WO2016153242A1 - Pharmaceutical composition for treating or preventing central nervous system disease - Google Patents

Abstract

The present invention relates to an amide derivative compound or a pharmaceutically acceptable salt thereof. Also, the present invention relates to a pharmaceutical composition for treating or preventing central nervous system disease, the composition comprising the compound or the pharmaceutically acceptable salt thereof.

Description

명세서  Specification

발명의명칭:중추신경계질환의치료또는예방용약학조성물 기술분야  NAME OF THE INVENTION: Therapeutic or prophylactic pharmaceutical compositions of central nervous system diseases

[1] 본발명은아미드유도체화합물또는이의약학적으로허용가능한염에관한 것이다.또한,본발명은상기화합물또는이의약학적으로허용가능한염을 포함하는증추신경계질환의치료또는예방용약학조성물에관한것이다. 배경기술  [1] The present invention relates to an amide derivative compound or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a pharmaceutical composition for the treatment or prevention of diseases of the nervous system comprising the compound or a pharmaceutically acceptable salt thereof. It's about. Background

[2] 중추신경계는뇌와척수를포함하는신경계로서 ,감각신경과운동신경을  [2] The central nervous system, including the brain and spinal cord, is a sensory and motor nerve.

제어하는중추적인역할을한다.말초신경계와달리 , ^추신경계는한번 손상되면다시정상으로회복하는것이어렵다고알려져있다.  Unlike the peripheral nervous system, the PS system is known to be difficult to recover once it is damaged.

[3] 중추신경계의손상으로인해야기되는질환의대표적인예에는,외상성  [3] Typical examples of diseases caused by damage to the central nervous system include: traumatic

뇌손상，뇌졸증，뇌경색,소아뇌성마비 ,다발성축삭경화증,근위축성측삭 경화증,척수손상，시신경손상,특히외상또는녹내장에의한시신경손상, 루게릭병,알츠하이머병，헌팅톤병，파킨슨병둥이포함된다.더욱이, 중추신경계의손상은신체기능의여러장애들을초래하며합병증을동반할수 있는위험을크게갖고있다.  Brain injury, stroke, cerebral infarction, pediatric cerebral palsy, multiple axonal sclerosis, amyotrophic lateral sclerosis, spinal cord injury, optic nerve injury, especially optic nerve damage caused by trauma or glaucoma, Lou Gehrig's disease, Alzheimer's disease, Huntington's disease, Parkinson's disease. Moreover, damage to the central nervous system leads to several disorders of the body's function and is at greater risk of accompanying complications.

[4] 중추신경계가손상된경우,그회복또는복구를방해하는요인은크게외인성 요인과내재성요인으로구분할수있다.  [4] In the case of damage to the central nervous system, factors that hinder its recovery or repair can be largely divided into exogenous and intrinsic factors.

[5] 상기외인성요인은신경세포밖에서축삭돌기의성장을조절하는역할을  [5] The exogenous factors play a role in regulating the growth of axons outside neurons.

하며,여기에는신경계를구성하는교세포 (oligodendrocyte)의세포막에존재하는 MAG(myelin-associated glycoprotein), OMgp(01igodendrocyte myelin glycoprotein), Nogo뿐만아니라신경손상부위에형성되는 CSPG(chondroitin sulfate proteoglycan)등이대표적으로알려져있다 (Fitch, M.T. et al., CNS injury, glial scars, and inflammation: inhibitory extracellular matrics and regeneration failure. Experimental Neurobiology, 2008).이러한외인성요인은손상된축삭돌기가다시 성장하는것을억제한다고보고되었으며，최근에는외인성요인으로서밝혀진 인자들의활성을저해시킴으로써신경손상을치료하려는연구가진행되고 있다.  In addition, MAG (myelin-associated glycoprotein) (MAG), OMgp (01igodendrocyte myelin glycoprotein), Nogo, and CSPG (chondroitin sulfate proteoglycan) formed on the nerve injury site are present in the membranes of oligodendrocytes constituting the nervous system. (Fitch, MT et al., CNS injury, glial scars, and inflammation: inhibitory extracellular matrics and regeneration failure. Experimental Neurobiology, 2008). Recently, research has been conducted to treat nerve damage by inhibiting the activity of factors identified as exogenous factors.

[6] 상기내재성요인은신경세포내에서축삭돌기의성장을조절하는역할을  [6] These endogenous factors play a role in regulating the growth of axons in neuronal cells.

하며 (Sun, F. et al., Neuronal intrinsic barriers for axon regeneration in the adult CNS. Current opinion in Neurobiology, 2010)，여기에는 2가지유형이있다.먼저, 축삭돌기의성장을촉진시키는내재성요인으로서 cAMP, mTOR(mammalian target of rapamycin), JAK/STAT신호전달체계둥이대표적으로알려져있으며 , 이들은손상된말초신경계에서다시활성화되지만손상된중추신경계에서는 여전히블활성화된상태로존재하는것으로보고되었다.반면,축삭돌기의 성장을억제시키는내재성요인으로서 , PTEN단백질은 mTOR단백질의활성을 저해하는것으로알려져있으며，세포분열에관여하는 APC-Cdhl단백질은성체 포유류의신경세포에서과발현되어축삭돌기의성장을억제하는것으로알려져 있다. (Sun, F. et al., Neuronal intrinsic barriers for axon regeneration in the adult CNS.Current opinion in Neurobiology, 2010), and there are two types: first, as intrinsic factors that promote the growth of axons. The cAMP, the mTOR (mammalian target of rapamycin) and the JAK / STAT signaling system are known to be representative, and they have been reported to be reactivated in the damaged peripheral nervous system but remain active in the damaged central nervous system. As an intrinsic factor that inhibits the growth of PTEN, PTEN protein may inhibit the activity of mTOR APC-Cdhl protein, which is involved in cell division, is known to inhibit the growth of axons by overexpression in neuronal cells of adult mammals.

[7] 축삭돌기의성장은배아의발달기간동안활발하게일어나지만，일단출생한 이후에는거의중지된다.이는축삭돌기의성장을촉진시키는신경세포내의 내재성요인이출생이후에는제대로기능하지못함으로써초래되는현상이다. 이와관련하여 ,감각신경과운동신경으로대표되는말초신경계는신경손상 이후에도회복이가능하다고알려져있는데，그이유는축삭돌기의성장을 촉진시키는내재성요인이신경손상후에다시활성화된다는이론에의해 설명되고있다.반면,중추신경계에존재하는내재성요인은신경손상이후에도 다시활성화되지않는다고보고되었다.따라서，신경손상이후에불활성화되어 있는내재성요인을다시활성화시켜줄수있는화합물을개발하는것이， 중추신경계질환을치료또는예방하기위한대책들중하나로서증요하게 고려될수있다.최근에,축삭돌기의성장을촉진시키는내재성요인 (예를들어， mTOR)의활성올인위적으로조절하는전략을통해，시신경손상모델에서 축삭돌기가재생된효과를확인한연구결과가보고되었다 (Park, KK, et al., Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science, 2008).이러한실험결과들은축삭돌기의성장을촉진하는 약물이손상된중추신경계의치료제로서개발될수있다는점을시사하는 것이다.  [7] The growth of axons occurs vigorously during embryonic development, but is rarely stopped after birth, as the intrinsic factors in neurons that promote the growth of axons do not function properly after birth. It is a phenomenon that results. In this regard, the peripheral nervous system, which is represented by the sensory and motor nerves, is known to be able to recover even after nerve damage, which is explained by the theory that the intrinsic factors that promote the growth of axons are reactivated after nerve injury. In contrast, it has been reported that intrinsic factors present in the central nervous system are not reactivated after neurological damage. Therefore, developing compounds that can reactivate intrinsic factors that are inactivated after neurological damage have been reported. It can be considered as one of the measures to treat or prevent it. Recently, the optic nerve damage model is through an artificially controlled strategy of intrinsic factors (eg mTOR) that promote the growth of axons. A study on the effects of axonal regeneration in humans has been reported (Park, KK, et al., Promoting axon regeneration in the adult CNS by modula) tion of the PTEN / mTOR pathway.Science, 2008) .These findings suggest that drugs that promote the growth of axons could be developed as treatments for damaged central nervous systems.

[8] 또한，중추신경계의손상은전기적자극의전달통로인축삭돌기의파괴및 신경세포자체의사멸과연관된다는점에주목하여야한다.따라서，손상된 중추신경을회복시키는것은,파괴된축삭돌기의재생및신경세포자체의 보호의 2개측면에서접근할수있다.이러한이유로인해，현재당해업계에서 연구되고있는약물들은대부분상기 2개측면에주안점을두고진행되고있다. 특히，축삭돌기의재생효과를갖는약물과신경세포의보호효과를갖는약물올 혼합하여사용하는조합요법에대한관심이점점더커지고있다 (Stakeholder opinions: Spinal Cord Injury, Datamonitor 2010).  [8] It is also important to note that damage to the central nervous system is associated with the destruction of the axons, which are the transmission pathways of electrical stimulation, and with the death of the neurons themselves. Two aspects of regenerative and neuronal cell protection are accessible. For this reason, most of the drugs currently being studied in the industry have been focused on these two aspects. In particular, there is a growing interest in combination therapies for the combination of drugs with regenerative effects of axons and those with neuroprotective effects (Stakeholder opinions: Spinal Cord Injury, Datamonitor 2010).

[9] 그러나,전술한기대와노력에도불구하고，손상된중추신경계를유의적으로 회복시킬수있는만족할만한약물은여전히개발되지못하고있는것이현재 상황이다.  [9] In spite of the above expectations and efforts, however, no satisfactory drugs are available that can significantly restore the damaged central nervous system.

발명의상세한설명  Detailed description of the invention

기술적과제  Technical task

[ 10] 본발명은중추신경계질환의예방또는치료에유용하게사용할수있는  [10] The present invention can be useful for the prevention or treatment of central nervous system diseases.

화합물또는이의약학적으로허용가능한염，및이를포함하는약학조성물을 제공하는것을목적으로한다.  It is an object to provide a compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the same.

과제해결수단 [11] 상기과제를해결하기위하여，본출원인 (재)경기과학기술진흥원 경기바이오센터내에구축되어있는약 18만여종의화합물들을이용하였다.본 발명자들이순차적으로수행한스크리닝과정은후술하는실시예에구체적으로 기재하였다.요약하면,먼저마우스의배아암종세포주인 P19세포모델에서 P19세포의분화및신경돌기의증식을촉진시키는화합물들을 Task solution [11] In order to solve the above problem, about 180,000 compounds built in the Gyeonggi Bio Center of the Gyeonggi Institute of Science and Technology were used. The screening process performed by the present inventors was performed in the following examples. In summary, in the P19 cell model, a mouse embryonic carcinoma cell line, compounds that promote differentiation and proliferation of neurites are first identified.

스크리닝하였으며,선별된화합물들중에서 SD래트배아의뇌  Screened and selected brains of SD rat embryos

해마 (hippocampus)신경세포의축삭돌기의성장을촉진시키는화합물들을 스크리닝하였으며,마지막으로 SD래트태아의전뇌피질 (cortex)신경세포의 사멸을억제시키는화합물을스크리닝하였다.  Compounds that promote the growth of axons of hippocampus neurons were screened and finally compounds that inhibited the death of cortex neurons in SD rat fetuses were screened.

[12] 이와같이본발명에서원하는후보화합물을스크리닝한후,본발명자들은 축삭돌기의길이측정시험,세포독성시험，신경재생시험등을통해손상된 증추신경계의재생에유의적인효과를나타내는화합물의구조를최적화할수 있었다.  [12] After screening the candidate compounds desired in the present invention, the present inventors developed a structure of a compound that exhibits a significant effect on the regeneration of the damaged cerebral nervous system through the measurement of axon projection, cytotoxicity, and nerve regeneration. I could optimize it.

[13] 그결과,하기화학식 1또는 2로표시되는아미드유도체화합물또는이의 약학적으로허용가능한염이중추신경계질환의예방또는치료용약학 조성물의유효성분으로서사용될때예측하지못한유의적효과를나타낸다는 것올발견하였다.  [13] As a result, when the amide derivative compound represented by the following formula (1) or (2) or a pharmaceutically acceptable salt thereof is used as an active ingredient in the preventive or therapeutic pharmaceutical composition of central nervous system disease, It was found.

[14] [화학식 1]  [14] [Formula 1]

[15] [15]

[16] 상기화학식 1에서，  [16] In Formula 1,

[17] - ¾은 수소원자， C1-C6알킬， C2-C6알케닐， C2-C6알키닐， C6-CK)

[17]-¾ is hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-CK)

아릴， C3-C10시클로알킬，또는 R₅로치환되거나비치환된 Ν, Ο및 S증에서 선택된하나이상의해테로원자를갖는 C3— 10해테로아릴또는 C3-10 heteroaryl having one or more heteroatoms selected from N, O and S substituted or unsubstituted with aryl, C3-C10 cycloalkyl, or R ₅

헤테로시클로알킬이며,  Heterocycloalkyl,

[18] •상기 R₅는수소원자，할로겐원자， C1-C6알킬, -OR₅, -0(CO)R₆, -N0₂, -N(R₆)₂ ， -CN, -COR₆, -NH(CO)R₆, -NH(CO)NHR₆, -NH(CS)NHR₆, -NH(S0₂)R₆, -SH, -SR₆₎ -SOR_fi, -S(CO)R_fi, -C0₂R₆, -α)Ν(¾)₂, -S0₃H, -≤0₂Ν(Ι _ή)₂및 -CF₃로이루어진 군에서독립적으로선택된 1개내지 5개의치환기로서，오르소，메타및파라 위치중하나이상의위치에결합되며, [18] The R ₅ is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl, -OR ₅ , -0 (CO) R ₆ , -N0 ₂ , -N (R ₆ ) ₂ , -CN, -COR ₆ , -NH (CO) R ₆ , -NH (CO) NHR ₆ , -NH (CS) NHR ₆ , -NH (S0 ₂ ) R ₆ , -SH, -SR ₆₎ -SOR _f i, -S (CO) _{R f i, -C0 2 R 6} , -α) Ν (¾) 2, -S0 3 H, -≤0 2 Ν (Ι ή) 2 and _3, 1 to 5 independently selected from the group consisting of -CF As a substituent, is bonded to at least one of the ortho, meta and para positions,

[19] •상기 R₆는서로독립적으로수소원자， C1-C6알킬， C2-C6알케닐， C2-C6 알키닐, C6-C10아릴, C3-C10시클로알킬，또는 Ν, Ο및 S중에서선택된하나 이상의헤테로원자를갖는 C3-10헤테로아릴또는헤테로시클로알킬이며; [20] - R₂는 ^ ^^ , ^， ° ¾r， oAo,수소원자, C1-C6알킬, [19] • R ₆ is independently selected from hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or N, O and S. C3-10 heteroaryl or heterocycloalkyl having one or more heteroatoms; [20]-R ₂ is ^ ^ ^, ^ ， ° ¾r, oAo, hydrogen atom, C1-C6 alkyl,

C2-C6알케닐, C2-C6알키닐， C6-C10아릴， C3-C10시클로알킬,토실기，또는 R₇ 로치환되거나비치환된 Ν, Ο및 S중에서선택된하나이상의헤테로원자를 갖는 C3-10헤테로아릴또는헤테로시클로알킬이며； C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, tosyl group, or R ₇ Roach ring or unsubstituted Ν, Ο and S C3- having one or more heteroatoms selected from 10 heteroaryl or heterocycloalkyl;

•상기 R₇는수소원자,할로겐원자, C1-C6알킬， -OR₈, -0(CO)R₈, -N0₂, -N(R_S)_: , -CN, -COR₈, -NH(CO)R₈, -NH(CO)NHR₈, -NH(CS)NHR₈, -NH(S0₂)R₈, -C0₂R₈, -CON(R₈)₂, -SR₈, -SOR₈, -S(CO)R₈, -SQ₃H, -S0₂N(R₈)₂, -S0₂R₈, -CF₃,

R ₇ is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl, -OR ₈ , -0 (CO) R ₈ , -N0 ₂ , -N (R _S ) _:, -CN, -COR ₈ , -NH ( CO) R ₈ , -NH (CO) NHR ₈ , -NH (CS) NHR ₈ , -NH (S0 ₂ ) R ₈ , -C0 ₂ R ₈ , -CON (R ₈ ) ₂ , -SR ₈ , -SOR ₈ , -S (CO) R ₈ , -SQ ₃ H, -S0 ₂ N (R ₈ ) ₂ , -S0 ₂ R ₈ , -CF ₃ ,

테트라졸릴로이루어진군에서독립적으로선택된 1개내지 5개의치환기로서 오르소，메타및파라위치중하나이상의위치에결합되며，  1 to 5 substituents independently selected from the group consisting of tetrazolyl, attached to one or more of ortho, meta and para positions,

[22] ·상기 R₈는서로독립적으로수소원자， C1-C6알킬, C2-C6알케닐， C2-C6 알키닐， C6-C10아릴， C3-C10시클로알킬,또는 N, O및 S중에서선택된하나 이상의헤테로원자를갖는 C3-10헤테로아릴또는헤테로시클로알킬이며; R ₈ is independently selected from a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or N, O and S C3-10 heteroaryl or heterocycloalkyl having one or more heteroatoms;

[23] - 수소원자, C1-C6알킬， C2-C6

[23]-hydrogen atom, C1-C6 alkyl, C2-C6

알케닐， C2-C6알키닐， C6-C10아릴， C3-C10시클로알킬,또는 R₉로치환되거나 비치환된 N, O및 S중에서선택된하나이상의해테로원자를갖는 C3-10 해테로아릴또는해테로시클로알킬이며; C3-10 heteroaryl having one or more heteroatoms selected from N, O and S substituted or unsubstituted with alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or R ₉ Heterocycloalkyl;

[24] ·상기 ¾는수소원자，할로겐원자， C1-C6알킬, -OR₁₀, -O(CO)R₁₀, -N0₂, -N(R 1₀)₂, -CN, -COR₁₀, -NH(CO)R₁₀, -NH(CO)NHR₁₀, -NH(CS)NHR₁₀, -NR₁₀(SO₂)R₁₀, -SR io, -SOR₁₀, -S(CO)R₁₀, -CO₂R₁₀, -CON(R₁₀)₂, -S0₃H, -SO₂N(R₁₀)₂, -CF₃,및 [24] The ¾ is hydrogen atom, halogen atom, C1-C6 alkyl, -OR ₁₀ , -O (CO) R ₁₀ , -N0 ₂ , -N (R 1 ₀ ) ₂ , -CN, -COR ₁₀ , -NH (CO) R ₁₀ , -NH (CO) NHR ₁₀ , -NH (CS) NHR ₁₀ , -NR ₁₀ (SO ₂ ) R ₁₀ , -SR io, -SOR ₁₀ , -S (CO) R ₁₀ , -CO ₂ R ₁₀ , -CON (R ₁₀ ) ₂ , -S0 ₃ H, -SO ₂ N (R ₁₀ ) ₂ , -CF ₃ , and

할로겐으로치환되거나비치환된피리디닐,디아졸릴,트리아졸릴및  Pyridinyl, diazolyl, triazolyl, substituted or unsubstituted with halogen, and

테트라졸릴로이루어진군에서독립적으로선택된 1개내지 5개의치환기로서, 오르소，메타및파라위치중하나이상의위치에결합되며，  1 to 5 substituents independently selected from the group consisting of tetrazolyl, bonded to one or more of ortho, meta and para positions,

[25] ·상기 。는서로독립적으로수소원자, C1-C6알킬, C2-C6알케닐, C2-C6 알키닐， C6-C10아릴， C3-C10시클로알킬,또는 Ν, Ο및 S중에서선택된하나 이상의헤테로원자를갖는 C3-10헤테로아릴또는해테로시클로알킬이며, [25] * is independently selected from hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or N, O and S C3-10 heteroaryl or heterocycloalkyl having the above hetero atom,

[26] ·상기 R„은서로독립적으로수소원자， C1-C6알킬， C2-C6알케닐， C2-C6 알키닐, C6-C10아릴， C3-C10시클로알킬, N, 0및 S중에서선택된하나이상의 헤테로원자를갖는 C3-10헤테로아릴또는헤테로시클로알킬, -OH, -OMe, -C0₂ CH₃또는 -C0₂CH₂CH₃이며， [26] The R 'is independently selected from hydrogen atoms, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, N, 0 and S C3-10 heteroaryl or heterocycloalkyl having at least the hetero atom, -OH, -OMe, -C0 ₂ CH ₃ or -C0 ₂ CH ₂ CH ₃ ,

[27] - R₄는수소원자, C1-C6알킬， C2-C6알케닐, C2-C6알키닐， C6-C10아릴， C3-C10시클로알킬,또는 N, 0및 S중에서선택된하나이상의헤테로원자를 갖는 C3-10헤테로아릴또는헤테로시클로알킬이며; [27]-R ₄ is a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or C 3-10 heteroaryl or heterocycloalkyl having one or more heteroatoms selected from N, 0 and S;

[28] -상기 R₃및 R₄는서로결합하여 N을포함하는 C3-10헤테로아릴또는 [28]-C3-10 heteroaryl containing N as R ₃ and R ₄ are bonded to each other;

헤테로시클로알킬을형성할수있음.  Can form heterocycloalkyl.

