-3-yl)-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (20) la 3-méthyl-5-(pyridin-3-yl)-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (21) la 3-méthyl-8-fluoro-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (22) la 3-allyl-8-fluoro-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (23) la 3-benzyl-8-fluoro-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (24) la 3,8-diméthyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (25) la 3-allyl-8-méthyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (26) la 3-(2-méthyl-allyl)-8-méthyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (27) la 3-benzyl-8-méthyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (28) la 3,5-diméthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (29) la 3-allyl-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (30) la 3-(3-butényl)-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (31) la 3-(2-méthyl-allyl)-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (32) la 3-benzyl-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (33) la 3-(4-fluoro-benzyl)-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (34) la 3-(4-bromo-benzyl)-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (35) la 3-(4-cyano-benzyl)-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (36) la 3-(2-(phénylsulfonylméthyl)-benzyl)-5-méthyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (37) la 3-allyl-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (38) la 3-((1-(4-méthoxyphényl)-1H-1,2,3-triazol-4-yl)méthyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (39) la 3-((1-benzyl-1H-1,2,3-triazol-4-yl)méthyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (40) la 3-méthyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione;

    (41) la 3-allyl-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (42) la 3-(4-fluoro-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione;

    (43) la 3-(4-trifluorométhyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (44) la 3-(4-cyano-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (45) la 3-(2-fluoro-6-trifluorométhyl-benzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (46) la 3-((1-phényl-1H-1,2,3-triazol-4-yl)méthyl)-5-phényl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;

    (47) la 3-(3-bromobenzyl)-5-isopropyl-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione ;et

    (48) la 5-isopropyl-3-(4-nitrobenzyl)-1-oxa-5-azaspiro[5,5]undéca-7,10-diène-4,9-dione.


     
    6. Procédé de préparation du composé représenté par la formule 1 de la revendication 1, comprenant l'étape de préparation du composé représenté par la formule 1 à partir du composé représenté par la formule 2 (étape 1), comme indiqué dans la formule de réaction 1 ci-dessous :

    dans lequel dans la formule de réaction 1, R1, R2, R3 et R4 sont tels que définis dans la formule 1 de la revendication 1.
     
    7. Procédé de préparation selon la revendication 6, dans lequel l'étape 1 est composée des sous-étapes suivantes, comme indiqué dans la formule de réaction 1' :

    préparation du composé représenté par la formule 1" à partir du composé représenté par la formule 2' (étape 2) ; et

    préparation du composé représenté par la formule 1 à partir du composé représenté par la formule 1" (étape 3)

    dans lequel dans la formule de réaction 1',

    R1, R3 et R4 sont tels que définis dans la formule 1 de la revendication 1 ;

    R2' est un alcynyle en C1-5 linéaire ou ramifié contenant une ou plusieurs triples liaisons ; et

    R2 est de préférence

    dans lequel, Ra est un alkylène en C1-5 linéaire ou ramifié,

    Rb est un atome d'hydrogène, un arylsulfonyle en C6-10 substitué ou non substitué, un arylsulfonyl en C6-10 alkyle en C1-5 substitué ou non substitué, un aryle en C6-10 substitué ou non substitué, un aryl en C6-10 alkyle en C1-5 substitué ou non substitué, un hétéroarylsulfonyle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryle de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un hétéroaryl alkyle en C1-5 de 5 à 10 chaînons substitué ou non substitué contenant un ou plusieurs hétéroatomes choisis dans le groupe constitué par N, O et S, un alkyle en C1-6 linéaire ou ramifié substitué ou non substitué, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène, un amino, un nitro ou un cyano, dans lequel l'arylsulfonyle en C6-10, l'arylsulfonyl en C6-16 alkyle en C1-5, l'aryle en C6-10, l'aryl en C6-10 alkyle en C1-5, l'hétéroarylsulfonyle de 5 à 10 chaînons, l'hétéroarylsulfonyl alkyle en C1-5 de 5 à 10 chaînons, l'hétéroaryle de 5 à 10 chaînons, l'hétéroaryl alkyle en C1-5 de 5 à 10 chaînons, ou l'alkyle en C1-6 linéaire ou ramifié substitué est indépendamment substitué par un ou plusieurs substituants choisis dans le groupe constitué par un alkyle en C1-6 linéaire ou ramifié, un alcoxy en C1-6 linéaire ou ramifié, un hydroxy, un atome d'halogène , un amino, un nitro et un cyano.


     
    8. Composé représenté par la formule 2 ci-dessous, stéréoisomère de celui-ci, ou sel pharmaceutiquement acceptable de celui-ci.

    dans lequel dans la formule de réaction 2, R1, R2, R3 et R4 sont tels que définis dans la formule 1 de la revendication 1.
     