[29] [화학식 2]  [29] [Formula 2]

[31] 상기화학식 2에서，  [31] In Formula 2,

[32] - R₁₂는 C1-C6알킬， C2-C6알케닐, C2-C6알키닐， C6-C10

[32]-R ₁₂ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10

아릴, C3-C10시클로알킬，또는 R₁₅로치환되거나비치환된 N, 0및 S중에서 선택된하나이상의헤테로원자를갖는 C3-10헤테로아릴또는 Aryl, C3-C10 cycloalkyl, or R ₁₅ roach ring or C3-10 heteroaryl with one or more heteroatoms selected from unsubstituted N, 0 and S, or aryl Beach

헤테로시클로알킬이며;  Heterocycloalkyl;

[33] •상기 R₁₅는수소원자,할로겐원자， C1-C6알킬， -OR₁₆, -0(CO)R₁₆, -N0₂, -N(R i₆)₂, CN, -COR₁₆, -NH(CO)R₁₆, -NH(CO)NHR₁₆, -NH(CS)NHR₁₆, -NH(S0₂)R₁₆, -SR₁₆ ， -SOR₁₆₎ -S(CO)R₁₆, -C0₂R₁₆, -CON(R₁₆)₂, -S0₃H및 -S0₂N(R₁₆)₂로이루어진군에서 독립적으로선택된 1개내지 5개의치환기로서，오르소,메타및파라위치중 하나이상의위치에결합되며; R ₁₅ is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl, -OR ₁₆ , -0 (CO) R ₁₆ , -N0 ₂ , -N (R i ₆ ) ₂ , CN, -COR ₁₆ , -NH (CO) R ₁₆ , -NH (CO) NHR ₁₆ , -NH (CS) NHR ₁₆ , -NH (S0 ₂ ) R ₁₆ , -SR ₁₆ , -SOR ₁₆₎ -S (CO) R ₁₆ ,- 1 to 5 substituents independently selected from the group consisting of C0 ₂ R ₁₆ , -CON (R ₁₆ ) ₂ , -S0 ₃ H and -S0 ₂ N (R ₁₆ ) ₂ , of ortho, meta and para positions Is coupled to one or more positions;

[34] •상기 R₁₆는서로독립적으로수소원자, C1-C6알킬， C2-C6알케닐， C2-C6 알키닐， C6-C10아릴， C3-C10시클로알킬,또는 Ν, Ο및 S중에서선택된하나 이상의헤테로원자를갖는 C3-10헤테로아릴또는헤테로시클로알킬이며； [34] • the R ₁₆ are each independently hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or Ν, Ο and S selected from the group consisting of C3-10 heteroaryl or heterocycloalkyl having one or more heteroatoms;

[35] - ,수소원자, C1-C6알킬， C2-C6알케닐， C2-C6알키닐， C6-C10

[35]-, a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10

아릴, C3-C10시클로알킬，또는 R₁₇로치환되거나비치환된 N, O및 S중에서 선택된하나이상의헤테로원자를갖는 C3-10헤테로아릴또는 Aryl, C3-C10 cycloalkyl, or R ₁₇ roach ring or C3-10 heteroaryl with one or more heteroatoms selected from the ring N, O or S, or aryl Beach

헤테로시클로알킬이며,  Heterocycloalkyl,

[36] •상기 R_l7는수소원자，할로겐원자, C1-C6알킬, -OR,₈, -0(CO)R_{l 8}, -N0₂, -N(R 1₈)₂, -CN, -COR₁₈, -NH(CO)R₁₈, -NH(CO)NHR₁₈, -NH(CS)NHR₁₈, -NH(S0₂)R₁₈, -SR₁₈ , -SOR,₈, -S(CO)R,₈, -CO,ᅳ R_l8, -CON(R_l8)₂, -S0₃H, -S0₂N(R₁₈)₂및 -CF₃로이루어진 군에서독립적으로선택된 1개내지 5개의치환기로서,오르소,메타및파라 위치중하나이상의위치에결합되며, [36] • wherein R _l7 is a hydrogen atom, a halogen atom, C1-C6 _{alkyl, -OR, 8, -0 (CO} ) R l 8, -N0 2, -N (R 1 8) 2, -CN, - COR ₁₈ , -NH (CO) R ₁₈ , -NH (CO) NHR ₁₈ , -NH (CS) NHR ₁₈ , -NH (S0 ₂ ) R ₁₈ , -SR ₁₈ , -SOR, ₈ , -S (CO) R, _8, -CO, eu _{R l8, -CON (R l8)} 2, -S0 3 H, -S0 2 N (R 18) 2 , and one to five substituents independently selected from the group consisting of -CF ₃ Is bonded to one or more of the ortho, meta, and para positions,

[37] •상기 R₁₈는서로독립적으로수소원자， C1-C6알킬, C2-C6알케닐, C2-C6 알키닐， C6-C10아릴, C3-C10시클로알킬,또는 N, 0및 S중에서선택된하나 이상의헤테로원자를갖는 C3-10해테로아릴또는헤테로시클로알킬이며; [37] • the R ₁₈ are each independently hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or a N, 0, and selected from the group consisting of S one C3-10 heteroaryl or heterocycloalkyl having the above hetero atoms;

[38] R_l4는

[38] R _l4 is

[39] 바람직한일구현예에서，상기화학식 1의치환기 은 2-메록시페닐,  In a preferred embodiment, the substituent of Formula 1 is 2-methoxyphenyl,

2ᅳ에특시페닐, 3-메톡시페닐 , 2,4-디메록시페닐, 3,4-디메록시페닐，  Phenyl, 2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl,

2-플루오로페닐， 3-클로로 -4-메록시페닐, 2,5-디메록시페닐， 2-메틸페닐， 4-플루오로페닐 , 2,4-디메틸페닐또는 2-클로로페닐이다.  2-fluorophenyl, 3-chloro-4-methoxyphenyl, 2,5-dimethoxyphenyl, 2-methylphenyl, 4-fluorophenyl, 2,4-dimethylphenyl or 2-chlorophenyl.

[40] 또다른바람직한일구현예에서，상기화학식 1의치환기 R₂는하기로이루어진 군중에서선택된기이다: In another preferred embodiment, substituent R ₂ in Formula 1 above is a group selected from the group consisting of:

[41] [41]

[42] 또다른바람직한일구현예에서，상기화학식 1의치환기 R₃은하기로이루어진 군증에서선택된기이다: In another preferred embodiment, substituent R _{3 in} Formula 1 above is a group selected from the group consisting of:

[43] [43]

[45] 특히,바람직하게는상기화학식 1또는 2의화합물은하기로이루어진  [45] In particular, preferably, the compound of Formula 1 or 2 is

군으로부터선택된다:  Is selected from the group:

[46] N-(2-에록시페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아口 [47] 2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도) -N-페닐아세트아미드，  [46] N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetaceu [47] 2- (N- (2-methoxyphenyl ) -4-methylphenylsulfonamido) -N-phenylacetamide ，

[48] N-(2-에톡시페닐) -2-(4-메틸 -N-페닐페닐술폰아미도)아세트아미드, [48] N- (2-ethoxyphenyl) -2- (4-methyl-N-phenylphenylsulfonamido) acetamide,

[49] N-(2-에록시페닐) -2-(N-(2-메록시페닐)페닐술폰아미도)아세트아미드, [5이 N- (벤조 [d]옥사졸 -2-일메틸) -N-(2-메톡시페닐) -4-메틸벤젠술폰아미드, [49] N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) phenylsulfonamido) acetamide, [5-di-N- (benzo [d] oxazol-2-ylmethyl) -N- (2-methoxyphenyl) -4-methylbenzenesulfonamide,

[51] N- (벤조 [d]티아졸 -2-일메틸 )-N-(2-메특시페닐 )-4-메틸벤젠술폰아미드，  [51] N- (benzo [d] thiazol-2-ylmethyl) -N- (2-mesoxyphenyl) -4-methylbenzenesulfonamide,

[52] N-(2-에틸페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미드， [52] N- (2-ethylphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[53] N-(2-브로모페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미드,[53] N- (2-bromophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[54] N-(2-플루오로페닐 )-2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드 [54] N- (2-fluorophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide

[55] Ν-(2-(1Η-테트라졸 -5-일)페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아 세트아미드， [55] Ν- (2- (1Η-tetrazol-5-yl) phenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[56] 2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-메특시피리딘 -3-일)아세트 아미드염산염,  [56] 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-mesoxypyridin-3-yl) acetamide hydrochloride,

[57] N-(2-((2-에특시페닐)아미노)에틸) -N-(2-메특시페닐) -4-메틸벤젠술폰아미드, [58] 메틸 2-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에이트， [59] 2-(N-(2-에톡시페닐) -4-메틸페닐술폰아미도) -N-(2-메특시 -5-메틸페닐)아세트 아미드,  [57] N- (2-((2-ethoxyphenyl) amino) ethyl) -N- (2-methoxyphenyl) -4-methylbenzenesulfonamide, [58] methyl 2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate, [59] 2- (N- (2-ethoxyphenyl) -4-methylphenylsulfonamido) -N- (2 -Methoxy-5-methylphenyl) acetamide,

[60] N-(2,5-디메톡시페닐 )-2-(4-메톡시 -N-(2-메톡시페닐)페닐술폰아미도)아세트아 미드,  [60] N- (2,5-dimethoxyphenyl) -2- (4-methoxy-N- (2-methoxyphenyl) phenylsulfonamido) acetamide,

[61] 2-(4-클로로 -N-(2-에록시페닐)페닐술폰아미도) -N-(2,5-디메록시페닐)아세트아 미드,  [61] 2- (4-chloro-N- (2-ethoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide,

[62] 2-(N-(5-클로로 -2-메특시페닐) -4-메틸페닐술폰아미도) -N-(2-메톡시페닐)아세 트아미드，  [62] 2- (N- (5-chloro-2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-methoxyphenyl) acetamide,

[63] N-(2,4-디메톡시페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미 드  [63] N- (2,4-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide

[64] N-(2-클로로페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드， [65] N-(4-클로로 -2-메¾페닐) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  [64] N- (2-chlorophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [65] N- (4-chloro-2-meth¾phenyl ) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[66] N-(3-클로로 -4-메틸페닐)— 2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  [66] N- (3-chloro-4-methylphenyl) — 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[67] N-(2-메특시 -5-메틸페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  [67] N- (2-methoxy-5-methylphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[68] N-(4-클로로벤질) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드， [69] N-벤질 -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미드,  [68] N- (4-chlorobenzyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [69] N-benzyl-2- (N- (2- Mesoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[70] 에틸 2-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에이트, [71] N-(3-브로모페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드, [72] N-(2-플루오로페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드 [70] Ethyl 2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate, [71] N- (3-bromophenyl) -2- ( N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [72] N- (2-fluorophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulphone Amido) acetamide

[73] N-(3-메톡시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드, [74] N-(5-클로로 -2-메록시페닐) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세 트아미드 [75] N-(2-메특시벤질) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트아미드, [76] N-(sec-부틸) -2-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤 자미드， [73] N- (3-methoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [74] N- (5-chloro-2-methoxy Phenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide [75] N- (2-mesoxybenzyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [76] N- (sec-butyl) -2- ( 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzamide,

[77] 2-(N-(2-에특시페닐) -4-메틸페닐술폰아미도) -N-(3-(N-메틸메틸술폰아미도)페 닐)아세트아미드，  [77] 2- (N- (2-ethoxyphenyl) -4-methylphenylsulfonamido) -N- (3- (N-methylmethylsulfonamido) phenyl) acetamide,

[78] N-(2,3-디클로로페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미 드  [78] N- (2,3-dichlorophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide

[79] N-(2-메톡시 -5-메틸페닐) -2-(4-메특시 -N-(2-메톡시페닐)페닐술폰아미도)아세 트아미드  [79] N- (2-methoxy-5-methylphenyl) -2- (4-methoxy-N- (2-methoxyphenyl) phenylsulfonamido) acetamide

[80] N-(2,5ᅳ디메톡시페닐) -2-(N-(2-에특시페닐) -4- (메틸티오)페닐술폰아미도)아세 트아미드  [80] N- (2,5'dimethoxyphenyl) -2- (N- (2-ethoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide

[81] N-(2-에톡시페닐) -2-(N-(2-플루오로페닐) -4-메틸페닐술폰아미도)아세트아미드 [82] 2-(N-(3,4-디메특시페닐) -4-메틸페닐술폰아미도) -N-(2-에특시페닐)아세트아미 드  [81] N- (2-ethoxyphenyl) -2- (N- (2-fluorophenyl) -4-methylphenylsulfonamido) acetamide [82] 2- (N- (3,4-dimethic) Cyphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide

[83] N-(2-에특시페닐) -2-(N-(4-이소프로필페닐) -4-메틸페닐술폰아미도)아세트아미 드  [83] N- (2-ethoxyphenyl) -2- (N- (4-isopropylphenyl) -4-methylphenylsulfonamido) acetamide

[84] N-(2-에톡시페닐) -2-(N-(4-메록시페닐) -4-메틸페닐술폰아미도)아세트아미드, [85] N-(2-에록시페닐) -2-(N-(3-메록시페닐) -4-메틸페닐술폰아미도)아세트아미드, [86] 2-(N-(2,5-디메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐)아세트아미  [84] N- (2-ethoxyphenyl) -2- (N- (4-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [85] N- (2-ethoxyphenyl) -2 -(N- (3-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, [86] 2- (N- (2,5-dimethoxyphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetami

[87] 2-(N-(3-클로로 -4-메록시페닐) -4-메틸페닐술폰아미도) -N-(2-에특시페닐)아세 트아미드 [87] 2- (N- (3-chloro-4-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide

[88] 2-(N-(4-브로모페닐) -4-메틸페닐술폰아미도) -N-(2-에록시페닐)아세트아미드, [89] 2-(N-(4-클로로페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐)아세트아미드, [90] N-(2-에톡시페닐) -2-(4-메틸 -N-(o-를릴)페닐술폰아미도)아세트아미드,  [88] 2- (N- (4-bromophenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide, [89] 2- (N- (4-chlorophenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide, [90] N- (2-ethoxyphenyl) -2- (4-methyl-N- (o-ryll) phenylsulfone Amido) acetamide,

[91] N-(2-에톡시페닐) -2-(N-(4-플루오로페닐) -4-메틸페닐술폰아미도)아세트아미드 [91] N- (2-ethoxyphenyl) -2- (N- (4-fluorophenyl) -4-methylphenylsulfonamido) acetamide

[92] 2-(N-(2,5-디메틸페닐) -4-메틸페닐술폰아미도) -N-(2-에특시페닐)아세트아미드, [93] 2-(N-(2-클로로페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐)아세트아미드， [94] N-(2-메특시페닐) -2-(4-메틸 -N-(o-를릴)페닐술폰아미도)아세트아미드， [92] 2- (N- (2,5-dimethylphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide, [93] 2- (N- (2-chlorophenyl ) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide, [94] N- (2-methoxyphenyl) -2- (4-methyl-N- (o-allyl) phenyl Sulfonamido) acetamide ，

[95] 2-(N-(3-클로로 -4-메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-메톡시페닐)아세 트아미드 [95] 2- (N- (3-chloro-4-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-methoxyphenyl) acetamide

[96] N-(2-메톡시페닐) -2-(4-메틸 -N-(3- (트리플루오로메틸)페닐)페닐술폰아미도)아 세트아미드,  [96] N- (2-methoxyphenyl) -2- (4-methyl-N- (3- (trifluoromethyl) phenyl) phenylsulfonamido) acetamide,

[97] 2-(N-(3,4-디메틸페닐) -4-메틸페닐술폰아미도) -N-(2-메톡시페닐)아세트아미드， [98] (S)-메틸  [97] 2- (N- (3,4-dimethylphenyl) -4-methylphenylsulfonamido) -N- (2-methoxyphenyl) acetamide, [98] (S) -methyl

1-(2-(Ν-(2-메특시페닐) -4-메틸페닐술폰아미도)아세틸)피를리딘 -2-카르복실레이 트 1- (2- (Ν- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetyl) pyridine-2-carboxylay T

[99] (R)-메틸  [99] (R) -methyl

2-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도) -2-페닐아세테이트 [100] (R)-에틸  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) -2-phenylacetate [100] (R) -ethyl

2-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도) -3-페닐프로피오네 이트,  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) -3-phenylpropionate,

[101] N-(5-브로모티아졸 -2-일) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  [101] N- (5-bromothiazol-2-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[102] N-(3-(4-플루오로페닐) -1H-피라졸 -5-일) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰 아미도)아세트아미드，  [102] N- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfon amido) acetamide,

[103] N-(5-히드록시 -1H-피라졸 -3-일) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아 세트아미드，  [103] N- (5-hydroxy-1H-pyrazol-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[104] N-(2-메톡시페닐) -4-메틸 -N-(2-옥소 -2-(4- (피리딘 -2-일)피페라진 -1-일)에틸)벤젠 술폰아미드，  [104] N- (2-methoxyphenyl) -4-methyl-N- (2-oxo-2- (4- (pyridin-2-yl) piperazin-1-yl) ethyl) benzene sulfonamide,

[105] N-(2-(4-(4-플투오로페닐)피페라진 -1-일) -2-옥소에틸) -N-(2-메톡시페닐) -4-메틸 벤젠술폰아미드,  [105] N- (2- (4- (4-fluorofluoro) piperazin-1-yl) -2-oxoethyl) -N- (2-methoxyphenyl) -4-methyl benzenesulfonamide,

[106] N-(5-(4-클로로페닐) -1,3,4-옥사디아졸 -2-일) -2-(N-(2-메록시페닐) -4-메틸페닐술 폰아미도)아세트아미드,  [106] N- (5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido Acetamide,

[107] N-(2-에톡시피리딘 -3-일) -2-(N-(2-메.톡시페닐) -4-메틸페닐술폰아미도)아세트 아미드， [107] N- (2-ethoxypyridin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[108] N-(2-이소프로폭시피리딘 -3-일) -2-(N-(2-메록시페닐 )-4-메틸페닐술폰아미도) 아세트아미드，  [108] N- (2-isopropoxypyridin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[109] N-(2-클로로피리딘 -3-일) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트 아미드，  [109] N- (2-chloropyridin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

[110] 2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(3-메톡시피리딘 -2-일)아세트 아미드，  [110] 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (3-methoxypyridin-2-yl) acetamide,

[111] 2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(4-메톡시피리딘 -3-일)아세트 아미드，  [111] 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide,

[112] N- (이소퀴놀린 -3-일) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미  [112] N- (isoquinolin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetami

[113] 2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도) -N- (퀴놀린 -5-일)아세트아미드, [114] 2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도) -N- (퍼플루오로페닐)아세트아미 [113] 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (quinolin-5-yl) acetamide, [114] 2- (N- (2-methoxyphenyl) ) -4-methylphenylsulfonamido) -N- (perfluorophenyl) acetami

[115] N-(2-에특시페닐) -2-(N-(2—메특시페닐)나프탈렌 -2-술폰아미도)아세트아미드，[115] N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) naphthalene-2-sulfonamido) acetamide,

[1 16] 2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N- (티아졸 -2-일)아세트아미드,[1 16] 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (thiazol-2-yl) acetamide,

[1 17] N-(2-에특시벤질) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미드[1 17] N- (2-ethoxybenzyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide

[1 18] N-( 1 H-이미다졸 -2-일 )-2-(N-(2-메톡시페닐 )-4-메틸페닐술폰아미도)아세트아미 드 [1 18] N- (1 H-imidazol-2-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetami De

N-(2-메톡시페닐) -2-(N-(2-메록시페닐) -4- (메틸티오)페닐술폰아미도)아세트아 미드，  N- (2-methoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

N-(2-에특시페닐) -2-(N-(2-메록시페닐) -4- (메틸티오)페닐술폰아미도)아세트아 미드,  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

N-(3-에톡시페닐) -2-(N-(2-메톡시페닐) -4- (메틸티오)페닐술폰아미도)아세트아 미드,  N- (3-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

Ν-(3-(1Η-이미다졸 -1-일)페닐) -2-(N-(2-메특시페닐) -4- (메틸티오)페닐술폰아미 도)아세트아미드염산염,  Ν- (3- (1Η-imidazol-1-yl) phenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide hydrochloride,

N-(2,5-디메특시페닐) -2-(N-(2-메특시페닐) -4- (메틸티오)페닐술폰아미도)아세 트아미드,  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

N-(2,5-디메특시페닐) -2-(N-(2-메톡시페닐) -4- (메틸술피닐)페닐술폰아미도)아 세트아미드，  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylsulfinyl) phenylsulfonamido) acetamide,

N-(2,5-디메특시페닐) -2-(N-(2-메톡시페닐) -4- (메틸술포닐)페닐술폰아미도)아 세트아미드，  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylsulfonyl) phenylsulfonamido) acetamide,

N-(2,5-디메록시페닐)ᅳ 2-(4-플루오로 -N-(2-메톡시페닐)페닐술폰아미도)아세트 아미드,  N- (2,5-dimethoxyphenyl) ᅳ 2- (4-fluoro-N- (2-methoxyphenyl) phenylsulfonamido) acetamide,

2-(4-시아노 -N-(2-메톡시페닐)페닐술폰아미도) -N-(2,5-디메록시페닐)아세트아 미드,  2- (4-cyano-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide,

N-(2,5-디메록시페닐 )-2-(N-(2-메톡시페닐 )-4-( 1 H-테트라졸 -5-일 )페닐술폰아미 도)아세트아미드，  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (1H-tetrazol-5-yl) phenylsulfonamido) acetamide,

2-(4-브로모 -N-(2-메톡시페닐)페닐술폰아미도) -N-(2,5-디메톡시페닐)아세트아 미드,  2- (4-bromo-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide,

2-(4-아세틸 -N-(2-메록시페닐)페닐술폰아미도) -N-(2,5-디메록시페닐)아세트아 미드,  2- (4-acetyl-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide,

메틸 4-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에이트， 메틸  Methyl 4- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate, methyl

6-(2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트아미도)니코티네이트, 메틸  6- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) nicotinate, methyl

2-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도) -5-메틸벤조에이트 메틸  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) -5-methylbenzoate methyl

4,5—디메특시 -2-(2-(Ν-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조 에이트，  4,5—dimethoxy-2- (2- (Ν- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate,

Ν-(3,4-디메특시페닐) -2-(Ν-(2-메특시페닐) -4ᅳ메틸페닐술폰아미도)아세트아미 2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도) -N- (퀴놀린 -6-일)아세트아미드, Ν-(5-(1Η-이미다졸 -1 -일) -2-메특시페닐) -2-(N-(2-메특시페닐) -4- (메틸티오)페닐 술폰아미도)아세트아미드염산염, Ν- (3,4-dimethoxyphenyl) -2- (Ν- (2-methoxyphenyl) -4 ᅳ methylphenylsulfonamido) acetami 2- (N- (2-methoxyphenyl) -4- Methylphenylsulfonamido) -N- (quinolin-6-yl) acetamide, Ν- (5- (1Η-imidazol-1-yl) -2-methoxyphenyl) -2- (N- (2-methic Cyphenyl) -4- (methylthio) phenyl Sulfonamido) acetamide hydrochloride,

[138] N-(2,5-디메톡시페닐 )-2-((2-메톡시페닐) (4-메틸벤질)아미노)아세트아미드, [139] N-(2,5-디메톡시페닐) -2-(4-(1-하이드록시에틸) -N-(2-메특시페닐)페닐술폰아미 도)아세트아미드， [138] N- (2,5-dimethoxyphenyl) -2-((2-methoxyphenyl) (4-methylbenzyl) amino) acetamide, [139] N- (2,5-dimethoxyphenyl) -2- (4- (1-hydroxyethyl) -N- (2-methoxyphenyl) phenylsulfonamido) acetamide,

[140] 4-클로로 -N-(2-((2,5-디메톡시페닐)아미노) -2-옥소에틸) -N-(2-메톡시페닐)벤자 미드，  [140] 4-chloro-N- (2-((2,5-dimethoxyphenyl) amino) -2-oxoethyl) -N- (2-methoxyphenyl) benzamide,

[141] 2-(4-브로모 -N-(2-메특시페닐)페닐술폰아미도) -N-(4-메톡시피리딘 -3-일)아세 트아미드염산염,  [141] 2- (4-bromo-N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide hydrochloride,

[142] 2-(N-(2-메톡시페닐) -4- (메틸티오)페닐술폰아미도) -N-(4-메록시피리딘 -3-일)아 세트아미드,  [142] 2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide,

[143] 2-(4-아세틸 -N-(2-메톡시페닐)페닐술폰아미도) -N-(4-메특시피리딘 -3-일)아세 트아미드,  [143] 2- (4-acetyl-N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-mesoxypyridin-3-yl) acetamide,

[144] 2-(4-(1-하이드록시에틸) -N-(2-메톡시페닐)페닐술폰아미도) -N-(4-메특시피리 딘 _3-일)아세트아미드,  [144] 2- (4- (1-hydroxyethyl) -N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-mesoxypyridin _3-yl) acetamide,

[145] 메틸 [145] methyl

2-히드록시 -5-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에 이트,  2-hydroxy-5 (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate,

[146] 메틸 [146] methyl

2-히드록시 -4-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에 이트,  2-hydroxy-4- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate,

[147] N-(2-에특시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-메틸아세트 아미드,  [147] N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N-methylacetamide,

[148] N-(2-에톡시페닐) -2-(N-(2-메톡시페닐) -4—메틸페닐술폰아미도) -N- (프로프 -2-인 -1-일)아세트아미드,  [148] N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4—methylphenylsulfonamido) -N- (prop-2-yn-1-yl) acetamide ,

[149] 2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N- (퀴놀린 -3-일)아세트아미드, [150] 2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(6-메록시피리딘 -2-일)아세트 아미드，및  [149] 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (quinolin-3-yl) acetamide, [150] 2- (N- (2-methoxyphenyl ) -4-methylphenylsulfonamido) -N- (6-methoxypyridin-2-yl) acetamide, and

[151] 2-(4-(1- (부틸아미노)에틸) -N-(2-메록시페닐)페닐술폰아미도) -N-(4-메록시피리 딘ᅳ 3—일)아세트아미드.  [151] 2- (4- (1- (butylamino) ethyl) -N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-methoxypyridinyl 3-yl) acetamide.

[152]  [152]

[153] 본발명의측면에서，알킬,알케닐，알키닐과같은용어는선형또는분지형을 모두포함하는것으로의도된다.  In terms of the present invention, terms such as alkyl, alkenyl and alkynyl are also intended to include both linear and branched forms.

[154] 본발명에서사용되는용어 "서로독립적으로"는，특정치환기가 2개이상 결합될경우서로에대해무관하게다른유형이선택될수있다는것을 의미한다ᅳ예를들어，상기화학식 1에서치환기 R₅가 - S0₂N(R₆)₂인경우， 2개의 ¾ 중하나는수소원자이고다른하나는메틸기가선택될수있다. [154] The term "independently of each other" used in the present invention means that when two or more specific substituents are combined, different types may be selected irrespective of each other. For example, in the above Chemical Formula 1, substituent R ₅ Is-S0 ₂ N (R ₆ ) ₂ , one of the two ¾ hydrogen atoms and the other methyl group can be selected.

[155] 상기화학식 1또는 2의화합물은비대칭탄소중심을가질수있으므로， R또는 S이성질체，라세미체，부분입체이성질체,또는이들의흔합물로서존재할수 있으며,이들은모두본발명의범위에포함된다. Since the compound of Formula 1 or 2 may have an asymmetric carbon center, the compound of Formula 1 or 2 may exist as an R or S isomer, racemate, diastereomer, or a mixture thereof. These are all included in the scope of the present invention.

[156] 후술하는실시예에서보는바와같이 ,본발명자들은상기화학식 1또는 2의 화합물또는이의약학적으로허용가능한염이신경세포로의분화,신경돌기의 증식촉진,축삭돌기의성장촉진，신경세포의사멸억제,세포무독성,신경재생 등의효과를나타낸다는사실을실험적으로확인하였다.따라서，본발명은 화학식 1또는 2의화합물또는이의약학적으로허용가능한염을포함하는것올 특징으로하는증추신경계질환의예방또는치료용약학조성물을제공한다.  As shown in the following examples, the present inventors have found that the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof can be differentiated into neural cells, promote growth of neurites, promote growth of axons, and nerves. It has been experimentally confirmed that it exhibits effects such as inhibition of cell death, cell nontoxicity, and nerve regeneration. Thus, the present invention is characterized by the fact that the present invention comprises a compound of formula 1 or 2 or a pharmaceutically acceptable salt thereof. Provided are pharmaceutical compositions for the prevention or treatment of neurological diseases.

[157] 또한,본발명은상기화학식 1또는 2의화합물또는이의약학적으로  In addition, the present invention is a compound of Formula 1 or 2 or

허용가능한염올유효성분으로포함하는약학조성물을대상체 (예컨대，인간 또는포유류)에게투여하는단계를포함하는중추신경계질환의치료또는예방 방법을제공한다.  A method of treating or preventing central nervous system diseases comprising administering a pharmaceutical composition comprising an acceptable salt active ingredient to a subject (eg, human or mammal) is provided.

[158] 상기 "중추신경계질환"은바람직하게는축삭돌기의파괴또는신경세포의 사멸로인해야기되는질환들을의미하며,여기에는외상성뇌손상,뇌졸중, 뇌경색,소아뇌성마비 ,다발성축삭경화증,근위축성측삭경화증，척수손상, 시신경손상，특히외상또는녹내장에의한시신경손상，루게릭병,  The central nervous system disease preferably refers to diseases caused by destruction of axons or death of nerve cells, including traumatic brain injury, stroke, cerebral infarction, pediatric cerebral palsy, multiple axon sclerosis, and muscle. Atrophic lateral sclerosis, spinal cord injury, optic nerve injury, especially optic nerve injury caused by trauma or glaucoma, Lou Gehrig's disease,

알츠하이머병，헌팅톤병,파킨슨병등이포함된다.  Alzheimer's disease, Huntington's disease and Parkinson's disease.

[159] 본발명에서사용되는용어 "예방 "은,상기약학조성물을중추신경계질환이 발생될위험이높은대상체에게투여함으로써중추신경계질환의발병을억제, 지연또는방지시키는모든행위들을의미한다.또한,본발명에서사용되는 용어 "치료 "는，상기약학조성물을중추신경계질환을앓고있거나  The term "prevention" as used in the present invention means any action that inhibits, delays or prevents the development of CNS diseases by administering the pharmaceutical composition to a subject at high risk of developing CNS diseases. , The term "treatment" used in the present invention, the pharmaceutical composition has a central nervous system disease or

중추신경계가손상된대상체에게투여함으로써증상을호전，역전，완치또는 개선시키는모든행위들을의미한다.  By central nervous system administration to damaged subjects is meant any action that improves, reverses, cures or improves symptoms.

[160] 본발명의약학조성물은상기화학식 1또는 2의화합물또는이의약학적으로 허용가능한염과함께,필요에따라서는축삭돌기재생에활성을갖는공지의 유효성분올 1종이상더함유할수도있다.  The pharmaceutical composition of the present invention, together with the compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof, may optionally contain one or more active ingredients of known active ingredient which is active in regenerating axons. .

[161] 본발명에서사용되는용어 "약학적으로허용가능한염 "은，당해기술  [161] The term "pharmaceutically acceptable salt" used in the present invention is a related art

분야에서통상적인방법에의해제조될수있는것으로，예를들면，염산, 브롬화수소,황산,황산수소나트륨,인산,탄산등의무기산과의 염또는개미산, 초산，옥살산,벤조산，시트르산,타르타르산，글루콘산，게스티스산,푸마르산， 락토비온산，살리실릭산，또는아세틸살리실릭산 (아스피린)과같은유기산과 함께약학적으로허용가능한이들의산의염을형성하거나，또는나트륨，칼륨 등의알칼리금속이온과반웅하여이들의금속염을형성하거나，또는암모늄 이온과반웅하여또다른형태의약학적으로허용가능한염을형성할수도 있다.  It can be produced by conventional methods in the field, for example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, or formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, and glutamic acid. Form salts of pharmaceutically acceptable salts of these acids with organic acids such as cholic acid, gustyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or alkalis such as sodium or potassium It may be reacted with metal ions to form their metal salts, or with ammonium ions to form another form of a pharmaceutically acceptable salt.

[162] 본발명에따른약학조성물은약학적으로허용되는담체 ,희석제또는  [162] The pharmaceutical composition according to the present invention may be a pharmaceutically acceptable carrier, diluent or

부형제를추가적으로포함할수있다.본발명에서사용되는용어 "약학적으로 허용가능한담체또는희석제 "는유기체에상당한자극을야기하지않고， 투여되는화합물의생물학적활성및성질을폐기하지않는담체또는희석제를 의미한다ᅳ또한,본발명에서사용되는용어 "약학적으로허용가능한부형제' '는 본발명의화합물또는염의투여를더욱용이하게하기위해약학조성물에 첨가되는불활성물질을의미한다.이러한부형제의예는탄산칼슴,인산칼슴， 다양한유형의당류및전분，샐를로오스유도체，젤라틴,식물성오일및 폴리에틸렌글리콜이있지만，이에한정되는것은아니다. The term "pharmaceutically acceptable carrier or diluent" as used in the present invention may additionally include an excipient that does not cause significant stimulation to the organism and does not destroy the biological activity and properties of the compound being administered. In addition, the term "pharmaceutically acceptable excipient" used in the present invention means an inert substance added to the pharmaceutical composition to further facilitate the administration of the compound or salt of the present invention. Examples of such excipients are There are, but are not limited to, carbonate, phosphate, various types of sugars and starches, salose derivatives, gelatin, vegetable oils and polyethylene glycols.

[163] 본발명에따른약학조성물은대상체에게다양한경로로투여될수있다.예를 들어,경구，직장또는정맥주사，국부또는비경구경로를통해투여될수 있지만，이러한투여경로에한정되는것은아니다.  [163] A pharmaceutical composition in accordance with the present invention may be administered to a subject in a variety of ways, including, but not limited to, oral, rectal or intravenous, local or parenteral.

[164] 본발명에따른조성물은특정제형에한정됨이없이경구투여용제제또는 비경구투여용제제로제형화할수있다.이때,본발명에따른유효성분은제형 내에단위용량이함유될수도있고,분취량으로나뉘어함유될수도있다.본 발명에따른조성물올제형화하는경우，당업계에서일반적으로사용되는 통상의층진제,증량제,결합제,습윤제，계면활성제등의희석제또는부형제를 추가로사용할수있다.경구투여를위한고형제제에는예를들어정계，환제， 산제，과립계,캡슐제등이포함되며，이러한고형제제는상기유효성분외에 하나이상의부형제，예를들어전분，탄산칼슴，수크로스，락토오스또는젤라틴 등올포함할수있다.경구투여를위한액상제제에는예를들어현탁제， 내용액제，유제및시럽제등이포함되며,이러한액상제제는통상적으로 사용되는단순희석제인물,리퀴드파라핀외에여러가지부형제들,예컨대 습윤제,감미겨ᅵ,방향제,보존제등을포함할수있다.비경구투여를위한 제제에는예를들어멸균된수용액,비수용성제,현탁용제，유제，동결건조제제， 좌제가포함될수있다.현탁용제로서프로필렌글리콜，폴리에틸렌글리콜， 올리브오일과같은식물성기름,에틸올레이트와같은주사가능한에스테르 등이사용될수있다.  [164] The composition according to the present invention can be formulated as a parenteral or parenteral formulation without being limited to a specific formulation, wherein the active ingredient according to the present invention may contain a unit dose in the formulation, When formulating the composition according to the present invention, it is possible to further use diluents or excipients such as conventional layering agents, extenders, binders, wetting agents, surfactants, etc. which are commonly used in the art. Solid preparations for the preparation include, for example, tablets, pills, powders, granules, capsules, etc.These solid preparations include one or more excipients, for example, starch, carbonate, sucrose, lactose or gelatin, in addition to the active ingredients. Liquid preparations for oral administration include, for example, suspending agents, solution solutions, emulsions and syrups, which are commonly used simple diluents, In addition to the liquid paraffin, various excipients may be included such as humectants, sweeteners, fragrances, preservatives, etc. Formulations for parenteral administration include, for example, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, As a suspending solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate can be used.

[165] 본발명에따른약학조성물의투여량은환자의나이 ,성별，체중및건강상태， 질환의중증도，발병시점,치료기간둥을고려하여당해기술분야의숙련된 의사또는수의사가적절하게선택할수있다.예를들어，몸무게가 70kg인 성인환자를기준으로할때일반적으로 0.01 mg/일내지 1000 mg/일이며，의사 또는약사의판단에따라일정시간간격으로 1일 1회내지수회로분할투여할 수도있다.  [165] The dosage of the pharmaceutical composition according to the present invention should be appropriately selected by a skilled physician or veterinarian in this field, taking into account the patient's age, sex, weight and health, severity of the disease, time of onset, and duration of treatment. For example, based on an adult patient weighing 70 kg, it is typically 0.01 mg / day to 1000 mg / day, divided into once-in-a-day exponents at regular time intervals as determined by the physician or pharmacist. You may.

[166]  [166]

[167] 화학식 1의화합물의제조방범  [167] Preparation of Compounds of Formula 1

[168] 본발명에따른화학식 1의화합물은예를들어하기반웅식 1내지 7중어느 하나에따라제조할수있다.하기반웅식 1내지 7에서 R_l5 R₂, R₃, R₄는각각 상기에서정의한바와같다. Compounds of formula 1 according to the present invention may be prepared according to any one of formulas 1 to 7 below. In formulas 1 to 7, wherein R _l5 R ₂ , R ₃ , and R ₄ are each Same as defined.

[ 169]  [169]

[170] [반웅식 1] R厂 NH₂ [170] [1] R 厂 NH ₂

A A

C D C D

：가수분 H

： Hot water H

G  G

[172] 상기반웅식 1에서，화합물 A와화합물 B를반응시켜화합물 C를수득하고， 이를에틸클로로아세테이트와반웅시켜가수분해하여화합물 E를제조한후, 화합물 F와아미드결합반웅을수행하여최종생성물로서화합물 G를 제조한다.최종생성된화합물 G는화학식 1에서 가11인화합물이다.  In Reaction Formula 1, Compound A was reacted with Compound B to obtain Compound C, which was then reacted with ethyl chloroacetate to hydrolyze to prepare Compound E, followed by reaction with Compound F to yield an amide bond reaction. Compound G is prepared as a product. The final compound G is a compound of formula 11 in Formula 1.

[173] 이때，마지막단계에서카르복실산화합물 E와아민화합물 1 ]아미드결합을 위해，옥살릴클로라이드,티오닐클로라이드등을이용하여카르복실산을 카르복실산클로라이드로전환시킨후아미드결합을시키는것이바람직하다. 또다른대안으로서， Ν,Ν'-디시클로핵실카르보다이미드 (DCC),  At this time, in the last step, for the carboxylic acid compound E and the amine compound 1, an amide bond is obtained by converting the carboxylic acid to carboxylic acid chloride using oxalyl chloride, thionyl chloride and the like. It is desirable. As another alternative, Ν, Ν'-dicyclonucleosilcarbodiimide (DCC),

히드록시벤조트리아졸 (HOBt),  Hydroxybenzotriazole (HOBt),

1 -bis (디메틸아미노)메틸렌 -1 H- 1 ,2,3-트리아졸로 [4,5-b]피리디늄 3-옥시드 핵사플루오로포스페이트 (HATU),  1-bis (dimethylamino) methylene-1 H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide nucleofluorophosphate (HATU),

Ν,Ν,Ν,Ν-테트라메틸 -0-(1Η-벤조트리아졸 -1-일)우로늄  Ν, Ν, Ν, Ν-tetramethyl -0- (1Η-benzotriazol-1-yl) uronium

핵사플루오로포스페이트 (HBTU),  Nuclear tetrafluorophosphate (HBTU),

(벤조트리아졸 -1 -일옥시 )트리피롤리디노포스포늄  (Benzotriazole-1-yloxy) tripyrrolidinophosphonium

핵사플루오로포스페이트 (PYBOP), Bis(2-옥소 -3-옥사졸이디닐)포스피닉 클로라이드 (BOP-C1)등을이용하여카르복실산을활성화킨후아민과반웅시켜 아미드결합을시키는것도고려될수있다.  It may also be considered to form amide bonds by reacting carboxylic acids with activated amines using nucleofluorophosphate (PYBOP), Bis (2-oxo-3-oxazolidinyl) phosphonic chloride (BOP-C1), and the like. have.

[174]  [174]

[175] [반웅식 ¾

[175] [Bunungsik ¾

C G  C G

[177] 상기반웅식 2에서,화합물 C와화합물 H를반웅시켜화합물 G를제조한다. 최종생성된화합물 G는화학식 1에서 ¾가11인화합물이다.  In Reaction Formula 2, Compound C is reacted with Compound H to prepare Compound G. The final compound G is a compound having ¾ of 11 in formula (1).

[178]  [178]

[179] [반웅식 3] [179] [Reaction 3]

[181] 3에서 ,화합물 Α와화합물 H를반응시켜화합물 I를제  [181] In 3, compound A is reacted with compound H to form compound I.

화합물 B와반웅시켜화합물 G를제조한다.최종생성된화합물 G는화학식 1에서 R₄가 H인화합물이다. Compound G is prepared by reaction with compound B. The final compound G is a compound wherein R ₄ is H in Formula 1.

[182]  [182]

[183] [반웅식 4] [183] [Bandungsik 4]

G 160°C, 20m in J  G 160 ° C, 20m in J

[ 185] 상기반웅식 4에서，화합물 G를요오드메탄과반웅시켜화합물 J를제조한다. 이때，상기반응식 1내지 3중어느하나에따라제조된화합물 G (즉，화학식 1에서 R₄가 H인화합물)가출발물질로서사용된다.최종생성된화합물 J는 화학식 1에서 ^가메틸인화합물이다. In Reaction Formula 4, Compound G was prepared by reacting Compound G with iodine methane. In this case, Compound G (ie, a compound of which R ₄ is H in Chemical Formula 1) prepared according to any one of Schemes 1 to 3 is used as a starting material. The final compound J is a compound wherein ^ is methyl in Chemical Formula 1. .

[186]  [186]

[ 187] [반웅식 5] [187] [Response 5]

[189] 상기반웅식 5에서,화합물 K mCPBA와반웅시켜산화시킨다.이때  In Reaction Formula 5, reaction with Compound K mCPBA is followed to oxidize.

3 를 , mCPBA의첨가량및반웅온도와같은조건에따라，화합물 L또는화합물 M이 제조된다.생성화합물 L은 가 이고 이 -SOC¾인화합물이다.  According to conditions such as the addition amount of mCPBA and the reaction temperature, compound L or compound M is prepared. The resulting compound L is a compound of -SOC¾.

생성화합물 M은화학식 1에서 R₂가 이고 R₇이 -S0₂CH₃인화합물이다.

Product M is a compound in which R _{2 And} R ₇ Is -S0 ₂ CH _{3 In} Formula ₁ .

[190]  [190]

[191] [반웅식 6] [191] [Bandungsik 6]

[193] 상기반응식 6에서 ,화합물 Ν을 NaN₃와반웅시켜화합물 O를제조한다.생성 화합물 0는화학식 1에서 R₂가 이고 R₇이테트라졸릴인화합물이다.

In Scheme 6, Compound Ν is reacted with NaN ₃ to prepare Compound O. Formed Compound 0 is a compound wherein R ₂ is and R ₇ itrazolyl in Formula 1.

[194]  [194]

[195] [반웅식 7] [195] [Bandungsik 7]

[196] .

[197] 상기반웅식 7에서，화합물 P를 NaBH4로환원시켜화합물 Q를제조한다.생성 화합물 Q는화학식 1에서 R₂가 이고 ¾이메틸인

[196].

In Reaction Formula 7, the compound P is reduced to NaBH 4 to prepare Compound Q. The resulting compound Q is represented by Formula 1 wherein R ₂ is and ¾ is methyl.

화합물이다.  Compound.

[198]  [198]

[199] 하학식 2의화함물의제조방법 [199] Manufacturing Method of Chemical Formula 2

[200] 본발명에따른화학식 2의화합물은예를들어하기반응식 8또는 9에따라 제조할수있다.하기반웅식 8및 9에서 R₁₂, R,3, R₁₄는각각상기에서정의한 바와같다. The compound of formula 2 according to the present invention may be prepared according to the following Schemes 8 or 9. In the following formulas 8 and 9, R ₁₂ , R, 3, and R ₁₄ are as defined above, respectively.

[201]  [201]

[202] [반응식 8]  [202] [Scheme 8]

[204] 상기반웅식 8에서，화합물 R과클로로아세틸클로라이드를반응시켜화합물 S를제조하고 PPA조건하에화합물 T를제조한후,화합물 Y에의한알킬화 반웅을통해최종생성물로서화합물 U를제조한다.최종생성된화합물 U는 화학식 2에서 R₁₄가 인화합물이다.

In Reaction Formula 8, Compound R is reacted with chloroacetyl chloride to prepare Compound S, and Compound T is prepared under PPA. Compound U is prepared as a final product by alkylation reaction with Compound Y. The final compound U is a compound in which R ₁₄ is phosphorus in formula (2).

[205]  [205]

[206] [반응식 9] [206] [Scheme 9]

[208] 상기반웅식 9에서，화합물 V와클로로아세틸클로라이드를반웅시켜화합물 W를제조한후,화합물 Y에의한알킬화반응을통해최종생성물로서화합물 X를제조한다.최종생성된화합물 X는화학식 2에서 R₁₄가

In Reaction Formula 9, Compound V is reacted with chloroacetyl chloride to prepare Compound W, and then Compound X is prepared as a final product through an alkylation reaction with Compound Y. At R ₁₄

화합물이다. [210] 전술한제조방법외에도,당해업계의통상의지식을가진자라면본발명에 따른화학식 1또는 2의화합물또는이의약학적으로허용가능한염을적절한 과정및조건을적용하여수득할수있을것이다. Compound. In addition to the above-described manufacturing method, those of ordinary skill in the art will be able to obtain the compound of Formula 1 or 2 according to the present invention or a pharmaceutically acceptable salt thereof by applying appropriate processes and conditions.

발명의효과  Effects of the Invention

[211] 본발명에따른화합물은신경세포의분화，신경돌기의증식，축삭돌기의길이 성장,산화적스트레스에의한신경세포의사멸억제，세포무독성,손상된 중추신경계의재생과같은유의적인효과를나타내는것으로실험올통해 입증되었다.  [211] The compounds according to the present invention have significant effects such as differentiation of nerve cells, proliferation of neurites, growth of axons, inhibition of neuronal cell death by oxidative stress, cell nontoxicity, and regeneration of damaged central nervous system. Experiments have been demonstrated throughout the year.

[212] 따라서 ,본발명에따른화합물은중추신경계의손상으로인해야기되는질환， 예를들어외상성뇌손상,뇌졸중，뇌경색,소아뇌성마비,다발성축삭경화증， 근위축성측삭경화증,척수손상，시신경손상，특히외상또는녹내장에의한 시신경손상,루게릭병,알츠하이머병，헌팅톤병，파킨슨병등을치료또는 예방하기위한약학조성물의활성성분으로유용하게사용될수있다.  [212] Therefore, the compounds according to the present invention are diseases caused by damage to the central nervous system, such as traumatic brain injury, stroke, cerebral infarction, pediatric cerebral palsy, multiple atrophic lateral sclerosis, spinal cord injury, optic nerve injury. In particular, it may be usefully used as an active ingredient in pharmaceutical compositions for treating or preventing optic nerve damage, Lou Gehrig's disease, Alzheimer's disease, Huntington's disease and Parkinson's disease caused by trauma or glaucoma.

도면의간단한설명  Brief description of the drawings

[213] 도 1은본발명에따른화합물의세포독성을확인하기위하여 SD래트의망막 신경세포의생존율을측정한결과를막대그래프로도시한것이다.  FIG. 1 is a bar graph showing the results of measuring the survival rate of retinal neurons in SD rats in order to confirm the cytotoxicity of the compounds according to the present invention.

대조군 (화합물비처리그룹)과실험군 (2, 10, 20 μΜ농도 CYM화합물처리 그룹)으로나누어진다.  The control group (compound untreated group) and the experimental group (2, 10, 20 μΜ concentration CYM compound treated group).

[214] 도 2및 3은본발명에따른화합물의축삭돌기성장촉진효과를확인하기  2 and 3 confirm the effect of promoting axon growth of the compound according to the present invention.

위하여 SD래트의망막신경세포의축삭돌기길이를측정한결과를  To determine the axon length of retinal nerve cells in SD rats,

막대그래프로도시한것이다.  It is shown as a bar graph.

[215] 구체적으로,도 2는축삭돌기의길이가 50 μπι이상인신경세포의총수를  Specifically, FIG. 2 shows the total number of neurons having axons of 50 μπι or more in length.

비교한것이며，도 3은축삭돌기의길이가 50 ~ 100 μιη, 100 ~ 200 μιη, 200 μιη 이상인신경세포의수를각각별도로나누어비교한것이다.  3 is a comparison of the number of neurons having axons of 50-100 μιη, 100-200 μιη, and 200 μιη or more, respectively.

[216] 도 4및 5는본발명에따른화합물의시신경재생정도를확인하기위한실험 결과를도시한것이다.  4 and 5 show experimental results for checking the degree of optic nerve regeneration of a compound according to the present invention.