    9. Composition pharmaceutique pour une utilisation dans la prévention ou le traitement d'une maladie neurologique comprenant le composé représenté par la formule 1, le stéréoisomère de celui-ci, ou le sel pharmaceutiquement acceptable de celui-ci selon la revendication 1 en tant que principe actif.
     
    10. Composition pharmaceutique pour une utilisation selon la revendication 9, dans laquelle la composition pharmaceutique est caractérisée en ce qu'elle est efficace dans la prévention ou le traitement d'une maladie neurologique par suppression de la suractivation des cellules microgliales.
     
    11. Composition pharmaceutique pour une utilisation selon la revendication 9, dans laquelle la composition pharmaceutique est caractérisée en ce qu'elle est efficace dans la prévention ou le traitement d'une maladie neurologique par suppression de l'activité de l'acétylcholine estérase.
     
    12. Composition pharmaceutique pour une utilisation selon la revendication 9, dans laquelle la composition pharmaceutique est caractérisée en ce qu'elle est efficace dans la prévention ou le traitement d'une maladie neurologique par suppression de l'activité de JNK1, CDK2/cycline O, DAPK1, PKCa, CDK1/cycline B, MST3/STK24, TLK1, JNK2, RIPK5, CDK3/cycline E, PKN2/PRK2, l'Haspine, STK25/YSK1, ARK5/NUAK1, PKCb2 ou JNK3.
     
    13. Composition pharmaceutique pour une utilisation selon la revendication 9, dans laquelle la maladie neurologique est la maladie d'Alzheimer, une démence, un accident vasculaire cérébral ou une inflammation neurologique.
     
    14. Composition pharmaceutique pour une utilisation selon la revendication 9, dans laquelle la maladie neurologique est une ou plusieurs maladies choisies dans le groupe constitué par la maladie d'Alzheimer, la maladie d'Huntington, le syndrome de Dandy-Walker, la maladie de Parkinson, la maladie de Parkinson-plus, la sclérose latérale amyotrophique (SLA), une ischémie, un accident vasculaire cérébral, une hémorragie intracrânienne, une hémorragie cérébrale, un trouble de la barrière encéphalique, une névralgie du trijumeau, une douleur de la langue et du pharynx, la paralysie de Bell, la myasthénie grave, une dystrophie, la dystrophie musculaire progressive, la sclérose latérale primitive (PLS), la fausse paralysie du bulbe rachidien, la paralysie progressive du bulbe rachidien, la paralysie supranucléaire progressive, l'amyotrophie spinale, la dystrophie musculaire héréditaire, le syndrome du disque invertébral, un trouble du plexus, la spondylose cervicale, un trouble du plexus, le syndrome du défilé thoracique, une neuropathie périphérique, une porphyrie, l'atrophie multisystématisée, la paralysie supranucléaire progressive, la dégénérescence corticobasale, la démence à corps de Lewy, la démence due au lobe temporal antérieur, une maladie liée à la déshydratation, le syndrome de Guillain-Barré, la sclérose en plaques, la maladie de Charcot-Marie-Tooth, une maladie à prions, la maladie de Creutzfeldt-Jakob, le syndrome de Gerstmann-Straussler-Scheinker (GSS), l'insomnie familiale fatale (FFI), l'encéphalopathie spongiforme bovine, la maladie de Pick, l'épilepsie, la démence associée au sida; les lésions nerveuses dues à une exposition à des composés toxiques choisis dans le groupe constitué par les métaux lourds, les solvants industriels, les médicaments et les agents chimiothérapeutiques ; les dommages au système nerveux causés par un traumatisme physique, mécanique ou chimique ; le glaucome, la dystrophie grillagée, la dégénérescence pigmentaire rétinienne, la dégénérescence maculaire liée à l'âge (DMLA), la dégénérescence des photorécepteurs associée aux habitudes ou à la DMLA sèche, une autre dégénérescence rétinienne, les drusen de la papille optique, la neuropathie optique et la névrite optique.
     
    15. Composition d'aliment fonctionnel diététique pour une utilisation dans la prévention ou l'amélioration d'une maladie neurologique comprenant le composé représenté par la formule 1, le stéréoisomère de celui-ci, ou le sel pharmaceutiquement acceptable de celui-ci selon la revendication 1 en tant que principe actif.
     
    16. Composition d'aliment fonctionnel diététique pour une utilisation selon la revendication 15, dans laquelle la maladie neurologique est la maladie d'Alzheimer, une démence, un accident vasculaire cérébral ou une inflammation neurologique.
     




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    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description




    Non-patent literature cited in the description