[217] 구체적으로，도 4는 SD래트의시신경압박손상모델에서화합물을처리한후 재생된시신경을염색후촬영한사진으로서，녹색으로염색된부분이시신경의 축삭돌기를나타낸다.도 4의상단부사진은대조군 (PBS처리그룹)을촬영한 것으로서손상된시신경이거의재생되지않았음을시사하며 ,도 4의하단부 사진은실험군 (CYM화합물처리그룹)을촬영한것으로서손상된시신경이 매우유의적으로재생되었음을시사한다.도 5는시신경압박손상부위에서 떨어져있는거리 (500 μηι, ΙΟΟΟ μηι, 1500 μτη)에따라축삭돌기의수를비교한 것이다.  Specifically, FIG. 4 is a photograph taken after staining of the regenerated optic nerve after the compound was treated in the optic nerve compression injury model of the SD rat, and the part stained in green shows the axon projection of the optic nerve. The photographs were taken of the control group (PBS treatment group), indicating that the damaged optic nerve was hardly regenerated, and the lower part of FIG. 4 was taken of the experimental group (CYM compound treatment group), indicating that the damaged optic nerve was reproduced significantly. 5 compares the number of axons according to the distance (500 μηι, ΙΟΟΟ μηι, 1500 μτη) away from the optic nerve compression injury site.

발명의실시를위한형태  Mode for Carrying Out the Invention

[218] 본발명에대해서는하기의실시예와본명세서에첨부된도면에기초하여 보다상세하게설명될것이나，이는본발명의권리범위를제한하려는것이 아니다.또한,당해기술분야에서통상의지식을가진자라면본발명의취지를 해하지않는범위내에서본발명에대해다양한변형및수정을가할수있을 것이다. [218] The present invention is based on the following examples and drawings attached to the present specification. It will be described in more detail, but it is not intended to limit the scope of the present invention. In addition, various changes and modifications to the present invention may be made by those skilled in the art without departing from the spirit of the present invention. You will be able to add

[219]  [219]

[220] 심시예 1:스크리닝제 1단계 - P19세포의신경세포로의분화및신경돌기의 Example 1 Screening Step 1-Differentiation of P19 Cells into Neurons and Neurites

、 증식촉진 、 Promoting growth

[221] (재)경기과학기술진흥원경기바이오센터내에구축된저분자화합물  [221] Low Molecular Compounds Established in Gyeonggi Bio Center, Gyeonggi Institute of Science and Technology Promotion

라이브러리 177,920개에대해， P19세포모델을이용하여신경세포로의분화및 신경돌기의증식을촉진시키는화합물을스크리닝하였다.  For 177,920 libraries, a P19 cell model was used to screen compounds that promote differentiation into neural cells and proliferation of neurites.

[222] 상기 P19세포는마우스의배아암종세포주로서，일반적인배양조건에서는 거의분화되지않는다.반면,신경세포특이적전사조절인자 NeuroD2를 P19 세포에전달해주면,신경돌기 (neurite)가증식하고신경세포로분화한다.  The P19 cells are mouse embryonic carcinoma cell lines, which are hardly differentiated under normal culture conditions. On the other hand, when neuroD2 is transferred to P19 cells, neurites proliferate and propagate neural cells. Differentiate into

[223] 따라서,본발명자들은신경세포특이적전사조절인자 NeuroD2 DNA  [223] Thus, the present inventors found that neuroD2 DNA, a neuronal cell specific transcriptional regulator,

플라스미드를 P19세포와함께배양하는 P19세포모델올구축하였다.이때， 어떠한화합물이 P19세포를신경세포로분화시키는것을촉진하고신경돌기의 증식을촉진하는지관찰하였다.  Plasmids were constructed with a P19 cell model incubated with P19 cells. It was then observed which compounds promoted the differentiation of P19 cells into neurons and the proliferation of neurites.

[224] 먼저， P19세포는 10%소태아혈청 (FBS), 50 U/mL페니실린및 50 g/mL  [224] First, P19 cells contained 10% fetal bovine serum (FBS), 50 U / mL penicillin and 50 g / mL.

스트랩토마이신， 2 mM Glutamax, 1 mM피투브산나트륨이첨가된  Strapmycin, with 2 mM Glutamax, 1 mM Sodium Pitobate

MEM (최소필수배지)을이용하여 37⁰C, 5% C0₂배양기에서배양하였다.상기 배양된 P19세포를 384-웰플레이트에 4,000세포 /웰로 80 씩분주하였으며, 이때사용한배지는 5.9%소태아혈청， 2 mM Glutamax, 1 mM피루브산나트륨이 포함된 MEM배지이다.그리고최종 150 nL/웰의 Fugene HD및최종농도 50 ng/웰의 NeuroD2 DNA플라스미드흔합 MEM배지 15}AL를첨가하여세포내로 유전자를도입 (transfection)시켰으며，이때소태아혈청의최종농도는 5%이다. MEM (minimum essential medium) was used to incubate in a 37 ⁰ C, 5% C0 ₂ incubator. The cultured P19 cells were dispensed at 4,000 cells / well in 384-well plates at 80, with 5.9% fetuses used. MEM medium containing serum, 2 mM Glutamax, 1 mM sodium pyruvate, and the final 150 nL / well Fugene HD and the final concentration of 50 ng / well NeuroD2 DNA plasmid mixed MEM medium 15} AL were added to the gene. Transfection, and the final concentration of fetal bovine serum is 5%.

[225] 36시간동안배양한후,리퀴드핸들러 (liquid handler)를이용하여각각의  [36] After 36 hours of incubation, each of the liquid handlers was

화합물을최종농도 10 μΜ로세포를처리하였다.양성대조군으로서최종농도 25 ηΜ의스타우로스포린 (Staurosporin)을이용하였다.화합물처리 48시간후에 , PBS에희석된 3.7%포름알데히드를이용하여 P19세포를고정시켰다.이어서 PBS로 5회세척하고， 0.25%트리톤 X-100을포함한 PBS를 8분동안처리하여 세포막투과성을증가시켰다.이어서 PBS로 5회세척한후 10%  The compound was treated with cells at a final concentration of 10 μΜ. As a positive control, a final concentration of 25 ηΜ staurosporin was used. After 48 hours of compound treatment, P19 cells were diluted with 3.7% formaldehyde diluted in PBS. This was followed by 5 washes with PBS and treatment with PBS containing 0.25% Triton X-100 for 8 minutes to increase cell membrane permeability. 5 washes with PBS and then 10%

BSA (소혈청알부민)가포함된 PBS로 30분동안처리하였으며, 5% BSA와 a-beta ΙΠ-류불린항체가포함된 PBS로 2시간동안반웅시켰다.이어서 PBS로 5회 세척한후， 594 nm파장대의형광단백질이부착되어있는이차항체를 1시간 동안반웅시키고， PBS로 5회이상세척하였다. 0.25%트리톤 x-100을처리하는 과정을제외한모든실험은 37°C배양기에서진행하였다.형광염색이종료된후 Cellomics의 NeuronalProfiling.V3.5프로그램을사용하여신경돌기의길이를 정량화하였다. [226] 염색된 P19세포를분석한결과, 184개의화합물들이신경세포특이적 전사조절인자 NeuroD2에의한 P19세포의분화및신경돌기증식 (즉, 신경돌기의길이신장)의촉진을나타낸다는점이확인되었다.특히,상기 화합물들은양성대조군으로사용된스타우로스포린 (Staurosporin)의신경돌기 길이신장활성에대비하여 0.5배이상의효과를나타내는것이관찰되었다. Treated with PBS containing BSA (bovine serum albumin) for 30 minutes, followed by reaction for 2 hours with PBS containing 5% BSA and a-beta ΙΠ-leubulin antibody. After washing 5 times with PBS, 594 Secondary antibodies with fluorescence protein attached to the nm wavelength band were reacted for 1 hour and washed 5 times with PBS. All experiments except for the treatment of 0.25% Triton x-100 were conducted in a 37 ° C. incubator. After fluorescence staining, the length of neurites was quantified using Cellomics' Neuronal Profiling. V3.5 program. [226] Analysis of stained P19 cells revealed that 184 compounds indicated the differentiation of P19 cells by neural cell-specific transcription regulators NeuroD2 and the promotion of neurogenesis (ie, neurogenesis). In particular, the compounds were observed to exhibit an effect of more than 0.5 times the neural dendritic kidney activity of Statausporin used as a positive control.

[227]  [227]

[228] 심시예 2:스크리닝체 2단계 -해미 · 1 세포의축식 ·듬기의성장촉 ?1  [228] Example 2 Screening sieve stage 2 -Haemi · 1 cell axial · growth stimulation of growth? 1

[229] 상기스크리닝제 1단계에서선별된 184개의화합물들에대해, SD래트배아의 뇌해마신경세포모델을이용하여축삭돌기의성장을촉진시키는화합물을 스크리닝하였다. , For the 184 compounds selected in step 1 of the screening agent, compounds that promote the growth of axons were screened using a brain hippocampal neuronal cell model of SD rat embryos. ,

[230] 먼저，임신 18일째 (E18)인 SD(Sprague Dawley)래트의배아로부터뇌 [230] First, brains from embryos of SD (Sprague Dawley) rats, 18 days pregnant (E18).

해마 (hippocampus)를분리하였다.상기분리된해마를 HBSS로세척하고 아큐테이즈 (Accutase)와함께 10분동안실온에서반응시켰다.이어서 , 2 mM Glutamax, 1 x B27이포함된 Neurobasal A배양액을첨가하고 1회세척한후， 피펫팅을통해조직을파쇄시켰다.이어서 , 1 X B27, 2 mM Glutamax가첨가된 Neurobasal A배양액으로 3회이상세척하고, 40 μιη나일론여과기로여과시켜 해마신경세포를획득하였다.상기신경세포를 2% Β27, 2 mM Glutamax가 포함된 Neurobasal A배양액에현탁한후， 384-웰플레이트에 2,000세포 /웰씩 분주하였다.  Hippocampus was isolated. The isolated hippocampus was washed with HBSS and reacted with Accutase at room temperature for 10 minutes. Then, Neurobasal A culture solution containing 2 mM Glutamax, 1 x B27 was added. After washing once, the tissues were crushed by pipetting. Then, the hippocampal neurons were obtained by rinsing three times with Neurobasal A culture medium containing 1 × B27, 2 mM Glutamax, and filtration with 40 μιη nylon filter. The neurons were suspended in Neurobasal A culture solution containing 2% β27, 2 mM Glutamax, and then dispensed at 2,000 cells / well in 384-well plates.

[231] 24시간후，각각의화합물을최종농도 10 μΜ로처리하고 48시간동안  [231] After 24 hours, each compound was treated with a final concentration of 10 μΜ for 48 hours.

배양하였다.본실험의음성대조군으로서 DMSO 0.5%를사용하였다.그후, α-beta m-튜불린염색및정량화과정을상기스크리닝계 1단계와동일하게 진행하였다.  DMSO 0.5% was used as the negative control of the present experiment. After that, α-beta m-tubulin staining and quantification were performed in the same manner as in the screening step 1 above.

[232] 염색된해마신경세포를분석한결과, 10개의화합물들이해마신경세포의 축삭돌기성장을촉진시키고축삭돌기의길이를증가시킨다는점이  [232] Analysis of stained hippocampal neurons showed that 10 compounds promoted axonal growth of hippocampal neurons and increased axon length.

확인되었다.특히，상기화합물들^음성대조군으로사용된 DMSO의축삭돌기 길이신장활성에대비하여 1.5배이상의더큰효과를나타내는것이 관찰되었다.  In particular, it was observed that the axon length of DMSO used as the compound-negative control showed more than 1.5 times greater effect on the kidney activity.

[233]  [233]

[234] 심시예 3:스크리닝제 3단계 -산화적스트레스에의하피짐시경세포의사^ 억제  Example 23 Screening Step 3 Screening Agent-Inhibition of Physiologic Cell Surgery by Subsequent Oxidative Stress

[235] 상기스크리닝제 2단계에서선별된 10개의화합물들에대해, SD래트배아의 전뇌피질신경세포모델을이용하여산화적스트레스 (oxidative damage또는 oxidative stress)에의한세포사멸을억제시키는화합물을스크리닝하였다.  [235] Screening for 10 compounds selected in the screening step 2, the compounds inhibiting cell death due to oxidative stress or oxidative stress using the whole brain cortical neuronal cell model of SD rat embryos. It was.

[236] 먼저，임신 18일째 (E18)인 SD래트의태아에서전뇌피질 (cortex)을분리및 회수하였다.상기회수된전뇌피질을 HBSS로 1회세척하고，  First, cortex was isolated and recovered from the fetus of SD rats (E18) on day 18 of pregnancy. The recovered whole cortex was washed once with HBSS,

아큐테이즈 (Accutase)를실은에서 10분동안처리하였다.아큐테이즈를 제거하고배양액 (NBG, Neurobal A배지， 1 X B27 supplement, 2 mM GlutaMax)으로 1회세척한후，배양액 2 mL을첨가하고피펫팅을통해조직을 파쇄시켰다.이어서，배양액으로 3회이상세척한후 , 40 μηι의나일론여과기를 이용하여피질신경세포를획득하였다.상기신경세포를 Accutase was treated for 10 minutes at room temperature. Accutate was removed and culture medium (NBG, Neurobal A medium, 1 × B27 supplement, 2 mM After washing once with GlutaMax), 2 mL of the culture solution was added and the tissue was crushed by pipetting. Then, after washing three times or more with the culture solution, cortical nerve cells were obtained using a 40 μηι nylon filter. Nerve cells

폴리 -디-라이신 (p₀ly-D-Lysine)이코팅된 96-웰폴레이트에 8xl0⁴세포 /웰의 밀도로 200 씩분주하였다.성숙한신경세포로성장시키기위하여, 37°C, 5% C0₂배양기에서 10일동안배양하였다. A 96-well folate coated with poly-di-lysine (p ₀ ly-D-Lysine) was dispensed at a density of 8xl0 ⁴ cells / well at 200. 37 ° C., 5% C0 to grow into mature neurons. Incubated for 10 days in ₂ incubators.

[237] 화합물을최종농도 10 μΜ, 20 μΜ, 30 M(DMSO 0.5%)가되도록각각 [237] The compounds were each concentrated to a final concentration of 10 μΜ, 20 μΜ, 30 M (DMSO 0.5%).

신경세포에첨가하여， 4시간동안배양기에서처리하였다.신경세포의사멸올 유도하기위하여과산화수소 ( 0₂)를사용하였다. 4시간동안전처리한 화합물을제거하고 50 μΜ의과산화수소가함유된배지 (NG: Neurobasal A배지，In addition to neurons, the cells were treated in the incubator for 4 hours. Hydrogen peroxide (0 ₂ ) was used to induce death of neurons. 4 hours of pretreated compound was removed and 50 μΜ of hydrogen peroxide medium (NG: Neurobasal A medium,

2 mM GlutaMax)를첨가하고 3분동안처리하였다.배지를제거한후 2 mM GlutaMax) was added and treated for 3 minutes.

배양액 (NBG)을 200 μί씩첨가하고,각각의화합물을전처리농도와동일한 농도로첨가하였다.  Culture medium (NBG) was added 200 μl each, and each compound was added at the same concentration as the pretreatment concentration.

[238] 배양기에서 24시간동안처리한후에， 30 [xL의 WST-8를첨가하여배양기에서 4시간동안반웅시켰다.상기 WST-8은수용성테트라졸륨염으로서세포 생존율을측정할수있도록해주며,이에따라화합물의신경세포사멸억제 효과를확인할수있다.즉,노란색의 WST-8은살아있는세포내에존재하는 탈수소효소에의해오렌지색의 WST-8포르마잔으로환원되며,이는  After treatment for 24 hours in the incubator, 30 [xL of WST-8 was added and reacted for 4 hours in the incubator. The WST-8 is a water-soluble tetrazolium salt which allows the measurement of cell viability. The neuronal cell death suppression effect can be confirmed, that is, yellow WST-8 is reduced to orange WST-8 formazan by dehydrogenase present in living cells.

약효평가시스템 (Hexstation)을이용하여흡광도 450 nm에서측정할수있다. 과산화수소를처리하지않은신경세포의생존율을 100%로설정하였다.본 실험의양성대조군으로서 NEU2000화합물을사용하고,음성대조군으로서 DMSO 0.5%를사용하였다.상기 NEU2000화합물은뇌신경성장인자들의 신경세포생존능력을증진시키고,뇌세포를괴사시키는뉴로트로핀단백질의 독성작용을억제하는물질로서알려져있다.  Absorption at 450 nm can be measured using a Hexstation. The survival rate of neurons without treatment with hydrogen peroxide was set to 100%. NEU2000 compound was used as a positive control group and 0.5% DMSO was used as a negative control group. Is known as a substance that inhibits the toxic effects of neurotrophin protein, which enhances the activity and kills brain cells.

[239] 과산화수소로처리한피질신경세포의생존율을분석한결과,  [239] Analysis of the survival rate of cortical neurons treated with hydrogen peroxide

N-(2-에톡시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드가 세포생존율이가장높았음이확인되었다.이는과산화수소에의한피질 신경세포의사멸을억제하는효과가가장우수하다는것을나타낸다.또한，상기 동정된화합물은본실험의양성대조군으로사용된 NEU2000화합물과 비교하였을때신경세포사멸억제효과가동등한수준으로확인되었다.  It was confirmed that N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide had the highest cell survival rate. In addition, the anti-apoptotic effect was shown to be the best. The identified compound was found to have the same level of neuronal cell death suppression effect as compared with the NEU2000 compound used as the positive control of the present experiment.

[240]  [240]

[241] 상기스크리닝제 1단계,제 2단계，제 3단계에서각각선별된화합물들의  [241] Compounds of the screening agents selected in the first, second and third stages, respectively

화학구조를종합하여분석한결과에기초하여,본발명자들은신경세포로의 분화를촉진시키고，신경돌기및축삭돌기의증식및길이성장을촉진시키고， 신경세포의사멸을억제하고재생을촉진시키는물질로서,화학식 1또는 2로 표시되는화합물을도출해내었다.  Based on the results of a comprehensive analysis of chemical structures, the present inventors promote the differentiation of neurons into cells, promote the proliferation and length growth of neurites and axons, inhibit neuronal cell death and promote regeneration. As a compound, a compound represented by the formula (1) or (2) was derived.

[242]  [242]

[243] 짐시예 4:화학식 1의화함물또는이의 약학적으로허용가능하염의제조 [244] 4-1.상기반용식 1에따 화학식 1의하함몰의체조 [243] Example 4 Preparation of a Compound of Formula 1 or a pharmaceutically acceptable salt thereof 4-1. Gymnastics of lower depression of Chemical Formula 1 according to Formula 1 above

4 5  4 5

[246] 시약및조건: (_a)토실클로라이드, K₂C0₃, DMF,실온, 8h; (b) Reagents and conditions: ( _a ) tosylchloride, K ₂ CO ₃ , DMF, room temperature, 8 h; (b)

에틸브로모아세테이트, K₂C0₃, DMF,실온， 12h; (c) 2.5N NaOH, THF,환류， 6h; (d) i)옥살릴클로라이드, CH₂C1₂,환류， 3h; ii) TEA, CH₂C1₂,실온， 8h. Ethyl bromoacetate, K ₂ CO ₃ , DMF, room temperature, 12 h; (c) 2.5 N NaOH, THF, reflux, 6 h; (d) i) oxalyl chloride, CH ₂ C1 ₂ , reflux, 3h; ii) TEA, CH ₂ C1 ₂ , room temperature, 8 h.

[247] 체 1다계: 한물 5름체조하는다계  [247] Sieve 1 multi-system: multi-body gymnastics

[248] 화합물 4(10.0 g, 81.2 mmol)를 DMF(150 mL)에녹이고 K₂C0₃(16.8g, [248] Compound 4 (10.0 g, 81.2 mmol) was dissolved in DMF (150 mL), and K ₂ CO ₃ (16.8 g,

122mmol)를첨가한후， 10분동안실온에서교반하였다.토실클로라이드 (16.3 g, 85.3 mmol)를천천히첨가하고,실온에서 8시간동안교반하였다.반웅종결후에 에틸아세테이트로추출하고，물과브라인 (brine)으로 3회씩세척하였다.  122 mmol) was added and stirred at room temperature for 10 minutes. Tosyl chloride (16.3 g, 85.3 mmol) was added slowly and stirred at room temperature for 8 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and water and brine ( brine) three times.

유기층에서무수황산나트륨으로물기를제거한후，감압증류하여용매를 제거하였다.석출된고체를핵산에현탁하고화합물 5를여과하여  The organic layer was dried over sodium sulfate anhydride, and distilled under reduced pressure to remove the solvent. The precipitated solid was suspended in nucleic acid, and the compound 5 was filtered.

수득하였다 (흰색결정 15.0 g,수율 67%).화합물 5는  Obtained (15.0 g of white crystals, 67% yield).

N-(2-메톡시페닐) -4-메틸벤젠술폰아미드이며，그식별데이터는다음과같았다:  N- (2-methoxyphenyl) -4-methylbenzenesulfonamide, the identification data were as follows:

[249] Ή NMR(CDC1₃) δ 2.32 (s, 3H), 3.60 (s, 3H), 6.67-6.72 (d, IH), 6.84-6.89 (t, IH),2 NMR (CDC1 ₃ ) δ 2.32 (s, 3H), 3.60 (s, 3H), 6.67-6.72 (d, IH), 6.84-6.89 (t, IH),

6.98-7.03 (t, IH), 7.07 (s, IH), 7.14-7.16 (d, 2H), 7.50-7.52 (d, IH), 7.62-7.64 (d, 2H); 6.98-7.03 (t, IH), 7.07 (s, IH), 7.14-7.16 (d, 2H), 7.50-7.52 (d, IH), 7.62-7.64 (d, 2H);

[250] ¹³C NMR 6 21.48, 55.54, 110.43, 120.76, 120.80, 125.08， 125.72, 126.97, 129.08,[250] ¹³ C NMR 6 21.48, 55.54, 110.43, 120.76, 120.80, 125.08, 125.72, 126.97, 129.08,

135.95, 143.35, 149.22. 135.95, 143.35, 149.22.

[251] 체 2다계 :하함물 6을체조하는다계  [251] Sieve 2 polysystem: Multiple gymnastics 6

[252] 상기제 1단계에서제조된화합물 5(15.0 g, 54.1 mmol)를 DMF(100 mL)에 Compound 5 (15.0 g, 54.1 mmol) prepared in step 1 was added to DMF (100 mL).

녹이고 K₂C0₃(18.6 g, 135 mmol)를첨가한후, 5분동안실은에서교반하였다. 에틸브로모아세테이트 (5.98 mL, 85.3 mmol)를천천히첨가하고,실온에서 12시간동안교반하였다.반웅종결후에에틸아세테이트로추출하고,물과 브라인으로 3회씩세척하였다.유기층에서무수황산나트륨으로물기를제거한 후,감압증류하여용매를제거하였다.이어서，진공건조하여화합물 6을 수득하였다 (19.0 g,수율 96%).화합물 6은에틸 After dissolving and adding K ₂ CO ₃ (18.6 g, 135 mmol), the mixture was stirred at room temperature for 5 minutes. Ethyl bromoacetate (5.98 mL, 85.3 mmol) was added slowly and stirred at room temperature for 12 hours. After completion of reaction, the mixture was extracted with ethyl acetate, The mixture was washed three times with brine. The organic layer was removed with sodium sulfate anhydride, and distilled under reduced pressure to remove the solvent. Then, the mixture was dried in vacuo to give Compound 6 (19.0 g, yield 96%). Compound 6 was ethyl

₂·_(Ν_(2-메톡시페닐) -4-메틸페닐술폰아미도)아세테이트이며,그식별데이터는 다음과같았다: ₂ · _(Ν _ (2-methoxyphenyl) -4-methylphenylsulfonamido) acetate, the identification data of which were as follows:

[253] Ή NMR(CDC1₃) δ 1.15-1.30 (t, 3H), 2.40 (s, 3H), 3.39 (s, 3H), 4.10-4.20 (q, 2H), 4.39 (s, 2H), 6.70-6.82 (d, 1H), 6.90-6.96 (t, 1H), 7.18-7.30 (m, 3H), 7.48-7.62 (m, 3H); 253 NMR (CDC1 ₃ ) δ 1.15-1.30 (t, 3H), 2.40 (s, 3H), 3.39 (s, 3H), 4.10-4.20 (q, 2H), 4.39 (s, 2H), 6.70 -6.82 (d, 1 H), 6.90-6.96 (t, 1 H), 7.18-7.30 (m, 3H), 7.48-7.62 (m, 3H);

[254] ^,3C NMR 0 14.16, 21.53, 51.11, 54.89, 61.13, 111.26, 120.42, 126.49, 127.35,[254] ^{, 3} C NMR 0 14.16, 21.53, 51.11, 54.89, 61.13, 111.26, 120.42, 126.49, 127.35,

128.76, 129.77, 133.53, 137.07, 142.79, 155.52, 169.12. 128.76, 129.77, 133.53, 137.07, 142.79, 155.52, 169.12.

[255] 제 3다계:화함물 7음제조하는다계 [255] The third multistage: Multistage to manufacture seven sounds

[256] 상기제 2단계에서제조된화합물 6(19.0 g, 52.3 mmol)을 THF(150 mL)에  [256] Compound 6 (19.0 g, 52.3 mmol) prepared in Step 2 was added to THF (150 mL).

녹이고, 2.5 N NaOH수용액 (63 mL, 157 mmol)올첨가하고환류하였다. 6시간 후에반응을종결하고,용액의온도를실온으로식힌후,감압증류하여 THF 용매를제거한후에 EA를첨가하였다.유기층에서 IN HC1수용액으로 pH를 2로 조정한후,유기층을물과브라인으로씻어주고，무수황산나트륨으로물기를 제거한후감압증류하여용매를제거하였다.석출된고체를 EA와 HX로 재결정하여화합물 7을수득하였다 (15.0 g,수율 86%).화합물 7은  It was dissolved, 2.5N aqueous NaOH solution (63 mL, 157 mmol) was added and refluxed. After 6 hours, the reaction was terminated, the solution was cooled to room temperature, distilled under reduced pressure to remove THF solvent, and then EA was added. The pH was adjusted to 2 with IN HC1 aqueous solution in the organic layer, and the organic layer was washed with water and brine. The solvent was removed, and the solvent was removed by distillation under reduced pressure. The precipitated solid was recrystallized from EA and HX to obtain Compound 7. (15.0 g, yield 86%).

2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트산이며,그식별데이터는 다음과같았다:  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetic acid, the identification data were as follows:

[257] Ή NMR(CDC1₃) δ 2.30 (s, 3H), 3.30 (s, 3H), 4.30 (s, 2H), 6.65-6.70 (d, 1H), 257 NMR (CDC1 ₃ ) δ 2.30 (s, 3H), 3.30 (s, 3H), 4.30 (s, 2H), 6.65-6.70 (d, 1H),

6.80-6.86 (t, 1H), 7.10-7.15 (d, 2H), 7.16-7.21 (m, 1H), 7.35-7.40 (dd, 1H), 7.40-7.45 (d, 2H);  6.80-6.86 (t, 1H), 7.10-7.15 (d, 2H), 7.16-7.21 (m, 1H), 7.35-7.40 (dd, 1H), 7.40-7.45 (d, 2H);

[258] '3C NMR 0 21.49, 51.15, 54.97, 111.36, 120.59, 126.27, 126.93, 127.27, 128.84, [258] '3C NMR 0 21.49, 51.15, 54.97, 111.36, 120.59, 126.27, 126.93, 127.27, 128.84,

129.08, 130.02, 133.06, 136.33, 143.12, 155.28, 171.75. 129.08, 130.02, 133.06, 136.33, 143.12, 155.28, 171.75.

[259] 제 4다계:최종생성물로서화합물 9를제조하는다계 [259] Fourth system: A multisystem for preparing Compound 9 as a final product.

[260] 상기제 3단계에서제조된화합물 7(500 mg, 1.49 mmol)을 DCM(20 mL)에 Compound 7 (500 mg, 1.49 mmol) prepared in Step 3 was added to DCM (20 mL).

녹이고옥살릴클로라이드 (384 μ 4.47 mmol)를천천히첨가하였다.온도를높여 환류하고， 3시간후에반웅을종결하였다.반웅용액을감압증류하고이를다시 DCM(5 mL)에녹였다.화합물 8(185 mg, 1.49 mmol)을 DCM(15 mL)에녹이고 TEA(416 μL, 2.98 mmol)로 10분동안활성화시킨후，화합물 7로부터만든 염산용액을천천히적하하였다 . 8시간후에반웅을종결하고용액에물을 첨가하고,유기층을브라인으로세척한후무수황산나트륨으로물기를 제거하고감압증류하였다.농축한용액을 EA/HX (1/1 )조건으로컬럼 크로마토그래피를수행하여화합물 9를수득하였다 (흰색고체 250 mg,수율 38%).화합물 9는  Dissolved and slowly added oxalyl chloride (384 μ 4.47 mmol). The temperature was raised to reflux, and the reaction was terminated after 3 hours. The reaction solution was distilled under reduced pressure and then dissolved in DCM (5 mL). Compound 8 (185 mg) , 1.49 mmol) was dissolved in DCM (15 mL), activated with TEA (416 μL, 2.98 mmol) for 10 minutes, and the hydrochloric acid solution prepared from Compound 7 was slowly added dropwise. After 8 hours, the reaction was terminated, water was added to the solution, the organic layer was washed with brine, dried over sodium sulfate anhydrous and distilled under reduced pressure. The concentrated solution was subjected to column chromatography under EA / HX (1/1) conditions. Compound 9 was obtained (250 mg of white solid, 38% yield).

2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도) -N-(4-메록시피리딘 -3-일 )아세트아 미드이며，그식별데이터는다음과같았다: [261] 'Η NMR (CDC1₃) δ 2.43 (s, 3H), 3.42 (s, 3H), 4.05 (s, 3H), 4.34 (s, 2H), 6.75-6.90 (m, 2H), 6.95 (s, IH), 7.20-7.40 (m, 4H), 7.53 (s, 2H), 8.30 (s, IH), 9.24 (s, IH), 9.39 (s, IH); 2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide, the identification data were as follows: [261] 'Η NMR (CDC1 ₃ ) δ 2.43 (s, 3H), 3.42 (s, 3H), 4.05 (s, 3H), 4.34 (s, 2H), 6.75-6.90 (m, 2H), 6.95 ( s, IH), 7.20-7.40 (m, 4H), 7.53 (s, 2H), 8.30 (s, IH), 9.24 (s, IH), 9.39 (s, IH);

[262] ^,3C NMR δ 21.61, 54.70, 55.02, 55.95, 105.55, 111.92, 120.75, 124.23, 126.89, 127.74, 129.10, 130.34, 131.46, 134.96, 141.43, 143.78, 146.37, 154.21, 155.45, 166.59. [262] ^{, 3} C NMR δ 21.61, 54.70, 55.02, 55.95, 105.55, 111.92, 120.75, 124.23, 126.89, 127.74, 129.10, 130.34, 131.46, 134.96, 141.43, 143.78, 146.37, 154.21, 155.45, 166.45.

[263]  [263]

[264] 4-2.상기반응식 2에따른화학식 1의화합물의제조4-2. Preparation of the Compound of Chemical Formula 1 According to Scheme 2

[266] 시약및조건: (a)클로로아세틸클로라이드，디클로로메탄，실은， 1 h; (b) K₂CO_; Reagents and conditions: (a) chloroacetyl chloride, dichloromethane, silver, 1 h; (b) K ₂ CO _;

, DMF, 80°C, 2 h.  , DMF, 80 ° C., 2 h.

[267] 겨 U다계:중?물짐로서사용되는화합물 12름제조하는단계  [267] B. U Multisystem: Preparation of 12 Compounds Used as Heavy Goods

[268] 화합물 11(10.0 g, 73.0 mmol)올디클로 메탄 (300 mL)에녹이고 TEA( 12.2 mL, 87.5 mmol)를첨가한후, 0°C에서 30분동안교반하였다.클로로아세틸 [268] Compound 11 (10.0 g, 73.0 mmol) was dissolved in oxidic methane (300 mL) and TEA (12.2 mL, 87.5 mmol) was added, followed by stirring at 0 ° C. for 30 minutes.

클로라이드 (8.66 mL, 109 mmol)를천천히적하하고실온에서 3시간교반한후, IN HC1수용액으로반웅을종결하였다.증류수로 3번세척한후 Na₂S0₄로 수분을제거하고감압여과,감압증류하였다.컬럼 Chloride (8.66 mL, 109 mmol) was slowly added dropwise, stirred at room temperature for 3 hours, and then the reaction was terminated with IN HC1 aqueous solution. After washing three times with distilled water, water was removed with Na ₂ S0 ₄ , and the pressure was reduced under reduced pressure. Column

크로마토그래피 (EA/HX=1/10)로분리하여화합물 12를수득하였다 (노란색고체 4.82 g,수율 66.7%).화합물 12는 2-클로로 -N-(2-에록시페닐)아세트아미드이며, 그식별데이터는다음과같았다:  Chromatography (EA / HX = 1/10) gave Compound 12 (4.82 g of yellow solid, yield 66.7%). Compound 12 is 2-chloro-N- (2-ethoxyphenyl) acetamide, The identification data was as follows:

[269] Ή NMR (CDC1₃) δ 1.41-1.45 (t, 3H), 4.04-4.06 (q, 2H), 4.15 (s, 2H), 6.82-6.83 (d, IH), 6.90-6.95 (t, IH), 7.01-7.03 (t, IH), 8.31-8.33 (d, IH), 9.02 (s, IH); 2 NMR (CDC1 ₃ ) δ 1.41-1.45 (t, 3H), 4.04-4.06 (q, 2H), 4.15 (s, 2H), 6.82-6.83 (d, IH), 6.90-6.95 (t, IH), 7.01-7.03 (t, IH), 8.31-8.33 (d, IH), 9.02 (s, IH);

[270] ^l3C NMR δ 14.690, 43.073, 64.144， 110.783, 119.066, 120.560, 124.201, 126.453, 147.259, 163.073. [270] ^{l 3} C NMR δ 14.690, 43.073, 64.144, 110.783, 119.066, 120.560, 124.201, 126.453, 147.259, 163.073.

[271] 제 2다겨ᅵ:최종생성물로서화합물 10.1음제조하는단계  [271] Second Phase: Production of Compound 10.1 Yin as Final Product

[272] 상기제 1단계에서제조된화합물 12(2.00 g, 7.22 mmol),화합물 10(1.54 g, 7.22 mmol), K₂CO₃(2.00g,14.4mmol)를 DMF(10 mL)에첨가하고 80°C에서 2시간동안 교반하였다.디클로로메탄으로추출한후 1N HC1수용액으로반웅을 종결하였다.증류수와브라인으로세척한후 Na₂S0₄로수분을제거하고 감압여과，감압증류하였다.컬럼크로마토그래피 (EA/HX=1/10)로분리하여 화합물 10.1을수득하였다 (연한노란색고체 1.78 g,수율 54.3%, mp 162°C). 화합물 10.1은 Compound 12 (2.00 g, 7.22 mmol), Compound 10 (1.54 g, 7.22 mmol), K ₂ CO ₃ (2.00 g, 14.4 mmol) prepared in Step 1 was added to DMF (10 mL). 2 hours at 80 ° C After stirring with dichloromethane, the reaction was terminated with 1N HC1 aqueous solution, washed with distilled water and brine, dried with Na ₂ S0 ₄ , filtered under reduced pressure, and distilled under reduced pressure. Column chromatography (EA / HX = 1 / Compound 10.1 was obtained by separating into 10) (light yellow solid 1.78 g, yield 54.3%, mp 162 ° C.). Compound 10.1 is

N-(2-에톡시페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미드이 며,그식별데이터는다음과같았다:  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, the identification data being as follows:

[273] Ή NMR (CDC1₃, 400 MHz) d 9.56 (S, 1 H), 8.36 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 2 H), 7.34-7.27 (m, 3 H), 7.09 (t, J = 6.4 Hz, 1 H), 6.99-6.97 (m, 3 H), 6.79 (d, J = 1.2 Hz, 1 H), 4.35 (s, 2 H), 4.26 (q, J = 8.8， 6.8 Hz, 2 H), 3.36 (s, 3 H), 2.45 (s, 3 H), 1.69 (t, J = 7.2 Hz, 3 H); [273] NMR (CDC1 ₃ , 400 MHz) d 9.56 (S, 1 H), 8.36 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.51 (d , J = 7.6 Hz, 2H), 7.34-7.27 (m, 3H), 7.09 (t, J = 6.4 Hz, 1H), 6.99-6.97 (m, 3H), 6.79 (d, J = 1.2 Hz, 1H), 4.35 (s, 2H), 4.26 (q, J = 8.8, 6.8 Hz, 2H), 3.36 (s, 3H), 2.45 (s, 3H), 1.69 (t, J = 7.2 Hz, 3 H);

[274] > 'C NMR δ 15.016, 15.087, 21.402, 21.584, 64.600, 111.522, 119.152, 120.426, 120.646, 126.751, 127.236, 127.532, 127.638, 128.836, 129.018, 130.065, 132.340, 135.412, 143.435, 147.515, 155.236, 166.475.  [274]> 'C NMR δ 15.016, 15.087, 21.402, 21.584, 64.600, 111.522, 119.152, 120.426, 120.646, 126.751, 127.236, 127.532, 127.638, 128.836, 129.018, 130.065, 132.340, 135.412, 143.435, 147.515, 147.515, 147.515 166.475.

[275]  [275]

[276]  [276]

[278] 제 1단계 :화합몸 14를제조하는단계  [278] First Step: Manufacturing the Compound Body 14

[279] 화합물 4(0.98 mL, 8.7 mmol),화합물 13(2.0 g, 8.7 mmol)을 DMF(17.4 mL)에 녹이고 K₂C0₃(1.8g, 13. lmmol)를첨가한후， 80°C에서 2시간동안교반하였다. 증류수를첨가하여반웅을종결시킨후,에틸아세테이트로추출한후유기층을 증류수와브라인으로세척하였다.유기층을분리하여 Na₂S0₄로수분을 제거하고감압여과,감압증류하였다.컬럼크로마토그래피 (ΕΑ/ΗΧ=1/2)를통해 화합물 14를수득하였다 (갈색고체 2.1 g,수율 76%).화합물 14는 [279] Compound 4 (0.98 mL, 8.7 mmol) and Compound 13 (2.0 g, 8.7 mmol) were dissolved in DMF (17.4 mL), K ₂ CO ₃ (1.8 g, 13. lmmol) was added, and then 80 ° C. Stir for 2 hours at. After the reaction was completed by adding distilled water, the mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and brine. The organic layer was separated, the moisture was removed with Na ₂ SO ₄ , reduced pressure filtration, and distillation under reduced pressure. Compound 14 was obtained through ΗΧ = 1/2) (brown solid 2.1 g, yield 76%).

N-(2,5-디메특시페닐) -2-((2-메록시페닐)아미노)아세트아미드이다.  N- (2,5-dimethoxyphenyl) -2-((2-methoxyphenyl) amino) acetamide.

[280] 체 2다계:최종생성물로서화합물 16을체조하는다계 [280] Sieve 2 polysystem: Multisystem that contemplates Compound 16 as the final product

[281 ] 상기제 1단계에서제조된화합물 14(20 mg, 0.06 mmol),화합물 15(13 mg, 0.07 mmol)를디클로로메탄 (0.3 mL)에녹이고피리딘 (25.0 μΐ 0.32 mmol)을첨가한 후,실온에서 3시간동안교반하였다.증류수를첨가하여반웅을종결시킨후， 디클로로메탄으로추출하고유기층을황산구리 (Π)오수화물수용액과증류수로 세척하였다.유기층을분리하여 Na₂S0₄로수분을제거하고감압여과， 감압증류하였다.컬럼크로마토그래피 (ΕΑ/ΗΧ=1/4)를수행하여화합물 16을 수득하였다 (연한노란색고체 22 mg,수율 78%).화합물 16은 2-(4-플루오로 -N-(2-메특시페닐)페닐술폰아미도) -N-(2-메특시페닐)아세트아미 드이며,그식별데이터는다음과같았다: Compound 14 (20 mg, 0.06 mmol) and Compound 15 (13 mg, 0.07 mmol) prepared in Step 1 were added to dichloromethane (0.3 mL) and pyridine (25.0 μΐ 0.32 mmol) was added. After stirring for 3 hours at room temperature, the reaction was terminated by adding distilled water, extracted with dichloromethane, and the organic layer was washed with an aqueous solution of copper sulfate (Π) pentahydrate and distilled water. The organic layer was separated, and the moisture was removed with Na ₂ SO ₄ . Pressure filtration and distillation under reduced pressure. Compound 16 was obtained by column chromatography (ΕΑ / ΗΧ = 1/4) (22 mg of pale yellow solid, yield 78%). 2- (4-fluoro-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2-methoxyphenyl) acetamide, the identification data being as follows:

[282] Ή NMR (DMSO-d6, 400MHz) d 9.25 (S, 1H), 7.75-7.72 (m, 3 H), 7.46-7.33 (m, 4 H), 7.01-6.98 (m, 3 H), 6.64 (dd, J=8.8, 2.8Hz, 1H), 4.42 (s,2H), 3.84 (s, 3H), 3.68 (s, 3H), 3.41 (s, 3H); LRMS found 475.1.  [282] Ή NMR (DMSO-d 6, 400 MHz) d 9.25 (S, 1H), 7.75-7.72 (m, 3H), 7.46-7.33 (m, 4H), 7.01-6.98 (m, 3H), 6.64 (dd, J = 8.8, 2.8 Hz, 1H), 4.42 (s, 2H), 3.84 (s, 3H), 3.68 (s, 3H), 3.41 (s, 3H); LRMS found 475.1.

[283]  [283]

[284] 4-4.상기바용식 4에따른화학식 1의화합물의제조4-4. Preparation of the Compound of Formula 1 According to Formula 4 above.

160°C, 20min 17  160 ° C, 20min 17

[286] 상기실시예 4-2에서최종생성물로제조된화합물 10.1(100mg, 0.22mmol), 요오드메탄 (i6|iL, 0.26mmo0를 VIF(0.22 mL)에녹이고 K₂C0₃(45mg, [286] Compound 10.1 (100 mg, 0.22 mmol), iodine methane (i6 | iL, 0.26 mmol) was dissolved in VIF (0.22 mL), and K ₂ C0 ₃ (45 mg,

O.33mmol)을첨가한후，마이크로웨이브 (50wt, 160°C)를이용하여 20분동안 반웅시켰다.증류수를첨가하여반웅을종결시킨후,에틸아세테이트로추출한 후유기층을증류수와브라인으로세척하였다.유기층을분리하여 Na₂S0₄로 수분을제거하고감압여과，감압증류하였다.컬럼 33 mmol) was added, and the reaction mixture was reacted for 20 minutes using microwave (50wt, 160 ° C). After the reaction was terminated by adding distilled water, the mixture was extracted with ethyl acetate and the organic layer was washed with distilled water and brine. The organic layer was separated, dried with Na ₂ S0 ₄ , filtered under reduced pressure and distilled under reduced pressure.

크로마토그래피 (ΕΑ/ΗΧ=1/2)를수행하여화합물 17을수득하였다 (연한노란색 고체 25 mg,수율 24%).화합물 17은  Chromatography (ΕΑ / ΗΧ = 1/2) was carried out to obtain Compound 17 (25 mg of pale yellow solid, yield 24%).

N-(2-에특시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-메틸아세트아 미드이며，그식별데이터는다음과같았다:  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N-methylacetamide, the identification data being as follows:

[287] Ή NMR (CDC1₃, 400MHz) d 7.61 (d, J=8.0Hz, 2H), 7.50 (d,J =7.6Hz, 1H), 7.33 (t, J=8.0Hz, IH), 7.26 (t, J=7.6Hz, 1H), 7.21 (d, J=8.4Hz, 2H), 7.04 (d, J=7.2Hz, 1H), 6.98-6.88 (m, 3H), 6.77 (d, J=8.0Hz, IH), 4.23 (q, J=l 1.6， 2.8Hz, 2H), 4.04-3.95 (m, 2H), 3.41 (s, 3H), 3.12 (s, 3H), 2.40 (s, 3H), 1.27 (t, J=6.8Hz, 3H); LRMS found 469.1. [287] Ή NMR (CDC1 ₃ , 400 MHz) d 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, IH), 7.26 ( t, J = 7.6Hz, 1H), 7.21 (d, J = 8.4Hz, 2H), 7.04 (d, J = 7.2Hz, 1H), 6.98-6.88 (m, 3H), 6.77 (d, J = 8.0 Hz, IH), 4.23 (q, J = l 1.6, 2.8 Hz, 2H), 4.04-3.95 (m, 2H), 3.41 (s, 3H), 3.12 (s, 3H), 2.40 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H); LRMS found 469.1.

[288]  [288]

[289] 4-5.상기바용식 5에따른하학식 1의화함물의제조

[289] 4-5. Preparation of Chemical Formula 1 of Formula 1 According to Bar Formula 5 above.

[291] 체 1다계 :하함물】9름체조하는다계  [291] Sieve 1 polysystem: Package multi-body gymnastics

[292] 화합물 18(50mg, 0.1mmol)을디클로로메탄 (1.0 mL)에녹인후， 0°C에서화합물 mCPBA(17 mg, 0.1 mmol)를천천히첨가하였다. 0°C에서 10분동안반웅시킨후 반웅용액으5 mL를덜어내어증류수를첨가하고반웅을종결시켰다.이어서, 디클로로메탄으로추출한후,유기층올증류수와브라인으로세척하였다. [292] Compound 18 (50 mg, 0.1 mmol) was dissolved in dichloromethane (1.0 mL) and obtained at 0 ° C. mCPBA (17 mg, 0.1 mmol) was added slowly. After 10 minutes of reaction at 0 ° C., 5 mL of the semi-aqueous solution was added to add distilled water and the reaction was terminated. The mixture was extracted with dichloromethane and washed with organic layer distilled water and brine.

유기층을분리하여 Na₂S0₄로수분을제거하고감압여과,감압증류하였다.컬럼 크로마토그래피 (ΕΑ/ΗΧ=1/4)를수행하여화합물 19를수득하였다 (연한노란색 고체 10 mg,수율 40 %).화합물 19는 The organic layer was separated, the water was removed with Na ₂ SO ₄ , reduced pressure filtration, and distillation under reduced pressure. Compound 19 was obtained by column chromatography (ΕΑ / ΗΧ = 1/4) (10 mg of pale yellow solid, yield 40%). Compound 19

N-(2,5-디메특시페닐) -2-(N-(2-메록시페닐) -4- (메틸술피닐)페닐술폰아미도)아세 트아미드이며,그식별데이터는다음과같았다:  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylsulfinyl) phenylsulfonamido) acetamide, the identification data of which were as follows :

[293] Ή NMR (DMS0-d6, 400MHz) d 9.24 (S, IH), 7.88 (dd, J=8.0Hz, 4H), 7.75 (s, IH), 7.43 (d, J=6.4Hz, IH), 7.36 (t, J=8.0Hz, IH), 7.00 (d, J=8.8Hz, 3H), 6.64 (dd, J=8.8, 2.8Hz, IH), 4.44 (s, 2H), 3.84 (s, 3H), 3.68 (s, 3H), 3.33 (s, 3H), 2.82 (s, 3H); LRMS found 519.1.  NMR (DMS0-d6, 400 MHz) d 9.24 (S, IH), 7.88 (dd, J = 8.0 Hz, 4H), 7.75 (s, IH), 7.43 (d, J = 6.4 Hz, IH) , 7.36 (t, J = 8.0 Hz, IH), 7.00 (d, J = 8.8 Hz, 3H), 6.64 (dd, J = 8.8, 2.8 Hz, IH), 4.44 (s, 2H), 3.84 (s, 3H), 3.68 (s, 3H), 3.33 (s, 3H), 2.82 (s, 3H); LRMS found 519.1.

[294] 제 2다계:화합물 20음체조하는다계  [294] Second Polysystem: Compound 20 Aqueous Polyphonic System

[295] 상기제 1단계에서화합물 19를제조하는것과병행하여,제 2단계에서는별도의 화합물 20을제조할수있다. In parallel with the preparation of compound 19 in the first step, a separate compound 20 can be prepared in the second step.

[296] 상기제 1단계에서덜어낸반웅용액 0.5 mL에 mCPBA(8.5 mg, O.lmmol)를  [296] mCPBA (8.5 mg, O.lmmol) was added to 0.5 mL of the semi-aqueous solution extracted in step 1 above.

0°C에서천천히첨가하였다.실온에서 20분동안반웅시킨후증류수를첨가하고 반웅을종결시켰다.이어서,디클로로메탄으로추출한후유기층올증류수와 브라인으로세척하였다.유기층을분리하여 Na₂S0₄로수분을제거하고 감압여과,감압증류하였다.컬럼크로마토그래피 (ΕΑ/ΗΧ=1/4)를수행하여 화합물 20을수득하였다 (연한노란색고체 13 mg,수율 52%).화합물 20은 The reaction was slowly added at 0 ° C. After reaction for 20 minutes at room temperature, distilled water was added and the reaction was terminated. Then, the mixture was extracted with dichloromethane and washed with distilled water and brine. The organic layer was separated and Na ₂ S0 ₄ was added. Water was removed, and the resultant was filtered under reduced pressure and distilled under reduced pressure. Compound 20 was obtained by column chromatography (ΕΑ / ΗΧ = 1/4) (13 mg of pale yellow solid, yield 52%).

N-(2,5-디메특시페닐) -2-(N-(2-메특시페닐) -4- (메틸술포닐)페닐술폰아미도)아세 트아미드이며，그식별데이터는다음과같았다:  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylsulfonyl) phenylsulfonamido) acetamide with the following identification data: :

[297] Ή NMR (DMSO-d6 ,400MHz) d 9.23 (S, IH), 8.15 (d, J=8.4Hz, 2H), 7.93 (d,  [297] NMR (DMSO-d 6, 400 MHz) d 9.23 (S, IH), 8.15 (d, J = 8.4 Hz, 2H), 7.93 (d,

J=8.4Hz, IH), 7.74 (s, IH), 7.44 (d, J=6.4Hz, IH), 7.39 (t, J=6.4Hz, IH), 7.02-6.97 (m, 3H), 6.41 (dd, J=8.8, 3.2Hz, IH), 4.47 (s, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.34 (s, 3H), 3.30 (s, 3H); LRMS found 535.1  J = 8.4 Hz, IH), 7.74 (s, IH), 7.44 (d, J = 6.4 Hz, IH), 7.39 (t, J = 6.4 Hz, IH), 7.02-6.97 (m, 3H), 6.41 ( dd, J = 8.8, 3.2 Hz, IH), 4.47 (s, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.34 (s, 3H), 3.30 (s, 3H); LRMS found 535.1

[298]  [298]

[299] 4-6.상기반용식 6에따른화학식 1의화합물의제조[299] 4-6. Preparation of Compound of Chemical Formula 1 According to Formula 6 above

[301] 화합물 21(10 mg, 0.02 mmol), NaN₃(4 mg, 0.06 mmol), NH₄CI(3.4mg, [301] Compound 21 (10 mg, 0.02 mmol), NaN ₃ (4 mg, 0.06 mmol), NH ₄ CI (3.4 mg,

0.06mmol)을 DMF(0.5 mL)에녹인후 120°C에서 6시간동안교반하였다. 증류수를첨가하여반웅을종결시킨후，에틸아세테이트로추출하고유기중을 증류수와브라인으로세척하였다.유기층을분리하여 Na₂S0₄로수분올 제거하고감압여과，감압증류하였다.컬럼크로마토그래피 (MC MeOH=10/l)를 수행하여화합물 22를수득하였다 (노란색고체 6 mg,수율 55 %).화합물 22는 N-(2,5-디메특시페닐 )-2-(N-(2-메톡시페닐) -4-(1Η-테트라졸 -5-일)페닐술폰아미도 )아세트아미드이다. 0.06 mmol) was dissolved in DMF (0.5 mL) and stirred at 120 ° C. for 6 hours. After the reaction was completed by adding distilled water, the mixture was extracted with ethyl acetate and the organic phase was washed with distilled water and brine. The organic layer was separated, the water was removed with Na ₂ SO ₄ , reduced pressure filtration and distillation under reduced pressure. MeOH = 10 / l) was carried out to give compound 22 (6 mg of a yellow solid, 55% yield). Compound 22 was N- (2,5-dimethoxyphenyl) -2- (N- (2-meth) Methoxyphenyl) -4- (1Η-tetrazol-5-yl) phenylsulfonamido) acetamide.

[302]  [302]

[303] 4-7.상기반용식 7에따른화학식 1의화합물의제조 4-7. Preparation of the compound of Formula 1 according to Formula 8 above.

[305] 화합물 23(20 mg, 0.04 mmol)을 MeOH(0.4 mL)에녹인후 0^oC에서 NaBH₄(3 mg, 0.12 mmol)를천천히첨가하였다.실은에서 2시간동안교반시킨후,증류수를 첨가하여반웅을종결시키고，에틸아세테이트로추출한후유기층을증류수와 브라인으로세척하였다.유기층을분리하여 Na₂S0₄로수분을제거하고 감압여과，감압증류하였다.컬럼크로마토그래피 (EA/HX=1/1)를수행하여 화합물 24를수득하였다 (흰색고체 8 mg,수율 38 %).화합물 24는 Compound 23 (20 mg, 0.04 mmol) was dissolved in MeOH (0.4 mL), and NaBH ₄ (3 mg, 0.12 mmol) was added slowly at 0 ^° C. After stirring for 2 hours at room temperature, distilled water was added. The reaction mixture was terminated, extracted with ethyl acetate, and the organic layer was washed with distilled water and brine. The organic layer was separated, dried with Na ₂ S0 ₄ , filtered under reduced pressure, and distilled under reduced pressure. Column chromatography (EA / HX = 1 / 1) was carried out to obtain Compound 24 (8 mg of white solid, 38% yield).

N-(2,5-디메톡시페닐) -2-(4-(1-히드록시에틸) -N-(2-메특시페닐)페닐술폰아미도) 아세트아미드이며,그식별데이터는다음과같았다:  N- (2,5-dimethoxyphenyl) -2- (4- (1-hydroxyethyl) -N- (2-methoxyphenyl) phenylsulfonamido) acetamide, the identification data of which were as follows: :

[306] Ή NMR (CDC1₃, 400 MHz) 9.26 (S, 1H), 7.37 (S, 1H), 7.57 (dd, J = 23.6, 8.4 Hz, 4 H), 7.37-7.32 (m, 2 H), 6.98 (t, J = 8.4 Hz, 3 H), 6.64 (dd, J = 8.8, 2.8 Hz, 1 H), 5.51 (S, 1H), 4.83-4.80 (m, 1 H), 4.36 (s, 2H), 3.84 (s, 3 H), 3.58 (s, 3 H), 3.30 (s, 3 H), 1.33 (d, J = 6.4 Hz, 3 H) LRMS found 501.1 [306] Ή NMR (CDC1 ₃ , 400 MHz) 9.26 (S, 1H), 7.37 (S, 1H), 7.57 (dd, J = 23.6, 8.4 Hz, 4 H), 7.37-7.32 (m, 2H) , 6.98 (t, J = 8.4 Hz, 3H), 6.64 (dd, J = 8.8, 2.8 Hz, 1H), 5.51 (S, 1H), 4.83-4.80 (m, 1H), 4.36 (s, 2H), 3.84 (s, 3H), 3.58 (s, 3H), 3.30 (s, 3H), 1.33 (d, J = 6.4 Hz, 3H) LRMS found 501.1

[307]  [307]

「3081 심시예 S:화학식 2의화합물또는이의 약학적으로허용가능하염의제조 3081 Exam Example S: Preparation of Compound of Formula 2 or a pharmaceutically acceptable salt thereof

[309] 5-1.상기반웅식 8에따른화학식 2의화합물의체조  5-1.Synthesis of Compound of Chemical Formula 2 According to Reaction Formula 8

[310]

[310]

[311] 제 1다계 :화합물 S 체조하는다계  [311] The first system: Compound S gymnastics

[312] 화합물 R(50 mg, 0.46 mmol)을디클로로메탄 (1.5 mL)에녹이고클로로  [312] Compound R (50 mg, 0.46 mmol) was dissolved in dichloromethane (1.5 mL) and chloro

아세틸클로라이드 (44.0[iL, O.55mmol)를첨가한후,실온에서 30분동안 교반하였다.증류수를첨가하여반응을종결시킨후,디클로로메탄으로 추출하고유기층을증류수와브라인으로세척하였다.유기층을분리하여 Na₂SO 4로수분을제거하고감압여과,감압증류하여화합물 S를수득하였다 (갈색액체 81 mg,수율 95%).화합물 S는 2-클로로 -N-(2-히드록시페닐)아세트아미드이다. After adding acetyl chloride (44.0 [iL, O.55 mmol), the mixture was stirred at room temperature for 30 minutes. After completion of the reaction by adding distilled water, the mixture was diluted with dichloromethane. The organic layer was extracted and washed with distilled water and brine. The organic layer was separated, dried with Na ₂ SO 4, filtered under reduced pressure, and distilled under reduced pressure to obtain Compound S (brown liquid 81 mg, yield 95%). -Chloro-N- (2-hydroxyphenyl) acetamide.

[313] 제 2다계:화함물 τ름제조하는다계  [313] Second polygraph: multi-layer manufacturing of chemicals

[314] 상기제 1단계에서제조된화합물 S(50 mg, 0.27 mmol)에폴리인산 (0.13 mL, 2.7 mmol)을첨가하고， 150^oC에서 30분동안교반하였다.증류수를첨가하여반웅을 종결시킨후，에틸아세테이트로추출하고유기층을증류수와브라인으로 세척하였다.유기층을분리하여 N S0₄로수분올제거하고감압여과, 감압증류하여화합물 T를수득하였다 (검은색액체 39 mg,수율 87%).화합물 T는 2- (클로로메틸)벤조 [d]옥사졸이다. To the compound S (50 mg, 0.27 mmol) prepared in step 1 was added polyphosphoric acid (0.13 mL, 2.7 mmol), followed by stirring at 150 ^° C. for 30 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with distilled water and brine. The organic layer was separated, the aqueous layer was removed with N SO ₄ , reduced pressure filtration, and distilled under reduced pressure to obtain Compound T (39 mg of black liquid, 87% yield). Compound T is 2- (chloromethyl) benzo [d] oxazole.

[315] 저 13다계:최종생성물로서화함물 25름제조하는다계  [315] The 13th polysystem: A multisystem that manufactures 25 chemicals as final products

[316] 상기제 2단계에서제조된화합물 T(15 mg, 0.05 mmol),화합물 10(9 mg, 0.05 mmol)을 DMF(0.18 mL)에녹이고 K₂C0₃(l lmg, 0.08mmol)을첨가한후， 80°C에서 2시간동안교반하였다.증류수를첨가하여반웅을종결시킨후， Compound T (15 mg, 0.05 mmol) and Compound 10 (9 mg, 0.05 mmol) prepared in Step 2 were dissolved in DMF (0.18 mL) and K ₂ CO ₃ (l lmg, 0.08 mmol) was added. After stirring at 80 ° C for 2 hours. After adding the distilled water to stop the reaction,

에틸아세테이트로추출하고유기층을증류수와브라인으로세척하였다.  Extracted with ethyl acetate and the organic layer was washed with distilled water and brine.

유기층을분리하여 Na₂S0₄로수분을제거하고감압여과,감압증류하였다.컬럼 크로마토그래피 (ΕΑ/ΗΧ=1/4)를수행하여화합물 25를수득하였다 (연한갈색 고체 14 mg,수율 64%).화합물 25는 The organic layer was separated, the water was removed with Na ₂ SO ₄ , reduced pressure filtration, and distillation under reduced pressure. Compound 25 was obtained by column chromatography (ΕΑ / ΗΧ = 1/4) (14 mg of light brown solid, 64% yield). Compound 25 is

N- (벤조 [d]옥사졸 -2-일메틸) -N-(2-메록시페닐) -4-메틸벤젠술폰아미드이며,그 식별데이터는다음과같았다:  N- (benzo [d] oxazol-2-ylmethyl) -N- (2-methoxyphenyl) -4-methylbenzenesulfonamide, the identification data were as follows:

[317] Ή NMR (CDC1₃, 400MHz) d 7.66-7.63 (m, 3 H), 7.55 (d, J=7.6Hz, 1H), 7.40-7.25 (m, 6H), 6.88 (t, J=7.2Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 5.12 (s, 2H), 3.37 (s, 3H), 2.44 (s, 3H); LRMS found 409.1. 317 NMR (CDC1 ₃ , 400 MHz) d 7.66-7.63 (m, 3H), 7.55 (d, J = 7.6Hz, 1H), 7.40-7.25 (m, 6H), 6.88 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.12 (s, 2H), 3.37 (s, 3H), 2.44 (s, 3H); LRMS found 409.1.

[318]  [318]

[319] ；-2.상기반응식 9에따른화학식 2의화합물의제조 [319];-2. Preparation of Compound of Chemical Formula 2 According to Scheme 9

[321] 체 1다계 :화함물 W롬계조하는다계  [321] Sieve 1 polysystem: Compound W rome gradation multiple system

[322] 화합물 V(50 mg, 0.40 mmol)를톨루엔 (으8 mL)에녹이고클로로 [322] Compound V (50 mg, 0.40 mmol) was dissolved in toluene (8 mL) and chloro

아세틸클로라이드 (38.0 μL, 0.48 mmol)를첨가한후，실온에서 30분동안 교반하였다.증류수를첨가하여반응올종결시킨후,에틸아세테이트로 추출하고유기층을증류수와브라인으로세척하였다.유기층을분리하여 Na₂SO 4로수분을제거하고감압여과,감압증류하여화합물 W를수득하였다 (갈색액체 45 mg,수율 62%).화합물 W는 2- (클로로메틸)벤조 [d]티아졸이다. After adding acetyl chloride (38.0 μL, 0.48 mmol), the mixture was stirred at room temperature for 30 minutes. After completion of the reaction by adding distilled water, the mixture was extracted with ethyl acetate and the organic layer was washed with distilled water and brine. Moisture was removed with Na ₂ SO 4, reduced pressure filtration, and reduced pressure distillation to obtain Compound W (brown liquid). 45 mg, yield 62%). Compound W is 2- (chloromethyl) benzo [d] thiazole.

[323] 체 2다계 :최종생성물로서화함물 26음제조하는다계 [323] Sieve 2 polysystem: The final product produced by producing 26 grams of chemicals

[324] 상기제 1단계에서제조된화합물 W(15 mg, 0.05 mmol),화합물 10(9 mg, 0.05 mmol)을 DMF(0.18 mL)에녹이고 K₂C0₃(llmg, 0.08mmol)을첨가한후， 80°C에서[324] Compound W (15 mg, 0.05 mmol) and compound 10 (9 mg, 0.05 mmol) prepared in step 1 were dissolved in DMF (0.18 mL), and K ₂ CO ₃ (llmg, 0.08 mmol) was added. After, at 80 ° C

2시간동안교반하였다.증류수를첨가하여반웅을종결시킨후, Stir for 2 hours. After adding the distilled water to stop the reaction,

에틸아세테이트로추출하고유기층을증류수와브라인으로세척하였다.  Extracted with ethyl acetate and the organic layer was washed with distilled water and brine.

유기층을분리하여 ^₂50₄로수분을제거하고감압여과,감압증류하였다.컬럼 크로마토그래피 (ΕΑ/ΗΧ=1/4)를수행하여화합물 26을수득하였다.화합물 26은The organic layer was separated, and the moisture was removed by ^ ₂ 50 ₄ , followed by reduced pressure filtration and reduced pressure distillation. Compound 26 was obtained by column chromatography (ΕΑ / ΗΧ = 1/4).

N- (벤조 [d]티아졸 -2-일메틸) -N-(2-메특시페닐) -4-메틸벤젠술폰아미드이며,그 식별데이터는다음과같았다: N- (benzo [d] thiazol-2-ylmethyl) -N- (2-mesoxyphenyl) -4-methylbenzenesulfonamide, the identification data were as follows:

[325] Ή NMR (CDC1₃, 400MHz) d 7.91 (t, J=7.6Hz, 2H), 7.61(d, J=6.4Hz, 2H), 7.52 (dd, J=6.4, 1.6Hz, 1H), 7.45-7.38 (m, 2H), 7.28-7.27 (m, 3H), 6.92 (t, J=7.2Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 5.26 (s,2 H), 3.35 (s, 3H), 2.45 (s, 3H); LRMS found 425.1. 325 NMR (CDC1 ₃ , 400 MHz) d 7.91 (t, J = 7.6 Hz, 2H), 7.61 (d, J = 6.4 Hz, 2H), 7.52 (dd, J = 6.4, 1.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.28-7.27 (m, 3H), 6.92 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.26 (s, 2H), 3.35 (s, 3 H), 2.45 (s, 3 H); LRMS found 425.1.

[326]  [326]

[327] 심시예 6:대뇌피짐시경세포름이용하.축삭돌기의증식및성장효과테스트  [Example] 6 Example 6: Test of the growth and growth effect of cerebral blood endoscopic cell axon and axon

[328] 본실험의목적은,상기실시예 4또는 5에따라제조된화학식 1또는 2의  The purpose of the present experiment, the formula 1 or 2 prepared in accordance with Example 4 or 5 of the

화합물들이축삭돌기를휴의적으로성장시키고증추신경을재생시킬수 있는지에대해확인하기위한것이다.  This is to check whether the compounds can grow axons ad libitum and regenerate the nerves.

[329] 먼저,임신 18일째인 SD래트의배아로부터대뇌피질을분리하였다.상기 분리된대뇌피질올 HBSS로세척한후,아큐테이즈 (Accutase)와함께 10분동안 실은에서반웅시켰다.이어서， 2 mM Glutamax, 1 x B27이포함된 Neurobasal A 배양액을첨가하고 1회세척한후，피펫팅을통해조직을파쇄시켰다.이어서, 1 X B27, 2 mM Glutamax가첨가된 Neurobasal A배양액으로 3회이상세척하고， 40 μπι나일론여과기로여과시켜피질신경세포를획득하였다.상기신경세포를 2% Β27, 2 mM Glutama가포함된 Neurobasal A배양액에현탁한후, 384-웰 플레이트에 2,000세포 /웰씩분주하였다.  [329] First, cerebral cortex was isolated from embryos of SD rats on the 18th day of pregnancy. After washing with the isolated cerebral cortex, HBSS, the reaction was repeated for 10 minutes in acetic acid with Accusease. Neurobasal A culture solution containing 2 mM Glutamax, 1 x B27 was added and washed once, and then tissue was crushed by pipetting. Cortical neurons were obtained by filtration with a 40 μπι nylon filter. The neurons were suspended in Neurobasal A culture solution containing 2% Β27, 2 mM Glutama, and then dispensed at 2,000 cells / well in 384-well plates.

[330] 24시간후，각각의화합물을최종농도 10 μΜ로처리하여 48시간동안  [330] After 24 hours, each compound was treated with a final concentration of 10 μΜ for 48 hours.

배양하였다.본실험의음성대조군으로서 DMSO 0.5%를사용하였다.그후， α-be m-류불린염색및정량화과정을상기실시예 1의스크리닝제 1단계와 동일하게진행하였다.  Incubated. 0.5% DMSO was used as the negative control of the present experiment. The α-be m-leubulin staining and quantification process were then carried out in the same manner as in the screening agent step 1 of Example 1 above.

[331] 염색된피질신경세포의축삭돌기의길이를측정하고，그평균값을  [331] Length of axons of stained cortical neurons was measured, and their average value was measured.

음성대조군 (DMSO 0.5%)의축삭돌기의길이에대해상대적인값으로서하기표 1의가장우측컬럼에나타내었다.예를들어，하기표 1의첫번째화합물 (이는 상기실시예 4-2에서제조된화합물 10.1임)로처리된그룹의축삭돌기는， 음성대조군 (DMSO 0.5%)그룹의축삭돌기에비해그길이가 3.16±038배가더 길었다. ] The relative value of the length of the axon of the negative control group (DMSO 0.5%) is shown in the rightmost column of Table 1 below. For example, the first compound of Table 1 (the compound prepared in Example 4-2 above) 10.1), the axons of the treated group were 3.16 ± 038 times longer than those of the negative control group (DMSO 0.5%). ]

C8Z00/9T0ZaM/X3d

C8Z00 / 9T0ZaM / X3d

503.41 !색고쳬 504.4 1.8

Color Balance 504.4 1.8

458.96 460.0 1.7 o ° ¹늬 458.96 460.0 1.7 o ° ¹

ᄂ^丫 ⁿT 438,54 훤색고제 439.5 2,6 卜」 丫 ^, ⁿ T 438,54 White High 439.5 2,6 卜 ''

S  S

442,5 흰색고쳬 443.5 2.2

442,5 White high 쳬 443.5 2.2

452.57 흰색고 ¾ 453.6 2,3 452.57 White High ¾ 453.6 2,3

1!색고제 460.0 2,6

연한노란색 1! Colorant 460.0 2,6

Light yellow

424.51 425.5 2.1 고제  424.51 425.5 2.1 Goze

474.96 476.0 1,9 474.96 476.0 1,9

[0쒜 C8Z00/9T0ZaM/X3d

[0 쒜 C8Z00 / 9T0ZaM / X3d

6ε 6ε

C8Z00/9T0ZaM/X3d

C8Z00 / 9T0ZaM / X3d

C8Z00/9T0ZaM/X3d

C8Z00 / 9T0ZaM / X3d

[347] 상기실시예 1및 2에서스크리닝을통해신경돌기의증식및축삭돌기의  [347] In Example 1 and 2, screening and growth of neurites and axons are screened.

성장이촉진된효과가관찰된것과마찬가지로,본발명에따른화학식 1또는 2의화합물들은상기표 1에서보는바와같이대뇌피질신경세포의축삭돌기를 유의적으로성장시킨다는것이입증되었다.  Similar to the observed growth-promoting effects, it has been demonstrated that the compounds of Formula 1 or 2 according to the present invention significantly increase the axons of cerebral cortical neurons, as shown in Table 1 above.

[348]  [348]

[349] 심시예 7:망막시 세포를이 —하.화함물의세포독 ^ 여부 측식—듬 71의 성장효과테스트  [349] Example 7 Retinal Cells—The Cytotoxicity of Chemical Compounds ^ Measurement of Growth—Test of Growth Effect of Rhythm 71

[350] 본실험의목적은,상기실시예 4또는 5에따라제조된화학식 1또는 2의  The purpose of the present experiment, the formula 1 or 2 prepared according to Example 4 or 5 of the

화합물들이세포독성이있는지여부를먼저확인하고,축삭돌기를유의적으로 성장시킬수있는지에대해확인하기위한것이다.이를위해, SD래트의망막 신경세포를이용하였으며,  To determine whether the compounds are cytotoxic, and whether they can grow axons significantly, we used retinal neurons in SD rats.

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(4-메톡시피리딘 -3-일)아세트아 미드를대표적인화합물로서사용하였다 (이하, CYM화합물이라고약칭함).  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide was used as a representative compound (hereinafter abbreviated as CYM compound). box).

[351]  [351]

[352] 7-1.망막시 세포의배양및형광염새  7-1.Culture and Fluorescence of Retinal Cells

[353] SD래트로부터망막신경세포를분리하여배양시켰다.상기망막신경세포가 함유된배양액에상기 CYM화합물을각각 0, 2, 10, 20 μΜ의농도로처리한후， 각각 3홀씩총 12홀에서배양하였다.이때 CYM화합물의농도가 0 μΜ인그룹은 대조군으로서사용되었다.  [353] Retinal nerve cells were isolated and cultured from SD rats. The CYM compounds were treated in culture medium containing the retinal nerve cells at concentrations of 0, 2, 10, and 20 μΜ, respectively, and each of 12 holes in total. At this time, a group having a concentration of 0 μΜ of the CYM compound was used as a control.

[354] 72시간동안배양한후,커버글라스위에서망막신경세포들을마우스  [354] After 72 hours of incubation, the retinal nerve cells were mouse over the cover glass.

항-신경미세섬유항체 (anti-neurofilament antibody) SMI™Covance를이용하여 일차형광염색하였다.그후,형광물질 (Alexa Fluor 594)이부착된염소항-마우스 면역글로불린 G로이차염색을수행하였다.여기서，각커버글라스의면적은 13.55 mm²이었으며， 0， 2， 10, 20 μΜ농도의 CYM화합물처리군은각각 3개의 커버글라스위에위치하여,총 12개의커버글라스가사용되었다. Anti-neurofilament antibody using SMI ™ Coveance Primary fluorescent staining was then performed with a goat anti-mouse immunoglobulin G secondary staining with fluorescent material (Alexa Fluor 594), where the area of each cover glass was 13.55 mm ² , 0, 2, 10, CYM compound treatment groups of 20 μΜ concentration were placed on 3 cover glasses each, for a total of 12 cover glasses.

[355]  [355]

[356] 7-2.화합뮬의세포독성테스트  [356] 7-2. Cytotoxicity Test of Compound Mule

[357] 본발명의화합물이세포에부작용을미치는지여부를확인하기위하여，  [357] To determine whether the compounds of the present invention adversely affect the cells,

커버글라스위에서형광염색된망막신경세포의수를카운팅하였다.총 12개의 커버글라스에대해 4회반복하여얻은값들의평균을도 1에막대그래프로 도시하였다.  The number of fluorescently stained retinal neurons was counted on the cover glass. The average of four replicates for a total of 12 cover glasses was shown in the bar graph in FIG.

[358] 그결과,도 1에서확인할수있는바와같이，망막신경세포의수는대조군 (0 μΜ농도)과 CYM화합물처리군 (각각 2, 10, 20 μΜ농도)사이에서유의적인 차이를나타내지않았다.오히려,대조군에비해 CYM화합물처리군에서망막 신경세포의수가더증가하였음을알수있다.따라서, CYM화합물은  As a result, as can be seen in Figure 1, the number of retinal neurons did not show a significant difference between the control group (0 μΜ concentration) and the CYM compound treatment group (2, 10, 20 μΜ concentration, respectively). Rather, the number of retinal neurons increased in the CYM compound treatment group compared to the control group.

세포독성과같은부작용이없으며세포의생존율에악영향을미치지않는 것으로입증되었다.  It has been proven to have no side effects such as cytotoxicity and not adversely affect cell viability.

[359]  [359]

[360] 7-3.화합물의축산돌기성장촉? ΐ테스트  [360] 7-3.Acquisition of Livestock Growth of Compounds? ΐ test

[361] 본발명의화합물이축삭돌기의성장을촉진시키는지여부를확인하기위하여, 커버글라스위에서형광염색된망막신경세포의축삭돌기의길이를  [361] The length of the axons of fluorescently stained retinal neurons on the cover glass to determine whether the compounds of the present invention promote the growth of axons.

측정하였다.상기실시예 7-2와마찬가지로총 12개의커버글라스에대해 4회 반복하여측정을수행하고평균값을산출하였다.  As in Example 7-2, the measurement was repeated four times for a total of 12 cover glasses, and an average value was calculated.

[362] 도 2는각그룹에서축삭돌기의길이가 50 μιη이상인신경세포의수를  2 shows the number of neurons having axons greater than 50 μιη in each group.

막대그래프로나타낸것이다.대조군 (Ο μΜ농도)에비해 CYM화합물  The bar graph shows CYM compounds compared to the control (Ο μΜ concentration).

처리군 (각각 2， 10, 20 μΜ농도)에서는축삭돌기의길이가 50 μιη이상인 신경세포의수가유의적으로더많음을알수있다.  In the treatment groups (2, 10 and 20 μΜ concentrations, respectively), the number of neurons with axons greater than 50 μιη was significantly higher.

[363] 도 3은축삭돌기의길이가 50 μηι이상인신경세포를각각 50 μιη이상 100 μηι 미만, 100 μπι이상 200 μηι미만, 200 μηι이상으로더욱구체적으로분류하여 막대그래프로나타낸것이다.축삭돌기의길이를각각 50 μιη이상 ΙΟΟ μιη미만， 100 μιη이상 200 μιη미만， 200 μηι이상으로분류하였을때에도,대조군 (0 μΜ 농도)에비해 CYM화합물처리군 (각각 2， 10, 20 μΜ농도)에서신경세포의수가 유의적으로더많았다.  3 shows neural cells with an axon length of 50 μηι or more, more specifically 50 μιη or more and less than 100 μηι, 100 μπι or more and less than 200 μηι and more than 200 μηι, respectively, and are represented by bar graphs. Even when the lengths were classified as 50 μιη or more, ΙΟΟ μιη or less, 100 μιη or more, 200 μιη or less, or 200 μηι or more, the neuronal cells were treated in the CYM compound treatment group (2, 10, 20 μΜ concentration, respectively) compared to the control (0 μΜ concentration). There were significantly more prostheses.

[364] 도 2및 3의결과로부터,본발명의화합물이처리된경우신경세포의  2 and 3, when the compound of the present invention was treated,

축삭돌기의길이가더신장되었으며，축삭돌기의성장이유의적으로  The length of the axon has been increased, and the growth of the axon

촉진되었음이입증되었다.  Promoted.

[365]  [365]

[366] 심시예 8:시시경압받 Φ상모템음이용하.시 채생효과테스트  [366] Psychologic Example 8: Poisoning Effect Test Using Φ Upper-Motion Sound.

[367] 본실험의목적은，시신경압박손상모델을이용하여상기실시예 4또는 5에 따라제조된화학식 1또는 2의화합물들이신경을재생할수있는지를확인하기 위한것이다. [367] The purpose of this experiment was to use the optic nerve compression injury model described in Example 4 or 5 above. This is to check whether the compounds of Formula 1 or 2 prepared according to the present invention can regenerate nerves.

[368] 실험동물로 SD래트 (8주령,수컷)를사용하였다.졸레틸과럼푼을이용하여 근육마취한후，결막을절개하여시신경을노출시켰다.이어서，미세한포셉으로 시신경을안구와시신경연결부위약 2 mm뒤에서 15초동안압박손상함으로써， 시신경을손상시켰다.실험군 (4마리 )에는 CYM화합물으022 μ_§을 DMSO및 인산칼륨완층액에녹여서안구초자체내에주입하였으며，대조군 (3마리)에는 PBS를주입하였다.안구내주입은수술당일부터시작하여 일에한번씩 안구내에주입하였으며,주입전에 SD래트의전방수를천자하여안구내압력을 감소시킨후안구초자체내에각용액을 5 μL·주사하였다. 3주후에, SD래트를 졸레틸과럼푼으로근육마취한후， 4%파라포름알데히드로관류고정시켰다. 이어서,시신경이부착되어있는안구를꺼내각막과수정체를제거하고, 냉동절편조직으로만들었다.래빗항 -생명연장형단백질항체 (anti-GAP43 Ab)를 이용하여일차염색하였으며,형광물질 (DyLight 488)이부착된항 -래빗 [368] SD rats (8 weeks old, males) were used as experimental animals. After muscle anesthesia using zoletil and lumpoon, the conjunctiva was dissected to expose the optic nerve. by placebo 2 mm pressure damage to the back for 15 seconds, were damaged to the optic nerve. in PBS group (4) has been injected into the CYM compound coming from 022 μ _§ in a dissolved ocular vitreous in DMSO and potassium phosphate complete cheungaek, the control (3) Intraocular injections were injected intraocularly once a day starting on the day of surgery, and before injection, 5 μL of each solution was injected into the ocular herb after reducing the intraocular pressure. Three weeks later, the SD rats were muscle anesthetized with zoletil and lumps, followed by 4% paraformaldehyde perfusion fixation. The optic nerve-attached eye was then removed to remove the cornea and lens, and made into frozen section tissue. Primary staining was performed using rabbit anti-life-extension protein antibody (anti-GAP43 Ab) and fluorescent material (DyLight 488). Attached Port-Rabbit

면역글로불린 G로이차염색하였다.  Immunoglobulin G was secondary stained.

[369] 도 4는염색후촬영한사진으로서,이때녹색으로염색된부분이시신경의  FIG. 4 is a photograph taken after dyeing, wherein the green dyed portion of the optic nerve

축삭돌기를나타낸다.도 4의상단부사진은대조군 (PBS처리그룹)올촬영한 사진이며,손상된시신경이거의재생되지않았음을알수있다.도 4의하단부 사진은실험군 (CYM화합물처리그룹)을촬영한사진이며,손상된시신경이 매우유의적으로재생되었음을알수있다.  Axons are shown. The upper part of Fig. 4 is a control group (PBS treatment group), and it can be seen that the damaged optic nerve was hardly regenerated. The lower part of Fig. 4 is the experimental group (CYM compound treatment group). It is a photograph and it can be seen that the damaged optic nerve was reproduced very meaningfully.

[370] 다음으로,시신경압박손상부위에서머리방향으로 500 μιη, 1000 μιη, 1500 μηι 떨어져있는지점에서， Steven Leon et al.의문헌 [The Journal of Neuroscience, June 15, 2000, 20(12):46154626]에개시된방법을이용하여,염색된축삭돌기의수를 카운팅하였다.그결과는시신경압박손상부위로부터떨어져있는거리를  [370] Next, at a distance of 500 μιη, 1000 μιη, 1500 μηι in the head direction from the optic nerve compression injury site, Steven Leon et al., The Journal of Neuroscience, June 15, 2000, 20 (12): 46154626] was used to count the number of stained axons. The result is a distance away from the site of optic nerve compression injury.

X-축으로하여도 5에나타내었다.손상된시신경부위를본발명에따른 화합물로처리하였을때，축삭돌기의수가유의적으로증가하였으며，시신경이 유효하게재생되었음이입증되었다.  The X-axis was also shown in Figure 5. When the damaged optic nerve area was treated with a compound according to the present invention, the number of axons increased significantly and it was proved that the optic nerve was effectively regenerated.

Claims

청구범위 Claim

[청구항 1] 하기화학식 1또는 2로표시되는화합물또는이의약학적으로  [Claim 1] A compound represented by the following Chemical Formula 1 or 2 or a pharmaceutically thereof

허용가능한염:  Acceptable salts:

상기화학식 1에서，  In Chemical Formula 1,

- RrS: ，수소원자， C1-C6알킬， C2-C6알케닐， C2-C6알키닐

RrS: hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl

C6-C10아릴, C3-CH)시클로알킬，또는 R₅로치환되거나비치환된 N, 0 및 S중에서선택된하나이상의해테로원자를갖는 C3-U)해테로아릴 또는해테로시클로알킬이며 , C 6 -C 10 aryl, C 3 -CH) cycloalkyl, or C 3 -U) heteroaryl or heterocycloalkyl having one or more heteroatoms selected from N, 0 and S substituted or unsubstituted with R ₅ ,

•상기 R₅는수소원자,할로겐원자, C1-C6알킬, -OR₆, -0(CO)R6, -N0₂, -Ν(¾)₂, -CN, -CORe, -ΝΗ( ))¾, -NH(CO)NHR₆, -NH(CS)NHR₆, -NH(SO_: )Re, -SH, -SRe, -SOR₆, -S(CO)R6, - )₂¾, -CON(R₆)₂, -S0₃H, -S0₂N(R₆)₂및 -CF₃로이루어진군에서독립적으로선택된 1개내지 5개의치환기로서 _: 오르소,메타및파라위치중하나이상의위치에결합되며， R ₅ represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl, -OR ₆ , -0 (CO) R 6, -N0 ₂ , -Ν (¾) ₂ , -CN, -CORe, -ΝΗ ()) ¾ , -NH (CO) NHR ₆ , -NH (CS) NHR ₆ , -NH (SO _:) Re, -SH, -SRe, -SOR ₆ , -S (CO) R6,-) ₂ ¾, -CON ( R ₆ ) 1 to 5 substituents independently selected from the group consisting of ₂ , -S0 ₃ H, -S0 ₂ N (R ₆ ) ₂ and -CF _{3 :} at one or more of the ortho, meta and para positions Combined,

•상기 R₆는서로독립적으로수소원자, C1-C6알킬, C2-C6알케닐, C2-C6알키닐, C6-C10아릴， C3-C10시클로알킬，또는 N, 0및 S중에서 선택된하나이상의헤테로원자를갖는 C3-10헤테로아릴또는 헤테로시클로알킬이며; R ₆ independently of each other is a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or N, 0 and S C3-10 heteroaryl or heterocycloalkyl having an atom;

— R₂는 C1-C6

— R ₂ is C1-C6

알킬， C2-C6알케닐， C2-C6알키닐， C6-C10아릴, C3-C10시클로알킬， 토실기，또는 R₇로치환되거나비치환된 N, O및 S중에서선택된하나 이상의헤테로원자를갖는 C3-10헤테로아릴또는 Having one or more heteroatoms selected from N, O and S substituted or unsubstituted with alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, tosyl, or R ₇ C3-10 heteroaryl or

헤테로시클로알킬이며;  Heterocycloalkyl;

•상기 R₇는수소원자,할로겐원자, C1-C6알킬, -OR₈, -0(CO)R₈, -N0₂, -N(R₈)₂, -CN, -COR₈, -NH(CO)R₈, -NH(CO)NHR₈, -NH(CS)NHR₈, -NH(SO: )R₈, -C0₂R₈, -CON(R₈)₂, -SRg, -SOR₈, -S(CO)R₈, -S0₃H, -S0₂N(R₈)₂, -S0₂R₈ 1개내지

R ₇ represents a hydrogen atom, a halogen atom, C 1 -C 6 alkyl, -OR ₈ , -0 (CO) R ₈ , -N0 ₂ , -N (R ₈ ) ₂ , -CN, -COR ₈ , -NH ( CO) R ₈ , -NH (CO) NHR ₈ , -NH (CS) NHR ₈ , -NH (SO:) R ₈ , -C0 ₂ R ₈ , -CON (R ₈ ) ₂ , -SRg, -SOR ₈ , -S (CO) R ₈ , -S0 ₃ H, -S0 ₂ N (R ₈ ) ₂ , -S0 ₂ R ₈ 1 to

5개의치환기로서，오르소，메타및파라위치중하나이상의위치에 결합되며，  5 substituents, coupled to at least one of the ortho, meta and para positions,

•상기 ¾는서로독립적으로수소원자, C1-C6알킬， C2-C6알케닐， C2-C6알키닐, C6-C10아릴， C3-C10시클로알킬,또는 N, O및 S중에서 선택된하나이상의헤테로원자를갖는 C3-10헤테로아릴또는

¾ is independently of each other a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or one or more heteroatoms selected from N, O and S C3-10 heteroaryl or

알케닐, C2-C6알키닐， C6-C10아릴, C3-C10시클로알킬,또는 1^로 치환되거나비치환된 Ν, Ο및 S중에서선택된하나이상의헤테로 원자를갖는 C3-10해테로아릴또는헤테로시클로알킬이며； Alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C10 cycloalkyl, or C3-10 heteroaryl or hetero having one or more hetero atoms selected from N, O and S substituted or unsubstituted with 1 ^. Cycloalkyl;

•상기 ¾는수소원자,할로겐원자， C1-C6알킬， -OR₁₀, -O(CO)R₁₀, -N0₂, -N(R₁₀)₂, -CN, -COR₁₀, -NH(CO)R₁₀, -NH(CO)NHR₁₀, -NH(CS) HR₁₀, -NR₁₀ (SO₂)R₁₀, -SR₁₀, -SOR₁₀, -S(CO)R₁₀, -CO₂R₁₀, -CON(R_I0)₂, -S0₃H, -SO₂N(R_I0)₂, -CF₃,및할로겐으로치환되거나비치환된피리디닐,디아졸릴， 트리아졸릴및테트라졸릴로이루어진군에서독립적으로선택된 1개 내지 5개의치환기로서,오르소,메타및파라위치중하나이상의위치에 결합되며, ¾ is hydrogen atom, halogen atom, C1-C6 alkyl, -OR ₁₀ , -O (CO) R ₁₀ , -N0 ₂ , -N (R ₁₀ ) ₂ , -CN, -COR ₁₀ , -NH (CO ) R ₁₀ , -NH (CO) NHR ₁₀ , -NH (CS) HR ₁₀ , -NR ₁₀ (SO ₂ ) R ₁₀ , -SR ₁₀ , -SOR ₁₀ , -S (CO) R ₁₀ , -CO ₂ R ₁₀ , -CON (R _I0 ) ₂ , -S0 ₃ H, -SO ₂ N (R _I0 ) ₂ , -CF ₃ , and pyridinyl, diazolyl, triazolyl and tetrazolylrosubstituted or unsubstituted 1 to 5 substituents independently selected from the group, bonded to one or more of ortho, meta and para positions,

•상기 R_l0는서로독립적으로수소원자， C1 -C6알킬， C2-C6알케닐, C2-C6알키닐， C6-C10아릴， C3-C10시클로알킬，또는 N, 0및 S중에서 선택된하나이상의해테로원자를갖는 C3-10헤테로아릴또는 R ₁₀ is independently selected from a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or N, 0 and S C3-10 heteroaryl with terato atoms or

헤테로시클로알킬이며， Heterocycloalkyl,

•상기 R_n은서로독립적으로수소원자, C1-C6알킬， C2-C6알케닐， C2-C6알키닐， C6-C10아릴， C3-C10시클로알킬， N, O및 S중에서선택된 하나이상의해테로원자를갖는 C3-10해테로아릴또는 R _n is independently selected from hydrogen atoms, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, N, O and S C3-10 heteroaryl having an atom or

헤테로시클로알킬， -OH, -OMe, -C0₂CH₃또는 -C0₂CH₂CH₃이며 , Heterocycloalkyl, -OH, -OMe, -C0 ₂ CH ₃ or -C0 ₂ CH ₂ CH ₃ ,

- ¾는수소원자， C1-C6알킬, C2-C6알케닐, C2-C6알키닐， C6-C10아릴， C3-C10시클로알킬，또는 Ν, Ο및 S중에서선택된하나이상의헤테로 원자를갖는 C3-10해테로아릴또는헤테로시클로알킬이며；  ¾ is a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or C 3-having one or more heteroatoms selected from N, O and S 10 heteroaryl or heterocycloalkyl;

-상기 R₃및 R₄는서로결합하여 N을포함하는 C3-10해테로아릴또는 헤테로시클로알킬을형성할수있음; R ₃ and R ₄ may combine with each other to form C 3-10 heteroaryl or heterocycloalkyl comprising N;

[화학식 2]

[Formula 2]

상기화학식 2에서, In Formula 2,

- 11₁₂는 ，수소원자, C1-C6알킬， C2-C6알케닐， C2-C6알키닐,

-11 ₁₂ is a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,

C6-C10아릴， C3-C10시클로알킬，또는 R₁₅로치환되거나비치환된 N, O 및 S중에서선택된하나이상의헤테로원자를갖는 C3-10헤테로아릴 또는헤테로시클로알킬이며; C 6-10 heteroaryl or heterocycloalkyl having one or more heteroatoms selected from N, O and S substituted or unsubstituted with C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or R ₁₅ ;

•상기 R₁₅는수소원자，할로겐원자, C1-C6알킬, -OR₁₆, -0(CO) ₁₆, -N0₂ -N(R₁₆)₂, -CN, -COR₁₆, -NH(CO)R₁₆, -NH(CO)NHR₁₆, -NH(CS)NHR₁₆, -NH(S0₂)R₁₆, -SR₁₆, -SOR₁₆, -S(CO)R₁₆, -C0₂R₁₆, -CON(R₁₆)₂₎ -S0₃H및 -S0₂ N(R₁₆)₂로이루어진군에서독립적으로선택된 1개내지 5개의 R ₁₅ is hydrogen atom, halogen atom, C 1 -C 6 alkyl, -OR ₁₆ , -0 (CO) ₁₆ , -N0 ₂ -N (R ₁₆ ) ₂ , -CN, -COR ₁₆ , -NH (CO) R ₁₆ , -NH (CO) NHR ₁₆ , -NH (CS) NHR ₁₆ , -NH (S0 ₂ ) R ₁₆ , -SR ₁₆ , -SOR ₁₆ , -S (CO) R ₁₆ , -C0 ₂ R ₁₆ , -CON (R ₁₆ ) ₂₎ 1 to 5 independently selected from the group consisting of -S0 ₃ H and -S0 ₂ N (R ₁₆ ) ₂

치환기로서，오르소，메타 _및파라위치중하나이상의위치에결합되며;As a substituent, is bonded to at least one of the ortho, meta_, and para positions;

•상기 R₁₆는서로독립적으로수소원자， C1-C6알킬, C2-C6알케닐， C2-C6알키닐, C6-C10아릴， C3-C10시클로알킬，또는 N, 0및 S중에서 선택된하나이상의헤테로원자를갖는 C3-10해테로아릴또는 헤테로시클로알킬이며; R ₁₆ independently of each other is a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or N, 0 and S C3-10 heteroaryl or heterocycloalkyl having an atom;

- R₁₃은 ,수소원자， C1-C6알킬， C2-C6알케닐， C2-C6알키닐,

R ₁₃ is a hydrogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,

C6-C10아릴， C3-C10시클로알킬,또는 R₁₇로치환되거나비치환된 N, O 및 S중에서선택된하나이상의헤테로원자를갖는 C3-10헤테로아릴 또는헤테로시클로알킬이며， C6-C10 aryl, a C3-10 heteroaryl or heterocycloalkyl having a C3-C10 cycloalkyl, or R ₁₇ roach or unsubstituted ring one or more hetero atoms selected from a ring N, O or S,

•상기 R_l7는수소원자,할로겐원자, C1-C6알킬， -OR, ₈, -0(CO)R,₈, -NO: -N(R₁₈)₂, -CN, -COR,g, -NH(CO)Ri₈, -NH(CO)NHR₁₈, -NH(CS)NHR₁₈, -NH(S0₂)R₁₈, -SR,g, -SOR,₈, -S(CO)R,₈, -C0₂R,₈, -CON(R,₈)₂, -S0₃H, -S0₂ N(R_I8)₂및 -0^₃로이루어진군에서독립적으로선택된 1개내지 5개의 치환기로서,오르소,메타및파라위치중하나이상의위치에결합되며,• the R _l7 is a hydrogen atom, a halogen atom, C1-C6 _{alkyl, -OR, 8, -0 (CO} ) R, 8, -NO: -N (R 18) 2, -CN, -COR, g, - NH (CO) Ri ₈ , -NH (CO) NHR ₁₈ , -NH (CS) NHR ₁₈ , -NH (S0 ₂ ) R ₁₈ , -SR, g, -SOR, ₈ , -S (CO) R, ₈ As one to five substituents independently selected from the group consisting of -C0 ₂ R, ₈ , -CON (R, ₈ ) ₂ , -S0 ₃ H, -S0 ₂ N (R _I8 ) ₂ and -0 ^ ₃ In one or more of the ortho, meta and para positions,

•상기 R₁₈는서로독립적으로수소원자, C1-C6알킬, C2-C6알케닐, C2-C6알키닐, C6-C10아릴, C3-C10시클로알킬，또는 N, O및 S중에서 선택된하나이상의해테로원자를갖는 C3-10해테로아릴또는 헤테로시클로알킬이며;

R ₁₈ is independently selected from hydrogen atoms, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, or N, O and S C3-10 heteroaryl or heterocycloalkyl having a hetero atom;

[청구항 2] 제 1항에있어서;  [Claim 2] in paragraph 1;

상기 은 2-메톡시페닐， 2-에록시페닐， 3-메록시페닐, 2,4-디메톡시페닐 The silver 2-methoxyphenyl, 2-ethoxyphenyl, 3-methoxyphenyl, 2,4-dimethoxyphenyl

3.4-디메특시페닐， 2-플루오로페닐, 3-클로로 -4-메특시페닐， 3.4-dimethoxyphenyl, 2-fluorophenyl, 3-chloro-4-methoxyphenyl,

2.5-디메록시페닐, 2-메틸페닐， 4-풀루오로페닐， 2,4-디메틸페닐또는 2-클로로페닐인것을특징으로하는，화합물또는이의약학적으로 허용가능한염.  A compound or a pharmaceutically acceptable salt thereof, characterized by being 2.5-dimethoxyphenyl, 2-methylphenyl, 4- pullophenyl, 2,4-dimethylphenyl or 2-chlorophenyl.

[청구항 3] 제 1항에있어서，  [Claim 3] In paragraph 1,

상기 R₂는하기로이루어진군중에서선택된기인것을특징으로하는， 화합물또는이의약학적으로허용가능한염： A compound or a pharmaceutically acceptable salt thereof, wherein R ₂ is a group selected from the group consisting of

[청구항 ₄] 제 i항에있어서, [Claim ₄ ] In paragraph i,

상기 R₃은하기로이루어진군중에서선택된기인것을특징으로하는， R ₃ is a group selected from the group consisting of

[청구항 5] 제 1항에있어서， [Claim 5] In paragraph 1,

하기로이루어진군중에서선택되는，화합물또는이의약학적으로 허용가능한염: A compound selected from the group consisting of Acceptable salts:

N-(2-에특시페닐) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트아 미드，  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-페닐아세트아미드， N-(2-에톡시페닐) -2-(4-메틸 -N-페닐페닐술폰아미도)아세트아미드， N-(2-에톡시페닐) -2-(N-(2-메톡시페닐)페닐술폰아미도)아세트아미드, N- (벤조 [d]옥사졸 -2-일메틸) -N-(2-메톡시페닐) -4-메틸벤젠술폰아미드, N- (벤조 [d]티아졸 -2-일메틸) -N-(2-메톡시페닐) -4-메틸벤젠술폰아미드， N-(2-에틸페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N-phenylacetamide, N- (2-ethoxyphenyl) -2- (4-methyl-N-phenylphenylsulfonami Acetamide, N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) phenylsulfonamido) acetamide, N- (benzo [d] oxazol-2-ylmethyl) -N- (2-methoxyphenyl) -4-methylbenzenesulfonamide, N- (benzo [d] thiazol-2-ylmethyl) -N- (2-methoxyphenyl) -4-methylbenzenesulfonamide , N- (2-ethylphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetami

N-(2-브로모페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아 미드， N- (2-bromophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(2-플투오로페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  N- (2-pleturophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

Ν-(2-(1Η-테트라졸 -5-일)페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미 도)아세트아미드，  Ν- (2- (1Η-tetrazol-5-yl) phenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-메록시피리딘 -3-일)아 세트아미드염산염,  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-methoxypyridin-3-yl) acetamide hydrochloride,

N-(2-((2-에특시페닐)아미노)에틸) -N-(2-메특시페닐) -4-메틸벤젠술폰아미 메틸  N- (2-((2-ethoxyphenyl) amino) ethyl) -N- (2-methoxyphenyl) -4-methylbenzenesulfonamimethyl

2-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에이트  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate

2-(N-(2-에록시페닐) -4-메틸페닐술폰아미도) -N-(2-메록시 -5-메틸페닐)아 세트아미드, 2- (N- (2-ethoxyphenyl) -4-methylphenylsulfonamido) -N- (2-methoxy-5-methylphenyl) acetamide,

N-(2,5-디메록시페닐) -2-(4-메톡시 -N-(2-메톡시페닐)페닐술폰아미도)아세 트아미드  N- (2,5-dimethoxyphenyl) -2- (4-methoxy-N- (2-methoxyphenyl) phenylsulfonamido) acetamide

2-(4-클로로 -N-(2-에록시페닐)페닐술폰아미도) -N-(2,5-디메톡시페닐)아세 트아미드  2- (4-chloro-N- (2-ethoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide

2-(N-(5-클로로 -2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-메특시페닐) 아세트아미드，  2- (N- (5-chloro-2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-methoxyphenyl) acetamide,

N-(2,4-디메특시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트 아미드，  N- (2,4-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(2-클로로페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아 미드，  N- (2-chlorophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(4-클로로 -2-메틸페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아 세트아미드，  N- (4-chloro-2-methylphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(3-클로로 -4-메틸페닐) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아 세트아미드, N- (3-chloro-4-methylphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) a Setamide,

N-(2-메톡시 -5-메틸페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드,  N- (2-methoxy-5-methylphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(4-클로로벤질) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아 미드，  N- (4-chlorobenzyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-벤질 -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미드, _. 에틸 N- benzyl -2- (N- (2- methoxy-phenyl) -4-phenyl sulfone amido) _acetamide,. ethyl

2-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에이트  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate

N-(3-브로모페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아 미드 ₅ N- (3-bromophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide ₅

N-(2-풀루오로페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  N- (2-Pluorophenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(3-메톡시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아 미드，  N- (3-methoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(5-클로로 -2-메톡시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) 아세트아미드,  N- (5-chloro-2-methoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(2-메톡시벤질) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아 미드,  N- (2-methoxybenzyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(sec-부틸) -2-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미 도)벤자미드,  N- (sec-butyl) -2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzamide,

2-(N-(2-에톡시페닐) -4-메틸페닐술폰아미도) -N-(3-(N-메틸메틸술폰아미 도)페닐)아세트아미드,  2- (N- (2-ethoxyphenyl) -4-methylphenylsulfonamido) -N- (3- (N-methylmethylsulfonamido) phenyl) acetamide,

N-(2,3-디클로로페닐) -2-(N-(2-메록시페닐) -4-메 ¾페닐술폰아미도)아세트 아미드，  N- (2,3-dichlorophenyl) -2- (N- (2-methoxyphenyl) -4-me ¾phenylsulfonamido) acetamide,

N-(2-메록시 -5-메틸페닐) -2-(4-메톡시 -N-(2-메톡시페닐)페닐술폰아미도) 아세트아미드，  N- (2-methoxy-5-methylphenyl) -2- (4-methoxy-N- (2-methoxyphenyl) phenylsulfonamido) acetamide,

N-(2,5-디메록시페닐) -2-(N-(2-에톡시페닐) -4- (메틸티오)페닐술폰아미도) 아세트아미드，  N- (2,5-dimethoxyphenyl) -2- (N- (2-ethoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

N-(2-에특시페닐) -2-(N-(2-플루오로페닐) -4-메틸페닐술폰아미도)아세트 아미드  N- (2-ethoxyphenyl) -2- (N- (2-fluorophenyl) -4-methylphenylsulfonamido) acetamide

2-(N-(3,4-디메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-에특시페닐)아세트 아미드  2- (N- (3,4-dimethoxyphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide

N-(2-에특시페닐) -2-(N-(4-이소프로필페닐)— 4-메틸페닐술폰아미도)아세 트아미드  N- (2-ethoxyphenyl) -2- (N- (4-isopropylphenyl) — 4-methylphenylsulfonamido) acetamide

N-(2-에톡시페닐) -2-(N-(4-메톡시페닐) -4-메틸페닐술폰아미도)아세트아 미드  N- (2-ethoxyphenyl) -2- (N- (4-methoxyphenyl) -4-methylphenylsulfonamido) acetamide

N-(2-에특시페닐) -2-(N-(3-메록시페닐) -4-메틸페닐술폰아미도)아세트아 미드， N- (2-ethoxyphenyl) -2- (N- (3-methoxyphenyl) -4-methylphenylsulfonamido) acetacea American drama,

2-(N-(2,5-디메특시페닐) -4-메틸페닐술폰아미도) -N-(2-에특시페닐)아세트 아미드,  2- (N- (2,5-dimethoxyphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide,

2-(N-(3-클로로 -4-메톡시페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐) 아세트아미드，  2- (N- (3-chloro-4-methoxyphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide,

2-(N-(4-브로모페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐)아세트아 미드，  2- (N- (4-bromophenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide,

2-(N-(4-클로로페닐) -4-메틸페닐술폰아미도) -N-(2-에록시페닐)아세트아 미드,  2- (N- (4-chlorophenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide,

N-(2-에록시페닐) -2-(4-메틸 -N-(o-롤릴)페닐술폰아미도)아세트아미드, N-(2-에특시페닐) -2-(N-(4-풀루오로페닐) -4-메틸페닐술폰아미도)아세트 아미드，  N- (2-hydroxyphenyl) -2- (4-methyl-N- (o-rollyl) phenylsulfonamido) acetamide, N- (2-ethoxyphenyl) -2- (N- (4- Pullourophenyl) -4-methylphenylsulfonamido) acetamide,

2-(N-(2,5-디메틸페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐)아세트아 미드，  2- (N- (2,5-dimethylphenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetamide,

2-(N-(2-클로로페닐) -4-메틸페닐술폰아미도) -N-(2-에톡시페닐)아세트아 미―,  2- (N- (2-chlorophenyl) -4-methylphenylsulfonamido) -N- (2-ethoxyphenyl) acetami,

N-(2-메록시페닐) -2-(4-메틸 -N-(o-를릴)페닐술폰아미도)아세트아미드, 2-(N-(3-클로로 -4-메특시페닐) -4-메틸페닐술폰아미도) -N-(2-메특시페닐) 아세트아미드,  N- (2-Methoxyphenyl) -2- (4-methyl-N- (o-allyl) phenylsulfonamido) acetamide, 2- (N- (3-chloro-4-methoxyphenyl) -4 -Methylphenylsulfonamido) -N- (2-methoxyphenyl) acetamide,

N-(2-메특시페닐) -2-(4-메틸 -N-(3- (트리플루오로메틸)페닐)페닐술폰아미 도)아세트아미드,  N- (2-methoxyphenyl) -2- (4-methyl-N- (3- (trifluoromethyl) phenyl) phenylsulfonamido) acetamide,

2-(N-(3,4-디메틸페닐) -4-메틸페닐술폰아미도) -N-(2-메특시페닐)아세트아 미드,  2- (N- (3,4-dimethylphenyl) -4-methylphenylsulfonamido) -N- (2-methoxyphenyl) acetamide,

( -메¾  (-Method

1- (2-(Ν-(2-메록시페닐) -4-메틸페닐술폰아미도)아세틸)피롤리딘 -2-카르복 실레이트，  1- (2- (Ν- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetyl) pyrrolidine-2-carboxylate,

(R)-메틸  (R) -methyl

2- (2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도) -2-페닐아세 테이트，  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) -2-phenylacetate,

(R)-에틸  (R) -ethyl

2-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도 )-3-페닐프로 피오네이트，  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) -3-phenylpropionate,

N-(5-브로모티아졸 -2-일) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아 세트아미드，  N- (5-bromothiazol-2-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(3-(4-플루오로페닐) -1H-피라졸 -5-일) -2-(N-(2-메톡시페닐) -4-메틸페닐 술폰아미도)아세트아미드，  N- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) -2- (N- (2-methoxyphenyl) -4-methylphenyl sulfonamido) acetamide,

N-(5-히드록시 -1H-피라졸 -3-일) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미 도)아세트아미드, N-(2-메특시페닐 )-4-메틸ᅳ N-(2-옥소 -2-(4-(피리딘 -2-일)피페라진 - 1 -일)에 틸)벤젠술폰아미드， N- (5-hydroxy-1H-pyrazol-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide, N- (2-methoxyphenyl) -4-methyl ᅳ N- (2-oxo-2- (4- (pyridin-2-yl) piperazin-1-yl) ethyl) benzenesulfonamide,

N-(2-(4-(4-플루오로페닐)피페라진 -1-일) -2-옥소에틸) -N-(2-메톡시페닐) -4 N- (2- (4- (4-fluorophenyl) piperazin-1-yl) -2-oxoethyl) -N- (2-methoxyphenyl) -4

-메틸벤젠술폰아미드， Methylbenzenesulfonamide,

N-(5-(4ᅳ클로로페닐 )- 1 ,3,4-옥사디아졸 -2-일 )-2-(N-(2-메특시페닐 )-4-메틸 페닐술폰아미도)아세트아미드,  N- (5- (4 ᅳ chlorophenyl) -1,3,4-oxadiazol-2-yl) -2- (N- (2-methoxyphenyl) -4-methyl phenylsulfonamido) acetamide ,

N-(2-에톡시피리딘 -3-일) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아 세트아미드，  N- (2-ethoxypyridin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(2-이소프로폭시피리딘 -3-일) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아 미도)아세트아미드，  N- (2-isopropoxypyridin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(2-클로로피리딘 -3-일) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아 세트아미드,  N- (2-chloropyridin-3-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(3-메톡시피리딘 -2-일)아 세트아미드,  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (3-methoxypyridin-2-yl) acetamide,

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(4-메록시피리딘 -3-일)아 세트아미드,  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide,

N- (이소퀴놀린 -3-일) -2-(N-.(2-메록시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  N- (isoquinolin-3-yl) -2- (N-. (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도) -N- (퀴놀린 -5-일)아세트아미 드  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (quinolin-5-yl) acetamide

₂__(N_₍₂ᅵ메톡시페닐 )ᅳ4-메틸페닐술폰아미도) -N- (퍼플루오로페닐)아세트 아미드， ₂ _ _(N _ ₍₂ methoxyphenyl) ᅳ 4-methylphenylsulfonamido) -N- (perfluorophenyl) acetamide,

N-(2-에톡시페닐) -2-(N-(2-메톡시페닐)나프탈렌 -2-술폰아미도)아세트아 미드，  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) naphthalene-2-sulfonamido) acetamide,

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N- (티아졸 -2-일)아세트아미 드  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (thiazol-2-yl) acetamide

N-(2-에톡시벤질) -2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아 미드,  N- (2-ethoxybenzyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(1H-이미다졸 -2-일) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세 트아미드，  N- (1H-imidazol-2-yl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

N-(2-메톡시페닐) -2-(N-(2-메톡시페닐) -4- (메틸티오)페닐술폰아미도)아세 트아미드  N- (2-methoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide

N-(2-에특시페닐) -2-(N-(2-메특시페닐) -4- (메틸티오)페닐술폰아미도)아세 트아미드，  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

N-(3-에톡시페닐) -2-(N-(2-메톡시페닐) -4- (메틸티오)페닐술폰아미도)아세 트아미드  N- (3-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide

N-(3-(l H-이미다졸 - 1 -일)페닐 )-2-(N-(2-메특시페닐 )-4- (메틸티오)페닐술폰 아미도)아세트아미드염산염, N-(2,5-디메특시페닐) -2-(N-(2-메특시페닐) -4- (메틸티오)페닐술폰아미도) 아세트아미드， N- (3- (l H-imidazol-1-yl) phenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfon amido) acetamide hydrochloride, N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) acetamide,

N-(2,5-디메톡시페닐) -2-(N-(2-메특시페닐) -4- (메틸술피닐)페닐술폰아미 도)아세트아미드,  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylsulfinyl) phenylsulfonamido) acetamide,

N-(2,5-디메톡시페닐) -2-(N-(2-메록시페닐) -4- (메틸술포닐)페닐술폰아미 도)아세트아미드,  N- (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylsulfonyl) phenylsulfonamido) acetamide,

N-(2,5-디메특시페닐) -2-(4-플루오로 -N-(2-메톡시페닐)페닐술폰아미도)아 세트아미드，  N- (2,5-dimethoxyphenyl) -2- (4-fluoro-N- (2-methoxyphenyl) phenylsulfonamido) acetamide,

2-(4-시아노 -N-(2-메특시페닐)페닐술폰아미도) -N-(2,5-디메특시페닐)아세 트이 "미드,  2- (4-cyano-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetide "mid,

N一 (2,5-디메톡시페닐 )-2-(N-(2-메톡시페닐) -4-(1Η-테트라졸 -5-일)페닐술폰 아미도)아세트아미드，  N1 (2,5-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (1Η-tetrazol-5-yl) phenylsulfon amido) acetamide,

2-(4-브로모 -N-(2-메특시페닐)페닐술폰아미도) -N-(2,5-디메톡시페닐)아세 트아미드,  2- (4-bromo-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide,

2-(4-아세틸 -N-(2-메톡시페닐)페닐술폰아미도) -N-(2,5-디메록시페닐)아세 트아미드  2- (4-acetyl-N- (2-methoxyphenyl) phenylsulfonamido) -N- (2,5-dimethoxyphenyl) acetamide

메틸 methyl

4-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도)벤조에이트 메틸  4- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate methyl

6-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도)니코티네이 트  6- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) nicotinate

메틸 methyl

2-(2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트아미도) -5-메틸벤조 에이트,  2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) -5-methylbenzoate,

메틸 methyl

4，5-디메톡시 -2-(2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트아미 도)벤조에이트,  4,5-dimethoxy-2- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate,

N-(3,4-디메록시페닐) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도)아세트 아미드,  N- (3,4-dimethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamide,

2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도) -N- (퀴놀린 -6-일)아세트아미  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (quinolin-6-yl) acetami

Ν-(5-(1Η-이미다졸 -1-일) -2-메톡시페닐) -2-(N-(2-메특시페닐) -4- (메틸티오Ν- (5- (1Η-imidazol-1-yl) -2-methoxyphenyl) -2- (N- (2-methoxyphenyl) -4- (methylthio

)페닐술폰아미도)아세트아미드염산염, ) Phenylsulfonamido) acetamide hydrochloride,

N-(2,5-디메톡시페닐) -2-((2-메특시페닐) (4-메틸벤질)아미노)아세트아미  N- (2,5-dimethoxyphenyl) -2-((2-methoxyphenyl) (4-methylbenzyl) amino) acetami

N-(2,5-디메특시페닐) -2-(4-(1-하이드록시에틸) -N-(2—메록시페닐)페닐술 폰아미도)아세트아미드， 4-클로로 -N-(2-((2,5-디메특시페닐)아미노) -2-옥소에틸) -N-(2-메록시페닐) 벤자미드， N- (2,5-dimethoxyphenyl) -2- (4- (1-hydroxyethyl) -N- (2-hydroxyphenyl) phenylsulfonamido) acetamide, 4-chloro-N- (2-((2,5-dimethoxyphenyl) amino) -2-oxoethyl) -N- (2-methoxyphenyl) benzamide,

2-(4-브로모 -N-(2-메특시페닐)페닐술폰아미도) -N-(4-메특시피리딘 -3-일) 아세트아미드염산염,  2- (4-bromo-N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide hydrochloride,

2-(N-(2-메록시페닐) -4- (메틸티오)페닐술폰아미도) -N-(4-메록시피리딘 -3- 일)아세트아미드，  2- (N- (2-methoxyphenyl) -4- (methylthio) phenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide,

2-(4-아세틸 -N-(2-메톡시페닐)페닐술폰아미도) -N-(4-메톡시피리딘 -3-일) 아세트아미드,  2- (4-acetyl-N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-methoxypyridin-3-yl) acetamide,

2-(4-(1-하이드록시에틸) -N-(2-메특시페닐)페닐술폰아미도) -N-(4-메톡시 피리딘 -3-일)아세트아미드,  2- (4- (1-hydroxyethyl) -N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-methoxy pyridin-3-yl) acetamide,

메틸  methyl

2-히드록시 -5-(2-(N-(2-메특시페닐) -4-메틸페닐술폰아미도)아세트아미도) 벤조에이트,  2-hydroxy-5 (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate,

메틸  methyl

2-히드록시 -4-(2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도)아세트아미도) 벤조에이트,  2-hydroxy-4- (2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) acetamido) benzoate,

N-(2-에록시페닐) -2-(N-(2-메록시페닐) -4-메틸페닐술폰아미도) -N-메틸아 세트아미드,  N- (2-hydroxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N-methylacetamide,

N-(2-에톡시페닐) -2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N- (프로프 -2-인 -1-일)아세트아미드,  N- (2-ethoxyphenyl) -2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (prop-2-yn-1-yl) acetamide,

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N- (퀴놀린 -3-일)아세트아미 드  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (quinolin-3-yl) acetamide

2-(N-(2-메톡시페닐) -4-메틸페닐술폰아미도) -N-(6-메특시피리딘 -2-일)아 세트아미드，및  2- (N- (2-methoxyphenyl) -4-methylphenylsulfonamido) -N- (6-methoxypyridin-2-yl) acetamide, and

2-(4-(1- (부틸아미노)에틸) -N-(2-메특시페닐)페닐술폰아미도) -N-(4-메특 시피리딘 -3-일)아세트아미드.  2- (4- (1- (butylamino) ethyl) -N- (2-methoxyphenyl) phenylsulfonamido) -N- (4-methoxy cipyridin-3-yl) acetamide.

[청구항 6] 제 1항에따른화합물또는이의약학적으로허용가능한염을포함하는， 중추신경계질환의치료또는예방용약학조성물. [Claim 6] A pharmaceutical composition for the treatment or prevention of central nervous system diseases, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

[청구항 7] 제 6항에있어서， [Claim 7] In paragraph 6,

상기증추신경계질환은외상성뇌손상，뇌졸중，뇌경색，소아뇌성마비, 다발성축삭경화증，근위축성측삭경화증，척수손상,시신경손상， 루게릭병，알츠하이머병,헌팅톤병또는파킨슨병인것을특징으로하는 약학조성물.  The CNS disease is a pharmaceutical composition characterized by traumatic brain injury, stroke, cerebral infarction, pediatric cerebral palsy, multiple axonal sclerosis, amyotrophic lateral sclerosis, spinal cord injury, optic nerve injury, Lou Gehrig's disease, Alzheimer's disease, Huntington's disease or Parkinson's disease. .